Enantio- and diastereoselective Michael addition reactions of α-cyanoketones to nitroalkenes catalyzed by binaphthyl-derived organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2012.04.095

The catalytic enantioselective and diastereoselective Michael addition reactions promoted by chiral bifunctional organocatalysts are described. The treatment of α-cyanoketones with nitroalkenes under mild reaction conditions afforded the corresponding γ-n

Full text of DOI:10.1016/j.tetlet.2012.04.095

Tetrahedron Letters 53 (2012) 3374–3377
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Enantio- and diastereoselective Michael addition reactions of
a-cyanoketones
to nitroalkenes catalyzed by binaphthyl-derived organocatalyst
⇑
Hyun Joo Lee, Saet Byeol Woo, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective and diastereoselective Michael addition reactions promoted by chiral
bifunctional organocatalysts are described. The treatment of -cyanoketones with nitroalkenes
under mild reaction conditions afforded the corresponding -niro -cyanoketones with excellent
diastereoselectivities (up to syn/anti >99/1) and excellent enantioselectivities (up to 99% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 21 February 2012
Revised 18 April 2012
Accepted 20 April 2012
Available online 27 April 2012
a
c
a
Keywords:
Organocatalysis
Michael reaction
Asymmetric catalysis
Cyanoketones
Nitroalkenes
One of the ultimate goal and challenges in organic synthesis is
the development of catalytic asymmetric construction of highly
functionalized organic molecules containing an all-carbon quater-
nary stereogenic center by asymmetric catalysis.1 The Michael
addition reaction is widely recognized as one of the most general
and versatile methods for formation of C–C bonds in organic syn-
thesis,2 and the development of enantioselective catalytic proto-
cols for this reaction has been a subject of intensive research.3 In
addition to the great success catalyzed by metal complexes, the
powerful and environmentally friendly organocatalyst-mediated
asymmetric Michael reaction has been explored intensively in re-
cent years.4,5 Michael reaction of nucleophiles to nitroalkenes rep-
resents a direct and most appealing approach to chiral nitroalkanes
that are versatile intermediates in organic synthesis, which can be
transformed into an amine, nitrile oxide, ketone, carboxylic acid,
hydrogen etc.6 Extensive studies have been devoted to the devel-
Michael additions of various active methines to nitroalkenes have
reported, up to now there is one example of Michael additions
a-
cyanoketones to nitroalkenes was reported by Lu with moderate
enantiselectivity.11 This addition reaction could provide a highly
attractive, convergent approach toward optically active
c-amino
nitriles and -amino carbonyl compounds. Bifunctional organocat-
c
alysts possessing a combination of hydrogen-bonding donors and
chiral tertiary amines have been developed for activation of both
electrophilic and nucleophilic components. They have emerged
as powerful tools for the enantioselective formation of carbon–
carbon bond and carbon–heteroatom bonds.4
As part of research program related to the development of syn-
thetic methods for the enantioselective construction of stereogenic
carbon centers,12 we recently reported chiral amine-thiourea I
(Fig. 1) to be a highly selective catalyst for the enantioselective
Michael addition reaction of active methines.13 Herein, we wish
to describe the direct enantioselective Michael addition reaction
opment of asymmetric conjugate addition using
a-substituted
1,3-dicarbonyl compounds as pronucleophiles for the construction
of
a-cyanoketones with nitroalkenes catalyzed by using
of an quaternary stereogenic center.7 However, related transforma-
bifunctional organocatalysts bearing both central and axial chiral
tions using
a-cyanocarbonyl compounds have been less ex-
elements.
