Highly enantioselective aza-henry reaction of ketoimines catalyzed by chiral N,N'-dioxide-copper(I) complexes

Article abstract of DOI:10.1021/ol802236h

(Chemical Equation Presented) The first example of catalytic enantioselective aza-Henry reaction of ketoimines has been realized using a simple chiral N,N-dioxide-Cu(I) complex as catalyst. It performs well over a range of substrates to give the corresponding products in moderate to good yields (up to 83%) with high enantioselectivities (up to 96% ee).

Full text of DOI:10.1021/ol802236h

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5305-5308
Highly Enantioselective Aza-Henry
Reaction of Ketoimines Catalyzed by
Chiral N,N′-Dioxide-Copper(I)
Complexes
Cheng Tan,† Xiaohua Liu,† Liwei Wang,† Jun Wang,† and Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, P. R. China, and State Key
Laboratory of Biotherapy, Sichuan UniVersity, Chengdu 610041, P. R. China
xmfeng@scu.edu.cn
Received September 25, 2008
ABSTRACT
The first example of catalytic enantioselective aza-Henry reaction of ketoimines has been realized using a simple chiral N,N′-dioxide-Cu(I)
complex as catalyst. It performs well over a range of substrates to give the corresponding products in moderate to good yields (up to 83%)
with high enantioselectivities (up to 96% ee).
The catalytic asymmetric aza-Henry (or nitro-Mannich)
reaction1 is one of the most powerful and efficient methods
for the synthesis of chiral vicinal diamines2 and R-amino
acids3 through C-C bond formation. Since the pioneering
work of Shibasaki4 and Jørgensen,5 various catalysts have
been developed over the past decade, including both metal
complexes6 and organocatalysts, such as chiral thioureas,7
chiral proton catalysts,8 chiral phase transfer catalysts,9 and
so on.10 However, the substrates are limited to only aldi-
mines. The catalytic enantioselective aza-Henry reaction of
ketoimines, which leads to a direct approach for the for-
mation of optically active quarternary carbon centers,11 is a
long-standing problem and has not been achieved so far.
† Key Laboratory of Green Chemistry & Technology.
‡ State Key Laboratory of Biotherapy.
(5) (a) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843. (b) Nishiwaki, N.;
Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2001, 40, 2992. (c) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem.
2005, 3, 1362.
(1) For recent reviews, see: (a) Westermann, B. Angew. Chem., Int. Ed.
2003, 42, 151. (b) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr.
Org. Chem. 2005, 9, 1315. (c) Friestad, G. K.; Mathies, A. K. Tetrahedron
2007, 63, 2541. (d) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797.
See also ref 3c.
(6) For other selected examples, see: (a) Lee, A.; Kim, W.; Lee, J.;
Hyeon, T.; Kim, B. M. Tetrahedron: Asymmetry 2004, 15, 2595. (b)
Anderson, J. C.; Howell, G. P.; Lawrence, R. M.; Wilson, C. S. J. Org.
Chem. 2005, 70, 5665. (c) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.;
Lo´pez, R. Angew. Chem., Int. Ed. 2006, 45, 117. (d) Gao, F. F.; Zhu, J.;
Tang, Y.; Deng, M. Z.; Qian, C. T. Chirality 2006, 18, 741. (e) Handa, S.;
Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007,
129, 4900. (f) Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9, 2023. (g)
Zhou, H.; Peng, D.; Qin, B.; Hou, Z. R.; Liu, X. H.; Feng, X. M. J. Org.
Chem. 2007, 72, 10302. (h) Chen, Z.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170.
(2) For a review of vicinal diamines, see: Lucet, D.; Le Gall, T.;
Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(3) (a) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol.
Chem. 2003, 1, 4275. For recent reviews on the synthesis of R-amino acids,
see: (b) Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007, 5, 406. (c) Na´jera,
C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584, and references therein.
(4) (a) Yamada, K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 3504. (b) Yamada, K.; Moll, G.; Shibasaki, M.
Synlett 2001, 980. (c) Tsuritani, N.; Yamada, K.; Yoshikawa, N.; Shibasaki,
M. Chem. Lett. 2002, 276.
10.1021/ol802236h CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

