Highly enantioselective Michael addition of malononitrile to α,β-unsaturated ketones

Article abstract of DOI:10.1039/b713129a

The highly enantioselective Michael addition of malononitrile to acyclic and cyclic α,β-unsaturated ketones has been developed. The Michael reaction catalyzed by a primary amine derived from quinidine proceeded smoothly and provided the desired adducts with excellent enantioselectivities (83-97% ee). This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b713129a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly enantioselective Michael addition of malononitrile to a,b-unsaturated
ketones†
Xuefeng Li,a,b Lingfeng Cun,a Chunxia Lian,a Ling Zhong,a Yingchun Chen,c Jian Liao,a Jin Zhua and
Jingen Deng*a
Received 28th August 2007, Accepted 14th November 2007
First published as an Advance Article on the web 3rd December 2007
DOI: 10.1039/b713129a
The highly enantioselective Michael addition of malononitrile to acyclic and cyclic a,b-unsaturated
ketones has been developed. The Michael reaction catalyzed by a primary amine derived from quinidine
proceeded smoothly and provided the desired adducts with excellent enantioselectivities (83–97% ee).
should be much more feasible than from a secondary amine;10a,f ,g
Introduction
(ii) a possible bifunctional activation4b,c,9a,b,10e,f would facilitate the
The Michael addition of carbon-base nucleophiles to a,b-
Michael-type coupling reaction (Fig. 1).
unsaturated systems represents one of the classical carbon–carbon
bond-forming reaction. The process often provides synthetically
useful adducts possessing various functional groups such as nitro,1
ester,2 ketone3 and other moieties4 for further elaboration. Ac-
cordingly, the development of enantioselective catalysis protocols
for this reaction has been the subject of intensive research.
In addition to the substantial progress realized with metallic
complexes,5 a number of asymmetric Michael additions catalyzed
by organocatalysts have received renewed attention.6 Although a
Fig. 1 A possible model for bifunctional activation.
variety of structurally diverse organocatalysts have been developed
to catalyze the asymmetric Michael reaction and impressive results
have been achieved, the reactions were mostly narrow in substrate
Results and discussion
scope and restricted to a particular combination of nucleophile
and electrophile type. Malononitrile is an equivalent of a 1,3-
dicarbonyl compound and the nitrile group is a versatile functional
group that can be converted to carboxylic acids,7 esters,8 and
amines.9e However, examples using malononitrile as a nucleophile9
have been relatively less explored and most of them didn’t achieve
high enantioselectivity in the presence of organocatalysts, except
that reported by Takemoto et al.9a
Recently we have reported the Michael addition of a,b-
unsaturated ketones catalyzed by a newly developed primary
amine derived from quinine; excellent enantioselectivities and high
efficiency were observed for almost all the adducts.10a However, the
substrates were generally limited to cyclic and alkyl enones. Herein
we report a highly enantioselective and efficient Michael addition
of malononitrile to acyclic and cyclic a,b-unsaturated ketones
catalyzed by primary amine 1a.10,11 The derivatives of 9-epi-amino
cinchona alkaloids are selected as primary amine organocatalysts
on the basis of two reasons: (i) the in situ generation of a
ketimine cation from a primary amine salt and the ketone carbonyl
To our delight, 9-amino-9-deoxy-epi-quinidine 1a (Fig. 2) in
combination with TFA exhibited high catalytic activity for the
asymmetric addition of malononitrile 2 to benzylideneacetone 3a
in THF at 22 ◦C. The reaction gave the Michael adduct 4a in 87%
yield with a promising 93% ee after 12 h (Table 1, entry 1). Use of
9-amino-9-deoxy-epi-cinchonine 1b10c,d,h resulted in a decrease in
both chemical yield and enantioselectivity (entry 2). 9-Amino-9-
deoxy-epi-quinine 1c,10a,b the pseudoenantiomer of 1a, afforded
the adduct in 94% ee with opposite configuration and lower
yield (entry 3). This also implied that both enantiomers of 4a
can be obtained in high selectivities. Encouraged by the excellent
results obtained with 1a, we subsequently investigated the effects
of the solvents and acid additives. In comparison with THF,
better reactivity and enantioselectivity were obtained in DCM
(entry 4). Excepting 1,4-dioxane, the reactions resulted in lower
enantioselectivities in other solvents (entries 5–9).
aNational Engineering Research Center of Chiral Drugs and Key Laboratory
of Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu
Institute of Organic Chemistry, The Chinese Academy of Sciences, Chengdu
610041, China. E-mail: jgdeng@cioc.ac.cn; Fax: +86 28 8522 3978
bGraduate School of the Chinese Academy of Sciences, Beijing 100049, China
Fig. 2 Structure of primary amine catalysts 1a, 1b and 1c derived from
quinidine, cinchonine and quinine, respectively.
