A simple and highly efficient procedure for construction of quaternary carbons centers by tributylphosphine catalyzed bis-Michael addition

Article abstract of DOI:10.1016/j.tet.2013.11.103

The tributylphosphine-catalyzed bis-Michael addition reaction of various kinds of α,β-unsaturated carbonyl compounds with active methylenes is described. This is a convenient and rapid method for generating quaternary carbons centers and useful procedure for the synthesis of branched core and highly substituted trans cyclohexanones. All the reactions were completed in 60 min and afford the corresponding products in excellent yields.

Full text of DOI:10.1016/j.tet.2013.11.103

Tetrahedron 70 (2014) 176e180
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple and highly efficient procedure for construction of
quaternary carbons centers by tributylphosphine catalyzed
bis-Michael addition
,
,
Da-Zhen Xu a b, Ming-Zhe Zhan b, You Huang a
*
a State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Nankai University, Tianjin 300071, People’s Republic of China
b National Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 August 2013
Received in revised form 22 November 2013
Accepted 29 November 2013
Available online 4 December 2013
The tributylphosphine-catalyzed bis-Michael addition reaction of various kinds of a,b-unsaturated car-
bonyl compounds with active methylenes is described. This is a convenient and rapid method for gen-
erating quaternary carbons centers and useful procedure for the synthesis of branched core and highly
substituted trans cyclohexanones. All the reactions were completed in 60 min and afford the corre-
sponding products in excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
Tributylphosphine
Quaternary carbons
Catalysis
Bis-adducts
1. Introduction
to construct the quaternary carbons centers.10 However there are
still disadvantages of these reagents. For example, the reagents
The synthesis of compounds with carbon atoms having four
different nonhydrogen substituents is an attractive area of research
because of their stereochemistry and biological activity.1 As a result
of extreme steric congestion, the construction of quaternary car-
bons is a formidable challenge for chemical synthesis. In the last
two decades, much attention was paid on construction of quater-
nary carbons. In terms of catalytic CeC bond-forming generations
were expensive,11 the reaction time was too long,10d and the re-
action needed other special conditions,10f such as microwave irra-
diation. In most cases, the range of
a,b-unsaturated carbonyl
compounds was limited to conjugated carboxylic esters, and a few
examples used conjugated ketones with good yields. Thus, there is
a demand for the development of a milder reagent for a general bis-
Michael addition to construct the quaternary carbons centers from
of quaternary centers, Heck reactions,2 enolate
late
-allylations4, and allylic substitution5 reactions have proven to
be valuable strategies.
a
-arylations,3 eno-
active methylenes and various kinds of
in a single step.
a,b-unsaturated compounds
a
In the early years of this century, an impressive development
took place in metal free catalytic methods. Exciting results in
organocatalysis attracted a deep attention, taking the advantages
of often simple, inexpensive and commercially available cata-
lysts.12 Organocatalysis induced by phosphines is a topic of in-
creasing interest. Owing to their comparatively strong and
readily tunable nucleophilicity, nucleophilic phosphine catalysis
has been shown to be a powerful tool in organic synthesis.13 As
a part of our continuing interests in phosphine catalysis,14 here,
we wish to disclose our study on the use of tributylphosphine as
The Michael reaction is widely recognized as one of the most
important carbonecarbon bond-forming procedures, and it plays
an important role in organic synthesis.6 Michael addition is
a powerful method to construct the quaternary carbons centers.
This procedure was often carried out in the presence of strong base7
that often lead to undesirable side reactions.8 A number of reagents
have been developed for this transformation, and most of the re-
actions referred to mono-Michael addition reaction.9 But to date,
only a few reagents have been reported on the bis-Michael addition
catalysts in construction of quaternary carbons from
a,b-un-
saturated carbonyl compounds and active methylenes by bis-
Michael addition.
