ARTICLES

PUBLISHED ONLINE: 2 NOVEMBER 2015 | DOI: 10.1038/NCHEM.2367

A steric tethering approach enables

palladium-catalysed C–H activation of primary
amino alcohols
Jonas Calleja†, Daniel Pla†, Timothy W. Gorman†, Victoriano Domingo†, Benjamin Haffemayer
and Matthew J. Gaunt*

Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing
molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the
construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general
palladium-catalysed strategy for the functionalization of aliphatic C–H bonds within amino alcohols, an important class of
small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols
into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C–H activation.
Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the
aliphatic amine substituents in an ideal geometry for C–H activation. This catalytic method directly transforms simple,
easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can
streamline the synthesis of biologically important amine-containing molecules.

M
ethods that enable the practical and selective functionaliza-
tion of traditionally unreactive aliphatic C–H bonds have
synthetic applications in fields that range from drug
discovery to advanced materials1–7. One of the major challenges
facing the continued advance of this field is the development of
strategically important reactions on aliphatic molecules containing
synthetically useful functional groups8. Over the past decade,
chemists have found ways to tailor the electronic properties of
directing functionalities and ligands to enable C–H activation in
aliphatic hydrocarbons displaying carboxylic acid, hydroxyl
or derivatives of these common motifs, via a process called
cyclometallation9–19. In light of these successful advances, it would
be expected that C–H activation reactions on aliphatic amines
would follow a similar pathway; the nitrogen motif in aliphatic
amines is an excellent coordinating group for electrophilic
transition-metal complexes such as Pd(II) salts and should provide
an ideal pathway to steer C–H activation via cyclometallation.
However, the strong metal binding properties of the amine give
rise to the formation of very stable bis(amine) Pd(II) complexes
that ultimately restrict the utility of these compounds in C–H

a c HO O O
O CH3
AcO H R
Pd(OAc)2 H Pd Fast AcO N H2N OH
N O Pd H
R–NH2 H OAc
H N
Slow Me
Aliphatic n R H
primary amine H
Synthetic building blocks:
Mono-amine Pd(II) complex: Bis(amine) Pd(II) complex: quaternary α-amino acids
essential for C–H activation stable complex
Me
OH NH2
b OH HO
OH
O O
N Me
H
HO Pd-catalysed HO Me
O OH
C–H bond S O
functionalization O
H2N N H2N
Simple ketone H Tether removal N
as steric tether H O nC H
8 17
H H
Me

Hindered secondary amine:

Simple amino alcohol: reactive towards C–H Complex amino alcohol: Natural products (lactacystin): Medicines (Gilenya):
inactive to C–H activation activation broad synthetic utility proteasome inhibitor multiple sclerosis

Figure 1 | C–H activation on aliphatic amines. a, Binding of primary amines to palladium acetate. Although the intermediate mono-amine Pd(II) complex is
transiently formed, the corresponding bis(amine) Pd(II) complex is stable and predominates. b, A sterically controlled strategy to enable C–H activation in
primary amino alcohols. c, The broad utility of fully substituted primary amino alcohol derivatives.

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. †These authors contributed equally to this work.
* e-mail: mjg32@cam.ac.uk

NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry 1

© 2015 Macmillan Publishers Limited. All rights reserved

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367

a Working hypothesis Hydrogen bond locks

amine orientation
O Amine association
CH3 CH3
O O
N H3C
H Amine dissociation H
H O O
O N N
Pd O
H O Amine association Pd O
1 int-I N
O
O H
CH3 CH3
H O
Pd(OAc)2 C–H bond
H3C
ideally positioned
C–H activation
int-II
CH3
H
O
N Hindered environment
O Pd O around Pd-centre
O int-III destabilizes bis(amine)
complex
N
Functionalization step
H c Molecular calculations

2 Pd(OAc)2

ΔG298 = –11.2 kcal mol –1

b Initial results for C–H activation and functionalization
H3 C CH3
1a
ΔG343 = –13.1 kcal mol –1

O O O O O
O H
1.5 equiv. Pd(OAc)2 H CH3
CH3 Pd N CH3 O
Pd
N CH3 N H
CHCl3 Pd O
H room temperature O O
CH3 O O N
O O Pd
O
1a H3C CH3
O
H3C
5 mol% Pd(OAc)2 int-IV-1a H CH3
PhI(OAc)2 PhI(OAc)2
PhMe int-I-1a
PhMe/Ac2O
60 ºC 60 ºC
ΔG298 = +1.2 kcal mol–1
1a
69% yield ΔG343 = +0.4 kcal mol–1
OAc
CH3
H O
CH3
O int-IV-1a (X ray) N Pd O O
O H3C CH3
CH3 H
O
N OAc N
O Pd
H H3C O
N
OAc Putative Pd(IV) intermediate, int-V-1a O H
H3C CH3
3a O
H3C

int-II-1a

Figure 2 | Conceptual approach and preliminary studies towards C–H activation of amino alcohols. a, Working hypothesis for the C–H activation strategy.
A crucial hydrogen bond (blue) locks the conformation of the amine with respect to the palladium, positioning the C–H bond in an ideal geometry for
activation and intensifies interactions between the amine substituents ligated across the Pd(II) centre. b, Cyclopalladation of the amino alcohol derivative and
functionalization of the resulting carbon–palladium bond leading to a catalytic C–H acetoxylation. Cyclopalladation via a five-membered ring intermediate was
confirmed by X-ray diffraction of a single crystal (int-IV–1a). c, The putative bis(amine) complex is disfavoured on the basis of interactions between the
ligated amines. Molecular calculations confirm that the mono-amine complex int-I–1a is 1.2 kcal mol−1 (ΔG298K) lower in energy than the bis(amine) complex
int-II–1a. The bis(amine) complex is not observed experimentally.

