Enantioselective Michael addition of malonates to 2-enoylpyridine N-oxides catalyzed by chiral bisoxazoline-Zn(II) complex

Article abstract of DOI:10.1021/ol202405v

An enantioselective Michael addition of malonates to 2-enoylpyridine N-oxides catalyzed by a chiral bisoxazoline-Zn(II) complex has been developed. The corresponding Michael adducts have been obtained in high yields with up to 96% ee. A plausible transiti

Full text of DOI:10.1021/ol202405v

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5812–5815
Enantioselective Michael Addition of
Malonates to 2-Enoylpyridine N-Oxides
Catalyzed by Chiral BisoxazolineÀZn(II)
Complex
Sumit K. Ray,† Pradeep K. Singh,† and Vinod K. Singh*,†,‡
Department of Chemistry, Indian Institute of Technology-Kanpur, Kanpur, UP 208 016,
India, and Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, ITI (Gas Rahat) Building, Govindpura, Bhopal, MP 462 023, India
vinodks@iitk.ac.in
Received September 6, 2011
ABSTRACT
An enantioselective Michael addition of malonates to 2-enoylpyridine N-oxides catalyzed by a chiral bisoxazolineÀZn(II) complex has been
developed. The corresponding Michael adducts have been obtained in high yields with up to 96% ee. A plausible transition-state model has been
proposed to explain the stereochemical outcome of the reaction.
The Michael reaction is one of the most fascinating and
powerful CÀC bond forming reactions and has wide utility
in organic synthesis.1 The asymmetric version of this
reaction can afford various chiral functionalized adducts
from numerous Michal acceptors and donors.2 Among
them, the enantioselective addition of malonates to R,β-
unsaturated carbonyls is an atom economical route to
optically active tricarbonyl Michael adducts, which are
key intermediates in synthesis.3 Due to their synthetic
versatility, considerable effort has been devoted to the
development of efficient synthetic methods for such
Michael reactions. As a result, several efficient methods
involving organocatalysis4 as well as organometallic
catalysis5 have been developed. Most of the reported
methods have a limited substrate scope. Thus, there is still
a need to develop catalyst systems for the Michael reaction
of R,β-unsaturated carbonyls, which can show substrate
generality.
† Indian Institute of Technology Kanpur.
‡ Indian Institute of Science Education and Research Bhopal.
(1) For a recent review, see: Tokoroyama, T. Eur. J. Org. Chem. 2010,
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(4) For recent examples, see: (a) Mase, N.; Fukasawa, M.; Kitagawa,
N.; Shibagaki, F.; Noshiro, N.; Takabe, K. Synlett 2010, 2340. (b)
Procopio, A.; DeNino, A.; Nardi, M.; Oliverio, M.; Paonessa, R.;
Pasceri, R. Synlett 2010, 1849. (c) Mao, Z.; Jia, Y.; Li, W.; Wang, R.
J. Org. Chem. 2010, 75, 7428. (d) Fleischer, I.; Pfaltz, A. Chem.;Eur.
J. 2010, 16, 95. (e) Sato, H.; Nagashima, F.; Oriyama, T. Chem. Lett.
2010, 39, 379. (f) Maltsev, O. V.; Kucherenko, A. S.; Zlotin, S. G. Eur. J.
Org. Chem. 2009, 5134. (g) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang,
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(2) (a) Sulzer Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123. (b)
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Almas-i, D.; Alonso, D. A.; Najera, C Tetrahedron: Asymmetry 2007, 18,
299. (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (d) Ballini, R.;
Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105,
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Ma, A.; Zhu, S.; Ma, D. Tetrahedron Lett. 2008,49, 3075. (k) Wascholowski,
V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem.;Eur. J. 2008,
(3) (a) Miyazaki, T.; Maekawa, H.; Yonemura, K.; Yamamoto, Y.;
Yamanaka, Y.; Nishiguchi, I. Tetrahedron 2011, 67, 1598. (b) Somaiah,
S.; Sashikanth, S.; Raju, V.; Reddy, K. V. Tetrahedron: Asymmetry
2011, 22, 1. (c) Fang, H.; Wu, X.; Nie, L.; Dai, X.; Chen, J.; Cao, W.;
Zhao, G. Org. Lett. 2010, 12, 5366. (d) Sun, Y.; Fan, R. Chem. Commun.
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14, 6155. (l) Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sunden, H.;
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r
10.1021/ol202405v
Published on Web 10/04/2011
2011 American Chemical Society

