Cinchona-diaminomethylenemalononitrile organocatalyst for asymmetric conjugate addition of 1,3-diketone to nitroalkene

Article abstract of DOI:10.1016/j.tetlet.2014.06.037

A diaminomethylenemalononitrile organocatalyst with a cinchona motif efficiently promotes the enantioselective conjugate addition of acetylacetone to various nitroalkenes to yield the corresponding addition products in high to excellent yields with up to 89% ee.

Full text of DOI:10.1016/j.tetlet.2014.06.037

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cinchona–diaminomethylenemalononitrile organocatalyst
for asymmetric conjugate addition of 1,3-diketone to nitroalkene
Shin-ichi Hirashima a, Kosuke Nakashima a, Yuki Fujino a, Ryoga Arai a, Takaaki Sakai a, Masahiro Kawada a,
Yuji Koseki a, Miho Murahashi b, 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:
A
diaminomethylenemalononitrile organocatalyst with
a
cinchona motif efficiently promotes the
Received 14 May 2014
Revised 3 June 2014
Accepted 9 June 2014
Available online xxxx
enantioselective conjugate addition of acetylacetone to various nitroalkenes to yield the corresponding
addition products in high to excellent yields with up to 89% ee.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Diaminomethylenemalononitrile
Conjugate addition
Michael addition
Nitroalkene
Organocatalytic conjugate addition is one of the most efficient
methodologies for the formation of carbonAcarbon bonds in the
synthesis of enantiomerically enriched molecules.1 Of numerous
asymmetric Michael additions that are mediated by organocata-
lysts, the conjugate addition of 1,3-diketones to nitroalkenes plays
an important role in modern organic chemistry because chiral
intermediates with a nitrodicarbonyl motif can be readily prepared
and easily converted to valuable synthetic scaffolds.2 However,
nearly all of the organocatalysts developed for this transformation
are based on thiourea3,4 or squaramide5 derivatives as double
hydrogen bond donating groups, and successful conjugate addi-
tions using organocatalysts with other types of double hydrogen
bonding functional groups have rarely been reported.6 Therefore,
the development of organocatalysts bearing novel hydrogen bond
donating groups other than thiourea and squaramide is a highly
challenging theme in the field of organocatalysis. Recently, we
reported that organocatalysts with the diaminomethylenemalono-
nitrile (DMM) motif are excellent catalysts for conjugate addi-
tions.7,8 DMM catalyst 1 with a primary amine group efficiently
promotes the reaction of branched aldehydes with vinyl sulfone
and the addition of malonates to enones, affording the correspond-
ing adducts with excellent stereoselectivities.7 Furthermore,
pyrrolidine-DMM 2 with a secondary amine group catalyzes the
conjugate addition of ketones to nitroalkenes to afford the desired
addition products with excellent stereoselectivities (Fig. 1).8
To demonstrate the further efficiency of organocatalysts with
the DMM skeleton, we envisaged the application of 1 and 2 to
other types of asymmetric Michael additions. Thus, the application
of DMM organocatalysts 1 and 2 to the conjugate addition of 1,3-
diketones to nitroalkenes was investigated (Table 1). The conjugate
additions were performed using nitrostyrene (7a) and acetylace-
tone (2 equiv) as test reactants in the presence of a catalytic
amount of 1 or 2 in Et2O at room temperature. Unfortunately,
organocatalysts 1 and 2 were poor catalysts for this reaction and
provided low yields and low enantioselectivities (entries 1 and
2). Given these results, it was predicted that a DMM catalyst with
a tertiary amine group would be superior to catalysts 1 and 2 with
their primary and secondary amines, respectively. Cinchona alka-
loids, which are tertiary amines, are excellent and powerful chiral
sources with nucleophilicity and are widely utilized as organocat-
alysts.9 As expected, DMM organocatalyst 3 provided both a high
yield and high enantioselectivity (entry 3). Herein, we describe
the efficient conjugate addition of 1,3-diketones to nitroalkenes
using the novel cinchona–DMM organocatalyst 3.