activation reactions (Fig. 1a)20. The pathway for C–H bond cleavage
with Pd(II) salts requires liberation of a coordination site occupied
by one of these amines, but their strong coordinating power
means that there is little driving force for the release of an amine
ligand from the bis(amine) Pd(II) complex. As a result, C–H
activation reactions on aliphatic amines remain a major challenge,
and successful examples require electronic modification of the
nitrogen with strongly electron-withdrawing sulfonyl or bespoke
carbonyl groups to attenuate the metal coordinating power
of the amino function21–24. Despite the elegance of these methods,
the auxiliary function can sometimes be difficult to remove after
the C–H activation step. Given the importance of aliphatic amines
to biological systems25, there is a need to develop new strategies to
harness the coordinating ability of the free (N–H) amine group in
order to fully explore the potential of amine-directed C–H activation
in complex molecule synthesis.
Steric parameters have been used to influence C–H activation
reactions, although they are less common than electronic control
strategies. For example, minimizing steric interactions between cat-
alyst, substrate or ligand has been shown to steer selectivity and
reactivity in arene borylation reactions26–30. However, the use of
the steric properties of a molecule to promote aliphatic C–H acti-
vation is a significantly less explored area31. Recently, we discovered
that a specific class of highly hindered, secondary aliphatic amine
can successfully direct Pd-catalysed C–H activation through a
novel four-membered ring cyclopalladation pathway32. Although a
useful and practical method to form a class of previously inaccess-
ible amines, the generality of the process is currently limited by
the structural requirements of the starting materials. Inspired by
these discoveries, we questioned whether a new strategy could be
designed for the functionalization of primary aliphatic amines (tra-
ditionally incompatible with catalytic C–H activation reactions but
extremely versatile synthetic building blocks) by transiently convert-
ing these substrates into secondary amines to facilitate C–H activation
(Fig. 1b). In this context, we recognized three factors that should
guide our C–H activation blueprint: (1) the sterically controlling

