Highly enantioselective aza-ene-type reaction catalyzed by chiral N,N′-dioxide-nickel(ii) complex

Article abstract of DOI:10.1039/b921042c

An efficient catalytic enantioselective aza-ene-type reaction of glyoxal derivatives with enamides and enecarbamates has been realized using a nickel(ii)-N,N′-dioxide complex as the catalyst.

Full text of DOI:10.1039/b921042c

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COMMUNICATION
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Highly enantioselective aza-ene-type reaction catalyzed by chiral
N,N0-dioxide-nickel(II) complexw
Ke Zheng, Xiaohua Liu, Jiannan Zhao, Yang Yang, Lili Lin and Xiaoming Feng*
Received 8th October 2009, Accepted 24th March 2010
First published as an Advance Article on the web 23rd April 2010
DOI: 10.1039/b921042c
An efficient catalytic enantioselective aza-ene-type reaction of
glyoxal derivatives with enamides and enecarbamates has been
realized using a nickel(II)-N,N0-dioxide complex as the catalyst.
aza-ene-type reaction of phenylglyoxal 1a with enamide 2a
smoothly to afford the adduct with 68% yield and 90% ee
(Table 1, entry 1). To further improve the reactivity and the
enantioselectivity, various N,N0-dioxides were investigated
(Fig. 1). As shown in Table 1, the (S)-pipecolic acid derived
N,N0-dioxide L2 was superior to the L-proline derived L1
(Table 1, entry 2 vs. 1). Intensive studies on the amide moiety
revealed that ligand L4 with bromine at the ortho position of
aniline could achieve best result (up to >99% ee, Table 1,
entries 2–5). A series of enecarbamates were also investigated
and most of them exhibited high reactivities and excellent
enantioselectivities (up to 99% yield, >99% ee; Table 1,
entries 6–9). The catalyst loading could be reduced to 1 mol %
or even as low as 0.25 mol %. The yields and enantio-
selectivities only slightly decreased (Table 1, entries 10-12).
Other conditions such as temperature, solvent, and additive
were also examined, but no superior results were obtained (see
ESI).w It should be noted that exclusion of air and moisture
was not necessary in the present process.
Enamides and enecarbamates are considered versatile synthetic
building blocks in organic synthesis, while they have been
rarely used as nucleophiles presumably due to their lower
reactivity compared with enamines and enols.1 Since
enamides were successfully utilized as reactive nucleophiles in
enantioselective reactions,4a several kinds of enamides and
enecarbamates such as enesulfonamides, aldehyde-derived
enecarbamates have been developed for different reactions.2,4,5
On the other hand, as one of the most fundamental bond
construction processes, the ene reaction has been widely
employed in the synthesis of complex natural products.3
Recently, the enantioselective aza-ene-type reaction using
enamides as nucleophiles, which involves a six-membered-ring
transition state, has received much attention. In 2004,
Kobayashi and coworkers developed
a chiral copper
Under the optimized conditions, a wide range of aromatic,
aliphatic, and heterocyclic glyoxal derivatives were investigated
with enecarbamate 3a as nucleophile (Table 2, entries 1–19).
To our delight, this catalyst system exhibited a remarkably
broad substrate scope (in range of 98–>99% ee), and most
substrates were realized for the first time in the enantio-
selective aza-ene-type reaction (Table 2, entries 2–18). The
aromatic glyoxal derivatives underwent the aza-ene-type reaction
smoothly in excellent enantioselectivities regardless of the
electronic nature and the position of the substituents at the
aromatic ring of glyoxals (98–>99% ee; Table 2, entries 1–14).
