Protection

Protection (and Deprotection) of Functional Groups in Organic Synthesis by
Heterogeneous Catalysis
Giovanni Sartori,*
,
Roberto Ballini,
Franca Bigi,
Giovanna Bosica,
Raimondo Maggi,
and Paolo Righi
Clean Synthetic Methodologies Group, Dipartimento di Chimica Organica e Industriale dellUniversita` , Parco Area delle Scienze 17A,
43100 Parma, Italy, Dipartimento di Scienze Chimiche dellUniversita` , Via S. Agostino 1, 62032 Camerino (MC), Italy, and
Dipartimento di Chimica Organica A. Mangini dellUniversita` , V.le Risorgimento 4, 40136 Bologna, Italy
Received June 11, 2003
Contents
1. Introduction 199
2. Hydroxy Protecting Groups 203
2.1. Esters 204
2.1.1. Protection 204
2.1.2. Deprotection 206
2.2. Silyl Ethers 207
2.3. Alkoxyalkyl Ethers 209
2.3.1. Protection as THP Ethers 209
2.3.2. Protection as Other Alkoxyalkyl Ethers 212
2.4. Tosylates 214
2.5. Selective Protection of Polyfunctional
Compounds
215
2.6. Selective Deprotection of Polyprotected
Compounds
217
2.7. Redox Deprotections 221
3. Thiol Protecting Groups 223
4. Carboxy Protecting Groups 223
4.1. Protection 224
4.2. Deprotection 226
5. Carbonyl Protecting Groups 227
5.1. Acetals 227
5.2. Dithioacetals 233
5.3. 1,3-Oxathiolanes 237
5.4. 1,1-Diacetates (Acylals) 238
5.5. Nitrogenous Derivatives 240
6. Amino Protecting Groups 242
6.1. Protection 242
6.2. Deprotection 244
7. Concluding Remarks 246
8. Acknowledgments 246
9. Abbreviations 246
10. References 246
1. Introduction
Fi ne chemi cal s are compl ex and mul ti functi onal
mol ecul es, often characteri zed by l ow vol ati l i ty and
l i mi ted thermal stabi l i ty, whose manufacture gener-
al l y i s based on mul ti step synthesi s performed i n the
l i qui d phase and frequentl y i nvol vi ng protecti on-
deprotecti on steps. The use of bl ocki ng functi ons i n
organi c synthesi s, devel oped for nearl y 100 years,
makes more compl ex the enti re syntheti c pl an si nce
i t requi res at l east two addi ti onal steps. At the same
ti me, envi ronmental and economi c consi derati ons
have created i nterest, i n both academi c and i ndus-
tri al research, i n desi gni ng syntheti c procedures that
are cl ean, sel ecti ve, hi gh-yi el di ng, and mani pul a-
ti vel y easy.
I n fact, as cl earl y recogni zed by Shel don, ...tradi -
ti onal concepts of process effi ci ency are changi ng
from an excl usi ve focus on chemi cal yi el d to one that
assi gns economi c val ue to el i mi nati ng waste....
1
An extensi ve appl i cati on of heterogeneous catal ysi s
i n syntheti c chemi stry can hel p to achi eve new
sel ecti ve reacti ons, to l ower the waste producti on,
and, fi nal l y, to render more attracti ve the syntheti c
process from both the envi ronmental and al so the
economi c poi nt of vi ew, i n agreement wi th some
parameters of the i deal synthesi s recentl y pre-
sented by Wender.
2
I ndeed, sol i d catal ysts can be easi l y separated from
the reacti on products by si mpl e fi l trati on and quan-
ti tati vel y recovered i n the acti ve form. They can be
recycl ed, maki ng l ess expensi ve the preparati on of
sophi sti cated fi ne chemi cal s and, at the same ti me,
avoi di ng contami nati on of the products by trace
amounts of metal s.
The heterogeneous catal ysi s that was ori gi nal l y
studi ed and appl i ed i n bul k chemi stry wi th parti cul ar
i nterest to petrochemi cal i ndustry was more recentl y
extended to syntheti c organi c chemi stry for produc-
ti on of fi ne chemi cal s and pharmaceuti cal s.
3
Among
the fi rst reacti ons performed under heterogeneous
catal ysi s are the hydrogenati ons and, i n general , the
redox processes whi ch are extensi vel y appl i ed i n
syntheti c organi c chemi stry. Aci d-base heteroge-
* To whom correspondence shoul d be addressed. Phone: +39 0521
905551. Fax: +39 0521 905472. E-mai l : gi ovanni .sartori @uni pr.i t.
Di parti mento di Chi mi ca Organi ca e I ndustri al e del l Uni versi ta`.
Di parti mento di Sci enze Chi mi che del l Uni versi ta`.
Di parti mento di Chi mi ca Organi ca A. Mangi ni del l Uni versi ta`.

199 Chem. Rev. 2004, 104, 199250
10.1021/cr0200769 CCC: $48.50 2004 American Chemical Society
Published on Web 12/12/2003
neous catal ysi s was successi vel y devel oped by ex-
pl oi ti ng the physi cochemi cal properti es of zeol i tes,
4
cl ays,
5
and metal oxi des.
6
However, many of these materi al s present some
l i mi tati ons when l arge reactants are i nvol ved, espe-
ci al l y i n l i qui d-phase systems, as frequentl y occur i n
the synthesi s of fi ne chemi cal s. Attempts to i mprove
the di ffusi on of reactants to catal yti cal l y acti ve si tes
have so far focused on i ncreasi ng the catal yst pore
si zes, such as i n the mesoporous MCM
7
and I TQ
8
type
materi al s. Fi nal l y, appl i cati on of catal ysts to manu-
facti ng technol ogi es, such as grafti ng and tetheri ng
combi ned wi th speci al copol ymeri zati on procedures,
ori gi nal l y addressed to materi al s chemi stry, made
accessi bl e a l arge number of (chi ral ) organi c catal ysts
as wel l as (chi ral ) metal compl exes coval entl y bound
to the surface of both organi c and i norgani c sup-
ports.
9,10
These materi al s are excel l ent catal ysts for organi c
synthesi s si nce they combi ne the properti es of a
stabl e organi c or i norgani c backbone wi th the fl ex-
i bi l i ty of the organi c deri vati ves; moreover, they are
al so characteri zed by hi gher thermal stabi l i ty i n
compari son wi th thei r homogeneous counterparts.
The appl i cati on of al l these l arge fami l i es of sol i d
catal ysts i n l i qui d-phase syntheti c chemi stry has
attracted a l ot of i nterest. They al so form the basi s
Giovanni Sartori was born in Casalmaggiore, Italy, in 1944. He studied
chemistry at the University of Parma, where he obtained his laurea degree
under the guidance of Prof. Giuseppe Casnati in 1971. In 1972, he began
his career at the University of Parma, working in the group of Prof. Casnati
on the regio- and stereoselective functionalization of ambidental reagents.
He was promoted to Associate Professor of Organic Chemistry in 1985
and Full Professor in 1994. He is currently the Head of the Clean Synthetic
Methodologies Groups of the University of Parma. His research interests
include all aspects of the heterogeneous catalysis applied to fine chemicals
and pharmaceuticals production, with particular attention to the preparation
and use of supported organic (chiral) catalysts. A special area of extensive
interest is also the development of new eco-compatible synthetic methods,
mainly based on the exploitation of solvent-free and multicomponent
reactions. He has published about 130 original studies and filed
approximately 20 patents.
Roberto Ballini received an S.B. degree in chemistry from the University
of Camerino, Italy. After an experience in the petrochemical industry
(ENI-ANIC, Ravenna), he began his academic career in 1975 at the
University of Camerino as a Research Fellow. He became Assistant
Professor in 1978, was promoted to Associate Professor of Organic
Chemistry, and then to full Professor (organic chemistry) in 2000. His
recent research interests include the chemistry of aliphatic nitrocompounds,
the formation and cleavage of CC bonds, the studies and application of
heterogeneous catalysis, the synthesis of natural products, and the use
of aqueous media in organic reactions.
Franca Bigi was born in Parma, Italy, in 1955. She received her laurea
degree (cum laude) in chemistry from the University of Parma in 1979.
After a two-year fellowship at Accademia Nazionale dei Lincei, from 1983
to 1992 she had a permanent position as Researcher at Parma University
in the group of Professor G. Casnati. In 1992, she was promoted to
Associate Professor of Organic Chemistry at the Faculty of Science of
the Parma University. Her research interests concern the development of
selective and environmentally friendly procedures under heterogeneous
catalysis for fine chemicals synthesis. More recently, she has been
interested in the preparation of chiral organicinorganic hybrid materials
to promote stereoselective processes, and she has developed uncatalyzed
Kno evenagel condensations in water.
Giovanna Bosica is a researcher at the Department of Chemical Sciences
of the University of Camerino. She received her Laurea in chemistry in
1993 from the University of Camerino and, four years later, from the same
institution her doctoral degree in chemical sciences, working under the
supervision of Prof. R. Ballini. She spent a research period in the labor-
atories of Prof. B. Zwanenburg (University of Nijmegen, The Netherlands,
1995). Her research interests concern the use of nitro compounds in new
synthetic methodologies, functional groups interconversion, synthesis of
biologically active natural products, and green chemistry.
200 Chemical Reviews, 2004, Vol. 104, No. 1 Sartori et al.
of some new i ndustri al processes whi ch have been
devel oped to repl ace tradi ti onal probl emati c syntheti c
methods.
11
As a consequence of the extensi ve appl i ca-
ti on of heterogeneous catal ysi s i n syntheti c organi c
chemi stry, a l arge number of arti cl es descri bi ng the
advantages of performi ng protecti on-deprotecti on
reacti ons over sol i d catal ysts have been publ i shed.
However, these studi es exami ned onl y margi nal l y
some cruci al aspects of the heterogeneous catal ysi s,
such as the quanti tati ve and correct eval uati on of
catal yst effi ci ency i n terms of the turnover number
(TON) and turnover frequency (TOF) val ues; i t i s
more frequentl y eval uated through the product yi el d
as a functi on of each cycl e. Si mi l arl y, di rect and
quanti tati ve determi nati on of the amount of recov-
ered catal yst and l eachi ng phenomena were scarcel y
taken i nto consi derati on.
12,13
On the other hand, these
arti cl es were focused on syntheti c organi c chemi stry,
and thei r major goal was to poi nt out the advantages
of performi ng protecti on-deprotecti on reacti ons over
heterogeneous catal ysi s, quanti fi ed as yi el d, easy
workup, and, i n parti cul ar, sel ecti vi ty when mul ti -
functi onal compounds are uti l i zed.
Due to the great i nterest i n protecti ng group
chemi stry, many books
14,15
and revi ews
16,17
have been
publ i shed on thi s topi c. Moreover, updated revi ews
are publ i shed yearl y by Koci enski
18
and Spi vey,
19
descri bi ng sel ected i mportant appl i cati ons. Several
revi ews have al so touched on more speci al i zed fi el ds,
such as enzymati c protecti ng group techni ques
20
and
protecti ng groups i n sol i d-phase organi c synthesi s.
21
However, unti l now, a ful l col l ecti on of the appl i ca-
ti ons of heterogeneous catal ysi s to protecti ng group
chemi stry, hi ghl i ghti ng the advantages rel ated to the
easi er workup of the reacti on mi xture and puri fi ca-
ti on of products as wel l as the hi gh l evel of sel ecti vi ty
frequentl y achi eved, has not been publ i shed. I n thi s
revi ew we descri be the appl i cati on of heterogeneous
catal ysi s i n protecti ng group chemi stry, focusi ng
mai nl y on that devel oped duri ng the past decade.
The vari ous reacti ons and procedures reported
wi thi n thi s revi ew are sorted i nto categori es based
on the functi onal group, accordi ng to Koci enski s
typi cal cl assi fi cati on. Si gni fi cant exampl es for every
cl ass of compounds are col l ected i n Tabl es 2-28,
accompani ed by the reference, the number of ex-
ampl es reported i n the paper, the yi el d range, and
i nformati on on the catal yst reusabi l i ty.
To provi de the reader wi th rapi d and easy i nforma-
ti on about the l arge number of catal ysts descri bed
i n the revi ew, Tabl e 1 summari zes the name (and/or
the abbrevi ati on) of every catal yst, accompani ed by
a short descri pti on of i ts avai l abi l i ty.
Some of the catal ysts are commerci al l y avai l abl e
(CA), such as many cl ays, zeol i tes, and metal oxi des.
I n some i nstances, due to thei r i nsuffi ci ent aci di ty,
prol onged reacti on ti mes or a l arge quanti ty of them
are usual l y necessary, and, consequentl y, they are
often modi fi ed by treatment wi th Lewi s aci ds or
proti c aci ds (SA) to i ncrease thei r catal yti c acti vi ty.
Si mi l ar procedures can be uti l i zed to prepare cata-
l ysts di spl ayi ng speci al redox properti es. Unfortu-
natel y, the majori ty of the more attracti ve catal ysts,
such as many metal phosphates, pol yoxometal ates,
and catal ysts i mmobi l i zed on sol i d supports, are not
commerci al l y avai l abl e and must be prepared by
tri cky methodol ogi es.
I n some cases, the catal ysts are prepared i n si tu
(I SP) by mi xi ng conveni ent reagents (i .e., Lewi s or
proti c aci ds wi th metal oxi des) wi th the reacti on mi x-
ture. Even though, i n these ci rcumstances, there are
sti l l many doubts about the effecti ve heterogenei ty
of the catal ysts, we report the appl i cati on si nce the
authors showed that use of these combi nati ons af-
fords cl eaner and more effi ci ent syntheti c procedures.
Si mi l arl y, rather sophi sti cated and useful catal ysts
are represented by acti ve mol ecul es i mmobi l i zed
through coval ent bonds on the surface of pol ymeri c
supports. I n spi te of the exci ti ng resul ts frequentl y
obtai ned by appl yi ng these catal ysts to vari ous areas
Raimondo Maggi was born in Parma, Italy, in 1963. He graduated from
the University of Parma in 1989 (working with Prof. Giuseppe Casnati),
and he received his Ph.D. in organic chemistry (under the direction of
Prof. Giovanni Sartori) from the same University in 1992. In 1995, he
carried out his postdoctoral research with Prof. Manfred Schlosser at the
Lausanne University. He began his career at the University of Parma in
1997 as Researcher, and in 2002 he was promoted to Associate Professor
of Organic Chemistry. His research interests include the preparation and
use of heterogeneous (chiral) catalysts for the environmentally friendly
synthesis of fine chemicals and pharmaceuticals. He has published about
80 original studies.
Paolo Righi was born in Modena, Italy, in 1963. He graduated cum laude
in 1987 under the tutorship of Prof. Antonino Fava, and got the Ph.D
degree in chemical sciences from the University of Bologna in 1991 under
the guidance of Prof. Goffredo Rosini. In 1992, he joined the group of
Prof. Goffredo Rosini at the University of Bologna as a research assistant,
working on novel tandem, domino, and multicomponent processes and
the preparation and utilization of bicyclo[3.2.0]heptenones for the synthesis
of natural products and new versatile building blocks. In 2002, he was
appointed Associate Professor at the Faculty of Industrial Chemistry.
Protection of Functional Groups in Organic Synthesis Chemical Reviews, 2004, Vol. 104, No. 1 201
Table 1. Heterogeneous Catalysts Utilized
entry
ref
catal yst [abbrevi ati on] type
z
preparati on
1 Bentoni te (Mexi can) CA
2 Kaol i n CA
3 montmori l l oni te K10 CA
4 montmori l l oni te KSF CA
5 Sepi ol i te (Spani sh) CA
6 Tonsi l CA
7 Envi rocat EPZ10 CA
8 Envi rocat EPZG CA
9
a
montmori l l oni te/Ce
3+
SA treatment of Na
+
-montmori l l oni te wi th Ce(NO3)3 i n aqueous acetone
10
102
montmori l l oni te K10/FeCl 3 SA treatment of montmori l l oni te K10 wi th FeCl 3 i n H2O
11
141
montmori l l oni te K10/Fe(NO3)3 SA treatment of montmori l l oni te K10 wi th Fe(NO3)3
12
b
montmori l l oni te K10/Fe(NO3)3 [cl ayfen] SA treatment of montmori l l oni te K10 wi th Fe(NO3)3 i n acetone
13
200
montmori l l oni te K10/K2FeO4 SA treatment of montmori l l oni te K10 wi th K2FeO4
14
140
montmori l l oni te K10/(Me3Si )2CrO4 SA treatment of montmori l l oni te K10 wi th Me3Si OSi Me3 and CrO3
i n CH2Cl 2
15
98
montmori l l oni te K10/NH4NO3 [cl ayan] SA treatment of montmori l l oni te K10 wi th NH4NO3 i n H2O
16
304
montmori l l oni te K10/(NH4)2S2O8 I SP mi xi ng of montmori l l oni te K10 wi th (NH4)2S2O8
17
211
montmori l l oni te K10/POCl 3 SA treatment of montmori l l oni te K10 wi th POCl 3 i n CH2Cl 2
18
182
montmori l l oni te/Ti
4+
SA treatment of Na
+
-montmori l l oni te wi th Ti Cl 4 i n H2O
19 beta zeol i te [BEA] CA
20
c
ferri eri te zeol i te [FER] SA mi xi ng of sodi um si l i cate, al umi num sul fate hexadecahydrate, and
pyrrol i di ne i n aci di c H2O
21 mordeni te zeol i te [MOR] SA
22 Y zeol i te CA
23 USY zeol i te CA
24 ZSM-5 zeol i te [MFI ] CA
25
69
del ami nated zeol i te I TQ-2 SA treatment of MCM-22 wi th CH3(CH2)15N(CH3)3Br,
(CH3CH2CH2)4NOH, and HCl
26
149
Cu-pentasi l borozeol i te/Cu(NO3)2 SA treatment of Cu-pentasi l borozeol i te wi th Cu(NO3)2
27
274
Y zeol i te/KMnO4 SA treatment of Y zeol i te wi th KMnO4 i n H2O
28
d
ZSM-5 zeol i te/Fe(NO3)39H2O [Zeofen] SA treatment of ZSM-5 zeol i te wi th Fe(NO3)39H2O
29
e
LaY zeol i te SA treatment of NaY zeol i te wi th LaCl 3 i n H2O
30 NaY zeol i te CA
31
91
mol ecul ar si eves/FeCl 3 SA shaki ng powdered Li nde 3- mol ecul ar si eves wi th FeCl 3
32
f,g
Si -MCM-41 SA mi xi ng of sodi um si l i cate sol uti on, tetramethyl ammoni um hydroxi de,
and cetyl tri methyl ammoni um chl ori de i n H2O
33
h
Si /Al -MCM-41 SA mi xi ng of CH3(CH2)15N(CH3)3Br, pseudobohemi te, and Aerosi l
34
i
TS-1 SA mi xi ng of a source of si l i con oxi de and a source of ti tani um oxi de
35
31
M-ETS-10 SA treatment thri ce of ETS-10 wi th a metal chl ori de sol uti on
36
j
Si O2/Al 2O3 SA mi xi ng of Al (NO3)3 wi th col l oi dal si l i ca sol uti on (30 wt % Si O2) and
then NH4OH
37 Si O2 CA
38
109
Si O2/Al 2(SO4)3 SA treatment of si l i ca gel wi th Al 2(SO4)3
39
111
Si O2/BF3 SA treatment of si l i ca gel wi th BF3.Et2O
40
k
Si O2/Ce(SO4)2 SA treatment of si l i ca gel wi th Ce(SO4)2 i n H2O
41
l
Si O2/[(CH3)3Si O]2CrO4 [Si O2/BTSC] SA treatment of si l i ca gel wi th (CH3)3Si OSi (CH3)3 and CrO3 i n CH2Cl 2
42
204
Si O2/[(CH3)3Si O]2SO2 [Si O2/BTS] I SP mi xi ng of si l i ca gel wi th [(CH3)3Si O]2SO2 i n CH2Cl 2
43
205
Si O2/CoBr2 SA treatment of si l i ca gel wi th anhydrous CoBr2
44
m
Si O2/Cu(NO3)2 SA treatment of si l i ca gel wi th Cu(NO3)21.5H2O
45
207
Si O2/Cu(OTf)2 SA treatment of si l i ca gel wi th Cu(OTf)2
46
n
Si O2/CuSO4 SA treatment of si l i ca gel wi th CuSO4 i n H2O
47
48
Si O2/Et3N SA treatment of si l i ca gel wi th Et3N
48
284
Si O2/Fe(Cl O4)36H2O SA treatment of si l i ca gel wi th Fe(Cl O4)36H2O
49
225
Si O2/Fe(NO3)39H2O SA treatment of si l i ca gel wi th Fe(NO3)39H2O
50
113
Si O2/GeCl 4 SA treatment of si l i ca gel wi th GeCl 4
51
72
Si O2/H2SO4 SA treatment of si l i ca gel wi th H2SO4 i n acetone
52
o
Si O2/K2FeO4 I SP treatment of si l i ca gel wi th K2FeO4 i n cycl ohexane
53
106,107
Si O2/NaHSO4 SA treatment of si l i ca gel wi th NaHSO4H2O
54
126
Si O2/(NH4)2Ce(NO3)6 [Si O2/CAN] SA treatment of si l i ca gel wi th (NH4)2Ce(NO3)6 i n H2O
55
p
Si O2/PBGSi Cl SA treatment of si l i ca gel wi th a preformed
tri methyl oxysi l ane-pol yal kyl guani di ni um i on
56
33
Si O2/P2O5 SA treatment of si l i ca gel wi th P2O5
57
112
Si O2/rare earth chl ori de SA treatment of si l i ca gel wi th sel ected chl ori de i n dry methanol
5
q
Si O2/SOCl 2 [si l i ca chl ori de] SA treatment of si l i ca gel wi th SOCl 2
59
74
Si O2/TaCl 5 I SP shaki ng si l i ca gel wi th TaCl 5
60
r
Si O2/Yb(OTf)3 SA treatment of si l i ca gel wi th Yb(OTf)3 i n CH3CN
61
206
Si O2/ZrCl 4 SA treatment of si l i ca gel wi th anhydrous ZrCl 4
62
234
Si O2-(CH2)3NH3Cl [APSGHCl ] SA treatment of Si O2-(CH2)3NH2 wi th HCl i n methanol
63 Al 2O3 CA
64
145
Al 2O3/CrO3 SA treatment of neutral al umi na wi th H2O and CrO3
65
133
Al 2O3/KF SA treatment of basi c al umi na and KF i n H2O
66
146
Al 2O3/KMnO4 SA treatment of neutral al umi na wi th KMnO4
67
134
Al 2O3/Oxone SA treatment of neutral al umi na wi th Oxone i n H2O
68
75
Al 2O3/ZnCl 2 I SP mi xi ng of al umi na wi th a THF sol uti on of ZnCl 2
of organi c synthesi s, further detai l ed i nformati on i s
needed to achi eve thei r opti mum performance i n
reproduci bl e experi ments and to better understand
the i nteracti on of the reactants and sol vent mol ecul es
wi th the surface of the catal yst.
2. Hydroxy Protecting Groups
Protecti on and deprotecti on of al cohol s have re-
cei ved attenti on i n recent years not onl y because of
thei r fundamental i mportance, but al so for thei r rol e
i n mul ti step synthesi s. Hi gh sel ecti vi ty i s frequentl y
requested for a gi ven hydroxy group i n pol yol chem-
i stry, as wel l as si mpl i ci ty and mi l dness i n prepari ng
and removi ng the speci fi c functi on. Moreover, even
when a substrate protects and deprotects effi ci entl y,
the reacti on frequentl y needs quenchi ng and products
must be i sol ated from the reacti on mi xture and
puri fi ed by sui tabl e methods. For substrates that are
Table 1 (Continued)
entry
ref
catal yst [abbrevi ati on] type
z
preparati on
69 Amberl yst 15 CA
70 Amberl yst A-21 CA
71 Amberl i te I R-120 CA
72 Dowex 50WX2 CA
73 Dowex 50WX8 CA
74 I RA-400(OH
-
) CA
75 Nafi on CA
76
156
D001/Al Cl 3 SA treatment of D001 wi th Al Cl 3 i n EtOH
77
157
sal i cyl i c aci d resi n/FeCl 3 SA treatment of sal i cyl i c aci d resi n wi th FeCl 3 i n CHCl 3
78
s
pol ymeri c di cyanoketene acetal SA copol ymeri zati on of monomeri c DCKA beari ng styrene moi ety wi th
[(P)-DCKA)] ethyl ene gl ycol di methacryl ate
79
83
pol y-p-styryl di phenyl acetonyl phosphoni um SA mul ti step synthesi s from p-bromobenzal dehyde, styrene, and
bromi de [(P)-ATPB] di vi nyl benzene
80
308
pol ystyrene-1-hydroxybenzotri azol e SA mul ti step synthesi s from pol ystyrene-di vi nyl benzene copol ymer,
[(P)-HOBT] 3-ni tro-4-chl orobenzyl al cohol , hydrazi ne monohydrate, and
ethyl ene gl ycol monoethyl ether
81
249
pol y(vi nyl chl ori de)/FeCl 3 [PVC/FeCl 3] SA treatment of pol y(vi nyl chl ori de) wi th FeCl 3 i n CH2Cl 2
82
137
sul fonated cross-l i nked pol ystyrene SA treatment of cross-l i nked gel -type pol ystyrene wi th H2SO4
83
159
Cel i te/CsF SA treatment of Cel i te 521 wi th CsF i n H2O
84
248
expansi ve graphi te SA treatment of graphi te wi th H2SO4, HNO3, and KMnO4 i n H2O
85
t
sul fonated charcoal SA treatment of acti ve charcoal wi th fumi ng H2SO4
86 Pd/C CA
87 PdO hydrate CA
88
u
hydrated zi rconi a SA mi xi ng ZrOCl 28H2O and NaOH i n H2O
89 sul fated zi rconi a [ZrO2/SO4
2-
] CA
90
187
yttri a-zi rconi a [Y2O3/ZrO2] SA mi xi ng Y(NO3)36H2O, ZrO(NO3)2xH2O, and NH3 i n H2O
91
40
WO3/ZrO2 SA treatment of ZrOx(OH)4-2x wi th (NH4)2WO4 i n H2O
92
154
MoO3/ZrO2 SA addi ti on of (NH4)6Mo7O244H2O oxal i c aci d aqueous sol uti on
to Zr(OH)4
93
190
Pt/MoO3/ZrO2 SA addi ti on of (NH4)6Mo7O244H2O aqueous sol uti on to Zr(OH)4;
after cal ci nati on, addi ti on of hexachl oropl ati ni c aci d
94
v
Zr(KPO4)2 SA ti trati on of exfol i ated R-zi rconi um phosphate wi th a
(KCl + KOH) 0.1 M aqueous sol uti on
95
231
Zr(CH3PO3)1.2(O3PC6H4SO3H)0.8 SA decomposi ti on of Zr(I V) fl uorocompl exes i n a sol uti on of
m-sul fophenyl phosphori c aci d and methanephosphoni c aci d
96
w
Al 2O3/Al PO4 SA mi xi ng al umi na wi th Al Cl 36H2O, H3PO4, and NH3 i n
propyl ene oxi de
97
x
Al PO4 SA mi xi ng Al Cl 36H2O, Al (NO3)39H2O, Al 2(SO4)318H2O,
98 H3PW12O40 CA H3PO4, and NH3
99
60
K5CoW12O403H2O SA treati ng (CH3CO2)2Co wi th Na2WO42H2O i n CH3COOH and H2O,
then wi th KCl , and fi nal l y wi th K2S2O8 i n H2SO4
100
y
sul fated SnO2 SA treati ng Sn(OH)4 wi th H2SO4
101
255
sul fated Ti O2 [Ti O2/SO4
2-
] SA mi xi ng Ti (OH)4 wi th H2SO4 i n H2O
102
155
MgSO4/H2SO4 I SP mi xi ng MgSO4 wi th concentrated H2SO4
a
Tatei wa, J.; Hori uchi , H.; Hashi moto, K.; Yamauchi , T.; Uemura, S. J . Org. Chem. 1994, 59, 5901.
b
Cornel i s, A.; Laszl o, P.