Organocatalyst 3 was readily prepared as shown in Scheme 1.
Treatment of 410 with 511 in THF provided intermediate 6 in quan-
titative yield. Intermediate 6 was then reacted with 3,5-bis(trifluo-
romethyl)benzylamine to give the desired DMM organocatalyst 312
in 41% yield.
⇑
Corresponding author. Tel./fax: +81 42 676 4479.
E-mail address: tmiura@toyaku.ac.jp (T. Miura).
http://dx.doi.org/10.1016/j.tetlet.2014.06.037
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hirashima, S.-i.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.037

2
S. Hirashima et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2
Study of solvents
NC CN
NC CN
F3C
F3C
N
H
N
H
N
H
N
H
O
O
NH2
HN
3
O
O
CF3
CF3
N
2
1
(2 equiv) (5 mol%)
NO2
7a
Ph
NO2
Ph
Solvent, rt, 24 h
8a
NC CN
F3C
N
H
N
H
Entry
Solvent (1.0 M)
Yielda (%)
eeb (%)
N
1
2
3
4
DMF
92
82
53
67
57
89
71
91
89
94
1
9
CF3
MeO
MeOH
MeCN
EtOAc
THF
Et2O
Et2O
Toluene
CH2Cl2
Neat
3
47
70
83
79
81
76
73
58
Figure 1. Structure of organocatalysts.
5
6
7c
8
Table 1
Selection of organocatalysts
9
10
O
O
O
O
catalysts
a
Isolated yield.
Determined by HPLC analysis.
The reaction was carried out in Et2O (0.5 M).
(2 equiv) (5 mol%)
b
NO2
Ph
NO2
c
Ph
7a
Et2O, rt, 24 h
8a
Entry
Catalyst
Yielda (%)
eeb (%)
Table 3
1
2
3
1
2
3
23
48
89
1
À24
79
Optimization of reaction conditions
additive
O
O
O
O
3
a
Isolated yield.
Determined by HPLC analysis.
(5 mol%)
(2 equiv)
b
NO2
NO2
Ph
Ph
Et2O, rt
7a
8a
Entry
Additive (mol %)
Time (h)
Yielda (%)
eeb (%)
NC CN
1
2
3
4
5
6
7
8
9
—
24
24
48
48
48
48
48
48
48
48
71
53
76
80
51
46
21
95
86
68
81
86
87
81
90
87
68
75
75
83
N
NC CN
N
PhCO2H (5)
PhCO2H (2.5)
PhCO2H (5)
PhCO2H (7.5)
PhCO2H (10)
p-NO2C6H4CO2H (2.5)
HCO2H (2.5)
AcOH (2.5)
MeS SMe
5
H2N
N
MeS
N
H
N
N
THF, reflux,
24 h
MeO
MeO
quant.
6
4
CF3
NC CN
N
10
TFA (2.5)
NH2
F3C
F3C
N
H
N
H
a
Isolated yield.
Determined by HPLC analysis.
THF, reflux, 24 h
41%
b
CF3
MeO
3
Scheme 1. Preparation of organocatalyst 3.
8b and 8c in high yields with high enantioselectivities (entries 2
and 3). The reaction of nitroalkenes 7d and 7e bearing electron-
withdrawing bromo and chloro substituents, respectively, with
acetylacetone proceeded to give the corresponding addition prod-
ucts 8d and 8e with high stereoselectivities (entries 4 and 5). The
Michael addition of substrates with a chloro group at the meta-
or ortho-position on the benzene ring also proceeded smoothly to
afford the adducts 8f and 8g, respectively, in excellent yields with
high stereoselectivities (entries 6 and 7). Moreover, 7h with a
naphthalene skeleton was a good substrate and provided the cor-
responding adduct 8h in 99% yield with 89% ee (entry 8). The con-
jugate additions to 7i and 7j with heterocyclic skeletons also
provided adducts 8i and 8j in 73% and 66% yields and 81% ee and
88% ee, respectively (entries 9 and 10).