It was noteworthy that excellent enantioselectivities (up to
99% ee) have also been achieved in the aza-ene-type reaction
of condensed-ring glyoxal (2-naphthylglyoxal) and the hetero-
aromatic glyoxals (Table 2, entries 15–17). Furthermore, the
aliphatic glyoxal could react with enecarbamate 3a to afford
the corresponding product in extremely high enantioselectivity
(99% ee, Table 2, entry 18). In addition, the ethyl glyoxylate
was also found to be an excellent substrate for the reaction,
and afforded the desired product 5s with 98% ee and 85%
yield (Table 2, entry 19).
complex to catalyze the enantioselective aza-ene-type reaction
of ethyl glyoxylate and imines.4 Subsequently, Terada’s
group reported the reaction using chiral phosphoric acid as
the catalyst.5 However, previous reports mostly focused on the
scope of the enamides and enecarbamates rather than the
carbonyl substrates due to the limitation of the glyoxylate
derivatives, while the glyoxal derivatives which could be easily
synthesized from the corresponding ketones have been rarely
reported.2d,4e In this communication, we present an efficient
chiral nickel(II) complex for the enantioselective aza-ene-type
reaction using enamides and enecarbamates as nucleophiles.
Excellent enantioselectivities (up to >99% ee) were obtained
for a broad range of substrates including both glyoxylate and
glyoxal derivatives.
Recently, we have demonstrated that chiral nickel(II)-
N,N0-dioxide complex was an excellent catalyst for the
enantioselective carbonyl-ene reaction.6 Thus, the nickel(II)-
N,N0-dioxide complexes were chosen as catalysts in our pre-
liminary investigation.7,8 It was interesting that product 4a
was rapidly converted to 5a as the terminal product under the
above reaction conditions without additional acidic treatment.4a
To our delight, the L1-Ni(BF4)2 complex promoted the
On the other hand, the enamides 2b–2h which were easily
synthesized from the corresponding ketones were also
Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China. E-mail: xmfeng@scu.edu.cn;
Fax: +86 28 85418249; Tel: +86 28 85418249
w Electronic supplementary information (ESI) available: Experimental
and NMR data. CCDC 750144 and 739905. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
b921042c
Fig. 1 Chiral ligands used in the study.
ꢀc
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Table 1 Optimization of the reaction conditions
Table 2 Substrate scope for the aza-ene-type reaction
Entrya
R
x (mol%) Product Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
C6H5
5
5
2.5
2.5
2.5
5
5
5
2.5
5
2.5
5
5
5
5
5
5
5
5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
93
89
85
90
84
99
92
87
85
85
82
82
80
72
86
75
86
70
85
99
>99
98
98
98
>99
>99
99
98
98
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-CH3OC6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
4-FC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
2-naphthyl
2-furyl
Entrya
Ligand
2 or 3
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
2a
2a
2a
2a
2a
3a
3b
3c
3d
3a
3a
3a
24
24
24
12
24
3
3
3
3
8
68
78
78
93
72
99
92
94
99
93
82
70
90
94
97
>99
65
>99
97
98
97
99
9
10
11
12
13
14
15
16
17
18
19
98
99d
99
99
99
99
98
99
98e
9
10d
11e
12f
24
48
97
92
2-thienyl
c-hexyl
OEt
a
Unless otherwise noted, the reaction was carried out with 0.1 mmol
phenylglyoxal 1a and 0.11 mmol enamide 2a in CH2Cl2 (1.0 mL) at
a
Unless otherwise noted, the reaction was carried out with 1–5 mol%
L4-Ni(BF4)2ꢁ6H2O, 0.1 mmol of glyoxal derivative (glyoxylate), and
1.1 equiv. of enecarbamate 3a in CH2Cl2 (1.0 mL) at 23 1C for 3–18 h.
Isolated yield. Determined by chiral HPLC analysis. The
absolute configuration of (S)-5l was determined by X-ray.10 e The
absolute configuration of (S)-5s was determined with literature data.5c
b
c
23 1C for 3–24 h. Isolated yield of 5a. Determined by chiral
HPLC. With 5 mol% catalyst. With 1 mol% catalyst. The
d
e
f
b
c
d
reaction was carried out with 2.0 mmol phenylglyoxal 1a and
2.2 mmol enecarbamate 3a using 0.25 mol% catalyst.
examined under optimized conditions. A wide spectrum of
enamides showed excellent enantioselectivities (generally
>99% ee) and high yields employing 10 mol% catalyst
(Table 3, entries 1–8). Generally, electron-donating substituent
such as OMe or Me on the aromatic ring slightly enhanced the
reactivity, while electron-withdrawing substituent such as F or
Cl at the para position diminished the reactivity (Table 3,
entries 2–5 vs. 6–7).