cWest China School of Pharmacy, Sichuan University, Chengdu 610041,
China
† Electronic supplementary information (ESI) available: 1H/13C NMR
spectra and HPLC/GC chromatograms of the products. See DOI:
10.1039/b713129a
The acid additives had an obvious effect on the reactivity of
the Michael addition and less than 30% yield was obtained after
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Table 1 Screening studies of organocatalytic Michael addition of
malononitrile 2 to benzylideneacetone 3aa
the ratio of malononitrile 2 to benzylideneacetone 3a also affected
both reaction rate and enantioselectivity (entries 18–20).
Having established the optimum reaction conditions for the
enantioselective Michael addition of benzylideneacetone 3a, we
next screened a series of analogues which bear various substituents
on the terminal double bond and the carbonyl group. The Michael
reaction was generally conducted with 20 mol% of 1a and 40 mol%
TFA at 22 ◦C (Table 2). As illustrated in Table 2, enones 3a–
k cleanly underwent conjugate addition and excellent enantios-
electivities were achieved regardless of the electronic properties
(entries 1–11). The coupling reaction with aryl substituents 3a–
e proceeded with 93–96% ee to afford the adducts 4a–e in high
yields (entries 1–5). Similarly, the substrate 3h with a 2-furanyl
group as the b-substituent underwent smooth reaction as well and
furnished the desired adduct 4h in 99% yield with 95% ee (entry 8).
Moreover, 3i, bearing an aliphatic group on the b-position, was
tolerated to exhibit 93% ee with 35% yield after 72 h (entry 9). On
the other hand, bulkier alkyl enone 3j was also tolerated to give
the highest enantioselectivity (97% ee, entry 10). Furthermore,
reaction of the cyclic acceptor 3k occurred smoothly to furnish
the desired adduct 4k with excellent enantioselectivity (95% ee),
but a by-product, a,a-dicyanoalkene 4ka (Fig. 3), was obtained in
30% yield with 90% ee (entry 11), which may be derived from the
desired adduct 4k and malononitrile.13 Gratifyingly, reaction of
chalcone 3l, which was inert with vinylogous donors,10a proceeded
smoothly to give the desired adduct 4l with 88% ee despite the
longer time required (entry 12). As aromatic ketones (R1 = R2 =
Ar) might be unfavorable for the formation of iminium ions with
amine catalysts, the Michael addition of chalcone analogues with
amine as catalyst has rarely been reported.10g It turned out that
the substituents on the phenyl group of chalcone had a large
influence on the yields and 3m, 3n and 3o gave ≤40% yield
with ≥83% ee (entries 13–15). It is notable that higher yields
were achieved at elevated temperature, yet the enantioselectivities
only slightly decreased. These observations indicated that the
temperature markedly affected the reaction rate while it only
slightly affected the enantioselectivity (Table 1, entry 4 vs. 15,
and Table 2, entries 13–15).
Entry
Solvent
Additive
Yield (%)b
ee (%)c
1
2d
THF
THF
THF
DCM
Et2O
Dioxane
Toluene
MeOH
DMF
DCM
DCM
DCM
THF
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
HOAc
TsOH
CF3SO3H
5a
87
46
59
93
68
74
87
41
77
5
90
26
69
49
91
95
63
67
49
72
93
86
3e
−94
4
5
6
7
8
9
10
11
12
13
14
15f
16f
17f
18g
19h
20i
95
82
94
59
19
28
−56
90
90
85
86
96
94
87
93
87
THF
5b
DCM
CHCl3
THF
DCM
DCM
THF
TFA
TFA
TFA
TFA
TFA
TFA
89
a Unless otherwise noted, the reaction was performed with 0.1 mmol of 3a,
0.2 mmol of 2, in the presence of 20 mol% of 1a and 40 mol% of TFA in
1 mL of solvent at 22 ◦C for 12 h. b Isolated yield. c Determined by◦chiral
HPLC analysis. d Using 20 mol% of 1b. e Using 20 mol% of 1c. f At 0 C for
96 h. g Using 20 mol% of TFA. h Using 10 mol% of 1a. i Using 0.1 mmol
of 2.
12 h in the presence of HOAc and CF3SO3H (entries 10 and
12). The Michael addition proceeded smoothly in the presence
of TsOH and provided the desired adduct in a somewhat lower
enantioselectivity in comparison with TFA (entry 4 vs. entry 11).
