Highly enantioselective synthesis of α-(perfluoroalkyl)amines via hydrogenation of enamide precursors in the presence of chiraphos-rhodium catalyst

Article abstract of DOI:10.1016/j.tetasy.2010.05.021

Highly (up to 99% ee) enantio-enriched perfluoroalkyl amines can be synthesized by the perfluoroalkylation of nitriles with Lewis acidic perfluoroalkyl titanate reagents and catalytic asymmetric hydrogenation with the chiraphos-Rh catalyst of the resultan

Full text of DOI:10.1016/j.tetasy.2010.05.021

Tetrahedron: Asymmetry 21 (2010) 1158–1161
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective synthesis of
a-(perfluoroalkyl)amines via
hydrogenation of enamide precursors in the presence of chiraphos-rhodium
catalyst
*
Koichi Mikami , Tatsushi Murase, Lili Zhai, Yoshimitsu Itoh , Shigekazu Ito
Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly (up to 99% ee) enantio-enriched perfluoroalkyl amines can be synthesized by the perfluoroalkyla-
tion of nitriles with Lewis acidic perfluoroalkyl titanate reagents and catalytic asymmetric hydrogenation
with the chiraphos-Rh catalyst of the resultant perfluoroalkyl enamides via base-mediated
tautomerization.
Received 2 February 2010
Accepted 26 April 2010
Available online 6 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
proposed a synthetically simple solution to this long-standing
problem with the development of novel and unusually stable per-
Currently fluoroorganic compounds occupy a privileged posi-
tion in the design of new pharmaceuticals, agrochemicals, and
functional materials.1 In particular, the generally beneficial out-
come of a fluorine substitution for hydrogen has led to the estab-
lishment of a ‘fluorine-scan’ approach for the optimization of
biological activity/stability of drug candidates.2 On the other hand,
the development of fluoroorganic methodology has been lagging
behind the growing demand for fluorine-containing products. In
fluoroalkyl-Ti/Mg ate-type reagents.8
We have also demonstrated that the corresponding imine inter-
mediates can be reduced catalytically with a high degree of asym-
metric induction (up to 93%).9 Continuing to explore the synthetic
opportunities associated with the discovery of these perfluoroalkyl
titanate reagents8,9 and drawing inspiration from the pioneering
work by Professor Kagan on rhodium-catalyzed asymmetric hydro-
genation,10,11 we report herein the first example of highly (up to
99% ee) enantioselective hydrogenation of perfluoroalkyl ena-
mides, obtained from nitriles and Lewis acidic titanate reagents,8
using the simple chiraphos12-rhodium complex (Scheme 1). It
should be noted that the hydrogenation conditions for non-fluori-
nated enamides,13 using simple chiraphos-rhodium com-
plexes12,14,15, generally give moderate levels of enantioselectivity
depending heavily on the geometry of starting enamides.
particular,
a-perfluoroalkyl amino compounds, as analogues of
naturally occurring amines and aminoacids, are of great impor-
tance in bioorganic, medicinal chemistry, and related areas.3 One
of the most general approaches to
a-perfluoroalkyl amino com-
pounds is a biomimetic transamination of
a-perfluoroalkyl car-
bonyl compounds with benzylamine and its derivatives.4 While
the stoichiometric asymmetric version of this reaction5 as well as
other chiral auxiliary-based methods6 provides reliable access to
the enantiomerically pure a-perfluoroalkyl amino derivatives, the
2. Results and discussion
catalytic asymmetric synthesis of these target compounds is
clearly under development.7
The fluorine-containing enamides (Scheme 2) were readily
available via our standard addition of the Lewis acidic perfluoroal-
kyl titanate reagents to the corresponding nitriles, followed by
base-mediated tautomerization and protection of the enamine
functionality.
Triethylamine (Et3N) was found to be the best among other organ-
icbases (DBU, DABCO, Et3N, etc) to completethe desired tautomeriza-
tion. In a typical procedure, after completion of perfluoroalkylation of
thestarting nitrilewith the perfluoroalkyl titanatereagent, the result-
ing mixture was treated with Et3N, followed by protection of the free
amino group with acetic anhydride or di-tert-butyl pyrocarbonate to
afford the corresponding perfluoroalkyl enamides in good isolated
yields (Table 1). In the absence of base (Et3N), acidic work-up of the
By analogy with fluorine-free organic methodology, one can
envision that addition of perfluoroalkyl Grignard reagents to ni-
triles, followed by asymmetric hydrogenation, would ultimately
provide a general approach for the preparation of a-perfluoroalkyl
amino compounds in enantiomerically pure form. However, reali-
zation of this method is generally plagued by the instability of fluo-
rine-containing Grignard-type reagents. Recently, we have
* Corresponding author. Tel.: +81 3 5734 2142; fax: +81 3 5734 2776.
E-mail address: mikami.k.ab@m.titech.ac.jp (K. Mikami).
Present address: Department of Chemistry and Biotechnology, School of Engi-
neering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.021