Even for a racemic or diastereoselective version, only a few
examples with limited substrate scope have been reported.12
The low reactivity and the difficulty in enantio-face dif-
ferentiation are the two main obstacles that make the
development of catalytic asymmetric addition to ketoimines
extraordinarily challenging and desirable.13 Having estab-
lished a general catalytic racemic aza-Henry reaction of
ketoimines,12c herein, we wish to report the first enantiose-
lective example using chiral N,N′-dioxide-Cu(I) complexes
as the catalyst.
The enantioselectivity was further increased to 83% ee
when phenyl ethyl ether was used as solvent; meanwhile the
amount of nitromethane could be reduced (Table 2, entry
Table 2. Selected Results for the Optimization of Reaction
Conditionsa
Initially, the reaction between ketoimine 2a and ni-
tromethane was selected as the model reaction. Nitromethane
was used as solvent considering the low reactivity. Screening
of catalysts revealed that the Cu(I) complexes of chiral N,N′-
dioxides14,15 derived from (S)-pipecolic acid16 and primary
amines (Figure 1) are superior for the reaction (Table 1,
entry
catalyst (mol %)
time (d)
yield (%)b
ee (%)c
1
10
10
10
10
20
20
5
5
5
5
5
16
22
25
29
39
64
83
88
81
79
88
88
2d
3d,e
4d,f
5d
6d
10
a Unless otherwise noted, reactions were carried out with 1e (10 mol
%), (CuOTf)2·C7H8 (5 mol %), 2a (0.1 mmol) and CH3NO2 (0.1 mL) in
PhOEt (0.5 mL) at 0 °C. b Isolated yield. c Determined by HPLC using
chiral OD-H column. d 4 Å MS (20 mg) was added. e i-Pr2NEt (10 mol %)
was added. f Et3N (10 mol %) was added.
Figure 1. N,N′-Dioxide ligands evaluated.
1). Excess nitromethane was essential to obtain the product.
After a screen of additives, it was found that the addition of
4 Å molecular sieves could improve both the yield and
enantioselectivity (22% yield and 88% ee; Table 2, entry
2).17 The use of amines as additives was also investigated.
However, the enantioselectivity was decreased obviously
without remarkable enhancement of the reactivity (Table 2,
entries 3 and 4). Further investigation showed that using
higher catalyst loading and prolonging the reaction time could
give good yield without decrease in enantioselectivity (64%
yield and 88% ee; Table 2, entries 5 and 6). No side reaction
was observed and unreacted ketoimine could be recovered
by flash column chromatography. Although extension of the
reaction time was indispensable to obtain higher yield due
to the awfully poor reactivity of ketoimines,18 the result was
significant in view of the enormous challenge and difficulty
of this reaction.
entries 1-4). While the typical ligand 1a gave the desired
product 3a in 14% yield and 67% ee (Table 1, entry 4), other
known ligands with different amine moieties including both
aliphatic and aromatic amines failed to accelerate the reaction
(Table 1, entries 5-7). Then the new ligand 1e, having
benzyl groups, was synthesized and tested. The enantiose-
lectivity was dramatically increased to 79% ee with some
improvement in yield (Table 1, entry 8). The benzyl
substituents in the ligand with appropriate steric hindrance
played a key role in this advancement.
Table 1. Screening of Metal Sources and Ligandsa
Having optimized the reaction conditions, substrate scope
was investigated and the results are summarized in Table 3.
High enantioselectivities were obtained with a series of
aromatic ketoimines bearing either electron-withdrawing
entry
ligand
metalb
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1e
Cu(OAc)2
Cu(acac)2
Cu(OTf)2
CuOTf
CuOTf
CuOTf
10
10
0
(7) (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005,
44, 466. (c) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y.
Chem. Eur. J. 2006, 12, 466. (d) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci,
A.; Sgarzani, V. Tetrahedron 2006, 62, 375. (e) Bode, C. M.; Ting, A.;
Schaus, S. E. Tetrahedron 2006, 62, 11499. (f) Chang, Y. W.; Yang, J. J.;
Dang, J. N.; Xue, Y. X. Synlett 2007, 2283. (g) Wang, C. G.; Zhou, Z. H.;
Tang, C. C. Org. Lett. 2008, 10, 1707. (h) Wang, C. J.; Dong, X. Q.; Zhang,
Z. H.; Xue, Z. Y.; Teng, H. L. J. Am. Chem. Soc. 2008, 130, 8606. (i)
Rampalakos, C.; Wulff, W. D. AdV. Synth. Catal. 2008, 350, 1785. (j) Han,
B; Liu, Q. P.; Li, R.; Tian, X.; Xiong, X. F.; Deng, J. G.; Chen, Y. C.
Chem. Eur. J. 2008, 14, 8094.
13
nre
14
67
trace
trace
trace
19
ndf
ndf
ndf
79
CuOTf
CuOTf
a Reactions were carried out with ligand (10 mol %), metal (10 mol %)
and 2a (0.1 mmol) in CH3NO2 (0.5 mL) at 0 °C for 5 days. b Cu(OAc)2·H2O,
Cu(acac)2·H2O, Cu(OTf)2, and (CuOTf)2·C7H8 were used as metal sources.
c Isolated yield. d Determined by HPLC using chiral OD-H column. e No
reaction occurred. f Not determined.
(8) (a) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 3418. (b) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N.
J. Am. Chem. Soc. 2007, 129, 3466. (c) Singh, A.; Johnston, J. N. J. Am.
Chem. Soc. 2008, 130, 5866.
5306
Org. Lett., Vol. 10, No. 22, 2008