Notably, the coupling reaction afforded the adducts with opposite
configuration in the presence of the weaker acid HOAc (en-
try 10). Considering that asymmetric counterion-directed catalysis
(ACDC)12 has recently been recognized as an efficient strategy
for enantioselective transformation, we combined (R) and (S)-
phosphoric acids derived from binol (Fig. 3, 5a and 5b) with 1a
and obtained the adducts with the same configuration and in
similar enantioselectivities (entries 13 and 14).
Conclusions
In summary, we have developed the first general and highly enan-
tioselective organocatalytic Michael addition of malononitrile14,15
with various a,b-unsaturated ketones in the presence of 9-amino-
9-deoxy-epi-quinidine 1a. Noticeably, this novel primary amine
organocatalyst can effectively activate chalcone and its analogues,
which were inert in the case of secondary amine organocatalysts.
Moreover, to the best our knowledge, no Michael additions of
malononitrile catalyzed by amine organocatalysts6,9 have been
reported. Further investigation into the synthetic application is
underway.
Fig. 3 Structure of additives 5a and 5b, and the adduct 4ka.
In the hope of enhancing the enantioselectivity, we carried
out the reaction at 0 C. Unfortunately, no beneficial effect was
◦
Experimental
observed (entries 15–17). At the same time, the Michael addition
proceeded somewhat faster in chloroform than DCM, however, it
resulted in lower enantioselectivity (entry 15 vs. entry 16). To our
surprise, the enantioselectivity in THF sharply decreased at 0 ◦C
(entry 17). Moreover, the composition of the catalyst system and
General Methods
1H NMR spectra were recorded at 300 MHz and 13C NMR spectra
were recorded at 75 MHz. Chemical shifts (d) are reported in
ppm relative to CHCl3 (d = 7.27 ppm) for 1H NMR and relative
350 | Org. Biomol. Chem., 2008, 6, 349–353
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Table 2 Asymmetric Michael addition of malononitrile 2 to a,b-unsaturated ketones 3a
Entry
R1
R2 (3)
4
Time/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
Me (3a)
Me (3b)
Me (3c)
Me (3d)
Me (3e)
Me (3f)
Me (3g)
Me (3h)
Me (3i)
4a
4b
4c
4d
4e
4f
4g
4h
4i
12
22
12
18
48
48
22
12
72
93
87
94
85
84
70
87
99
95
93
94
96
93
87
88
95
93e
92ef
97
95e
90
88g
87
85f
83
80f
87
87f
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
2-Naphthyl
2-Furanyl
n-Pr
9
35 (95)d
39f (94)d
85
60
30
60
10
11
Ph
Et (3j)
4j
12
12
-C4H8- (3k)
4k
4ka
4l
12
13
Ph
Ph (3l)
Ph (3m)
72
72
p-MeOC6H4
4m
20
80f
40
14
15
p-FC6H4
Ph (3n)
4n
4o
72
72
78f
36
Ph
p-MeOC6H4 (3o)
79f
a Unless otherwise noted, the reaction was performed with 0.1 mmol of 3a, 0.2 mmol of 2, in the presence of 20 mol% of 1a and 40 mol% of TFA in 1 mL
of DCM at 22 ◦C◦. b Isolated yield. c Determined by chiral HPLC analysis. d Yield in parentheses is based on recovered 3i. e Determined by GC analysis.
f Performed at 40 C. g The absolute configuration of 4l was the (S)-form determined by comparison of the specific optical rotation with that reported in
the literature,8 and the other adducts were assigned accordingly.
to the central CDCl3 resonance (d = 77.0 ppm) for 13C NMR
spectroscopy. Coupling constants (J) are given in Hz. ESI-HRMS
spectra were measured with a Finnigan LCQDECA ion trap mass
spectrometer. Optical rotation data were recorded on Perkin-
Elmer Polarimeter-341. Enantiomeric excess was determined by
HPLC analysis on chiral columns and GC analysis on a chiral
CP-Chirasil-DEX CB column in comparison with the authentic
racemates. TLC was performed on glass-backed silica plates.
Column chromatography was performed using silica gel (200–
300 mesh) eluting with ethyl acetate and petroleum ether.
Commercial grade solvents were dried and purified by standard
literature procedures.16 Primary aminocatalysts 1a–1c were pre-
pared according to literature procedures.11
3.70 (m, 1H), 3.24–3.04 (m, 2H), 2.21 (s, 3H) ppm. 13C-NMR
(CDCl3, 75 MHz) d 205.3, 136.2, 129.3, 129.1, 127.8, 111.7, 111.5,
44.7, 40.8, 30.3, 28.5 ppm. ESI-HRMS calcd for C13H12N2O − H
211.0866, found 211.0859. 96% ee determined by HPLC on AS-H
column, hexane–i-propanol (70 : 30), 1.0 mL min−1, UV 254 nm,
tmajor = 13.886 min, tminor = 16.383 min.