plored.8,9 The rich chemistry of functional group interconversion
of nitriles allows for the elaboration of the conjugate addition
products. Recently, Deng, Shibasaki and our groups have reported
a highly enantio- and diastereoselective Michael or Mannich reac-
To determine suitable reaction conditions for the catalytic
enantioselective Michael addition reaction of
a-cyanoketones, we
initially investigated the reaction system with 2-cyano-1-indanone
(1a) and nitrostyrene (2a) in the presence of 10 mol % of catalyst in
toluene at room temperature. We first examined the impact of the
structure of catalysts I–VI on enantioselectivities (15–75% ee,
Table 1, entries 1–6). The best results have been obtained with
catalyst VI. These results indicate that the strength and steric
hindrance of the multiple hydrogen-bonding donor may play
tion of
a-cyanoketones, catalyzed by chiral metal complexes and
organocatalysts.10 Although a number of catalytic enantioselective
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.095

H. J. Lee et al. / Tetrahedron Letters 53 (2012) 3374–3377
3375
Table 2
Variation of the nitroalkenes 2
O
O
R
N
N
cat. VI (10 mol%)
CH2Cl2, -40°C
NO2
CN
+
R
NO2
HN
HN
CN
S
O
2
3
1a
HN
HN
Entry
2, R
2a, C6H5
2b, 4-FC6H4
2c, 4-ClC6H4
2d, 2-ClC6H4
2e, 4-BrC6H4
2f, 2-BrC6H4
2g, 4-MeC6H4
2h, 4-MeOC6H4
2i, 3-NO2C6H4
2j, 2-NO2C6H4
2k, 2-furyl
2l, 2-thienyl
2m, 1-naphthyl
2n, PhCH2CH2
2o, i-Bu
Time (h)
Yielda (%)
drb (%)
Eec (%)
CF3
CF3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
11
24
24
42
24
40
24
24
12
40
54
10
10
10
12
94
3a, 98
3b, 95
3c, 98
3d, 97
3e, 98
3f, 97
3g, 98
3h, 98
3i,, 90
3j, 97
3k, 90
3l, 97
3m, 96
3n, 93
3o, 97
3p, 95
97:3
98:2
93:7
72:28
94:6
68:32
96:4
96:4
96:4
70:30
86:14
90:10
98:2
97:3
97:3
99:1
97
97
97
95
97
95
97
97
97
93
92
95
95
93
91
93
F3C
F3C
I
II
Ph
Ph
N
N
Ph
S
Ph
O
HN
HN
HN
HN
CF3
CF3
F3C
F3C
III
IV
2p, n-Bu
a
b
c
Combined yield of both diastereomers.
Diastereomeric ratio was determined by 1H NMR spectroscopic analysis.
Enantiopurity of major diastereomer was determined by HPLC analysis using
N
N
chiralpak IA (for 3b, 3h, and 3j) and IB (for 3a, 3c–g, 3i, 3k, and 3l–p) columns.
HN
HN
HN
S
SO2
ꢀ40 °C with catalyst VI improved the diastereoselectivity
(syn/anti = 97/3) and enantioselectivity (97% ee, entry 13). We then
explored the possibility of using a wide range of nitroalkene deriv-
F3C
F3C
F3C
HN
SO2
CF3
atives 2 with a-cyanoketone 1a in the presence of 10 mol % of cat-
V
VI
alyst VI in THF ꢀ40 °C (Table 2). A range of electron-donating and
withdrawing substitutions on the aryl ring of the nitrostyrenes
2b–j provided reaction products in high yields (90–99%), high to
excellent diastereoselectivities (syn/anti = 68/32–99/1), and excel-
lent enantioselectivities (92–97%). meta- and para-substituted
nitrostyrenes gave excellent diastereoselectivities. However,
ortho-substituted nitrostyrenes gave moderate diastereoselectivi-
ties. Heteroaryl- and naphthyl-substituted nitroalkenes 2k–m pro-
vided products with high selectivity (entries 11–13). The aliphatic
nitroalkenes system, including 1-nitro-4-phenyl-1-butene (2n)
and 4-methyl-1-nitropent-1-ene (2o), and 1-nitrohexene (2p),
was also acceptable starting materials and provided corresponding
Michael adducts with high yields and excellent enantioselectivities
(entries 14–16).
Figure 1. Structures of chiral binaphthyl-derived organocatalysts.