It is presumed that the conjugate addition of acetylacetone to
nitroalkenes using DMM organocatalyst 3 proceeds via the transi-
tion state shown in Figure 2. The tertiary amine group of 3 receives
a proton from the enol group generated from acetylacetone. Two
hydrogen bonding donor protons of the DMM motif then success-
fully interact with the two oxygen atoms in the nitro group in the
nitroalkene to direct the approach of the enolate (attack on the Si
face). This transition state subsequently affords the corresponding
adduct with high stereoselectivity.
First, the solvent conditions were examined for the Michael
addition using 3, as shown in Table 2. Among the representative
solvents examined, diethyl ether was found to be the most suitable
solvent considering both the yield and enantioselectivity (entry 6).
Furthermore, more dilute conditions (0.5 M) led to
improvement in the enantioselectivity (entry 7).
a slight
Encouraged by these results, the reaction conditions for the
Michael additions were then optimized by adding a representative
protic acid as shown in Table 3. High enantioselectivity (87% ee)
was obtained when 2.5 mol % benzoic acid was added (entry 3).
The addition of other protic acids (2.5 mol %), including p-nitroben-
zoic acid, formic acid, acetic acid, and trifluoroacetic acid, was also
investigated; however, benzoic acid was found to be the most suit-
able additive (entries 7–10).
With these optimal conditions in hand, the scope and limita-
tions of the Michael addition of acetylacetone to various nitroal-
kenes 7 were examined (Table 4).13 Substrates 7b and 7c bearing
methyl and methoxy substituents as representative electron-
donating groups on the aromatic ring reacted with acetylacetone
in the presence of catalyst 3, affording the corresponding adducts
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S. Hirashima et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 4
In conclusion, the novel readily prepared cinchona–DMM
organocatalyst 3 efficiently catalyzes the conjugate addition of
acetylacetone to nitroalkenes 7 at room temperature in diethyl
ether to afford the corresponding addition products 8 in high yields
with high enantioselectivities. On the other hand, the reaction of
7a with acetylacetone using the similar cinchona–thiourea
organocatalyst (10 mol %) provided high enantioselectivity;
however, the yield of 8a was modelate.3b Application of
cinchona–DMM catalyst to other types of asymmetric reactions
and the development of additional novel DMM-organocatalysts
are currently underway in our laboratory.
Conjugate additions using organocatalyst 3
PhCO2H
O
O
(2.5 mol%)
O
O
3
(2 equiv)
(5 mol%)
NO2
Ar
NO2
Ar
Et2O, rt, 48 h
7
8
Entry
1
Product
Yielda (%)
76
eeb (%)
87
O
O
NO2
8a
O
O
Acknowledgment
2
3c
4
83
60
65
88
81
82
81
85
NO2
The authors would like to thank Enago (www.enago.jp) for the
English language review.
8b
Me
O
O
NO2
References and notes
8c
MeO
Br
1. For reviews, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033; (b)
Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171; (c) Berner, O. M.; Tedeschi,
L.; Enders, D. Eur. J. Org. Chem. 2002, 1877; (d) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688; (e) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
2. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346; (b) Ballini, R.; Bosica, G.; Fiorini,
D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933; (c) Liu, K.; Cui, H. F.; Nie,
J.; Dong, K. Y.; Li, X. J.; Ma, J. A. Org. Lett. 2007, 9, 923; (d) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 11, 1701; (e) Zhou, W. M.; Liu, H.; Du, D. M. Org. Lett. 2008, 10,
2817; (f) Ban, S.; Du, D. M.; Liu, H.; Yang, W. Eur. J. Org. Chem. 2010, 27, 5160.