Synthesis 1985, 909.
c
Ahedi , R. K.; Kotasthane, A. N. J . Porous Mat. 1997, 4, 171.
d
Heravi , M. M.; Ajami , D.; Aghapoor, K.;
Ghassemzadeh, M. J . Chem. Soc., Chem. Commun. 1999, 833.
e
Yang, S.; Navrotsky, A. Microporous Mesoporous Mater. 2000,
37, 175.
f
Kresge, C. T.; Leonowi cz, M. E.; Roth, W. J.; Vartul i , J. C.; Beck, J. S. Nature1992, 359, 710.
g
Beck, J. S.; Vartul i , J.
C.; Roth, W. J.; Leonowi cz, M. E.; Kresge, C. T.; Schmi tt, K. D.; Chu, W.; Ol son, D. H.; Sheppard, E. W.; McCul l en, S. B.; Hi ggi ns,
J. B.; Schl enker, J. L. J . Am. Chem. Soc. 1992, 114, 10834.
h
Kresge, C. T.; Leonowi cz, M. E.; Roth, W. J. Vartul i , J. C. U.S.
Patent 5 098 684, 1992; Chem. Abstr. 1992, 117, 72621.
i
Taramasso, M.; Perego, G.; Notari , B. U.S. Patent 4 410 501, 1981;
Chem. Abstr. 1981, 95, 206272.
j
Matsumoto, Y.; Mi ta, K.; Hashi moto, K.; Tokoroyama, T. Appl. Catal. A: General 1995, 131, L1.
k
Ni si guchi , T.; Kami o, C. J . Chem. Soc., Perkin Trans. 1 1989, 707.
l
Lee, J. G.; Lee, J. A.; Yun Sohn, S. Synth. Commun. 1996,
26, 543.
m
Ni shi guchi , T.; Asano, F. Tetrahedron Lett. 1988, 29, 6265.
n
Cabal l ero, G. M.; Gros, E. G. J . Chem. Res. (S) 1989, 320.
o
Del aude, L.; Laszl o, P. J . Org. Chem. 1996, 61, 6360.
p
Gauthi er, P.; Gros, P.; Le Perchec, P.; Senet, J. P. U.S. Patent 5 348 923,
1993; Chem. Abstr. 1993, 119, 203156.
q
Fi rouzabadi , H.; I ranpoor, N.; Kari mi , B.; Hazarkhani , H. Synlett 2000, 263.
r
Kotsuki ,
H.; Ari mura, K. Tetrahedron Lett. 1997, 38, 7583.
s
Masaki , Y.; Tanaka, N.; Mi ura, T. Tetrahedron Lett. 1998, 39, 5799.
t
Patney,
H. K. Tetrahedron Lett. 1991, 32, 413.
u
Pati l , M. L.; Jnaneshwara, G. K.; Sabde, D. P.; Dongare, M. K.; Sudal ai , A.; Deshpande,
V. H. Tetrahedron Lett. 1997, 38, 2137.
v
Costanti no, U.; Curi ni , M.; Marmotti ni , F.; Rosati , O.; Pi sani , E. Chem. Lett. 1994,
2215.
w
Campel o, J. M.; Garc a, A.; Luna, D.; Mari nas, J. M.; Marti nez, M. I . Mater. Chem. Phys. 1989, 21, 409.
x
Campel o, J. M.;
Garci a, A.; Luna, D.; Mari nas, J. M. J . Catal. 1988, 111, 106.
y
Chavan, S. P.; Zubai dha, P. K.; Dantal e, S. W.; Keshavaraja, A.;
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z
CA, commerci al l y avai l abl e; I SP, i n si tu prepared; SA,
si mpl y added.
parti cul arl y l abi l e, these operati ons can cause further
degradati on. I n these si tuati ons, the use of sol i d
catal ysts al l ows al l the above-descri bed operati ons
to be performed i n a more effi ci ent way.
2.1. Esters
2.1.1. Protection
The acetyl ati on of al cohol s represents an i mportant
reacti on for the syntheti c organi c chemi st; i t i s
frequentl y used for deri vati zati on and characteri za-
ti on of al cohol s as wel l as for further transformati ons.
The reacti on i s usual l y performed by usi ng acyl
chl ori des or the correspondi ng anhydri des i n the
presence of a base such as tri ethyl ami ne or pyri di ne;
faster reacti on rates can be achi eved by addi ng
4-(di methyl ami no)pyri di ne (DMAP) as cocatal yst.
Under these condi ti ons, base-sensi ti ve substrates
may undergo decomposi ti on. To avoi d thi s drawback,
proti c and Lewi s aci ds can be uti l i zed, such as
p-tol uenesul foni c aci d, zi nc chl ori de, cobal tous chl o-
ri de, and scandi um tri fl ate.
Di fferent sol i d aci ds have al so been successful l y
uti l i zed to promote the reacti on.
Thus, the acetyl ati on of al cohol s and phenol s was
performed at room temperature usi ng aceti c anhy-
dri de as acyl ati ng reagent i n the presence of mont-
mori l l oni tes KSF and K10. No sel ecti vi ty between
pri mary and secondary hydroxy groups was observed,
whereas the terti ary al cohol s were recovered un-
changed (Tabl e 2, entry 1).
22,23
Ful l y acetyl ated
sugars, whi ch are i nexpensi ve and very useful i nter-
medi ates for the synthesi s of many natural l y occur-
ri ng gl ycosi des, ol i gosacchari des, and gl ycoconju-
gates, coul d be prepared by reacti on of several
di sacchari des and tri sacchari des wi th aceti c anhy-
dri de; under these condi ti ons, parti al anomeri zati on
and acetol ysi s may occur (Tabl e 2, entry 2).
24
A more attracti ve route for the protecti on of al co-
hol s as esters from the envi ronmental and economi c
standpoi nts i s represented by thei r di rect reacti on
wi th carboxyl i c aci ds. By usi ng natural montmori l -
l oni te i tsel f or exchanged wi th Na
+
cati ons, a wi de
vari ety of pri mary, secondary, benzyl i c, al l yl i c, ho-
mocycl i c, and heterocycl i c al cohol s has been acety-
l ated wi th aceti c aci d (Tabl e 2, entry 3).
25
I n addi ti on,
upon i ncreasi ng the chai n l ength of the carboxyl i c
aci d, an i ncrease of the reacti on rate was observed,
probabl y due to the fact that a l ong carbon chai n
carboxyl i c aci d i s more hydrophobi c and dri ves away,
from the cl ay acti ve si tes, the water formed duri ng
the reacti on more effecti vel y than the hydrophi l i c
l ower chai n aci ds.
Chavan et al . expl oi ted the surface aci di ty of
di fferent types of zeol i tes to perform the acetyl ati on
of al cohol s and phenol s under sol ventl ess condi ti ons
usi ng aceti c anhydri de. I n the presence of a catal yti c
amount of FER zeol i te, several al cohol s and phenol s,
i ncl udi ng those contai ni ng chi ral centers and aci d-
sensi ti ve groups (acetal , tetrahydropyranyl ether,
C-C doubl e and tri pl e bonds), were transformed i nto
the correspondi ng acetates under mi l d reacti on con-
di ti ons (Tabl e 2, entry 4).
26
More conveni entl y, Sar-
tori et al . descri bed the acetyl ati on of al cohol s and
phenol s wi th aceti c anhydri de i n the presence of the
commerci al l y avai l abl e Y zeol i te HSZ-360. Functi on-
al i ti es such as doubl e and tri pl e bonds, ketal s, and
chi ral centers survi ve under the reacti on condi ti ons
(Tabl e 2, entry 5).
27
Of parti cul ar i nterest i s the
effi ci ent acyl ati on of -ni tro al cohol s whi ch, very
often, produce ni trool efi ns upon treatment wi th
aci ds.
28
As expected, the bul ki ness of the reagents
represents a cruci al factor i n the process: for ex-
ampl e, compl ete conversi on of R- and -naphthol s to
the correspondi ng acetates needs 1.5 h, whereas that
of bi naphthol takes 12 h. I n thi s parti cul ar case, the
bul ki ness of the reagent l i mi ts or compl etel y i nhi bi ts
i ts di ffusi on through the pores of the catal yst, and
the reacti on probabl y occurs onl y on the external
surface or on the external aci di c si tes. Zeol i tes were
al so uti l i zed for the protecti on of sugars. Beta zeol i te
represented an effi ci ent catal yst for the per-O-acety-
l ati on of monosacchari des, di sacchari des, and al kyl
gl ycosi des (Tabl e 2, entry 6).
29
Parti al anomeri zati on
and ri ng modi fi cati on occurred under these condi -
ti ons; no acetol ysi s was observed wi th di sacchari des.
Acetyl ati on of al cohol s wi th aceti c aci d was per-
formed i n the presence of metal -exchanged zeol i tes.
By usi ng LaY zeol i te, di fferent pri mary and second-
ary al cohol s were acetyl ated i n al most quanti tati ve
yi el d (Tabl e 2, entry 7).
30
The same reacti on was
cl ai med to be catal yzed by metal -exchanged ti tano-
si l i cal i te M-ETS-10 (Tabl e 2, entry 8).
31
I n contrast
to the report for the reacti on carri ed out i n the
presence of montmori l l oni te,
25
i ncreasi ng the chai n
l ength of the carboxyl i c aci d l ed to a decrease i n the
rate of the acyl ati on, together wi th the formati on of
byproducts.
Proti c and Lewi s aci ds adsorbed on di fferent or-
gani c and i norgani c pol ymeri c materi al s can be
prepared easi l y by mi xi ng the reagents and the
supports. Despi te the l i vel y and deep di scussi on on
the real nature of the acti ve si tes, wi th parti cul ar
emphasi s on the possi bl e l eachi ng of aci di ty i nto
sol uti on, these materi al s have been extensi vel y uti -
l i zed as heterogeneous catal ysts i n di fferent fi el ds of
syntheti c organi c chemi stry, i ncl udi ng thei r use i n
the protecti on-deprotecti on of hydroxyl ated com-
pounds.
Vari ous metal oxi des and oxi de-supported reagents
were empl oyed i n the protecti on of hydroxy groups.
Usual l y, the di rect reacti on of a carboxyl i c aci d wi th
an al cohol resul ts i n an equi l i bri um whi ch requi res
the use of excess reagent or el i mi nati on of water
through azeotropi c di sti l l ati on or addi ti on of dehy-
drati ng agents. Rezende descri bed the use of sul furi c
aci d supported on si l i ca gel i n chl oroform as an
effi ci ent catal yst to i rreversi bl y convert carboxyl i c
aci ds and al cohol s i nto the correspondi ng esters i n
hi gh yi el d (Tabl e 2, entry 9).
32
I t must be stressed
that no reacti on was observed when the reagents
were sti rred i n the same sol vent i n the absence of
si l i ca, even i f drops of concentrated sul furi c aci d were
added; i n addi ti on, the use of si l i ca gel wi thout the
addi ti on of sul furi c aci d fai l ed to promote the acyl a-
ti on process. The method i s restri cted to short-chai n
al i phati c aci ds, probabl y due to the fact that the l ong-
chai n l i pophi l i c aci ds dri fted away from the sol i d
support i nto the nonpol ar sol vent. Thi s observati on,
together wi th the fact that the reacti on was not
reversi bl e, poi nts to a process that takes pl ace on the
surface of the sol i d catal yst: the aci d and the al cohol ,
Table 2. Protection of Hydroxylated Compounds as Acetates
a
The catal yst has been recycl ed (number of recycl es).
both adsorbed on the pol ar si l i ca gel , react to gi ve
the l ess pol ar ester, whi ch returns to the nonpol ar
di chl oromethane. Esteri fi cati on of phenol s wi th car-
boxyl i c aci ds has al so been reported i n combi nati on
wi th phosphorous pentoxi de supported on si l i ca gel
as catal yst (Tabl e 2, entry 10).
33
Transesteri fi cati on of pri mary al cohol s and di ol s
wi th ethyl acetate used as sol vent reagent has been
performed i n the presence of ceri um sul fate-sup-
ported si l i ca gel (Tabl e 2, entry 11).
34
The corre-
spondi ng (di )acetates were obtai ned i n very hi gh
yi el d, whereas phenol s carryi ng el ectron-donati ng
groups were not acetyl ated; thei r protecti on as esters
coul d, however, be achi eved by usi ng methyl benzoate
i n the presence of i ron(I I I ) sul fate-supported si l i ca
gel .
34
The acti vati on of aceti c anhydri de for conversi on
of al cohol s (phenol and R-naphthol ) i nto the corre-
spondi ng acetates coul d be accompl i shed wi th thal -
l i um chl ori de-supported si l i ca gel (Tabl e 2, entry
12).
35
The onl y l i mi tati on of the method was repre-
sented by the fact that, wi th terti ary al cohol s, the
producti on of ol efi ns was strongl y competi ti ve.
Basi c al umi na was a versati l e catal yst for acety-
l ati on of phenol s under sol vent-free condi ti ons and
mi crowave i rradi ati on i n the presence of pyri di ne.
Usi ng aceti c anhydri de, phenyl acetates were i sol ated
after a very short i rradi ati on ti me (1-6 mi n) i n hi gh
yi el ds (Tabl e 2, entry 13),
36
wi th the sol e excepti on
of R- and -naphthol s, whose ethyl esters were
prepared i n 65% and 62% yi el d, respecti vel y. The
method represents an envi ronmental l y fri endl y pro-
cedure si nce aceti c aci d (byproduct) remai ns adsorbed
over the basi c al umi na and there i s no evaporati on
i nto the atmosphere.
Potassi um fl uori de supported on al umi na, earl i er
used for the O-al kyl ati on of al cohol s and phenol s,
37
has been successful l y appl i ed by Yadav et al . to
protect pri mary and secondary al cohol s i n the pres-
ence of terti ary ones and phenol s. The reacti on,
carri ed out wi th acetyl chl ori de i n tol uene, afforded
the correspondi ng acetates i n al most quanti tati ve
yi el d (Tabl e 2, entry 14);
38
di acetates were obtai ned
from di ol s, and, i nteresti ngl y, 1,3-di ketones, whi ch
do not exi st i n cycl i c hydrogen-bonded structures,
underwent monoacetyl ati on (Scheme 1).
The reacti on showed an enormous rate enhance-
ment i n the absence of the sol vent; for exampl e, the
acetyl ati on of -naphthol (90% yi el d) requi red 30 h
i n tol uene, whereas i n the absence of di l uent the
reacti on was compl ete wi thi n 30 mi n.
I norgani c-organi c l ayered sol i ds bel ongi ng to the
cl ass of metal (I V) phosphonates and beari ng sui t-
abl e functi onal groups are excel l ent catal ysts for
organi c synthesi s, si nce they combi ne the properti es
of a stabl e i norgani c backbone wi th the fl exi bi l i ty of
the organi c deri vati ves. Thus, zi rconi um methane-
sul fophenyl phosphonate was abl e to catal yze the
acetyl ati on of not onl y pri mary, secondary, benzyl i c,
and acetyl eni c al cohol s but al so terti ary al cohol s and
phenol s wi th the use of aceti c anhydri de (Tabl e 2,
entry 15);
39
under these condi ti ons, sugars were
peracetyl ated. I n a si mi l ar way, WO
3
/ZrO
2
was uti -
l i zed as catal yst for producti on of acetates of vari ous
al cohol s and phenol s (Tabl e 2, entry 16).
40
Heteropol y compounds provi de a good basi s for the
desi gn of mi xed oxi de catal ysts wi th hi gh capabi l i ty
for practi cal uses. Thei r catal yti c performance coul d
be conveni entl y tai l ored on the basi s of chemi cal and
physi cal properti es, mol ecul ar and bul k composi ti on,
structure, and method of synthesi s.
Esteri fi cati on of al cohol s wi th aceti c aci d was
reported by Habi bi et al . to be performed i n the pres-
ence of potassi um dodecatungstocobal tate tri hy-
drate (K
5
CoW
12
O
40
3H
2
O). I t i s i mportant to menti on
that bul ky terti ary al cohol s coul d al so be acetyl ated
i n hi gh yi el d (Tabl e 2, entry 17).
41,42
The reacti on
coul d al so be performed effi ci entl y wi th the use of
ethyl acetate as acetyl ati ng agent
41
or i n the presence
of a sol vent, namel y acetoni tri l e, i sol ati ng the corre-
spondi ng acetates i n good yi el ds and wi th shorter
reacti on ti mes.
42
Expansi ve graphi te represents a good heteroge-
neous catal yst for the protecti on of pri mary and
secondary al cohol s and phenol s as acetates; pol yhy-
droxyl ated compounds (i .e., sal i cyl i c al cohol , hydro-
qui none, and benzene-1,3,5-tri ol ) are al so converted
i nto thei r pol yacetates (Tabl e 2, entry 18).
43
Fi nal l y,
the commerci al l y avai l abl e Nafi on, a sol i d aci d cata-
l yst commonl y used i n organi c synthesi s,
44
was
uti l i zed for the acetyl ati on of pri mary and secondary
al cohol s wi th aceti c anhydri de (Tabl e 2, entry 19);
45
monosacchari des underwent peracetyl ati on wi th the
use of aceti c anhydri de as sol vent reagent. Aci d-
sensi ti ve groups such as ketal , acetal , tetrahydropy-
ranyl (THP) ether, and cycl opropane uni ts survi ved
under these reacti on condi ti ons.
2.1.2. Deprotection
The regenerati on of al cohol s from thei r esters can
be carri ed out under heterogeneous condi ti ons by
usi ng some sol i d catal ysts, such as zeol i tes, si l i ca,
al umi na, and aci di c resi ns.
Neutral al umi na combi ned wi th mi crowave i r-
radi ati on was uti l i zed by Varma et al . to promote
sel ecti ve de-esteri fi cati on of aryl acetates and al kyl
acetates under sol ventl ess condi ti ons (Tabl e 3, entry
1),
46
whereas ZSM-5 zeol i te al one promoted the
deacetyl ati on of al kyl acetates i n an aqueous medi um
47
Due to the pore di mensi on of thi s
type of zeol i te (5.1-5.6 ), no reacti on i n the case of
cycl ododecanol acetate was observed, ascri babl e to
the nondi ffusi bi l i ty of thi s reagent i nto the pores of
the sol i d catal yst. A typi cal reactant shape sel ecti vi ty
was observed when competi ti ve deacetyl ati on reac-
ti ons were carri ed out: for exampl e, by treati ng a 1/1
mi xture of R-methyl benzyl acetate/di phenyl carbi nol
acetate, the correspondi ng al cohol s were i sol ated i n
a 100/21 mol ar rati o.
A very si mpl e and effi ci ent method for the ful l
deprotecti on of bi stri fl uoroacetates of di ol s coul d be
performed wi th a si l i ca gel -based catal yst upon
Scheme 1
treatment wi th tri ethyl ami ne (Tabl e 3, entry 3).
48
Fi nal l y, the de-esteri fi cati on of sugar and nucl eosi de
acetates has been accompl i shed by usi ng I RA-400-
(OH
-
) resi n. Compl ete O-deacetyl ati on was observed
upon treati ng peracetyl ated sugar/nucl eosi des di s-
sol ved i n methanol (Tabl e 3, entry 4).
49
2.2. Silyl Ethers
2.2.1. Protection
Protecti on of hydroxy groups through the formati on
of si l yl ethers has been extensi vel y uti l i zed i n organi c
synthesi s. Si l yl ethers are easi l y prepared, they show
resi stance to oxi dati on, good thermal stabi l i ty, and
l ow vi scosi ty, and they are easi l y recoverabl e from
thei r parent compounds. Moreover, numerous si l y-
l ati ng methods can be uti l i zed today; among them,
tri methyl si l yl ati on i s one of the most often used.
Al cohol s and phenol s coul d be conveni entl y con-
verted i nto the correspondi ng si l yl ethers by treat-
ment wi th 1,1,1,3,3,3,-hexamethyl di si l azane (HMDS)
i n the presence of a natural kaol i ni ti c cl ay treated
wi th 2 M hydrochl ori c aci d (Tabl e 4, entry 1)
50
or
montmori l l oni te K10 (Tabl e 4, entry 2).
51
The l atter
procedure was qui te general , as a wi de range of
hydroxy-containing compounds, including some highly
bul ky ones, were protected. A smal l substi tuent effect
was observed (Tabl e 5, compare entri es 1, 2, 3, 4, and
6). Phenol s carryi ng el ectron-rel easi ng groups af-
forded the products i n nearl y quanti tati ve yi el d i n
shorter reacti on ti mes.
Si l yl ati on of al cohol s and phenol s wi th HMDS has
been al so performed by usi ng Envi rocat EPZG (Tabl e
4, entry 3).
52
The reacti on tol erates the presence of
ami nes and thi ol s. Si mi l arl y, good resul ts of tri meth-
yl si l yl ati on of al cohol s and phenol s, i ncl udi ng tert-
butyl al cohol , have been achi eved by usi ng zi rconi um
sul fophenyl phosphonate [R-Zr(O
3
PCH
3
)
1.2
(O
3
PC
6
H
4
-
SO
3
H)
0.8
] (Tabl e 4, entry 4).
53
Table 3. Deprotection of Acetates
Table 4. Protection of Hydroxylated Compounds as Silyl Ethers
a
Phenol i c 2-(tr i methyl si l yl )ethoxymethyl (SEM)
ethers coul d be prepared by reacti on wi th SEMCl i n
the presence of potassi um fl uori de supported on
al umi na (Al
2
O
3
/KF) i n order to repl ace terti ary ami ne
bases. The method i s si mpl er than most of those
avai l abl e, as i t avoi ds aqueous workup and the
products are i sol ated after fi l trati on and removal of
the sol vent (Tabl e 4, entry 5).
54
The method i s
effecti ve for both el ectron-ri ch and el ectron-poor
phenol s, but al cohol s cannot be converted i nto the
al kyl -SEM ethers.
2.2.2. Deprotection
The deprotecti on of tri methyl si l yl (TMS) ethers i s
commonl y carri ed out i n the presence of catal ysts
such as i ron(I I I ) or ti n(I I ) chl ori des, copper(I I ) or
ceri um(I I I ) ni trates, ci tri c aci d, and sodi um hydrox-
i de
55,56
or vari ous fl uoro deri vati ves.
57
Removal of the si l yl protecti ng group from hydroxy
functi ons of carbohydrates and nucl eosi des i n aque-
ous methanol has been performed by Arakura et al .
wi th montmori l l oni te K10. Thus, 3,5-di -O-tert-bu-
tyl di methyl si l yl -2-deoxyuri di ne coul d be effi ci entl y
deprotected to 2-deoxyuri di ne (Tabl e 6, entry 1).
58
Di fferentl y protected nucl eosi de deri vati ves 1, 2, and
3 (Fi gure 1) afforded the compl etel y deprotected
compounds i n hi gh yi el d upon treatment wi th mont-
mori l l oni te K10 i n methanol /water.
The authors showed al so the appl i cabi l i ty of the
pr esent catal yst for depr otecti on of acetal and
di methoxytri tyl (DMTr)-protected sugars.
The same catal yst was uti l i zed for the desi l yl ati on
of pri mary and secondary al cohol i c and phenol i c
tri methyl si l yl ethers. Compl ex mol ecul es, such as
betul i n bi stri metyhl si l yl ether, coul d be compl etel y
Table 5. Protection of Phenols as TMS Ethers
entry R ti me (h) yi el d (%)
1 H 1 95
2 3-CH3 0.6 90
3 4-OCH3 0.75 94
4 2-OH 0.35 92
5 3-OH 1 85
6 2-Cl 5 96
7 2,3-CHsCHdCHsCH 1.5 92
8 3,4-CHsCHdCHsCH 6 76
Table 6. Deprotection of Silyl Ethers
a
The catal yst has been recycl ed.
