One-pot synthesis of malononitriles by free radical reactions of ylidenemalononitrile with Et3B and iodoalkane in a water-ether biphase medium

Article abstract of DOI:10.1016/j.tetlet.2006.06.061

The one-pot synthesis of malononitrile derivatives 4, 6, and 7 in moderate to high yields by the reaction of ylidenemalononitriles 3, prepared in situ from carbonyl compounds 1 and malononitrile 2 in the presence of ammonium acetate in aqueous solution at

Full text of DOI:10.1016/j.tetlet.2006.06.061

Tetrahedron Letters 47 (2006) 6133–6137
One-pot synthesis of malononitriles by free radical reactions of
ylidenemalononitrile with Et3B and iodoalkane in a water–ether
biphase medium
Zhijay Tu, Chunchi Lin, Yaochung Jang, Yeong-Jiunn Jang, Shengkai Ko, Hulin Fang,
Ju-Tsung Liu and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, No. 88, Sec. 4, Tingchow Road, Taipei 116, Taiwan, ROC
Received 30 March 2006; revised 15 May 2006; accepted 10 June 2006
Available online 10 July 2006
Abstract—The one-pot synthesis of malononitrile derivatives 4, 6, and 7 in moderate to high yields by the reaction of ylidenemalo-
nonitriles 3, prepared in situ from carbonyl compounds 1 and malononitrile 2 in the presence of ammonium acetate in aqueous
solution at 50–60 °C, with Et3B or RI 5/Et3B in a water–diethyl ether biphase medium under an atmosphere of room temperature
is reported. The reaction of Et3B with adamantyl iodides 8 and 10 under similar conditions gave 9 and 11 in high yields, respectively.
However, low yields of the monoalkylated combined with dialkylated malonates 14 were obtained when benzaldehyde 1a was con-
densed with dimethylmalonate 12 followed by parallel free radical treatment in benzene solution.
Ó 2006 Published by Elsevier Ltd.
The Knoevenagel reaction, the reaction of carbonyl
compounds with a methylene group with increased acid-
ity, as is found in malononitrile, malonic, and cyanoace-
tic esters is a special case of an aldol reaction that can be
catalyzed by weak bases. Owing to their versatile and
powerful application as organic synthons, various pro-
cedures and conditions for the preparation of ylidene-
malononitriles have been reported.1–3 Of importance is
the development of mild and environmental-friendly
strategies which have been a subject of considerable
interest.1e
the presence of a,b-unsaturated nitriles or dinitriles
affords alkylated nitriles or dinitriles.8 The above results
indicate that ylidenemalononitriles can react with a vari-
ety of organometallic reagents to yield 1,4-addition prod-
ucts by an ionic, SET, or free radical mechanism.
Carbon–carbon bond formation through a free radical
pathway has led to a variety of useful applications in or-
ganic synthesis.10 In view of the excellent characteristics
of triethylborane as a free radical initiator in aqueous
solution under aerobic conditions, we were prompted
to examine the feasibility of Et3B-mediated free radical
functionalized reactions of ylidenemalononitriles at
ambient temperature under economical and eco-friendly
conditions. Herein we report on some of our preliminary
results.
Reactions of benzylidenemalononitriles with the Grig-
nard reagent t-BuMgX4 or free radicals generated from
different precursors such as t-Bu2Hg,4 t-BuHgSiMe3,4
t-BuHgX/KI,5a,b benzoyl peroxide/Et3Al,5c Zr com-
plex,6a and from organohalides/allylic stannanes6b to
generate malononitriles have been reported. It also has
been reported that Reformatsky reagents can react with
various 1,1-dicyanoalkenes to give addition products.7
Similarly, the photoinduced hydrogen abstraction from
aliphatic hydrocarbons by triplet aromatic ketones in
When benzylidenemalononitrile 3a was reacted with
Et3B in diethyl ether solution under an argon atmo-
sphere at room temperature for 15 min, the staring
material was completely consumed and the expected
product 1-phenylpropylmalononitrile 4a was produced
in 40% yield (Eq. 1 and entry 1 of Table 1). Similarly,
4a was obtained in 56% yield when the reaction was con-
ducted under a nitrogen atmosphere (entry 2). It was
surprising to find that 4a was obtained in 71% yield
when 10 mol% dibenzoyl peroxide was added as a
*
Corresponding author. Tel./fax: +886
cheyaocf@scc.ntnu.edu.tw
2
29309092; e-mail:
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.06.061