* Corresponding author. Fax: þ86 22 2350 3627; e-mail addresses: hyou@nankai.
edu.cn, hyou18@163.com (Y. Huang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.103

D.-Z. Xu et al. / Tetrahedron 70 (2014) 176e180
177
2. Results and discussion
Table 2 (continued)
Entry Product R1
R2
X
Y
Time (min) Yield (%)b
Initially, we selected the Michael addition of malononitrile (2a)
with methyl acrylate (1a) catalyzed by 10 mol % tributylphosphine
as a model reaction for investigation of different reaction param-
eters. As shown in Table 1, the yields of bis-adduct 3a differed
significantly in different solvents at room temperature (Table 1,
entries 1e6). Initially, the reaction was carried out under solvent-
free conditions, bis-adducts 3a was formed in a high yield of 83%
within 1 h (Table 1, entry 1). When H2O and THF were used as the
solvent, the product was obtained in very low yields (Table 1, en-
tries 2 and 3). When the reaction was carried in other organic
solvent, such as toluene, CH2Cl2, CH3CN, moderate to excellent
yields were obtained (Table 1, entries 4e6). We were pleased to
observe the formation of bis-adduct 3a with near quantitative yield
in CH3CN (Table 1, entry 6). In absence of catalyst tribu-
tylphosphine, this Michael addition reaction did not progress at all
(Table 1, entry 7). Other organic bases, such as triethylamine and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), were also used in the
reaction, but no better results were provided (Table 1, entries 8, 9).
6
7
8
9
3f
EtO
EtO
EtO
EtO
H
H
H
H
CN
CO2Et
30
20
24
5
98
94
98
98
3g
3h
3i
CO2Me CO2Me
CO2Et
NO2
CO2Et
Me
a
Reaction conditions: conjugated alkene (3.0 mmol), active methylene com-
pound (1.0 mmol), n-Bu3P (25 mL, 10 mol %), CH3CN (5.0 mL), room temperature
(25 ꢀC).
b
Isolated yield.
reaction, the product 3e was formed in near a quantitative yield
(Table 2, entry 5).
The Michael addition of nitroalkanes with conjugated carboxylic
esters is the key step for the synthesis of dendrimers.15 But long
reaction time and low yield often puzzled in the synthesis of the
branched core. In the previously reported procedures, a mixture of
monoaddition products, double addition products and triple addi-
tion products were often formed when nitromethane was used in
the Michael reaction with acrylates.16 Here, we report a synthetic
method to yield pure double addition products and triple addition
products near a quantitative yield just by controlling the ratio of
substrates between acrylates and nitromethane in a very short
time. Under the optimal reaction conditions, double Michael ad-
ducts were formed when the ratio of acrylates/nitromethane was
1:2. While a 4:1 ratio of the substrates acrylates/nitromethane was
used, the reaction gave treble Michael adducts as the main products
(Scheme 1). This new synthetic method reported here would
greatly contribute to synthesize of dendrimers.
Table 1
Optimization of reaction conditions for the Michael addition of malononitrile to
conjugated alkenesa
O
O
O
CN
n-Bu3P (10 mol%)
+
MeO
OMe
MeO
Solvent, r.t.
CN
NC CN
3a
1a
2a
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
Neat
H2O
THF
Toluene
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
60
120
120
60
25
25
600
40
90
83
<5
<5
75
88
98
0
O
O
4a : R = MeO, 75%
4b : R = EtO, 93%
4c : R = n-BuO, 97%
A
B
O
+
R
R
NO2
R
R
4
n-Bu3P (10 mol%)
CH3CN, r.t.
7c
8d
9e
O
91
0
CH3NO2
O
O
5a : R = MeO, 58%
5b : R = EtO, 98%
5c : R = n-BuO, 98%
R
R
a
Reaction conditions: methyl acrylate (271
m
L, 3.0 mmol), malononitrile (66 mg,
NO2
5
1.0 mmol), n-Bu3P (25
m
L, 10 mol %), solvent (5.0 mL), room temperature (25 ꢀC).
Conditions: A) acrylate / nitromethane = 1:2; B) acrylate / nitromethane = 4:1
b
Isolated yield.
Catalyst-free.
c
Scheme 1. Michael reaction of nitromethane to acrylates.
d
DBU (14
Et3N (14
m
m
L, 10 mol %) was used.
