Pyrrolidine-diaminomethylenemalononitrile organocatalyst for Michael additions of carbonyl compounds to nitroalkenes under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2014.03.042

The novel pyrrolidine-diaminomethylenemalononitrile organocatalyst 7 promotes the asymmetric conjugate addition of a carbonyl compound to a nitroalkene to afford the corresponding adduct in high yield with up to 99% ee, under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2014.03.042

Tetrahedron Letters 55 (2014) 2703–2706
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pyrrolidine-diaminomethylenemalononitrile organocatalyst
for Michael additions of carbonyl compounds to nitroalkenes under
solvent-free conditions
Kosuke Nakashima a, Shin-ichi Hirashima a, Masahiro Kawada a, Yuji Koseki a, Norihiro Tada b,
Akichika Itoh b, Tsuyoshi Miura a,
⇑
a Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel pyrrolidine-diaminomethylenemalononitrile organocatalyst 7 promotes the asymmetric con-
jugate addition of a carbonyl compound to a nitroalkene to afford the corresponding adduct in high yield
with up to 99% ee, under solvent-free conditions.
Received 17 February 2014
Revised 6 March 2014
Accepted 7 March 2014
Available online 17 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Michael addition
Solvent-free
Diaminomethylenemalononitrile
Nitroalkene
Over the past decade, bifunctional organocatalysts with both
thiourea and amine groups, such as 1 and 2, have been identified
as being some of the most effective and environmentally benign
catalysts for synthesizing various enantiomerically pure synthetic
intermediates (Fig. 1).1 Organocatalysts with squaramide motifs
have recently been developed by several research groups, and this
development took place since Rawal and co-workers pioneered the
use of squaramide catalyst 3.2,3 Efficient double hydrogen bonding
interactions between thiourea or squaramide and the target sub-
strate play an important role in the efficiency of such catalysts.
Organocatalysts with double hydrogen bonding functional groups
other than the thiourea group have been reported by several re-
search groups.4 We have recently developed the stereoselective
construction of all-carbon quaternary centers using the asymmet-
ric Michael addition of branched aldehydes to vinyl sulfone using
organocatalysts 4–6, which each have a diaminomethylenemalon-
onitrile (DMM) skeleton and a primary amine group.5
additions available, the direct asymmetric Michael addition of a
carbonyl compound to a nitroalkene is a fundamental and impor-
tant organocatalytic route for synthesizing enantiomerically pure
c
-nitroketones.7 It is also significant that, from the green chemistry
CF3
CF3
S
S
F3C
N
H
N
H
F3C
N
N
H
H
NMe2
O
HN
2
1
H
O
N
H
F3C
N
H
HN
CF3
N
3
NC CN
Organocatalytic conjugate addition is an important synthetic
route for the stereoselective construction of carbon–carbon bonds,
because valuable intermediates can be produced by selecting
different donors and acceptors.6 Out of the range of conjugate
NC CN
F3C
R
N
H
N
H
N
H
N
H
HN
NH2
CF3
4
5
: R = Ph
: R = Bn
7
6: R = 3,5-(CF3)2C6H3CH2
⇑
Corresponding author. Tel./fax: +81 42 676 4479.
E-mail address: tmiura@toyaku.ac.jp (T. Miura).
Figure 1. Structure of organocatalysts.
http://dx.doi.org/10.1016/j.tetlet.2014.03.042
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2704
K. Nakashima et al. / Tetrahedron Letters 55 (2014) 2703–2706
presence of catalytic amounts of 7 and a carboxylic acid, at room
F3C
NH2
NC CN
temperature. A number of solvents were tested, but solvent-free
conditions were the most suitable for the desired reactions (entries
1–10). It is worth noting that we found high yields and enantiose-
lectivity even when the conjugate additions were carried out in
water or brine (entries 8 and 9). A significant decrease in the yield
was observed when no benzoic acid was added, despite using long-
er reaction times (entry 11). We therefore investigated the effects
of adding other carboxylic acids, and found that acetic acid was the
most suitable additive (entries 12–19). Adding 0.2 equiv or
0.05 equiv of acetic acid slightly decreased the yield and/or stere-
oselectivity (entries 20 and 21). The optimal conditions were found
to be 0.1 equiv of 7 and acetic acid under neat condition at room
temperature (entry 14).