N-oxides in place of indole and pyrrole in a Michael
fashion, expanding the scope and versatility of the tem-
plate. In this communication, we report the Michael addi-
tionof malonates to2-enoylpyridineN-oxidescatalyzed by
bisoxazolineÀZn(II) complexes (Figure 1).
Table 1. Screening of Various Ligands for Enantioselective
Michael Reactiona
entry
ligand
time
yield (%)b
ee (%)c
1d
2
1a
1a
1b
1c
1d
1e
1f
3 d
36 h
4 d
nre
75
40
53
76
50
90
90
92
nre
ndf
0
3
0
Figure 1. Chiral bisoxazoline ligands used in enantioselective
Michael reaction.
4
48 h
24 h
72 h
24 h
24 h
20 h
24 h
0
5
16
0
6
Recently, Pedro and co-workers introduced 2-enoylpyr-
idine N-oxides as excellent prochiral chelating substrates
for chiralmetal complex catalyzed DielsÀAlder reactions.6
Later, the use of 2-enoylpyridine N-oxides was extended in
a hetero DielsÀAlder reaction7 and nitrone cycloaddition
reaction.8 We have also used these substrates in an en-
antioselective FriedelÀCrafts alkylation reaction of
indoles9 and pyrroles10 furnishing products in high yields
and enantioselectivities (up to >99% ee). Apart from the
higher reactivity and enantioselectivity associated with this
template in comparison to 2-enoylpyridine, an additional
attractive feature with 2-enoylpyridine N-oxide is that the
pyridine N-oxide ring can be cleaved to give the corre-
sponding acid, allowing further transformations. Further-
more, the characteristic chemistry ofpyridineN-oxides can
be used to perform several attractive transformations.11
Inspired by our previous studies, it was thought that an
active methylene group could be added to 2-enoylpyridine
7
57
0
8
1g
1h
À
9
10g
76
ndf
a All reactions were run on a 0.2 mmol scale in 1.0 mL of solvent,
10 mol % 1-Zn(OTf)2 complex, and 10 mol % Et3N. b Isolated yield.
c Determined by HPLC using Chiralpak IA3 column. d Reaction was
carried without Et3N. e nr = no reaction. f nd = not determined.
g Reaction was carried out only with 10 mol % Et3N.
Since 1a12 was an efficient ligand in an enantioselective
FriedelÀCrafts alkylation reaction,9,10 it was worthwhile
to try it, in the first instance, for the enantioselective
Michael reaction. The catalyst 1aÀZn(OTf)2 failed to
catalyze the Michael addition of dimethyl malonate to
benzylidene-2-acetylpyridine-N-oxide 2a (Table 1, entry
1). So, a catalytic amount of base such as Et3N was added
for the activation of dimethyl malonate. Thus, the electro-
phile as well as nucleophile both were activated toward the
Michael reaction under dual acid/base catalysis. Under
this condition, the reaction did proceed, but there was no
enantioselectivity (Table 1, entry 2). Two other pybox
ligands, 1b and 1c, also gave disappointing results as the
product was obtained as a racemic mixture (Table 1, entries
3 and 4). Next, various bidentate bisoxazoline ligands were
examined. Ligands 1d and 1e gave 16% ee and no ee,
respectively (Table 1, entries 5 and 6). Because, in our earlier
study, we had successfully used the ligand 1f in carbonyl
ene reactions,13 we investigated its use in an enantioselec-
tive Michael reaction. The catalyst 1fÀZn(II) complex
furnished the desired product in 90% yield and with 57%
ee(Table 1, entry 7). Encouraged by this result, the effect of
ꢁ
(5) For recent examples, see: (a) Albada, H. B.; Rosati, F.; Coquiere,
D.; Roelfes, G.; Liskamp, R. M. J. Eur. J. Org. Chem. 2011, 1714. (b)
Zhou, L.; Lin, L.; Wang, W.; Ji, J.; Liu, X.; Feng, X. Chem. Commun.
2010, 46, 3601. (c) Yang, H.-M.; Gao, Y.-H.; Li, L.; Jiang, Z.-Y.; Lai,
G.-Q.; Xia, C.-G.; Xu, L.-W. Tetrahedron Lett. 2010, 51, 3836. (d)
Megens, R. P.; Roelfes, G. Org. Biomol. Chem. 2010, 8, 1387. (e) Dijk,
E. W.; Boersma, A. J.; Feringa, B. L.; Roelfes, G. Org. Biomol. Chem. 2010,
8, 3868. (f) Chen, D.;Chen, Z.;Xiao, X.;Yang, Z.;Lin, L.;Liu, X.;Feng, X.
Chem.;Eur. J. 2009, 15, 6807. (g) Agostinho, M.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 2430. (h) Naka, H.; Kanase, N.; Ueno, M.; Kondo,
ꢀ
Y. Chem.;Eur. J. 2008, 14, 5267. (i) Conquiere, D.; Feringa, B. L.; Roelfes,
G. Angew. Chem., Int. Ed. 2007, 46, 9308. (j) Park, S.-Y.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 2815. (k)
Kantam, M. L.; Ranganath, K. V. S.; Mahendar, K.; Chakrapani, L.;
Choudary, B. M. Tetrahedron Lett. 2007, 48, 7646.
(6) Barroso, S.; Blay, G.; Pedro, J. R. Org. Lett. 2007, 9, 1983.
~
(7) Barroso, S.; Blay, G.; Munoz, M. C.; Pedro, J. R. Adv. Synth.
Catal. 2009, 351, 107.
(8) (a) Barroso, S.; Blay, G.; Munoz, M. C.; Pedro, J. R. Org. Lett.
~
2011, 13, 402. (b) Livieri, A.; Boiocchi, M.; Desimoni, G.; Faita, G.
Chem.;Eur. J. 2011, 17, 516.
(9) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121.
(10) Singh, P. K.; Singh, V. K. Org. Lett. 2010, 12, 80.
(11) Katritzky, A. R. Chemistry of the Heterocyclic N-Oxides;
Academic Press: London, 1971.
(12) (a) Singh, P. K.; Singh, V. K. Pure Appl. Chem. 2010, 82, 1845.
(b) Bisai, A.; Singh, V. K. Tetrahedron 2011 (doi:10.1016/j.
tet.2011.05.114).
(13) Pandey, M. K.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2006,
47, 897.
Org. Lett., Vol. 13, No. 21, 2011
5813