2 NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry

© 2015 Macmillan Publishers Limited. All rights reserved

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367 ARTICLES
Table 1 | Palladium-catalysed C–H acetoxylation of amino would serve two important purposes: (1) to orient the amine substi-
alcohol derivatives. tuents in the bis(amine) Pd(II) complex (int-II) in such a way that
interactions between the aliphatic groups would be intensified,
O O
enabling amine dissociation to form the κ2-bound acetate inter-
5 mol% Pd(OAc)2
N N mediate (int-I) empirically required for C–H bond cleavage (to
H
PhI(OAc)2, PhMe/Ac 2O
H int-III)36,37; (2) to lock the conformation of the amine with
60 ºC
OAc
respect to the palladium centre (in int-I), thereby projecting the
1 H 3
targeted C–H bond into an optimal trajectory for activation. (It is
possible that the inductive electron-withdrawing effect of the C–O
O O O Me
bond may also influence the capacity for the nitrogen to bind to
Me
N N
Me
N
Me the palladium centre; this could possibly disfavour the formation
H H H
of the bis(amine) complex and promote C–H bond cleavage
through the mono-ligated species.) Reaction of the carbon–
OAc OAc OAc
3a, 69% 3b, 82% 3c, 84% palladium bond in int-III can be achieved via the action of a
3 g scale number of external reagents, forming functionalized products (2).
O O O To test this hypothesis we first prepared a representative
N,O-ketal 1a from a commercial amino alcohol and cyclohexanone
N Me
N 2 N 3 (see Supplementary page 6 for details). This ketone was selected for
H
H H two reasons. First, we reasoned that it should provide the requisite
OAc OAc OAc bulk to facilitate the amine dissociation step when bound to the pal-
3d, 75% 3e, 12% 3f, 63%
ladium centre. Second, the methylene C–H bonds in the cyclohexyl
motif are less likely to undergo activation than substituents derived
O O O O
from a ketone containing terminal C–H bonds. To investigate the
OMe OTIPS OnBu
N N N 6
C–H activation step we attempted to prepare the bis(amine) Pd(II)
H H H complex (corresponding to int-II), which we anticipated would be
OAc OAc OAc
the resting state of any catalytic reaction (Fig. 2b). However, when
3g, 80% 3h, 82% 3i, 83% we treated secondary amine 1a with palladium acetate at room
Ts temperature, none of the expected bis(amine) complex was observed,
O O N O and instead we directly isolated the corresponding trinuclear cyclo-
O
Me palladation complex int-IV–1a (determined by X-ray diffraction of
N N CO2Me
4
N 2
a single crystal) in reasonable yield. Not only does this result
H H
H
OAc contrast with those found for other amines, which readily form a
OAc OAc stable bis(amine) complex at room temperature32, but this reaction
3j, 79% 3k, 63% 3l, <5% is also a rare example of a remarkably mild palladium-mediated
C–H bond cleavage within an aliphatic framework38. Interestingly,
O O Me O
calculations performed on the basis of the proposed pathway sup-
OTBS Me
N N Me Me N
ported the presence of a hydrogen bond between palladium-
H bound amine(NH) and acetate ligands, but also identified that the
H H
Me
putative mono-amine Pd(II) complex, int-I–1a, was slightly lower
OAc OAc OAc
3m, 69% 3n, 39% 3o, 0% in energy than the corresponding bis(amine) Pd(II) complex
int-II–1a, most probably due to interactions between the two
amines ligated to the palladium centre (Fig. 2c). This also supports
component should not be a permanent aspect of the amine substrate; our hypothesis that although these two species may be in equili-
(2) a broad range of C–H transformations should be amenable to the brium, the hindered nature of the amine means that the crucial
C–H activation strategy; (3) the starting amines should have well- mono-amine Pd(II) complex is both thermodynamically and kineti-
established synthetic utility, such that the products of C–H activation cally favoured over the bis(amine) Pd(II) complex and leads to facile
could be used to streamline the synthesis of biologically and pharma- C–H activation (Supplementary page 222). Encouraged by the facile
ceutically important molecules. Taken together, we proposed that nature of the C–H activation we were able to quickly establish that
aliphatic amino alcohols containing a fully substituted carbon atom the carbon–palladium bond in the cyclopalladation complex was
would represent a particularly useful class of molecules upon reactive towards chemical oxidants such as iodosobenzene diacetate
which to test this C–H activation strategy via a broadly applicable (PhI(OAc)2) to generate the acetoxylation product 3a, formed
five-membered ring cyclopalladation pathway. Highly functionalized from a reductive elimination from a high-valent palladium
variants of this very useful building block are a common feature in intermediate39. Moreover, this stoichiometric reaction could be
many biologically important molecules (Fig. 1c)33–35. readily converted to a catalytic process, and after a brief assessment
of the reaction parameters, optimal conditions enabled the con-
Results and discussion version of amine 1a to the acetoxylated product 3a in 69% yield
A detailed description of our working hypothesis towards the C–H on a 3 g scale.
activation of primary amino alcohol derivatives is outlined in The new catalytic C–H acetoxylation reaction displayed broad
Fig. 2a. Central to our design was a simple ketone, deployed tempor- scope, as demonstrated by successful transformations on substrates
arily to bridge the oxygen and nitrogen atoms of the amino alcohol, containing simple alkyl chains of varying substitution patterns, aryl
forging a hindered N,O-ketal motif (1) and masking the primary groups, protected hydroxyl functionality, carbonyl motifs and
amine function. We predicted that this secondary amine (1) nitrogen-containing heterocycles (3a–d, f–k, Table 1). Interestingly,
would bind to the palladium catalyst in such a way that the com- a methyl-substituted amino alcohol derivative (forming 3e)
plexation would be accompanied by the formation of a hydrogen performed poorly in this reaction, which is possibly a reflection of
bond between the acetate ligand on the palladium and the free the reduced steric hindrance around the nitrogen atom that
(N–H) of the amine (to int-I). This non-covalent interaction precludes effective ligand dissociation from the palladium centre.

NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry 3

© 2015 Macmillan Publishers Limited. All rights reserved

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367

Table 2 | Palladium-catalysed C–H arylation of amino alcohol derivatives.

O O
15 mol% Pd(OAc)2
N N
Ar(Mes)–I–OTf, NaOAc
H 1,2-DCE, 70 ºC H

1 H 4 Ph

Me Me Me Me Ts
Me
O O O Me O N
Me O
Me 2
Me
N N N N 2 N 2
Me H Me H Me H Me H
Me H
Ph Ph Ph Ph
4a, 74% 4b, 74% 4c, 82% 4d, 71% 4e, 84% Ph

Me Me Me Me Me
O O O O O O O O

On-Bu OTBS Me O
N 3 N 6 N N 4 N
Me H Me H Me H Me H Me H

Ph Ph Ph Ph Ph
4f, 68% 4g, 71% 4h, 68% 4i, 75% 4j, 68%

Me
O Me

Me
N CF3 CO2Et O
Me H Me
Cl Br F CO2Et Me OMe O

Me
Ar 4k, 77% 4l, 70% 4m, 71% 4n, 64% 4o, 72% 4p, 62% 4q, 63% 4r, 60% 4s, 70% 4t, 45%