Table 3 Substrate scope for the aza-ene-type reaction
We then examined several a-substituted enecarbamates as
nucleophiles in the aza-ene-type reaction. As shown in
Scheme 1, the (E)-enecarbamates reacted with the compound
1 smoothly, giving anti adducts in high yields with both
excellent diastereo- and enantioselectivities. However, the
reaction of (Z)-enecarbamates required longer reaction times
and the corresponding syn adducts as the major products were
only obtained with low diastereo- and enantioselectivities.9
To gain preliminary insight into the reaction mechanism, N-
methyl-substituted enamide 2i bearing no hydrogen on nitro-
gen was investigated under optimized conditions. As expected,
no adduct was obtained and almost all the starting materials
were recovered (Table 3, entry 9). This fact indicated that the
hydrogen on the nitrogen of enamide was necessary for
the reaction.2a The structure of the L3-Ni(II) complex was
determined by X-ray crystallography.9,10 As shown in Fig. 2,
both carbonyl oxygens and N-oxide oxygens were coordinated
with nickel(II) in the complex. In addition, when 5 mol%
crystal of L3-Ni(II) complex was utilized as catalyst under the
standard conditions, almost the same result was obtained
(97% ee, 75% yield), which was consistent with the study of
L3-Ni(II) complex generated in situ (97% ee, 78% yield,
Entrya
2
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
5a
5t
93
92
92
94
95
87
87
91
>99
>99
>99
>99
99
99
99
>99
—
5u
5v
5w
5x
5y
5z
—
N.R.
a
Unless otherwise noted, the reaction was carried out with 10 mol%
L4-Ni(BF4)2ꢁ6H2O, 0.1 mmol of phenylglyoxal 1a, and 1.1 equiv. of
b
enamide 2 in CH2Cl2 (1.0 mL) at 23 1C for 6–16 h. Isolated yield.
Determined by chiral HPLC.
c
Table 1, entry 3). So the structure of the most active catalytic
species maybe the same as the X-ray structure of the crystal.
On the basis of the X-ray crystal structure of the
catalyst and the experimental results, as well as the absolute
ꢀc
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J. Am. Chem. Soc., 1982, 104, 6697; (c) L. Eberson, M. Malmberg
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2 For the reports on the use of enamides and enecarbamates as
nucleophiles, see: (a) R. Matsubara and S. Kobayashi, Acc. Chem.
Res., 2008, 41, 292; (b) R. Matsubara and S. Kobayashi, Angew.
Chem., Int. Ed., 2006, 45, 7993; (c) F. Berthiol, R. Matsubara,
N. Kawai and S. Kobayashi, Angew. Chem., Int. Ed., 2007, 46,
7803; (d) R. Matsubara, T. Doko, R. Uetake and S. Kobayashi,
Angew. Chem., Int. Ed., 2007, 46, 3047; (e) L. Zu, H. Xie, H. Li,
J. Wang, X. Yu and W. Wang, Chem.–Eur. J., 2008, 14, 6333;
(f) Y. Hayashi, H. Gotoh, R. Masui and H. Ishikawa, Angew.
Chem., Int. Ed., 2008, 47, 4012; (g) H. Liu, G. Dagousset,
G. Masson, P. Retailleau and J. P. Zhu, J. Am. Chem. Soc.,
2009, 131, 4598.
Scheme 1 Substrate scope for the aza-ene-type reaction.
3 For a general review of the ene reaction, see: (a) K. Mikami and
M. Shimizu, Chem. Rev., 1992, 92, 1021; (b) D. J. Berrisford and
C. Bolm, Angew. Chem., Int. Ed. Engl., 1995, 34, 1717;
(c) K. Mikami, M. Terada, S. Narisawa and T. Nakai, Synlett,
1992, 255; (d) K. Mikami, Pure Appl. Chem., 1996, 68, 639;
(e) K. C. Nicolaou, D. W. Kim and R. Baati, Angew. Chem., Int.