Table 2. Effect of Solvent and Basic Additives on
Enantioselective Michael Reactiona
Table 3. Effect of Temperature and Catalyst Loading on
Enantioselective Michael Reactiona
entry
solvent
base
Et3N
time (h)
yield (%)b
ee (%)c
entry
catalyst
temp
rt
time (h)
yield (%)b
ee (%)c
1
CH2Cl2
CH2Cl2
CHCl3
DMF
20
40
24
48
72
30
30
16
60
30
48
24
35
30
24
20
92
80
85
60
82
84
80
95
70
90
88
80
90
56
79
85
76
25
63
70
68
70
72
68
78
55
0
1
2
3
4
5
6
7
10 mol %
15 mol %
5 mol %
2 mol %
5 mol %
5 mol %
5 mol %
20
16
24
30
24
30
48
92
90
92
86
93
96
90
76
73
78
75
87
92
89
2d
3
Et3N
rt
Et3N
rt
4
Et3N
rt
5
DMSO
Toluene
Benzene
THF
Et3N
À5 °C
À25 °C
À35 °C
6
Et3N
7
Et3N
8
Et3N
a All reactions were run on a 0.2 mmol scale in 1.0 mL of solvent and
10 mol % Et3N. b Isolated yield. c Determined by HPLC using Chiralpak
IA3 column.
9
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
10
11
12
13
14
15
16
iPr2NEt
DBU
NMM
K2CO3
1-Me-Im
Pyridine
DMAP
65
37
15
50
38
Table 4. Substrate Scope of Enantioselective Michael Reactiona
a All reactions were run on a 0.2 mmol scale in 1.0 mL solvent, 10 mol %
1h-Zn(OTf)2 complex and 10 mol % base. b Isolated yield. c Determined
by HPLC using chiralpak IA3 column. d 4 A MS were used.
ꢀ
˚
substitution was tested on the bridging carbon of the
bisoxazoline ring. To our surprise, the ligand 1g with
gem-dimethyl substitution at the bridging carbon gave
the racemic product (Table 1, entry 8). However, spirobis-
(oxazoline) ligand 1h having a cyclopropyl ring at the
bridging carbon gave the product in good yield and 76%
ee (Table 1, entry 9). A control experiment showed that
Et3N alone, intheabsenceof1h-Zn(OTf)2, didnotcatalyze
the reaction (Table 1, entry 10).14 Subsequently, the effect
of solvent and basic additives was investigated. Among
various solvents used, a good yield (95%) was obtained in
THF, but the enantioselectivity was only 68% (Table 2,
entry 8). Acetonitrile gave 78% enantioselectivity, but the
lower yield and prolonged reaction time discouraged us
from using this solvent (Table 2, entry 9). Considering both
the chemical yield and the enantioselectivity, dichloro-
methane gave the best results, and it was chosen as a
solvent of choice for further studies. Since the addition of
base is essential for the reaction to proceed, various bases
were screened in the reaction (Table 2, entries 10À16). It
was found that triethylamine was superior to all other
screened basic additives for the reaction.
entry R1
R2
4
t (h) yield (%)b ee (%)c
1
Me Ph (2a)
Et Ph (2a)
4a
4b
4c
4d
4e
4f
30
36
12
24
24
30
48
36
30
48
30
48
36
72
96
100
96
90
86
84
60
95
87
92
97
96
95
83
96
75
70
nre
92
85d
79
74
16
90
88
88
91
87
96
96
94
86
92
ndf
2
3
iPr Ph (2a)
Bn Ph (2a)
tBu Ph (2a)
4
5
6
Me 4-FC6H4 (2b)
Me 4-MeOC6H4 (2c)
Me 3-NO2C6H4 (2d)
Me 4-ClC6H4 (2e)
Me 3-ClC6H4 (2f)
Me 2-ClC6H4 (2g)
Me 1-naphthyl (2h)
Me 2-furyl (2i)
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
4j
4k
4l
4m
Me (E)PhCHdCH (2j) 4n
Me cyclohexyl (2k)
Me tBu (2l)
4o
a All reactions were run on a 0.2 mmol scale in 1.0 mL of solvent,
5 mol % 1h-Zn(OTf)2 complex, and 10 mol % Et3N. b Isolated yield.
c Determined by HPLC using chiral columns. d ee was determined after
N-deoxygenation of the product. e nr = no reaction. f nd = not determined.
To improve the enantioselectivity further, the effects of
the catalyst loading and reaction temperature were inves-
tigated (Table 3). It was found that the catalyst was equally
efficient at the 5 mol % catalyst loading, producing 4a in
92% yield and 78% ee (Table 3, entry 3). Further, lowering
the catalyst loading to 2 mol % causes a slight loss in
enantioselectivity of the corresponding product. So, with
optimization of 5 mol % catalyst, the effect of temperature
was studied. Lowering of the temperature to À25 °C
improved the enantioselectivity to 92% ee (Table 3, entry
6). After optimizing the reaction conditions, the substrate
scope of the catalyst system was investigated. First, the effect
of various nucleophiles was studied (Table 4, entries 1À5).
(14) In order to demonstrate the role of an additive, a control
experiment was performed according to a reviewer’s comment. We
thank the reviewer for his valuable suggestion.
5814
Org. Lett., Vol. 13, No. 21, 2011

