Enantioselective Pd-catalyzed hydrogenation of fluorinated imines: Facile access to chiral fluorinated amines

Article abstract of DOI:10.1021/ol1020256

An enantioselective hydrogenation of simple fluorinated imines has been developed using Pd(OCOCF₃)₂/(R)-Cl-MeO-BIPHEP as a catalyst, and up to 94% ee was achieved. This method provides an efficient route to enantioenriched fluorinated amines.

Full text of DOI:10.1021/ol1020256

ORGANIC
LETTERS
2
010
Vol. 12, No. 21
075-5077
Enantioselective Pd-Catalyzed
Hydrogenation of Fluorinated Imines:
Facile Access to Chiral Fluorinated Amines
5
Mu-Wang Chen, Ying Duan, Qing-An Chen, Duo-Sheng Wang, Chang-Bin Yu, and
Yong-Gui Zhou*
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
ygzhou@dicp.ac.cn
Received August 26, 2010
ABSTRACT
3 2
An enantioselective hydrogenation of simple fluorinated imines has been developed using Pd(OCOCF ) /(R)-Cl-MeO-BIPHEP as a catalyst, and
up to 94% ee was achieved. This method provides an efficient route to enantioenriched fluorinated amines.
3
Because of the unusual and often profound effects on
physical and biological properties imparted by introduction
of the fluorine atom into organic molecules, perfluoroalky-
achieved by employing substrate transformation, catalytic
4
5
asymmetric reduction, and enantioselective addition. We
envision that asymmetric hydrogenation of the corresponding
fluorinated ketimines is one of the most convenient routes
1
lamines have become important building blocks in various
fluorinated biologically active compounds, and asymmetric
synthesis of chiral perfluoroalkylamines is a significant task
(
3) (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2436. (b)
Wang, Y.; Mosher, H. S. Tetrahedron Lett. 1991, 32, 987. (c) Ishii, A.;
Higashiyama, K.; Mikami, K. Synlett 1997, 1381. (d) Soloshonok, V. A.;
Ono, T. J. Org. Chem. 1997, 62, 3030. (e) T o¨ r o¨ k, B.; Prakash, G. K. S.
AdV. Synth. Catal. 2003, 345, 165. (f) Soloshonok, V. A.; Yasumoto, M. J.
Fluor. Chem. 2007, 128, 170. (g) Hughes, G.; Devine, P. N.; Naber, J. R.;
O’Shea, P. D.; Foster, B. S.; McKay, D. J.; Volante, R. P. Angew. Chem.,
Int. Ed. 2007, 46, 1839. (h) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem.,
Int. Ed. 2007, 46, 786. (i) Gauthier, J. Y.; Black, W. C.; Courchesne, I.;
Cromlish, W.; Desmarais, S.; Houle, R.; Lamontagne, S.; Li, C. S.; Mass e´ ,
F.; McKay, D. J.; Ouellet, M.; Robichaud, J.; Truchon, J. F.; Truong, V. L.;
Wang, Q.; Percival, D. Bioorg. Med. Chem. Lett. 2007, 17, 4929. (j)
Soloshonok, V. A.; Catt, H. T.; One, T. J. Fluor. Chem. 2009, 130, 512.
(4) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.-Y.;
Volante., R. P. Org. Lett. 2005, 7, 355.
2
of organic synthesis. In the past decades, some progress on
asymmetric synthesis of perfluoroalkylamines has been
(
1) (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1.
b) Asymmetric Fluoroorganic Chemistry; Ramachandran, P. V., Ed.; ACS
Symposium Series; American Chemical Society: Washington, DC, 2000.
c) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, ReactiVity,
(
(
Applications; Wiley-VCH: Weinheim, 2004. (d) Muller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (e) Fluorine in Medicinal Chemistry
and Chemical Biology; Ojima, I., Ed.; Blackwell: Oxford, 2009. (f) Krska,
S. W.; Mitten, J. V.; Dormer, P. G.; Mowrey, D.; Machrouhi, F.; Sun, Y.;
Nelson, T. D. Tetrahedron 2009, 65, 8987.
(5) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589. (b) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.;
Shibata, N. Angew. Chem., Int. Ed. 2009, 48, 6324. (c) Li, Y.; Hu, J. Angew.
Chem,. Int. Ed. 2005, 44, 5882. (d) Li, Y.; Hu, J. Angew. Chem., Int. Ed.
2007, 46, 2489. (e) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett.
2001, 3, 2847. (f) Truong, V. L.; Pfeiffer, J. Y. Tetrahedron Lett. 2009,
50, 1633. (g) Truong, V. L.; M e´ nard, M. S.; Dion, I. Org. Lett. 2007, 9,
683. (h) Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.-Y.; Volante, R. P.
