Terrahedron.

PII: SOO40-4020(96)009 1 l-8

Vol. 52, No. 48, pp. 15031-15070, 1996 Copyright 0 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0040.4020/96 $15.00 + 0.00

TETRAHEDRON

REPORT NUMBER

410

Recent Progress in the Synthesis of 1,2,3,4=Tetrahydroquinolines

Alan R. Katritzky,* Stanislaw Rachwal, and Bogumila Rachwal Center for Heterocyclic Compounds, Lkpurtment of Chemistry,
University of Florida, Gainesville FL 3261 l-7200

Contents
Introduction 1a. Scope of this review lb. Tetrahydroquinolines lc. Other applications 2. From Unsaturated as natural and pharmaceutical of tetrahydroquinolines Ring products 15032 15032 15032 15033 15034 15034 via 15036 15039 15041 15041 I5043 15045 15047 15048 system 15051 15053 from Aniline Imines 15054 I5055 15056 Fragment 15057 15058 15059 15031

to Saturated Heterocyclic

2a. Reduction of the heterocyclic 2b. Conversions

ring in quinolines

of quinolines to 1,2,3,4-tetrahydroquinolines

1,2-dihydroquinolines 2c. Derivatization 3. Heterocyclic of 1,2,3,4-tetrahydroquinolines bond bond

Ring Synthesis by Closure of One Bond

3a. Formation of the N-(Cl)

3b. Formation of the C(4)-C(4a) 4. 5. Condensations

of Anilines with Two Molecules of an Aldehyde Cations with Olefins

Reactions of N-Aryl Methyleneiminium 5a. Benzotriazole methodology

5b. Other groups X in the ARNCH,X 5c. Oxidation of N-methylanilines 6. Preparation of 2-Substituted

Tetrahydroquinolines

6a. Reactions of Schiff bases 6b. Aniline alkylimines I. 8. 9. Preparation by Insertion of a C(2)-C(3) Ring Contraction Summary and Ring Expansion

15032

A. R. KATRITZKY et al.

1. Introduction

la. Scope of this Review Rapid recent developments and classify all their major in the chemistry of 1,2,3,4-tetrahydroquinolines synthetic methods currently in use. has prompted this report 2-0x0-, us to review to 1,2,3,4-

We restrict

tetrahydroquinolines

in which the C-2, C-3, and C-4 atoms are all sp hyhridized. (classiiied as such by Chemical Abstracts)

4-0x0-, and 2,4with one and quite

dioxo-1,2,3,4-tetrahydroquinolines

and related compounds

or more sp* carbon atoms form a large group of quinoline derivatives distinct synthetic methods: they are considered

with their own properties

here only if they are used in the synthesis

of saturated

tetrahydroquinolines.

This review is intended to cover the literature of the last ten years,

1986-95.

lb. Tetrahydroquinolines

as Natural and Pharmaceutical

Products is due to their biological activities. Several of these is present in human brain.

The greatest interest in 1,2,3,4-tetrahydroquinolines compounds are naturally occuring.

2-Methyl- 1,2,X4-tetrahydroquinoline

Discohahdin C, a polycyclic system based on tetrahdyroquinoline,

is a marine alkaloid.27 Dynemycin, a natural system.x. The 2,4,6trisuhstituted and

antitumor untihiotic, has a complex structure built on the tetrahydroquinoline tetrahydroquinoline 1, isolated from Martinella iquitosensis, and muscarinic receptors.

exhibits activity as a hradykinin antagonit

with cr-adrenergic, histaminergic,

Many relatively simpt

synthetic of 1,2,3,4-tetrahydroquinolines

are already used or have kn nicainoprol(3),

tested as

potential drugs. Among them, oxamniquine (2), a schistosomicide,~

an antiarrhytmic drug,t7L-6X9.560 (5) is one of

and virantmycin (4) a novel antihioticz2*24 are the best known. Tetrahydroquinoline the most potent NMDA antagonists yet found.z5-2

2, oxamniquine

iI

3, nicainoprol

kNJJ

Synthesis of I ,2,3,4-tetrahydroquinolines

15033

4, viratmycin

5, L-689,560

Hundreds biochemial

of tetrahydroquinolines

bearing

various

simple

or complex

substituents

have

interesting 2-methyl-S1,2,3,4are I

activity; some are potential

pharmaceutical

agents. Thus, a very simple derivative,

hydroxy-1,2,3,4-tetrahydroquinoline, Tetrahydroquinoline-4-carboxylic potent inhibitors converting

exhibits analgestic

activity one eighth as potent as morphine.

acid is used in tissue irrigating solutions.s4 triphosphatase,

Some tetrahydroquinoliues oxidase, angiotensin

of (H+K+) adenosine lipoxygenase,3

blood serum monoamine

enzyme,7

lipid peroxidation.Y bone resorption,4 are antagonists

leukotriene

synthesis4142 and

bacterial dihydrofolate receptor,

45

reductase.43 Other tetrahydroquinolines or agonists of dopamine potent

of vasopresin,44 adrenergic cl,are potential inotropic,54

and

ca1cium,46 nervous

D2. 47,4x Tetrahydroquinolines

antidepressants4 antithrombotic,s56 anticonvulsant, the glycine myotilament

system depressants,

antiu1cer,5.2 cardiovascular,s3 antirheumatic, are recognized

positive

antiarrhytmic,s7

antiaIlergenic,5R

antitumor,

immunosuppressant,.62 as high uffiiity ligands at transmissions,

66.67

or antifertility64 agents. site of the NMDA sensitizers

Some tetrahydroquinolines other as facilitators loadirgh*

receptor,

of noradrenergic

or

without affecting cell Ca

In this group are also promising drugs for the

treatment of cerebra1 ischemia6 and osteoporosis7

lc Other Applications Besides antioxidants,

of Tetrahydroquinolines applications, tetrahydroquinoline derivatives are useful as pesticides,7-7s is a specific

pharmaceutical
76-70

and corrosion inhibitors.* 2,2,4-Trimethyl-S-hydroxydetermination

1,2,X4-tetrahydroquinoline

reagent for photometric

of iron(II1) salts. Tetrahydroquinolines

are used as active components

in various types of dyes: for hair,x2 for acrylic tibers,Rs4 for polyesters,x5.w and for polyamides.x7~xx (28)-2,6Dimethyl-1,2,3,4-tetrahydroquinoline properties. Tetrahydroquinoline transporting sensitive derivatives are also widely used in modern photoconductors,n recording technologies: as chargewas used in synthesis of china1 polymethine dyes with interesting optical

agents for electrophotographic as antiirradiation media,0

as tuco

dyes for thermal and pressure of optical for colored

materials,7-0 recording

filter dyes in photography, J~ in the preparation for photographic couplers,K as dyes

information

as intermediates

electrostatographic

toners,io7 and as high sensitivity photosensitizers

in photography.s

15034

A. R. KATRITZKY et al.

2. From Unsaturated

to Saturated Heterocyclic Ring

2a. Reduction of tbe Heterocyclic Ring in Quinolines

&spite

the recent availability of many alternations direct reduction Hydrogenation of the heterocyclic

(see below), when the appropriate

quinolines

are of

easily accessible,

ring can still he the hest option for the preparation

tetrahydroquinolines. tetrahydroquinolines hy conversion of

over platinum is a common approach, 4R.lW-z which gives high yields of substituents (6a) and on the heterocyclic ring, as is illustrated (fib)

when there are electron-withdrawing methyl quinohne-2-carboxylate

quinoline-2-carhaldehydeLL4

to

tetrahydroquinolines

7a and 7b, respectively.

Hydrogenation

of quinaldinic

acid over platinum dioxide in pressure.:.

methanol proceeds well under very mild conditions, at room temperature and under atmospheric

R 6a. R = CC&Me 6b, R = CHO

R ti 7a, R = C&Me (92%) 7b, R = C&OH (95%)

Electron-donor

groups at C-3 have practically no effect on the hydrogenation

(conversion

of Sa to 9aX5 of 8b to

and 10 to 1147), whereas even a methyl group at C-4 retards the reaction dramatically 9b3).

(conversion

6a, R 1 = 3-Me, Bb, R 1 = 4-Me,

# = CH*OH R2 = C&OH

9a. R 1 =3-Me, w = C&OH 9b, R 1 = 4-Me, R2 = CbOH

(90%) (27%)

NHCHO

10

11(69%)

Other metal catalysts can also he used in the hydrogenation Thus, cobalt stearate in the presence of triethylaluminum

of quinolines to give tetrahydroquinolines. 2-methylquinoline (12) into 2-methyl-

converts

1,2,3,4-tetrahydroquinoline carbon monoxide methylquinolines

(13) quite well.6 The use of rhodium complexes agent were considered

as a catalyst and of a mixture of for example,

and water as a hydrogenating 12 and 14 were hydrogenated

as a breakthroughs:

to tetrahydroquinolines

13 and 15 in high yields. 7~x

Synthesis of 1,2,3,4-tetrahydroquinolines

15035

12

13 (76%)

12, R = 2-Me 14, R = 4-Me

13, R = 2-Me i95%) 15, R =4-Me (91%)

To avoid pressure reactors, hydrogen transfer can be utilized. Thus, quinoline 12 is reduced efficiently to tetrahydroquinohne Nickel-aluminum 13 by mixing formic acid and triethylamine in the presence of a palladium catalyst. acids, as shown hy the

alloy is a convenient

agent in the reduction of quinolinecarboxylic

conversion of 16a, 16b, and 16c to 17a, 17b, and 17c, respectively.

COOH

13 (85%)

16a, Z-COOH 16b. 3-COOH 16c, 4-COOH

17a, 2-COOH (97%) 17b. 3-COOH (78%) 17c, 4-COOH (87%)

Alcohol-sodium

systems

have also been applied

but are less selective

in causing

reduction

of the

carbocyclic ring, thus for example

18 is reduced to a mixture of 19 and 20.2

k/J
18

f-

Na, n-BuOH w H 19

f-0 Nd
+ 20

r-0 Nd

(50%, isolated)

Alternatively, 14 to 15. However,

quinolines are reduced by borohydrides better results are obtained

under strongly acidic conditions,4

for example, of nickel

when borohydrides

are applied in the presence

dichloride, ),l, 2 as illustrated by the example of the conversion

Me Me

of 12 to 13.

Me

Me

15036

A. R.

&UFUTZKY

et al.