Once the optimal conditions had been determined, we exam-
ined the scope and limitations of the conjugate addition reactions
between ketones and nitroalkenes (Table 2).12 We selected methyl
and methoxy substituents as representative electron-donating
groups on the benzene ring and selected halogen substituents as
electron-withdrawing groups. The reactions of the nitroalkenes
13b–e with cyclohexanone (14) proceeded smoothly to give the
corresponding adducts 15b–e in good to high yields with excellent
stereoselectivities, giving 92–99% ee (entries 1–4). We also exam-
ined the reaction of 14 with nitroalkene 13f, which possesses a
naphthalene skeleton, and this afforded the corresponding adduct
15f with 91% ee (entry 5). The reactions using nitroalkenes with
heterocyclic rings (13g–i) gave the corresponding Michael adducts
15g–i with high enantioselectivities (entries 6–8). Acetone reacted
with nitroalkene 13a to give the corresponding adduct 16 in 73%
yield but poor enantioselectivity, giving 33% ee (entry 9). Unfortu-
nately, isobutyraldehyde was a poor substrate, and adduct 17 was
obtained in only 6% yield (entry 10).
NC CN
F3C
CF3
N
H
SMe
10
9
MeS SMe
THF, reflux, 23 h
98%
8
CF3
NC CN
H2N
Boc
N
F3C
N
H
N
11
H
N
Boc
THF, reflux, 20 h
12
CF3
NC CN
F3C
TFA
N
H
N
H
HN
CH2Cl2, rt, 30 min
34% (2 steps)
7
CF3
Scheme 1. Preparation of organocatalyst 7.
viewpoint, solvent-free (i.e., in the absence of organic solvents)
asymmetric organocatalytic reactions have attracted a great deal
of attention because solvent-free reaction conditions provide a
number of benefits, including short reaction times, simple appara-
tus requirements, easy work-up procedures, and being environ-
mentally benign.8
Organocatalyst 7 was prepared as shown in Scheme 1. Treating
of 89 with 3,5-bis(trifluoromethyl)benzylamine (9) in THF afforded
10 in 98% yield. The pyrrolidine derivative 11,10 which can easily
be prepared from L-proline, reacted with 10 to give 12. Finally,
the Boc group in 12 was removed by TFA in CH2Cl2, to give the de-
sired pyrrolidine-DMM organocatalyst 7.11
We determined the optimal reaction conditions for enantiose-
lective conjugate addition using different solvents and additives,
as shown in Table 1. The Michael additions were carried out using
nitrostyrene (13a) and cyclohexanone (14) as test reactants in the
We assumed that the Michael addition of a ketone to a nitroalk-
ene using organocatalyst 7 would proceed via a plausible transition
Table 1
Optimization of reaction conditions
NC CN
F3C
N
H
N
H
HN
O
O
Ph
7
CF3
Additive
NO2
(0.1 equiv)
Solvent, r.t.
NO2
+
Ph
15a
13a
14
Entry
Solvent
14 (equiv)
Additive (equiv)
Time (h)
Yielda (%)
syn/antib
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Hexane
Toluene
CH2Cl2
THF
MeCN
MeOH
DMF
H2O
Brine
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
5
5
5
5
5
5
5
5
5
5
10
5
5
5
5
5
5
5
5
5
5
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
Benzoic acid (0.1)
None
Butanoic acid (0.1)
Propanoic acid (0.1)
Acetic acid (0.1)
Formic acid (0.1)
Chloroacetic acid (0.1)
4-Nitrobenzoic acid (0.1)
2,4-Dinitrobenzoic acid (0.1)
Trifluoroacetic acid (0.1)
Acetic acid (0.2)
24
24
24
24
24
24
24
24
24
24
72
24
24
24
24
24
24
24
24
24
24
85
71
81
81
71
8
66
80
81
74
17
80
75
86
82
82
83
16
7
90:10
85:15
89:11
91:9
85:15
48:52
87:13
90:10
91:9
89:11
73:27
87:13
88:12
88:12
91:9
85
84
84
88
91
80
89
89
87
90
86
90
91
96
88
87
89
86
85
93
97
91:9
92:8
67:33
47:53
89:11
86:14
Neat
Neat
Neat
83
78
Acetic acid (0.05)
a
b
c
Isolated yield.
Determined by 1H NMR spectroscopic analysis.
Determined by HPLC analysis.

K. Nakashima et al. / Tetrahedron Letters 55 (2014) 2703–2706
2705
Table 2
Conjugate additions using organocatalyst 7
NC CN
O
F3C
N
H
N
H
acetic acid
(0.1 equiv)
HN
7
NO2
+
Ar
(0.1 equiv)
neat, r.t.
