Highly enantioselective conjugate addition of nitroalkanes to enones catalyzed by cinchona alkaloid derived primary amine

Article abstract of DOI:10.1016/j.tetlet.2013.05.019

A cinchona alkaloid derived primary amine catalyzed conjugate addition of nitroalkanes to enones is described. The process affords the Michael adducts in good yield and with up to 99% ee for both acyclic and cyclic enones.

Full text of DOI:10.1016/j.tetlet.2013.05.019

Tetrahedron Letters 54 (2013) 3791–3793
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective conjugate addition of nitroalkanes to enones
catalyzed by cinchona alkaloid derived primary amine
a,b,
Wenjing Liu a, Desheng Mei b, Wei Wang a,c, , Wenhu Duan
⇑
⇑
a School of Pharmacy, East China University of Science & Technology, Shanghai 200237, PR China
b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
c Department of Chemistry & Chemical Biology, University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 February 2013
Revised 2 May 2013
Accepted 6 May 2013
Available online 13 May 2013
A cinchona alkaloid derived primary amine catalyzed conjugate addition of nitroalkanes to enones is
described. The process affords the Michael adducts in good yield and with up to 99% ee for both acyclic
and cyclic enones.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric conjugate addition
Cinchona alkaloids
Enones
Chiral primary amine catalysis
Nitroalkanes
The catalytic conjugate addition of nitroalkanes to
a,b-unsatu-
S
S
rated ketones is one of the important reactions in organic synthe-
sis. The corresponding products are versatile building blocks for
transforming into a variety of new functionalities, such as amino
alkanes, amino carbonyls, lactones, and pyrrolidines.1 Recently,
the asymmetric version of this reaction has drawn considerable
attention, and a number of organocatalysts have been developed
in this regard,2,3 including proline rubidium salts,4 proline,5
Ar
Ph
NHTf
N
H
N
H
NHTf
N
H
N
H
N
H
O
NH
O
NH
NH2
1a
HN
HN
1c
1b
1d: Ar = Ph
1e: Ar = 3,5-(CF3)2C6H3
trans-4,5-methano-L
-proline,6 imidazoline,7 pyrrolidine tetrazole,8
and cinchona thioureas.9 Despite these significant advancements,
there is still room for improvement in terms of substrate scope
and enantioselectivity. It is expected that chiral organocatalysts
enabling to achieve a useful level of enantioselectivity (>90%) are
highly desirable with a more broad substrate scope.
Chiral primary amine-promoted reactions have emerged as a
powerful means in asymmetric synthesis.10 These catalysts display
better catalytic efficiency than secondary amines in many cases.11
As part of our ongoing research effort toward development of the
primary amine catalyzed enantioselective reactions,12 we are par-
ticularly interested in developing new organocatalytic reactions
utilizing primary amine-induced iminium activation, which in
some cases are difficult to control with chiral secondary amine
catalysis. Herein, we reported a chiral cinchona alkaloid derived
N
N
H
N
S
H
N
N
Ph
NH2
NH2
H
Ar
H
H
H
N
H
N
H
H
S
H
MeO
MeO
N
N
1h
1f: Ar = Ph
1g: Ar = 3,5-(CF3)2C6H3
N
N
1i
1j
Fig. 1. Structures of the catalysts studied.
primary amine 1i for a conjugate addition of nitroalkanes to acyclic
and cyclic enones with high enantioselectivity.
Previous studies revealed that both chiral cinchona alkaloid de-
rived catalysts and cyclohexane diamine derived bifunctional cata-
lysts could promote the asymmetric Michael addition reactions.13
With the precedents in mind, we decided to screen the two series
of catalysts (Fig. 1) to probe their capacity in promoting a model
asymmetric Michael addition reaction of 4-phenylbut-3-en-2-one
(2a) with nitromethane (3a) (Table 1).
⇑
Corresponding authors. Tel.: +1 505 277 0756; fax: +1 505 277 2609 (W.W.);
tel.: +86 21 5080 6032 (W.D.).
E-mail addresses: wwang@unm.edu (W. Wang), whduan@simm.ac.cn (W.