Figure 1.
desi l yl ated (Tabl e 6, entry 2),
51
but the steri cal l y
crowded tri methyl si l yl oxy tri phenyl methane was de-
si l yl ated onl y i n 40% conversi on after 4 h, probabl y
due to the steri c hi ndrance whi ch hampers the access
to the acti ve si tes of the catal yst. The reacti on can
be carri ed out i n shorter reacti on ti mes by combi ni ng
the use of cl ay wi th mi crowave i rradi ati on under
sol vent-free condi ti ons (Tabl e 6, entry 3).
59
Si mi l arl y, TMS ethers of al cohol s coul d be ef-
fi ci entl y cl eaved by potassi um dodecatungstocobal -
tate tri hydrate (K
5
CoW
12
O
40
3H
2
O) (Tabl e 6, entry
4).
60
Phenol i c TMS ethers were resi stant toward
deprotecti on wi th thi s catal yst.
The tert-butyl di methyl si l yl (TBDMS) group, one of
the most wi del y used protecti ng groups i n organi c
synthesi s for hydroxy functi onal i ty, was removed by
a mani pul ati vel y easy and sol vent-free method. The
reacti on was performed i n hi gh yi el d and i n a short
ti me on an al umi na surface under mi crowave i r-
radi ati on (Tabl e 6, entry 5).
61
The mi crowave effect
i s not purel y thermal , as i t i s borne out by the fact
that l onger reacti on peri ods are requi red for si mi l ar
yi el ds usi ng al ternati ve heati ng modes at the same
temperature. Some drawbacks are rel ated to the
great amount of i norgani c support requi red to adsorb
the organi c compound to be deprotected (i .e., 35 g of
al umi na for 2 mmol of TBDMS ether). The reacti on
coul d be performed wi th good resul ts by usi ng si l i ca
i nstead of al umi na as the support, but i n the case of
nucl eosi de anal ogues, cl eaner products are obtai ned
onl y wi th basi c al umi na.
Bl ass et al . reported the use of potassi um fl uori de
supported on neutral al umi na to effi ci entl y and
sel ecti vel y remove a vari ety of si l yl protecti ng groups
from phenol s. I t was possi bl e to di fferenti ate between
el ectron-ri ch and el ectron-poor phenol i c ethers on the
basi s of the strong sol vent effect. For exampl e, TMS-
4-bromophenol was readi l y deprotected wi th neutral
Al
2
O
3
/KF i n 1,2-di methoxyethane (DME) or 1,4-
di oxane after onl y 4 h at 25 C, whereas TBDMS-4-
bromophenol was found to be stabl e after 16 h i n
DCE. Swi tchi ng the sol vent to DME faci l i tated the
cl eavage of the TBDMS group, whi ch was accom-
pl i shed onl y after 4 h at 25 C (Tabl e 6, entry 6).
54
Potassi um-exchanged l ayered zi rconi um phosphate
represents another sol i d, not commerci al l y avai l abl e,
base catal yst that i s useful to deprotect phenol i c si l yl
deri vati ves. The catal yst was effi ci entl y appl i ed for
the cl eavage of parti cul arl y hi ndered compounds
such as TBDMS, tri ethyl si l yl (TES), and tert-butyl -
di phenyl si l yl (TBDPS) ethers of phenol s (Tabl e 6,
entry 7).
62
2.3. Alkoxyalkyl Ethers
2.3.1. Protection as THP Ethers
THP ethers have found extensi ve use i n organi c
synthesi s; they can be easi l y synthesi zed from a
vari ety of hydroxy-contai ni ng compounds by aci d-
catal yzed reacti on wi th 3,4-di hydro-2H-pyran (DHP).
They are stabl e to bases, but the protecti on i s
removed through aci d hydrol ysi s. I t i s i mportant to
poi nt out that the i ntroducti on of the THP ether onto
a chi ral mol ecul e resul ts i n the formati on of di aste-
reoi somers because of the addi ti onal stereogeni c
center present i n the tetrahydropyran ri ng, whi ch
can make both the NMR spectra i nterpretati on and
the handl i ng of the reacti on crude somewhat troubl e-
some.
14
Some i nexpensi ve and readi l y avai l abl e natural l y
occurri ng cl ays, often uti l i zed as effi ci ent and versa-
ti l e catal ysts for organi c reacti ons
63
and al ready
menti oned i n thi s revi ew, were uti l i zed for the
tetrahydropyranyl ati on of hydroxy compounds. For
exampl e, the protecti on of a l arge vari ety of hydroxy
compounds was performed under very mi l d reacti on
condi ti ons wi th DHP i n the presence of K10 cl ay
(Tabl e 7, entry 1)
64
or Spani sh sepi ol i te cl ay (Tabl e
7, entry 2).
65
Both procedures gave nearl y quanti ta-
ti ve yi el ds for most pri mary, secondary, terti ary,
al l yl i c, and pol yfuncti onal al cohol s, as wel l as for
phenol s. More effi ci entl y, a natural kaol i ni ti c cl ay,
preacti vated by washi ng wi th 2 M hydrochl ori c aci d,
was appl i ed i n the reacti on wi th al cohol s, i ncl udi ng
terti ary ones (Tabl e 7, entry 3).
50
The acti vi ty of the
catal yst was attri buted to the presence of the surface
proti c and Lewi s aci d si tes due to the di sordered Al
3+
and Fe
3+
i ons and surface water mol ecul es.
Envi rocat EPZG, whi ch exhi bi ts both Brnsted and
Lewi s aci d characteri sti cs, coul d be uti l i zed for the
hi ghl y effi ci ent tetrahydropyranyl ati on of al cohol s
and phenol s i n a short reacti on ti me at 0-5 C. The
products were i sol ated si mpl y by treatment of the
fi nal reacti on mi xture wi th di chl oromethane, fi l tra-
ti on, and removal of the sol vent under reduced
pressure (Tabl e 7, entry 4).
66
Aci d zeol i tes have al so been uti l i zed to protect
al cohol s and phenol s. Good yi el ds of THP deri vati ves
of a wi de range of hydroxy compounds, such as
pri mary, secondary, terti ary, al l yl i c, acetyl eni c and
pol yfuncti onal al cohol s, coul d be obtai ned by usi ng
a Y zeol i te wi th a si l i ca/al umi na rati o (SAR) of 4.86
67
However, reacti on of bul ky
substrates was sl ower, and l onger reacti on ti mes
were requi red (i .e., sec-butanol , 90% yi el d i n 2 h;
benzyl al cohol , 70%yi el d i n 10 h). More conveni entl y,
the protecti on of phenol s and al cohol s coul d be
performed under sol ventl ess condi ti ons by usi ng
zeol i tes wi th di fferent SARs (5.9 and 13.9, respec-
ti vel y) (Tabl e 7, entry 6).
68
Frequentl y, zeol i tes present some l i mi tati ons when
l arge reactant mol ecul es are i nvol ved, especi al l y i n
l i qui d-phase systems, as i s often the case i n the
synthesi s of fi ne chemi cal s. To thi s end, Corma et al .
uti l i zed the new zeol i ti c materi al I TQ-2; i n thi s
materi al , the zeol i te-type catal yti c si tes are contai ned
wi thi n thi n and readi l y accessi bl e sheets.
8
I TQ-2 was
found to be an effi ci ent catal yst to protect al cohol s
and phenol s, i ncl udi ng naphthol s and steroi ds (Tabl e
7, entry 7).
69
Mesoporous H-MCM-41 mol ecul ar si eves (SAR )
51.8) represent another zeol i te-type materi al uti l i zed
for the reacti on wi th bul ky mol ecul es. Thi s materi al
possesses a hexagonal arrangement of uni forml y
si zed, uni di mensi onal mesopores (di ameter from 15
to 100 ), whi ch gi ve mol ecul es access to the l arge
i nternal surface that enhances catal yti c acti vi ty and
adsorpti on capaci ty. Thus, al cohol s and phenol s coul d
be protected by treatment wi th a smal l excess of DHP
Table 7. Protection of Hydroxylated Compounds as THP Ethers
i n hexane (Tabl e 7, entry 8).
70
I mprovement of the
effi ci ency of the process was obtai ned by addi ng the
DHP dropwi se.
Furthermore, THP ethers of al cohol s and phenol s
were effi ci entl y prepared by carryi ng out the reac-
ti ons i n the presence of sul furi c aci d adsorbed on
si l i ca gel . I n most cases the reacti ons were compl ete
on si mpl e mi xi ng reagents and catal yst i n a mortar
71
When the reacti on was carri ed
out i n the presence of di chl oromethane as sol vent,
more compl ex and pol yfuncti onal substrates coul d be
protected i n al most quanti tati ve yi el d and i n very
short reacti on ti mes (1-10 mi n). The method avoi ded
aqueous workup, reduced to merel y fi l trati on and
sol vent evaporati on. Steroi ds, ci nnami c and propar-
gyl i c al cohol s, were quanti tati vel y converted i nto the
correspondi ng THP ethers (Tabl e 7, entry 10).
72
The
same reacti on coul d be performed sel ecti vel y by usi ng
si l i ca chl ori de, a materi al prepared from si l i ca and
thi onyl chl ori de (Tabl e 7, entry 11).
73
Si O
2
/TaCl
5
represents a si l i ca-supported Lewi s aci d
that was effi ci entl y uti l i zed i n the producti on of THP
ethers from al cohol s. I nteresti ngl y, i t was noted that
thi s materi al acts as a more effi ci ent catal yst, even
at l ow concentrati ons, and requi res shorter reacti on
ti mes wi th respect to TaCl
5
al one. The reacti on coul d
be appl i ed effi ci entl y to benzyl oxy and aci d-l abi l e
sugar substrates contai ni ng acetal groups (Tabl e 7,
entry 12).
74
Ranu et al . uti l i zed al umi na-supported zi nc chl o-
ri de for tetrahydropyranyl ati on of al cohol s through
a si mpl e sol vent-free reacti on (Tabl e 7, entry 13).
75
Al so i n thi s case, the authors menti oned that the
reacti on catal yzed by zi nc chl ori de al one i n the
absence of al umi na i n tetrahydrofuran (THF) or on
the al umi na surface wi thout zi nc chl ori de was sl ug-
gi sh. On the other hand, when the reacti on was
carri ed out i n sol vents (CH
2
Cl
2
or THF) under i denti -
cal condi ti ons wi th zi nc chl ori de-supported al umi na,
the progress of THP producti on was practi cal l y ni l .
Thus, the combi nati on of the sol i d surface of al umi na
and zi nc chl ori de wi th the absence of sol vent i s
essenti al for a sati sfactory reacti on; al though thi s fact
was not rati onal i zed, the process showed great and
i nteresti ng appl i cabi l i ty, and some aci d-sensi ti ve
functi onal i ti es, such as ketal s, were safe under thi s
procedure.
Zi rconi a i n i ts pure and modi fi ed form has been
empl oyed i n many syntheti c and i ndustri al processes.
Mi crowave-accel erated tetrahydropyranyl ati on of al -
cohol s and phenol s, catal yzed by hydrated zi rconi a,
was recentl y reported. Al l yl i c and acetyl eni c al cohol s
were protected wi thout i someri zati on of doubl e and
tri pl e bonds, and the correspondi ng THP ethers were
i sol ated as the onl y products. I n addi ti on, parti cul arl y
bul ky substrates, such as chol esterol and naphthol s,
were protected i n hi gh yi el ds wi thi n a very short
ti me. Phenol s contai ni ng a di oxol ane protecti ve group
coul d be converted i nto THP ethers i n hi gh yi el d
wi thout further transformati ons (Tabl e 7, entry 14).
76
Sul fated zi rconi a (ZrO
2
/SO
4
2-
) i s a popul ar sol i d
superacid catalyst exhibiting the highest acid strength
(H
0
e -16.04).
77
Treatment of a vari ety of al cohol s
and phenol s wi th DHP i n the presence of a catal yti c
amount of sul fated zi rconi a gave the correspondi ng
THP ethers i n hi gh yi el d. The procedure coul d al so
be effi ci entl y appl i ed to hi ghl y aci d-sensi ti ve al cohol s
such as al l yl and propargyl al cohol s (Tabl e 7, entry
15).
78
Thi s sol i d catal yst was uti l i zed for the tetrahy-
dropyranyl ati on of hydroqui none protected as the
benzyl ether (Tabl e 7, entry 16).
79
Campel o et al . uti l i zed Al PO
4
as a sol i d aci d
catal yst for the protecti on of al cohol s and phenol s.
The reacti on, carri ed out i n the presence of an excess
of DHP, proceeded sel ecti vel y under mi l d condi ti ons
i n very good yi el ds, wi th short reacti on ti mes (15
mi n) and wi thout the formati on of troubl esome
ol ygomeri c pyrans (Tabl e 7, entry 17).
80
Si mi l arl y,
R-Zr(O
3
PCH
3
)
1.2
(O
3
PC
6
H
4
SO
3
H)
0.8
promoted the tet-
rahydropyranyl ati on of al cohol s and phenol s; the
reacti on tol erates C-C doubl e and tri pl e bonds, and
the yi el ds are not affected by the steri c hi ndrance of
reagents (Tabl e 7, entry 18).
81
A l arge seri es of al cohol s and phenol s has been
protected by usi ng sul fated charcoal , i n combi nati on
wi th 3- mol ecul ar si eve; i n the absence of mol ecul ar
si eves, the reacti on was very sl ow. The process
showed general appl i cabi l i ty, and i n the majori ty of
cases, due to the very hi gh yi el ds, the puri fi cati on of
THP ethers was achi eved si mpl y by fi l trati on (Tabl e
7, entry 19).
82
Very recentl y, the reacti on was performed usi ng
catal yst supported on organi c pol ymers, materi al s
that are of growi ng i nterest i n organi c synthesi s.
Thus, by usi ng acetonyl tri phenyl phosphoni um bro-
mi de (ATPB) supported on pol ystyrene (Fi gure 2),
Hon et al . obtai ned good yi el ds i n the protecti on of a
l arge vari ety of phenol s and al cohol s, i ncl udi ng
Table 7 (Continued)
a
Figure 2.
terti ary ones and al cohol s carryi ng addi ti onal func-
ti onal groups, such as a carbonyl group (Tabl e 7,
entry 20).
83
Fi nal l y, Ol ah et al . reported the use of Nafi on for
the tetrahydropyranyl ati on of pri mary and secondary
al cohol s. To avoi d the formati on of a bl ack charry
materi al , the reacti on was performed by sl owl y
addi ng a sol uti on of THP i n di chl oromethane to a
mi xture of the al cohol and Nafi on i n the same sol vent
84
2.3.2. Protection as Other Alkoxyalkyl Ethers
The methoxymethyl moi ety i s an i mportant pro-
tecti ng group for al cohol s. I t i s stabl e to a vari ety of
commonl y used reagents, such as strong bases,
Gri gnard reagents, al kyl l i thi ums, and l i thi um al u-
mi num hydri de, and i t i s readi l y removed by aci d
treatment.
85
Kumar et al . prepared methoxymethyl (MOM)
ethers of al cohol s, i ncl udi ng terti ary ones, i n sati sfac-
tory yi el ds by reacti on wi th chl oromethyl methyl
ether (MOMCl ) i n the presence of NaY zeol i te (Tabl e
8, entry 1).
86
Lower yi el ds and sel ecti vi ti es have been
obtai ned wi th the aci d Y zeol i te or wi th other zeol i tes
such as ZSM-5, mordeni te, and 4- or 5- mol ecul ar
si eves.
A very si mpl e procedure for methoxymethyl ati on
of pri mary and secondary al cohol s through a sol vent-
free reacti on was based on the use of the same
reagent and al umi na catal yst under soni cati on. Thus,
MOMCl was added dropwi se to the al cohol adsorbed
on the surface of al umi na, acti vated by heati ng at
200 C. The product was i sol ated by si mpl e extracti on
of the sol i d mass wi th methyl ene chl ori de (Tabl e 8,
entry 2).
87
However, i t must be emphasi zed that the
use of MOMCl i s restri cted due to i ts hi gh carci no-
geni ci ty.
To overcome the probl ems and l i mi tati ons con-
nected wi th the toxi ci ty of MOMCl , the l ess prob-
l emati c reagent di methoxymethane has been effi -
ci entl y uti l i zed. Expansi ve graphi te (Tabl e 8, entry
3)
88
and two commerci al l y avai l abl e heterogeneous
catal ysts, namel y Envi rocat EPZG (Tabl e 8, entry 4)
89
and montmori l l oni te K10 (Tabl e 8, entry 5),
90
have
been effi ci entl y uti l i zed to promote the conversi on of
di fferent pri mary and secondary al cohol s i nto the
correspondi ng MOM ethers. Chi ral centers were
preserved i n the reacti ons.
I ron tri chl ori de, di spersed on powdered 3- mol ec-
ul ar si eves, was cl ai med by Patney to promote the
MOM protecti on of pri mary and secondary al cohol s
at room temperature for short reacti on ti mes (Tabl e
8, entry 6).
91
A l i mi tati on of the method i s repre-
sented by the fact that i t requi res quenchi ng wi th
di l uted sodi um hydroxi de, suggesti ng a possi bl e
doubt that i ron tri chl ori de coul d act as a real catal yst.
Sul fated ti tani a i s a catal yst whi ch has been l i ttl e
uti l i zed i n organi c synthesi s. Thi s materi al was abl e
to convert pri mary and secondary (chi ral ) al cohol s
i nto the correspondi ng MOM ethers by reacti on wi th
di methoxymethane i n chl oroform (Tabl e 8, entry 7).
92
The 2-methoxypropyl group represents one of the
most aci d-sensi ti ve protecti ng groups for al cohol s and
phenols. p-Methoxybenzyl alcohol reacted with 2-meth-
oxypropene i n the presence of the i nexpensi ve Si O
2
/
H
2
SO
4
, affor di ng the cor r espondi ng 1-methyl -1-
methoxyethyl ether i n 89% yi el d. The reacti on coul d
be appl i ed to steroi ds, phenol s, and ci nnami c al cohol s
93
Usual l y the crude products were
pure enough that the puri fi cati on steps were ski pped
due to both the hi gh yi el ds of the process and the
soft reacti on condi ti ons.
2.3.3. Deprotection
Di fferent sol i d catal ysts have been uti l i zed to
remove the protecti ve group from O-protected al co-
hol s and phenol s, i ncl udi ng natural l y occurri ng cl ays
and aci d-treated si l i ceous materi al s and pol ymers.
Table 8. Protection of Hydroxylated Compounds as Methoxyalkyl Ethers
a
Tonsi l , a commerci al l y avai l abl e Mexi can bentoni te
earth, and montmori l l oni te K10 cl ays have been
uti l i zed to deprotect THP ethers of al cohol s and
phenol s by methanol ysi s (Tabl e 9, entri es 1-3).
94-96
An i nteresti ng appl i cati on i s represented by the
deprotecti on of reagents 4 to gi ve al cohol s 5 i n
acceptabl e yi el ds (73-77%), savi ng the epoxy func-
ti onal i ty (Scheme 2).
Removal of the MOM functi on often requi res
rel ati vel y harsh aci di c condi ti ons because of i ts
chemi cal stabi l i ty, whi ch has somewhat restri cted i ts
uti l i zati on i n mol ecul es contai ni ng other aci d-sensi -
ti ve functi onal i ti es. Behar et al . performed the depro-
tecti on of phenol i c MOM ethers by usi ng montmo-
ri l l oni te K10 cl ay. The reacti on proceeded at room
temperature i n benzene and showed general ap-
pl i cabi l i ty for a vari ety of ortho-substi tuted, MOM-
protected phenol s, though i t requi res the presence of
a functi onal group beari ng a heteroatom i n thi s
posi ti on. A mechani sm i nvol vi ng chel ati on-assi sted
cl eavage of the MOM ether by the Lewi s aci di c
montmori l l oni te cl ay was al so proposed (Fi gure 3).
Moreover, the method coul d be successful l y appl i ed
to di fferenti ate phenol i c groups i n naphthoqui none-
and anthraqui none-contai ni ng anti tumor anti bi oti cs
wi th hi ghl y oxygenated frameworks (Tabl e 9, entry
4).
97
Methoxyphenyl methyl (MPM) ethers have been
frequentl y uti l i zed i n organi c synthesi s because of
Table 9. Deprotection of Alkyl Ethers
a
Scheme 2
Figure 3.
thei r stabi l i ty toward aci d, al kal i , and a number of
other reagents; thus, thei r sel ecti ve deprotecti on i nto
the parent hydroxy groups showed i ncreased i mpor-
tance. Cl eavage of MPM ethers contai ni ng a wi de
range of functi onal i ti es coul d be performed by usi ng
cl ayan i n dry medi a, combi ned wi th mi crowave
i rradi ati on. Di fferent functi onal i ti es survi ve the treat-
ment, such as the C-C doubl e and tri pl e bonds
(Tabl e 9, entry 5)
98
and ami no, hal o, and carboxyl i c
groups.
A further method for deprotecti on of THP ethers
of al cohol s and phenol s i nvol ves the use of si l i ca gel -
supported sul furi c aci d (Tabl e 9, entry 6)
99
and
hydrated zi rconi a (Tabl e 9, entry 7).
76
The process
wi th the l atter catal yst was markedl y accel erated by
mi crowave i rradi ati on.
Seto et al . reported the use of Dowex 50WX2
cati oni c-exchanged resi n as an acti ve catal yst for the
hi ghl y effi ci ent and sel ecti ve removal of the MOM
functi on from di fferent protected al cohol s; terti ary
al cohol s, whi ch are prone to dehydrati on to the
correspondi ng ol efi ns, coul d be recovered i n al most
quanti tati ve yi el d. The method was appl i ed to a
seri es of compl ex gi bberel l i ni c aci d deri vati ves; al l
skel etal rearrangements of the C/D ri ng system were
compl etel y el i mi nated. Thi s behavi or was i n contrast
to the resul ts from p-tol uenesul foni c aci d-catal yzed
hydrol ysi s, whi ch afforded a consi derabl e amount of
the rearrangement products (Tabl e 9, entry 8).
100
Some organi c catal ysts supported on pol ymeri c
materi al s have been uti l i zed i n the regenerati on of
al cohol s from thei r protected deri vati ves. For ex-
ampl e, pol y-p-styryl di phenyl acetonyl phosphoni um
bromi de [(P)ATPB], a copol ymer of styrene, p-styryl -
di phenyl phosphi ne, and di vi nyl benzene, was uti l i zed
to perform the methanol ysi s of THP, 1-ethoxyethyl
(EE), and tetrahydrofuranyl ethers of al cohol s and
phenol s (Tabl e 9, entry 9).
83
The authors observed
that the catal yst coul d be reused, but i ts catal yti c
acti vi ty decreased sl i ghtl y each ti me. I n fact, i t i s wel l
known that phosphoni um bromi des react wi th re-
fl uxi ng methanol to gi ve the correspondi ng debromi -
nated ketone; however, si nce the present deprotecti on
was carri ed out at room temperature, thi s si de
reacti on mi ght occur onl y i n smal l porti ons.
Masaki et al. utilized poly(ethylene glycol) dimethac-
ryl ate-supported di cyanoketene acetal [(P)-DCKA]
(Fi gure 4), a materi al showi ng a qui te i nteresti ng
chemi cal behavi or wi th respect to the deacetoni dati on
of 1,2-di ol acetoni des (Tabl e 9, entry 10).
101
Wi th use
of the monomeri c di cyanoketene acetal (DCKA) cata-
l yst i n acetoni tri l e/water mi xture as sol vent, com-
pound 7was obtai ned i n no more than 2%yi el d wi th
90% recovery of 6, whereas 59% yi el d of 7 was
obtai ned when (P)-DCKA was used as heterogeneous
catal yst, probabl y due to the posi ti ve effect of the
l i pophi l i ci ty of substrate and catal yst (Scheme 3).
Fi nal l y, these authors observed that, i n the presence
of (P)-DCKA, compound 9was produced i n 94%yi el d
when the reacti on was carri ed out i n water as the
sol e sol vent.
2.4. Tosylates
Tosyl ati on of al cohol s was used occasi onal l y as a
protecti ve i nstrument i n organi c synthesi s.
14,15
The
reacti on was usual l y performed by uti l i zi ng sul fonyl
chl ori des or anhydri des i n the presence of pyri -
di ne, tri ethyl ami ne, or 1,4-di azabi cycl o[2.2.2]octane
(DABCO); the major probl ems were the moi sture
sensi ti vi ty and the hi gh reacti vi ty of the reported
tosyl ati ng agents. Further, undesi rabl e conversi on of
tosyl ates i nto thei r chl ori des occurred duri ng tosy-
l ati on when TsCl /pyri di ne was used. Moreover, the
bases whi ch were used i n mol ar excess for the
sulfonylation of alcohols generated significant amounts
of byproducts i n the form of di ssol ved sal ts.
An envi ro-economi c route for the tosyl ati on of
al cohol s and phenol s medi ated by metal -exchanged
montmori l l oni te K10, empl oyi ng p-tol uenesul foni c
aci d (TsOH), has been recentl y reported by Choudary
et al . The reacti on requi red the azeotropi c removal
of water si nce water l owers the rate of the reacti on
by bl ocki ng the aci d acti ve si tes of cl ay. Fe
3+
, Zn
2+
,
Cu
2+
, and Al
3+
-exchanged montmori l l oni tes K10 were
tested i n the tosyl ati on of cycl ohexanol : the Fe
3+
-
montmori l l oni te showed the best acti vi ty.
102
The
hi gher acti vi ty of the Fe
3+
-montmori l l oni te was there-
fore ascri bed to the i nducti on of Lewi s aci di c si tes
through the exchange of i ron i n montmori l l oni te and
al so by the hi gher densi ty of Brnsted aci d si tes.
These authors suggested a pl ausi bl e mechani sm for
the reacti on (Scheme 4).
The aquo compl ex of metal -exchanged montmori l -
l oni te 8protonates al cohol to form the hydroxy metal
aquo compl ex 9, whi ch i n turn reacts wi th TsOH to
form the metal tosyl ate sal t 10. The i nteracti on of
metal tosyl ate and protonated al cohol gi ves the
tosyl ated product and regenerates the metal aquo
compl ex 8.