L, 10 mol %) was used.
e
This procedure was also applicable to the intramolecular double
Michael reaction of active methylenes to dienones, and afforded the
Having established the optimal reaction conditions for bis-
compound, containing
a new quaternary carbon center, 1,1-
addition of malononitrile (2a) to methyl acrylate (1a), we then
examined other active methylenes with conjugated carboxylic es-
ters and ketones in CH3CN catalyzed by tributylphosphine
(10 mol %) at room temperature to establish the general utility of
this transformation. As shown in Table 2, excellent yields of bis-
adducts were obtained with both terminal unsubstituted conju-
gated carboxylic esters and ketones in very short reaction time.
Although a longer reaction time (300 min) was needed when the
terminal substituted alkene, ethyl crotonate, was employed in the
disubstituted-2,6-diarylcyclohexane-4-ones, which were often
employed as starting materials for the synthesis of compounds
with possible biological activity17 and used to prepare a variety of
spiro heterocycles.18 As can be seen from the solvents screened
results summarized in Table 3, when the reaction was performed in
CH2Cl2 in the presence of 10 mol % of tributylphosphine as the
catalyst, the reaction proceeded smoothly and gave exclusively the
Table 3
Optimization of reaction conditions for the Michael addition of malononitrile to
Table 2
dibenzylidene acetonea
Michael addition of active methylene compounds to conjugated alkenesa
R2 R2
O
O
O
O
X
Y
n-Bu3P (10 mol%)
O
R1
+
R1
R1
CN
n-Bu3P (10 mol%)
CH3CN, r.t.
+
X
Y
Ph
Ph
R2
Ph
Ph
solvent, r.t.
CN
2a
1
2
6a
3
NC CN
7a
Entry Product R1
R2
X
Y
Time (min) Yield (%)b
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
3a
3b
3c
3d
3e
MeO
EtO
n-BuO
Me
H
H
H
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
25
40
25
20
300
98
98
98
95
97
1
2
3
CH3CN
THF
Toluene
90
300
90
32
0
21
EtO
Me CN
(continued on next page)

178
D.-Z. Xu et al. / Tetrahedron 70 (2014) 176e180
generates M-20, which reacts again to olefin through intermolecular
Table 3 (continued )
Yield (%)b
(1) or intramolecular (2) Michael addition. Then product 3 or 7 was
Entry
Solvent
Time (min)
released, and deprotonated active methylene was regenerated.
4
5
CH2Cl2
H2O
5
90
95
10
n-Bu3P
a
Reaction conditions: dibenzal acetone (234 mg, 1.0 mmol), malononitrile
(66 mg, 1.0 mmol), n-Bu3P (25 mL, 10 mol %), solvent (5.0 mL), room temperature
Pn-Bu3
(25 ꢀC).
R3
1 or 6
R3
M-1
R4
R4
b
Isolated yield.
CN
CN
trans-1,1-disubstituted-2,6-diarylcyclohexane-4-one (7a) in the
best yield of 95% within only 5 min (Table 3, entry 4).
Under the standard reaction conditions, a variety of dienones (6)
and active methylenes (2) were examined to explore the scope of
the reaction. The results are shown in Table 4, high isolated yields
were obtained for all the products, regardless of the electronic
nature of the aromatic substituents. Compared to the Michael re-
actions of malononitrile with dibenzal acetone, which contained
donating and moderately electron withdrawing groups, the re-
actions of ethyl cyanoacetate with the same substrates needed
a longer reaction time. When the substrates 6 with strong electron
withdrawing groups (4-CN and 4-NO2), the opposite results were
obtained. A shorter time was often needed when they reacted with
ethyl cyanoacetate.
NC
R3
CN
R4
Pn-Bu3
R3
M-1'
CN
CN
M-2
R4
NC
R3
CN
R4
M-2'
3 or 7
CN
3' or 7'
CN
O
O
O
NC
CN
R1
R2
M-2'
or
O
R1
R1
=
(1)
(2)
3'
R1
R2
R2
R2
Table 4
n-Bu3P catalyzed Michael addition of active methylenes to dienonesa
NC CN
O
NC
CN
Ar2
O
M-2'
=
Ar1
7'
Ar1
Ar2
CN
NC
Scheme 2. Possible mechanism for the bis-addition catalyzed by tributylphosphine.