Duan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.019

3792
W. Liu et al. / Tetrahedron Letters 54 (2013) 3791–3793
Table 1
Table 3
Asymmetric Michael addition of (E)-4-phenylbut-3-en-2-one (2a) to nitromethane
Asymmetric Michael addition of nitroalkanes 3 to enones 2 catalyzed by 1ia
(3a)a
O
O
R3
NO2
COCH3
R2
NO2
O
1i (10% mol)
R1
R2
+
cat. (10 mol%)
R4
3
THF, rt, 5 d
NO2
R1
CH3NO2
3a
+
2
R3 R4
4
CHCl3, rt, 5 d
4a
2a
Entry R1
R2
R3
R4
4
Yieldb (%) eec (%)
(dr)f
Entry
Cat.
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
32
56
36
72
22
58
93
59
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
67
63
67
63
61
78
80
81
62
67
72
53
99
99
95
99
99
95
95
95
95
98
92
96
94
91
92
94
p-CH3OC6H4
o-CH3OC6H4
3,4-(CH3)2OC6H3 Me
p-N(CH3)2C6H4
p-FC6H4
p-BrC6H4
p-NO2C6H4
m-NO2C6H4
o-NO2C6H4
2-Furanyl
(CH2)4
53
37
Me
Me
Me
Me
Me
Me
Me
NDd
NDd
NDd
63
NDd
NDd
NDd
97
9
1j
36
89
10
11
12d
13d
14d
15d
16d
17d
18d
19d
20
21d
22d
23d
4j
4k
4l
a
Unless specified, reactions were carried out with 2a (0.14 mmol) and 3a
(2.1 mmol, 15.0 equiv) in the presence of 10 mol % organocatalyst in 0.2 mL of
CHCl3 at rt for 5 d.
n-Me(CH2)4
Ph
Me
4m 12
b
Me Me Me 4n
Me Me Me 4o
Me Me Me 4p
Me Me Me 4q
Me Me Me 4r
Me Me 4s
Me (CH2)4
Me Me
Me Me
Me
49
55
82
53
51
65
Isolated yield.
Determined by HPLC analysis (chirapak AS-H column).
Not determined.
c
p-BrC6H4
o-CH3OC6H4
o-NO2C6H4
2-Furanyl
(CH2)4
d
94
88
93
92
Ph
Ph
4t
45h
78e
40e
77e
Table 2
H
H
H
4u
4v
4w
94g (1/1)
94g (1.6/1)
96g (2/1)
Effects of solvents and additives on the asymmetric Michael addition of 4-phenylbut-
3-en-2-one (2a) to nitromethane (3a)a
p-CH3OC6H4
(CH2)4
COCH3
O
a
cat. 1i (10 mol%)
Reaction conditions: unless specified, reactions were carried out with 2a
(0.14 mmol) and 3a (2.1 mmol, 15.0 equiv) in the presence of 10 mol % of cat 1i at rt
for 5 d.
NO2
CH3NO2
3a
+
additive (10 mol%)
CHCl3, rt, 5 d
b
4a
2a
Solvent
Isolated yields.
c
Determined by chiral HPLC analysis (chiralpak AS-H or AD-H).
Reactions were carried out with 2a (0.3 mmol) and nitroalkane (15.0 equiv) in
d
Entry
Additive
Yieldb (%)
eec (%)
the presence of 10 mol % catalyst 1i in 0.4 mL of THF at rt for 5 d.
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
Toluene
Et2O
None
None
None
None
None
None
None
None
None
None
None
PhCO2H
p-TSA
AcOH
CF3CO2H
Et3N
35
63
35
50
36
63
54
32
50
70
67
7
11
7
<5
35
32
97
97
95
97
98
97
89
92
99
90
99
98
92
97
NDd
93
93
e
Total yield for both diastereomers.
dr determined by 1H NMR.
f
g
ee for both diasteroisomers.
Nitrocyclohexane with 2.5 equiv used.
h
1,4-Dioxane
EtOAc
MeOH
i-PrOH
DMSO
DMF
(entries 6–8). No reactions were observed in these cases. Moreover,
the new catalysts 1b, 1d, and 1e we used did not give rise to
encouraging outcomes either. The most promising results came
from studies with quinine amine 1i.15 Notably, good yield (63%)
and high level of enantiocontrol (97% ee, entry 10) were achieved.