The cl eavage of tosyl ates of phenol s and al cohol s
usual l y requi res drasti c condi ti ons due to thei r hi gh
stabi l i ty. An effi ci ent and rel ati vel y mi l d method was
represented by the use of potassi um fl uori de sup-
ported on al umi na as catal yst under mi crowave
i rradi ati on. Other functi onal i ti es i n the substrate,
such as benzyl , N-tert-butoxycarbonyl (N-Boc), and
al l yl groups, al i phati c acetates, acetal s, and sul fi des,
were tol erated, whereas epoxi des were not stabl e; the
hydroxyl ated compounds coul d be recovered i n hi gh
yi el d.
103
Figure 4.
Scheme 3
2.5. Selective Protection of Polyfunctional
Compounds
Protecti on and deprotecti on of hydroxy groups i n
pol yhydroxyl ated compounds and, i n general , i n
mul ti functi onal compounds represents a fundamental
tool i n the synthesi s of el aborated target compounds
such as those usual l y encountered i n carbohydrate,
ami no aci d, and nucl eosi de/nucl eoti de chemi stry. Due
to the compl exi ty of the compounds i nvol ved, hi gh
sel ecti vi ty i s normal l y requested as wel l as si mpl i ci ty
and mi l dness i n i ntroduci ng and removi ng the spe-
ci fi c functi on. I n thi s secti on, exampl es of sel ecti ve
protecti on of pol yfuncti onal compounds wi l l be re-
ported.
Sel ecti ve monotosyl ati on of pri mary al cohol s i n the
presence of secondary ones, i ncl udi ng termi nal 1,2-
di ol s, has been performed by Choudary et al . wi th
TsOH i n combi nati on wi th Fe
3+
-exchanged montmo-
ri l l oni te cl ay K10 (Tabl e 10, entry 1).
102
The reacti on
requi red azeotropi c removal of the water produced,
parti cul arl y when carri ed out i n l arge scal e. I n al l
cases exami ned, tosyl ati on of the pri mary hydroxy
group wi th respect to the secondary one occurred i n
a rati o of more than 99/1. I n the case of symmetri cal
di ol s, the reacti on wi th 1 mol equi v of TsOH provi ded
sel ecti ve monotosyl ati on, and wi th more than two
mol ar quanti ti es, di tosyl ati on occurred. The observed
hi gh sel ecti vi ty for pri mary al cohol s wi th respect to
the secondary ones was attri buted to the effecti ve
steri c crowdi ng i n the mesoporous system of the sol i d
aci d that renders the pri mary al cohol s rel ati vel y
uncrowded.
Y zeol i te (SAR ) 13.9) was uti l i zed for the sel ecti ve
tetrahydropyranyl ati on of the al cohol i c group of
sal i cyl i c al cohol and for the monoprotecti on of sym-
metri cal di ol s (Tabl e 10, entry 2).
68
More i nterest-
i ngl y, the protecti on of sugars as i sopropyl i dene
deri vati ves was performed by condensati on wi th
acetone i n the presence of ammoni um-exchanged Y
zeol i te. Protected D-gal actose, D-gl ucose, D-xyl ose,
D-ri bose, methyl -D-ri bofuranosi de, D-gl ucurono-6,3-
l actone, L-arabi nose, and L-sorbose were obtai ned i n
moderate to sati sfactory yi el ds (Tabl e 10, entry 3).
104
These authors reported that, i n the protecti on of
D-gal actose, the furanose di acetal was formed i n 40%
yi el d, together wi th the pyranose di acetal obtai ned
onl y i n 20% yi el d. Thi s method made i t possi bl e to
synthesi ze i n sati sfactory yi el d the gal actofuranose
di acetal , whi ch was previ ousl y produced onl y i n l ow
yi el d.
Ogawa et al . uti l i zed si l i ca for the sel ecti ve mono-
acetyl ati on of 1,n-di ol s wi th acetyl chl ori de. The hi gh
sel ecti vi ty was ascri bed to the formati on of a mono-
mol ecul ar l ayer of the di ol on the surface of the
catal yst, whi ch pl ayed a fundamental rol e i n the
monoprotecti on (Tabl e 10, entry 4).
105
The onl y draw-
back was represented by the l arge amount of si l i ca
requi red (0.32 mmol of reagent per gram of si l i ca).
A method for the sel ecti ve monoacetyl ati on of
unsymmetri cal di ol s such as 1,5-hexanedi ol 11wi th
ethyl acetate, promoted by Si O
2
/NaHSO
4
, has been
reported by Breton (Scheme 5).
106
Sel ecti vi ty for monoacetate 12 rel ati ve to 13 i n-
creased from 90/10 at 1 h to 95/5 at 9 h and fi nal l y
to 97/3 at 10 h, after whi ch i t remai ned constant; at
that ti me the yi el d of 14began to be si gni fi cant. Thi s
method el i mi nates the need for corrosi ve reagents
(i .e., aceti c anhydri de and acetyl chl ori de) and does
not requi re aqueous washi ng. The process was ap-
pl i cabl e to several acycl i c 1,n-di ol s (n ) 2-16),
l eadi ng to thei r sel ecti ve monoprotecti on as acetates.
Si mi l ar good yi el ds of monoacetate were achi eved
wi th compl ex mol ecul es; acetyl ati on of betul i n 15
afforded the pri mary monoacetate i n 69% yi el d,
al though a 72-h reacti on ti me was requi red (Fi gure
5). The l ower reacti vi ty of 15 rel ati ve to the acycl i c
di ol s may be attri buted to the greater steri c bul k
encountered by thi s compound upon approach toward
the surface of the si l i ca gel .
The same catal yst promoted sel ecti ve acetyl ati on
of al i phati c hydroxy groups i n the presence of phe-
nol i c ones (Tabl e 10, entry 5). The reacti on coul d be
successful l y appl i ed to more compl ex compounds: for
exampl e, the saturated secondary hydroxy group of
-estradi ol 16(Fi gure 5) was preferenti al l y acyl ated.
Si mi l arl y, monoprotecti on of symmetri c 1,n-termi -
nal di ol s (n ) 2-6, 8, 10, 12, and 16), i ncl udi ng cis-
and trans-1,4-butenedi ol s and -1,4-butynedi ol , by
acyl ati on wi th ethyl acetate/hexane i n the presence
of Si O
2
/NaHSO
4
catal yst was reported by Ni shi guchi
et al . (Tabl e 10, entry 6).
107
Ki neti c studi es confi rm
that the maxi mum rate of monoester formati on i s
roughl y twi ce that of the di ester. Thi s suggests that
the reacti vi ty of the hydroxy groups of the di ol and
Scheme 4
Scheme 5
Figure 5.
the monoester are vi rtual l y i denti cal . Moreover, the
i ncreased sel ecti vi ty observed i n the presence of the
sol i d catal yst can be expl ai ned by postul ati ng that
(i ) onl y the al cohol s that were adsorbed on the surface
of the catal yst were esteri fi ed, (i i ) the di ol reacted
preferenti al l y as l ong as i t was present, and (i i i ) the
monoester was adsorbed but reacted onl y after most
of the adsorbed di ol had been consumed. Unsup-
ported NaHSO
4
al so catal yzed monoacyl ati on, but the
sel ecti vi ty was l ess than that i n monoacyl ati on
catal yzed by the supported reagent.
The same authors reported the preparati on of
mono-THP ethers of 1,n-di ol s by reacti on wi th DHP/
hexane mi xtures, catal yzed by Al
2
(SO
4
)
3
supported
on si l i ca gel (Tabl e 10, entry 7).
108,109
The catal yti c
acti vi ty was ascri babl e to the Lewi s or proti c aci d
si tes of the supported sul fate, and i t was demon-
strated that unsupported sul fate showed no catal yti c
acti vi ty. An al ternati ve but more probl emati c catal yst
to perform the same sel ecti ve reacti on was repre-
sented by the si l i ca chl ori de (Tabl e 10, entry 8).
73
Sel ecti ve acyl ati on of al i phati c hydroxy groups wi th
ethyl acetate uti l i zed as sol vent-reagent i n the
presence of phenol i c groups was performed on si l i ca
gel -supported BF
3
. For exampl e, the conversi on of the
natural anti tumor coumari no l i gnoi d cl eomi scosi n A
i nto i ts anal ogue venkatasi n
110
has been achi eved i n
sati sfactory yi el d (Tabl e 10, entry 9).
111
The unsup-
ported BF
3
showed l ower acti vi ty.
A further method for regi osel ecti ve acetyl ati on of
pri mary hydroxy groups i s based on the use of methyl
orthoacetate i n methanol and i n the presence of a
chl ori de of a rare earth (erbi um, l anthanum, europ-
i um, or neodymi um) di spersed on si l i ca. The reacti on
can be successful l y appl i ed to pol yhydroxyl ated com-
pounds, i n parti cul ar to sugars and rel ated sub-
Table 10. Selective Protection of Hydroxylated Compounds
a
stances. I n al l cases, the regi osel ecti ve protecti on of
pri mary hydroxy functi ons i n very hi gh yi el ds i n the
presence of secondary and terti ary ones coul d be
achi eved. A representati ve exampl e i s the case of the
methyl ester of the N-acetyl neurami ni c aci d, whi ch
was acetyl ated at the pri mary hydroxy group i n 98%
yi el d (Tabl e 10, entry 10).
112
Germani um chl ori de di spersed on si l i ca gel (Si O
2
/
GeCl
4
) afforded the sel ecti ve protecti on of vi ci nal di ol s
i n pol yhydroxyl ated compounds wi th methyl orthoac-
etate. An i nteresti ng appl i cati on i s represented by
the quanti tati ve protecti on of the hydroxy groups at
the 3 and 4 posi ti ons of methyl qui nate (Tabl e 10,
entry 11).
113
The use of tungstophosphori c aci d (H
3
PW
12
O
40
) was
cl ai med by Fi rouzabadi et al . to sel ecti vel y protect
the phenol hydroxy group i n the presence of the
aromati c ami no group by reacti on wi th HMDS (Tabl e
10, entry 12).
114
Competi ti ve experi ments showed a
good sel ecti vi ty i n the protecti on of di fferent al cohol s.
Thus, a pri mary benzyl i c hydroxy group was pro-
tected i n the presence of a secondary al i phati c al cohol
wi th a 80/20 rati o, and a secondary al i phati c al cohol
i n the presence of a terti ary al cohol was protected
wi th a 95/5 rati o. The reacti ons proceeded easi l y wi th
the evol uti on of ammoni a gas and the producti on of
the correspondi ng si l yl ethers. A catal yti c reacti on
cycl e was proposed (Scheme 6) i n whi ch the produc-
ti on of [(Me
3
Si )
2
NH
2
]
3
PW
12
O
40
and (NH
4
)
3
PW
12
O
40
as
catal ysts and the producti on of si l yl ethers and
ammoni a gas as the products were hypothesi zed.
Ni shi guchi et al . reported the monoesteri fi cati on
of symmetri cal 1,n-di ol s usi ng a mi xture of ethyl
propi onate and octane i n the presence of Dowex
50WX2 i on-exchange resi n (Tabl e 10, entry 13).
115
The reacti on coul d be appl i ed onl y to the producti on
of saturated al i phati c esters. The sel ecti vi ty for
monoester formati on was ascri bed to the hi gher
reacti vi ty of the di ol than that of the monoester. Thi s
i s probabl y the consequence of the fact that the
sul foni c aci d-type i on-exchange resi ns usual l y contai n
50-80% water. Thus, a strongl y aci di c water l ayer
i s formed on the surface of the resi n, and a parti ti on
equi l i bri um between the aqueous l ayer and the
aproti c ester/octane l ayer i s set up; thus, the di ol s
have a hi gher parti ti on coeffi ci ent than the mo-
noesters.
A si mi l ar route to the sel ecti ve monotetrahydro-
pyranyl ati on of pri mary and secondary symmetri cal
di ol s has been recentl y reported by the same authors;
the method sti l l uti l i zes wet-type Dowex 50WX2 resi n
as a strong sol i d aci d i n DHP/tol uene or DHP/hexane
mi xtures (Tabl e 10, entry 14).
116,117
The reacti on was
performed at room temperature, and the monoether
was obtai ned i n hi gh yi el d and better sel ecti vi ty wi th
respect to the previ ousl y descri bed methods. As i n
the previ ous case, each di ol requi red a parti cul ar
DHP/hydrocarbon rati o that gi ves the hi ghest sel ec-
ti vi ty. General l y, the l arger the number of carbon
atoms of the di ol , the smal l er the DHP/hydrocarbon
rati o needed to real i ze the hi ghest sel ecti vi ty. Ki neti c
studi es confi rm that the sel ecti vi ty of the monoether
formati on resul ts from the hi gher reacti vi ty of the
di ol wi th respect to that of the monoether.
Sel ecti ve O-acetyl ati on of al cohol s i n the presence
of ami no groups was achi eved by reacti on wi th aceti c
anhydri de i n benzene and i n the presence of a strong
aci di c Amberl yst 15 i on-exchange resi n. Presumabl y,
under these condi ti ons, the ami no functi on i s proto-
nated and hence prevented from undergoi ng acety-
l ati on (Tabl e 10, entry 15).
118
2.6. Selective Deprotection of Polyprotected
Compounds
Montmori l l oni te K10cl ay was uti l i zed by Ogasawara
et al . for the sel ecti ve deprotecti on vi a methanol ysi s
of a vari ety of THP ethers i n the presence of an
addi ti onal O-protected functi onal group i n thei r
mol ecul es (Tabl e 11, entry 1).
95
Among the com-
pounds exami ned, the THP protecti ng group was
sel ecti vel y removed from substrates carryi ng al so
benzyl , al l yl , MOM, acetyl , and TBDPS groups on
hydroxy functi ons to gi ve the correspondi ng al cohol s
i n good to excel l ent yi el ds (Tabl e 12). On the other
hand, TBDMS, ,,-tri chl oroethyl i mi dyl , and ketal
functi onal i ti es were unstabl e under these condi ti ons.
Deprotecti on of aryl acetates i n the presence of
other sensi ti ve functi onal groups, i ncl udi ng al i phati c
esters, represents a further exampl e of sel ecti ve
deprotecti on of phenol hydroxy groups. The reacti on
was performed by usi ng natural kaol i ni ti c cl ay wi th
a seri es of aryl acetates contai ni ng other protecti ng
groups, such as oxi me, THP ether, thi oacetal , ami de,
and tert-butoxycarbonyl groups. An i mportant feature
of thi s method i s that the opti cal puri ty of chi ral
ami no aci ds remai ned unal tered (99% ee based on
opti cal rotati on) (Tabl e 11, entry 2).
119
A bentoni ti c earth (Tonsi l ) was uti l i zed for sel ecti ve
deprotecti on of THP ethers from compounds contai n-
i ng another hydroxy group, protected as the (2-
methoxyethoxy)methyl (MEM) or MOM deri vati ve
94
I ndeed, when some experi ments
were carri ed out wi th THP-MOM and THP-MEM
mi xed ethers, the THP ether was cl eaved and the
other remai ned unchanged. I t i s remarkabl e that,
fol l owi ng thi s procedure, i t was possi bl e to prepare
farnesyl hydroqui none, a natural product i sol ated
from Wigandia kunthii.
120
Meshram et al . uti l i zed cl ayan i n the sel ecti ve
removal of MPM ether; the sel ecti vi ty of the method
i s demonstrated by the survi val of other protected
groups, such as ester, si l yl ether, acetoni de, Boc,
acetate, and benzyl ether, by mi crowave treatment
of a mi xture of the protected substrate and cl ayan
under sol ventl ess condi ti ons (Tabl e 11, entry 4).
98
Acetoni de bi s-protected pol yol s can be sel ecti vel y
Scheme 6
Table 11. Selective Deprotection of Polyprotected Hydroxylated Compounds
monodeprotected i n hi gh yi el d wi th the use of the
same catal yst (Tabl e 11, entry 5).
121
Sel ecti ve deprotecti on of the TES group i n the
presence of the TBDMS group of mi xed si l yl ethers
of di ol s was achi eved wi th si l i ca MCM-41 (Tabl e 11,
entry 6).
122
Due to the very mi l d reacti on condi ti ons,
di fferent protected di ol s coul d be sel ecti vel y depro-
tected i n si mi l ar hi gh yi el d, i ncl udi ng propargyl i c-
and al l yl i c-type al cohol s. I t i s noteworthy that the
use of ZSM-5 and Y zeol i tes, whi ch are too strongl y
aci di c catal ysts, resul ted i n unsel ecti ve deprotecti on.
Matsumoto et al . descri bed the deprotecti on of
pri mary, secondary, and terti ary al cohol s protected
wi th THP, EE, 1-methyl -1-methoxyethyl (MME),
TMS, and MOM groups, promoted by a si l i ca-
al umi na gel catal yst (Tabl e 11, entry 7).
123
I n the
presence of THP, EE, and MOM groups, sel ecti ve
removal of the MME group coul d be attai ned quan-
ti tati vel y. When the THP and TMS groups were
present i n the same mol ecul e, the si l yl group was
cl eaved sel ecti vel y. The catal yst coul d al so be uti l i zed
to sel ecti vel y cl eave some ether protecti ng groups i n
di ol deri vati ves wi th di fferent cl asses of protected
hydroxy groups. Thus, a di ol contai ni ng a terti ary
and a pri mary hydroxy group, both protected as
MOM ethers, underwent sel ecti ve deprotecti on to the
terti ary al cohol (Tabl e 11, entry 8).
123
The cri ti cal
sel ecti ve cl eavage of gl ycerol deri vati ves, protected
as ether and acetal , was al so achi eved usi ng thi s
catal yst. For exampl e, the TMS group was sel ecti vel y
removed by carryi ng out the reacti on at room tem-
perature (Tabl e 11, entry 9),
123
whereas the acetal
group was cl eaved, wi th the survi val of MOM func-
ti onal i ty, when the reacti on was performed at 65 C
123
Deprotecti on of the anomeri c center of per-O-
acetyl ated 2-ami no sugar deri vati ves wi th di fferent
homogeneous catal ysts, such as Lewi s aci ds, ni trogen
bases, or enzymes, frequentl y resul ts i n the produc-
ti on of anomeri c mi xtures that consti tute a severe
l i mi tati on of these procedures. The mi l d anomeri c
deprotecti on of per-O-acetyl ated 2-ami no-2-deoxy-
gl ycopyranose deri vati ves was shown by Pal aci os et
al . to occur wi th total or hi gh stereosel ecti vi ty and
wi th excl usi ve producti on of R-anomers by mechani -
cal l y sti rri ng a suspensi on of substrate and si l i ca gel
i n methanol . I n general , reacti ons wi th R-anomers
were faster than those wi th -anomers. Starti ng
materi al s havi ng ei ther R- and -confi gurati on gave
excl usi vel y 1-O-deacetyl ated R-anomers, and no pres-
ence of -anomers coul d be detected (by
1
H NMR
anal ysi s) (Tabl e 11, entry 11).
124
The supposed mech-
ani sm coul d i nvol ve a transesteri fi cati on on the si l i ca
gel surface. Thi s feature offers a pl ausi bl e expl ana-
ti on for the di fferent reacti on rates observed wi th R-
and -anomers. R-Anomers can i nteract easi l y wi th
aci di c centers of si l i ca gel . I n contrast, the approach
of -anomers to the support wi l l be markedl y i m-
peded by axi al i nteracti on (Fi gure 6).
The great stereosel ecti vi ty of the process shoul d be
a consequence of a very fast mutarotati on i n the pol ar
reacti on medi um. The deacetyl ati on woul d be there-
fore stereospeci fi c i ni ti al l y, but the anomeri c effect
had favored the excl usi ve formati on of the thermo-
dynami cal l y more stabl e R-anomers.
Table 11 (Continued)
a
Table 12. Selective Removal of THP in Diprotected
1,4-Butanediols
entry R yi el d (%)
1 Bn 92
2 al l yl 82
3 MeOCH2 98
4 t-BuPh2Si 82
5 MeCO 92
6 PhCO 97
Figure 6.
Ceri c ammoni um ni trate (CAN) represents a one-
el ectron-transfer catal yst uti l i zed for removal of
tri phenyl methyl (Tr), monomethoxytri tyl (MMTr),
and Boc groups from organi c compounds. Under the
neutral condi ti ons appl i ed, several aci d-sensi ti ve
groups survi ve, i ncl udi ng i sopropyl i dene, (di methyl -
ami no)methyl i dene, tert-butyl di methyl si l yl , and acyl
functi onal i ti es.
125
Hwu et al . reported that CAN
adsorbed on si l i ca gel (Si O
2
/CAN) effi ci entl y removed
the Tr, MMTr, DMTr, TBDMS, and tri i sopropyl si l yl
(TI PS) functi onal i ti es from a vari ety of pol yprotected
ri bonucl eosi de substrates, rapi dl y converti ng them
to the parent monodeprotected al cohol s (Tabl e 11,
entry 12).
126
Compari son of the resul ts obtai ned from
detri tyl ati on i n the presence and i n the absence of
si l i ca gel as sol i d support suggests that the above
reacti ons were much faster than those performed
wi th CAN al one. On thi s subject, qui te i nteresti ng
i s the compari son of acti vi ty of CAN and Si O
2
/CAN
wi th the reagent 17. The Tr group was sel ecti vel y
cl eaved by treatment of 17wi th CAN, affordi ng 18,
whereas the i sopropyl i dene group was cl eaved
when Si O
2
/CAN was uti l i zed, affordi ng product 19
(Scheme 7).
A further appl i cati on of thi s powerful catal yst i s
represented by the sel ecti ve removal of a TI PS group
from di - and tri si l yl ethers i n very good yi el ds (Tabl e
13); however, the use of CAN al one resul ted i n the
compl ete recovery of the starti ng reagents.
Acti vated commerci al neutral al umi na has been
uti l i zed by Guerrero et al . as a heterogeneous catal yst
to promote sel ecti ve cl eavage of a pri mary TBDMS
group i n the presence of a secondary one (Tabl e 11,
entry 13).
127
Si nce the catal yst i s i nacti ve wi th some
aci d-sensi ti ve groups, such as THP and MOM, the
method coul d al so be effi ci entl y appl i ed to the sel ec-
ti ve removal of TBDMS group i n the presence of the
THP functi on. The method coul d not be uti l i zed wi th
mol ecul es contai ni ng si l yl ated phenol i c groups si nce,
al though compl ete deprotecti on occurs under reacti on
condi ti ons si mi l ar to those requested for al cohol s, the
resul ti ng phenol i c compound remai ns hi ghl y adsorbed
to the support and cannot be compl etel y recovered.
By conveni entl y combi ni ng the steri c hi ndrance
and the nature of the protecti ve group, i t was possi bl e
to sel ecti vel y deprotect vari ousl y bi s-protected di -
ol s.
128
Whi l e thi s process i n pri nci pl e shoul d not
represent any probl em when the more l abi l e si l yl
group (TMS) i s on a pri mary carbon, taki ng i nto
account al so the order of stabi l i ty of protecti ng groups
(TMS ,TBDMS < TBDPS),
129
the reverse case, wi th
the l ess resi stant si l yl moi ety occupyi ng a secondary
posi ti on, shoul d be much more troubl esome, as the
hi gher accessi bi l i ty at the more steri cal l y hi ndered
ether on the pri mary posi ti on counterbal ances the
hi gher reacti vi ty of the l ess steri cal l y hi ndered
secondary ether. However, when the di fference i n
steri c hi ndrance was l arge enough, i t was possi bl e
to remove the secondary TMS group i n the presence
of a pri mary TBDMS moi ety (Tabl e 11, entry 14). No
sel ecti ve desi l yl ati on coul d be attai ned when the
secondary posi ti on was occupi ed by the TBDMS
group.
By usi ng the same catal yst, the sel ecti ve deacety-
l ati on of compound 21 was accompl i shed under
mi crowave i rradi ati on by accuratel y sel ecti ng the
reacti on ti me; i ndeed, when the reacti on was carri ed
out for 30 s, the monoacetate 20was i sol ated i n 93%
yi el d, whereas when the i rradi ati on ti me was pro-
l onged to 2.5 mi n, compl ete deacetyl ati on was
achi eved, and product 22 was i sol ated i n 92% yi el d
(Scheme 8).
46
Si mi l arl y, sel ecti ve deprotecti on at the 6 posi ti on
of a ful l y protected pi val oyl methyl gl ycosi de was
achi eved by treatment wi th neutral al umi na i n
combi nati on wi th mi crowave i rradi ati on (Tabl e 11,
entry 15).
130
Potassi um fl uori de supported on al umi na (Al
2
O
3
/
KF) appears to be uni que among vari ous supported
catal ysts; i ndeed, Wei nstock et al . showed vi a Raman
and i nfrared spectroscopi es that, i n contrast to Si O
2
/
KF, Cel i te/KF, and mol ecul ar si eves/KF, Al
2
O
3
/KF
exhi bi ts a surpri si ng degree of basi ci ty.
131
The hi gh
acti vi ty of Al
2
O
3
/KF, combi ned wi th the possi bi l i ty
of control l ed access to fl uori de i on, provi ded an
opti mum envi ronment for desi l yl ati on. Treatment of
TBDMS ethers of phenol s i n acetoni tri l e wi th basi c
Al
2
O
3
/KF resul ted i n conversi on to the free phenol
i n excel l ent yi el ds. I n general , hi gher reacti vi ty was
observed wi th basi c Al
2
O
3
/KF than wi th the aci di c
one. Reacti ons were even further faci l i tated by the
Scheme 7
Table 13. Selective Removal of TIPS in Polyprotected
Compounds
entry R R B yi el d (%)
1 TI PS TI PS uracyl -yl 87
2 H TI PS uracyl -yl 91
3 TI PS H uracyl -yl 85
4 H TI PS cytosi n-yl 80
5 TI PS H cytosi n-yl 83
Scheme 8
use of ul trasound combi ned wi th Al
2
O
3
/KF. TBDMS
ethers of phenol s versus those of benzyl al cohol s were
sel ecti vel y cl eaved. Thi s system i s known to gi ve both
possi bl e monosi l yl ated products upon treatment wi th
tetraal kyl ammoni um fl uori des, presumabl y due to
base-catal yzed i ntramol ecul ar si l yl transfer.