6134
Z. Tu et al. / Tetrahedron Letters 47 (2006) 6133–6137
Table 1. Reaction of benzylidenemalononitrile 3a with Et3B in diethyl
ether solution under different atmospheres at room temperature to
generate 1-phenylpropylmalononitrile 4a
ence of ammonium acetate in aqueous solution, with
Et3B only or with RI 5/Et3B in the indicated biphase
solvent system at room temperature in the presence of
atmospheric oxygen as a free radical initiator under
one-pot conditions (Eq. 3).
Entry Atmosphere Additives
Time (min) 4aa (%)
1
2
3
4
5
6
Argon
Nitrogen
Argon
Argon
Pure oxygen
Air
—
—
15
15
15
40
56
71
25
100
100
Typical experimental procedures for the one-pot synthe-
sis of malononitriles 4, 6, and 7 are as follows.13 Benzal-
dehyde 1a (1.5 equiv) and malononitrile 2 (1.0 equiv)
were added to an aqueous solution (10 mL) containing
ammonium acetate (0.1 equiv) as a catalyst. The reac-
tion mixture was stirred at 50–60 °C (oil bath). When
the reaction started, benzylidenemalononitrile 3a was
immediately formed in the solid state. If necessary, the
solid product can be isolated on a filter (100% yield)
and all spectral data are consistent with the reported lit-
erature data.12 After 20 min, the mixture was allowed to
cool to room temperature and diethyl ether was added
to the aqueous solution to give an ether–water biphase
mixture. Triethylborane (3.0 equiv) was added to the
solution under an atmosphere of air and the mixture
was stirred for 5 min. The ether layer was separated,
washed with dilute aqueous hydrochloric acid, dried
over MgSO4, filtered, and finally evaporated to give
10% Bz2O2
50% Galvinoxyl 15
—
—
5
5
a NMR yields.
radical initiator to the mixture under an argon atmo-
sphere (entry 3). However, only a 25% yield of 4a was
observed and no 3a was recovered when 50% of galvin-
oxyl, an efficient free radical scavenger,9 was added to
the system under similar conditions (entry 4). Oxygen
is not only known to be a free radical scavenger but also
to be a free radical initiator. When the reaction was con-
ducted under an atmosphere of pure oxygen for 5 min,
4a was obtained in quantitative yield (entry 5). To our
surprise, a 100% yield of 4a was also obtained when
the reaction was conducted under an atmosphere of
air at room temperature for the same period of time (en-
try 6). Based on these results, we conclude that the reac-
tions proceed through a free radical pathway which can
be accelerated in the presence of dibenzoyl peroxide or
oxygen, and inhibited or retarded in the presence of gal-
vinoxyl. Compared to the use of dibenzoyl peroxide or
pure oxygen, the use of air to initiate the reaction is
advantageous and entails no additional cost.
1
the crude product. The crude H NMR of the crude
product indicated that it consisted of almost entirely
pure 4a. This product could be further purified by flash
column chromatography to give pure 4a (93% yield)
(Table 2, entry 1). All of the spectral data for 4a are fully
consistent with previously reported data.4,5 Similarly,
high yields of 6a and 7a were obtained when 3a was re-
acted with Et3B (3 equiv) and isopropyl iodide 5a
(20 equiv) or tert-butyl iodide 5b (6 equiv) under similar
conditions (entries 2 and 3). In addition to 1a, valeralde-
hyde 1b, and cyclohexanone 1c were also used to synthe-
size 4b,c, 6b,c, and 7b,c,14 respectively. For substrate 1b,
the generation of intermediate 3b was completed within
Ph
H
CN
CN
Ph
H
Et
CN
CN
Et2O
+
Et3B
atmosphere
3a
4a
ð1Þ
Table 2. One-pot synthesis of malononitrile derivatives 4, 6, and 7
from carbonyl compound 1, malononitrile 2, Et3B, and i-PrI 5a or
t-BuI 5b
We previously reported that different trans-b-alkylstyr-
enes can be prepared under one-pot conditions by the
reaction of trans-b-nitrostyrenes, prepared in situ from
aryl aldehydes and nitromethane in an acetic acid solu-
tion, with different radicals formed from Et3B or Et3B/
RI in a biphase medium of diethyl ether and water at
room temperature (Eq. 2).11b
Entry Substrate RI Product NMR yield Isolated yield
(%)
(%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
—
5a 6a
5b 7a
4a
100
100
93
100
100
100
88
96
97
85
95
96
96
80
75
40
—
5a 6b
5b 7b
4b
Based on literature results and our own studies,4–8,11 we
attempted to apply the above methodology to the prep-
aration of malononitriles 4, 6, and 7 by reaction of ylid-
enemalononitrile 3, which was prepared in situ from
carbonyl compounds 1 and malononitrile 2 in the pres-
—
5a 6c
5b 7c
4c
81
45
Ar
H
H
Ar
H
Et2O-H2O
Et B
HOAc-NH OAc
4
CH NO
3
+
ArCHO
2
ð2Þ
100 oC, 3 hr or
70 oC, overnight
3
Et
H
NO
2