Notably, we do not see any products that could arise from the
potentially competitive four-membered ring cyclopalladation
pathway. Strongly electron-withdrawing groups adjacent to the
amine motif also failed to produce the desired product (3l) in
acceptable yield; however, the protected hydroxymethyl motif is
readily accommodated and produces the desired orthogonally
protected trifunctional amine (3m).
We assumed that C–H acetoxylation most probably proceeds via
a pathway involving a high-valent palladium intermediate and
hence reasoned that the strategy should be amenable to other
mechanistically linked transformations and, in particular, those
involving carbon–carbon bond formation39. Accordingly, the
N,O-ketal 1a was treated with a related hypervalent iodine reagent,
diphenyliodonium triflate, and we were pleased to find that the cor-
responding arylated amine product was formed in modest yield. A
survey of reaction conditions (not shown, see Supplementary page 45)
revealed an optimal process that involved the treatment of the starting
amine with 15 mol% Pd(OAc)2 and Ph2IOTf in the presence of
sodium acetate in 1,2-dichloroethane and stirring at 70 °C to
yield the desired arylated product. The triflate counterion of
the diaryliodonium species provided the best reaction compared
with other salts, and the presence of a base was essential for a
productive reaction and probably serves to quench the trifluoro-
methanesulfonic acid that is formed as a byproduct from the diary-
liodonium salt. Interestingly, slight modification to the N,O-ketal
motif proved to be most important for obtaining a good yield of
the arylated products (Table 2, 4a–j). We found that palladium-cat-
alysed arylation with N,O-ketals derived from cis-3,5-dimethyl
cyclohexanone afforded a routinely superior yield to the parent
cyclohexanone congeners, and we ascribe this reactivity to a subtle
conformational effect that stabilizes the N,O-ketal in its reactive con-
formation40. The scope of the arylation process revealed the phenyla-
tion of a range of N,O-ketals in good yields to provide an interesting
class of functionalized phenethyl amine derivatives. Similarly, aryl
groups displaying electron-rich, electron-deficient and synthetically
useful functionality could be transferred using substituted diaryliodo-
nium triflates41, providing further versatility to the increasingly broad
activation process (Table 2, 4k–t).
To further demonstrate the utility of this C–H activation strategy,
we sought to adapt the reactivity of the key cyclopalladation inter-
mediate towards a catalytic cycle involving the Pd(II)/Pd(0) redox
shuttle, thereby enabling a different type of transformation on this
amino alcohol scaffold (Table 3). We reasoned that interception
of the cyclopalladation complex with carbon monoxide would
lead to a one carbon homologation and concomitant cyclization
to form a pyrrolidinone, a five-membered nitrogen-containing
heterocyclic motif common to many natural products42. We tested
this hypothesis by subjecting a solution of int-IV–1a to a CO atmos-
phere and found that the corresponding pyrrolidinone 5a was
formed in modest yield. A comprehensive optimization study
towards a catalytic reaction led to a number of key observations:
(1) palladium acetate is the optimal catalyst; (2) silver salts are
crucial to the success of the reaction; and (3) a commercial gas
mixture composed of 6.25% CO in air and used at a slight positive
pressure provides the best results. Although the role of the silver salt
may be solely that of a terminal oxidant, it is also possible that it
forms a bimetallic complex with the palladium, which could be
important for the observed reactivity43,44.
The scope of the carbonylation reaction proved to be general and
provided good yields of pyrrolidinone products (5) containing a
variety of useful functionality (Table 3). In addition to the routine
alkyl substituents (in 5a–d), we found that amino-alcohol deriva-
tives displaying aryl (5e), protected hydroxyl (5f,g) and amino
motifs (5h) all worked well in the C–H carbonylation process.
The reaction proceeded diastereoselectively when presented with
the choice of two methyl groups (5i). In the case of the formation
of 5d, the palladium has to choose between a four- and five-mem-
bered ring cyclopalladation and we observe that the reaction pro-
ceeds through the larger ring pathway, in contrast to our previous
studies32. Although the reaction is less efficient when there is a

