Organocatalytic Enantioselective Michael Reaction of Malononitrile with β,β-Disubstituted Nitroalkenes

Article abstract of DOI:10.1002/adsc.201500079

We have developed and optimized an enantioselective Michael reaction of malononitrile with β,β-disubstituted nitroalkenes. This reaction was catalyzed by a cinchona alkaloid derived thiourea catalyst, producing products of high yields (up to 98 %) and ste

Full text of DOI:10.1002/adsc.201500079

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DOI: 10.1002/adsc.201500079
Very Important Publication
Organocatalytic Enantioselective Michael Reaction of Malononi-
trile with b,b-Disubstituted Nitroalkenes
Shengwei Chen,a Qinxin Lou,a Yuyang Ding,a Shasha Zhang,a Wenhui Hu,a,*
and Junling Zhaoa,*
a
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of
Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, Peopleꢀs Republic of China
Fax: (+86)-20-3201-5299; e-mail: hu_wenhui@gibh.ac.cn or zhao_junling@gibh.ac.cn
Received: January 27, 2015; Revised: March 26, 2015; Published online: June 2, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500079.
Abstract: We have developed and optimized an
enantioselective Michael reaction of malononitrile
with b,b-disubstituted nitroalkenes. This reaction
was catalyzed by a cinchona alkaloid derived thio-
urea catalyst, producing products of high yields (up
to 98%) and stereoselectivities (up to 93% ee).
One of the adducts was used as an intermediate for
the synthesis of dihydropyrrole derivative bearing
a synthetically valuable quaternary chiral center.
riety of nucleophiles, with the corresponding adduct
readily transformable to b-amino acids that are an im-
portant motif for b-peptides, b-lactams, and other bio-
logically important compounds.[7] Enones,[6a] aldehy-
des,[6b] indoles,[6c–e] oximes,[6f] and thiols[6g] have been
documented as ideal nucleophiles for this asymmetric
Michael addition process. Despite those recent advan-
ces, there is still a need for the development of new
nucleophilic reagents that are capable of generating
structurally diverse quaternary chiral centers through
Michael reaction with a-substituted-b-nitroacrylate.
Malononitrile is an equivalent to a 1,3-dicarbonyl
compound, and the nitrile group is a versatile func-
tional group for many further transformations.[8] Or-
ganocatalytic asymmetric Michael reactions using ma-
lononitrile as the nucleophile are relatively less ex-
plored due to its high reactivity and incapability of
Keywords: asymmetric; malononitrile; Michael re-
action; organocatalysis; b,b-disubstituted nitroal-
kenes
The catalytic asymmetric conjugate addition reaction two-point binding with the catalyst. Most of the ef-
of nucleophiles to electron-deficient alkenes has gar- forts in this field have been focused on the employ-
nered attention due to its wide applicability in the ment of a,b-unsaturated carbonyls as electrophiles.[9]
synthesis of biologically relevant compounds.[1] One There have been very few studies using nitroolefins as
of the most extensively studied asymmetric conjugate Michael reaction acceptors. Takemoto[10a] and
addition reactions is the Michael reaction of nitroole- Yuan,[10b] respectively, reported the bifunctional thio-
fins, which represents a convenient access to nitroal- urea catalyzed Michael reactions of malononitrile to
kanes that are versatile intermediates in organic syn- nitroolefins with modest enantioselectivity. Arai[10e]
thesis.[2] However, the studies reported to date have synthesized a neural, chiral bis(imidazolidine)-derived
primarily focused on more reactive b-monosubstitut- NCN-type palladium pincer complex and was able to
ed[3] or a,b-disubstituted[4] nitroolefins. The catalytic show an improved stereoselectivity. Although those
asymmetric Michael reaction of b,b-disubstituted ni- impressive reports have been published about this re-
troalkenes is less studied, primarily because steric hin- action, the introduction of new electrophiles for the
drance poses a potential problem. Particularly note- synthesis of structurally more diversified compounds
worthy is that the synthetically important quaternary with high enantioselectivity remains a challenging
chiral centers could be generated through the Michael task. Taking advantage of the high reactivity of malo-
reaction of b,b-disubstituted nitroolefins with nucleo- nonitrile, we envisaged that the use of the more steri-
philes. However, only a handful of studies have fo- cally congested b,b-disubstituted nitroolefins, such as
cused on this particular reaction, likely due to low ac- a-substituted-b-nitroacrylate (2), as Michael reaction
tivity profiles.[5–6]
acceptors might improve the stereoselectivity of this
a-Substituted b-nitroacrylate has recently been reaction.
documented as a Michael reaction acceptor with a va-
Adv. Synth. Catal. 2015, 357, 2437 – 2441
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Shengwei Chen et al.