K. Mikami et al. / Tetrahedron: Asymmetry 21 (2010) 1158–1161
1159
Ti-(OiPr)4Mg+Br
N
RfTi(OiPr)4MgBr
RCN
R
Rf
NHPG
PG2O
Base
H2
Rh / chiraphos*
NHPG
∗
R'
R'
Rf
Rf
up to 98% yield, 99% ee
Scheme 1. Enantioselective hydrogenation of perfluoroalkyl enamides by chiraphos-Rh.
1) RfTi(OiPr)4MgBr (2.5 eq.)
2) NEt3 (1.0 eq.)
3) PG2O (2.0 eq.)
Base
Base
NPG
NHPG
Rf
H
H
R
R
CN
Rf
NPG
>
Rf
Et2O, r.t.,
R
H
H
R
Scheme 2. One-pot preparation of perfluoroalkyl enamides.
Z
E
Scheme 3. Stereoselective deprotonation of imine intermediate.
Table 1
Stereoselective synthesis of perfluoroalkyl enamides
phos. Most interestingly, the observed stereochemical outcome did
not depend on the ratio of the corresponding geometrical isomers
(Scheme 4). The absolute configuration of the (R)-(+)-perfluorobu-
tyl phenethyl amine was determined by comparison of the specific
rotation of the authentic sample of (R)-(+)-perfluorobutyl phen-
ethyl amine prepared.9
Entry
Substrate
Product
% Yielda (Z/E)
CN
CN
NHAc
C4F9
NHAc
Ph
1
87 (96:4b)
Ph
Ph
CN
2
3
43 (67:33b)
52 (88:12b)
Ph
C4F9
NHAc
In sharp contrast to the stereochemical outcome of non-fluori-
nated enamide reactions, hydrogenation of the perfluoroalkyl ena-
mides using the Rh-chiraphos complex gave the acyclic
perfluoroalkyl sec-amine in high chemical yield and, most signifi-
cantly, with high enantioselectivity (Table 2). In all cases of the
starting perfluoroalkyl enamides, the chiral perfluoroalkylated
amines were obtained with high enantioselectivities (91–99% ee)
(entries 1–8). Even in the case of the phenylacetonitrile-derived
enamide, a high level of enantioselectivity (98% ee) was obtained,
regardless of the relatively high proportion of the minor geometri-
cal isomer (entry 6). The use of a MonoPhos (phosphoramidite)-Rh
complex17 also gave the perfluoroalkylated amine with similar
yield and enantioselectivity (entry 5). However, in the case of a
phenyl-bearing starting enamide, the MonoPhos-catalyzed reac-
tion did not produce the expected perfluoroalkyl amine (entry 7).
When a generally more synthetically useful Boc-protecting group
was employed, the perfluoroalkyl amines were obtained with sim-
ilarly high enantioselectivities (entry 8). Based on the results ob-
tained, we believe that the application of the less sterically
demanding CHIRAPHOS ligand has a practical advantage providing
virtually complete enantioselectivity constantly, irrespective of the
steric and electronic properties of the substituents on the starting
perfluoroalkyl enamides.
The high enantioselectivity observed in this study is in sharp
contrast to non-fluorinated enamides with the application of
CHIRAPHOS, and can be rationalized by taking into account the sig-
nificant stereoelectronic effects of a perfluoroalkyl group. The
‘unsaturate/dihydride’ mechanism in the hydrogenation of non-
fluorinated enamides13 with the chiraphos-Rh complex has been
extensively investigated by Halpern18 and Brown.19
The Rh complex with (R,R)-CHIRAPHOS and the enamides are
reported to reversely interact in a bi-dentate fashion leading irre-
versibly to the dihydride complex oxidative addition of molecular
hydrogen. There are two diastereomeric complexes S and R,
depending on the Si/Re-face selection at the enamide, respectively
(Scheme 5). Hydrogen in the less favorable diastereomeric complex
C2H5
C2H5
C3F7
4
5
6
Rf = C4F9
C3F7
C6F13
48
45
54
NHAc
Rf
NHBoc
CH3CN
CH3CN
7
88
C4F9
a
Isolated.
19F NMR analysis.
b
resulting reaction mixtures led to noticeable hydrolysis of the inter-
mediary perfluoroalkyl imines giving rise to the corresponding
ketones.
Both Ac (entries 1–6) and Boc (entry 7) groups enabled the ster-
eoselective formation of the protected enamides. In the case of ali-
phatic nitriles, the corresponding perfluoroalkyl enamides were
obtained essentially as the (Z)-isomers (entries 1, 3, and 7). Various
perfluoroalkyl groups such as C3F7, C4F9, and C6F13 could be intro-
duced into the perfluoroalkyl enamides. Even when R was a steri-
cally demanding and electron-withdrawing aromatic group, the
perfluoroalkyl enamide was also obtained in good yield, however,
as a mixture of the geometric (E/Z)-isomers (entry 2).
The (Z)-geometry of the resultant perfluoroalkyl imines was
proven by NOE experiments. Irradiation at the benzylic methylene
protons showed an increase in the integration of the acetyl-pro-
tecting group (entry 1). The preferential formation of the (Z)-iso-
mers can be rationalized by stereoselective deprotonation of the
imine intermediate because of the severe A(1,2) steric repulsion16
in E between the imine
groups (Rf) (Scheme 3).
We found that highly enantioselective synthesis of chiral sec-
amines could be realized by the catalytic asymmetric hydrogena-
tion of the starting enamides using rhodium complexes with chira-
a-substituents (R) and perfluoroalkyl