4 NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry

© 2015 Macmillan Publishers Limited. All rights reserved

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367 ARTICLES
Table 3 | Palladium-catalysed C–H carbonylation of amino corresponding allylic amine and so the reaction mixture was
alcohol derivatives to pyrrolidinones. directly hydrogenated to the form saturated pyrrolidine. We
showed that the reaction displayed a broad substrate scope and
O O
supported the presence of different useful functional groups.
10 mol% Pd(OAc)2
N N We also noticed a modest improvement in yield when the size of
6.25% CO in air at 2 bar. the alkyl substituent increases (6a–c). In some cases, however, we
H 2 equiv. AgOAc, PhMe, 100 ºC; H2
H
O found that the acetone-derived N,O-ketal (to 6e, 6f and 6m)
1 5
performed better than the corresponding cyclohexyl group,
highlighting the subtle steric balance at work in this process.
O O O
In addition to the coupling with acrylates, we were also able to
N Me N Me N Me show that vinyl sulfones work well in the C–H alkenylation
Me process (to 6o), providing useful products with opportunities for
O O O further elaboration via well-established methods.
5a, 95% 5b, 89% 5c, 89%
Applications of the C–H activation strategy. Taken together, the
O O O
series of four amine directed C–H activation reactions enables a
3
Me single amino alcohol derivative to be transformed into a diverse
N N N OTBS
range of architecturally complex amines. The C–H activation
O O O strategy provides a convenient gateway to a wide range of
5d, 83% 5e, 61% 5f, 93%
subsequent transformations by manipulation of the intrinsic
functionality within the products and could be used to readily
O O O access the core framework of various natural products, biologically
Ts
3 Me
N N N N
OTBS
Et Me
O
Table 4 | Palladium-catalysed C–H alkenylation of amino
O O
alcohol derivatives to pyrrolidines.
5g, 79% 5h, 82% 5i, 37% (4:1 d.r.) O O
O 10 mol% Pd(OAc)2
O O N N
CO2Me N Me H CO2TFE (3 equiv.) TFEO2C
N N Me AgOAc, Li3PO4, DCE, 120 ºC; Pd/C/H2
1 H 6 H
O
O O
5j, 40% 5k, 95% O O O
5l, 83%
N N Me N Me
Me

RO2C RO2C RO2C Me

strongly electron-withdrawing group adjacent to the amine func- H H H
tion, useful yields of the desired product can still be obtained (5j). 6a, 65% 6b, 74% 6c, 82%
In all of these cases, we observe a small amount of the α,β-unsaturated
pyrrolidinone product that we believe originates from C(sp 2)–H O
4
Me O Me O

activation of an allylic amine derivative formed from β-hydride

2 3

N Me Me N Me N
elimination of a cyclopalladation intermediate. This product can
RO2C RO2C RO2C
be readily processed to the saturated pyrrolidinone by direct hydro-
H H H
genation of the reaction mixture. The intermediacy of the allylic
amine was confirmed by selective carbonylation of the sp 2 hybri- 6d, 70% 6e, 54% 6f, 65%

dized C–H bond to give the expected unsaturated pyrrolidinone O O O

product in excellent yield (5k). 6 2 2

In a final venture to establish the generality of this activation N OEt N N O

strategy, we sought to address a traditionally challenging carbon– RO2C O RO2C N RO2C

O
carbon forming process based on C–H alkenylation. Although H H Ts H
examples of this coupling reaction have recently emerged for ali- 6g, 67% 6h, 67% 6i, 54%
phatic systems, combining C(sp 3)–H bonds with alkenes remains
an important goal45,46. Guided by our experience with the C–H car- O O O

bonylation, we first assessed the reaction of amine 1a with trifluoro- OTBS OAc
N N N
ethyl acrylate in the presence of palladium acetate and silver acetate.
RO2C NPhth RO C RO2C
Pleasingly, we observed the formation of pyrrolidine 6a, 2
H H H
which formed from a C–H alkenylation reaction followed by
intramolecular aza-Michael addition (Table 4). After surveying a 6j, 72% 6k, 73% 6l, 50%

range of reaction conditions we found that Li3PO4 and the use of Me O O O

the trifluoroethyl acrylate as the alkene coupling partner were also Me
Me N Me
essential for a good yield. When these were combined in an N OTBS
O
N
Me
optimal process, which involved the treatment of amine 1a with RO2C Ar PhO2S Me
H
trifluoroethyl acrylate, 10 mol% Pd(OAc)2 , AgOAc and Li3PO4 in H O H
1,2-dichloroethane at 120 °C, pyrrolidine 6a was isolated in 65% 6m, 71% 6n, 65% Ar = 3,5-(CF3)2-C6H3 6o, 77%
yield as a single diastereomer. Again, we observed a small
R = TFE (2,2,2-trifluoroethyl).
amount of an unsaturated pyrrolidine product derived from the

NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry 5

© 2015 Macmillan Publishers Limited. All rights reserved

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367

a Derivatization of pyrrolidinones

HO O
aq. HCl LiHMDS, THF, –78 ºC;
HN N Me
Me
>95% yield MeI
(from 5a) 86% yield (4.1:1 d.r.) O
O O
7 (from 5a) 8 Me
N R

O OTBS O
HO
Tf2O then 5a, g HCl then
N
HN Me
2 equiv. EtMgBr LiAlH4
51% yield 82% yield
Me 9 (from 5g) (from 5a) 10

b Sequential C–H activation to complex amines 10 mol% Pd(OAc)2

O
6.25% CO in air at 2 atm.
N OAc
2 equiv. AgOAc, PhMe, 115 ºC
then H2, 84% yield 11
O

R
O 5 mol% Pd(OAc)2 O 10 mol% Pd(OAc)2 O
Me PhI(OAc)2 TFEO2C
OAc OAc
N N N
PhMe/Ac 2O, 60 ºC AgOAc, Li3PO4, 120 ºC
R H Me 69% yield H Me DCE, 50% yield 6l
TFEO2C
3a H
1a R = H, 1as R = Me Me
Me
5 mol% Pd(OAc)2 O 15 mol% Pd(OAc)2 O
PhI(OAc)2 Ph2IOTf
OAc OAc
N N
PhMe/Ac 2O, 60 ºC NaOAc, DCE, 70 ºC H
65% yield Me H 40% yield Me
Me 12
3p Ph

c Synthesis of fingolimod (Gilenya)