Entry Product Ar1
Ar2
Z
Time (min) Yield (%)b
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
Ph
Ph
CN
CN
5
25
16
2
120
60
10
10
7
95
82
95
95
93
89
88
>99
85
93
90
94
97
>99
85
96
90
91
85
91
98
p-CH3C6H4
p-OCH3C6H4 p-OCH3C6H4 CN
p-ClC6H4
p-CH3C6H4
3. Conclusion
p-ClC6H4
p-CNC6H4
p-NO2C6H4
o-ClC6H4
m-ClC6H4
m-CH3C6H4
Ph
Ph
Ph
Ph
Ph
p-CH3C6H4
p-ClC6H4
p-NO2C6H4
m-CH3C6H4
m-ClC6H4
Ph
CN
CN
CN
CN
CN
CN
CN
CN
p-CNC6H4
p-NO2C6H4
o-ClC6H4
m-ClC6H4
m-CH3C6H4
p-CH3C6H4
p-ClC6H4
p-CNC6H4
p-NO2C6H4
Ph
p-CH3C6H4
p-ClC6H4
p-NO2C6H4
m-CH3C6H4
m-ClC6H4
p-CH3C6H4
p-NO2C6H4
In conclusion, we have successfully demonstrated a new pro-
cedure for construction of quaternary carbons centers in a single
step by intermolecular and intramolecular bis-Michael addition.
The compound tributylphosphine was employed as a highly effi-
9
10
11
12
13
14
15
16
17
18
19
20
21
7j
7k
7l
20
4
cient catalyst for the Michael reaction of a broad range of a,b-un-
saturated carbonyl compounds and active methylenes. The reaction
condition is mild and the method is operationally simple. The
products, containing a new quaternary carbons center, were ob-
tained in good to excellent yields in short times.
CN
CN
70
60
60
40
60
20
60
40
50
15
7m
7n
7o
7p
7q
7r
7s
7t
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
4. Experimental section
7u
Ph
4.1. General procedure for the Michael addition of active
methylene compounds to conjugated alkenes (3a as an
example)
a
Reaction conditions: dienone (1.0 mmol), active methylene compound
(1.0 mmol), n-Bu3P (25
m
L, 10 mol %), CH2Cl2 (5.0 mL), room temperature (25 ꢀC).
b
Isolated yield.
A mixture of malononitrile (2a) (66 mg, 1 mmol), methyl acry-
We also tried this intramolecular double Michael reaction out on
grams scale, compound 7a was chosen as the target compound. The
reaction was carried out on a ten-mmol scale with only 5 mol % of
tributylphosphine as the catalyst. Product 7a could be obtained in
2.82 g with 94% yield within 30 min.
late (1a) (271 mL, 3 mmol), tributylphosphine (25 mL, 0.1 mmol), and
anhydrous CH3CN (5.0 mL) was magnetically stirred in a flask under
nitrogen atmosphere at room temperature. The reaction progress
was monitored by thin layer chromatography (TLC) until malono-
nitrile was consumed. Then, the reaction mixture was diluted with
H2O (10 mL) and extracted with AcOEt (3ꢁ10 mL), the organic
phase was washed with brine (10 mL), dried over anhydrous
Na2SO4. After the removal of the solvent under reduced pressure,
the residue was subjected to chromatography on a silica gel
(200e300 mesh) column using petroleum ether/ethyl acetate (4:1)
as eluent to afford 3a (233 mg, 98% yield) as a colorless liquid.
Base on the results and the reported literature,19 a proposed
mechanism for the double Michael addition reaction is shown in
Scheme 2. Initial attack of the tributylphosphine on the substrate of
olefin (1 or 6) generates a zwitterion M-1, which deprotonates
a molecule of the active methylene. The addition of deprotonated
active methylene to the olefin (1 or 6) followed by proton transfer

D.-Z. Xu et al. / Tetrahedron 70 (2014) 176e180
179
4.1.1. Diethyl 4,4-dicyano-3,5-dimethylheptanedioate (3e). 1H NMR
[MꢂH]ꢂ. HRMS calcd for C22H13N4Oꢂ [MꢂH]ꢂ 349.1168; found
(400 MHz, CDCl3):
d
¼1.21e1.30 (12H, m), 2.36e2.53 (2H, m),
349.1165.