132
Sel ec-
ti ve removal of TBDMS i n the presence of SEM-
phenol i c ethers was reported by Sawyer et al . to occur
i n the presence of KF supported on basi c al umi na
133
Even i n thi s case, l ower
reacti vi ty was observed wi th the KF on aci d al umi na,
as was evi dent through compari son of reacti on ti mes.
Sel ecti vi ty was observed between TBDMS ethers of
phenol s versus benzyl i c al cohol s. The most l i kel y
mechani sm of desi l yl ati on i nvol ves the nucl eophi l i c
addi ti on of fl uori de i on. The cooperati ve acti on of
fl uori de i on on the al umi na surface resul ts i n a strong
naked nucl eophi l i c matri x that i s not possi bl e wi th
KF al one.
Al
2
O
3
/Oxone represents another catal yst-reagent
combi nati on that has been effi ci entl y uti l i zed for the
sel ecti ve deprotecti on of acetal s i n substrates con-
tai ni ng aci d-l abi l e i sopropyl i dene, Tr, or TBDMS
groups. The i sopropyl i dene group on at l east a
pri mary hydroxy moi ety underwent rapi d cl eavage
i n the presence of TBDMS or Tr groups (Tabl e 11,
entry 17).
134
When the reagent system was appl i ed
to more compl ex mol ecul es, the TBDMS or Tr groups
were sel ecti vel y cl eaved, preservi ng the i sopropy-
l i dene functi on attached to secondary or terti ary
hydroxy moi eti es (Tabl e 11, entry 18).
The heterogeneous aci d Dowex 50WX8 has been
successful l y uti l i zed for the sel ecti ve cl eavage of the
termi nal acetoni de group i n vari ousl y protected pol y-
hydroxyl ated compounds al so contai ni ng OTs and
OBn groups (Tabl e 11, entry 19). Qui te si mi l ar hi ghl y
sel ecti ve cl eavage of termi nal acetoni de groups was
achi eved wi th pol yhydroxyl ated compounds contai n-
i ng protected ami no groups (Tabl e 11, entry 20).
135
The uti l i ty of tri phenyl methyl (Tr), MMTr, and
DMTr ethers i s attri buted to the hi gh sel ecti vi ty for
pri mary hydroxy groups i n pol yol s as wel l as the
si mpl i ci ty and mi l dness i n prepari ng and removi ng
the tri tyl functi on.
15
Wi th certai n compounds, such
as nucl eosi des and pentoses, the standard deprotec-
ti on methods, based on proti c and Lewi s aci d treat-
ment or catal yti c hydrogenati on, were not sui tabl e
due to the aci d sensi ti vi ty of the starti ng materi al ,
resul ti ng, for exampl e, i n degl ycosyl ati on. The DMTr
group, whi ch has been extensi vel y uti l i zed to protect
the 5-hydroxy functi on i n nucl eosi de chemi stry,
136
coul d be removed by benzene- or p-tol uenesul foni c
aci d treatment, causi ng depuri nati on. Sal unkhe et
al . reported that, by usi ng sul fonated cross-l i nked gel -
type and macroporous pol ystyrene resi ns, effecti ve
detri tyl ati on was sel ecti vel y achi eved i n short reac-
ti on ti me wi th quanti tati ve i sol ati on of the products
137
The DMTr group was cl eaved
wi th quanti tati ve survi val of the TBDMS group. Thi s
method has the advantage over the other aci di c
catal ysts used i n that the resi n i s fi l tered off i m-
medi atel y after the reacti on and does not remai n i n
contact wi th the product, thus avoi di ng depuri nati on
and possi bl e gl ycosi de cl eavage.
An i nteresti ng appl i cati on of the sel ecti ve depro-
tecti on of compl ex mol ecul es i s represented by the
sel ecti ve cl eavage of a myo-i nosi tol trans-i sopropyl i -
dene acetal i n the presence of a cis-i sopropyl i dene
acetal . The reacti on coul d be performed by treatment
wi th the aci di c i on-exchanged resi n Amberl i te I R-120.
Thi s mi l d and si mpl e procedure can be appl i ed to
vari ousl y protected compounds and, therefore, pre-
cl udes the requi rement of chromatographi c puri fi ca-
ti on procedures (Tabl e 14).
138
2.7. Redox Deprotections
As previ ousl y shown, tetrahydropyranyl ati on rep-
resents one of the most frequentl y used processes to
protect hydroxy groups i n the mul ti step organi c
synthesi s under both homogeneous and heteroge-
neous catal ysi s. The possi bi l i ty to perform di rect
conversi on of THP ethers to the correspondi ng car-
bonyl compounds under heterogeneous catal ysi s rep-
resents an economi cal l y advantageous and envi ron-
mental l y beni gn process.
Heravi et al . devel oped a number of sol i d reagent-
catal yst combi nati ons to perform the process. Some
exampl es are reported i n Tabl e 15. Bi s(tri methyl si -
l yl )chromate (BTSC) supported on montmori l l oni te
K10 was uti l i zed to perform the oxi dati ve deprotec-
ti on of THP ethers to al dehydes and ketones (Tabl e
15, entry 1);
139
i t must be stated that the unsupported
BTSC was compl etel y i nert. I t i s al so noteworthy that
overoxi dati on of pri mary THP ethers to carboxyl i c
aci ds was never observed. Mechani sti c i nvesti gati ons
showed that THP ethers were i ni ti al l y cl eaved to the
correspondi ng al cohol s and successi vel y oxi di zed to
carbonyl compounds. The reacti on was effi ci entl y
accel erated through mi crowave i rradi ati on (Tabl e 15,
entry 2).
140
I ron(I I I ) ni trate sal t supported on montmori l l oni te
K10 have al so been uti l i zed to perform the oxi dati ve
deprotecti on of THP ethers to carbonyl compounds
141
A great advantage i s the easy
mani pul ati on and treatment of the reacti on mi xture
si nce, i n the absence of the cl ay, the reacti on was
sl uggi sh, and more seri ousl y sti cky ferri c ni trate and/
or i ts degradati on products gave an i ntractabl e sol i d
mass, maki ng di ffi cul t the i sol ati on of the carbonyl
compounds. Qui te si mi l ar good resul ts were achi eved
by usi ng the same i ron sal t supported on ZSM-5
zeol i te (Tabl e 15, entry 4)
142
or potassi um ferrate
(K
2
FeO
4
) supported on si l i ca gel (Tabl e 15, entry 5).
143
Two methods for the di rect oxi dati on of tri meth-
yl si l yl ethers to the correspondi ng carbonyl com-
pounds are based on the use of bi s(tri methyl si l yl )-
Table 14. Selective Removal of Isopropylidene
Moiety in Polyprotected Sugar Derivatives
entry R R yi el d (%)
1 Bn Bn 93
2 Ts Bn 98
3 TBDMS Bn 97
4 Bz Bz 94
chromate on si l i ca (Si O
2
/BTSC)
144
and chromi um
oxi de on wet al umi na (Al
2
O
3
/CrO
3
).
145
I n the fi rst
case, the reacti on was carri ed out si mpl y by addi ng
the Si O
2
/BTSC catal yst-reagent to a sol uti on of
pri mary or secondary al cohol (Tabl e 15, entry 6). I n
the second case, the fi nel y ground Al
2
O
3
/CrO
3
re-
agent-catal yst was added to the neat ether i n a
mortar and mi xed thoroughl y (Tabl e 15, entry 7). I n
both cases, the reacti on was hi ghl y sel ecti ve, and no
overoxi dati on products were recovered when the
reacti on was performed wi th pri mary al cohol s, the
sol e excepti on bei ng represented by tri methyl si l yl
ci nnamyl ether, whi ch was oxi dati vel y deprotected
to ci nnami c al dehyde, accompani ed by benzal dehyde
i n a 7/3 mol ar rati o, showi ng that the benzyl i c doubl e
bond i s prone to cl eavage under both reacti on condi -
ti ons.
Alumina-supported potassium permanganate (Al
2
O
3
/
KMnO
4
) was uti l i zed for the hi ghl y sel ecti ve depro-
tecti on-oxi dati on of benzyl i c TMS and THP ethers
to the correspondi ng carbonyl compounds (Tabl e 15,
entry 8).
146
The reacti on shows a sl ower rate i n the
absence of al umi na; moreover, al l yl i c substrates af-
forded compl ex mi xtures of overoxi dati on compounds.
The synthesi s of pol yhydroxyl ated compounds often
requi res orthogonal protecti ng strategi es to di sti n-
gui sh between hydroxy groups. I t woul d be hi ghl y
desi rabl e to devel op a range of benzyl -type protecti ng
groups wi th di fferent reacti vi ti es that can be sequen-
ti al l y removed vi a catal yti c hydrogenol ysi s over Pd/C
and, i n general , reducti ve deprotecti on. Spencer et
al . showed that when competi ti on experi ments were
conducted on model systems contai ni ng two di ffer-
entl y substi tuted benzyl groups attached to ethyl ene
gl ycol , the unsubsti tuted one was cl eaved fi rst, i n
competi ti on wi th any of the substi tuted benzyl groups
(Tabl e 16). I n the presence of thi s heterogeneous
catal yst, the aromati c ri ng must l i e fl at on the metal
surface for opti mal coordi nati on.
147
I t i s possi bl e that substi tuti on on the aromati c ri ng
coul d have an adverse steri c effect that woul d hamper
the pl anar geometry requi red for bi ndi ng and thus
l ower i ts reacti vi ty. Thus, for a rati onal desi gn of
sel ecti ve benzyl -type protecti ng group, both el ectroni c
factors and adsorpti on must be taken i nto account.
To thi s end, the 2-naphthyl methyl (NAP) group
woul d ful fi l l these cri teri a, si nce i t i s el ectron-ri ch
and shoul d have hi gh affi ni ty to the pal l adi um
surface due to i ts fl at extended aromati c system. The
hydrogenol ysi s of NAP/benzyl -protected di hydroxy
compounds shows that the NAP group can be se-
l ecti vel y deprotected (Tabl e 15, entry 9).
148
I nterest-
i ngl y, the deprotecti on of the benzyl group i s
strongl y i nhi bi ted, even after the NAP group has
Table 15. Redox Deprotections
been compl etel y removed. I t i s possi bl e that the
2-methyl naphthal ene rel eased duri ng the reacti on
can compete wi th the benzyl groups for the acti ve
si tes on the pal l adi um. The syntheti c uti l i ty of thi s
fi ndi ng i s shown i n the hi ghl y sel ecti ve removal of
the NAP group i n di fferent substrates contai ni ng
benzyl protecti ng groups, some of whi ch are reported
i n Fi gure 7.
Fi nal l y, the reducti ve ri ng openi ng of 1,3-di oxanes
vi a hydrogenati on was catal yzed by 4% copper(I I )
ni trate i mpregnated i n the pentasi l -type borozeol i te
149
Compounds obtai ned were
3-oxoal kyl propanol s used as i ntermedi ates contai ni ng
a monoprotected di ol as benzyl ether. The reacti on
coul d be appl i ed to a great number of symmetri cal
1,3-di oxanes i n hi gh yi el d and sel ecti vi ty. No i nfor-
mati on i s avai l abl e about the regi ochemi stry of the
ri ng-openi ng of unsymmetri cal 1,3-di oxanes.
I n concl usi on, i t must be emphasi zed that, even i f
the majori ty of exampl es reported i n Tabl e 15 and
di scussed i n thi s paragraph deal wi th supported
reagents, the authors showed that the i norgani c
support notabl y enhances the reacti on rate, renders
more easy the i sol ati on and puri fi cati on of product,
and mi ni mi zes or compl etel y avoi ds producti on of
byproducts and/or tar materi al s.
3. Thiol Protecting Groups
Under heterogeneous catal ysi s, thi ol s are usual l y
protected as acetates; the few arti cl es on thi s topi c
deal wi th methodol ogi es previ ousl y studi ed and ap-
pl i ed for al cohol s. A versati l e method i s represented
by the use of aceti c anhydri de wi th montmori l l oni te
KSF; no sel ecti vi ty was observed when the reacti on
was carri ed out wi th 2-mercaptoethanol (Tabl e 17,
entry 1).
22,23
Another sol vent-free method i s repre-
sented by the use of FER zeol i te; the thi ol acetates
were recovered i n hi gh puri ty (Tabl e 17, entry 2).
26
The reacti on rate of thi s process can be i ncreased by
appl yi ng mi crowave i rradi ati on; thus, by empl oyi ng
basi c al umi na i n the presence of pyri di ne, the acety-
l ati on of thi ophenol s was accompl i shed wi th aceti c
anhydri de i n a few mi nutes (Tabl e 17, entry 3).
36
Qui te i nteresti ngl y, under these condi ti ons, sel ecti ve
protecti on at the SH group i n some ami nothi ophenol s
was achi eved.
Another sol i d aci d catal yst that i s effi ci ent i n
thi ophenol acetyl ati on i s represented by the com-
merci al l y avai l abl e Nafi on (Tabl e 17, entry 4).
45
Thi ol s can al so be protected wi th DHP as tetrahy-
dropyranyl thi oethers. The reacti on catal yzed by
hydrated zi rconi a and accel erated by mi crowave
i rradi ati on was very sel ecti ve, as no thi ol di meri za-
ti on occurred (Tabl e 17, entry 5).
76
I nteresti ngl y, by
usi ng the same catal yst, the detetrahydropyranyl a-
ti on coul d be accompl i shed si mpl y by addi ng metha-
nol to the mi xture of acetate/hydrated zi rconi a.
65
4. Carboxy Protecting Groups
Al though many useful and rel i abl e methods for
esteri fi cati on of carboxyl i c aci ds are usual l y em-
pl oyed, there i s sti l l a need to fi nd versati l e processes
to repl ace the cl assi cal methodol ogi es wi th more
beni gn al ternati ves, characteri zed by general ap-
pl i cabi l i ty.
Table 16. Selective Deprotection of Diprotected
Ethylene Glycols
entry R yi el d (%)
1 CF3 88
2 CH3 81
3 OCH3 78
4 t-Bu 85
Table 17. Protection of Thiols
a
Figure 7.
4.1. Protection
Sel ecti ve esteri fi cati on of carboxyl i c aci ds repre-
sents an i mportant reacti on for the mani pul ati on of
functi onal groups i n mul ti step organi c synthesi s.
Here we present a sel ecti on of procedures ai med at
obtai ni ng esters as protecti ve groups under hetero-
geneous catal ysi s, al though esters often represent
target mol ecul es as fi ne chemi cal s.
The protecti on of carboxyl i c aci ds as esters i s
usual l y performed by reacti ng the aci d wi th a sui t-
abl e al cohol i n the presence of di fferent heteroge-
neous aci d catal ysts.
Most of the reported methods suffer from some
drawbacks, whi ch i ncl ude the use of hazardous and
expensi ve reagents, drasti c reacti on condi ti ons, l ong
reacti on ti mes, and i ncompati bi l i ty wi th other func-
ti onal groups i n the mol ecul e. I n thi s respect, two
papers reported the sel ecti ve esteri fi cati on of al i -
phati c carboxyl i c aci ds i n the presence of aromati c
ones under mi l d and heterogeneous condi ti ons.
150,151
Si l i ca gel -supported NaHSO
4
promoted the sel ec-
ti ve formati on of esters i n good yi el d, reacti ng wi th
a wi de range of al i phati c carboxyl i c aci ds and al cohol s
150
The methyl ester of ci nnami c
aci d was obtai ned i n l ower yi el d (42%). The sel ecti vi ty
was demonstrated by usi ng mol ecul es possessi ng
both aromati c and al i phati c carboxyl i c groups as wel l
as by competi ti ve experi ments; thus, i n the reacti on
wi th homophthal i c aci d, the al i phati c aci d was se-
l ecti vel y esteri fi ed (Scheme 9a).
I n the second paper, nonconjugated carboxyl i c aci ds
were sel ecti vel y esteri fi ed i n the presence of conju-
gated ones over Amberl yst 15 as condensi ng agent
i n methanol or ethanol (Tabl e 18, entry 2).
151
Thus,
i taconi c aci d was sel ecti vel y protected at the al l yl i c
carboxyl i c group (Scheme 9b).
The same catal yst was empl oyed to obtai n ami no
aci d esters, whi ch are key raw materi al s i n the
manufacture of i mportant compounds such as phar-
maceuti cal s and fl avors. The common probl em i n the
esteri fi cati on process i s the vul nerabi l i ty of the ami no
group to al kyl ati on and the possi bl e racemi zati on.
Chi ral ami no aci ds were esteri fi ed i n hi gh yi el d and
opti cal puri ty by sti rri ng wi th Amberl yst 15 i n
methanol or ethanol (Tabl e 18, entry 3).
152
A sal t-free esteri fi cati on of R-ami no aci ds catal yzed
by ul trastabl e Y zeol i te (USY), ori gi nal l y prepared
Table 18. Protection of Carboxylic Acids
a
Scheme 9
for l arge-scal e i ndustri al processes, has been recentl y
reported by Shel don et al . The authors showed that
esteri fi cati on over a sol i d aci d catal yst coul d, i n
pri nci pl e, yi el d the ester as the free base i n a sal t-
free, noncorrosi ve process. I ndeed, i n conventi onal
homogeneous processes, the generati on of the free
ami no aci d esters i mpl i es the concomi tant generati on
of at l east 1 equi v of i norgani c sal t. Vari ous R-ami no
aci ds, i .e., D-phenyl gl yci ne, L-phenyl al ani ne, D,L-
homophenyl al ani ne, and D-p-hydroxyphenyl gl yci ne,
reacted wi th al cohol s over H-USY (SAR ) 5), gi vi ng
the correspondi ng esters (Tabl e 18, entry 4).
153
To
expl ai n the parti al racemi zati on observed, the au-
thors showed that the ami no aci d ester undergoes
thermal racemi zati on, even i n refl uxi ng methanol .
A general method to convert aromati c and al i phati c
mono- and di carboxyl i c aci ds i nto the correspondi ng
esters was reported empl oyi ng pri mary al cohol s over
the bi nary oxi de MoO
3
/ZrO
2
154
Secondary al cohol s were recovered unchanged.
The protecti on of carboxyl i c aci d as tert-butyl esters
i s a useful syntheti c procedure due to the rel ati ve
resi stance to nucl eophi l i c attack and ready removal
by aci dol ysi s. A speci fi c and conveni ent preparati on
of tert-butyl ester s, pr omoted by sul fur i c aci d-
i mpregnated anhydrous magnesi um sul fate, was
reported by Wri ght et al . I ndeed, al i phati c, ol efi ni c,
heteroaromati c, and N-protected ami no aci ds reacted
wi th an excess of tert-butyl al cohol as i n si tu source
of i sobutyl ene, affordi ng tert-butyl esters i n good
yi el ds (Tabl e 18, entry 6).
155
The sul furi c aci d i s
adsorbed onto the magnesi um sul fate, and the pH of
the reacti on sol vent remai ns neutral . The use of
magnesi um sul fate or sul furi c aci d al one fai l ed to
afford the product ester. Thi s method i s qui te speci fi c
for tert-butyl al cohol , si nce other terti ary al cohol s,
e.g., tert-amyl al cohol , afforded a l ower yi el d of the
correspondi ng ester and pri mary and secondary
al cohol s were converted i nto thei r tert-butyl ethers.
The use of Lewi s aci ds supported on sul fonated
cross-l i nked pol ystyrene or sal i cyl i c aci d resi n was
reported to promote the synthesi s of al i phati c aci d
esters (Tabl e 18, entri es 7 and 8).
156,157
Both methods
present the drawback that an excess of al cohol must
be empl oyed.
An i nteresti ng study on the synthesi s of 2,4-
di chl orophenoxy aceti c aci d esters has been publ i shed
by Rui z-Hi tzky et al .; they reported the synthesi s of
these esters usi ng mi croparti cul ate i norgani c sol i ds
such as si l i ca, cl ay, and zeol i te as reacti on medi a,
wi thout organi c sol vents, ei ther by conventi onal
heati ng or by usi ng mi crowaves. Under mi crowave
i rradi ati on, the esters were obtai ned i n hi gh yi el d i n
shorter reacti on ti me (3-10 mi n vs 2-6 h) (Tabl e 18,
entry 9).
158
A di fferent approach to esteri fi cati on i nvol ved the
use of al kyl hal i des or chl oroformates as reagents
i nstead of al cohol s. Aromati c, al i phati c, and het-
eroaromati c carboxyl i c aci ds were converted i nto the
correspondi ng esters by reacti on wi th al l yl and benzyl
bromi des or al kyl i odi des over Cel i te/CsF as a sol i d
base i n refl uxi ng acetoni tri l e (Tabl e 18, entry 10).
159
Esteri fi cati on of chi ral R-substi tuted carboxyl i c aci ds
proceeded i n excel l ent yi el ds wi th retenti on of con-
fi gurati on (Fi gure 8). Chemosel ecti ve esteri fi cati on
was obtai ned for phenol i c carboxyl i c aci ds, accompa-
ni ed by a sl i ght amount of di al kyl ated products.
An effi ci ent and sel ecti ve esteri fi cati on of carboxyl i c
aci ds wi th chl oroformates was reported usi ng si l i ca-
supported hexaal kyl guani di ni um sal t (Si O
2
/PBGS-
i Cl ) (Tabl e 18, entry 11)
160
(Fi gure 9). Al i phati c and
aromati c carboxyl i c aci ds, al so steri cal l y hi ndered,
reacted wi th phenyl , benzyl , and 2,2,2-tri chl oroethyl
chl oroformate wi thout sol vent at 120 C, gi vi ng the
correspondi ng esters i n hi gh yi el ds (Scheme 10).
Methyl chl oroformate was unsuccessful , as i t was
unstabl e under the reacti on condi ti ons.
Thi s supported catal yst promoted the sel ecti ve
formati on of esters, avoi di ng anhydri de and carbon-
ate producti on. The authors suggested the formati on
of carboxyl i c aci d-guani di ni um compl exes whi ch
easi l y reacted wi th chl oroformates, affordi ng the acyl
chl ori des and al cohol s, whi ch fi nal l y recombi ned i nto
the correspondi ng esters. I t i s noteworthy that the
process requi red a smal l amount of catal yst (1%).
Parti cul arl y i nteresti ng i s the sel ecti vi ty obtai ned
by Ni shi guchi et al . i n the monoesteri fi cati on of
symmetri cal di carboxyl i c aci ds catal yzed by i on-
exchanged resi ns. Di carboxyl i c aci ds wi th 4-14
carbon atoms were converted i nto monoesters by
heati ng wi th a butyl formate-octane mi xture over
wet Dowex 50WX2 resi n (Tabl e 18, entry 12).
161,162
The use of propyl formate or ethyl propi onate i nstead
of butyl formate afforded the propyl or ethyl mo-
noesters of hexanedi oi c aci d. The reacti on sel ecti vi ty
was hi gh, the di esters bei ng obtai ned i n onl y 3-8%
yi el d. The amount of catal yst was cruci al : to real i ze
hi gh sel ecti vi ti es, 1 g/mmol wi th respect to the
di carboxyl i c aci d was empl oyed, whi ch i s about 10
ti mes as much as that used i n the sel ecti ve acyl a-
ti on
163
and tetrahydropyranyl ati on
164
of di ol s. The
authors showed that a certai n amount of water i n
the resi n i s essenti al for the hi gh sel ecti vi ty. Taki ng
i nto account that the di aci d reacts much more rapi dl y
than the monoester, they presumed that the sel ec-
ti vi ty ari ses from a parti ti on equi l i bri um between
the aqueous l ayer and the aproti c ester-hydrocar-
bon l ayer whi ch i s di fferent for the di aci d and
monoester.
Figure 8.
Figure 9.
Scheme 10
Recentl y, the esteri fi cati on of sal i cyl i c aci d over
zeol i tes has been reported usi ng di methyl carbonate
(DMC) (Tabl e 18, entry 13).
165
Thi s reagent over-
comes the mai n drawback of esteri fi cati on reacti ons
i nvol vi ng al cohol s, i .e., the necessi ty to remove the
water formed whi ch woul d deacti vate the catal yst.
DMC i s an envi ronmental l y fri endl y methyl ati ng
agent that affords methanol as an esteri fi cati on
byproduct, whi ch can be recycl ed for the producti on
of DMC. BEA (SAR ) 16) and ZSM-5 zeol i tes (SAR
) 50) were effecti ve catal ysts, gi vi ng the methyl
sal i cyl ate, an i mportant i ndustri al i ntermedi ate, i n
hi gh yi el d and sel ecti vi ty (>95%). Ki neti c studi es
reveal ed that catal yst aci di ty, especi al l y i n the strong
aci d si tes, i s the mai n characteri sti c that expl ai ns the
acti vi ty order, i .e., BEA > ZSM-5 . Y (SAR ) 60).
4.2. Deprotection
Sel ecti ve deprotecti on of esters i n the presence of
sensi ti ve functi onal groups i s an i mportant goal i n
syntheti c organi c chemi stry, i n parti cul ar when di f-
ferent ester functi onal i ti es are present i n the same
compound.
Al l yl and ci nnamyl esters coul d be chemosel ecti vel y
deprotected by kaol i ni ti c cl ay (Tabl e 19, entry 1)
166
and Envi rocat EPZG (Scheme 11). Upon heati ng the
esters at refl ux i n tol uene i n the presence of ani sol e
as nucl eophi l e, both catal ysts promoted the conver-
si on to the parent aci ds wi th i denti cal resul ts. The
catal yst acti vi ty was attri buted to Brnsted and
Lewi s aci d centers present on thei r surface. The
authors showed that al kyl esters remai n unchanged
under the reacti on condi ti ons. An i nteresti ng sub-
sti tuent effect, not rati onal i zed, was observed for
ci nnamyl esters of aromati c aci ds: meta-substi tuted
esters were hydrol yzed quanti tati vel y to the corre-
spondi ng aci ds, and ortho-substi tuted esters were
hydrol yzed i n moderate yi el ds (46-60%), whereas
para-substi tuted esters remai ned al most unal tered.