CF3
14
Product
13
(5 equiv)
Entry
1
Nitroalkenes
Product
CH3
Time (h)
Yielda (%)
syn/antib
eec (%)
NO2
H3C
13b
24
89
90:10
96
O
NO2
15b
OCH3
NO2
H3CO
13c
2
3
24
72
73
53
88:12
88:12
91
99
O
O
NO2
15c
Cl
NO2
Cl
Br
13d
13e
NO2
15d
NO2
Br
4
5
72
24
48
24
74
86
84
86
91:9
93:7
94:6
89:11
92
91
90
93
O
O
NO2
15e
NO2
NO2
15f
13f
NO2
O
O
O
O
13g
6d
O
O
O
NO2
15g
NO2
13h
S
S
7
NO2
15h
NO2
NO2
O
O
8
24
24
87
73
89:11
—
89
33
NO2
13i
15i
9e
O
13a
NO2
NO2
16
NO2
O
10f
96
6
—
62
13a
H
17
a
b
c
d
e
f
Isolated yield.
Determined by 1H NMR spectroscopic analysis.
Determined by HPLC analysis.
Cyclohexanone (10 equiv) was used.
The reaction was conducted with acetone (5 equiv) instead of cyclohexanone.
The reaction was conducted with isobutyraldehyde (5 equiv) instead of cyclohexanone.
state, as shown in Figure 2, based on the stereochemistry of the
addition products 15.4h,7d,g The secondary amine group in 7 will
condense with ketone 14 to give enamine intermediates, then
the two acidic protons from the DMM group will interact strongly
with the two oxygens in the nitro group of 13 to control the
direction (the Re face) in which the nitroalkene will approach the

2706
K. Nakashima et al. / Tetrahedron Letters 55 (2014) 2703–2706
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CF3
Ar
Figure 2. Plausible transition state model.
Re face
enamine intermediate. This will ultimately afford the addition
product with a high degree of stereoselectivity.
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Y.-J.; Xiao, W.-J. Tetrahedron Lett. 2007, 48, 21; (i) Chi, Y.; Guo, L.; Kopf, N. A.;
Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608; (j) Enders, D.; Wang, C.; Bats, J.
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C.; Du, D.-M. Synthesis 2011, 1968; (r) Gauchot, V.; Gravel, J.; Schmitzer, A. R.
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conjugate addition using thiourea organocatalyst 2 requires high
catalyst loading (0.2 equiv), large excess of cyclohexanone
(20 equiv), low reaction temperature (0 °C), and long reaction time
(38 h) to obtain 15a from 13a and 14.7d On the other hand, the pyr-
rolidine-DMM organocatalyst 7 is a more efficient catalyst for con-
jugate addition because the reaction using 7 is completed by using
lower amounts of catalyst and 14 in a shorter reaction time under
mild conditions (room temperature) and affords higher enantiose-
lectivity (Table 1, entry 14). Therefore, we have demonstrated that
the DMM skeleton can function as an efficient double hydrogen
bond donor for Michael additions to nitroalkenes under solvent-
free conditions. Further applications of DMM catalysts in synthe-
sizing bioactive compounds are currently being investigated in
our laboratory.
References and notes
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20
11. Organocatalyst 7: Colorless powder; Mp = 104–106 °C; [
a
]
À12.0 (c = 1.00,
D
MeOH); 1H NMR (400 MHz, CD3OD): d = 1.39–1.48 (m, 1H), 1.62–1.79 (m, 2H),
1.86–1.94 (m, 1H), 2.52 (ddd, J = 7.1, 7.1, 14.2 Hz, 1H), 2.80 (ddd, J = 5.1, 7.1,
11.0 Hz, 1H), 3.22 (dd, J = 7.4, 14.2 Hz, 1H), 3.2–3.38 (m, 2H), 4.77 (s, 2H), 7.95
(s, 1H), 7.80 (s, 2H); 13C NMR (100 MHz, CD3OD): d = 27.3, 29.6, 32.7, 46.7, 47.8,
1
2
50.3, 59.8, 120.2, 122.5, 124.8 (q, JC–F = 272 Hz), 129.3, 133.6 (q, JC–
F = 33.3 Hz), 142.5, 166.4; Anal. Calcd for C18H17F6N5: C, 51.80; H, 4.11; N,
16.78. Found: C, 51.63; H, 4.15; N, 16.61.
12. A typical procedure of the conjugate additions using 7 is as follows: To a
solution of nitrostyrene (13a, 29.8 mg, 0.200 mmol) and organocatalyst
(8.3 mg, 0.020 mmol) in cyclohexanone (14, 105 L, 1.00 mmol) was added
acetic acid (1.1 L, 0.020 mmol) at room temperature. After stirring at room
7
l
l
temperature for 24 h, the reaction mixture was directly purified by flash
column chromatography on silica gel with a 5:1 mixture of hexane and AcOEt
to afford the pure 15a (42.5 mg, 86%) as a colorless powder.