As shown above, reduction of the heterocyclic of 1,2,3,4-tetrahydroquinolines. their synthesis may outweigh used, e.g., conversion heterocyclic

ring of quinolines is a simple method for the preparation

However, when the starting quinolines have to be prepared, the complexity of the simplicity of the reduction step. Although such approaches are still widely of the saturated can

of aniline 21 to tetrahydroquinoline

23 via quinoline 22,4 construction

ring of 1,2,3,4-tetrahydroquinolines

from building blocks containing the desired suhstituents

frequently provide a hetter alternative.

Cl POW*

k 0 N2H4 NHNH, (78%) HCHO HC02H Ye -

(98%) (94%)

2b. Conversions Strong

of Quinolines add can

to 1,2,3,4-Tetrahydroquinolines readily k to the C=N upon hond

via 1,2-Dihydroquinolines of quinoliies reduction providing to 2-substituted 1,21,2,3,4-

nucleophiles which

dihydroquinolines, tetrahydroquinolines. reduced

converted

subsequent

2-suhstituted

Thus, the reaction of quinoline with hutyllithium gives dihydroquinoline (25) in excellent yield.42.4 Reaction

24, which is then of quinoline with

to 2-hutyl-1,2,3,4-tetrahydroquinoline

ethylmagnesium

hromide followed by methyl chloroformate

gives dihydroquinoline

26, which is then reduced

to tetrahydroquinoline nucleophiles,

27.12 Q ua t ernization of the nitrogen atom of yuinoline allows the attack of even weaker

as it is illustrated hy the preparation of 29 via 28.*

24 (97%)

25 (96%)

Synthesis

of 1,2,3,4-tetrahydroquinolines

15037

:I 0

\
/
Et &Me 27 (92%) CHCl3 /NaOH CCI, tie 28 (66%) 29 (6%) H2, Pd/C * CCI,

In some instances, the addition does not stop on 1,2-dihydroquinolines, the heterocyclic organohoron ring becomes saturated. Reactions with an organosilicon

but the process continues until

reagent27 (30 and 31) and with an

reagents

(32) depicted below illustrate such cases.

MegSiCI, Li THF SiMe, 30 (40%)

A
32 (40%)

Reduction tetrahydroquinolines.

is not

the

only

method

for

the conversion

of

1.2-dihydroquinolines

into

1,2,3,4-

The C(3)-C(4)

bond of 1,2-dihydroquinolines

has the typical properties

of an electron

rich double bond which allows a wide range of addition reactions. Thus, hromination 34.12 Formation assigned. of dihydroquinoline

These additions are usually stereospecific.

33 in methanol yields the pentasuhstitutcd of 34 was reported; with NBS however,

1,2,3,4-tetrahydroquinoline
the stereochemistry dihydroquinoline was not 35 into

of only one stereoisomer example,

In another

hromination

in water

converts

tetrahydroquinoline tetrahydroquinoline tetrahydroquinoline

Me

36.13 38. systems.

m-Chloroperknzoic These additions

acid converts enable the

dihydroquinoline of

37 into epoxy-1,2,3,4substituted 1.2,3,4-

preparation

highly

33

35 34 (60%)

36 (99%)

15038

A. R. KATRITZKY et al.

m-CPBA

, / b 37

NOz

\ , b
40 derivative 41, which

N4

38 (70%)

Sodium

cyanohorohydride 39) to

reduces give

3,4-dichlorotetrahydroquinoline

(obtained the

hy chlorination high lability of

of a

dihydroquinoline tetrahydrnquinoline

monochloro

illustrates

suhstituent at C-4.24

1,2_Dihydroquinolines synthetic routes besides

suitahle for conversion nucleophilic additions

to tetrahydro to quinolines.

analogs can he obtained Cyclocondensation-additions

on several other of anilines to

alkynes are the most common.

Thus, alkylation of p-toluidine

with dimethylpropargy?

chloride gives the Nto dihydroquinoline

propargyl derivative 42, which in the presence of a cuprous chloride catalyst is converted 43. Conversion of the aniline derivative 44 to dihydroquinoline

45 is another such synthesis.

Me0 CICMe&=CH NH, w

Me0

42

HCSCOMe

Synthesis

of 1,2,3,4-tetrahydroquinolines

15039

A further method involves reactions of anilines with a&unsaturated an example, condensation gives aminoalcohol of N-methylaniline with cinnamaldehyde

carhonyl compounds.

As

in the presence of phenylhorun 47.?*

dichloride

46, which is then cyclized to dihydroquinoline

OH PhCH=CHCHO PhBCh

46

47 (57%)

2c. Derivatization

of 1,2,3,4-Tetrahydroquinolines and its simple alkyl derivatives can be used as sources for of 1,2,3,4-tetrahydroquinolines at C-2 is

Easily available 1,2,3,4-tetrahydroquincline more complex analogs. A well developed

method for derivatization

oxidation by hydrogen peroxide in the presence of sodium tungstate.34 hydroxamic acids 4Sa and 48b from 1,2,3,4-tetrahydroquincline hydroxamic acids thus ohtained can he easily

This is illlustrated hy formation of respectively. The

and its 4-methyl derivative, to the corresponding

converted

2-axo- 1,2,3,4-

tetrahydroquinolines

hy hydrogenation R

over a platinum catalyst. R H202, Na,W04

MeOH, H @a, 4&, r.t.

-ti

:I

N bH

R = H (84%) R = Me (83%)

Several treatment with

methods

of regioselectivc have been

lithiation developed.

of 1,2,3,4-tctrahydroquinolinls According to one of

on C-2 followed these methods, suhstituent

hy

electrophiles

1,2,3,4in these with

tetrahydroquinoline

is first converted

to a formamidine

derivative (4Y). The formamidine

derivatives plays hoth the rule, of an activating and a directing group. electrophiles gives 2-suhstituted 1-formamidinotetrahydroqumolines.

Lithiation of 4Y and

treatment

e.g. 50. Finally, the protection organozirconium

is removed

in a reaction with hydrazine to give tetrahydroquinoline milder reaction conditions preparation of compound (no need fur turf-hutyllithium), 51.tq7- 14

13.? Use of

reagents allows for as shown hy the

simplifying the whole procedure,

Me A

Me

15040

A. R.

KATFUTZKY

et al.

* Cp&?!rMeCI A

BuLi

PrcECPA

q+
51 (85%)

In another approach,14 tetrahydroquinoline consecutive treatment

is converted

to its lithium carbamate

derivative

52 by

treatment with hutyllithium and carbon dioxide. In the following step, carhamate 52 is lithiated by with tert-butyllithium, and finally subjected to a reactions with clectrophiles to give suhstituted giving, e.g.,

1,2,3,4-tetrahydroquinolines; compound 53b

it was originally thought

that lithiation occurcd

at the 2-position

from a reaction with cyclohexanone,41

but it has since been shown that the lithiation takes

place at the 4-position

and that 53a is the correct structure of the product.4h

1) BuLi
iiT J$ %

kO,Li 52

A 53a (55%)

A 53b

Biochemical on
~_4.42,14

oxidation of tetrahydroquinolines

by the fungus Cunninghamclla

elegans occurs exclusively

Conversions

of 54 to a mixture of 55 and 56, and of 57 to a mixture of 58 and 59 illustrate such

biochemical derivatization

oxidation. Contrary to the ahove methods, a reaction with elemental sulfur allows for simultaneous at C-l and C-4; thus, converting tetrahydroquinoline 60 into the tricyclic dihydroquinoline

derivative 61.44

Cunninghamella elegans )

OH

0 +

ti

:I

PhAO 56

Cunninghamella elegans b

Me

Me

Me

.Me

OH

59

Synthesis

of 1,2,3,4-tetrahydroquinolines

15041

Me

S
MeA Me

Me

ti

:I
A
60

Me

03
:I
k
61 (47%)

s, S
Me Me

3. Heterocyclic Ring Synthesis by Closure of one Bond

Very often, by constructing

desired substitution

of the heterocyclic

ring in tetrahydroquinolines,

is more simply achieved ring

this ring from smaller fragments than from the corresponding in many ways.

quinoline. The heterocyclic

can he constructed

3a. Formation of the N-(Cl) Bond In general, N-C bond formation ortho-substituted is one of the simpler tasks in organic synthesi to the corresponding and, if appropriately is easy.

anilines are available, cyclization

1,2,X4-tetrahydroquinolines

Convenient syntheses of 2-aminochalcones45 aryl-1,2,3,4-tetrahydro-4-quinelines.

makes them attractive starting materials for the preparation of 2(62) is converted to 2-(4acid.14

In a given example, 2-amino-4-methylchalcone

methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline The carhonyl group of 63 can be subjected substitution on C-4.47 Bromination

(63) in a cyclization process catalyzed by phosphoric to reduction and addition reactions providing

a wide range of of the on

of the double hand of chalcone 64, followed hy cyclocondensation

bromo derivative 65 in methanolic sodium hydroxide, leads to a tetrahydroquinoliie c-3 (66).14

additionally substituted

62

63 (65%)

0
Br,

Br Ph NaOH MeOH

Me0

OMe

AC 64

AC 65

AC 66 (25%)

15042

A. R. KATRITZKY et al.

A 3C linkage at the Thus, hromination yields derivative hydroxide

ortha

position of aniline can be constructed

by the addition of 1C and 2C fragments. with diethyl malonate with sodium

of the toluidine derivative 67 with NBS followed by condensation 68, which is then cyclized reduction to 2-oxotetrdhydroquinoline

69 upon treatment

in ethanol.47 Subsequent

with lithium aluminum hydride eliminates

the 2-0~0 function

giving 3-aminotetrahydroquinoline Me

70 in good yield.47

(n-Pr)pNCH(C02Et)p NAc, OMe 67 NBS, CC& OMe 66

COOEt

_)

N(n-Pr), NaOH ) EtOH 69 (56%) 70 (66%) LiAIH4

In another example, the 3C linkage (in 72) is constructed with 71. In the next step, catalytic reduction

onto 2-nitrohenzaldehyde

in a Wittig reaction to an amino group

on palladium, the nitro group ti reduced

followed hy cyclization to give derivative 73.4R When the hydrogenation and atmospheric temperature pressure, compound 73 can he isolated

is carried out at room temperature mixture (94%). At elevated

from the reaction

and 40 atm of H,, the reaction does not stop on 73, which is then decarboxylated 74.14
EtO,C +
NO2

and reduced to

tetrahydroquinoline
CHO

Ph,P=HC 71

) toluene

THF

_
ortho

HP, P&C

40 atm, 90C NHCOPh 74 (71%)

In another approach, the

nitro group is added later, after the 3C linkage unit is already constructed, 76 is prepared hy nitration of 75 under mild conditions. from the amino group to

as shown in the example given.4 Nitro derivative Catalytic hydrogenation

of 76 reduces the nitro group and then removes protection 77. Methylation

give 2-oxo-tetrahydroquinoline reduced to

of the amino group at C-3 gives 78, which is con.secuGvely (23), a precursor of positive

6,7-dimethoxy-3-(dimethylamino)-l,2,3,4-tetrahydroquio~e

inotropic agents. This synthesis of 23 can he compared with the alternative approach, which proceeds through quinoline system 22.