Org. Lett. 2004, 6, 641. (i) Fries, S.; Pytkowicz, J.; Brigaud, T. Tetrahedron
Lett. 2005, 46, 4761. (j) Fustero, S.; del Pozo, C.; Catal a´ n, S.; Alem a´ n, J.;
Parra, A.; Marcos, V.; Ruano, J. L. G. Org. Lett. 2009, 11, 641.
(
2) For recent reviews, see: (a) Fluorine-Containing Synthons; Solos-
honok, V. A., Ed.; ACS Symposium Series 911; American Chemical
Society: Washington, DC, 2005. (b) Current Fluoroorganic Chemistry. New
Synthetic Directions, Technologies, Materials and Biological Applications;
Soloshonok, V. A., Mikami, K., Yamazaki, T., Welch, J. T., Honek, J.,
Eds.; ACS Symposium Series 949; American Chemical Society: Washing-
ton, DC, 2006. (c) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, 2006. (d) Bucsi, I.; T o¨ r o¨ k, B.; Marco, A. I.; Rasul, G.; Prakash,
G. K. S.; Olah, G. A. J. Am. Chem. Soc. 2002, 124, 7728. (e) Ma, J.-A.;
Cahard, D. Chem. ReV. 2004, 104, 6119.
10.1021/ol1020256  2010 American Chemical Society
Published on Web 10/04/2010

to obtain chiral amines in terms of simplicity and atom
efficiency. However, because of difficulties in the stereose-
lective synthesis and asymmetric hydrogenation of fluorinated
imines, to date only a few examples of the metal-catalyzed
asymmetric hydrogenation of perfluoroalkylimines have been
Table 1. Optimization of the Asymmetric Hydrogenation of
Imine 1a
a
6
6a,b
6c
reported. Uneyama
and Mikami described the asym-
metric hydrogenation of activated R-fluorinated iminoesters
and N-Boc or N-Ac imines with moderate to high enanti-
oselectivity, respectively. For the asymmetric hydrogenation
of simple acyclic fluorinated imines, only low conversion
and enantioselectivity were obtained using the chiral Ir- or
6
d,e
Rh-complexes.
Therefore, developing an efficient and
general method to simple fluorinated ketimines and their
asymmetric hydrogenation is highly desirable. Herein, we
describe the enantioselective hydrogenation of simple flu-
orinated imines (Scheme 1).
Scheme 1
.
Asymmetric Hydrogenation of Simple Fluorinated
Imines
a
3 2
Conditions: 0.125 mmol imine 1a, Pd(OCOCF ) (4 mol %), chiral
c
b
ligand (4.8 mol %), 3 mL of solvent, 16 h, rt. Isolated yield. Determined
by HPLC. Determined by H NMR. With 2 mol % catalyst. With 40
mg 4 Å MS. Conditions: 0.125 mmol imine 1a, [Ir(COD)Cl] (1 mol %),
2
S,S)-f-Binaphane (2.2 mol %), I (10 mol %), 24 h.
d
1
e
f
Perfluoroalkyl ketimines 1 were synthesized according to
g
7
,8
2
slightly modified literature procedures. It is noteworthy
that the ketimines 1 are single (Z)-isomers except 1l with a
difluoromethyl group. The formation of the single (Z)-isomer
may be attributed to hyperconjugative interaction of a lone
electron pair of nitrogen into the σ* orbital of the
(
luoroethanol (TFE) being the most effective solvent. Some
chiral bisphosphine ligands were tested, high enantioselec-
tivities were obtained (entries 5-11), and the best result was
achieved with (R)-Cl-MeO-BIPHEP L6 (entry 9, 93% ee).
The use a lower catalyst loading (2 mol % Pd) did not affect
the ee of 2a, but the yield was slightly lower (entry 12), the
main reason for which may be the hydrolysis of fluorinated
9
,6c
carbon-carbon bond between the imine and Rf group.
Ketimine (1a) was chosen as a model substrate, and
1
0,11
Pd(OCOCF
3
)
2
/(R)-SynPhos was used as a catalyst
for
optimization of reaction conditions. Initial investigations were
concentrated on finding optimal solvents, and we found that
solvent effect played a crucial role in obtaining both good
activity and enantioselectivity (Table 1, entries 1-4), trif-
1
0b
imines. Gratifyingly, when 4 Å MS was added,
conversion with the identical enantioselectivity was obtained
entry 13, 93% ee). The Ir/f-Binaphane/I system was also
tested for the asymmetric hydrogenation of 1a with poor
full
(
2
(
6) (a) Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313. (b)
Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org. Chem. 2004, 69, 5132.
c) Mikami, K.; Murase, T.; Zhai, L.; Kawauchi, S.; Itoh, Y.; Ito, S.