The synthetic potential of this catalytic approach is due
to the formation of useful chiral building blocks,19 for
example, vicinal diamines.20 The optically active product
such as 3a was readily converted into the corresponding
N-protected 1,2-diamine 4a in good yield by zinc-mediated
reduction21 without loss of enantioselectivity (Scheme 1).
Table 3. Substrate Scope for the Catalytic Enantioselective
Aza-Henry Reaction of Ketoiminesa
Scheme 1. Conversion of the Product to 1,2-Diamine
entry
R1
Ph (2a)
2-FC6H4 (2b)
4-FC6H4 (2c)
4-ClC6H4 (2d)
3-ClC6H4 (2e)
4-BrC6H4 (2f)
4-MeC6H4 (2g)
R2 time (d) yield of 3 (%)b ee (%)c
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
5
5
5
5
5
39 (64)
50 (80)
48 (75)
58 (81)
70 (80)
61 (83)
21 (42)
30
44
49
36
47
88 (88)d
91 (90)
92 (91)
93 (92)
96 (96)
92 (92)
90 (90)
88
87
85
92
88
5
5
This method leads to a simple procedure for the synthesis
of a new class of optically active vicinal diamines with a
quaternary stereogenic center.
4-MeOC6H4 (2h) Me
2-MeOC6H4 (2i) Me
3-MeOC6H4 (2j) Me
10
10
10
10
10
5
9
10
11
12
13
14
15
16
In conclusion, the first catalytic enantioselective aza-Henry
reaction of ketoimines has been realized using a simple chiral
N,N′-dioxide-Cu(I) complex as catalyst. It performed well
over a range of substrates to give the desired products in
moderate to good yields (up to 83%) with high enantiose-
lectivities (up to 96% ee). The optically active products can
be easily converted into chiral vicinal diamines with a
quaternary stereogenic center. Further studies of the reaction
mechanism as well as improvement of the reaction efficiency
are in progress.
Ph (2k)
Et
2-naphthyl (2l)
2-furyl (2m)
2-thienyl (2n)
Ph(CH2)2 (2o)
cyclohexyl (2p)
Me
Me
Me
Me
Me
Me
51 (82)
43
91 (91)
78
10
5
10
47 (76)
35
71 (71)
83
17e Ph (2a)
5
33
87
a Unless otherwise noted, reactions were carried out with 1e (0.02 mmol),
(CuOTf)2·C7H8 (0.01 mmol), 4 Å MS (20 mg), 2 (0.1 mmol) and CH3NO2
(0.1 mL) in PhOEt (0.5 mL) at 0 °C. b Isolated yield. The reaction time for
the data in parentheses was 10 days. c Determined by HPLC using
commercial chiral columns. The reaction time for the data in parentheses
was 10 days. d The absolute configuration was determined to be S. See
Supporting Information for details. e Reaction was carried out on 1 mmol
scale.
(11) For recent reviews on asymmetric synthesis of quaternary stereo-
centers, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005,
347, 1473. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (d) Hatano, M.;
Ishihara, K. Synthesis 2008, 1647. (e) Cozzi, P. G.; Hilgraf, R.; Zimmer-
mann, N. Eur. J. Org. Chem. 2007, 5969, and references therein. See also
ref 13.
or electron-donating substitutents (85-96% ee; Table 3,
entries 1-10), while substrates with electron-donating
groups provided lower reactivity and extended reaction