Table 1
Optimazation of the reaction conditions
O
O
Ph
cat. (10 mol%)
solvent, rt
NO2
+
CN
Ph
NO2
CN
1a
2a
3a
drb (%)
Entry
Cat.
solvent
Time (h)
Yielda (%)
Eec (%)
1
2
3
4
5
6
7
8
9
10
11
12d
13e
I
II
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
THF
CH2Cl2
CH2Br2
DCE
CH2Cl2
CH2Cl2
1
1
1
1
3
1
7
3
2
2
2
11
11
95
98
93
95
92
95
87
89
95
95
93
98
98
56:44
67:33
70:30
60:40
52:48
68:32
56:44
65:35
74:26
63:37
70:30
90:10
97:3
40
15
67
58
30
75
37
43
79
79
79
89
97
III
IV
V
To examine the generality of the catalytic enantioselective
Michael addition reaction of
bifunctional organocatalyst VI,16 we studied the Michael addition
reaction of various -cyanoketones 1b–i with nitrostyrene (2a).
As it can be seen by the results summarized in Table 3, the corre-
sponding -nitro- -cyanoketones 3q–x were obtained in excellent
yields and enantioselectivities. The cyclic -cyanoketones 1a–g,
with cyclic aromatic ketones 1a–d, and cyclic aliphatic ketones
1e–g, reacted with nitrostyrene (2a) to give the corresponding
nitro- -cyanoketones 3a–q in 95–98% yields and 92–99% ee (Table
a-cyanoketones 1 by using chiral
VI
VI
VI
VI
VI
VI
VI
VI
a
c
a
a
c-
a
a
b
c
Combined yield of both diastereomers.
3, entries 1–7). Acyclic
a-cyanoketones 1h–i reacted with nitrosty-
Diastereomeric ratio was determined by 1H NMR spectroscopic analysis.
Enantiopurity of major diastereomer was determined by HPLC analysis using a
rene (2a) to afford the
c
-nitro- -cyanoketones 3r–o with 95 and
a
chiralpak IB column.
85% ee (Table 3, entries 8–9). The absolute configuration of adducts
3 has been determined for some derivatives by comparison of their
optical and HPLC properties with literature values.11
d
This reaction was carried out at ꢀ20 °C.
e
This reaction was carried out at ꢀ40 °C.
To determine the absolute configuration of the generated stere-
ogenic center by chemical correlation, the Michael adduct 3a was
readily converted into the corresponding methyl ester 4a without
loss of enantioselectivity (Scheme 1). The absolute configuration
of 4a was established by comparison of the optical rotation and
chiral HPLC analysis with previously reported values.11,15
important roles in the catalytic activity and the level of enantiose-
lectivity achieved.14 Concerning the solvent (entries 6–11), the use
of halogenated solvents gave the best results in the yield and the
enantiomeric excess (entries 9–11). Lowering the temperature to

3376
H. J. Lee et al. / Tetrahedron Letters 53 (2012) 3374–3377
M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 1877, 2002; (c) Krause, N.;
Table 3
Hoffmann-Röder, A. Synthesis 2001, 171.
Variation of the a-cyanoketones 1
4. For selected recent reviews for bifunctional organocatalysts, see: (a) Connon, S.
J. Synlett 2009, 354; (b) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516; (c) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (d) Tylor, M. S.; Jacobson, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520; (e) Connon, S. J. Angew. Chem., Int. Ed.
2006, 45, 3909; (f) Connon, S. J. Chem. Eur. J. 2006, 12, 5418; (g) Akiyama, T.;
Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999; (h) Takemoto, Y. Org.
Biomol. Chem. 2005, 3, 4299; (i) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138.
O
Ph
O
cat. VI (10 mol%)
CH2Cl2, -40°C
NO2
CN
R1
NO2
R1
+
Ph
R2
CN
R2
1
2a
3
5. For recent reviews of organocatalytic asymmetric Michael addition, see: (a)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701; (b) Almasi, D.; Alonso, D. A.;
Najera, D. Tetrahedron: Asymmetry 2007, 18, 299.
6. (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001;
(b) Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68, 1592; (b) Rosini, G.;
Ballini, R. Synthesis 1988, 833; (c) Barrett, A. G. M.; Graboski, G. Chem. Rev.
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Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 612.
O
O
O
CN
CN
CN
R1
R2
n
n
R
1h : R1 = Ph, R2 = Ph
1i : R1 = Me, R2 = Ph
1e : n = 0
1f : n = 1
1g : n = 2
1a : n = 0, R = H
1b : n = 0, R = 5-MeO
1c : n = 0, R = 5,6-(MeO)2
1d : n = 1, R = H
7. For selected examples of catalytic asymmetric conjugate addition of
a-
substituted-1,3-dicarbonyl compounds, see: (a) Wynberg, H.; Helder, R.