Ed., 2002, 41, 3701; (f) K. R. Hornberger, C. L. Hamblett and
J. L. Leighton, J. Am. Chem. Soc., 2000, 122, 12894; (g) Y. Yuan,
X. Zhang and K. Ding, Angew. Chem., Int. Ed., 2003, 42, 5478;
(h) J. F. Zhao, H. Y. Tsui, P. J. Wu, J. Lu and T. P. Loh, J. Am.
Chem. Soc., 2008, 130, 16492, and references therein.
4 (a) R. Matsubara, Y. Nakamura and S. Kobayashi, Angew. Chem.,
Int. Ed., 2004, 43, 1679; (b) R. Matsubara, Y. Nakamura and
S. Kobayashi, Angew. Chem., Int. Ed., 2004, 43, 3258;
(c) R. Matsubara, P. Vital, Y. Nakamura, H. Kiyohara and
S. Kobayashi, Tetrahedron, 2004, 60, 9769; (d) J. S. Fossey,
R. Matsubara, P. Vital and S. Kobayashi, Org. Biomol. Chem.,
2005, 3, 2910; (e) R. Matsubara, N. Kawai and S. Kobayashi,
Angew. Chem., Int. Ed., 2006, 45, 3814; (f) H. Kiyohara,
R. Matsubara and S. Kobayashi, Org. Lett., 2006, 8, 5333.
5 (a) M. Terada, K. Machioka and K. Sorimachi, Angew. Chem., Int.
Ed., 2006, 45, 2254; (b) M. Terada, K. Machioka and
K. Sorimachi, J. Am. Chem. Soc., 2007, 129, 10336;
(c) M. Terada, K. Soga and N. Momiyama, Angew. Chem., Int.
Ed., 2008, 47, 4122.
Fig. 2 Proposed transition-state and the X-ray crystallographic
structure of the (S)-product 5l.
configuration of product,9,10 a concerted transition-state model
was proposed.11 As shown in Fig. 2, the glyoxal derivative
tended to coordinate to the nickel(II) in a bidentate fashion.4b
The Re face of the glyoxal derivative was shielded by the
neighboring 2,6-diisopropylphenyl group of the ligand, and
the nucleophile (enamide or enecarbamate) attacked from the
Si face predominantly to give the S-configured product.
In conclusion, we have developed an efficient chiral N,N0-
dioxide-nickel(II) complex catalyst for the enantioselective
aza-ene-type reaction of glyoxal derivatives as well as
glyoxylate. The extremely high enantioselectivity, broad
substrate scope, operational simplicity, and mild reaction
conditions demonstrated that the N,N0-dioxide-nickel(II)
complex was excellent catalyst for the synthesis of optical
2-hydroxy-1,4-dicarbonyl compounds. Further studies of the
reaction mechanism and application of this catalyst to other
reactions are under way.
6 K. Zheng, J. Shi, X. H. Liu and X. M. Feng, J. Am. Chem. Soc.,
2008, 130, 15770.
7 For reviews on chiral N-oxides in asymmetric catalysis, see:
(a) G. Chelucci, G. Murineddu and G. A. Pinna, Tetrahedron:
Asymmetry, 2004, 15, 1373; (b) A. V. Malkov and P. Kocovsky
´ ,
Eur. J. Org. Chem., 2007, 29, and references therein.
8 For other examples of metal-N,N0-dioxide complex, see:
(a) Z. P. Yu, X. H. Liu, Z. H. Dong, M. S. Xie and X. M. Feng,
Angew. Chem., Int. Ed., 2008, 47, 1308; (b) X. Yang, X. Zhou,
L. L. Lin, L. Chang, X. H. Liu and X. M. Feng, Angew. Chem., Int.
Ed., 2008, 47, 7079; and references therein.
We appreciate the National Natural Science Foundation of
China (Nos. 20732003 and 20872096) and PCSIRT (No.
IRT0846) and National Basic Research Program of China
(973 Program) (No. 2010CB833300) for financial support. We
also thank Sichuan University Analytical & Testing Center for
NMR and X-ray analysis and the State Key Laboratory of
Biotherapy for HRMS analysis.
9 More data see Supporting Informationw.
10 CCDC-750144 and CCDC-739905 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 3771–3773 | 3773