2-(3-Oxo-1-p-tolylbutyl)malononitrile (4b). Light yellow oil.
1
Yield 87%. [a]2D5 = −33.0 (c = 0.13, CHCl3). H-NMR (CDCl3,
300 MHz) d 7.25–7.19 (m, 4H), 4.45 (d, J = 5.3 Hz, 1H), 3.73–
3.67 (m, 1H), 3.21–3.02 (m, 2H), 2.36 (s, 3H), 2.20 (s, 3H)
ppm. 13C-NMR (CDCl3, 75 MHz) d 205.4, 139.1, 133.2, 129.9,
127.6, 111.8, 111.6, 44.8, 40.5, 30.3, 28.7, 21.1 ppm. ESI-HRMS
calcd for C14H14N2O − H 225.1022, found 225.1032. 93% ee
determined by HPLC on OD-H column, hexane–i-propanol
General procedure for asymmetric Michael addition of
malononitrile to a,b-unsaturated ketones
(70 : 30), 1.0 mL min−1, UV 254 nm, tminor = 11.208 min, tmajor
=
13.161 min.
Benzylideneacetone 3a (14.6 mg, 0.1 mmol), malononitrile 2
(13.2 mg, 0.2 mmol), 9-amino-9-deoxy-epi-quinidine 1a (6.4 mg,
0.02 mmol) and TFA (3.0 lL, 0.04 mmol) were stirred in DCM
(1 mL) at 22 ◦C for 12 h. Then the reaction was quenched by
adding 1 mol L−1 HCl (1.0 mL). The mixture was extracted with
EtOAc (10 mL) and dried with anhydrous sodium sulfate. The
solvent was removed and flash chromatography on silica gel (20%
ethyl acetate–petroleum ether) gave 4a as a white solid (19.7 mg,
93% yield).
2-(1-(4-Methoxyphenyl)-3-oxobuty◦l)malononitrile (4c). Light
yellow solid. Yield 94%, mp 84–87 C. [a]2D5 = −35.5 (c = 0.47,
1
CHCl3). H-NMR (CDCl3, 300 MHz) d 7.28 (d, J = 8.7 Hz,
2H), 6.92 (d, J = 8.7 Hz, 2H), 4.44 (d, J = 5.3 Hz, 1H),
3.81 (s, 3H), 3.72–3.68 (m, 1H), 3.21–3.00 (m, 2H), 2.21 (s,
3H) ppm. 13C-NMR (CDCl3, 75 MHz) d 205.4, 160.2, 129.0,
128.1, 114.6, 111.8, 111.6, 55.3, 44.9, 40.2, 30.3, 28.8 ppm. ESI-
HRMS calcd for C14H14N2O2 − H 241.0972, found 241.0978.
94% ee determined by HPLC on OJ-H column, hexane–i-propanol
2-(3-◦Oxo-1-phenylbutyl)malononitrile (4a). White solid. Mp
1
72–74 C. [a]2D5 = −38.1 (c = 0.40, CHCl3). H-NMR (CDCl3,
(70 : 30), 1.0 mL min−1, UV 254 nm, tminor = 29.937 min, tmajor
=
300 MHz) d 7.45–7.34 (m, 5H), 4.48 (d, J = 5.5 Hz, 1H), 3.77–
36.018 min.
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◦
2-(1-(4-Chlorophenyl)-3-oxobutyl)malononitrile (4d). Color-
dioxolane on CP-Chirasil-DEX CB column, 135 C isothermal,
tmajor = 21.863 min, tminor = 22.678 min.
1
less oil. Yield 85%. [a]D25 = −45.0 (c = 0.20, CHCl3). H-NMR
(CDCl3, 300 MHz) d 7.42–7.38 (m, 2H), 7.33–7.28 (m, 2H), 4.47
(d, J = 5.3 Hz, 1H), 3.76–3.69 (m, 1H), 3.21–3.01 (m, 2H), 2.23
(s, 3H) ppm. 13C-NMR (CDCl3, 75 MHz) d 204.9, 135.3, 134.6,
129.5, 129.3, 111.5, 111.3, 44.6, 40.3, 30.3, 28.4 ppm. ESI-HRMS
calcd for C13H11ClN2O − H 245.0476, found 245.0477. 96% ee
determined by HPLC on AS-H column, hexane–i-propanol
2-(3-Oxo-1-phenylpentyl)malononitrile (4j). Colorless oil.