3. For successful the Michael additions at room temperature using thiourea or
urea organocatalysts, see: (a) Takemoto, O.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119; (b) Wang, J.; Li, H.; Duan, W.; Zu,
L.; Wang, W. Org. Lett. 2005, 7, 4713; (c) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.;
Wu, X.-J. Chem. Commun. 2008, 1431; (d) Puglisi, A.; Benaglia, M.; Annunziata,
R.; Rossi, D. Tetrahedron: Asymmetry 2008, 19, 2258; (e) Peng, F.-Z.; Shao, Z.-H.;
Fan, B.-M.; Song, H.; Li, G.-P.; Zhang, H.-B. J. Org. Chem. 2008, 73, 5202; (f) Pu, X.;
Li, P.; Peng, F.; Li, X.; Zhang, H.; Shao, Z. Eur. J. Org. Chem. 2009, 4622; (g) Flock,
A. M.; Krebs, A.; Bolm, C. Synlett 2010, 1219; (h) Pu, X.-W.; Peng, F.-X.; Zhang,
H.-B.; Shao, Z.-H. Tetrahedron 2010, 66, 3655; (i) Gavin, D. P.; Stephens, J. C.
ARKIVOC 2011, 407; (j) Puglisi, A.; Benaglia, M.; Raimondi, L.; Lay, L.; Polleti, L.
Org. Biomol. Chem. 2011, 9, 3295; (k) Reddy, B. V. S.; Swain, M.; Reddy, S. M.;
Yadav, J. S. RSC Adv. 2013, 3, 8756.
4. For successful the Michael additions at low temperature using thiourea or urea
organocatalysts, see: (a) Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C. Eur. J. Org.
Chem. 2008, 4563; (b) Andrés, J. M.; Manzano, R.; Pedrosa, R. Chem.-Eur. J. 2008,
14, 5116; (c) Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang, J.;
Wang, R. J. Org. Chem. 2009, 74, 5562; (d) Nemoto, T.; Obuchi, K.; Tamura, S.;
Fukuyama, T.; Hamada, Y. Tetrahedron Lett. 2011, 52, 987; (e) Shi, X.; He, W.; Li,
H.; Zhang, X.; Zhang, S. Tetrahedron Lett. 2011, 52, 3204; (f) Ma, Z.-Y.; Liu, Y.-X.;
Huo, L.-J.; Gao, X.; Tao, J.-C. Tetrahedron: Asymmetry 2012, 23, 443; (g) Li, H.;
Zhang, X.; Shi, X.; Ji, N.; He, W.; Zhang, S.; Zhang, B. Adv. Synth. Catal. 2012, 354,
2264.
O
O
O
O
NO2
8d
O
5
NO2
8e
Cl
O
NO2
6
7
93
99
83
88
8f
Cl
O
O
NO2
8g
Cl
O
O
8
9
99
73
66
89
81
88
NO2
8h
O
O
NO2
O
O
8i
O
5. For successful the Michael additions using squaramide organocatalysts, see: (a)
Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416; (b)
Dong, Z.; Jin, X.; Wang, P.; Min, C.; Zhang, J.; Chen, Z.; Zhou, H.-B.; Dong, C.
ARKIVOC 2011, 367; (c) Bae, H. Y.; Some, S.; Oh, J. S.; Lee, Y. S.; Song, C. E. Chem.
Commun. 2011, 9621; (d) Dong, Z.; Qiu, G.; Zhou, H.-B.; Dong, C. Tetrahedron:
Asymmetry 2012, 23, 1550; (e) Liu, B.; Han, X.; Domg, Z.; Lv, H.; Zhou, H.-B.;
Domg, C. Tetrahedron: Asymmetry 2013, 24, 1276.
6. For successful the Michael additions using other types of organocatalysts, see:
(a) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454; (b) Almaßsi,
D.; Alonso, A. A.; Gómez-Bengoa, E.; Nájera, C. J. Org. Chem. 2009, 74, 6163; (c)
Isik, M.; Tanyeli, C. J. Org. Chem. 2013, 78, 1604.
10
NO2
S
8j
a
b
c
Isolated yield.
Determined by HPLC analysis.
Catalyst (10 mol %) and benzoic acid (5 mol %) were used.