Tetrahedron Lett. 1975, 16, 4057; (b) Hamashima, Y.; Hotta, D.; Sodeoka, M. J.
Am. Chem. Soc. 2002, 124, 11240; (c) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew.
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K. Angew. Chem., Int. Ed. 2003, 42, 3796; (f) Ogawa, C.; Kizu, K.; Shimizu, H.;
Entry
1
Time (h)
Yielda (%)
drb (%)
Eec (%)
1
2
3
4
5
1a
1b
1c
1d
1e
1f
1g
1h
1i
11
24
24
42
24
40
24
24
24
3a, 98
3q, 95
3r, 98
3s, 97
3t, 98
3u, 97
3v, 98
3w, 98
3x, 89
97:3
95:5
97:3
98:2
>99:1
90:10
>99:1
79:21
80:20
97
97
97
99
99
95
92
95
85
´
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6
7
8d
9
a
b
c
Combined yield of both diastereomers.
Diastereomeric ratio was determined by 1H NMR spectroscopic analysis.
Enantiopurity of major diastereomer was determined by HPLC analysis using
chiralpak AD–H (for 3u), IA (for 3v–x), IB (for 3a and 3q–r), IC (for 3s), and chiralcel
OD–H (for 3t) columns.
8. For selected examples of catalytic asymmetric conjugate addition of
a-
substituted -cyanocarbonyl pronucleophiles, see: (a) Sawamura, M.;
a
d
This reaction was carried out at ꢀ70 °C.
Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295; (b) Taylor, M. S.;
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O
O
Ph
Ph
NO2
CO2Me
4a, 96% ee
HCl
NO2
CN
3a, 97% ee
MeOH, rt
Scheme 1. Determination of the absolute configuration of 3a by chemical
correlation: synthesis of the known 4a.
9. For reviews on a-cyanocarboanions, see: (a) Arseniyadis, S.; Kyler, K. S.; Watt,
In conclusion, we have developed a highly efficient catalytic
D. S. Org. React. 1984, 31, 1; (b) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58,
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L.; Yang, Y.-Q.; Wang, H.-F.; Zheng, C.-W.; Cai, Y.-P.; Zhao, G.; Zhu, S.-Z. Chem.
Commun. 2009, 1, 7369; (e) Wang, H.-F.; Li, P.; Cui, H.-P.; Wang, X.-W.; Zhang,
J.-K.; Lin, W.; Zhao, G. Tetrahedron 2011, 67, 1774.
enantioselective Michael addition reaction of
using chiral bifunctional organocatalyst bearing multiple hydro-
gen-bonding donors. The desired -nitro- -cyanoketones were ob-
a-cyanoketones
c
a
tained in good to high yields, and excellent enantioselectivities (up
to 99% ee) were observed for all the substrates examined in this
work. We believe that this method provides a practical entry for
10. (a) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928; (b) Wang, B.;
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the preparation of chiral
c-nitro-a-cyanoketone derivatives. Fur-
ther study of these new bifunctional organocatalysts in other
asymmetric reactions is being under investigation.
Acknowledgment
This research was supported in part by the Soonchunhyang
University Research Fund.
11. Luo, J.; Xu, L. W.; Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437.
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Soc. 2010, 132, 11847; (d) Moon, H. W.; Kim, D. Y. Tetrahedron Lett. 2010, 51,
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H.; Kim, D. Y. Synlett 2011, 1125.
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1195; (f) Yoon, S. J.; Kang, Y. K.; Kim, D. Y. Synlett 2011, 420.
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H. J. Lee et al. / Tetrahedron Letters 53 (2012) 3374–3377
3377
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2009, 11, 1265; (d) Shi, X.; He, W.; Li, H.; Zhang, X.; Zhang, S. Tetrahedron Lett.
2011, 52, 3204; (e) Dong, X.-Q.; Fang, X.; Wang, C.-J. Org. Lett. 2011, 13, 4426.
15. (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. J. Am. Chem. Soc.
2005, 127, 119; (b) Kwon, B. K.; Kim, D. Y. Bull. Korean Chem. Soc. 2009, 30,
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Lett. 2010, 12, 964.