1
2,13
results.
Under the optimized reaction conditions [Pd(OCOCF
(R)-Cl-MeO-BIPHEP, TFE, 600 psi H , 4 Å MS and rt], a
(
3 2
) /
Tetrahedron Lett. 2010, 51, 1371. (d) Imamoto, T.; Iwadate, N.; Yoshida,
K. Org. Lett. 2006, 8, 2289. (e) Goulioukina, N. S.; Bondarenko, G. N.;
Lyubimov, S. E.; Davankov, V. A.; Gavrilov, K. N.; Beletskaya, I. P. AdV.
Synth. Catal. 2008, 350, 482.
2
(10) For recent examples on Pd-catalyzed asymmetric hydrogenation
developed by us, see: (a) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. Org. Lett.
2005, 7, 3235. (b) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006, 1189. (c) Wang,
Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem. 2007, 72, 3729. (d) Wang,
Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G. Org. Lett. 2008,
10, 2071. (e) Yu, C.-B.; Wang, D.-W.; Zhou, Y.-G. J. Org. Chem. 2009,
74, 5633. (f) Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.;
Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909.
(
7) (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757. (b)
Ohkura, H.; Handa, M.; Katagiri, T.; Uneyama, K. J. Org. Chem. 2002,
7, 2692. (c) Tam, N. T. N.; Magueur, G.; Our e´ vitch, M.; Crousse, B.;
6
B e´ gu e´ , J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2005, 70, 699. (d) Ruano,
J. L. G.; Alem a´ n, J.; Catal a´ n, S.; Marcos, V.; Monteagudo, S.; Parra, A.;
del Pozo, C.; Fustero, S. Angew. Chem., Int. Ed. 2008, 47, 7941
.
(
8) (a) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32. (b) Li, C.-L.; Chen, M.-W.; Zhang, X.-G.
J. Fluor. Chem. 2010, 131, 856. (c) Wu, Y.-M.; Li, Y.; Deng, J. J. Fluor.
(11) (a) Yang, Q.; Shang, G.; Gao, W.; Deng, J.; Zhang, X. Angew.
Chem., Int. Ed. 2006, 45, 3832. (b) Nanayakkara, P.; Alper, H. Chem.
Commum. 2003, 2384. (c) Rubio-P e´ rez, L.; P e´ rez-Flores, F. J.; Sharma, P.;
Velasco, L.; Cabrera, A. Org. Lett. 2009, 11, 265.
Chem. 2005, 126, 791
9) Corey, E. J.; Link, J. O.; Sarsha, S.; Shao, Y. Tetrahedron Lett. 1992,
3, 7103
.
(
3
.
(12) 24% yield and 5% ee were obtained.
5076
Org. Lett., Vol. 12, No. 21, 2010

wide variety of imines 1 were tested to examine the reaction
scope, as shown in Table 2. Different aryl groups on the
aryl substituents can be successfully hydrogenated to give
the corresponding fluorinated amines with high ee’s. It is
noteworthy that the enantioselectivities achieved with Pd
catalyst for the hydrogenation of simple fluorinated imine 1
are the highest reported to date. Subsequently, alkyl-
substituted fluorinated imines 1j and 1k were also tested,
and 89% and 92% ee’s were obtained, respectively (entries
a
Table 2. Pd-Catalyzed Hydrogenation of Fluorinated Imines 1
1
0 and 11). The imines 1n-1p bearing longer perfluoroalkyl
chains were also hydrogenated smoothly with 84-86% ee’s
entries 14-16). Difluoroalkyl-substituted substrates were
also subjected to asymmetric hydrogenation under the
standard condition, giving 69% and 86% ee’s (entries 12
and 13).