O
(1) Me
O HO
(3) 15 mol% Pd(OAc)2
Me OTBS
HO NaOAc, DCE, 90 ºC
Me Me O N (4) HCl, dioxane
72% yield H2N
TsOH H
Me OTBS Me
H2 N (2) TBSCl,
nC H
8 17 95% yield
N HO
nC
8H17
DMF, imidazole H
75% yield Me Me Me
HO Me
(over two steps) Fingolimod (Gilenya) 16a
13 (commercial) 14 15 4u
Me I
nC
OTf 8H17

HO
HO
HO HO HO
H2N
H2N
H2N H2N H2N
nC H
8 17
nC H n Br
8 17 Me C8H17 HO

16b OH 16c Me 16d 16e

Readily prepared analogues
N
Ts Fingolimod analogues prepared by these methods

Figure 3 | Synthetic applications of functionalized amino alcohol derivatives. a, Derivatization of pyrrolidinones. A range of transformations of the
pyrrolidinone core are shown including ketal-hydrolysis to 7; diastereoselective enolate alkylation to 8; a reductive Grignard addition to a highly substituted
pyrrolidine (9); and direct reduction to a simple pyrrolidine (10). b, Sequential C–H activation to complex amines. The new C–H activation reactions can be
sequenced to convert a simple amino alcohol derivative into complex products. c, A synthesis for the straightforward preparation of fingolimod (Gilenya, 16a),
a drug for the treatment of multiple sclerosis, is shown in four steps from commercial materials. The strategy can also be applied to the rapid synthesis of
potentially interesting analogues (16b–e).

relevant molecules and active pharmaceutical agents. A number of groups can be functionalized using sequential C–H activation
simple transformations could be applied to each of these products processes via C–H acetoxylation and then C–H carbonylation
to formulate value-added functional molecules: (1) the functional (to 11), C–H alkenylation (to 6l) and C–H arylation (to 12) to
groups within the pyrrolidinones (5) derived from the C–H form complex amino alcohol derivatives form simple precursors
carbonylation reaction can be subjected to N,O-ketal hydrolysis (Fig. 3b). Finally, to illustrate the potential efficacy of this C–H
(to 7), alkylation (to 8), Grignard addition (to 9) and reduction activation strategy, we were able to apply the C–H arylation
(to 10), further modifying the heterocyclic ring (Fig. 3a); (2) using process to the synthesis of Gilenya (fingolimod 16a), Novartis’
the symmetrical amino alcohol derivative 1a/1as, each of the ethyl billion-dollar-per-year drug for the treatment of multiple sclerosis