2.63e2.78 (4H, m), 4.16 (4H, q, J1¼14.0 Hz, J2¼7.2 Hz). 13C NMR
(100 MHz, CDCl3):
d
¼14.15, 16.10, 34.41, 37.09, 47.97, 61.35, 113.72,
4.2.2. 4-Oxo-2,6-dim-tolylcyclohexane-1,1-dicarbonitrile
(7i). 1H
170.40. MS (ESI): m/z¼317.1 [MþNa]þ. HRMS calcd for
NMR (400 MHz, CDCl3):
d
¼2.36 (6H, s), 3.01e3.14 (4H, m), 3.77 (2H,
C
15H22N2O4Naþ [MþNa]þ 317.1477; found 317.1479.
t, J¼6.4 Hz), 7.09e7.31 (8H, m). 13C NMR (100 MHz, CDCl3):
¼21.71,
d
30.52, 42.64, 45.74, 114.20, 126.09, 129.23, 130.01, 130.52, 135.36,
4.1.2. 1,5-Diethyl 3,3-dimethyl pentane-1,3,3,5-tetracarboxylate
(3g). 1H NMR (400 MHz, CDCl3):
¼1.19 (t, 6H, J¼7.2 Hz),
139.17, 205.03. MS (ESI): m/z¼327.6 [MꢂH]ꢂ. HRMS calcd for
d
C
22H19N2Oꢂ [MꢂH]ꢂ 327.1503; found 327.1507.
2.12e2.17 (m, 4H), 2.21e2.26 (m, 4H), 3.67 (s, 6H), 4.06 (q, 4H,
J1¼7.2 Hz, J2¼14.4 Hz). 13C NMR (100 MHz, CDCl3):
d
¼14.34, 28.46,
4.2.3. 2-(4-Cyanophenyl)-4-oxo-6-phenylcyclohexane-1,1-
dicarbonitrile (7l). 1H NMR (400 MHz, CDCl3):
29.67, 52.77, 56.35, 60.79, 171.26, 172.65. MS (ESI): m/z¼355.4
[MþNa]þ. HRMS calcd for C15H24O8Naþ [MþNa]þ 355.1363; found
355.1366.
d
¼3.04 (1H, dd,
J1¼16.4 Hz, J2¼5.2 Hz), 3.12e3.18 (3H, m), 3.85e3.93 (2H, m),
7.31e7.33 (2H, m), 7.42e7.47 (5H, m), 7.71 (2H, d, J¼7.6 Hz). 13C
NMR (100 MHz, CDCl3):
d
¼41.96, 42.07, 44.49, 44.87, 46.05, 113.35,
4.1.3. Dimethyl 4-nitroheptanedioate (4a). 1H NMR (300 MHz,
113.60, 118.60, 129.11, 129.32, 129.81, 132.95, 134.75, 140.07, 203.85.
MS (ESI): m/z¼324.2 [MꢂH]ꢂ. HRMS calcd for C21H14N3Oꢂ [MꢂH]ꢂ
324.1215; found 324.1219.
CDCl3):
d
¼2.09e2.31 (m, 4H), 2.37e2.48 (m, 4H), 3.69 (s, 6H), 4.65
(m, 1H). 13C NMR (100 MHz, CDCl3):
d
¼28.76, 30.02, 52.15, 86.80,
172.37. MS (ESI): m/z¼256.1 [MþNa]þ. HRMS calcd for C9H15O6N-
Naþ [MþNa]þ 256.0795; found 256.0799.
4.2.4. Ethyl
1-cyano-4-oxo-2,6-dip-tolylcyclohexanecarboxylate
(7o). 1H NMR (400 MHz, CDCl3):
d
¼0.92 (3H, t, J¼7.2 Hz), 2.31 (3H,
4.1.4. Dibutyl 4-nitroheptanedioate (4c). 1H NMR (300 MHz, CDCl3):
s), 2.33 (3H, s), 2.77 (1H, dd, J1¼16.4 Hz, J2¼3.6 Hz), 3.02 (1H, dd,
J1¼16.4 Hz, J2¼5.6 Hz), 3.10e3.17 (2H, m), 3.78e3.87 (2H, m),
3.90e3.93 (2H, m), 7.03e7.26 (8H, m). 13C NMR (100 MHz, CDCl3):
d
¼0.93 (t, 3H, J¼7.2 Hz), 2.31e1.43 (m, 4H), 1.56e1.65 (m, 4H),
2.07e2.49 (m, 8H), 4.10 (t, 6H, J¼6.8 Hz), 4.61e4.69 (m, 1H). 13C
NMR (100 MHz, CDCl3):
d
¼14.27, 14.34, 14.41, 28.85, 30.38, 61.14,
d
¼13.69, 21.31, 42.13, 42.26, 43.35, 47.99, 56.00, 62.94, 128.55,
92.12, 171.90. MS (ESI): m/z¼340.2 [MþNa]þ. HRMS calcd for
128.61, 129.60, 133.96, 134.64, 138.32, 138.66, 166.53, 207.73. MS
ꢂ
C
15H27O6NNaþ [MþNa]þ 340.1733; found 340.1735.