Synthesis

of 1,2,3,4-tetrahydroquinolines

15043

75

76 (76%)

77 (91%)

76 (90%)

23 (28%)

The 3C linkage can he added in one step hy palladium catalywd iodoanilines. 4Y For example, the palladium intermediate 79, obtained

annulation

of 1,4-dienes using ortho of 2-iodoanihne (82), with

hy treatment

palladium acetate,

reacts with 1,Cpentadiene

to give 2-vinyl-1,2,3,4-tetrahydroquinoline

via 80 and

81. 4y

60

3b. Formation of the C(4) - C(4a) Bond

The high reactivity of the aniline orthn carbon atoms towards clectrophiles anilines with an N-alkyl group carrying compounds can be ohtained hy reactions an electrophilic center at the C-3 atom. allows easy cyclization of As shown bromide. Mow, such

of N-alkylidene~nilines

with allylmagnesium

In the first hromide, 1,2,3,4-

example, derivative 84, ohtained from the reaction of N-benzylideneaniline

(83) with allylmagnesium

(86)

undergoes sulfuric acid catalyzed cyclization to a mixture of cis (85) and trms tetrahydroquinolines.O In the second example, a mixture of tetrahydroquinolines 88, ohtained from N-cyclohexylidene-3methylaniline

4-methyl-2-phenyl-

89 and 90 is produced hy the (87).

cyclization of intermediate

CH2=CHC&MgBr @Ph
63 A 64 (78%)

I
predommant \
i6.

. .
&

minor ,

50%

15044

A. R. KATRITZKY et al.

Me

:I b8
87

Cb=CHCWp

&A%
99

q
. 99

+&%
90 , I:1 mixture

The concept preparation

is well

illustrated

by the synthesis

of tetrahydroquinoline

Y7, a key intermediate

in the

of antiulcer agents.51 In the first step, the hydroxy and the amino group in 2-(hydroxymethyl)as benzoxazine 91 by reaction with trichloromethyl chloroformate. The N-H lmnd of 91

aniline are protected

adds to methyl acrylate to give aminopropionate which undergoes cyclocondensation

92 in high yield. Hydrolysis of the ester function gives acid 93, acid to form 4-oxotetrahydroquinoline

in the presence of polyphosphoric

91

(74%)

92

(90%)

93 (92%)

94 (60%)

95 (79%)

96 (94%)

97 (64%)

system 94. Reduction

of the carbonyl group of 94 followed by methylation 97, via intermediates 95 and 96.

and deprotection

of the N-H and

OH functions leads to tetrahydroquinoline

Use of aldehydes or their derivatives in the cyclization step instead of carboxylic acids allows simplification of the procedure hy obviating reduction of the carbonyl group. Soft nucleophiles present in the

reaction mixture tend to substitute hard nucleophiles reactions. Comhination

at C-4, stabilizing the products and preventing side

of both these ideas was utilized in the work presented below. Thus, the derivative 98,

. 92% (6:l mixture)

Synthesis of 1,2,3,4-tetrahydroquinolines

15045

obtained in a reaction of 3-methoxyaniline with benzenesulfonyl benzene-sulfmate chloride, undergoes

with 3-iodopropionaldehyde first cyclocondensation,

diethyl acetal followed then a substitution

hy treatment with the

reaction

anion to give a mixture of tetrahydroquinolines

99 and 100 in high yield.

4. Condensations

of Anilines with Two Molecules of an Aldehyde.

As known stereochemistry crystallography report,

for over of the

one century,

anilines

react

with enolizahle produced

aldehydes.s3s4 was not known

However, until

the X-ray

4-hydroxy-1,2,3,4-tetrahydroquinolines became

and high field NMR spectroscopy and two molecules

widely available. Thus, according

to a recent

p-toluidine

of acetaldehyde

gives a mixture of the cis (101) and truns (102) in an approximate ratio of 1:2. The isomers by NMR methods.s and

isomers of 2,6-dimethyl-4-hydroxy-1,2,3,4-tetrabydroquinoline were separated by selective recrystallization,

and their stereochemistry

was assigned

Under a different set of reaction conditions glycolaldehyde crystallography give tetrahydroquinoline data.15

(1:l molar ratio and lack of acidic catalysis), N-methylaniline 103, the stereochemistry of which was assigned

based on X-ray

HCI-Hz0

L2MeCHo

2 tile

+ 2 HOW&HO

the 103 (45%) to product 103 is substitution of the 4-hydroxy group in the

The probable corresponding

mechanism

leading

4-hydroxytetrahydroquinobne

by excess N-methylaniline;

however other possibilities

cannot be

excluded. Thus, formation of a simiiar product, tetrahydroquinoline first, condensation of aniline with acetaldehyde

105, is explained by a two step process: cycloaddition of 104 to its enamine

to imine 104; second,

tautomer.ls7 The stereochemistry

of 105 was not reported. t-$,Jh

MeCHO / aL
' eMe

H+h

h
TiCh, k 104 105 (34%) Me

15046

A. R.

KATRITZKY

et al.

The detailed

mechanism

of such reactions

is discussed in a recent paper. gives imiiium salt 106. Addition cyclization

Thus, condensation

of N-

methylaniium propionaldehyde

perchlorate

with propionaldehyde aldehyde

of another molecule of 108. to

to 106 produces

107, which undergoes for 14 h, compound

to tetrahydroquinoline undergoing dehydration

Under the reactions,

refluxing in chloroform

10s is unstable

109 and then oxidation to quinolinium salt 110. Other aldehydes, unhranched producing homologs of 110with yields in the range of S-30%~.sx

at the or-position, react similarly

Me

108

109

110 (45%)

According tetrahydroquinoline

to our own

findings,

addition

of benzotriazole

to the reaction

mixture

stabilizes

the

system by suhstitution

with the benzotriazol-I-y1

or 2-yl moiety of the hydroxy group in

108, and in analogues obtained from other aldehydes.s

Thus, in the case of phenylacetaldehyde,

2 PhCH&HO benzotriazole *

\ R \,
N NN

an almost

NXH
the

p-TsOH

+
Me Ph 112 mixture of stereoisomers(lOO%)

* Me Ph

PhMgBr

LiAIHl

113 (90%)

Me Ph 114 (39%)

115 (78%)

quantitative yield of a mixture of stereoisomers 114 is separated hy recrystallization.

111 and 112 is achieved, from which the predominant moiety on C-4 of tetrahydroquinoline 114 can be

isomer

The benzotriazolyl

Synthesis of 1,2,3,4-tetrahydroquinolines

15047

relatively easily substituted 115.

hy strong nucleophiles,

as illustrated hy preparation of tetrahydroquinolines

113 and

Mixtures of isomers 116 obtained from reactions of N-methylaniline difficult to separate. (117a and llSa, However, the corresponding

with typical aliphatic aldehydes are 2,Zbdialkyltetrahydroquinolines are easily

pairs of diastereomeric

or 117b and 118b), ohtained

after reduction

with lithium aluminum hydride,

separated by column chromatography. 0t R LiAIH,_ :I dx, Y Me 116

Bt = benzotriazol-1 -yl or -2-yl

a; Lie R

q Lie R

117a, R = Me (45%)
117b, R = Pr (55%)

118a, R = Me (35%)
IlSb, R = Pr (33%)

Irradiation of a solution of a nitrobenzene corresponding

in ethanol, in the presence of titanium(N) (e.g., 119). via reduction

oxide, produces the of the nitro to the

4-ethoxy-2-methyl-1,2,3,4-tctrahydroquinnoline

amino group, oxidation of ethanol to acetaldehyde,

and subsequent condensation

of these reagents.

EtOH I TQ
350nm
NO2 * Me-Me + ON&

H 119 (71%)

minor

5. Reactions of N-Aryl Methyleneiminium

Cations with Olefins

This unsuhstituted

approach

allows

the

preparation

of

various

3,4-disuhstituted

1.2,3,4-tetrahydroquinolines cation 121

at C-2. The concept is to generate from an aniline derivative 120 a methyleneiminium attack on an oletii leads to an intermediate cation 122 and spontaneous rule, regioselectivity

which by electrophilic tetrahydroquinoline in the reaction

cyclization to is achieved

123. Because the addition step follows the Markovnikov

when the suhstituents

R2 and R3 differ significantly in their electronic character.

N
Al 120

pH2
RI x121

R&H=CHR3

aFR2

dR2

Al 122

Al 123

15048

A. R. KATRI'IZKY

etal.

5a. Benmtriazole Methodology The benzotriazolyl these reactions: substituent Bt (benzotriazol-l-y1 and/or -2-yl) is very advantageous and characterized, as group X in but also reactive

it renders derivatives

120 stable enough to be separated

enough to produce solutions.161 condensation

readily iminium cations 121. In practice, examples of such reactions,

species 120 and 121 coexist at equilihrium in derivative 125 (obtained readily hy

In two

diphenylamine

of diphenylamine

with formaldehyde

and knzotriazob)

reacts, with styrene to give 124 and

isoprene to give 126.162

Ph PhCH=CH* y Ph 124 (45%) flBt ;h 125 CH,=CHCMe=CH, LiBF, Ph 126 (60%)

The reaction proceeds derivative

even better when olefms are activated by a heteroatom63 Thus, N-methylaniline adduct 128 stabilized by the ethoxy group,

127 with ethyl vinyl ether yields an intermediate cyclization to 4-ethoxytetrahydroquinoline

eventually undergoing the reaction benzotriazole is stopped

129. Compound

129 can ht: isolated when hy

in its earlier stage; however,

the ethoxy

group is usually quickly substituted 130 can conveniently

giving finally the more stable product l-30. Compound tetrahydroquinolines,

be used as a starting

material for the synthesis of 4-substituted

u shown by three examples, 131a-131c.