Yield 85%. [a]2D5 = −34.0 (c = 0.45, CHCl3). H-NMR (CDCl3,
1
300 MHz) d 7.42–7.34 (m, 5H), 4.50 (d, J = 5.4 Hz, 1H),
3.78–3.72 (m, 1H), 3.21–3.02 (m, 2H), 2.54–2.42 (m, 2H), 1.07
(t, J = 7.3 Hz, 3H) ppm. 13C-NMR (CDCl3, 75 MHz) d 208.2,
136.3, 129.3, 129.1, 127.8, 111.7, 111.6, 43.5, 40.9, 36.4, 28.6,
7.5 ppm. ESI-HRMS calcd for C14H14N2O − H 225.1022,
found 225.1019. 97% ee determined by HPLC on OJ-H column,
(70 : 30), 1.0 mL min−1, UV 254 nm, tmajor = 13.307 min, tminor
=
16.906 min.
hexane–i-propanol (70 : 30), 1.0 mL min−1, UV 254 nm, tminor
12.339 min, tmajor = 15.397 min.
=
2-(1-(4-Bromophenyl)-3-oxobutyl)malononitrile (4e). Color-
1
less oil. Yield 84%. [a]D25 = −31.2 (c = 0.50, CHCl3). H-NMR
(CDCl3, 300 MHz) d 7.55 (d, J = 8.2 Hz, 2H), 7.24 (d, J =
8.5 Hz, 2H), 4.47 (d, J = 5.2 Hz, 1H), 3.74–3.68 (m, 1H),
3.21–3.00 (m, 2H), 2.22 (s, 3H) ppm. 13C-NMR (CDCl3, 75 MHz)
d 204.9, 135.1, 132.5, 129.5, 123.4, 111.5, 111.3, 44.5, 40.4, 30.3,
28.3 ppm. ESI-HRMS calcd for C13H11BrN2O − H 288.9971,
found 288.9968. 93% ee determined by HPLC on OD-H column,
13
2-(3-Oxocyclohexyl)malononitrile (4k).
Light yellow oil.
Yield 60%. [a]2D5 = +16.0 (c = 0.12, CHCl3). H-NMR (CDCl3,
300 MHz) d 3.75 (d, J = 4.9 Hz, 1H), 2.67–2.64 (m, 1H), 2.48–
2.19 (m, 6H), 1.77–1.73 (m, 2H) ppm. 13C-NMR (CDCl3, 75 MHz)
d 206.1, 111.0, 110.8, 44.2, 40.2, 39.4, 28.7, 28.1, 23.6 ppm. ESI-
HRMS calcd for C9H10N2O − H 161.0709, found 161.0726. 95% ee
determined by GC on CP-Chirasil-DEX CB column, 150 ◦C
isothermal, tmajor = 30.681 min, tminor = 32.768 min.
1
hexane–i-propanol (85 : 15), 1.0 mL min−1, UV 254 nm, tminor
22.636 min, tmajor = 24.013 min.
=
2-(1-(4-Nitrophenyl)-3-oxobutyl)malononitrile
(4f). Brown
2,2ꢀ-(Cyclohexan-1-yl-3-ylidene)dimalononitrile (4ka). 13 Light
◦
solid. Yield 70%, mp 136.3–138.5 C. [a]2D5 = −32.0 (c = 0.33,
CHCl3). 1H-NMR (CDCl3, 300 MHz) d 8.31–8.27 (m, 2H),
7.60–7.56 (m, 2H), 4.55 (d, J = 5.4 Hz, 1H), 3.91–3.84 (m, 1H),
3.29–3.07 (m, 2H), 2.25 (s, 3H) ppm. 13C-NMR (CDCl3, 75 MHz)
d 204.4, 148.4, 143.0, 129.1, 124.5, 111.2, 110.9, 44.4, 40.6, 30.2,
27.9 ppm. ESI-HRMS calcd for C13H11N3O3 − H 256.0717,
found 256.0716. 87% ee determined by HPLC on AS-H column,
◦
yellow solid. Yield 30%, mp 98–100 C. [a]2D5 = −76.0 (c = 0.18,
1
CHCl3). H-NMR (CDCl3, 300 MHz) d 3.92 (d, J = 3.6 Hz,
1H), 3.18 (d, J = 10.6 Hz, 1H), 3.07 (d, J = 13.8 Hz, 1H),
2.41–2.13 (m, 5H), 1.66–1.56 (m, 2H) ppm. 13C-NMR (CDCl3,
75 MHz) d 178.8, 111.0, 110.9, 110.8, 85.2, 39.5, 36.5, 33.2, 28.4,
27.7, 24.8 ppm. ESI-HRMS calcd for C12H10N4 − H 209.0822,
found 209.0823. 90% ee determined by HPLC on AD-H column,
hexane–i-propanol (70 : 30), 1.0 mL min−1, UV 254 nm, tminor
24.079 min, tmajor = 33.490 min.