7. (a) Kanada, Y.; Yuasa, H.; Nakashima, K.; Murahashi, M.; Tada, N.; Itoh, A.;
Koseki, Y.; Miura, T. Tetrahedron Lett. 2013, 54, 4896; (b) Hirashima, S.; Sakai,
T.; Nakashima, K.; Watanabe, N.; Koseki, Y.; Mukai, K.; Kanada, Y.; Tada, N.;
Itoh, A.; Miura, T. Tetrahedron Lett. 2014, 55. http://dx.doi.org/10.1016/
j.tetlet.2014.05.100. in press.
8. Nakashima, K.; Hirashima, S.; Kawada, M.; Koseki, Y.; Tada, N.; Itoh, A.; Miura,
T. Tetrahedron Lett. 2014, 55, 2703.
9. For reviews, see: (a) Marcelli, T.; Maarseveen, J. H.; Hiemstra, H. Angew. Chem.,
Int. Ed. 2006, 45, 7496; (b) Connon, S. J. Chem. Commun. 2008, 2499; (c) Duan, J.;
Li, P. Catal. Sci. Technol. 2014, 4, 311.
N
NC
CN
MeO
CF3
N
H
O
N
H
N
Me
H
O
CF3
O
O
N
10. Tominaga, Y.; Kohra, S.; Honkawa, H.; Hosomi, A. Heterocycles 1989, 29, 1409.
11. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967.
20
Me
12. Organocatalyst 3: White powder; Mp = 104–106 °C;
[a
]
D
À202.3 (c 1.00,
MeOH); 1H NMR (400 MHz, CD3OD): d = 0.79 (t, J = 7.3 Hz, 3H), 0.88–0.93 (m,
1H), 1.15–1.29 (m, 3H), 1.46–1.70 (m, 4H), 2.48 (ddd, J = 13.6, 6.0, 2.0 Hz, 1H),
2.67 (ddd, J = 14.6, 10.8, 4.3 Hz, 1H), 3.11–3.20 (m, 3H), 4.0 (s, 3H), 4.59–4.72
(m, 2H), 5.59 (br s, 1H), 7.37 (d, J = 4.5 Hz, 1H), 7.45 (dd, J = 9.3, 2.5 Hz, 1H),
Figure 2. Plausible transition state model.
Please cite this article in press as: Hirashima, S.-i.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.037

4
S. Hirashima et al. / Tetrahedron Letters xxx (2014) xxx–xxx
7.65 (br s, 1H), 7.70 (br s, 2H), 7.87 (br s, 1H), 7.95 (d, J = 9.3 Hz, 1H), 8.53 (d,
13. A typical procedure for the conjugate additions using 3 is as follows: Acetylacetone
(103 L, 1.00 mmol) was added to a solution of nitrostyrene (7a, 74.6 mg,
0.500 mmol), benzoic acid (1.5 mg, 0.0125 mmol), and organocatalyst
J = 4.8 Hz, 1H); 13C NMR (100 MHz, CD3OD): d = 13.1, 27.0, 27.2, 29.3, 30.0,
l
36.4, 39.3, 42.8, 48.2, 57.4, 58.8, 80.3, 103.5, 120.3, 123.6, 124.9, 125.5
3
1
2
(q, JC–F = 272 Hz), 129.7, 132.7, 133.9 (q, JC–F = 33.7 Hz), 142.8, 146.0, 148.8,
160.8; HRMS (ESI): Calcd for C33H33F6N6O [M+H]+, 643.2620. Found, 643.2603;
Anal. Calcd for C33H33F6N6O: C, 61.68; H, 5.02; N, 13.08. Found: C, 61.88; H,
5.23; N, 12.97.
(16.0 mg, 0.025 mmol) in Et2O (1 mL) at room temperature. After stirring at
room temperature for 48 h, the reaction mixture was directly purified by flash
column chromatography on silica gel with hexane and ethyl acetate (gradually
5:1–2:1) to afford the pure 8a (95.3 mg, 76%) as a white powder.
Please cite this article in press as: Hirashima, S.-i.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.037