OEt CH,=CHOEt CBt -

rlr e
127

p-TsOH Me 128 Bt Me 129

BtH p-TsOH Me 130 (48%)

RMgX toluene

:I co
R

the

131a, R = Me (79%) 131 b, R = Bu (46%) 131c, R = Ph (62%)

With 2,3-dihydrofuran, henzotriazolyl

compound

127 gives a mixture consisting

of tricyclic system 132 and four

derivatives 133 (two pairs of diastereomeric

benzotriazol- 1-yl and -2-yl isomers). Product 132

Synthesis of 1,2,3,4-tetrahydroquinolines

15049

can be separated

from the reaction mixture by fractional distillation (in 61% yield); however,

treatment

with

lithium aluminum hydride in refluxing an&sole converts reaction of 127 with 3,4-dihydro-2H-pyran tetrahydroquinoline (137), via intermediates proceeds

the whole mixture into a single product

134. The

similarly yielding 3-(3hydroxypropyl)-l-methyl-1,2,3,4-

135 and 136.?

Bt OH

rib
132

tile 136

Reactions

of N-[(benzotriazol-

1-yl)methyl]anilines

138 with enolizahle

aldehydes

proceeds

similarly to intermediates

those with enol ethers. However,

in reactions of 138 with acetaldehyde,

the assumed hydroxy

139, cannot be isolated, as the hydroxy group undergoes rapid substitution with knzotriazole 130 and 142. Iminium cation 140 is implicated as a key intermediate 142, and also in subsequent conversions in which the benzotriazolyl starting for the preparation

to give products 130 and

of compounds

moiety is suhstituted materials

hy an electrophile. of other by conversion 1,4of

4-(Benzotriazol-1-yl)tetrahydroquinolines disuhstituted tetrahydroquinolines

are convenient

in preparation

due to their reactivity with electrophiles,

as demonstrated

130 to tetrahydroquinolines

141a and 143a, and conversion

of 142 to tetrahydroquinolines

141b an_! 143b.15

N-Bt Al 136

14la, Rl=Me, &decyl(79%) 14lb, Rl=Et, R2=Et (51%)

130, ~1 =Me (64%) 142, RI =Et (65%)

143a, Rl=Me, R2=octyl(92%) 143b. Rl= Et, R3=Ph (77%)

15050

A. R.

KATRITZKY

et al.

Reactions benzotriazol-l-y1

of 127 with higher aldehydes

produce

mixtures

of diastcreomers

144, each as a pair of in reactions with lithium

and 2-yl isomers. These complex mixtures, are converted into single products

without purification.

aluminum hydride,

(145a and 145b). Reactions

with phenyhnagnesium

bromide similarly give single products introduction

146a and 146b. This is the best method currently available for the ring.4

of a substituent at C-3 of the tetrahydroquinoline

Bt y-Bt Me 127 \ RCH&HO Me 144 .,#R +

Bt Rl

Me J

Ph

the 145a, Rl=Ph (92%) 145b, R1=Me (96%)

he

146a, R=Ph (95%) 146b, Rl=Me (80%)

4-(Dialkylamino)tetrahydroquinohnes methodology.

can

be

also

conveniently

prepared

using

benzotriazole give 4-

Thus, reactions of N-[benzotriazol-l-yl)methyl]anilines

138 with I-vinyl-2-pyrrolidinone

(2-pyrrolidinon-l-yl)tetrahydroquinolines

147 in high yields.5 Reduction

of the curbonyl group with lithium 148. N-Vinylacetamide 150.This method allows groups, for

aluminum hydride converts these products into 4-(pyrrolidin-1-yl)tetrahydroquinolines reacts similarly, as it is shown in preparation also for convenient syntheses of julohdines of 151from 14Y, via amide intermediate suhstituted at C-l

and/or C-7 with dialkylamino

example, julolidine 152.1G4

l-3 N
LiAIH, *

:I 05
N

I4

136

147a, R = Me (90%) 147b, R = Et (82%) 147c, R = PhC& (92%)

146a, R = Me (95%) 146b, R = Et (75%) 148c, R = PhCH2 (70%)

Synthesis

of 1,2,3,4-tetrahydroquinolines

15051

Me.N,Et Me y-0 Me AcNMeCH=CH, Me Me.N.Ac

5b. Other Groups Condensations

X in the ARNCHaX

System

of anilines with formaldehyde cations hy added

under acidic conditions Nitrotoluidine

allow dir& 153

trapping of generated converted into of

N-arylmethyleneiminium tetmhydroquinohnes trifluoroacetic acid.

alkenes.

iv thus

154a and 154b upon treatment

with fornu~ldehyde

and a styrene

in the presence

37% CH,O 4N , PhC(R)=CH2 * P 02N @ / J Me

R Ph

NH2
Me

CF,CO,H

153

154a, R = H (90%) 154b, R = Me (60%)

Other

methods

for the generation 1,3,5triazine

of the methytne

iminium

cations

121 involve

ionization and of

of NN-

triphenylhexahydro(alkoxymethyl)anilines

(155), prepared

hy condensation

of aniline with formaldehyde or ruthenium catalywd71 oxidation

(157), prepared

by electrochemical~

methylanilines in alcohols. Despite some inconvenience

in the preparation

and handling of these reagents, these

methods have heen used in the synthesis of tetrahydroquinolines,

e.g. 15617 and 158.

Ph..N/lN/Ph C,J bh 155 + H 156 (46%)

15052

A. R. KATRllZKY

et al.

TiCb NAOMe k 157 + &SiMe, A 166 (42%)

N-(Phenylthiomethyl)anilines, to provide a good alternative, based on reactions tmns-1-phenylpropene of

available by reactions of anilines with formaldehyde

and thiophenol 74

seem

except for odor problems. Four examples of syntheses

of tetrahydroquinolincs, (MO),

N-methyl-N-(phenylthiomethyl)aniline (147b), and cis-1-phenylpropane

(159) with styrene (131~). cyclopentane by Tic&-PPhs,

(161) catalywl

are given helow.

Ph

160 (87%)

147b (75%)

161 (67%)

Crystalline a-arylaminosulfones, acid are convenient with styrene

prepared hy condensation

of anilines with formaldehyde sulfones this

and arylsulfimic 162and 163 approach. a-

reagents. 76 Thus, two examples of reactions of cc-arylaminomethyl tetrahydroquinolines 131~ and 164, respectively,

to give

illustrate

Arylaminomethylnitriles

react similarly, as in the conversion of 165 to tetrahydroquinoline

131~.~

NH
he

162 (92%)

131~ (72%)

Synthesis

of 1,2,3,4-tetrahydroquinolines

15053

Me

163 (87%)

164 (92%) Ph

HCHO PCN Me Me 165

iI8 131c (83%)

5c. Oxidation of N-Methylanilines Oxidation of N-methylanilines N-methylaniline hydroperoxide. 7x producing (166) is prepared can give N-arylmethyleneiminium conveniently of Lewis cations. Thus, N-(t-hutylperoxymethyl)in a reaction with terr-hutyl anion of

from NJ-dimethylaniline acids, compound Four

In the presence

166 eliminates examples using

terr-hutylperoxide 166 in syntheses

N-methyl-N-phenylmethyleneiminium

cation.

tetrahydroquinolines

(129 and 167-169) from the corresponding

&fins

are shown he10w. ~

OEI

167 (77%)

166 (71%)

169 (41%)

Tetrahydroquinolines protection: tetrachloride e.g., conversion

unsuhstituted of derivative

at N atom can also IX produced 170 to tetrahydroquinoline

hy this method

using A -silyl

158 vi& intermediate

171.17 Titanium

is used as a Lewis catalyst in these reactions.

15054

A. R. KATRrIZKY

et al.

f-EuOOH -

CH,=CHCH,SiMe, rnCOCMea
Sit&&Me3 171 (63%) H 158 (64%)

RuCI,(PPhs)s Sitvle,@le,
170

N-(Arylamino)-N-methylmethyleneiminium N,N-dimethylanilines

cations can he directly ohserved hy NMR during oxidation of The cations can he trapped hy olefms of N,N-dimethylaniline with oxygen to

with nitric oxide in the presence of Lewis acids. e.g., 172. Iron salts catalyze oxidation

to give tetrahydroquinolines, methyleneiminium (example: 173) catalyst character.

cations, which are efficiently trapped hy vinyl ethers to give 4-alkoxytetrahydroquinolines Reaction of aniline N-oxides with olefms in the presence of an iron(II1) C&capped porphyrin (174). hut the mechanism involved i klieved to have radical

also gives tetrahydroquinolines

182

NO ,,,,Me
tie
BF,

M%C=CMe, ) I
tie 0 ,Bu-n tie 172

n-BuOCH=CH, O2 I FeCb ,Me p; Me -

be 173

N + kr%e 0 Me

Me Me Me

TPPCpzap/FellkbF, f!le 174 (36%)

Mve

6. Preparation

of 2-Substituted

Tetrabydroquinolines

from Aniline Imines

Condensations tetrahydroqumolines

of anilines with two molecules possessing

of an enolizahle

aldehyde

RCHzCHO

give 1,2,X4-

hoth an RCHZ group on C-2 and an R group on C-3. In instances where it is hut not C-3, direct derivatization of tetrahydroquinolines discussed earlier may

desired that C-2 he substituted, he a solution.

Synthesis

of 1,2,3,4-tetrahydroquinolines

15055

6a. Reactions For aryl intermediate conversion

of Schiff Bases substituents unsaturated on C-2, amines the Schiff bases can be treated with allyhnagnesium cyclized to tetrahydroquinolines under reagents and the The

obtained

acidic catalysis.

of phenyliminomethylpyridines

175 to 4-methyl-2-pyridyl-1,2,3,4-tetrahydroquinolines

(177), via

amines 176,t5 illustrates this approach. Some additional examples of such reactions are given earlier (83%).

175

A 176 R = 2-. 3-, or 4-pyridyl

k 177

Schiff base complexation

with Lewis acids activates the a carbon to ekctrophilic with olefms. Comparison

attacks allowing direct

cyclization to tetrahydroquinohnes withdrawing substituents

of the yields of 17Ya-c.X shows that electronThe milder yterhium Lewis of 180 to

on the aniline ring of 178 help to prevent side products.

acid catalyst works well even with electron-donating 181a and 181b;4 the ratio given in parentheses

groups, as shown hy examples of conversion to two diastereomeric

Ph

corresponds

products.