=
hexane–i-propanol (80 : 20), 1.0 mL min−1, UV 254 nm, tminor
9.411 min, tmajor = 11.315 min.
=
2-(1-(Naphthalen-2-yl)-3-ox◦obutyl)malononitrile (4g). White
solid. Yield 87%, mp 132–133 C. [a]2D5 = −50.4 (c = 0.43, CHCl3).
1H-NMR (CDCl3, 300 MHz) d 7.91–7.83 (m, 4H), 7.56–7.50
(m, 2H), 7.47–7.44 (m, 1H), 4.55 (d, J = 5.5 Hz, 1H), 3.96–
3.89 (m, 1H), 3.34–3.14 (m, 2H), 2.23 (s, 3H) ppm. 13C-NMR
(CDCl3, 75 MHz) d 205.2, 133.6, 133.3, 133.2, 129.3, 128.1,
127.7, 127.4, 126.8, 126.7, 124.9, 111.7, 111.6, 44.9, 41.0, 30.3,
28.5 ppm. ESI-HRMS calcd for C17H14N2O − H 261.1022, found
261.1009. 88% ee determined by HPLC on AS-H column, hexane–
i-propanol (70 : 30), 1.0 mL min−1, UV 254 nm, tminor = 13.128 min,
tmajor = 15.598 min.
2-(3-Oxo-1,3-diphenylpropyl)malononitrile (4l). White solid.
Yield 60%. [a]2D5 = −12.5 (c = 0.20, CHCl3), lit.8 ee = 11%,
[a]2D5 = −1.6 (c = 1.0, CHCl3). H-NMR (CDCl3, 300 MHz) d
1
7.98–7.96 (m, 2H), 7.63–7.61 (m, 1H), 7.53–7.40 (m, 7H), 4.64
(d, J = 5.1 Hz, 1H), 3.99–3.93 (m, 1H), 3.77–3.62 (m, 2H)
ppm. 88% ee determined by HPLC on OD-H column, hexane–i-
propanol (70 : 30), 1.0 mL min−1, UV 254 nm, tminor = 12.312 min,
tmajor = 19.071 min.
2-(1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl)malononitrile (4m).
Colorless oil. Yield 20%. [a]2D5 = −11.0 (c = 0.21, CHCl3). H-
1
NMR (CDCl3, 300 MHz) d 7.98–7.95 (m, 2H), 7.62–7.59 (m, 1H),
7.52–7.47 (m, 2H), 7.39–7.36 (m, 2H), 6.96–6.93 (m, 2H), 4.60
(d, J = 5.1 Hz, 1H), 3.95–3.89 (m, 1H), 3.81 (s, 3H), 3.73–3.58
(m, 2H) ppm. 13C-NMR (CDCl3, 75 MHz) d 196.7, 159.9, 135.7,
134.1, 129.1, 128.8, 128.4, 128.0, 114.5, 111.9, 111.8, 55.2, 40.4,
40.1, 29.0 ppm. ESI-HRMS calcd for C19H16N2O2 + Na 327.1104,
found 327.1118. 87% ee determined by HPLC on AS-H column,
2-(1-(Furan-2-yl)-3-oxobutyl)malononitrile (4h). Brown oil.
1
Yield 99%. [a]2D5 = −12.0 (c = 0.23, CHCl3). H-NMR (CDCl3,
300 MHz) d 7.43 (br, 1H), 6.38 (br, 2H), 4.45 (d, J = 5.3 Hz, 1H),
3.96–3.89 (m, 1H), 3.13–3.10 (m, 2H), 2.24 (s, 3H) ppm. 13C-NMR
(CDCl3, 75 MHz) d 204.6, 149.2, 143.4, 111.4, 111.1, 110.8, 109.2,
43.1, 35.3, 30.1, 26.9 ppm. ESI-HRMS calcd for C11H10N2O2 − H
201.0659, found 201.0673. 95% ee determined by HPLC on AS-H
column, hexane–i-propanol (70 : 30), 1.0 mL min−1, UV 230 nm,
tmajor = 16.057 min, tminor = 25.791 min.
hexane–i-propanol (70 : 30), 1.0 mL min−1, UV 254 nm, tminor
13.304 min, tmajor = 23.322 min.
=
2-(2-Oxoheptan-4-yl)malononitrile (4i). Colorless oil. Yield
39%. [a]2D5 = +41.7 (c = 0.40, CHCl3), lit.9e ee = 94%, [a]2D5 = +45
2-(1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl)malononitrile (4n).