Table 19. Deprotection of Esters
a
Scheme 11
An i mprovement i n deprotecti on of al l yl esters was
then shown by carryi ng out a sol vent-free, mi crowave-
assi sted reacti on catal yzed by montmori l l oni te K10
(Tabl e 19, entri es 2 and 3).
167
The ti me requi red for
compl eti on of the reacti on was appreci abl y shorter
(10-20 mi n) than that requi red when usi ng thermal
condi ti on (5-20 h). Tol uene was used as the nucl eo-
phi l e when al l yl i c esters were hydrol yzed, whereas
more nucl eophi l i c aromati c speci es, such as ani sol e,
were empl oyed for ci nnamyl esters. Aryl and al kyl
esters remai ned unaffected under these reacti on
condi ti ons.
Al l yl esters were easi l y deprotected al so by sul fated
SnO
2
i n refl uxi ng tol uene (Tabl e 19, entry 4).
168
Ani sol e was used as the nucl eophi l i c aromati c re-
agent when ci nnamyl and crotyl esters were reacted.
The authors showed that thi s reacti on consti tutes
hydrol ysi s under anhydrous condi ti ons and that
methyl esters remai n unaffected.
Recentl y, a hi ghl y chemosel ecti ve hydrol ysi s of tert-
butyl esters promoted by montmori l l oni te KSF was
reported by Yadav et al . (Tabl e 19, entry 5).
169
The
authors attri buted the wi de range of functi onal
groups tol erated to the mi l d condi ti ons and to the
short reacti on ti me. I ndeed, thi s method sel ecti vel y
cl eaves tert-butyl esters, l eavi ng benzyl , methyl , and
al l yl esters i ntact (Scheme 12).
Moreover, tert-butyl esters can be sel ecti vel y re-
moved i n the presence of other aci d-sensi ti ve protect-
i ng groups, such as carbamates, ethers, and ol efi ns
(Scheme 13). I nteresti ngl y, i t was reported that when
a stereogeni c center i s present i n the R-posi ti on, the
parent aci ds can be i sol ated wi th compl ete retenti on
of confi gurati on.
The cl eavage of tert-butyl esters was previ ousl y
reported usi ng si l i ca gel i n refl uxi ng tol uene (Tabl e
19, entry 6).
170
The sel ecti vi ty obtai ned for tert-butyl
esters over tert-butyl ethers was substrate-dependent
(product rati o from 9/1 to 2.1/1), whereas i t was
compl ete over tri methyl si l yl ethyl esters (Scheme 14).
The reacti on requi red a l arge amount of si l i ca (5
g/mmol of ester). I nteresti ngl y, the hydrophobi c
substrates needed l onger reacti on ti mes than the
more pol ar ami no aci d deri vati ves, due to the rel ati ve
affi ni ty of the starti ng materi al for the si l i ca gel .
Aromati c and al i phati c benzyl esters were easi l y
deprotected under mi l d condi ti ons on neutral or
aci di c al umi na when subjected to mi crowave i rradi a-
ti on for short ti mes (Tabl e 19, entry 7).
171
Mi crowave
i rradi ati on was more effi ci ent than conventi onal
heati ng. The amount of catal yst requi red for opti -
mum yi el d was hi gh, i .e., 12-14 g/mmol ester.
Two general procedures for esters hydrol ysi s were
reported usi ng i mpregnated catal ysts. Al i phati c, al i -
cycl i c, and aromati c carboxyl i c aci ds were obtai ned
i n hi gh yi el ds on moi st si l i ca gel i mpregnated wi th
i ndi um tri i odi de under mi crowave i rradi ati on (Tabl e
19, entry 8).
172
The reacti on condi ti ons were tol erant
to ketone, hydroxy, methoxy, and CdC moi eti es.
Fi nal l y, potassi um fl uori de-doped al umi na pro-
moted the hydrol ysi s of a vari ety of esters deri ved
from aromati c, vi nyl , and al i phati c aci ds and pri -
mary, secondary, and terti ary al cohol s under mi cro-
wave i rradi ati on. The correspondi ng aci ds were ob-
tai ned i n excel l ent yi el ds (Tabl e 19, entri es 9 and
10).
173
5. Carbonyl Protecting Groups
The el ectrophi l i c nature of the carbonyl group i s a
domi nant feature of i ts extensi ve chemi stry. One of
the major chal l engi ng probl ems duri ng many mul -
ti use syntheses i s how to protect a carbonyl from
nucl eophi l i c attack unti l i ts el ectrophi l i c properti es
can be expl oi ted. The protecti on of al dehydes and
ketones has been served by a rel ati vel y smal l reper-
toi re of protecti ng groups and, of these, acetal s,
thi acetal s, oxathi ol anes, 1,1-di acetates, and ni trog-
enous deri vati ves have proven to be the most servi ce-
abl e.
5.1. Acetals
5.1.1. Protection
Due to the great i mportance of these protecti ng
groups, many methods for thei r formati on under
heterogeneous catal ysi s have been reported i n recent
years (Tabl e 20).
Montmori l l oni te KSF has been reported for the
protecti on of carbonyl compounds as 1,5-di hydro-3H-
2,4-benzodi oxepi nes (Tabl e 20, entry 1).
174
Under
these condi ti ons, al dehydes and al i phati c ketones
were easi l y protected, but aromati c ketones were
hi ghl y resi stant, and benzophenone was unreacti ve.
The same catal yst has been empl oyed, wi thout any
sol vent, under mi crowave i rradi ati on, to protect
al dehydes and ketones wi th orthoformates or by
Scheme 12
Scheme 13
Scheme 14
Table 20. Protection of Carbonyl Groups as Acetals
di oxol ane exchange wi th 2,2-di methyl -1,3-di oxol ane
(DMD) (Tabl e 20, entry 2).
175
The acetal i zati on of carbonyl compounds wi th
methanol was i nvesti gated by Uemura et al . i n the
presence of a cati on-exchanged montmori l l oni te
(M
n+
-Mont; M
n+
) Ce
3+
, Zr
4+
, Fe
3+
, Al
3+
, Zn
2+
, H
+
,
and Na
+
) (Tabl e 20, entry 3).
176
The order of catal yti c
effi ci ency of the montmori l l oni te/M
n+
i s montmori l -
l oni te/Ce
3+
> Fe
3+
, Al
3+
, Zr
4+
. Zn
2+
, Na
+
, H
+
.
However, l i near ketones and al dehydes were con-
verted i ncompl etel y under these condi ti ons. I t must
be poi nted out that the acetal i zati on of 4-acetyl ben-
zal dehyde occurred onl y at the formyl group (Scheme
15).
Natural kaol i ni ti c cl ay was found to be a conve-
ni ent catal yst for the chemosel ecti ve protecti on, wi th
ethyl ene gl ycol , of a vari ety of al i phati c, aromati c,
heteroaromatic, and R,-unsaturated aldehydes (Table
20, entry 4), whi l e ketones fai l ed to undergo protec-
ti on.
177
Envi rocat EPZG has been reported to gi ve acetal s
wi th 1,2-benzenedi methanol (Tabl e 20, entry 5),
178
and, because the protecti on of the ketones needs
l onger reacti on ti mes, the chemosel ecti ve protecti on
of an al dehyde i n the presence of a ketone coul d be
achi eved by the appropri ate choi ce of the reacti on
ti me. The same catal yst was effi ci entl y appl i ed for
the acetal i zati on of the carbonyl compounds wi th eth-
yl ene gl ycol (Tabl e 20, entry 6).
179
When 2,2-di methyl -
1,3-propanedi ol was empl oyed under Envi rocat EPZG
catal ysi s, both ketones and al dehydes (Tabl e 20,
entry 7) were easi l y protected.
180
Moreover, some
more reacti ve compounds were acetal i zed i n the
presence of l ess reacti ve or steri cal l y hi ndered ones;
a
Scheme 15
for exampl e, when a mi xture of o-ni trobenzal dehyde
and 3-methyl -4-hydroxybenzal dehyde was al l owed to
react wi th 1 equi v of 2,2-di methyl -1,3-propanedi ol
and a catal yti c amount of Envi rocat EPZG, a 93%
yi el d of the former protected al dehyde was obtai ned,
whereas the l atter one was recovered unchanged
(Scheme 16).
A seri es of 2-substi tuted and 2,2-di substi tuted 1,3-
benzodi oxol anes has been synthesi zed by reacti on of
catechol and pi rogal l ol wi th al dehydes and ketones,
catal yzed by montmori l l oni te KSF or K10 (Tabl e 20,
entry 8). Ketones gave better yi el ds than al dehydes,
al though hi ghl y steri cal l y hi ndered ones such as
steroi dal ketones or di aryl ketones fai l ed to react at
al l . Di carbonyl compounds can sel ecti vel y provi de
monobenzodi oxol anes wi th the use of an excess of
ketone (Scheme 17).
181
Kaneda et al . r epor ted the use of ti tani um-
exchanged montmori l l oni te for the sel ecti ve acetal -
i zati on of carbonyl compounds wi th ethyl ene gl ycol
(Tabl e 20, entry 9); the catal yst smoothl y transforms
vari ous ki nds of cycl i c, al i phati c, and aromati c ke-
tones i nto acetal s. Remarkabl y, bul ky ketones gave
quanti tati ve yi el ds of the correspondi ng acetal s. The
catal yst was effi ci entl y empl oyed for the chemose-
l ecti ve acetal i zati on of pol yfuncti onal yzed compounds
(Scheme 18).
182
For exampl e, 4-oxo-4H-1-benzopyran-
3-carboxyal dehyde was excl usi vel y protected at the
formyl group (Scheme 18a), whereas ethyl 2-oxocy-
cl opentanecarboxyl ate afforded an acetal , l eavi ng the
ester functi on i ntact (Scheme 18b). More i nterest-
i ngl y, the unconjugated keto functi on of the Wi el and-
Mi escher ketone was sel ecti vel y protected wi th re-
spect to the conjugated one (Scheme 18c).
Y zeol i te HSZ-360 has been demonstrated to be
effecti ve i n the formati on of 1,3-di oxol anes wi th
several al dehydes or ketones wi thout the need for
water removal . The method (Tabl e 20, entry 10)
shows good sel ecti vi ty si nce other functi onal i ti es such
as phenol i c and al cohol i c hydroxy groups, (Z)-carbon-
carbon doubl e bond, cyano, ether, bromi de, and
sul fone were preserved. When 1,4- and 1,3-di ketones
were empl oyed as starti ng materi al s, doubl e 1,3-
di oxol anes were obtai ned, whi l e wi th hi gh enol i zabl e
starti ng compounds the mono-1,3-di oxol ane was pro-
duced, i n moderate yi el d. Chi ral 1,3-di oxol anes were
al so prepared i n excel l ent yi el d from (R,R)-di meth-
yl tartrate, wi th compl ete retenti on of opti cal acti vi ty
(Scheme 19).
183
The use of other Y zeol i tes was reported by Corma
et al . for the preparati on of di methyl and cycl i c
ethyl ene acetal s by treatment of the correspondi ng
carbonyl compounds wi th tri methyl orthoformate
(Tabl e 20, entry 11)
184
or wi th ethyl ene gl ycol . Better
yi el ds were obtai ned wi th the fi rst procedure; i n thi s
case, the l evel of aci di ty of the zeol i te on the i ni ti al
reacti on rate reveal ed that onl y strong aci d si tes (pK
a
< 0) were acti ve.
A mi l d catal yti c method for acetal i zati on of car-
bonyl compounds, such as 1,5-di hydro-2,4-benzodi -
oxepi nes (Tabl e 20, entry 12), wi th benzene 1,2-
di methanol usi ng aci di c ZSM-5 zeol i tes has been
reported. Removal of water wi th thi s catal yst was not
necessary; however, a drawback of thi s procedure
was the need to acti vate the catal yst by heati ng at
400 C for 6 h before use.
185
The catal yti c acti vi ty of del ami nated zeol i tes (I TQ-
2) i n the acetal i zati on of al dehydes wi th tri methyl
orthoformate (Tabl e 20, entry 13) has been compared
wi th mesoporous MCM-22 al umi nosi l i cate, beta zeo-
l i tes, and amorphous al umi nosi l i cate, al l of them wi th
si mi l ar SAR. The resul ts obtai ned i ndi cate that when
the reacti ons i nvol ve bul ky reactants, I TQ-2 shows
the hi ghest acti vi ty as a consequence of the combi na-
ti on of i ts del ami nated structure, whi ch al l ows easy
access to the acti ve si tes, and the presence of strong
aci d si tes.
69
Sul furi c aci d adsorbed on si l i ca gel has been found
to be a good catal yst for the ketal i zati on of ketoster-
oi ds wi th ethyl ene gl ycol (Tabl e 20, entry 14),
93
whi l e
Scheme 16
Scheme 17
Scheme 18
Scheme 19
si l i ca gel -supported metal l i c sul fates were found to
effi ci entl y promote the protecti on of both aromati c
and al i phati c al dehydes as 1,3-di oxol anes under
mi crowaves, i n sol vent-free condi ti ons (Tabl e 20,
entry 15). Several al i phati c, aromati c, R,-unsatur-
ated, and heterocycl i c al dehydes were sel ecti vel y
protected i n hi gh yi el ds. Among vari ous metal l i c
sul fates supported on si l i ca gel [Ce(SO
4
)
2
, MgSO
4
, and
NaHSO
4
], the l ast was found to be the most effec-
ti ve.
186
The hi ghl y aci di c sul fated zi rconi a (ZrO
2
/SO
4
2-
),
wi th H
o
e -16.04, has been proposed for the synthe-
si s of acetal s from al dehydes and ketones wi th 2,2-
di methyl -1,3-propanedi ol (Tabl e 20, entry 16) and
wi th removal of water.
78
The same reacti on has been
successful l y tested wi th yttri a-zi rconi a i n chl oroform
at room temperature (Tabl e 20, entry 17).
187
2,2-Di substi tuted and 2-monosubsti tuted 1,3-ben-
zodi oxol es were prepared by ZrO
2
/SO
4
2-
catal ysi s
(Tabl e 20, entry 18). When catechol was heated wi th
several al dehydes or ketones and i n the presence of
ZrO
2
/SO
4
2-
sol i d superaci d, the 1,3-benzodi oxol es
were obtai ned i n good yi el ds. Ketones al l owed better
yi el ds than al dehydes, and the authors found that
the reacti on rate of cycl i c ketones was i nfl uenced by
the ri ng si ze (fi ve- and si x-membered ri ng ketones
gave hi gher yi el ds).
188
Zi rconi um sul fophenyl phosphonate [Zr(CH
3
PO
3
)
1.2
-
(O
3
PC
6
H
4
SO
3
H)
0.8
] has been i nvesti gated for the
preparati on of 1,3-di oxol anes, 1,3-di oxanes, and 1,3-
di oxepane from several carbonyl compounds (Tabl e
20, entry 19). The reacti on i n general occurs i n
sati sfactory to good yi el ds, whereas i t fai l ed when
R,-unsaturated and aromati c ketones were reacted
wi th propane-1,3- and butane-1,4-di ol s.
189
A method for the protecti on of carbonyl compounds
has been carri ed out under Pt/MoO
3
/ZrO
2
, a catal yst
that i s not easi l y avai l abl e (Tabl e 20, entry 20).
Vari ous al dehydes and ketones, i ncl udi ng R,-unsat-
urated ones, can be protected wi th ethyl ene gl ycol .
190
Carbonyl compounds were acetal i zed, wi th ethyl -
ene gl ycol , on Al PO
4
(Tabl e 20, entry 21) or Al
2
O
3
/
Al PO
4
catal ysi s. Both catal ysts are abl e to effi ci entl y
promote the acetal i zati on reacti on, al though Al PO
4
seems to be more adequate for ketones whi l e Al
2
O
3
/
Al PO
4
was more effecti ve wi th al dehydes.
191
An i nteresti ng study of di fferent catal ysts for the
preparati on of di methyl acetal s of al dehydes by reac-
ti on wi th tri methyl orthoformate has been made by
Corma et al .
192
Large-pore Y and beta zeol i tes as wel l
as mesoporous and amorphous si l i ca-al umi nas have
been used as catal ysts. I t was found that, wi th smal l
si ze al dehydes, zeol i tes were i ntri nsi cal l y more acti ve
than the mesoporous materi al s. However, when usi ng
reactants wi th mol ecul ar si ze l arger than 7 (as i t
i s commonl y done i n the fi el d of fi ne chemi cal s),
geometri c constrai nts do not al l ow thei r di ffusi on
i nsi de the pores, and onl y the external surface area
of these materi al s becomes avai l abl e to the reactants.
I n these ci rcumstances, the l arge pores of MCM-41
make thi s materi al more adequate for carryi ng out
the acetal i zati on reacti ons (Tabl e 20, entry 22). A
si mi l ar mesoporous catal yst was al so empl oyed by
I wamoto et al . for the acetal i zati on of al dehydes and
ketones wi th methanol (Tabl e 20, entry 23).
193
Some exampl es of appl i cati on of resi ns showi ng
Lewi s as wel l as proti c aci di ty have been reported.
For exampl e, the sal i cyl i c aci d resi n-supported FeCl
3
was uti l i zed for the acetal i zati on of di fferent al de-
hydes and ketones (Tabl e 20, entry 24), showi ng a
good effi ci ency combi ned wi th a noncorrosi ve effect.
157
Si mi l arl y, R-hal oketones were acetal i zed i n the pres-
ence of Nafi on/TMS (Tabl e 20, entry 25)
194
wi th 1,2-
bi s(tri methyl si l yl oxy)ethane (BTSE). The reacti on
was usual l y performed i n refl uxi ng chl oroform, but
for steri cal l y crowded hal oketones and di hal oketones,
heati ng at 90-100 C i n the absence of sol vent was
needed. Thi s i s an i mportant advantage si nce R-ha-
l oketones are prone to rearrange under aci di c condi -
ti ons.
5.1.2. Deprotection
The regenerati on of carbonyl compounds from thei r
acetal s i s general l y performed under aci di c condi ti ons
and, for thi s purpose, di fferent heterogeneous cata-
l ysts have been proposed.
Cycl i c acetal s of ketosteroi ds were cl eaved by usi ng
sul furi c aci d
93
or copper(I I ) sul fate
195
supported on
si l i ca (Tabl e 21, entri es 1 and 2). Concerni ng the sec-
ond procedure, from the resul ts reported i t i s evi dent
that the method was useful for removal of cycl i c
acetal s i n sol vents of l ow pol ari ty, such as di chl o-
romethane, chl oroform, or benzene, whi l e more pol ar
sol vents, l i ke tetrahydrofuran, ethyl acetate, or ac-
etone, compl etel y i nhi bi ted the reacti on. I t shoul d be
noted that, under appropri ate condi ti ons, the method
al l owed chemosel ecti ve removal of cycl i c acetal s i n
the presence of cycl i c thi oacetal s (Scheme 20) and di d
not affect cyanohydri n and ester functi ons.
Commerci al l y avai l abl e montmori l l oni te K10 has
been uti l i zed for the easy cl eavage of acetal s (Tabl e
21, entri es 3 and 4);
196,197
i t shoul d be noted that a
l arger amount of catal yst was needed for cycl i c
acetal s.
NaY zeol i tes promoted the cl eavage of acetal s i n
the presence of ni trobenzene at room temperature
184
I t has been demonstrated that
water mol ecul es that remai ned adsorbed on the
zeol i te after thermal acti vati on were acti ve duri ng
the hydrol yti c cl eavage. When no external water was
added to the system, the progress of the reacti on
depended on the water absorbed on the zeol i te.
Mordeni te zeol i te (SAR ) 19.2) has al so been uti l i zed
for the cl eavage of acetal s (Tabl e 21, entry 6). The
resul ts showed that a wi de range of acetal s, i ncl udi ng
saturated, R,-unsaturated, al i phati c, aromati c, and
heteroaromati c compounds, can be cl eaved under
these condi ti ons.
198
(P)-DCKA was found to be an effecti ve water-
tol erant catal yst i n the sel ecti ve deprotecti on of
di methyl and ethyl ene acetal s (Tabl e 21, entri es 7
and 8). Chemosel ecti ve hydrol ysi s of the ethyl ene
acetal s i n the presence of aci d-l abi l e OH-protecti ng
groups such as MOM, THP, TBDMS, and TBDPS
coul d be performed under these condi ti ons.
101,199
A mi l d and easy regenerati on of the carbonyl
compounds from thei r benzyl i c di oxol anes has been
carri ed out by Habi bi et al . under potassi um dode-
catungstocobal tate tri hydrate (Tabl e 21, entry 9). The
method seems to be unaffected by the bul ki ness of
the starti ng acetal s.
60
Oxi dati ve deprotecti on of l i near and cycl i c acetal s
to thei r correspondi ng carbonyl deri vati ves coul d be
performed by a conveni ent combi nati on of oxi dant
and heterogeneous supports. For exampl e, potassi um
ferrate supported on montmori l l oni te K10 al l owed
the cl eavage of acetal s under mi crowave i rradi ati on
i n dry medi a (Tabl e 21, entry 10). I t i s noteworthy
that the use of the unsupported catal yst resul ted i n
i ncompl ete deprotecti on, even for prol onged reacti on
ti me under mi crowaves.
200
A further effi ci ent procedure for the sel ecti ve
cl eavage of acetal s has been carri ed out by usi ng
Oxone wi th al umi na under mi crowaves and sol vent-
free condi ti ons (Tabl e 21, entry 11). I t i s worthy of
note that the reacti on al l ows the easy regenera-
ti on of a vari ety of al dehydes wi thout overoxi da-
ti on.
201
Fi nal l y, a mani pul ati vel y si mpl e and rapi d method
for the oxi dati ve deprotecti on of ethyl ene acetal s was
obtai ned wi th Al
2
O
3
/KMnO
4
under sol vent-free condi -
ti ons wi thout overoxi dati on reacti ons (Tabl e 21, entry
12).
146
The yi el d and rate of the transformati on of
ethyl ene acetal s i nto the correspondi ng carbonyl
Table 21. Deprotection of Acetals
a
compounds wi th potassi um permanganate al one were
l ower.
5.2. Dithioacetals
5.2.1. Protection
Di thi oacetal s are obtai ned by proti c or Lewi s aci d-
catal yzed condensati on of carbonyl compounds wi th
thi ol s or by transdi thi oacetal i zati on of acetal s, and
recentl y several heterogeneous catal ysts have been
proposed for thi s goal .
Di fferent Lewi s aci ds supported on si l i ca gel were
reported to effi ci entl y promote the thi oacetal i zati on
of carbonyl compounds. The mai n advantages deri ved
from the use of these supported catal ysts are (i ) the
hi gher acti vi ty of the supported catal yst wi th respect
to the unsupported counterpart and (i i ) the easi er
removal of the catal yst from the reacti on medi um.
A rapi d, mi l d, and effi ci ent method for thi oacetal -
i zati on has been proposed by Patney based on the
use of anhydrous i ron(I I I ) chl ori de di spersed on si l i ca
gel . Di fferent ethyl ene thi oacetal s have been obtai ned
(Tabl e 22, entry 1) from al dehydes as wel l as from
ketones, i n nearl y quanti tati ve yi el ds and i n very
short reacti on ti me.
202
Moreover, the protecti on of
carbonyl compounds as 1,5-di hydro-2,4-benzodi thi -
epi nes (Tabl e 22, entry 2) coul d be possi bl e wi th
aromati c, al i phati c, and R,-unsaturated al dehydes.
203
The drawback of thi s methodol ogy i s represented by
the consumpti on of the catal yst, si nce the reacti on
resul ts i n producti on of water.
The same author cl ai med the use of bi s(tri meth-
yl si l yl )sul fate on si l i ca gel to promote thi oacetal i za-
ti on of carbonyl compounds (Tabl e 22, entry 3). I t
shoul d be noted that i n the absence of si l i ca, the
reacti on requi red forci ng condi ti ons such as boi l i ng
benzene wi th azeotropi c removal of water.
204
More-
over, anhydrous Si O
2
/CoBr
2
205
and Si O
2
/ZrCl
4
206
were found to be good catal ysts for the thi oacetal -
i zati on of the carbonyl compounds i n di chl oromethane
(Tabl e 22, entry 4 and 5). Wi th both catal ysts, l ess
reacti ve aromati c ketones al so reacted at room tem-
perature, affordi ng the correspondi ng di thi oacetal s
i n hi gh yi el ds. Fi nal l y, sol vent-free thi oacetal i zati on
was performed usi ng Si O
2
/Cu(OTf)
2
catal ysi s (Tabl e
22, entry 6). The procedure needed shorter reacti on
ti mes for the protecti on of al dehydes wi th respect to
ketones; consequentl y, a moderate chemosel ecti ve
thi oacetal i zati on of an al dehyde i n the presence of a
ketone functi onal i ty coul d be achi eved. The keto
group of a -ketoester coul d al so be thi oacetal i zed i n
sati sfactory yi el d. Hi ndered ketones, such as ben-
zophenone and camphor, di d not react i n the sol vent-
free condi ti ons at room temperature; however, the
reacti on coul d be effi ci entl y performed i n tol uene at
80 C.
207
Producti on of di thi anes and di thi ol anes coul d be
achi eved i n the presence of montmori l l oni te KSF cl ay
wi thout sol vent (Tabl e 22, entry 7). Qual i tati ve
ki neti c studi es suggested the possi bi l i ty of performi ng
the reacti on wi th chemosel ecti ve control ; i n fact, i n
a competi ti ve experi ment carri ed out wi th an equi mo-
l ar mi xture of benzal dehyde, acetophenone, and
ethane-1,2-di thi ol , onl y the di thi ol ane of benzal de-
hyde was quanti tati vel y formed. On the basi s of these
resul ts, 4-acetyl benzal dehyde was subjected to reac-
ti on wi th ethane-1,2-di thi ol excl usi vel y, affordi ng the
thi oacetal i zati on of the formyl group.