Table 1. Reaction condition optimization.[a]
Entry
Catalyst
Solvent
Time [h]
Yield [%][b]
ee [%][c, g]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EA
CH2Cl2
THF
Et2O
CH3CN
C6H5Cl
ClCH2CH2Cl
CH3Cl
m-xylene
C6H5Cl
C6H5Cl
20
20
20
20
20
20
20
20
24
12
18
18
18
13
20
13
20
27
32
93
64
67
79
92
95
92
93
trace
89
trace
44
67
98
73
95
95
96
79 (S)
31 (S)
20 (R)
85 (R)
86 (R)
83 (S)
86 (S)
83 (S)
–
87 (S)
–
81 (S)
4 (S)
90 (S)
86 (S)
89 (S)
88 (S)
91 (S)
92 (S)
7
8[d]
9
10
11
12
13
14
15
16
17
18[e]
19[f]
98
[a]
Unless noted reactions were performed with 2a (0.1 mmol), 3 (0.2 mmol), 1a–g (10 mol%), and 3 Š MS (40 mg) in
0.5 mL of solvent at À108C.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
Determined by HPLC analysis using a chiral stationary phase.
Conducted without 3 Š MS.
Conducted at À258C.
Conducted at À308C.
[g]
The absolute configurations were determined by comparing the specific rotations of adducts with 4g.
To begin our investigation, the reaction of (Z)-tert- of the catalysts is also an important factor for the re-
butyl 3-nitro-2-phenylacrylate (2a) and malononitrile action to proceed smoothly.[9] Organocatalysts having
(3) was chosen as an initial model. This asymmetric both a thiourea moiety and tertiary amino group al-
Michael reaction was evaluated with 10 mol% of bi- lowed the corresponding adduct to have both a high
functional organocatalysts (1a–g)[11] in toluene under yield and high stereoselectivity (Table 1, entries 1, 4–
À108C with 3 Š molecular sieves as additive. The re- 7). The best result was obtained when cinchonine-de-
sults are summarized in Table 1. The thiourea moiety rived thiourea 1g was used, producing a 92% yield
is essential for the high stereoselectivity of this reac- and 86% ee (Table 1, entry 7).
tion; replacing the thiourea group with a squaramide
Having identified the best catalyst (1g), the effects
moiety resulted in a low enantioselectivity of the of solvent and temperature were also investigated to
adduct 4a (Table 1, entry 3). The tertiary amine group further improve the efficiency of this Michael reac-
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Organocatalytic Enantioselective Michael Reaction
Table 2. Substrate scope of nitroacrylate.[a]
Entry
R1
R2
Product
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
t-butyl
isopropyl
benzyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
32
32
40
32
40
45
45
48
33
32
36
48
45
42
48
36
98
90
95
85
98
87
86
92
95
78
83
89
70
98
84
80
92
86
73
90
91
89
90
92
93
89
90
90
87
92
92
7
3-MeC6H4
3-MeOC6H4
3-FC6H4
3-ClC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
2-naphthyl
2-thienyl
2-phenylethyl
9
10
11
12
13
14
15
16
[a]
Unless noted reactions were performed with 2a–p (0.1 mmol), 3 (0.2 mmol), 1g (10 mol%) and 3 Š MS (40 mg) in
0.5 mL of chlorobenzene at À308C.
[b]
[c]
Isolated yield.