◦
White solid. Yield 40%, mp 99–101 C. [a]2D5 = −18.0 (c = 0.14,
1
(c = 0.98, CHCl3). H-NMR (CDCl3, 300 MHz) d 4.29 (d, J =
CHCl3). 1H-NMR (CDCl3, 300 MHz) d 7.99–7.96 (m, 2H), 7.64–
7.61 (m, 1H), 7.53–7.43 (m, 4H), 7.16–7.10 (m, 2H), 4.63 (d,
J = 5.0 Hz, 1H), 3.99–3.93 (m, 1H), 3.75–3.57 (m, 2H) ppm.
13C-NMR (CDCl3, 75 MHz) d 196.4, 162.9 (d, JC1 F = 248.9 Hz),
4.5 Hz, 1H), 2.79–2.73 (m, 1H), 2.66–2.64 (m, 1H), 2.57–2.51 (m,
1H), 2.20 (s, 3H), 1.64–1.37 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H) ppm.
92% ee determined by GC and derivation to the corresponding 1,3-
352 | Org. Biomol. Chem., 2008, 6, 349–353
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135.6, 134.2, 132.2, 129.8 (d, J3CF = 8.3 Hz), 128.9, 128.1, 116.3
(d, J2CF = 21.7 Hz), 111.7, 111.5, 40.5, 40.7, 28.8 ppm. ESI-
HRMS calcd for C18H13FN2O + Na, 315.0904, found 315.0909.
83% ee determined by HPLC on AS-H column, hexane–i-
propanol (90 : 10), 1.0 mL min−1, UV 254 nm, tminor = 9.562 min,
tmajor = 11.143 min.
W. Wa n g , J. Am. Chem. Soc., 2006, 128, 12652; (c) C.-L. Gu, L. Liu,
Y. Sui, J.-L. Zhao, D. Wang and Y.-J. Chen, Tetrahedron: Asymmetry,
2007, 18, 455.
5 For reviews of the Michael additions catalyzed by metallic complexes,
see: (a) M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033;
(b) N. Krause and A. Hoffmann-Roder, Synthesis, 2001, 171; (c) J.
Christoffers, G. Koripelly, A. Rosiak and M. Ro¨ssle, Synthesis, 2007,
1279.
6 For reviews of asymmetric Michael additions catalyzed by organocat-
alysts, see: (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004,
43, 5138; (b) J. Seayad and B. List, Org. Biomol. Chem., 2005, 3, 719;
(c) M. S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed., 2006,
45, 1520; (d) A. Berkessel and H. Gro¨ger, Asymmetric Organocatalysis,
Wiley-VCH, Germany, 2005, ch. 4.
2-(3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl)malononitrile (4o).
Colorless oil. Yield 79%. [a]2D5 = +11.0 (c = 0.10, CHCl3). 1H-NMR
(CDCl3, 300 MHz) d 7.97–7.94 (m, 2H), 7.47–7.39 (m, 5H), 6.97–
6.94 (m, 2H), 4.70 (d, J = 5.1 Hz, 1H), 3.97–3.90 (m, 1H), 3.88 (s,
3H), 3.71–3.55 (m, 2H) ppm. 13C-NMR (CDCl3, 75 MHz) d 195.0,
164.3, 136.6, 130.5, 129.7, 129.1, 128.8, 127.9, 114.0, 111.9, 111.7,
55.6, 41.2, 39.6, 28.7 ppm. ESI-HRMS calcd for C19H16N2O2 + Na
327.1104, found 327.1099. 87% ee determined by HPLC on AS-H
column, hexane–i-propanol (70 : 30), 0.8 mL min−1, UV 254 nm,
tmajor = 22.195 min, tminor = 25.903 min.
7 Y.-C. Chen, D. Xue, J.-G. Deng, X. Cui, J. Zhu and Y.-Z. Jiang,
Tetrahedron Lett., 2004, 45, 1555.
8 K. Yasuda, M. Shindo and K. Koga, Tetrahedron Lett., 1996, 37, 6343.
9 For examples of asymmetric conjugate additions of malononitriles
catalyzed by chiral thiourea, see: (a) Y. Hoashi, T. Okino and Y.
Takemoto, Angew. Chem., Int. Ed., 2005, 44, 4032; (b) T. Inokuma, Y.
Hoashi, T. Okino and Y. Takemoto, J. Am. Chem. Soc., 2006, 128, 9413;
for the examples catalyzed by metallic complexes, see: (c) S. Kanemasa
and K. Ito, Eur. J. Org. Chem., 2004, 4741 and references therein;
(d) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125,
11204; (e) M. S. Taylor, D. N. Zalatan, A. M. Lerchner and E. N.