130.7, 131.2, 133.0, 133.2, 133.6, 134.8, 145.4, 183.4; HRMS(ESI) : m/z calcd for
43H43F6N4O2S2 [M+H]+ : 825.2732.; found 825.2737.Typical procedure for the
Michael addition reaction of -cyanoketone 1a with b-nitrostyrene (2a):
mixture of 2-cyano-1-indanone (1a, 31.4 mg, 0.2 mmol) and catalyst VI
(16.5 mg, 0.02 mmol) in dichoromethane (0.4 mL) was stirred at room
C
a
A
temperature for 5 min and then was cooled to ꢀ40 °C.
A solution of
nitrostyrene (2a, 35.8 mg, 0.24 mmol) was added. The reaction mixture was
stirred for 11 h at ꢀ40 °C. After completion of the reaction, the resulting
solution was allowed to warm to room temperature, concentrated in vacuo and
the obtained residue was purified by flash chromatography (EtOAc–Hexane,
1:5) to afford the 60.0 mg (98%) of Michael adduct 3a. (R)-2,3-dihydro-2-
16. Synthesis of bifunctional organocatalyst VI: To
a
solution of N-((1S,2S)-2-
(185 mg,
aminocyclohexyl)-3,5-bis(trifluoromethyl)benzene-sulfonamide
((S)-2-nitro-1-phenylethyl)-1-oxo-1H-indene-2-carbonitrile
(3a):
Major
0.6 mmol) in anhydrous THF (2 mL) was added (R)-4-((1S,2S)-2-
isothiocyanatocyclohexyl)-4,5-dihydro-3H-dinaphtho[2,1-c:10,20-e]azepine
(217 mg, 0.5 mmol). The mixture was stirred at room temperature for 60 h and
then it was concentrated in vacuo. The residue was purified by column
chromatography (EtOAc–Hexane, 1:5) to give catalyst VI (129 mg, 32%) as a
diastereoisomer. ½a D25
ꢁ
= +69.12 (c = 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) d
3.20 (d, J = 17.9 Hz, 1H), 3.38 (d, J = 17.9 Hz, 1H), 3.73 (dd, J = 4.0 Hz, 11.2 Hz,
1H), 5.14 (dd, J = 11.2 Hz, 13.7 Hz, 1H), 5.65 (dd, J = 4.0 Hz, 13.7 Hz, 1H), 7.39–
7.41 (m, 5H), 7.48–7.55 (m, 2H), 7.69–7.77 (m, 1H), 7.86–7.90 (m, 1H); 13C
NMR (50 MHz, CDCl3) d 37.6, 46.8, 49.2, 76.2, 118.1, 126.2, 126.4, 128.5, 129.1,
129.4, 129.5, 132.4, 134.8, 137.1, 149.9, 196.2; HRMS (ESI) : m/z calcd for
yellow solid. ½a D26
ꢁ
= ꢀ71.46 (c = 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) d 0.85–
1.90 (m, 16H), 2.46–2.59 (m, 2H), 3.17–3.26 (m, 1H), 3.58–3.75 (m, 4H), 4.00–
4.17 (m, 1H), 6.33 (br s, 1H), 7.17–7.33 (m, 4H), 7.40–7.62 (m, 4H), 7.90–7.98
(m, 4H), 8.06 (s, 1H), 8.45 (s, 2H); 13C NMR (50 MHz, CDCl3) d 24.0, 24.3 (ꢂ2),
C
18H14N2NaO3 [M+Na]+ : 329.0902.; found 329.0910. HPLC (90:10, n-hexane–i-
PrOH, 254 nm, 1.0 mL/min) Chiralpak IB, (major diastereomer) tR = 12.65 min
(major), 15.24 min (minor), (minor diastereomer) tR = 20.23 min (minor),
41.17 min (major), 97% ee.
25.1, 26.9, 29.6, 28.6, 32.6, 33.2, 34.0, 51.2 (ꢂ2), 56.5, 60.1, 68.0, 122.6 (q, JC–F
=
271.7 Hz), 125.7, 125.9, 127.0, 127.4, 128.1, 128.8, 131.9 (q, JC–F = 34.0 Hz),