time was needed (Table 3, entries 7-10). The more
sterically hindered substrates such as 2k and 2l could also
gave the corresponding products in moderate yields with
high enantioselectivities (Table 3, entries 11 and 12). In
the cases of heteroaromatic ketoimines 2m and 2n, the
reaction was obviously affected by the heteroatom of the
heteroaromatic ring, and 2m afforded much better result
than 2n (Table 3, entry 13 vs 14). The reaction was also
applicable to primary alkyl-substituted ketoimine 2o and
aliphatic ketoimine 2p (Table 3, entries 15 and 16). In
addition, preliminary investigation showed that the reac-
tion could be carried out on 1 mmol scale without decrease
in enantioselectivity (Table 3, entry 17). Other nitroalkanes
including nitroethane and nitropropane were also tested
under the optimized conditions, but only trace of products
could be detected.
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Liu, X. H.; Huang, J. L.; Wen, Y. H.; Feng, X. M. J. Org. Chem. 2007, 72,
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Feng, X. M. AdV. Synth. Catal. 2008, 350, 287. (e) Gao, B.; Wen, Y. H.;
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350, 385. (f) Shang, D. J.; Xin, J. G.; Liu, Y. L.; Zhou, X.; Liu, X. H.;
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Li, X.; Liu, X. H.; Fu, Y. Z.; Wang, L. J.; Zhou, L.; Feng, X. M. Chem.
Eur. J. 2008, 14, 4796. (i) Kokubo, M.; Ogawa, C.; Kobayashi, S. Angew.
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other examples, see also ref 14.
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(16) Ligands derived from other chiral amino acids such as L-proline
and (S)-ramipril acid gave very poor results (less than 20% ee).
(17) The role of 4 Å molecular sieves in the reaction has not yet been
established. Using other additives, including 3 Å and 5 Å molecular sieves,
was less efficient.
(18) Imines with other N-protecting groups, such as N-phenyl and
N-diphenylphosphinoyl ketoimines, were also tested, but no reaction
occurred.
(10) (a) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc.
2007, 129, 15110. (b) Rueping, M.; Antonchick, A. P. Org. Lett. 2008, 10,
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Org. Lett., Vol. 10, No. 22, 2008
5307

Acknowledgment. We thank the National Natural Science
Foundation of China (20732003 and 20702033) and the
Ministry of Education (20070610019) for financial support.
We also thank Sichuan University Analytical & Testing
Center for NMR analysis and the State Key Laboratory of
Biotherapy for HRMS analysis.
Supporting Information Available: Experimental pro-
cedures, spectral and analytical data for the products, and
determination of the absolute configuration of 3a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802236H
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Org. Lett., Vol. 10, No. 22, 2008