PhCH=CH* N+Ph 178 178a, R = NO, (99%) 179b, R = CN (80%) 179q R = H (39%) FeC$ Ph

@Ph 180

Yb(OTFh

181a, R = Ph (88:12, 64%) 181 b, R = Me (82:18, 60%) Treatment

of mixtures

of Schiff

hase

182 and an olefm

with

DDQ

produces

2,4-disuhstituted

tetrabydroquinolines

183 and 185 along with the corresponding

quinolines (184 and 186).

15056

A. R. KATRITZKY et al.

182 \ n-BuOCH=CH2

183 (20%)

184 (51%)

185 (16%)
Often, the whole process

188 (5%)

can be accomplished

in one step without isolation

of the intermediate

Schti

bases. Examples are preparations is the correct regioisomer

of tetrahydroquinolines

187 and 188; lR6however, no proof that structure 188

is provided.
S

,f=h

+ PhCHO + PhSCH=CY NH2

Ln(OTf), MgSO.,, CH&N 187 (83%) H

Ln(OTf), + PhCOCHO NH2 + MgS04. CH&N

6b. Aniline Alkylimines In place of aromatic synthesis of antagonists rings, alkoxycarbonyl groups can stabilize the intermediate imines. Thus, in a 190z5 and 1926 are

for the glycine site of the NMDA receptors, esters 189 and 191, respectively.

tetrahydroyuinolines

prepared from iminocarboxylic

NaOMe MeOH reflux BF, OEI, c&Vans = 1: 1

Synthesis

of 1,2,3,4-tetrahydroquinolines

1.5057

+
cl 191 @CO,Me

0-Ph

COfie

The stahizing influence of an electron-withdrawing -methoxyalkyl)anilines trifluoroethyl)anilines 194a and 194b hy electrophilic

trifluoromethyl

group allows the preparation of the corresponding

of N-(a N-(2,2,2-

anodic oxidation

193. In the presence of titanium tetrachloride, intermediates 194a and 194b react with as
trtms

styrene to give tetrahydroquinolines 195~1~~and 195blR7, predominantly higher stability of N-[a-(benzotriazol-I-yl)alkyl]anilines,

isomers.

Because of the are then and give

no electron-withdrawing of N-methylaniline reacts with

suhstituents

necessary: intermediate benzotriazole. Under

1% is simply prepared hy condensation acidic conditions, compound 196

with isohutyraldehyde to

I-vinyl-2-pyrrolidinone

tetrahydroquinoline

197, predominantly

as the cis isomer.16

y-C4 R 193a. R = Et 193b, R = Ph

2e
CFs R 194a, R = Et l94b, R = Ph 195a, R = Et (63%) 195b, R = Ph (63%)

MeOH

cHM~

4-MeCGH4S0,H Me 197 (64%)

he

tile
196 Bt = benzotriazol-1 -yl or -2-yl

7. Preparation

by Insertion of a C(2)-C(3) Fragment

Although

less common,

this method based on DiebAlder substituted

reactions

of nrtho-methyleneiminoquinones patterns

allows for synthesis

of 1,2,3,4-tetrahydroquinolines

at C-2 and C-3 with suhstitutbn depending

difficult to achieve hy other methods. intermediate nrtho-methyleneimincquinone,

Variants of thi.. method,

primarily on the source of the

are summarized helow. Thus, 2.1~benzoisothiazt~line-2,2-dioxide

15058

A. R. KATRITZKY

et al.

(198) eliminates sulfur dioxide upon heating to produce ortho-methyleneiminoquinone dienophiles to give 2,3-disuhstituted-1,2,3,4-tetrahydroquinolines, azido-1-methylindole

199, which b rrapped by

e.g., 200.1XXThermal ring cleavage of 2fumarate to yield tetrahydroquinoline

(201) gives 202, which is trapped by dimethyl 1,Celimination

203. In the last example, ortho methyleneiminoquinone

from silylated ammonium salt 204 catalyzed hy tluoride generates 206

205, which is trapped hy diethyl fumarate to give tctrahydroquinoline a

1 -A.+
c ---L

,_,,

CN dimethyl fumarate * tie 201 file 203 (43%)

Brdiethyl fumarate L

204

205

205 (85%)

8. Ring Contraction

and Ring Expansion

Chlorinations

of the corresponding

tetrahydrohenzazepines which react

with phosphorus with amines

pentaehloride, to form

give Schloro

-2,3,4,5-tetrahydro-lH-1-benzazepin-2-ones tetrahydroquinolines tetrahydroquinoline

2-amino-1,2,3,4-

in high yields.* As an example, Sphenyl derivative 208 upon heating with piperidine at retlux for 2 hours.

207 is converted to 2,2_disuhstituted

Ph Cl piperidine D 208 (98%)

207 Reductions of 1-methoxyaminoindanes

lead to ring expansion to the corresponding

tetrahydroquinolines

in high yields. Thus, 2-methyl-1,2,3,4-tetrahydroquinoline

(13) was ohtdined from I-(methoxyamino)-l-

Synthesis

of 1,2,3,4-tetrahydroquinolines

15059

methylindane

(209)

upon

treatment

with

lithium

aluminum

hydride.

The

opposite

conversion, of

from

tetrahydroquinolines

to indanes4 has already 210.74

found practical applications

in preparation

fungicide 211

from tetrahydroquinoline

LiAIH., Me Med 209

Me Me--t-\

HP04

9. Summary

Tahle. Recommended Substitution Pattern

Synthetic Methods for Suhstituted Preferred Methods

1,2,3,4-Tetrahydroquinolines Section of this Review 2a 2h 2c 2a sa 2a sa 5tl 4 7 6a

2-monosuhstituted

(i) from quinolines hy reduction (ii) from dihydroquinolines (iii) from tetrahydroquinolines by substitution (i) from quinolines hy reduction (ii) using henzotriazole methodology (i) from quinolines by reduction (ii) using henzotriaole methodology (iii) other ArNCH2 methodology (i) from aniline with two moles of RCHO (ii) from ortho methyleneiminoquinolines (i) from Schiff bases using benzotriazole methodology

3-monosubstituted

4-monosuhstituted

2,3-disubstituted

2,4-disuhstituted 3,4-disuhstituted 2,3,4-trisuhstituted

sa
2h 4 6a

(i) from dihydrcquinolines (ii) from anilines and two moles of RCHO (iii) from Schiff bases

15060

A. R. &+SRllZKY et ai.

Many good synthetic methods for 1,2,3,4-tetrahydroquinolines ring have been recently developed. parameters Table. to consider

bearing substituents

on the heterocyclic arc the key in the 4-

The nature, number and relative location of the substituents a method. Recommended the best synthetic for methods making

before choosing methodology

are summarized Smonosuhstituted atom

Benzotriazole

is frequently

method Suhstitution

monosuhstituted

and 3,4-disuhstituted

tetrahydroquinolines.

at the nitrogen

and at the

aromatic ring, not considered in this review, may also influence the choice of the optimum method.

10. References 1. Niwa, T.; Takeda,

1987,144,

N.; Kaneda, N.; Hashizume,

Y.; Nagatsu,

T. Biochem.

Biophys. Rus. Comm.un.

10X4-1089.

2. 3. 4. s. 6. 7. X. 9. 10.

Perry, N. B.; Blunt, J. W.; McComhs, J. D.; Munro, M. H. G. J. Org. Chrm. 1986. 51. ~54765478. Perry, N. B.; Blunt, J. W.; Munro, M. H. G. TetrrLhrdron 1988,44, 1727-1734.

Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Higa, T.. Sakai, R. J. Org. Chrm. 1988, .53,4127-412X. Nishiyama, S.; Cheng, J.-F.; Tao, X. L.; Yamamura, S. Tetruhrdron Left. 1991,32,4151-4154. Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am. Chrm. Sot. 1992. 114.217.5-2180. White, J. D.; Yager, K. M.; Yakura, T. 1. Am. Chrm. Sot. lYY4, 116, 1X31-1X3X. Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T. J. Am. Chrm. Sot. lYy0, 112, 3715-3716. Wender, P. A.; Zercher, C. K.; Beckham, S.; Hauhold, E.-M. J. Org. Chem. lYY3,5X, 5X67-5869. Witherup, K. M.; Ransom, R. W.; Varga, S. L.; Pitzenbqcr, Pat. US .5,2X8,725, 1994; Chrm. Ahstr. 1994, 121, 91779s. S. M.; Lotti, V. J.; Lumma, W. J. U.S.

11. 12. 13. 14. 15. 16. 17. 1X.

Kokwaro, G. 0.; Taylor, G. Drug Chem. Toxicnl. 1990, 13, 347-3.54. Wong, L.-J. C.; Tsao, G.-C.; Bruce, J. I.; Wang, S. S. Exptv?entia lYYo,46,461-464. El Ragehy, N. A.; El Tarras, M. F.; Khattah, F. I.; Ahmad, A. K. S. Spuctmsc. Lett. lY91, 24, X1-97. El Tahir, K. E. H.; Al-Kharji, A. M. H.; Ageel, A. M. Cm. Pharmnc. 1992. 23, 131-139. Prankerd, R. J.; Ahmed, S. M. J. Pharm. Pharmacol. 1992,44, Prankerd R. J.; Ahmed, S. M. J. Pharm. Pharmocnl. 19Y2,44, 259-261. 26 I-263

Kimura, T.; Imanishi, S.; Arita, M. J. Currliovtwc. Phnrmucol. lY8Y, 13, 767-773. Hashimoto. K.; Akiyama, K.; Mitsuhashi, H. Jpn. J. Pharmwol. lY8Y, 4Y, 24.5-254.

Synthesis

of 1,2,3,4-tetrahydroquinolines

15061

19. 20. 21. 22. 23. 24. 2.5.

Weirich,

J.; Antoni, H. Nuunyn-Schmie~~brrgs

Arch. Phurmucol. 1989,340,4%-464 H. Biochrm. Phnrmacol. 1990,3Y, 95-100.

Rekka, E.; Mannhold, R. M.; Bast, A.; Timmerman,

Weirich, J.; Antoni, H. 1. Curdiovusc. Pharmacol. 1990, 15,998- 1009 Omura, S.; Nakagawa, A. Tetruhedron Lett. 1981,22,2199-2202. Francis, C. L.; Ward, A. D. Aust. J. Chem 1994,47, Williamson, 2109-2117.