Determined by HPLC analysis using a chiral stationary phase.
tion. As shown in Table 1, the reaction media has tivity was low (Table 2, entry 16). The ester group on
a substantial influence on the reactivity and stereose- the a-position of 2 affected the stereoselectivity sig-
lectivity. The reaction proceeded sluggishly in tetrahy- nificantly as a result of steric hindrance. Use of iso-
drofuran and ethyl acetate; only trace amounts of propyl and benzyl a-phenyl-b-nitroacrylate (2b and
product 4a were detected. A less polar solvent like 2c) yielded products with low stereoselectivities
chlorobenzene was shown to be the optimal solvent (Table 2, entries 2 and 3).
for this transformation with the highest enantioselec-
The absolute configuration of 4g was determined
tivity (Table 1, entry 14). The temperature also slight- to be S based on the single crystal X-ray structure
ly affected the stereoselectivity of this reaction. At analysis (Figure 1).[12] A plausible transition state is
À308C with a prolonged reaction time, the reaction depicted in Figure 2, based on this analysis and previ-
gave the product in 98% yield and 92% ee (Table 1, ous reported results on cinchona alkaloid derived thi-
entry19).
ourea catalysis. As we have described in the catalyst
Using those optimized reaction conditions, we in- screening part, the thiourea moiety and tertiary
vestigated the asymmetric Michael reactions of malo- amine group of the catalyst 1g are important factors
nonitrile with a variety of a-substituted-b-nitroacry- for the high yields and stereoselectivities of this reac-
lates (2a-p), with the results presented in Table 2. In tion. The a-aryl-b-nitroacrylate (2) is activated
general, the electronic nature of the substituents on through double hydrogen bonding of the thiourea
the phenyl ring of a-aryl-b-nitroacrylates (2d–m) had moiety to the nitro group, while the deprotonated ma-
little effect on the reactivity and stereoselectivity of lononitrile becomes a pronucleophile through hydro-
the reaction; both the electron-donating and electron- gen bonding with the protonated tertiary amine of 1g.
withdrawing groups were well tolerated and produced The Re face attack at the a-position of a-aryl-b-nitro-
the corresponding products in excellent yields and acrylate (2) is favored to afford the corresponding
enantioselectivities (Table 2, entries 4–13). It is note- product in S configuration.
worthy that 2-naphthyl and 2-thienyl substrates react-
Finally, the synthetic utility of the asymmetric Mi-
ed smoothly to afford the products in 98 and 84% chael reaction was investigated. The reaction was
yields, respectively, both in 92% ee (Table 2, en- scaled up to 4 mmol of 2a and 8 mmol of malononi-
tries 14 and 15). However, alkylated substrate 2p re- trile (3). Product 4a was isolated with an 86% yield
acted well with malononitrile (3), but the stereoselec- retaining high enantioselectivity (Scheme 1). The cor-
Adv. Synth. Catal. 2015, 357, 2437 – 2441
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Shengwei Chen et al.
In conclusion, we have developed an enantioselec-
tive Michael reaction of malononitrile to a-substitut-
ed-b-nitroacrylates. This reaction was catalyzed effi-
ciently by a cinchonine-derived bifunctional thiourea
catalyst, and the corresponding adducts bearing qua-
ternary chiral centers were obtained in high yields
and enantioselectivities. More importantly, this strat-
egy could be used for the synthesis of dihydropyrrole
derivatives for biological and pharmaceutical applica-
tions.
Experimental Section
Typical Procedure for the Asymmetric Michael
Reaction
A sample bottle equipped with a magnetic stirring bar was
charged with 2 (0.1 mmol), 3 (13.2 mg, 0.2 mmol, 2.0 equiv),
chlorobenzene (0.5 mL) and 3 Š molecular sieve (40 mg).
After the temperature had been cooled down to À308C, 1g
(5.6 mg, 0.01 mmol, 0.1 equiv) was added. The reaction mix-
ture was stirred at À308C until 2 was consumed (determined
by TLC). The reaction mixture was directly purified by
silica gel column chromatography (petroleum ether/ethyl
acetate=15:1 v/v as eluent) to give the product 4.
Figure 1. X-ray structure of 4g.
Acknowledgements
We thank the National Natural Science Foundation of China
(grant 21102145) and the Guangdong Pearl River Nova Pro-
gram (grant 2012J2200014) for financial support. We thank
Prof. Jinsong Liu at Guangzhou Institutes of Biomedicine
and Health, Chinese Academy of Sciences for X-ray structure
determination.
Figure 2. Proposed transition state of this Michael reaction.
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