Jacobsen, J. Am. Chem. Soc., 2005, 127, 1313.
10 (a) J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen,
Y. Wu, J. Zhu and J.-G. Deng, Angew. Chem., Int. Ed., 2007, 46, 389;
(b) J.-W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J.-G. Deng and Y.-C.
Chen, Org. Lett., 2007, 9, 413; (c) W. Chen, W. Du, L. Yue, R. Li, Y. Wu,
L.-S. Ding and Y.-C. Chen, Org. Biomol. Chem., 2007, 5, 816; (d) T.-Y.
Liu, H.-L. Cui, Y. Zhang, K. Jiang, W. Du, Z.-Q. He and Y.-C. Chen,
Org. Lett., 2007, 9, 3671; (e) W. Chen, W. Du, Y.-Z. Duan, Y. Wu, S.-Y.
Yang and Y.-C. Chen, Angew. Chem., Int. Ed., 2007, 46, 7667; (f) S. H.
McCooey and S. J. Connon, Org. Lett., 2007, 9, 599; (g) G. Bartoli,
M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri and P. Melchiorre, Org.
Lett., 2007, 9, 1403; (h) B.-L. Zheng, Q.-Z. Liu, C.-S. Guo, X.-L. Wang
and L. He, Org. Biomol. Chem., 2007, 5, 2913.
11 (a) U. Sundermeier, C. Do¨bler, G. M. Mehltretter, W. Baumann and M.
Beller, Chirality, 2003, 15, 127; (b) H. Brunner, J. Bu¨gler and B. Nuber,
Tetrahedron: Asymmetry, 1995, 6, 1699.
12 (a) N. J. A. Martin and B. List, J. Am. Chem. Soc., 2006, 128, 13368;
(b) S. Mayer and B. List, Angew. Chem., Int. Ed., 2006, 45, 4193.
13 P. J. Black, M. G. Edwards and J. M. J. Williams, Tetrahedron, 2005, 61,
1363. Moreover, it is notable that cyclohexen-1-ylidenemalononitrile
reacted with malononitrile to give a racemate under the same condi-
tions.
Notes and references
1 For selected examples of asymmetric conjugate additions of nitroalka-
nes, see: (a) S. Hanessian and V. Pham, Org. Lett., 2000, 2, 2975; (b) E. J.
Corey and F.-Y. Zhang, Org. Lett., 2000, 2, 4257; (c) N. Halland, R. G.
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(e) B. M. Nugent, R. A. Yoder and J. N. Johnson, J. Am. Chem. Soc.,
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Org. Lett., 2005, 7, 3897; (h) C. E. T. Mitchell, S. E. Brenner and S. V.
Ley, Chem. Commun., 2005, 5346.
2 For selected examples of asymmetric conjugate additions of malonates,
see: (a) N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001,
123, 4370; (b) N. Halland, P. S. Aburel and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2003, 42, 661; (c) H. Li, Y. Wang, T. Tang and L.
Deng, J. Am. Chem. Soc., 2004, 126, 9906; (d) T. Okino, Y. Hoashi, T.
Furukawa, X. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119;
(e) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
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Commun., 2006, 66.
3 (a) For a selected example of asymmetric conjugate addition of
ketoesters, see: F. Wu, H. Li, R. Hong and L. Deng, Angew. Chem., Int.
Ed., 2006, 45, 947; (b) for a selected example of asymmetric conjugate
addition of 1,3-diketones, see: J. Wang, H. Li, W.-H. Duan, L. Zu and
W. Wa n g , Org. Lett., 2005, 7, 4713.
4 For selected examples, see: (a) T.-Y. Liu, R.-L. Li, Q Chai, J. Long,
B.-J. Li, Y. Wu, L.-S. Ding and Y.-C. Chen, Chem.–Eur. J., 2007, 13,
319; (b) J. Wang, H. Li, L.-S. Zu, W. Jiang, H.-X. Xie, W.-H. Duan and
14 Under the same conditions, no product was observed with 3a and
nitromethane or diethyl malonate as substrates.
15 For the Michael addition of ethyl a-cyanoacetate,4a,c,9e the reaction
activity of 3a is low and the desired product was obtained in 10%
yield with a 61 : 39 ratio of syn- and anti-isomers after 108 h.
16 W. L. F. Armarego and D. D. Perrin, Purification of Laboratory
Chemicals, Butterworth Heinemann, Oxford, UK, 4th edn, 1997.
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The Royal Society of Chemistry 2008
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