208
The same
catal yst was uti l i zed for the protecti on of carbonyl
compounds wi th 1,2-benzenedi methanethi ol (Tabl e
22, entry 8).
209
Si mi l ar good resul ts wi th regard to
both yi el d and chemosel ecti vi ty were achi eved by
uti l i zi ng natural kaol i ni ti c cl ay (Tabl e 22, entry 9).
177
A commerci al Mexi can bentoni ti c cl ay was reported
to be an excel l ent catal yst for the preparati on of
di thi oacetal s i n hi gh yi el ds vi a condensati on of 1,3-
propanedi thi ol (Tabl e 22, entry 10) and benzyl and
butyl mer captans wi th sever al car bonyl i c com-
pounds.
210
Compari son experi ments showed that thi s
cl ay was more acti ve than the montmori l l oni te KSF;
thi s i s probabl y due to the great di fference of the
surface area (200 vs 10 m
2
/g). From the mechani sti c
poi nt of vi ew, the i nteracti on wi th the aci d si tes of
the bentoni ti c cl ay shoul d enhance the el ectrophi l i c
character of the carbonyl substrate, faci l i tati ng the
nucl eophi l i c acti on of the thi ol .
Two Lewi s aci d-supported cl ays, namel y montmo-
ri l l oni te K10/POCl
3
211
and En-
vi rocat EPZG (Tabl e 22, entry 12),
212
have been
uti l i zed for a rapi d and sel ecti ve thi oacetal i zati on
wi th 1,2-ethanedi thi ol . I t must be stated that by
usi ng montmori l l oni te K10/POCl
3
as catal yst, a good
degree of chemosel ecti vi ty was observed; i n fact,
benzal dehyde and ci nnamal dehyde both were nearl y
quanti tati vel y thi oacetal i zed i n the presence of ac-
etophenone.
Kumar et al . reported the use of Y zeol i te (SAR )
4.8) to prepare thi oacetal s of al dehydes (Tabl e 22,
entry 13)
213
and ketones, i ncl udi ng the more hi ndered
ones such as benzophenone. I t shoul d be menti oned
that the use of zeol i tes such as ZSM-5 (SAR ) 90)
and mordeni te (SAR ) 20.2) was not very encourag-
i ng. The observed best performance of Y zeol i te
compared to ZSM-5 (pore si ze 0.54 0.56 and 0.51
0.55 nm) and mordeni te (pore si ze 0.67 0.79 nm)
coul d be attri buted to i ts l arger openi ngs (0.74 nm),
the presence of a three-di mensi onal channel system,
and the hi gher concentrati on of aci d si tes. Further
studi es on the use of mordeni tes or Y zeol i tes were
l ater devel oped by the same (Tabl e 22, entry 14)
214
and other authors (Tabl e 22, entry 15).
215
Y zeol i te HSZ-360 can be conveni entl y used for the
thi oacetal i zati on under mi l d condi ti ons (Tabl e 22,
Scheme 20
Table 22. Protection of Carbonyl Groups as Dithioacetals
entry 16). Sati sfactory to hi gh yi el ds were obtai ned,
even wi th steroi dal ketones and aromati c al dehydes
possessi ng el ectron-wi thdrawi ng or el ectron-rel easi ng
groups. The method i s mi l d enough to preserve other
functi onal i ti es such as (Z)-doubl e bond, ni tro, cyano,
tetrahydropyranyl , and ester groups.
216
Zi rconi um sul fophenyl phosphonate has been pro-
posed for the preparati on of 1,3-di thi ol anes (Tabl e 22,
entry 17) and 1,3-di thi anes i n refl uxi ng di chl o-
romethane from several carbonyl deri vati ves, i ncl ud-
i ng aromati c, al i phati c, and R,-unsaturated al de-
hydes and ketones. No di fferences i n the reacti vi ty
dependi ng on the structure of the carbonyl compound
or di thi ol have been observed.
189
Fi rouzabadi et al . reported an i nteresti ng appl i ca-
ti on of tungstophosphori c aci d (H
3
PW
12
O
40
) as het-
erogeneous catal yst for the chemosel ecti ve thi oace-
tal i zati on of al dehydes and ketones (Tabl e 22, entry
18).
217
The method can even be successful l y appl i ed
for the protecti on of hi ndered ketones such as (+)-
camphor and benzophenone. I n addition, the chemose-
l ecti ve conversi on of R- or -di ketones i nto the
correspondi ng mono-di thi oacetal was al so achi eved
(Scheme 21).
Dowex 50W-X8 was reported to catal yze the forma-
ti on of thi oacetal s wi th ethane-1,2-di thi ol (Tabl e 22,
entry 19) i n the absence of any sol vent and i n the
mi ni mum reacti on ti me.
218
Thi s catal yst, pretreated
wi th HCl , presumabl y i ncreases the el ectrophi l i ci ty
of the carbonyl group, favori ng the addi ti on of the
di thi ol , and can be uti l i zed for the protecti on of aci d-
sensi ti ve speci es (i ndol e and methyl enedi oxi de de-
ri vati ves).
5.2.2. Deprotection
The l arge number of methods whi ch address the
probl em of dethi oacetal i zati on may be taken as
evi dence that the reacti on often proves refractory,
especi al l y i n sensi ti ve substrates, and, i n thi s context,
a wi de range of reagents and catal ysts i s avai l abl e
for the cl eavage of thi oacetal s to the parent carbonyl
deri vati ves, and heterogeneous catal ysi s pl ays an
i mportant rol e.
Natural kaol i ni ti c cl ay has been uti l i zed by Band-
gar et al . for the sel ecti ve cl eavage of thi oacetal s,
under sol ventl ess condi ti ons (Tabl e 23, entry 1). Due
to i ts speci fi c acti vi ty i n the regenerati on of al de-
hydes, the methodol ogy i s useful for the chemosel ec-
ti ve removal of a thi oacetal i n the presence of a
thi oketal (Scheme 22). I t i s al so perti nent to note that
phenol i c, methyl enedi oxy, and methoxy groups tol er-
ate the reacti on condi ti ons.
219
Di fferent cl ay-supported ni trates have been suc-
cessful l y uti l i zed to cl eave cycl i c and acycl i c thi oac-
etal s deri ved from al dehydes and ketones. Cl ayfen
was empl oyed by Varma et al . to deprotect thi oacetal
deri vati ves under sol vent-free condi ti ons and wi th
the hel p of mi crowaves (Tabl e 23, entry 2). No si de
products were formed, the onl y excepti on bei ng
substrates beari ng free phenol i c moi eti es, where
some ri ng ni trati on occurred. However, the protocol
avoi ds the use of excess of sol vent and toxi c oxi dants,
and no further oxi dati on of the carbonyl compound
was observed.
220
The same catal yst has been reported
to gi ve good yi el ds i n the cl eavage of 1,3-di thi ol anes
and 1,3-di thi anes, but wi thout the need for mi cro-
wave i rradi ati on (Tabl e 23, entry 3).
221
Cl ayan was
al so reported by Meshram et al . to be a good catal yst/
reagent for thi s deprotecti on reacti on, carri ed out i n
di chl oromethane (Tabl e 23, entry 4),
222
or under
sol ventl ess condi ti ons usi ng mi crowave i rradi ati on
223
Al though both methods tol erate
common groups such as esters and ethers, they fai l ed
i n the sel ecti ve cl eavage of thi oacetal s i n the presence
of acetoni des.
Si l i ca gel has been uti l i zed as a support for metal
ni trates, affordi ng reagent-catal yst combi nati ons
that are useful for the thi oacetal s deprotecti on. An
effi ci ent regenerati on of carbonyl compounds from
1,3-di thi ol anes and 1,3-di thi anes can be carri ed out
under Si O
2
/Cu(NO
3
)
2
catal ysi s (Tabl e 23, entry 6)
224
by recoveri ng the correspondi ng ketones and the
al dehydes i n quanti tati ve yi el d. Si mi l arl y, a combi -
nati on of Fe(NO
3
)
3
and si l i ca gel regenerated al de-
a
Scheme 21
Scheme 22
hydes and ketones fr om 1,3-di thi anes and 1,3-
di thi ol anes under an i nert atmosphere (Tabl e 23,
entry 7, 8).
225,226
I n the case of aromati c substrates,
the el ectroni c property of the substi tuents and thei r
posi ti on on the benzene ri ng di d not affect the rate
nor the product sel ecti vi ty. I t i s i mportant to poi nt
out that i n the absence of si l i ca gel , the reacti on was
sl uggi sh. I t must be noted that i n al l cases, the
catal yst was prepared i n si tu si mpl y by mi xi ng the
oxi dant wi th si l i ca gel . Qui te si mi l arl y, Curi ni et al .
reported the cl eavage of cycl i c thi oacetal s usi ng
Oxone on al umi na (Tabl e 23, entry 9).
227
Di methyl sul foxi de i n combi nati on wi th si l i ca gel
chl ori de has been effi ci entl y used for the deprotecti on
of thi oacetal s i nto al dehydes.
228
The authors suggest
a mechani sm i n whi ch di methyl sul foxi de, si l i ca
Table 23. Deprotection of Dithioacetals
a
chl ori de, and di methyl sul foni um chl ori de pl ay a
cooperati ve rol e i n the enti re process. Thi oacetal s
deri ved from ketones show a qui te di fferent behavi or;
i n fact, i n the case of thi oacetal s deri ved from ketones
wi thout enol i zabl e hydrogens, deprotecti on proceeded
very wel l to gi ve the correspondi ng ketones i n hi gh
yi el ds (Tabl e 23, entry 10). I n contrast, thi oketal s
wi th enol i zabl e methyl and methyl ene groups un-
dergo ri ng-expansi on reacti ons, affordi ng 1,4-di thi -
epi ns and 1,4 di thi i ns.
Commerci al l y avai l abl e aci di c resi ns such as Am-
berl yst 15 (Tabl e 23, entry 11)
229
and Dowex 50W
230
have been empl oyed for the
dethi oacetal i zati on vi a equi l i bri um exchange wi th
aqueous acetone/paraformal dehyde. Usi ng thi s meth-
od, aci d-sensi ti ve groups, such as esters or ethers,
were not affected; i n addi ti on, cis-methyl pi nonoate
was regenerated without epimerization at C-3 (Scheme
23). The method i s appl i cabl e to more compl ex
i ntermedi ates i nvol ved i n the al kal oi ds synthesi s.
Layered zi rconi um sul fophenyl phosphonate has
al so been uti l i zed wi th si mi l ar good resul ts for the
mi l d hydrol ysi s of 1,2-di thi ol anes and 1,3-di thi anes
to thei r parent carbonyl compounds (Tabl e 23, entry
13). I n thi s case, the gl yoxyl i c aci d monohydrate was
empl oyed as exchange reagent.
231
5.3. 1,3-Oxathiolanes
1,3-Oxathi ol anes consti tute an i mportant cl ass of
compounds that are more stabl e than the corre-
spondi ng O,O-acetal s under aci di c condi ti ons and,
compared wi th S,S-acetal s, are more easi l y depro-
tected. Moreover, they can al so be uti l i zed as acyl
ani on equi val ents i n C-C bond formati on; conse-
quentl y, di fferent procedures for thei r preparati on
from carbonyl compounds have been reported under
both homogeneous and heterogeneous catal ysi s.
Natural cl ays promoted the effi ci ent chemosel ecti ve
producti on of a vari ety of oxathi ol anes by a di thi ol ane
exchange reacti on from al dehydes or ketones wi th
2,2-di methyl -1,3-oxathi ol ane (Scheme 24)
232
under
mi crowave i rradi ati on or by reacti on of al dehydes and
ketones with 2-mercaptoethanol (Scheme 25).
233
When
-keto esters were treated under these condi ti ons,
both transesteri fi cati on and ketone protecti on coul d
be possi bl e. The authors suggest that the catal yti c
acti vi ty of the aci d-acti vated cl ay coul d be attri buted
to the si gni fi cant amount of both Lewi s aci di ty
deri ved from Al remai ni ng i n the edges of the
pl atel ets and Brnsted aci di ty of coordi nated hydroxy
groups of Al
3+
, Fe
3+
, and Ti
4+
i ons rel ocated i n the
i nterl amel l ar space of the cl ay.
The formati on of oxathi ol anes from R,-unsatur-
ated carbonyl derivatives was also achieved by Dunach
et al . i n good yi el ds usi ng ami nopropyl ated si l i ca gel
hydr ochl or i de (APSGHCl ) wi th 2-mer captoetha-
nol .
234
The presence of 1 equi v of tri methyl orthofor-
mate as desi ccant was needed, si nce dehydrati ng
agents such as magnesi um sul fate or 4- mol ecul ar
si eves l ed to a l ower conversi on. I t i s wel l known that
the di rect producti on of oxathi ol anes from R,-
unsaturated carbonyl compounds i s accompani ed by
some drawbacks that l ower the sel ecti vi ty. For thi s
reason, i t i s i mportant to prepare the above-men-
ti oned deri vati ves vi a transoxathi ol anati on from
acetal s. The authors showed that, wi th APSGHCl ,
the di rect oxathi ol anati on of R,-unsaturated al de-
hydes and ketones has been performed sel ecti vel y
and i n good i sol ated yi el ds. A further i nteresti ng
resul t i s the protecti on of pul egone wi th the same
catal yst wi th a good di astereosel ecti ve control (98%
de) (Scheme 26).
Amberl yst 15 can be uti l i zed for the conversi on of
carbonyl compounds to 1,3-oxathi ol anes.
235
Fol l owi ng
the above procedure, a wi de range of carbonyl com-
pounds can be effi ci entl y transformed i nto thei r
correspondi ng 1,3-oxathi ol anes, and the protecti on of
an al dehyde i n the presence of a ketone group can
be performed i n hi gh yi el d and chemosel ecti vi ty
(97%), the reacti on of the al dehydes bei ng faster than
that of ketones (Scheme 27).
Carbonyl compounds were regenerated from the
parent 1,3-oxathi ol anes vi a an equi l i bri um exchange
wi th gl yoxyl i c aci d and Amberl yst 15, under sol vent-
free condi ti ons at room temperature or under mi cro-
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
wave i rradi ati on.
236
A wi de vari ety of oxathi ol anes
deri ved from ketones and al dehydes was shown to
undergo faci l e cl eavage under these condi ti ons. How-
ever, because the ketones are regenerated faster than
al dehydes, thi s process was uti l i zed i n effecti ng
sel ecti ve deprotecti on, as shown i n Scheme 28.
5.4. 1,1-Diacetates (Acylals)
5.4.1. Protection
Montmori l l oni tes K10 and KSF were uti l i zed by
Zhang et al . as catal ysts to convert both aromati c and
al i phati c al dehydes i nto thei r 1,1-di acetates (Tabl e
24, entry 1).
237
I t i s worth noti ng that hydroxy groups
i n 2-hydroxy- and 3-methoxy-4-hydroxybenzal dehyde
were al so acetyl ated; qui te surpri si ngl y, the authors
reported that wi th 4-hydroxybenzal dehyde and 4-(di -
methyl ami no)benzal dehyde, no reacti on occurred at
al l . As an expl anati on, they proposed the sel ecti ve
adsorpti on of the phenol i c and ami no groups on the
catal yst that keeps the al dehyde functi onal group
away from the acti ve si te of the cl ay, thus bl ocki ng
the reacti ve si tes and i nhi bi ti ng the reacti on. Under
mi crowave i rradi ati on, the preparati on of acyl al s was
performed i n remarkabl y l ower reacti on ti mes (Tabl e
24, entry 2).
238
Envi rocats, exhi bi ti ng both Lewi s and Brnsted
aci di ty, have been uti l i zed by Bandgar et al . for the
acetyl ati on of a vari ety of al dehydes (Tabl e 24, entri es
3 and 4). A faster reacti on rate was observed wi th
the use of EPZ10 (ZnCl
2
-exchanged cl ay)
239
under
mi crowave i rradi ati on wi th respect to the use of
EPZG (FeCl
3
-exchanged cl ay)
240
al one. The effi ci ency
of the catal yst was cl earl y vi sual i zed i n the case of
aromati c al dehydes havi ng an el ectron-wi thdrawi ng
group (Tabl e 24, entry 3), where the correspondi ng
acyl al s have been obtai ned i n excel l ent yi el ds and i n
very short ti me. A drawback of the use of these
catal ysts was represented by the i nhi bi ti on of thei r
acti vi ty under heati ng or cool i ng i n ai r.
Di fferent ki nds of commerci al l y avai l abl e zeo-
l i tes have been empl oyed for the acetyl ati on of
carbonyl compounds wi th aceti c anhydri de. For ex-
Scheme 28
Table 24. Protection of Carbonyl Group as 1,1-Diacetates
a
ampl e, Kumar et al . reported that hi gh conversi ons
and hi gh yi el ds can be achi eved usi ng beta zeo-
l i te (SAR ) 60) wi th smal l -si zed al dehydes (Tabl e
24, entry 5);
241
however, the reacti on wi th bul ky
substrates, such as 2-methyl -3,5-di methoxybenzal -
dehyde, was sl uggi sh and the yi el d was l ower. Two
Y zeol i tes wi th di fferent SAR were al so uti l i zed i n
protecti ng aromati c and al i phati c al dehydes. Wi th
an Y zeol i te showi ng SAR ) 8, very fast reacti on
ti mes were observed (Tabl e 24, entry 6),
242
except
for p-ni trobenzal dehyde, whi ch requi red prol onged
ti mes, possi bl y due to the strong el ectron-wi thdraw-
i ng ni tro substi tuent that l owers the i nteracti on of
the formyl group wi th the surface aci d si tes of the
catal yst. Y zeol i te HSZ-360 (SAR ) 14), uti l i zed
wi thout previ ous thermal or chemi cal treatment, has
been cl ai med to be a reusabl e catal yst for the sol -
vent-free synthesi s of di acetates of al dehydes (Tabl e
24, entry 7).
243
Other functi onal i ti es, such as ni tro,
ether, cyano, furyl , and (Z)-doubl e bond, were pre-
served, and, more i mportantl y, si nce ketones were
not reacti ve wi th thi s reagent, the method offers
the advantage to perform the protecti on of an al de-
hyde functionality in the presence of a ketone (Scheme
29).
HZSM-5 catal yst (SAR ) 180) was empl oyed to
promote the protecti on of di fferent al dehydes (Tabl e
24, entry 8),
244
showi ng a remarkabl e shape sel ecti v-
i ty; i n fact, a substanti al di fference i n the reacti on
rate for the ortho- and para-substi tuted aromati c
al dehydes was observed.
Acyl al s were synthesi zed i n a few mi nutes and i n
hi gh yi el d by acyl ati on of al dehydes wi th aceti c
anhydri de i n the presence of Si O
2
/FeCl
3
under mi -
crowave i rradi ati on (Tabl e 24, entry 9).
245
The use of sul fated zi rconi a, reported by Raju,
represents the sol e exampl e of effi ci ent conversi on
of both al dehydes and ketones i nto thei r 1,1-di ac-
etates (Tabl e 24, entry 10).
246
The reacti on was qui te
general , probabl y due to the great effi ci ency of the
sul fated zi rconi a, whi ch exhi bi ts both Lewi s and
Brnsted superaci d si tes (H
a
) -26). Layered zi rco-
ni um sul fophenyl phosphonate was found to catal yze
the synthesi s of acyl al s from al dehydes (Tabl e 24,
entry 11).
247
The aci d strength of the catal yst l i es
between pK
a
val ues of -5.6 and -8.2, si mi l ar to that
of montmori l l oni te and hi gher than that of Amberl yst
15; however, thi s catal yst promotes the same reacti on
i n shorter ti mes.
Fi nal l y, other two heterogeneous catal ysts, namel y
expansi ve graphi te (Tabl e 24, entry 12)
248
and pol y-
(vi nyl chl ori de)-supported ferri c chl ori de (Tabl e
24, entry 13),
249
were al so found to convert, i n
hi gh yi el ds, al dehydes i nto 1,1-di acetates. I t i s i m-
portant to emphasi ze that both catal ysts must be
prepared i n the l aboratory and that the expansi ve
graphi te preparati on i s qui te tedi ous, di ffi cul t, and
harmful si nce i t requi res the use of concentrated
sul furi c aci d, ni tri c aci d, and potassi um permanga-
nate.
248
5.4.2. Deprotection
The conventi onal deprotecti on of acyl al s i s achi eved
under basi c condi ti ons by usi ng ei ther sodi um hy-
droxi de or potassi um carbonate i n aqueous tetrahy-
drofuran.
The use of montmori l l oni te K10 or KSF has been
devel oped by Li et al . as a general method for the
regenerati on of al dehydes from thei r acyl al s (Tabl e
25, entry 1).
250
Both catal ysts afforded si mi l ar good
resul ts i n terms of yi el d and sel ecti vi ty. The reac-
ti ons were usual l y carri ed out i n di chl oromethane at
40 C, apart from those wi th aromati c al dehydes
beari ng el ectron-wi thdrawi ng groups, whi ch requi red
refl uxi ng i n benzene. Di fferent functi onal i ti es, such
as ethers, acetal s, and furan ri ngs,
251
coul d be
preserved. The mechani sm of the present reacti on i s
obvi ousl y di fferent from that of the cl assi cal hydrol y-
si s i n aqueous hydrochl ori c aci d, si nce the process i s
carri ed out i n the absence of water; furthermore,
si nce nei ther addi ti onal water nor anhydrous condi -
ti ons affect the reacti on rate, the authors concl ude
that the reacti on undergoes a uni mol ecul ar decom-
posi ti on of 1,1-di acetate to gi ve the correspondi ng
al dehyde and aceti c anhydri de, i n whi ch the cl ay
pl ays a Lewi s aci d rol e. A si mi l ar mechani sm has
been proposed for the reacti on carri ed out wi th
Envi rocat EPZG under mi crowave i rradi ati on (Tabl e
25, entry 2).
252
The combi nati on of commerci al l y avai l abl e sol i d
catal ysts such as Y zeol i te (Tabl e 25, entry 3)
243
and
neutral al umi na (Tabl e 25, entry 4)
253
wi th mi cro-
wave i rradi ati on has been demonstrated to be effi -
ci ent for the cl eavage of di fferent acyl al s; i t must be
menti oned that i n both procedures, a l arge amount
of sol i d catal yst was needed, probabl y due to the fact
that the reactants must be compl etel y adsorbed on
the surface of the catal yst i n order to achi eve good
resul ts.
Deprotecti on of aromati c al dehyde di acetates was
sel ecti vel y carri ed out by Cotel l e et al . usi ng CAN
coated on si l i ca gel (Tabl e 25, entry 5);
254
the reacti on
occurred sel ecti vel y onl y wi th aromati c al dehydes,
and some si de reacti ons, such as the parti al ni trati on
and oxi dati on of the el ectron-ri ch aromati c ri ngs,
have been observed due to the nature of CAN. Of par-
ti cul ar i nterest was the survi val of the aryl acetate
functi on usual l y cl eaved under aci di c or al kal i ne
condi ti ons.
Strongl y aci di c materi al s have been al so appl i ed
for the sel ecti ve cl eavage of aromati c or ci nnami c
di acetates; Ti O
2
/SO
4
2-
255
promoted
the reacti on i n very short ti mes (5-10 mi n), whereas
zi rconi um sul fophenyl phosphonate (Tabl e 25, entry
7)
248
needed l onger ti mes (1-24 h). I n both cases,
ni tro deri vati ves provi ded l ower conversi on rates i n
refl uxi ng di chl oromethane, whereas good yi el ds were
achi eved i n refl uxi ng benzene.
Scheme 29
5.5. Nitrogenous Derivatives
5.5.1. Protection
The easy protecti on of al dehydes and ketones as
i mi nes or enami nes has been reported to occur by
si mpl y mi xi ng the carbonyl compounds wi th pri mary
and secondary ami nes and submi tti ng the mi xture
to mi crowave i rradi ati on i n the presence of a catal yti c
amount of Envi rocat EPZG (Tabl e 26, entry 1).
256
Thi s approach avoi ded the need for a l arge excess of
mi neral support, l ong reacti on ti mes, and l arge quan-
ti ti es of aromati c sol vents needed i n the conventi onal
Table 25. Deprotection of 1,1-Diacetates
a
Table 26. Protection of Carbonyl Groups as Nitrogeneous Derivatives
a
sol uti on phase, whi ch al so requi res azeotropi c re-
moval of water.
Sri ni vasan et al . have reported the use of Y and
di val ent cati on-exchanged aci di c zeol i tes i n protecti ng
the carbonyl group of ketones and al dehydes as
phenyl hydrazones (Tabl e 26, entry 2).
215
The authors
stressed that when the nonaci di c NaY zeol i te was
empl oyed as catal yst, no hydrazones were i sol ated;
thi s rul ed out any si gni fi cant rol e of the basi c zeol i te
framework i n the deri vati zati on and i ndi cated the
need for the presence of aci di c si tes i n the framework.
Thus, when aci di c zeol i tes such as Y, CaY, and MgY
were used, the formati on of protected carbonyl com-
pounds was cl ean and smooth. The aci di ty i n CaY
and MgY zeol i tes can be expl ai ned by the di ssoci ati on
of coordi nati vel y bound water mol ecul es under the
acti on of the el ectrostati c fi el d associ ated wi th the
di val ent cati ons. Qui te si mi l ar hi gh yi el ds were
obtai ned i n the protecti on of al dehydes and ketones
as oxi mes by usi ng 3- mol ecul ar si eves as water
scavenger under sol ventl ess condi ti ons (Tabl e 26,
entry 3).
257
Haji pour reported the synthesi s of oxi mes, hydra-
zones, and semi carbazones of al dehydes and ketones
i n nearl y quanti tati ve yi el d under sol ventl ess dry
condi ti ons usi ng si l i ca gel i n the presence of sodi um
hydroxi de (Tabl e 26, entry 4).