N. M.; March, D. R.; Ward, A. D. Tetrahedron Lrtt. 1995, 36, 7721-7724. G.; Chan, T.;

Leeson, P. D.; Carling, R. W.; Moore, K. W.; Moseley, A. M.; Smith, J. D.; Stevenson, Baker, R.; Foster, A. C.; Grimwood, 1992,35, 1954-1968. S.; Kemp, J. A.; Marshall, G. R.; Hoogsteen,

K. J. Mud. Chem

26.

Pangalos, M. N.; Francis, P. T.; Foster, A. C.; Pearson, R. C. A.; Middlemiss, Bruin Res. 1992, 596, 223-230.

D. N.; Bowen, D. M.

27.

Foster, A. C.; Kemp, J. A.; Leeson, P. D.; Grimwood, Smith, J. D.; Carling, R. W. Mol. Phurmucol. 1992,41,

S.; Donald, A. E.; Marshall, G. Ii.; Priestley, T.; 914-922. 1992,

28.

Grimwood, 41.923-930.

S.; Moseby,

A. M.; Carling, R. W.; Leeson. P. D.; Foster, A. C. I%/. Phurmacol.

29. 30. 31.

Yoneda, Y.; Suzuki, T.; Ogita, K.; Han, D. 1. Neumchem. P. P. Mager, Drug Des. Disc. 1994,11, Stauch Slusher, B.; Rhsolo, 97, 175-185. 185-196.

1993, 60, 634-644.

K. C.; Jackson, P. F.; Pullan. L. M. J. Nrtrrd Trrmsm.:

Grn.

Sm.

1994,

32.

Grimwood, 122,969SSm.

S.; Le Bourdelles,

B.; Whiting, P. J. J. Nwrochrm.

1995, 64, 525-530; Chem. Abstr. 19y5,

33.

Ferranti, A.; Garuti, L.; Giovanninetti, 42, 237-249; Chum_ Abstr. 1987,107,

G.; Gag@, R.; Roncada, P.; Nardi. P. Frrrmrrco, Ed. Sci. 1987, 17237h. G.; De Burlet, G.; Dietz, M. U.S. Patent US 4,952,573, 1990;

34.

L&xc,

G.; Ruhland, B.; Andermann,

Chem. Abstr. 1991, 114, 619Sod. 35. Uchida, M.; Chihiro, M.; Morita, S.; Kanbe, T.; Yamashita, H.; Yamasaki, K.; Yahuuchi, Y.;

Nakagawa, K. Chem. Phurm. BUM 1989, 37, 2109-2116. 36. Gracheva, I. N.; Gridneva, L. I.; Tochilkin. A. I.; Gorkin, V. Z. Khim.-Furm. Chem. Abstr. 1989, 110, 165944~. 31. Miller, K. E.; Huang, C.-T.; Portlock, D. E.; Wright, G. C. fife Sci. 1987,40,63-70. Zh. 1988, 22, 13361339;

15062

A. R.

KATIUTZKY

et al.

38.

Stevens, R. W.; Ikeda, T.; Wakahayashi, H.; Nakane, M. U.S. 1994,121, 57344m.

Pnt. US 5,256,7X9, 1993; Chem. Abstr.

39.

Kihara, N.; Tomino, I.; Tan, H.; Ishihara, T. Eur. Pat. EP 289.36.5, 1988; Chum. Abstr. 1989, 111, 234028.

40. 41.

Kojima, E.; Saito, K. Eur. Pat EP 402,859, 1990; Chum. Abstr. 1991, 115. 106017~. Youssefyeh, R. D.; Magnien, E.; Lee, T. D. Y.; Chan, W.-K.; Lin, C. J.; Gulemmo, Jr. R. A.; Johnson, C. A.;

Jr. W. H.; Tan, J.; Campbell, H. F.; Huang, F.-C.; Nuss, G. W; Carnathan, G. W.; Sutherland, Van Inwegen, R. G. J. Med. Chum. 1990,33. 42. Paris, D.; Cottin, M.; Demonchaux, D. J. Med. Chem. 1995, 38, 669-685. 43. 44. Rauckman, B. S.; Tidwell, M. Y.; Johnson, J. V.; Roth, B. J. Md. Ckm_ 1989, 32, 1927-193s. 1186-l 194.

P.; Augert, G.; Dupassieux,

P.; Lenoir, P.; Peck, M. J.; Jasserand,

Ogawa, H.; Miydmoto, H.; Kondo, K.; Yamashita, H.; Nakaya, K.; Komatsu, H.; Tanaka, M.; Takara, S.; Tominaga, M.; Yahuchi, Y. Kokai Tokkyo Koho JP, 04,321,66Y, lYY2; Chum. Abstr. 1993, IIY, 249979~.

4.5. 46.

Bigg, D.; Mangane, M. Fr. Pat. FR 2,.576,308, 1986; Chum. Abstr. 1987, 106, 1022x4~. Nagasaka, T.; Kosugi, Y.; Kawahara, T.; Kakimoto, M.; Tamuru, K.; Himta, A. Jpn. Pat. OS, 379,267, 1993; Chrm. Abstr. 1994, 120,244692q.

41.

Moon, M. W.; Morris, J. K.; Heier, R. F.; Chidester, C. G.; Hoffmann, W. E.; Piercey. J. S.; VonVoigtlander, 1092.

M. F.; Althaus,

P. F.; Evans, D. L.; Figur, L. M.; Lahti, R. A. J. Mrrl. Chrm. 1992, 35, 1076-

48. 49.

Moon, M. W.; Hsi, R. S. P. J. Lr~brllrd Compd. Rdiophrrrm.

1992, 31, Y37-943.

Buzas, A.; Ollivier, R.; El Ahmad, Y.; Laurent, E. PCT Int. Appl. WO 93 16,057, lYY3; Chrm. Abstr. 1994,120, 13452%.

so.

Agarwal, S. K.; Saxena, A. K.; Jam, P. C.; Sur, R. N.; Srimal, R. C.; Dhawan, B. N.; Anand, N. Indian .J. Chrm., Sect. E 1987,26B, 642-646; Chum. Abstr. 1989, 1 IO, 1147XYj. S.; Yamdshita, H.; Yamasaki, K.; Kunk, T.; Yahuuchi. Y.;

Sl.

Uchida,

M.; Chihiro,

M.; Morita,

Nakagawa, K. Chem. Phrrrm. Bull. 1990,38, 52. s3. s4.

1575-1586.

Uchida, M.; Morita, S.; Chihiro, M. Eur. Pat. EP 239,129, 19X7; Chem. Abstr. 1988, 108, 18674Ot. Atwal, K. Eur. Pat. EP 488,6 16, 1992; Chem. Abstr. 1992, 117, XYY7Xc. Santangelo, F.; Casagrande, C.; Miragoli, G.; Vecchietti, V. Em=..I. Mtd. Chrm. 1994,2Y, X77-X82.

Synthesis

of 1,2,3,4-tetrahydroquinolines

15063

55. 56. 57.

Galtier, D.; Lassalle, G. Eur. Pat.. EP 643,046, 199.5; Chrm Abstr. 1995, 122, 265264h. Lassalle, G.; Galtier, D.; Galli, F. Eur. Pat. EP 643,047, 1995; Chrm. Ahstr. 1995, 122, 26.5377x. Baumgarth, M.; Lues, I.; Minck, K.O.; Beier, N. Ger. Pat. DE 4,321,366. 1995; Chrm. Ahstr. 1995,

122, 187620e. 58. 59. Biller, S. A.; Misra, R. N. U.S. Pat. US 4,843,0X2, 19X9; Chrm Ahstr. 1989, 111, 2326oOj. Lukevics, E.; Lapina, T.; Segals, I.; Augustane, 951; Chem. Abstr. 1988, 109, 222016t.
60.

I.; Verovskii, V. N. Khim.-Furm.

Zh. 1988, 22, 947-

Kohno, Y.; Kojima, E. Eur. Potent EP 403,980 (1990); Chem. Abstr. 1991, 114, 207OShr. Kohno, Y.; Awano, K.; Ishizaki, T.; Kojirna, E.; Kudoh, S.; Sakoe. Y.; Saito, K. PCT Int. Appl. WO 92 18,482, 1992; Chem. Abstr. 1993, 119, 11713Sq.

61.

62.

Kono, Y.; Kojima, E.; Saito, K.; Kudo, S.; Sekoe, Y. Kokai Tokkycl Koho JP 06 .56,78X, 1994; Chew. Abstr. 1994, 121) 157.53611.

63.

Carling, R. W.; Leeson, P. D.; Moseley, A. M.; Smith, J. D.; Saywell, K.; Triclehank, M. D.; Kemp, J. A.; Marshall, G. R.; Foster, A. C.; Grimwood, Abstr. 1993, 119, 911Sz. S. Bioorg. Med. Chrm. Lutr. 1993, 3, 65-70; Chpm.

64.

Sanpwan,

N. K.; Malik, M. S.; Dhindsa, K. S.; Chim. Acrrr Turc. 1985, 13, 129-134; Chrmrx Ahtsr.

1987, 107, 77597k. 65. Stevenson, G. L.; Leeson, P. D.; Rowley, M.; Sandarson, I.; Stanslield, I. Binorg. Med. Chrm. Mt.

1992, 2, 371-374; Chem. Abstr. 1993, 119, 180629u. 66. Regnier, G.; Guillonneau, C.; Lepagnol, J.; Lestage, P. Eur. Pat. EP 427.60.5, 1991; Chrm. Abstr. 1991, 115, 136113q. 67. Boursier-Neyret, lI,llhl-1166. 6X. Ventura, C.; Miller, R.; Wolf, H.-P.; Beier, N.; Jonas. R.; Klockow, M.; Lucs. I.; Hano. 0.; Spurgeon, H. A.; Lakatta, E. G.; Capogrossi, 69. Regnier, G.; Guillonneau, M. C. Cir. Res. 1992. 70, 10X1-1090. J. Eur. Pat. EP 2X6,49.5, 19xX; Chew_ C.; Baune, A.; Klippert, P.; Castagne, 1.; Sauveur, C. J. Pharm. Biomrd. And. 1993,

C.; Lepagnol,

70. 1474772. 71. Walter, H. Eur. Pat. 555,183, 1993; Chem. Abstr. 1994, 12O,S4SSlv.