(ESI): m/z¼375.1 Mþ. HRMS calcd for C24H24NO3 [MꢂH]ꢂ
374.1746; found 374.1770.
4.1.5. Dimethyl 4-(2-(methoxycarbonyl)ethyl)-4-nitroheptanedioate
(5a). 1H NMR (400 MHz, CDCl3):
d
¼2.17e2.62 (m, 12H), 3.62 (s,
4.2.5. Ethyl 2,6-bis(4-chlorophenyl)-1-cyano-4-oxocyclohexa
9H). 13C NMR (100 MHz, CDCl3):
d
¼28.58, 30.35, 52.20, 92.03,
necarboxylate (7p). 1H NMR (400 MHz, CDCl3):
d
¼0.96 (3H, t,
172.33. MS (ESI): m/z¼342.3 [MþNa]þ. HRMS calcd for
J¼7.2 Hz), 2.77 (1H, dd, J1¼16.6 Hz, J2¼3.6 Hz), 3.00 (1H, dd,
J1¼16.6 Hz, J2¼5.6 Hz), 3.08e3.17 (2H, m), 3.84e3.93 (4H, m,
C
13H21NO8Naþ [MþNa]þ 342.1159; found 342.1156.
COCH2), 7.09e7.33 (8H, m). 13C NMR (100 MHz, CDCl3):
42.67, 42.14, 42.78, 47.43, 55.61, 63.37, 118.21, 129.20, 130.07,
d
¼13.76,
4.1.6. Dibutyl 4-(2-(butoxycarbonyl)ethyl)-4-nitroheptanedioate
(5c). 1H NMR (400 MHz, CDCl3):
¼0.89 (t, 9H, J¼7.2 Hz),
d
134.64, 134.98, 135.26, 135.82, 166.20, 206.52. MS (ESI): m/z¼415.9
ꢂ
1.28e1.37 (m, 6H), 1.52e1.59 (m, 6H), 2.23 (s, 6H), 2.24 (s, 6H), 4.03
Mþ. HRMS calcd for C22H18Cl2NO3 [MꢂH]ꢂ 414.0669; found
(t, 6H, J¼6.8 Hz). 13C NMR (100 MHz, CDCl3):
d
¼13.85, 19.27, 28.84,
414.0663.
30.42, 30.73, 65.07, 92.10, 171.98. MS (ESI): m/z¼368.5 [MþNa]þ.
HRMS calcd for
468.2568.
C
22H39NO8Naþ [MþNa]þ 468.2568; found
4.2.6. Ethyl 1-cyano-2,6-bis(4-nitrophenyl)-4-oxocyclohexa
necarboxylate (7q). 1H NMR (400 MHz, CDCl3):
d
¼0.80 (3H, t,
J¼7.2 Hz), 2.77 (1H, dd, J1¼16.4 Hz, J2¼2.8 Hz), 2.91 (1H, dd,
J1¼16.8 Hz, J2¼5.2 Hz), 3.03e3.10 (2H, m), 3.72e3.97 (4H, m), 7.23
4.2. General procedure for the Michael addition of active
methylenes to dienones (7a as an example)
(2H, d, J¼8.4 Hz); 7.35 (2H, d, J¼8.0 Hz); 8.03 (4H, t, J¼9.2 Hz). 13
C
NMR (100 MHz, CDCl3):
d
¼13.63, 41.08, 42.07, 42.49, 47.27, 54.73,
63.74, 117.34, 124.02, 129.67, 143.85, 148.02, 165.54, 204.96. MS
ꢂ
A mixture of malononitrile (2a) (66 mg, 1 mmol), dibenzyli-
dene acetone (6a) (234 mg, 1 mmol), tributylphosphine (25
(ESI): m/z¼437.0 Mþ. HRMS calcd for C22H18N3O7 [MꢂH]ꢂ
mL,
436.1223; found 436.1220.