Therefore, 1i was chosen for further optimization of reaction
conditions.
Next, other reaction conditions such as reaction media and
additives were investigated. As shown in Table 2, reaction solvents
had a significant effect on the Michael addition reaction yield but
limited impact on enantioselectivity. However, there is no clear
relationship between the reaction efficacy and media property
such as polarity (entries 1–11). Among solvents probed, reaction
in THF gave a good yield (67%) and the highest enantioselectivity
(99% ee) (entry 11). It appeared that additives were not beneficial
(entries 12–17). They inhibited the reaction and led to dropping
the yields dramatically, though excellent enantioselectivity was
maintained.
With the optimized reaction conditions in hand, the scope of
the addition of nitroalkanes 3 to enones 2 was explored. The re-
sults were summarized in Table 3. Notably, cinchona alkaloid de-
rived primary amine 1i catalyzed the conjugate addition of
nitromethane to enones and afforded the desired products with
excellent enantioselectivities (92–99% ee, entries 1–13), but the
yields were varied. In general, those enones bearing electron-with-
drawing groups (such as F, Br, and NO2) at o-position of the
9
10
11
12
13
14
15
16
17
THF
THF
THF
THF
THF
THF
THF
AcONa
a
Reaction conditions: reactions were carried out with 2a (0.14 mmol) and 3a
(2.1 mmol, 15.0 equiv) in the presence of 10 mol % cat 1i and without or with
10 mol % additive at rt for 5 d.
b
Isolated yield.
Determined by HPLC analysis (chirapak AS-H column).
Not determined.
c
d
The initial reactions were performed by using 10 mol % of a cat-
alyst (Fig. 1) at room temperature (rt) in chloroform. Examination
of the results from the survey revealed that their catalytic activities
varied significantly (Table 1). For example, the process promoted
by pyrrolidine trifluoromethane sulfonamide 1a proceeded with
both low yield (32%) and poor enantioselectivity (22%) (entry
1).14 1,2-Cyclohexanediamine derivative 1c12b and cinchonine
derivative 1j gave high enantioselectivity (93% and 89%, respec-
tively) but low yields (36% and 36%, respectively) (entries 3 and
10). N,N-Dimethyl-1,2-cyclohexanediamine thioureas 1f and
1g,13b and quinine thiourea 1h9a were not effective in this process

W. Liu et al. / Tetrahedron Letters 54 (2013) 3791–3793
3793
aromatic ring afforded the desired products with high isolated
References and notes
yields (78–81%) (entries 6–8). Heterocyclic furyl enone also per-
formed well to give the desired product in 72% yield and 92% ee
(entry 11). Moreover, the reaction could also be extended to the
cyclic substrates with 53% isolated yield and excellent enantiose-
lectivity (96% ee) (entry 12). However, a sharp decrease in isolated
yield (12%) was observed for the aliphatic substrate, though a 94%
ee was obtained (entry 13). The low yield is due to the slow con-
1. For reviews, see: (a) Sibi, M.; Manyem, S. Tetrahedron 2001, 56, 8033; (b)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688; (c) Ballini, R.;
Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2007, 107, 933; (d)
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 12, 1877; (e)
Ballini, R.; Bosica, G.; Petrini, M. Chem. Rev. 2005, 105, 933; (f) Roberto Ballini,
R.; Petrini, M. Tetrahedron 2004, 60, 1017.