Chrm. Abstr.

1993, II&

15064

A. R. KATRITZKY al. et

72.

Ohsumi, T.; Mito, N.; Oshio, H.; Itaya, N. Nippon Noyaku Gokkuishi 1988, 13, 71-75; Chum. Abstr. 1988,109, XX070a. Zh. V.; Shikhaliev, Kh. S.; Shpanig, E. B. Izv. Vyssh. Uchubn. Zuvrd, Khim. Khim.

73.

Shmyreva,

Tekhnol. 1988,31,45-4X; 74. 7s.

Chem. Abstr. 1989, I1 I, 23363~.

Tsushima, K.; Osumi, T.; Matsuo, N.; Itaya, N. Agric. Bin/. Cham. 1989,53,2529-2530. Kurahashi, Y.; Shiokawa, K.; Goto, T.; Kagahu, S.; Kamochi, A.; Moriya, K.; Hayakawa, H. Eur. Pat. EP 198,264, 1986; Chcvn. Abstr. 1987,106,9XllSw.

76.

Luzhkov,

V. B.; Fentsov,

D. V.; Kasaikima, 0. T. Zh. Strukt. Khim. 1988, 2Y, 37-41. Chrm. Abstr.

1989, 111,22774t. 77. 78. Meier, H. R.; Evans, S. Eur. Pat EP 273.868, 1988; Chem Abstr. 1989, Ill), 98.598~. Fentsov, D. V.; Lohanova, T. V.; Kassaikiia, 0. T. Nrftukhchimiya lYy0, 30, 103-10X; Chem_ Abstr.

1990,112,234619s. 79. 80. Evans, S. Eur. Pat. EP 497,735, 1992; Chrm.. Abstr. lYY2, 117, 233X6Xp. Shikhaliev, Kh. S.; Shmyreva, Zh. V.; Gurova, E. M. Izv. V$sh. Uchebn. Zuvrd, Khim. Khim..

Trkhnol. 1989,32, Xl.

X5-89; Chem. Abstr. 1990,112,216hS9a.

Zimakova, E. V.; Mamadaliev, Sh. T.; Ivanov, Yu. A. Uzb. Khim. Zh. 1988. 13-16; Chrm Abstr. 1989, 111, 224601~.

x2.

Knuehel, G.; Konrad, 0.; Hoe&es, 122, X9OXlk.

H.; Lieske, E. Ger. Pat. DE 4,319,646,

1994; Chem. Abstr. 19y5,

X3. X4. X5. X6.

Hahn, E.; Kraeh, C.; Mayer, U. Ger. Pat. DE 4.215.3Yl.

1993: Cbrm. Absrr. 1994, 120, 301123f.

Moser, P. Ger. Pat. DE 3,540,090, 1986; Chrm. Abstr. 1987, 106, IYYS4t. Himeno, K.; Yoshihara, J. Kokai Tokkyo Koho JP 62 39.663, 19X7; Chrm. Abstr. lY87, 1117. 1169Slt. Zhang, Y.; Hou, Y. Huqong 1193Xhw. Xuebao (Chin. Ed) 1992, 43, 2YX-303; Chrm. Abstr. 1993, 119,

x7. xx. x9. 90. 91.

Zhang, Y.; Zhang, R.; Hou, Y. Chin. Pat. 1,04099X, 19YO; Chrm. Abstr. 1991, 114. 104357k. Walter, H. Ger. Pat_ DE 3,X17,565, 1988; Chrm. Abstr. lY8Y,llO, 175142~.

Reichardt, C.; Harms, K.; Kinzel, M.; Schafer, G.; Stein, J.; Wocadlo, S. Livbigs Ann. 1995, 3 17-327. Kuroda, M.; Sugata, Y.; Furusho, N. Ger. Pat. DE 3,930,933, lYY0; Chem. Abstr. lyy0, 113, 123813h. Hanatani, 2911632. Y.; Mizuta, Y.; Nakatani, K. Jpn. Pat. JP 03,144,653, 1991; Chrm. Abstr. 1991, 115,

Synthesis

of 1,2,3,4-tetrahydroquinolines

15065

92. 93. 94. 95. 96.

Kodera, T.; Ito, A. Kokai Tokkyo Koho JP 02,284,149,

Suzuki, Y.

1990; Chum. Ahsrr. 19!H, 115, 822 15d.

Kokai Tokkyo Koho JP 03,293,673,

1991; Chcm. Ahstr. 1992, 117, lotl973x.

Chrm.

Mabuchi, M. Kokai Tokkyo Koho JP 62,289,845,1987; Tanaka, H. Kokai Tokkyo Koho JP 63,220,160,

Ahstr. 1981). 108, 213943~.

1988; Chem. Abstr. 1989. 110, 24017Op. 1988;

Chrm.

Suda, Y.; Sakamoto, M.; Kikuchi, K.; Shimazaki, S. Kokai Tokkyo Koho JP 63,151,955, Absrr. 1989, 111, 31283.

97. 98.

Eckstein, U. Eur. Pat. EP 330,040, 1989; Chem. Abstr. 1990, 112, 100676~. Yamada, M.; Uda, Y.; Mizuno, K.; Tsunemitsu, Abstr. 1990,112, 28246q. 1987; Chum. Abstr. 1988, 10X. 23340~.
Chrm. Chem.

K. Kokai Tokkyo Koho JP 01,165,687,

1989; Chem

99. 100. 101. 102. 103. 104. 105. 106. 107. 10X.

Eckstein, U. Ger. Pat. DE $609,344, Heidenreich, Hashimoto,

H.; Jabs, G. Ger. Pat. DE 3,612,440, 1987; K.; Suzuki, Y. Jpn. Pat. JP 01 47,.587, 1989; 1987;

Abstr. lY#l, 109, 30233q. Abstr. 1989, 111, 105906p.

Tanaka, A.; Miura, T. Jpn. Pat. JP 62,13X453,

Chem.

Ahstr. 1988, ION, 29333~.

Oono, S.; Okada, M.; Adachi, K. Jpn. Pat. JPOl 90,442. lY8Y; Chrm. Abstr. 1989, 111, 184oY6a. Kojima, K.; Nakanishi, H.; Hioki, T. Jpn. Pat. 62,231,795, 19X7; Chum. Abstr. 1988, 109, 64433~. Hioki, T.; Tomioka, A. Jpn. Pat. JP Ol,lS7,944, 1989;
Chem.

Abstr. 1990. 112, 14344h.

Lau, P. T. S. Eur. Pat. EP 38.5,271, 1990; Chem. Abstr. 1991. 114, 12207.5~. Moore, W. H. U.S. Pat. US 4,788,121, Yamaoka, 1988;
Chrm

Abstr. 1989,110,

24016Ok. 1994;
Chem.

T.; Koseki, K.; Suga, S.; Mitekura,

H.; Yasui, S. Jpn. Pat. JP 06,107,71Y,

Abstr. 1994, 121, 180456b. 109. Hlasta, D. J.; Luttinger, 1555-1562. 110. 111. 112. 113. Jones, R. C. F.; Smallridge, M. J.; Chapleo, C. B. J.
Chem. Sot., Ptrkin Trams. I 1990,

D.; Perrone, M. H.; Silbernagel, M. J.: Ward, S. J. .I. Serf. Chem. 1987, 30,

385-391.

Shuman, R. T.; Omstein, P. L.; Paschal, J. W.; Gesellchen, Schaus, J. M.; Huser, D. L.; Titus, R. D. Vecchietti,
Synth.

P. D. J. Org Chrm. lYyO,55, 738-741. 3553-3562.

Chrm.

C<>mmun. 1990,20,

V.; Clarke, G. D.; Colle, R.; Giardima, G.; Petrone. G.; Shacchi, M. J. &cl.

1991,

34,2624-2633. 114. 11s. Cmbb, T. A.; Heywood, G. C. Mugn.

Resnn. Chem. 1988.26, SIX-522.

Nagata, R.; Tanno, N.; Kodo, T.; Ae. N.; Yamaguchi,

H.; Nishimura. T.; Antoku, F.; Tatsuno, T.;

Kate, T.; Tanaka, Y.; Nakamura, M. J. Med Chum. 1994, 37. 3YS6-3YhX.

15066

A. R. KATRI'IZKY et al.

116. 117. 118. 119. 120. 121.

Alvanipour, A.; Kispert. L. D. J. Mol. Cutal. 1988.48, Murahashi, S.-I.; Imada, Y.; Hirai, Y. Tetrahedron Mt.

277-283. 1987,2X, 77-80. 2968-2976.

Marahashi, S.-I.;. Imada, Y.; Hirai, Y. Bull. Chem. Sot. Jpn. 1989.62, Bouyssou, P.; Le Goff, C.; Chenault, .I. J. Heterncycl. Chrm

1992,2Y, X95-898. Truns.) 1988,6.5-67.

Gracheva, I. N.; Tochilkin, A. I. Chem. Heterocycl. Comp.(Engl.

DAmbra, T. E.; Estep, K. Cl.; Bell, M. R.; Eissenstat, M. A.; Josef, K. A.; Ward, S. J.; Haycock, D. A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C.; Chippari, S. M.; &ego, T. J. Med. Chcm. 1992,35, 124- 135. Bull. 1986, 34, 390%3YOY. 15291.533. J. D.; Kullnig, R. K.; Daley, G.

122. 123. 124. 12s. 126. 127. 128. 129. 130.

Nose, A.; Kudo, T. Chem. Pharm

Nose, A.; Kudo, T. Chem. Pharm. Bull. 1988,36, Goldstein,

S. W.; Damhek, P. J. Synthrsis 1989, 221-222.

Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chrm. 1992. 57,4404-4414. Maeda, M. Chem. Phnrmn Bull. 1990, 38, 2577-2580. Grignon-Duhois, M.; Fialeix, M.; Rezzonico, B. Gun. J. Chrm. 1990,6X, 2153-2158.

Buhnov, Yu. N. Pure & Appl. Chrm. 1994,66,23S-244. Sugiura, M.; Sakurai, Y.; Hamada, Y. Hrtuwycles Ashwood, 3267. 1992, 34, %1-56X. 1991. 34, X261-

V. A.; Cassidy, F.; Evans, J. M.; Gagliardi, S.; Stemp, G. J. MA. Chrm.

131. 132. 133. 134. 13.5. 136. 137. 138. 139. 140. 141.