1160
K. Mikami et al. / Tetrahedron: Asymmetry 21 (2010) 1158–1161
[Rh(nbd)2]BF4 / (R,R)-CHIRAPHOS (3 mol%)
NHPG
NHPG
Rf
+
H2 (35 atm)
R
R
CH2Cl2, r.t., 20 h
∗
Rf
(S)
up to 98% yield
Ph2P
PPh2
99% ee
(R,R)-CHIRAPHOS
Scheme 4. Highly enantioselective synthesis of chiral sec-amines by chiraphos-Rh.
repulsion
H
Rf
N
H
N
Rf
P
O
O
P
P
Rh
P
Rh
Ph
Ph
(R)
(S)
unfavored but
more reactive
favored but
less reactive
(R, R)-CHIRAPHOS
(S)
(R)
Scheme 5. Highly enantioselective hydrogenation of perfluoroalkyl enamides by chiraphos-Rh.
Table 2
ily available via perfluoroalkylation of nitriles with new Ti/Mg-re-
agents, and allowing for the generalized preparation of virtually
enantiomerically pure acyclic perfluoroalkyl sec-amines. To our
knowledge, this is the first successful example of a highly enantio-
selective catalytic asymmetric hydrogenation of acyclic perfluoro-
alkyl enamides with chiraphos-derived rhodium complexes.
Enantioselective hydrogenation of perfluoroalkyl enamides by chiraphos-Rh
Entry Substrate
Product
% Yielda %eeb
NHAc
C4F9 Ph
NHAc
∗
1
94
91 (S)
Ph
C4F9
(96: 4)
NHAc
2
3
Rf = C4F9 96
96c (S)
95c (S)
Acknowledgment
NHAc
∗
C3F7
98
98
96
4
C6F13
94c (S)
93c (R)
Rf
Rf
We are grateful to Professor Vadim Soloshonok of University of
Oklahoma, for his discussions and suggestions.
5d
NHAc
C4F9
NHAc
∗
Ph
Ph
C4F9
6
98
98 (S)
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