0.1 mmol), and anhydrous CH2Cl2 (5.0 mL) was magnetically stir-
red in a flask under nitrogen atmosphere at room temperature.
The reaction progress was monitored by thin layer chromatogra-
phy (TLC) until the starting materials were completely consumed.
Then, the reaction mixture was diluted with H2O (10 mL) and
extracted with Et2O (3ꢁ10 mL), the organic phase was washed
with brine (10 mL), dried over anhydrous Na2SO4. After the re-
moval of the solvent under reduced pressure, the residue was
subjected to chromatography on a silica gel (200e300 mesh)
column using petroleum ether/ethyl acetate (4:1) as eluent to
afford 7a (286 mg, 95% yield) as a light yellow solid (mp
170e171 ꢀC).
4.2.7. Ethyl
1-cyano-4-oxo-2,6-dim-tolylcyclohexanecarboxylate
(7r). 1H NMR (400 MHz, CDCl3):
d¼0.91 (3H, t, J¼7.2 Hz), 2.31 (3H,
s), 2.33 (3H, s), 2.78 (1H, dd, J1¼17.2 Hz, J2¼3.6 Hz), 3.02 (1H, dd,
J1¼16.6 Hz, J2¼5.6 Hz), 3.11e3.18 (2H, m), 3.77e3.86 (2H, m),
3.90e3.94 (2H, m), 6.96e7.24 (8H, m). 13C NMR (100 MHz, CDCl3):
d
¼13.67, 21.66, 42.03, 42.46, 43.31, 48.38, 55.90, 62.88, 118.70,
125.62, 125.76, 128.79, 128.88, 129.29, 129.54, 137.01, 137.65, 138.50,
138.61, 166.55, 207.58. MS (ESI): m/z¼375.1 Mþ. HRMS calcd for
ꢂ
C
24H24NO3 [MꢂH]ꢂ 374.1746; found 374.1751.
4.2.8. Ethyl 2,6-bis(3-chlorophenyl)-1-cyano-4-oxocyclohex
anecarboxylate (7s). 1H NMR (400 MHz, CDCl3):
d¼0.97 (3H, t,
4.2.1. 2,6-Bis(4-cyanophenyl)-4-oxocyclohexane-1,1-dicarbonitrile
J¼7.2 Hz), 2.78 (1H, dd, J1¼16.6 Hz, J2¼3.6 Hz), 3.02 (1H, dd,
(7e). 1H NMR (400 MHz, CDCl3):
d
¼2.84e2.91 (4H, m), 3.64 (2H, t,
J1¼16.6 Hz, J2¼5.2 Hz), 3.08e3.20 (2H, m), 3.87e3.94 (4H, m),
J¼6.0 Hz), 7.23 (4H, d, J¼7.6 Hz), 8.32 (4H, d, J¼7.6 Hz). 13C NMR
7.06e7.34 (8H, m). 13C NMR (100 MHz, CDCl3):
d
¼13.73, 41.64,
(100 MHz, CDCl3):
d
¼41.72, 45.48, 53.59, 112.93, 113.94, 117.79,
42.27, 42.86, 47.85, 55.50, 63.47, 109.97, 118.01, 126.56, 126.87,
128.96, 129.20, 130.37, 134.75, 134.97, 138.72, 139.25, 166.09, 206.19.
129.25, 129.87, 133.05, 139.50, 202.83. MS (ESI): m/z¼349.6

180
D.-Z. Xu et al. / Tetrahedron 70 (2014) 176e180
ꢂ
MS (ESI): m/z¼415.0 Mþ. HRMS calcd for C22H18Cl2NO3 [MꢂH]ꢂ
5. (a) Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun. 2004, 1779;
(b) Helmchen, G.; Ernst, M.; Paradies, G. Pure Appl. Chem. 2004, 76, 495; (c)
Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461; (d) Bruneau, C.;
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6. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, UK, 1992.