Ukhin, L. Yu.; Orlova, Z. I. Mrntldrrv

Commun. 1995, 234-235.

Migneault, D.; Bernstein, M. A.; Lau,C. K. Gun. J. Chem. 1995. 73. lSO6-1513. Murahashi, Murahashi, S.-I.; Oda, T.; Sugahara, T.; Masui, Y. J. Chrm. Sot., Chem. Commzm. 1987. 1471-1472. S.-I.; Oda, T.; Sugahara, T.; Masui, Y. J. Org. Chum. 1990, SS, 1744-1749.
Chrm_ 1984,21, 643-646.

McCord, T. J.; DuBose, C. E.; Shafer, P. L.; Davis, A. L. J. Hetrroqcl. Meyers, A. I.; Milot, G. J. Org. Chrm. 1993, 58, 6.538-6.540.

Coles, N.; Harris, M. C. J.; Whithy, R. 3.; Blagg, J. Org~~nomrt[l/lics 1994, 23, lYO-199. Harris, M. C. J.; Whitby, R. J.; Blagg, J. Tetruhedmn Lctt. 1994. 35, 2431-2434.

Coles, N.; Whitby, R. J.; Blagg, J. Synlrtt 1990,271-272. Coles, N.; Whitby, R. J.; Blagg, J. Synlett 1992, 143-145. (a) Katritzky, results A. R.; Sengupta, S. J. Chum. Sot., Pcrkin Twns. I 1989, 17- IY; (h) - unpublished

Synthesis

of 1,2,3,4-tetrahydroquinolines

15067

142. 143. 144.

Crahh, T. A.; Soilleux, S. L. Tetrahedron 1986, 42, 5407-5413. Crahb, T. A.; Soilleux, S. L. J. Chem. Snc. Pukin Truns. I 1985. 13X l- 1385. Nuuk SSSR, Srr. Khim. 1989, 191-

Shikhaliev, Kh. S.; Kasaikina, 0. T.; Shmyreva, Zh. V. Izv. A/d. 192.

14s. 146. 147. 148. 149.

Donnelly, J. A.; Farrell, D. F. J. Org. Chem. 1990, 55, 1757-1761. Tokes, A. L.; Litkei, Gy.; Szilagyi, L. Synth. Commun. 1992.22. Tokes, A. L. Synth. Commun. 1989, 19, 20X1-2086. Bombarda, C.; Erba, E.; Gelmi, M. L.; Pocar, D. J. Hrtrrocycl. Larock, R. C.; Berrios-Pena, 58, 4.509-4s 10. Chrm. lYY2, 29, 1577-1581. 2433-2445.

N. G.; Fried, C. A.; Yum, E. K.; Tu, C.; Leong, W. J. Org. Chrm. lYY3,

150.

Kuznetsov, 64-6X.

V. V.; Al&,

A. E.; Prostakov,

N. S. Chum. Htvrrqd.

Cornp.(Engl. Trunsl.) lYY4, 30.

151.

Kuznetsov, Comp.(Engl.

V. V.; Aliev, A. E.; Palma. A. R.; Varlamov. A. V.; Prostakov, Trcmsl.) 1991, 7Sh-761.

N. S. C/tern. Hetrrocycl.

152. 1.53. 154. 1.55. 156. 157. 1sx. 159. 160. 161. 162. 163. 164. 165. 166. 167.

McComhie.

S. W.; Ortiz, C.; Ganguly, A. K. Trtrclhrclron Left. lYY3, 34, WWXO3h.

Jones, H. 0.; White, E. J. J. Chrm. Sot. Truns. 1910, 97, 632-644. Miller, W. V.; Plochl, J. Brrichtr Dtsch. Chum. Ges. 1896, 20, 1462-72. Crahh, T. A.; Canfield, L. M.; Bowen, D. J. Chem. SK, Turner, A. B.; McBain, B. I.; Howie, R. A. 1. Ckm. Prrkin Trams. 1 lYY4, 9-13.

Sot. Perkin Turns 1 lY86, I IS I- 1155.

Clerici, A.; Porta, 0. Trtrrrhrdron Lutt. 1990, 31, 2069-2072. Westerwelle, U.; Keuper, R.; Risch, N. J. Org Chrm. lYY5.60, 2263-2266.

Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chrm. lYY5.60, 7631-7640. Park, K. H.; Joe, H. S.; Ahn, K. II.; Jun. K. Trtrohrtlron Katritzky, A. R.; Rachwal, S;. Rachwal, B.; Frankenfcld, Let., lYY5, 36, 594%SY46. .I. W. ht. J. Chew. Kinut. 1995, 27, 351-3.57.

Katritzky A. R.; Gordeev, M. F. J. Org. Chrm. 19Y3, 5X, 4049-4053. Katritzky, A. R.; Rachwal, B.; Rachwal, S. .J. Org. Chrm. 1995, 60,2%X-25%. Katritzky, A. R.; Rachwal, B.; Rachwal, S; Ahhoud, K. A. J. Org. Chew. lY96, 61, in press. Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chrm. 1995,611, 3YY3-4001. Mellor, J. M.; M&man, G. D.; Riviere, P. Trtruhrdron Lrtt. 1991, 32, 7 103-7106. 1995,51, 6115-6132.

Mellor, J. M.; Merriman, G. D. Tetrdwdron

15068

A. R. KATRITZKY et al.

168.

Wakae, M.; Konishi, K. Osuku Furitsu Kogyo-Shorrikun 6280h.

Hokoku, 1%3, 47-W; ChrmAbstr.

1963, 5Y,

169.

Shone. T.; Matsumura, Y.; Inoue, K.; Ohmizu, H.; Kashimura, S. J. Am. Chum. Sot. 1982, 104, S75357s7.

170. 171. 172. 173. 174. 17s. 176. 177. 17X. 179. 180. 181. 182. 1X3. 1x4. 185. 186. 1x7. 188. 189. 190. 191. 192. 193. 194.

Fuchigami, T.; Ichikawa, S. J. Org. Chem. 1994, .5Y, 607-615. Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Nakato, T. TrtrrIhnlron Lrtt. 1992, 33,6991-6994. 1986, 24. 33X5-3395.

Kametani, T.; Takeda, H.; Suzuki, Y.; Kasai, H.; Honda, T. H&rocy/rs

Ha, H.-J.; Ahn, Y.-G.; Chon, J.-K. J. Chem. Sot., Prrkin Trrms. I 1995, 2631-2634. Grillat, G. F.; Schaffrath, R. E. J. Org. Chem. 1959. 24, 1035-1038. Beifuss U.; Ledderhose, S. J. Chem SW., Chem. Commun. 1995, 2137-213X. S.; Taraschewski,
Chrm. Grs.

Beifuss, U.; Kunz, 0.; Ledderhose,

M.; Tonko, C. Synlctt 19%. 34-36.

37, 2636-2639. Sot.

Warunis, T. St.; Sachs, F. Ber. Dtsch.

1904,

Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am. Cbrm. Murahashi, Brownstein,

1988, 110. X2.56-X25X.

S.-I.; Naota, T.; Nakato, T. Synlett 1992, X35-X36. S.; Gahe, E.; Lee, F.; Louie, B. J. Org. Chrm.
1988, 53.95 I-9.54.

Murata, S.; Miura, M.; Nomura, M. J. Org. Chrm. 1989, 54. 4700-4702. Dicken, C. M.; Lu, F.-L.; Bruice, T. C. Trtrrihedron Lett. 1986, 27, 5967-5970. Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri F. J. Org. Chrm. 1992, 57. 1X42-1848. Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthfsi.s 1995, X01-X04. Bortolotti, B.; Leardini, R.; Nanni, D.; Zanardi, G. Trtrrlh&on 1993, 4Y, 10157- 10174.

Kohayashi, S.; Ishitani, H.; Nagayama, S. Chem. Lrtt. 1995, 423-424. Fuchigami, T.; Ichikawa, S.; Kandeel, Z. E.; Konno, A.; Nonaka, T. Heturocyckes 1990. 31, 415-417. Wojciechowski, Wojciechowski, K. Synlett 1991, S71-S72. K. Trtruhedron 1993,49,7277-72X6.
Prrkin Id, Trams. I 19SY. 1354-56.

Foresti, E.; Spagnolo, P.; Zanirato, P. J. Chem. SM., Ito, Y.; Nakajo, E.; Saegusa, T. Synth. Commun. Hino, K.; Nagai, Y.; Uno, H. Chrm Pharm.
Bull.

1986, 1988, SM..

1073-1()X().

36, 23X6-2400. Chem. Commw~.

Booth, S. E.; Jenkins, P. R.; Swain, C. J. J. Chrm. Cliffe, W. H.; Dodman, D.; Meth-Cohn,

19Y3, 147-149.

0. J. Chum. SM.

C 1%6, 5 14-S 17.

(Received 25 June 1996)

Synthesis of 1,2,3,4-tetrahydroquinolines

15069

Biographical

Sketch

Alan R. Katritzky, born in 1928 in London, U.K., is Kenan Professor Director of the Institute for Heterocyclic hearted overview account of his life appeared Compounds

of Chemistry and

at the University of Florida. A light1994, 31, ~~569-692, and an

in J. Het. Chem.,

of his scientific

work in Heterocycles,

1994, 37, pp.3130.

He is actively travel, and

engaged in research and teaching, editing, industrial consulting, windsurfing.

international

Stanislaw

Rachwal, born in 1949, received his Ph.D. in organic chemistry

in 1978 at

JagielIonian University, Krakow, Poland. He was an Assistant Professor University (1980-88). and group leader in the Katritzky

at the Agiellonian University of

group at the

Florida (1988-93).

Currently

he is Senior Scientist at Pharmos

Inc., Alachua, Florida.

Major topics of his 60 scientific papers include benzotriazole the preparation sterenchemical of amines and ethers, studies based on NMR. various aspects

as a synthetic auxiliary for chemistry, and

of heterocyclic

Bogumila Jagiellonian

Rachwal, University,

horn in 1949, received

her MS in chemistry

in 1980 at the

Krakow, Poland. She was a chemistry from 1978-88, and a research

teacher at the Technical at the University of

High School in Krakow Florida (with Professor

specialist

Katritzky) from 1988-96. She is currently a Research Scientist at

Pharmos Inc., Alachua, Florida and the proud mother of four children and over SO0 new compounds.

15070

A. R. KATRITZKY

et al.

Alan R. Katritzky

Stanislaw Rachwal

Bogumila Rachwal