258,259
The reacti on was
very fast wi th both al dehydes and ketones, but
competi ti ve experi ments carri ed out wi th an equi mo-
l ecul ar mi xture of an al dehyde and a ketone i n the
presence of hydroxyl ami ne showed that onl y the
al dehydi c functi on was protected, whereas the ketone
one was recovered unchanged. I n the absence of si l i ca
gel , ni trogen deri vati ves were obtai ned i n l ower yi el d
(20%).
Basi c Al
2
O
3
has been tested, i n two di fferent ways,
for the preparati on of keto- and al doxi mes. The fi rst
method empl oyed i rradi ati on of the reactants i n a
domesti c mi crowave oven (Tabl e 26, entry 5). The
second method made use of l ocal heat produced by
gri ndi ng the reactants i n the presence of mol ecul ar
si eves for dri vi ng the chemi cal reacti on. Al though the
two techni ques al l owed the formati on of oxi mes,
mi crowave treatment produced better yi el ds i n a
shorter reacti on ti me.
260
The method showed general
appl i cabi l i ty wi th respect to both aromati c and
al i phati c al dehydes and ketones, i ncl udi ng R,-
unsaturated ones and hydroxybenzal dehydes.
Sul fated ti tani a was uti l i zed by Ji n et al . i n a green
syntheti c procedure for the generati on of aromati c
oxi mes (Tabl e 26, entry 6).
261
Aromati c ketones were
not as acti ve as aromati c al dehydes owi ng to thei r
steri c hi ndrance and l ower el ectrophi l i ci ty, whereas
anthrone di d not react at al l . The authors found that
the aci di ty of Lewi s aci d centers on the surface of the
catal yst was enhanced owi ng to the strong i nducti ve
effect of the SdO group; i n addi ti on, when the
catal yst absorbed some water, Brnsted aci d centers
were produced. These two ki nds of aci d centers coul d
readi l y i nterconvert, thus synergi sti cal l y enhanci ng
the aci di ty of the sul fated ti tani a (Fi gure 10).
Fi nal l y, Amberl yst A-21 was reported to catal yze
the synthesi s of oxi mes of al dehydes and ketones
262
The catal yst di d not affect l abi l e
functi onal groups (ether, cyano, sul fone, ni tro, hy-
droxy, tetrahydropyranyl , (Z)-C-C doubl e bond), and
i ts mi l dness was demonstrated by the survi val of
R-ni trocycl ohexanone duri ng the oxi mati on process
that di d not undergo the ri ng cl eavage. The method
al l owed the sel ecti ve monooxi mati on of the carbo-
nyl group at posi ti on 3 of 1-phenyl -1,3-butanedi one
(Scheme 30); thi s behavi or can be expl ai ned wi th the
hi gh enol i zati on of the -di carbonyl compounds.
5.5.2. Deprotection
Deprotecti on of ni trogenous deri vati ves of carbonyl
compounds such as oxi mes, hydrazones, and semi -
carbazones was performed under heterogeneous con-
di ti ons by oxi dati on, reducti on, or hydrol ysi s i n the
presence of another carbonyl compound accordi ng to
the methods previ ousl y reported under homogeneous
condi ti ons. I n fact, usual l y the reacti ons are per-
formed by mi xi ng the ni trogenous deri vati ve wi th the
oxi di zi ng or reduci ng reagent (frequentl y uti l i zed i n
a l arge excess) i n the presence of a heterogeneous
materi al . However, i t i s qui te di ffi cul t to i magi ne that
under the above condi ti ons, a real heterogeneous
catal ysi s occurs, even i f i t cannot be excl uded a
synergi c acti vati on effect. More real i sti cal l y, we coul d
thi nk that the rol e of the heterogeneous materi al i s
si mpl y that of maki ng the workup easi er by absorb-
i ng tar materi al s. For these reasons, i n the fi rst part
of thi s secti on we wi l l bri efl y summari ze these meth-
ods on the basi s of the nature of the support/catal yst,
and then we wi l l di scuss some deprotecti on reacti ons
occurri ng under real heterogeneous catal ysi s.
Vari ous ammoni um and metal ni trates mi xed wi th
cl ays were reported to regenerate carbonyl com-
pounds from oxi mes and semi carbazones.
263-269
I n
some cases, the reacti on occurs si mpl y by gri ndi ng
al l the reagents i n a mortar. The same reacti ons can
be performed i n shorter ti mes by mi crowave i rra-
di ati on.
270-273
Y
274
and ZSM-5
275
zeol i tes, combi ned wi th potas-
si um permanganate or i ron ni trate, respecti vel y,
have been effi ci entl y uti l i zed i n deoxi mati on reacti ons
of ketones; l ower yi el ds were observed wi th al de-
hydes, probabl y due to the overoxi dati on processes.
Si l i ca gel has been more extensi vel y empl oyed
than cl ays and zeol i tes as heterogeneous support i n
performi ng oxi dati ve deprotecti on of ni trogenous
deri vati ves. A wi de number of oxi di zi ng reagents,
namel y ni trates,
276,224
chromates,
277-279
persul -
Figure 10.
Scheme 30
fates,
280,281
i odates,
282
chl ori des/O
2
,
283
and perchl or-
ates,
284
were reported to be effecti ve i n performi ng
the cl eavage. I n many cases, by usi ng mi crowave
i rradi ati on, the deprotecti on reacti ons occurred faster
and cl eaner;
285-294
i n fact, i t has been reported that
si l i ca gel , i n contrast to other cheap sol i d materi al s,
i s a good mi crowave conductor.
285
Chl orochromates,
295-299
fl uorochromates,
300
and per-
manganates
301
i n combi nati on wi th al umi na have
been uti l i zed for the regenerati on of carbonyl com-
pounds from semicarbazones, hydrazones, and oximes.
The reacti ons showed general appl i cabi l i ty for both
al dehyde and ketone deri vati ves, i ncl udi ng camphor
and benzophenone.
Concerni ng a more real i sti c heterogeneous catal y-
si s i n the deprotecti on reacti on of ni trogenous deri va-
ti ves, Bal l i ni et al . reported the use of the fami l i ar
sol i d aci d Envi rocat EPZG for the sel ecti ve regenera-
ti on of ketones from thei r tosyl hydrazones carri ed out
i n acetone/water. The reacti on seems to i nvol ve a
hydrol yti c transfer of the protecti ve group to acetone.
Al dehyde tosyl hydrazones were l ess reacti ve, even
after l ong reacti on ti mes, and these resul ts suggested
that the procedure coul d be empl oyed for the sati s-
factory regenerati on of ketone i n the presence of both
ketone and al dehyde tosyl hydrazones, as reported i n
Scheme 31.
302
A qui te si mi l ar strategy has been
appl i ed wi th the use of l ayered zi rconi um sul fophenyl
phosphonate.
303
The same deprotecti on reacti on was reported by
Varma et al . to occur i n the presence of ammoni um
persul fate adsorbed on montmori l l oni te K10 under
the i nfl uence of mi crowaves.
304
The authors sug-
gested the mechani sm reported i n Scheme 32.
Ammoni um persul fate, i n the presence of the water
adsorbed on the cl ay, generates O
2
and NH
4
HSO
4
;
the HSO
4
-
speci es i s responsi bl e for the oxi dati ve
cl eavage of the hydrazone. I t i s remarkabl e that i n
the absence of mi neral supports, the attempted
cl eavage of semi carbazones fai l ed wi th ammoni um
persul fate under both mi crowave and ul trasoni c
i rradi ati on condi ti ons, even after prol onged reacti on
peri ods. The cruci al rol e of the aci di c cl ay i s al so
probabl y ascri babl e to the acti vati on of the carbon-
ni trogen doubl e bond through protonati on.
A sol i d catal yst l argel y uti l i zed i n oxi dati ve reac-
ti ons, ti tani um si l i cate mol ecul ar si eves (TS-1), has
been cl ai med to catal yze the oxi dati ve cl eavage of
vari ous tosyl hydrazones to the parent al dehydes and
ketones i n moderate to good yi el ds. The method i s
parti cul arl y conveni ent si nce di l uted hydrogen per-
oxi de i s uti l i zed as an oxi di zi ng reagent.
305
The
authors descri bed the catal yti c cycl e reported i n
Scheme 33, where the cl eavage of the carbon-
ni trogen doubl e bond was attri buted to the presence
of randoml y di stri buted Ti
4+
i ons i n the l atti ce.
The speci es 23 present on the surface of the
catal yst fi rst reacts wi th H
2
O-H
2
O
2
, l eadi ng to the
peroxo speci es 25 vi a an i ntermedi ate hydroxy-
peroxy ti tani um compl ex 24. Thi s speci es i s respon-
si bl e for the formati on of the unstabl e oxazi ri di ne 27
from tosyl hydrazone 26, whi ch decomposes, affordi ng
the ketone 28 and restori ng the catal yst.
6. Amino Protecting Groups
Ni trogen protecti on conti nues to attract a great
deal of attenti on i n a wi de range of chemi cal fi el ds,
such as pepti de, nucl eosi de, pol ymer, and catal yst
l i gand synthesi s. Moreover, i n recent years, a number
of ni trogen-protected groups have been used as chi ral
auxi l i ari es. Thus, the desi gn of new, mi l der, and more
effecti ve methods for ni trogen protecti on sti l l i s an
acti ve topi c i n syntheti c chemi stry.
6.1. Protection
Among the di fferent means for protecti on of the
ami no groups, acyl ati on has recei ved the greatest
attenti on, and i t i s a very i mportant transformati on
al so from an i ndustri al poi nt of vi ew. The use of aceti c
aci d rather than aceti c anhydri de or acetyl chl ori de
i s both economi cal l y and envi ronmental l y advanta-
geous, produci ng onl y water as a byproduct i nstead
of aceti c aci d or hydrochl ori c aci d.
A few such procedures have been devel oped over
the past decade (Tabl e 27, entri es 1-3). Kul karni et
al . (Tabl e 27, entry 1)
306
reported that al kyl , aryl , and
heterocycl i c ami nes were converted to the corre-
Scheme 31
Scheme 32
spondi ng acetami des wi th aceti c aci d over Y zeol i te
(SAR ) 5.2). No l eachi ng of al umi num or si l i con was
observed. Aryl ami nes reacted faster than al kyl -
ami nes. The authors al so observed a sel ecti ve acy-
l ati on of an ami no group i n the presence of a hydroxy
group (Scheme 34).
Y zeol i te can al so be used for the same transforma-
ti on usi ng mi crowave acti vati on (Tabl e 27, entry 2).
307
The reacti on i s si mpl e, produci ng no toxi c byproducts.
I t i s appl i cabl e to a vari ety of saturated and unsatur-
ated ami nes. Yi el ds are much l ower wi thout mi cro-
wave i rradi ati on.
Acyl ati on of an ami no group has al so been per-
formed at room temperature usi ng Nafi on i n the
presence of a methyl ene chl ori de sol uti on of the
ami ne and aceti c aci d (Tabl e 27, entry 3).
45
Scheme 33
Table 27. Protection of Nitrogen-Containing Functional Groups
a
Scheme 34
Ami no groups coul d al so be acyl ated wi th aceti c
anhydri de i n sol ventl ess condi ti ons usi ng FER zeol i te
26
The mi l dness of the method i s
evi dent by the retenti on of confi gurati on of the chi ral
center. The system tol erates other aci d-sensi ti ve
functi onal i ti es.
Modi fi ed al umi na has been used by Yadav et al .
as a sol i d-phase catal yst to prepare acetami des. I t
was reported that KF over neutral Al
2
O
3
coul d
promote the acyl ati on of al i phati c and aromati c
ami nes (Tabl e 27, entry 5).
38
I n thi s case, aceti c
anhydri de was superi or to acetyl chl ori de. Under
these condi ti ons, al i phati c ami nes such as tert-
butyl ami ne reacted very qui ckl y, affordi ng the cor-
respondi ng ami de. As expected, aromati c ami nes
carryi ng el ectron-wi thdrawi ng groups (e.g., 4-ni troa-
ni l i ne, 4 h) reacted more sl owl y than other aromati c
ami nes (e.g., 4-chl oroani l i ne, 6 mi n). A rate enhance-
ment was observed when the reacti on was run
wi thout any sol vent. Under these condi ti ons, 4-ni -
troani l i ne afforded the correspondi ng acetani l i de i n
onl y 15 mi n.
Aceti c anhydri de and pyri di ne over basi c al umi na
have been used as sol i d catal ysts to carry out acety-
l ati on of al i phati c, aromati c, and heterocycl i c ami nes
under sol vent-free condi ti ons and mi crowave i rradi a-
ti on (Tabl e 27, entry 6).
36
Si gni fi cantl y l ower yi el ds
were obtai ned usi ng oi l -bath heati ng rather than
mi crowave i rradi ati on. The aceti c aci d byproduct
remai ned adsorbed on the al umi na, and i t was not
rel eased i nto the atmosphere. The authors suggested
that thi s rate enhancement coul d be expl ai ned by the
mi crowave stabi l i zati on of the di pol e formed i n the
transi ti on state (Scheme 35).
Pol ymer-supported 1-hydroxybenzotri azol e [(P)-
HOBT] (Fi gure 11) from macroporous SM-2 pol ysty-
rene beads was used by Kal i vretenos et al . for the
preparati on of vari ous ami des from carboxyl i c aci ds
and pri mary and secondary ami nes. The method
effi ci entl y gave ami des i n hi gh yi el ds and puri ty. I n
contrast to Merri fi el d resi ns, SM-2 beads do not swel l
or contract and can thus be used i n a vari ety of
sol vents, i ncl udi ng water (Tabl e 27, entry 7).
308
I mi des were prepared from the correspondi ng aci d
anhydri des and ami nes usi ng a base-free and sol vent-
free procedure (Tabl e 27, entry 8).
309
Thi s methodol -
ogy made use of tantal um pentachl ori de supported
on si l i ca as catal yst, whi ch was admi xed thoroughl y
to the reagents adsorbed on acti vated si l i ca gel . The
mi xture was then i rradi ated i n a mi crowave oven for
5 mi n. Thi s procedure has proven to be superi or i n
the preparati on of mal ei mi de deri vati ves, and l ess
reacti ve succi ni c and gl utari c anhydri de coul d be
converted to the correspondi ng i mi des. The mi l dness
of the method was proven by the retenti on of opti cal
puri ty observed i n the preparati on of (+)-(R)-R-
methyl benzyl ami ne mal ei mi de (Scheme 36).
N-Al kyl ati on was used as a protecti ve method for
ni trogen, especi al l y when benzyl groups are i ntro-
duced. I n thi s regard, cesi um fl uori de supported on
Cel i te coul d be used as the sol i d base to accompl i sh
the reacti on. I n thi s way, Bayer et al . benzyl ated
ani l i nes, carboxami des, and heterocycl i c compounds
at the ni trogen i n acetoni tri l e (Tabl e 27, entry 9).
310
When pri mary ami nes were reacted, sati sfactory
sel ecti vi ti es of the monobenzyl ated product coul d be
obtai ned. The authors reported that Cel i te/CsF was
l ess reacti ve than potassi um and tetral kyl ammoni um
fl uori des and requi red l onger reacti on ti mes. On the
other hand, i t i s easi er to handl e and cheaper.
The same benzyl ati on coul d be obtai ned, i n certai n
i nstances, i n the gas phase at ca. 300 C, usi ng benzyl
al cohol as the al kyl ati ng agent and -al umi na as the
catal yst (Tabl e 27, entry 10).
311
The al cohol served
al so as the di l uent (al cohol /ami ne rati o of 20/1 was
used), and the onl y byproduct was water. Benzyl ati on
of benzyl ami ne wi th benzyl al cohol afforded the bi s-
al kyl ated product i n 78% yi el d.
The sol vent-free preparati on of al di mi nes and
enami nes was achi eved usi ng montmori l l oni te K10
cl ay. Equi mol ar amounts of carbonyl compound and
pri mary or secondary ami ne were added wi th the cl ay
i n an open gl ass contai ner and i rradi ated i n a
mi crowave oven for a few mi nutes (Tabl e 27, entry
11).
312
Thi s method afforded the products qui ckl y (oi l -
bath heati ng, reacti on ti mes of a few hours) and
avoi ded the use of sol vents for azeotropi cal removal
of water. Other functi onal groups, such as phenol s,
phenol ethers, and terti ary ami nes, were unaffected.
A sol vent-free preparati on of N-deri vati ves of
N-aryl pi perazi ne usi ng si l i ca as the sol i d support and
mi crowave i rradi ati on was reported by Wi l l i ams
313
The method coul d be used to
prepare N-sul fonyl , N-acyl , and N-benzyl deri va-
ti ves of pi perazi nes. I t was si mpl e, hi gh-yi el di ng, and
afforded products wi th hi gh puri ty. The si l i ca gel
support al so removed al l the hydrochl ori c aci d formed
i n the reacti on, and no aci d scavenger was needed.
The reacti on parameters were i ni ti al l y opti mi zed by
i rradi ati on of reagents supported on gl ass-backed
TLC si l i ca pl ates, thi s techni que bei ng appl i cabl e to
a combi natori al preparati on of such deri vati ves.
6.2. Deprotection
The tert-butoxycarbonyl group sti l l i s one of the
most popul ar ami no protecti ng groups. The most
common method for i ts removal i s the use of tri fl uo-
Scheme 35
Figure 11.
Scheme 36
roaceti c aci d ei ther neat or i n di chl oromethane sol u-
ti on. Other mi neral aci ds or Lewi s aci ds have al so
been used, al though l ess frequentl y. Methods based
on sol i d catal ysts have been devel oped onl y recentl y.
I n the course of a preparati on of i ndol e-3-aceti c
aci ds, any attempted N-Boc deprotecti on under the
usual condi ti ons was unsuccessful , affordi ng mai nl y
l arge amounts of resi nous materi al s. Adsorbi ng the
reagent onto si l i ca gel and keepi ng i t at 50 C under
reduced pressure cl eanl y afforded the free i ndol e
314
When the reacti on was per-
formed at atmospheri c pressure, onl y trace amounts
of the product coul d be detected after 24 h. The
method was l ater appl i ed to the deprotecti on of
N-Boc-protected ani l i nes and i ndol es (Tabl e 28, entry
2).
315
An i nteresti ng sel ecti vi ty was noted for the
deprotecti on of Boc groups attached to ani l i ne, i ndol e,
or i mi dazol e ni trogens over Boc groups attached to
al i phati c ami nes (Scheme 37).
Montmori l l oni te K10 and kaol i ni ti c cl ays were
found by Bedekar et al . to be effecti ve catal ysts i n
the removal of aromati c N-Boc groups (Tabl e 28,
entry 3).
316
The method worked on chl oro-, ni tro-,
methoxy-, and hydroxy-substi tuted aromati c ami nes
and was compati bl e wi th a seri es of other functi on-
al i ti es, such as acetal s. A cl ean sel ecti vi ty for aro-
mati c ami nes over al i phati c ones was observed
(Scheme 38).
A sol vent-free deprotecti on of N-Boc-protected
ami des and ami nes was achi eved by i rradi ati ng wi th
mi crowaves the si l i ca gel -adsorbed substrates. Thi s
methodol ogy turned out to be noti ceabl y cl eaner and
faster than deprotecti on wi thout mi crowave i rradi a-
ti on (Tabl e 28, entry 4).
317
Thi s method was ex-
tremel y mi l d and, avoi di ng aci di c condi ti ons, i t was
compati bl e wi th a seri es of aci d-sensi ti ve groups,
such as si l yl ethers (Scheme 39).
Modi fi ed si l i ca gel was al so used for the same
deprotecti on. Thus, Si O
2
/Yb(OTf)
3
promoted the ther-
Table 28. Deprotection of Nitrogen-Containing Functional Groups
Scheme 37
Scheme 38
Scheme 39
mal deprotection of N-Boc carboxamides under solvent-
free condi ti ons (Tabl e 28, entry 5).
318
N-Benzyl oxy-
carbonyl (N-Cbz) or N-Boc ami no groups di d not react
under these condi ti ons. The reacti on i n the presence
of an organi c sol vent under heterogeneous condi ti ons
took a l onger ti me than the sol vent-free methodol ogy.
Thi s procedure l eft esters, ketones, and cycl i c acetal s
unaffected.
Li et al . reported an effi ci ent deprotecti on of the
N-p-tol uenesul fi nyl group of -branched Bayl i s-
Hi l l man adducts wi th the use of Amberl i te I R-120
(pl us) i on-exchange resi n (Tabl e 28, entry 6).
319
The
deprotecti on of these substrates i s parti cul arl y i n-
teresti ng si nce i t affords free R-al kyl i dene -ami no
aci d esters, whi ch are empl oyed i n the preparati on
of -l actam anti bi oti cs, pepti domi meti cs, and other
bi ol ogi cal l y i mportant mol ecul es.
320-323
Another i n-
teresti ng feature of thi s procedure i s that at the end
of the reacti on, the product remai ns adsorbed on the
resi n. Thi s al l ows for a very easy puri fi cati on of the
ami no ester: the resi n i s thoroughl y washed wi th
methanol and then the product i s rel eased wi th 15%
NH
4
OH i n methanol overni ght. No racemi zati on was
observed duri ng the debl ocki ng, and N-Boc groups
remai ned unaffected. The authors suggest that the
true deprotecti ng agent was the methoxoni um i on
(MeOH
2
+
) generated i n si tu. The hypothesi s was
supported by the fact that thi s deprotecti on di d not
work i n other proti c sol vents.
I midazopyridine trifluoroacetamides could be mildly
deprotected by usi ng si l i ca gel (Tabl e 28, entry 7).
324
Al l attempts to perform thi s debl ocki ng usi ng basi c
condi ti ons such as NaOH or Huni gs base fai l ed,
l eadi ng i nstead to i mi dazo ri ng openi ng.
7. Concluding Remarks
The preparati on of compl ex organi c mol ecul es
demands the avai l abi l i ty of di fferent protecti ve groups
to al l ow the survi val of reacti ve functi onal groups
duri ng the vari ous syntheti c operati ons, fi nal l y re-
sul ti ng i n the sel ecti ve producti on of the target
mol ecul e.
As shown i n thi s revi ew, a l arge number and
extreme di versi ty of heterogeneous catal ysts have
been uti l i zed i n the fi el d of protecti ve groups chem-
i stry duri ng the past decade. Thi s i s the consequence
of both the attenti on to envi ronmental l y fri endl y
methods of maki ng organi c compounds and the
conti nuous need for i mprovi ng the sel ecti vi ty i n
protecti ve groups chemi stry appl i ed to mul ti func-
ti onal mol ecul es.
Some of the catal ysts descri bed i n thi s revi ew are
commerci al l y avai l abl e, such as most of the cl ays,
zeol i tes, and metal oxi des; some others must be
expressl y prepared, such as the supported aci ds,
bases, and transi ti on metal compl exes. Obvi ousl y, the
appl i cati on of heterogeneous catal ysi s i n organi c
synthesi s makes the reacti on handl i ng easi er wi th
speci al attenti on to product puri fi cati on. A further
advantage i s represented by the possi bi l i ty of per-
formi ng reacti ons under sol ventl ess condi ti ons and
i n very short ti mes under mi crowave i rradi ati on.
Many exampl es of hi ghl y sel ecti ve protecti on of
mul ti functi onal mol ecul es have been reported wi thi n
the revi ew, and i n some cases they are assumed to
be promoted by a synergi c contri buti on of the cata-
l yti c si te and some speci fi c surface pecul i ari ti es, such
as the pol ari ty, hydrophobi ci ty, hydrophi l i ci ty, and
pore di mensi on, i n a way resembl i ng the enzymati c
catal ysi s.
However, sti l l more questi ons remai n, especi al l y
concerni ng the nature of the catal yti c si tes and thei r
i nteracti on wi th reactant and sol vent mol ecul es i n
order to rati onal i ze the catal yti c acti vi ty and to
achi eve the opti mum performance. Moreover, al -
though theoreti cal l y al l the heterogeneous catal ysts
coul d be recovered from the reacti on mi xtures si mpl y
by fi l trati on and reused, thi s aspect has been scantl y
taken i nto consi derati on. I n fact, the catal yst reus-
abi l i ty was veri fi ed i n onl y about 20% of the ci ted
papers.
Thi s presentati on and di scussi on hi ghl i ghts a
growi ng fi el d where the i nterdi sci pl i nary cooperati on
between syntheti c organi c chemi stry, physi cal chem-
i stry, and anal yti cal chemi stry has made i t possi bl e
to obtai n i nteresti ng and promi si ng resul ts i n protec-
ti ve group chemi stry.
8. Acknowledgments
The authors thank the Consorzi o I nteruni versi tari o
Nazi onal e La Chi mi ca per l Ambi ente (I NCA) and
the Mi ni stero del l I struzi one, del l Uni versi ta` e del l a
Ri cerca (MI UR) for fi nanci al support.
9. Abbreviations
ATPB acetonyl tri phenyl phosphoni um bromi de
BTSC bi s(tri methyl si l yl )chromate
BTSE 1,2-bi s(tri methyl si l yl oxy)ethane
Bz benzoyl
DCKA di cyanoketene acetal
DHP 3,4-di hydro-2H-pyran
DMC di methyl carbonate
DMD 2,2-di methyl -1,3-di oxol ane
DMTr di methoxytri tyl
EE 1-ethoxyethyl
Fmoc 9-fl uorenyl methoxycarbonyl
HMDS 1,1,1,3,3,3,-hexamethyl di si l azane
MME 1-methyl -1-methoxyethyl
MMTr monomethoxytri tyl
MPM methoxyphenyl methyl
MW mi crowave
NAP 2-naphthyl methyl
SAR si l i ca/al umi na rati o
SEM 2-(tri methyl si l yl )ethoxy methyl
TES tri ethyl si l yl
THP tetrahydropyranyl
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Protection (and Deprotection) of Functional Groups in Organic Synthesis by

and Paolo Righi

Di parti mento di Chi mi ca Organi ca e I ndustri al e del l Uni versi ta`.

Di parti mento di Chi mi ca Organi ca A. Mangi ni del l Uni versi ta`.

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