It was observed that the enantioselectivity of the product
was dependent on the ester group. Sterically hindered
malonates gave poor enantioselectivities. Dimethyl malonate
gave the best results (Table 4, entry 1).
The reaction was then extended to different β-substi-
tuted 2-enoylpyridine N-oxides (Table 4, entries 6À16). A
maximum of 96% ee was obtained in the reaction. The
catalyst works well with heteroaromatic and aliphatic
substrates (Table 4, entries 13À15). The substrate with
the cinnamyl group at the β-position also underwent a
Michael reaction and gave the corresponding product with
86% ee. However, the reaction did not proceed with
sterically hindered substrate 2l, and no product was ob-
served even after 100 h.
Figure 2. Plausible transition state.
in Figure 2. The addition of malonate takes place from the
sterically less demanding Re face as the Si face is hindered
by the aryl ring of the ligand, giving the (S)-isomer of the
product.
Scheme 1. Determination of the Absolute Configuration of 4a
In conclusion, 2-enoylpyridine N-oxides have been suc-
cessively used in an enantioselective Michael reaction with
malonate. The reaction was catalyzed by a highly efficient
bisoxazolineÀZn(II) complex with a 5 mol % catalyst
loading. A possible transition state has been proposed
based on the stereochemical outcome of the product.
Further investigation to explore the 2-enoylpyridine N-
oxides template in an asymmetric Michael reaction with
other nucleophiles is in progress in our laboratory.
The absolute stereochemistry of the product was deter-
mined by converting the product to a literature known
compound. The product 4awas transformed to a triester 5
via cleavage of a pyridine N-oxide ring followed by ester-
ification of acid with diazomethane, without any loss in
enantioselectivity. The comparison of optical rotation of
triester 5 with literature, elucidated the absolute config-
uration of the product to be (S) (Scheme 1).5i
Acknowledgment. V.K.S. thanks the Department of
Science and Technology, Government of India for a
research grant through J.C. Bose Fellowships. S.K.R.
thanks the Council of Scientific and Industrial Research,
New Delhi for a Senior Research Fellowship.
The stereochemical outcome in the above Michael reac-
tion has been rationalized by a proposed transition state. It
is proposed that the ligand 1h and 2-enoylpyridine N-oxide
coordinate toZn(II) giving a tetrahedral complex asshown
Supporting Information Available. General experimen-
tal procedures and full characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 21, 2011
5815