Z. Tu et al. / Tetrahedron Letters 47 (2006) 6133–6137
6135
R2
R1
Et
CN
CN
Et3B
Et2O-H2O
R1
R2
CN
CN
H2O-NH4OAc
4
R1COR2
+
CH2(CN)2
R2
R1
R
CN
CN
RI (5)/Et3B
1
2
3
Et2O-H2O
ð3Þ
6,7
1, 3, 4
5
6
7
a; R1 = Ph, R2 = H
a; R = i-Pr
b; R = t-Bu
a; R1 = Ph, R2 = H, R= i-Pr
b; R1 = C4H9, R2 = H, R= i-Pr
c; R1 + R2 = -(CH2)5-, R= i-Pr
a; R1 = Ph, R2 = H, R= t-Bu
b; R1 = C4H9, R2 = H, R= t-Bu
c; R1 + R2 = -(CH2)5-, R= t-Bu
b; R1 = C4H9, R2 = H
c; R1 + R2 = -(CH2)5-
O
H
1. H2O-NH4OAc
CN
CN
CH2(CN)2
+
2. Et3B/iodoadamantane (8)
Et2O-H2O
ð4Þ
ð5Þ
Cl
Cl
9 (100%)
2
1d
O
O
H
1. H2O-NH4OAc
CN
CN
CH2(CN)2
+
2. Et3B/5-iodo-2-adamantanone (10)
Et2O-H2O
Cl
Cl
11 (100%)
1d
2
Ph
COOMe
benzene
RI (5)/Et3B
H
R
COOMe
COOMe
Y
CH2(COOMe)2
PhCHO
+
Ph
benzene
H
COOMe
13 (100%)
12
14
1a
ð6Þ
a1: R = Et, Y = H (trace)
a2: R = Et, Y = Et (38%)
b1: R = i-Pr, Y = H (36%)
b2: R = i-Pr, Y = i-Pr (15%)
c: R = t-Bu, Y = H (19%)
15 min and the free radical reactions were completed
within 5 min as well. However, more than 4 h were
required to generate 90% (NMR yield) of 3c with only
traces of unreacted ketone 1c remaining when substrate
1c was used. Likewise, more than 1 h was required for
completion of the free radical reactions, and the yields
of 4c,14 6c, and 7c were 88%, 81%, and 45%, respec-
tively, which are also lower than in the case where 1b
and 1c were used. On the basis of these results, we con-
clude that steric effects play an important role in these
reactions, especially in the case of 1c.
Not only the iso-propyl and tert-butyl radicals, but other
radicals which were generated from Et3B and iodo-
adamantane 8 (6 equiv) or 5-iodo-2-adamantanone 10
(4 equiv) also reacted with 4-chlorobenzylidenemalono-
nitrile 1d to yield 9 or 11 quantitatively under analogous
conditions (Eqs. 4 and 5).