6 NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry

© 2015 Macmillan Publishers Limited. All rights reserved

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367
(Fig. 3c). Using the new C–H arylation, we can synthesize the active
pharmaceutical agent in four steps from an inexpensive material
(13). The C–H arylation of 14 with the readily available
diaryliodonium salt 15 proceeds in high yield to construct the
framework of fingolimod 4u. Acid hydrolysis of the protecting
groups affords the active pharmaceutical ingredient 16a. Given
that fingolimod has multiple indications and is currently in
seven clinical trials across a number of therapeutic areas47, a
streamlined strategy for the synthesis of analogues would be
extremely useful. By changing the amine starting material, the
diaryliodonium salt or using the sequential functionalization
tactic (vide supra), we were able to rapidly access a representative
selection of potentially interesting fingolimod analogue molecules
using this strategy (16b–e).
The advances outlined here demonstrate that amino alcohols are
ideal candidates for a remarkably broad C–H activation strategy. We
believe that two factors are responsible for this facile C–H activation:
(1) the presence of a putative hydrogen bond between the palladium
bound amine and acetate ligands is important in facilitating the
C–H activation step as it locks the conformational relationship
between the two groups and projects the C–H bond into an ideal
trajectory for palladation; (2) the hindered nature of the amine sub-
strates destabilizes the off-cycle bis(amine) palladium complex to
favour the mono-ligated species required for C–H activation.
The range of palladium-catalysed C–H activation reactions shown
here enable either simple functional group additions or frame-
work-changing transformations on a versatile and synthetically
useful amino alcohol scaffold. Taken together, the broad scope
and applications of these transformations suggest that the C–H acti-
vation strategy will be beneficial to the synthesis of complex amines
with both established and unexplored biological properties and will
be of widespread utility to chemists in both academic and
industrial institutions.
Received 27 May 2015; accepted 2 September 2015;
published online 2 November 2015
References
1. Jia, C., Kitamura, T. & Fujiwara, Y. Catalytic functionalization of arenes and
alkanes via C−H bond activation. Acc. Chem. Res. 34, 633–639 (2001).
2. Godula, K. & Sames, D. C–H bond functionalization in complex organic
synthesis. Science 312, 67–72 (2006).
3. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal
carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008).
4. Davies, H. M. L., Du Bois, J. & Yu, J.-Q. C–H functionalization in organic
synthesis. Chem. Soc. Rev. 40, 1855–1856 (2011).
5. Yamaguchi, J., Yamaguchi, A. D. & Itami, K. C–H bond functionalization:
emerging synthetic tools for natural products and pharmaceuticals. Angew.
Chem. Int. Ed. 51, 8960–9009 (2012).
6. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F.
C–H activation for the construction of C–B bonds. Chem. Rev. 110,
890–931 (2010).
7. Wencel-Delord, J., Dröge, T., Liu, F. & Glorius, F. Towards mild metal-catalyzed
C–H bond activation. Chem. Soc. Rev. 40, 4740–4761 (2011).
8. Jazzar, R., Hitce, J., Renaudat, A., Sofack-Kreutzer, J. & Baudoin, O.
Functionalization of organic molecules by transition-metal-catalyzed C(sp 3)–H
activation chemistry. Chem. Eur. J. 16, 2654–2672 (2010).
9. Daugulis, O., Do, H.-Q. & Shabashov, D. Palladium- and copper-catalyzed
arylation of carbon–hydrogen bonds. Acc. Chem. Res. 42, 1074–1086 (2009).
10. Engle, K. M., Wu, H.-C. & Yu, J.-Q. Weak coordination as a powerful means for
developing broadly useful C–H functionalization reactions. Acc. Chem. Res. 45,
788–802 (2012).
11. Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and
selectivity in a synthetically versatile aryl C–H olefination. Science 327,
315–319 (2010).
12. Wasa, M., Engle, K. M. & Yu, J.-Q. Pd(0)/PR3-catalyzed intermolecular arylation
of sp 3 C–H bonds. J. Am. Chem. Soc. 131, 9886–9887 (2009).
13. Simmons, E. M. & Hartwig, J. F. Catalytic functionalization of unactivated
primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012).
14. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of
sp 3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127,
13154–13155 (2005).
NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry
© 2015 Macmillan Publishers Limited. All rights reserved
ARTICLES
15. Desai, L. V., Hull, K. L. & Sanford, M. S. Palladium-catalyzed oxygenation of
unactivated sp 3 hybridized C–H bonds. J. Am. Chem. Soc. 126,
9542–9543 (2004).
16. Dupont, J., Consorti, C. C. & Spencer, J. The potential of palladacycles: more
than just precatalysts. Chem. Rev. 105, 2527–2572 (2005).
17. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H
functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
18. Ackermann, L. Carboxylate-assisted transition-metal-catalyzed C–H bond
functionalizations: mechanism and scope. Chem. Rev. 111, 1315–1345 (2011).
19. Colby, D. A., Bergman, R. G. & Ellman, J. A. Rhodium-catalyzed C–C bond
formation via heteroatom directed C–H bond activation. Chem. Rev. 110,
624–655 (2010).
20. Ryabov, A. D. Mechanisms of intramolecular activation of carbon–hydrogen
bonds in transition-metal complexes. Chem. Rev. 90, 403–424 (1990).
21. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of
azetidines, pyrrolidines, and indolines via palladium-catalyzed intramolecular
amination of C(sp 3)–H and C(sp 2)–H bonds at the γ and δ positions. J. Am.
Chem. Soc. 134, 3–6 (2012).
22. Zhang, S.-Y. et al. Palladium-catalyzed picolinamide-directed alkylation of
unactivated C(sp 3)–H bonds with alkyl iodides. J. Am. Chem. Soc. 135,
2124–2127 (2013).
23. Chan, K. S. L. et al. Ligand-enabled cross-coupling of C(sp 3)-H bonds with
arylboron reagents via Pd(II)/Pd(0) catalysis. Nature Chem. 6, 146–150 (2014).
24. Yuan, J., Liu, C. & Lei, A. Construction of N-containing heterocycles via
oxidative intramolecular N–H/X–H coupling. Chem. Commun. 51,
1394–1409 (2015).
25. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation
as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).
26. Cho, J.-Y., Tse, M. K., Holmes, D., Maleczka, R. E. Jr. & Smith, M. R. III.
Remarkably selective iridium catalysts for the elaboration of aromatic C–H
bonds. Science 295, 305–308 (2002).
27. Ishiyama, T. et al. Mild iridium-catalyzed borylation of arenes. High turnover
numbers, room temperature reactions, and isolation of a potential intermediate.
J. Am. Chem. Soc. 124, 390–391 (2002).
28. Ferreira, E. M. & Stoltz, B. M. Catalytic C−H bond functionalization with
palladium(II): aerobic oxidative annulations of indoles. J. Am. Chem. Soc. 125,
9578–9579 (2003).
29. Zhang, Y.-H., Shi, B.-F. & Yu, J.-Q. Pd(II)-catalyzed olefination of electron-deficient
arenes using 2,6-dialkylpyridine ligands. J. Am. Chem. Soc. 131, 5072–5074 (2009).
30. Emmert, M. H., Cook, A. K., Xie, Y. J. & Sanford, M. S. Remarkably high
reactivity of Pd(OAc)2/pyridine catalysts: nondirected C−H oxygenation of
arenes. Angew. Chem. Int. Ed. 50, 9409–9412 (2011).
31. Giri, R., Lan, Y., Peng, L., Houk, K. N. & Yu, J.-Q. Understanding reactivity and
stereoselectivity in palladium-catalyzed diastereoselective sp 3 C−H bond
activation: intermediate characterization and computational studies. J. Am.
Chem. Soc. 134, 14118–14126 (2012).
32. McNally, A., Haffemayer, B., Collins, B. S. L. & Gaunt, M. J. Palladium-catalysed
C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature
510, 129–133 (2014).
33. Bera, K. & Namboothiri, I. N. N. Asymmetric synthesis of quaternary α-amino
acids and their phosphonate analogues. Asian J. Org. Chem. 3, 1234–1260 (2014).
34. Reichard, G. A. & Corey, E. J. Total synthesis of lactacystin. J. Am. Chem. Soc.
114, 10677–10678 (1992).
35. Strader, C. R., Pearce, C. J. & Oberlies, N. H. Fingolimod (FTY720): a recently
approved multiple sclerosis drug based on a fungal secondary metabolite. J. Nat.
Prod. 74, 900–907 (2011).
36. Gorelsky, S., Lapointe, D. & Fagnou, K. Analysis of the concerted metalation–
deprotonation mechanism in palladium-catalyzed direct arylation across a broad
range of aromatic substrates. J. Am. Chem. Soc. 130, 10848–10849 (2008).
37. Garcia-Cuadrado, D., Braga, A. A. C., Maseras, F. & Echavarren, A. M. Proton
abstraction mechanism for the palladium-catalyzed intramolecular arylation.
J. Am. Chem. Soc. 128, 1066–1067 (2006).
38. Giri, R., Chen, X. & Yu, J.-Q. Palladium-catalyzed asymmetric iodination of
unactivated C–H bonds under mild conditions. Angew. Chem. Int. Ed. 44,
2112–2115 (2005).
39. Hickman, A. J. & Sanford, M. S. High-valent organometallic copper and
palladium in catalysis. Nature 484, 177–185 (2012).
40. Darabantu, M. et al. Synthesis and stereochemistry of some 1,3-oxazolidine
systems based on TRIS (α,α,α-trimethylolaminomethane) and related
aminopolyols—skeleton (II): 1-aza-3,7-dioxabicyclo[3.3.0]octanes. Tetrahedron
56, 3799–3816 (2000).
41. Deprez, N. R., Kalyani, D., Krause, A. & Sanford, M. S. Room temperature
palladium-catalyzed 2-arylation of indoles. J. Am. Chem. Soc. 128,
4972–4973 (2006).
42. Donohoe, T. J., Bataille, C. J. R. & Churchill, G. W. Highlights of natural product
synthesis. Annu. Rep. Prog. Chem. B 102, 98–122 (2006).
43. Kozitsyna, N. Y. et al. Novel heterometallic palladium–silver complex. Inorg.
Chim. Acta 370, 382–387 (2011).
7
ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2367