(
b
c
entry
PG
R
Rf
yield (%) ee (%)
1
2
3
4
5
6
7
8
4-MeO-C
Ph
6
H
4
Ph
Ph
Ph
CF
3
3
3
3
3
3
3
3
3
3
3
2
2
99 (2a)
91 (2b)
88 (2c)
92 (2d)
95 (2e)
90 (2f)
97 (2g)
95 (2h)
87 (2i)
99 (2j)
97 (2k)
88 (2l)
93 (R)
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
CF
93 (R)
93 (R)
92 (R)
93 (R)
84 (R)
92 (R)
93 (R)
94 (R)
89 (R)
92 (R)
69 (R)
86 (R)
84 (R)
84 (R)
86 (R)
The p-methoxyphenyl (PMP) group of hydrogenated
products can be readily removed under the known condi-
4-Me-C
6
H
4
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
4-MeO-C
6
6
6
6
6
6
6
6
6
6
6
6
6
H
4
4
4
4
4
4
4
4
4
4
4
4
4
4-Me-C
3-Me-C
2-Me-C
6
6
6
H
H
H
4
14
H
H
H
H
H
H
H
H
H
H
H
H
4
tions. Oxidative cleavage of the hydrogenation product 2a
with Ce(NH (NO (CAN) gave 2,2,2-trifluoro-1-phen-
ethyl-amine (R)-3a (Scheme 2). The (R)-stereochemistry was
4
)
4 2
3 6
)
4-MeO-C
4-CF -C
-C
6
H
4
3
6 4
H
9
3,5-F
n-Bu
2
6
H
3
d
10
11
12
13
14
15
16
d
2 2
PhCH CH
Scheme 2
.
Removal of the p-Methoxyphenyl (PMP) Group of
Fluorinated Amine 2a
Ph
Ph
Ph
Ph
H
Et 94 (2m)
C
C
C
2
3
6
F
F
F
5
95 (2n)
85 (2o)
97 (2p)
7
d
Ph
13
a
Conditions: 0.125 mmol imine 1, Pd(OCOCF
3 2
) (2 mol %), (R)-Cl-
MeO-BIPHEP (2.4 mol %), 40 mg of 4 Å MS, 3 mL of TFE, 16 h, rt.
b
c
d
Isolated yield. Determined by HPLC. (R)-SynPhos as ligand.
nitrogen atom of imines can be tolerated with excellent
enantioselectivities and full conversions (entries 1-3).
Considering the ease with which the p-methoxylphenyl
assigned by comparison of optical rotation with that in the
20
3b
literature ([R]
D
-21.6 for 100% ee (c 3.1, EtOH) and
20
3d
[R]
D
-17.7 for 81% ee (c 3.4, EtOH) ).
(
PMP) group can be removed, PMP was selected for the
additional studies. Substrates with electron-donating (entries
-7) or electron-withdrawing (entries 8 and 9) groups on
In summary, a direct approach to chiral perfluoroalky-
lamine has been successfully developed via Pd-catalyzed
asymmetric hydrogenation of the simple fluorinated imines
under mild conditions with up to 94% ee; simple fluorinated
ketimines can be conveniently synthesized from the com-
mercially available fluorinated carboxylic acids. Our ongoing
experiments are focused on exploring other palladium-
catalyzed asymmetric hydrogenation reactions.
4
(13) For some recent examples of transition-metal-catalyzed asymmetric
hydrogenation of imines, see: (a) Xiao, D.; Zhang, X. Angew. Chem., Int.
Ed. 2001, 40, 3425. (b) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (c) Yun, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 767. (d) Solinas, M.; Pfaltz, A.; Cozzi, P. G.;
Leitner, W. J. Am. Chem. Soc. 2004, 126, 16142. (e) Moessner, C.; Bolm,
C. Angew. Chem., Int. Ed. 2005, 44, 7564. (f) Zhu, S.-F.; Xie, J.-B.; Zhang,
Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886. (g) Ngai,
M. Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12644.
Acknowledgment. The authors are grateful for financial
support from NSFC (20921092 and 20872140), MOST (973
(
h) Li, C.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 13208. (i) Li, C.; Wang,
C.; Villa-Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450. (j)
Mr sˇ i c´ , N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am. Chem.
Soc. 2009, 131, 8358. (k) Han, Z.; Wang, Z.; Zhang, X.; Ding, K. Angew.
Chem., Int. Ed. 2009, 48, 5345. (l) Hou, G.; Gosselin, F.; Li, W.;
McWilliams, C.; Sun, Y.; Weisel, M.; O’Shea, P. D.; Chen, C.-Y.; Davies,
I. W.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 9882. (m) Hou, G.; Tao,
R.; Sun, Y.; Zhang, X.; Gosselin, F. J. Am. Chem. Soc. 2010, 132, 2124.
2
010CB833300) Chinese Academy of Sciences (K2010F1).
Supporting Information Available: Experimental, spec-
troscopic, computational, and crystallographic details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
14) (a) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem. 2003, 68, 4120.
b) Palacios, F.; Aparicio, D.; Garcia, J.; Rodriguze, E. Eur. J. Org. Chem.
998, 1413.
(
1
OL1020256
Org. Lett., Vol. 12, No. 21, 2010
5077