2. For recent reviews of organocatalyzed conjugate addition reactions, see: (a)
Almaßsi, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299; (b)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
3. (a) Tsogoeva, S. B.; Jagtap, S. B.; Aredmasova, Z. A. Eur. J. Org. Chem. 2004, 19,
4014; (b) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897; (c)
Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876; (d) Mitchell, C. E. T.;
Brenner, S. E.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039; (e) Malmgren, M.;
Granander, J.; Amedjkouh, M. Tetrahedron: Asymmetry 2008, 19, 1934; (f)
Pansare, S. V.; Lingampally, R. Org. Biomol. Chem. 2009, 7, 319.
version and
remained.
a significant amount of starting materials still
Moreover, structural variation of nitroalkanes was found to be
tolerated (entries 14–23). Excellent enantioselectivity and moder-
ate to high yield were also obtained when the nucleophilic re-
agents were expanded to the steric hindrance compounds, such
as nitrocyclopentane, 2-nitro-propane, and nitroethane (entries
14–23). It is noteworthy that when nitroethane was used, two dia-
stereomers were produced in high enantioselectivity, but poor dr
(entries 21–23).
In summary, a cinchona alkaloid derived primary amine 1i was
reported as an efficient tool for the asymmetric conjugate addition
reaction of nitroalkanes to enones. This promoter catalyzed the
conjugate addition with a broad substrate scope worked for both
acyclic and cyclic enones, and afforded the adducts in good yields
and with 91–99% ee. Therefore, the study has expanded the do-
main of organocatalyzed enantioselective conjugate addition pro-
cess of nitroalkanes to enones at a useful level.
4. Yamaguchi, M.; Shiraishi, T.; Igarashi, Y. Tetrahedron Lett. 1994, 35, 8233.
5. Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975.
6. Hanessian, S.; Shao, Z.-H.; Warrier, J. S. Org. Lett. 2006, 8, 4787.
7. Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331.
8. Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem. Commun. 2005, 42, 5346.
9. (a) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967; (b) Li, P.;
Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008, 3302.
10. For recent reviews of primary amine catalyzed reactions, see: (a) Xu, L.-W.; Lu,
Y.-X. Org. Biomol. Chem. 2008, 6, 2047; (b) Chen, Y.-C. Synlett 2008, 1919; (c)
Peng, F.; Shao, Z.-H. J. Mol. Catal. A: Chem. 2008, 285, 1; (d) Xu, L.-W.; Luo, J.; Lu,
Y.-X. Chem. Commun. 2009, 1807; (e) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol.
2011, 354; (f) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748.
11. Bartoli, G.; Bosco, M.; Carlone, A. Org. Lett. 2007, 9, 1403.
12. (a) Xue, F.; Zhang, S.-L.; Duan, W.-H.; Wang, W. Adv. Synth. Catal. 2008, 350,
2194; (b) Mei, K.; Jin, M.; Zhang, S.-L.; Li, P.; Liu, W.-J.; Chen, X.-B.; Xue, F.;
Duan, W.-H.; Wang, W. Org. Lett. 2009, 11, 2864.
13. (a) Wang, J.; Li, H.; Wang, W. Chem. Eur. J. 2006, 12, 4321; (b) Okino, T.; Hoashi,
Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
14. Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369.
15. (a) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.;
Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389; (b) Li, P.; Wang, Y.;
Liang, X.; Ye, J.-X. Chem. Commun. 2008, 3302; (c) Lv, J.; Zhang, J.; Lin, Z.; Wang,
Y.-M. Chem. Eur. J. 2009, 15, 972; (d) Dong, L.-T.; Lu, R.-J.; Du, Q.-S.; Zhang, J.-
M.; Liu, S.-P.; Xuan, Y.-N.; Yan, M. Tetrahedron 2009, 65, 4124; (e) Liu, C.; Lu, Y.-
X. Org. Lett. 2010, 12, 2278; (f) Cui, H.-F.; Li, P.; Wang, X.-W.; Chai, Z.; Yang, Y.-
Q.; Cai, Y.-P.; Zhu, S.-Z.; Zhao, G. Tetrahedron 2011, 67, 312; (g) Kwiatkowski, P.;
Dudzin´ ski, K.; Łyzwa, D. Org. Lett. 2011, 13, 3624.
Acknowledgments
Financial support of this research from the Chinese National
Natural Science Foundation (Nos. 81102461, 81021062, and
90813034), the Chinese National Programs for High Technology
Research and Development (No. 2012AA020302), and the NSF
(CHE-1057569) is gratefully acknowledged.
Supplementary data
Supplementary data (the syntheses, 1H and 13C NMR copies of
new compounds) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.019.