44. Li, S., Chen, G., Feng, C.-G., Gong, W. & Yu, J.-Q. Ligand-enabled γ-C–H
olefination and carbonylation: construction of β-quaternary carbon centers.
J. Am. Chem. Soc. 136, 5267–5270 (2014).
45. Wasa, M., Engle, K. M., & Yu, J.-Q. Pd(II)-catalyzed olefination of sp 3 C−H
bonds. J. Am. Chem. Soc. 132, 3680–3681 (2010).
46. Stowers, K. J., Fortner, K. C. & Sanford, M. S. Aerobic Pd-catalyzed sp 3 C−H
olefination: a route to both N-heterocyclic scaffolds and alkenes. J. Am. Chem.
Soc. 133, 6541–6544 (2011).
47. Kunkel, G. T., Maceyka, M., Milstien, S. & Spiegel, S. Targeting the sphingosine-
1-phosphate axis in cancer, inflammation and beyond. Nature Rev. Drug Discov.
12, 688–702 (2013).
Acknowledgements
The authors acknowledge the Marie Curie Foundation (D.P. and J.C.), the Engineering and
Physical Sciences Research Council (EPSRC) (T.W.G. and M.J.G.) and European Research
Council (V.D. and M.J.G.). The authors thank A. Smalley for density functional theory
calculations and Y. Shimidzu for assistance with optimization of the C–H acetoxylation
reaction. Mass spectrometry data were acquired at the EPSRC UK National Mass
Spectrometry Facility at Swansea University.
Author contributions
J.C., T.W.G., D.P., V.D. and B.H. discovered and developed the reactions. M.J.G. conceived,
designed and directed the investigations and wrote the manuscript.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to M.J.G.
Competing financial interests
The authors declare no competing financial interests.

8 NATURE CHEMISTRY | ADVANCE ONLINE PUBLICATION | www.nature.com/naturechemistry

© 2015 Macmillan Publishers Limited. All rights reserved