7. (a) Kohler, E. P.; Helmkamp, R. W. J. Am. Chem. Soc. 1924, 46, 1018; (b)
Padmavathi, V.; Basha, S. M.; Subbaiah, D. R. C. V.; Reddy, T. V. R.; Padmaja, A. J.
Heterocycl. Chem. 2005, 42, 797; (c) Loganathan, D.; Varghese, T.; Trivedi, G. K.
Org. Prep. Proced. Int. 1984, 16, 115.
414.0669; found 414.0665.
4.2.9. Ethyl
1-cyano-4-oxo-2-phenyl-6-p-tolylcyclohexanecarbox-
ylate (7t). 1H NMR (400 MHz, CDCl3):
d
¼0.90 (3H, t, J¼7.2 Hz), 2.32
(3H, s), 2.79 (1H, dd, J1¼16.4 Hz, J1¼3.2 Hz), 3.04 (1H, dd, J1¼14.6 Hz,
J2¼5.6 Hz), 3.09e3.20 (2H, m), 3.77e3.96 (4H, m), 7.02e7.32 (9H,
m). 13C NMR (100 MHz, CDCl3):
d
¼13.64, 21.29, 41.86, 42.16, 42.34,
42.51, 43.12, 43.35, 48.09, 48.17, 62.96, 118.70, 128.51, 128.68,
128.75, 128.91, 129.62, 133.93, 134.52, 137.70, 138.71, 166.58, 207.63.
MS (ESI): m/z¼361.2 Mþ. HRMS calcd for C23H23NOþ3 Mþ 361.1678;
found 361.1675.
8. (a) Kobayashi, S. Synlett 1994, 689; (b) Iwamura, M.; Gotoh, Y.; Hashimoto, T.;
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€
ꢁ
ꢂ
9. (a) Alexakis, A.; Backvall, J.-E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev.
2008, 108, 2796; (b) Harutyunyan, S. R.; Hartog, T.; Geurts, K.; Minnaard, A. J.;
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4.2.10. Ethyl 1-cyano-2-(4-nitrophenyl)-4-oxo-6-phenylcyclohexane
carboxylate (7u). 1H NMR (400 MHz, CDCl3):
d
¼0.81 (3H, t,
J¼7.2 Hz), 2.77 (1H, dd, J1¼16.0 Hz, J2¼2.0 Hz), 2.96e3.15 (3H, m),
3.73 (2H, q, J1¼14.0 Hz, J2¼6.8 Hz), 3.96 (1H, t, J¼6 Hz), 4.03 (1H, dd,
J1¼13.6 Hz, J2¼2.0 Hz), 7.03e7.09 (2H, m), 7.21e7.27 (3H, m), 7.46
(2H, d, J¼8.4 Hz), 8.05 (2H, d, J¼8.0 Hz). 13C NMR (100 MHz, CDCl3):
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(b) Valentine, D. H.; Hillhouse, J. H. Synthesis 2003, 317; (c) Methot, J. L.;
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d
¼13.43, 41.79, 42.49, 48.17, 53.73, 55.06, 63.23, 117.99, 123.82,
128.51, 128.85, 128.92, 129.71, 136.42, 144.78, 147.67, 165.75, 205.89.
MS (ESI): m/z¼392.2 Mþ. HRMS calcd for C22H20N2Oþ5 Mþ 392.1372;
found 392.1376.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (NSFC) (grant numbers 20972076,
21172115, 21302101), the Research Fund for the Doctoral Program of
Higher Education of China (grant number 20120031110002), and
the Fundamental Research Funds for the Central Universities. We
also thank the Nankai University State Key Laboratory of Elemento-
Organic Chemistry for support.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.103
14. (a) Li, E.; Xie, P.; Yang, L.; Liang, L.; Huang, Y. Chem.dAsian J. 2013, 8, 603; (b)
Ma, J.; Xie, P.; Hu, C.; Huang, Y.; Chen, R. Chem.dEur. J. 2011, 17, 7418; (c) Hu, C.;
Geng, Z.; Ma, J.; Huang, Y.; Chen, R. Chem.dAsian J. 2012, 7, 2032.
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