6136
Z. Tu et al. / Tetrahedron Letters 47 (2006) 6133–6137
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J.-T.; Yao, C.-F. Tetrahedron Lett. 2001, 42, 6147.
12. (a) Cabello, J. A.; Campelo, J. M.; Garcia, A.; Luna, A.;
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Choudary, B. M.; Lakshmi Kantam, M.; Kavita, B.;
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Yamamoto, Y. Chem. Commun. 2002, 8, 852; (d) Ren, Z.;
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In addition to malononitrile 2, dimethylmalonate 12 was
also reacted with benzaldehyde 1a in benzene solution
with a Dean–Stark apparatus under refluxing overnight
to produce 13 which then underwent free radical reac-
tions with Et3B or RI 5/Et3B in the same solution at
room temperature to give 14. Although the yield of 13
was very high (NMR yield 100%), the yields of the free
radical product 14 were much lower as compared with
reactions using 2. Not only the monoalkylated products
14a1, 14b1, and 14c1 but also the disubstituted products
14a2 and 14b2 were isolated. In the case of ethyl radical,
the major product was the dialkylated compound 14a2
(38%), and only a trace amount of the monoalkylated
product 14a1 was observed. Both the monoalkylated
product 14b1 (36%) and the dialkylated product 14b2
(15%) were produced when isopropyl iodide was em-
ployed. Nevertheless, only a low yield of the mono-
alkylated product 14c1 (19%) was obtained when tert-
butyl radical was used. All of these results are shown
as Eq. 6.
In conclusion, we developed an easy and effective
method for preparing medium to high yields of alkyl-
ated malononitrile or dimethyl malonate derivatives
using a carbonyl compound, malononitrile or dimethyl
malonate, and triethylborane or iodoalkanes/
triethylborane in an ether–water biphase medium in
the presence of atmospheric oxygen under one-pot
conditions.
Acknowledgements
Financial support of this work by the National Science
Council of the Republic of China is gratefully
acknowledged.
13. Typical procedures: 4-chlorobenzaldehyde 1d (211 mg,
1.5 equiv), malononitrile
2
(66 mg, 1.0 mmol) and
NH4OAc (8 mg, 0.1 equiv) were added to water (10 mL).
The mixture was heated at 50–60 °C for 20 min. After
cooling to room temperature, ether (10 mL) was then
added to the mixture with stirring to form a biphase
system. 5-Iodo-2-adamantanone 11 (1104 mg, 4.0 equiv)
followed by 1 M Et3B(hex.) (3 mL, 3.0 equiv) were added to
the above solution equipped with an automatic air-
pumping apparatus. Several minutes later, the ether layer
was washed with dilute HCl(aq), dried over MgSO4, filtered
and the filtrate concentrated in vacuo to give the crude
product 11. The pure compound was obtained as a white
solid by flash column chromatography on silica gel using
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1
hexane–EA (3:1) as the eluent. Mp 171–172 °C. H NMR
(400 MHz, CDCl3): d 7.42–7.40 (d, J = 8.5 Hz, 2H), 7.32–
7.30 (m, 2H), 4.28–4.27 (d, J = 5.2 Hz, 1H), 2.95–2.93 (d,
J = 5.2 Hz, 1H), 2.58 (s, 2H), 2.23 (s, 1H), 1.96 (s, 10H).
13C NMR (100 MHz, CDCl3): d 215.5, 135.2, 132.9, 130.7,
129.2, 112.8, 112.5, 55.7, 45.7, 45.6, 41.8, 40.9, 38.8, 38.0,
37.9, 36.3, 27.5, 24.0. GC–MS (EI): m/z (%) 338 (10) [M+],
163 (39), 149 (100), 121 (39), 93 (41), 79 (31), 67 (8), 55 (8),
41 (8). IR (KBr): m (cmꢀ1) 3455, 2931 (CH stretch, vs),
2860, 2254 (CN stretch, m), 1714 (C@O stretch, vs), 1595,
1494, 1455, 1416, 1363, 1300, 1271, 1223, 1096, 1066, 1014.
14. Selected data:
Compound 4c: Colorless oil. 1H NMR (400 MHz,
CDCl3): d 3.76 (s, 1H), 1.77–1.71 (q, J = 7.5 Hz, 2H),
1.67–1.52 (m, 9H), 1.42–1.36 (m, 1H), 0.95–0.91 (t,
J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 112.0,
40.8, 32.2, 32.0, 26.6, 25.1, 21.2, 7.4. GC–MS (EI): m/z (%)
176 (trace) [M+], 175 (trace), 147 (17), 111 (100), 81 (38),

Z. Tu et al. / Tetrahedron Letters 47 (2006) 6133–6137
6137
69 (84), 55 (20), 41 (20). IR (KBr): m (cmꢀ1) 3583, 2936
(CH stretch, vs), 2863, 2252 (CN stretch, m), 1736, 1457,
1388, 1018. Compound 7b: Colorless oil. 1H NMR
(400 MHz, CDCl3): d 3.94–3.93 (d, J = 1.7 Hz, 1H),
1.82–1.73 (m, 2H), 1.69–1.57 (m, 2H), 1.48–1.36 (m,
3H), 1.02 (s, 9H), 0.98–0.94 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 114.0, 112.5, 50.8, 34.4, 30.9, 28.2,
27.5, 23.0, 22.7, 13.7. GC–MS (EI): m/z (%) 192 (trace)
[M+], 191 (trace), 177 (8), 135 (6), 108 (3), 69 (4), 57 (100),
41 (19). IR (KBr): m (cmꢀ1) 3583, 2962 (CH stretch, vs),
2875, 2253 (CN stretch, m), 1729, 1469, 1404, 1374, 1227,
1113.