Regioselective alkylation of isopropylidene- and cyclohexylidenepropanedinitrile with phenacyl bromides

Article abstract of DOI:10.1134/S1070428015120040

Alkylation of isopropylidene- and cyclohexylidenepropanedinitrile with phenacyl bromides gave 2,2-bis(2-aryl-2-oxoethyl)propanedinitriles. Direct alkylation of propanedinitrile with phenacyl bromides afforded only 2-(2-aryl-2-oxoethyl)propanedinitriles.

Full text of DOI:10.1134/S1070428015120040

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 12, pp. 1693–1696. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.D. Dyachenko, A.N. Pavlova, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 12, pp. 1728–1731.
Regioselective Alkylation of Isopropylidene-
and Cyclohexylidenepropanedinitrile with Phenacyl Bromides
V. D. Dyachenko and A. N. Pavlova
Taras Shevchenko Lugansk University, ul.Oboronnaya 2, Lugansk, 91011 Ukraine
e-mail: dyachvd@mail.ru
Received March 21, 2015
Abstract—Alkylation of isopropylidene- and cyclohexylidenepropanedinitrile with phenacyl bromides gave
2,2-bis(2-aryl-2-oxoethyl)propanedinitriles. Direct alkylation of propanedinitrile with phenacyl bromides
afforded only 2-(2-aryl-2-oxoethyl)propanedinitriles.
DOI: 10.1134/S1070428015120040
Cycloalkylidene- and isopropylidenepropanedini-
triles are known to act as Michael acceptors, and this
property was utilized in the synthesis of spiropyrans
[1, 2] and dihydro- [3–5] and tetrahydropyridines
[6, 7]. These compounds are also capable of under-
going dimerization in the presence of bases according
to a Michael type reaction [8, 9], which suggests that
they can also act as electron pair donors due to acidity
of proton on the α-carbon atom with respect to the
double bond.
N-(4-bromophenyl)-2-chloroacetamide (5) in DMF in
the presence of aqueous potassium hydroxide. As
a result, we isolated substituted propanedinitriles 6a
and 6b and N-(4-bromophenyl)-3,3-dicyano-3-(cyclo-
hex-1-en-1-yl)propanamide (7) (Schemes 1, 2).
A plausible reaction path includes deprotonation of
1 to carbanion A which may be represented by canon-
ical structure B. Regioselective alkylation of the latter
at the C2 atom of the propanedinitrile fragment gives
intermediate C whose alkaline hydrolysis leads to
carbanion D. The subsequent alkylation of D with the
second phenacyl bromide molecule yields final product
6. Compounds 6a and 6b were also formed as the only
products when the initial reactants 1–3 and 4 were
Taking into account that the behavior of ylidene-
propanedinitriles 1–3 as electron pair donors has been
poorly studied, we were the first to examine their
alkylation with phenacyl bromides 4a and 4b and
Scheme 1.
CN
H
H
N
N
KOH, DMF
CN
Cl
+
CN
NC
O
O
Br
Br
1
5
7
CN
CN
CN
O
BrCH2C(O)Ar (4a, 4b)
KOH
1
CN
CN
Ar
–H2O
CN
A
B
C
CN
O
O
CN
O
KOH
4a, 4b
O
NC
Ar
Ar
Ar
CN
6a, 6b
–
D
Ar = Ph (a), 4-ClC6H4 (b).
1693

DYACHENKO, PAVLOVA
1694
Scheme 2.
CN
CN
O
CN
O
4a, 4b, KOH
4a, 4b, KOH
Me
Ph
CN
CN
Ar
Ar
CN
6a, 6b
Me
Me
2
3
Ar = Ph (a), 4-ClC6H4 (b).
taken at a ratio of 1:1, but the best yields of 6 were
obtained at a 1–3-to-4 ratio of 1:2. Thus, the second
alkylation step is so fast that intermediate monoalkyl
derivative C cannot be isolated. In contrast, the reac-
tion of 1 with N-(4-bromophenyl)-2-chloroacetamide
(5) afforded only the monoalkylation product, propan-
amide 7. This result may be rationalized by reduced
reactivity of chloroacetamides as alkylating agents
compared to α-bromo ketones.
afforded only previously reported [10, 11] monoalkyla-
tion products 9a and 9b, regardless of the reactant ratio
(Scheme 3).
By alkylation of CH acid 10a [12] with 2 equiv of
4-chlorophenacyl bromide 4b we obtained substituted
butanenitrile 11, whereas cyclohexylideneacetonitrile
10b reacted with an equimolar amount of 4a or 4b in
DMF/KOH to give the corresponding monoalkyl
derivative, 4-aryl-4-oxo-2-[4-(4-nitrophenyl-1,3-
thiazol-2-yl)]-2-(cyclohex-1-en-1-yl)butanenitrile 12a
or 12b (Scheme 4).
Scheme 3.
O
CN
4a, 4c, KOH
Substituted ethyl acrylates 13–15 were readily
alkylated with phenacyl bromides 4a and 4b under
analogous conditions with formation of ethyl cyano-
acetates 16a and 16b; the highest yield of 16a and 16b
was achieved with the use of 2 equiv of 4 (Scheme 5).
Presumably, the reaction path is similar to that leading
to compounds 6.
NC
CN
Ar
CN
8
9a, 9b
4, Ar = Ph (a), 4-BrC6H4 (c); 9, Ar = Ph (a), 4-BrC6H4 (b).
Under analogous conditions, direct alkylation of
propanedinitrile 8 with phenacyl bromides 4a and 4c
Scheme 4.
CN
O
O
CN
O
CN
Ar
4a, 4b, KOH
4b, KOH
N
N
S
Ar
N
S
S
Cl
Cl
Ph
NO2
12a, 12b
10a, 10b
11
10, Ar = Ph (a), 4-O2NC6H4 (b); 12, Ar = Ph (a), 4-ClC6H4 (b).
Scheme 5.
CN
COOEt
CN
O
CN
O
4a, 4b, KOH
4a, 4b, KOH
Ph
13
COOEt
Ar
Ar
COOEt
16a, 16b
CN
Me
Me
15
COOEt
Me
14
16, Ar = Ph (a), 4-ClC6H4 (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

REGIOSELECTIVE ALKYLATION OF ISOPROPYLIDENE- ...
1695
The structure of the isolated compounds was con-
firmed by spectral data. Their IR spectra contained
absorption bands at 2235–2252 and 1666–1711 cm–1
due to stretching vibrations of the cyano and carbonyl
groups, respectively. In the 13C NMR spectra we
observed signals from all carbon atoms present in their
molecules. Compounds 7, 11, 12a, 16a, and 16b
Mass spectrum: m/z 301 (Irel 100%) [M – 1]+. Found,
%: C 75.33; H 4.55; N 9.16. C19H14N2O2. Calculated,
%: C 75.48; H 4.67; N 9.27. M 302.336.
2,2-Bis[2-(4-chlorophenyl)-2-oxoethyl]propane-
dinitrile (6b). Yield 76 (from 1), 81 (from 2), 84%
(from 3); colorless powder, mp 250‒252°C (from
AcOH). IR spectrum, ν, cm–1: 2251 (C≡N), 1698
1
1
displayed in the H NMR spectra nonequivalence of
(C=O). H NMR spectrum, δ, ppm: 4.22 s (4H, CH2),
methylene protons in the CH2CO fragment (2J = 16.8‒
18.2 Hz), indicating restricted rotation of the ArCOCH2
substituent about the single carbon–carbon bond.
7.59 t (4H, Harom, J = 8.6 Hz), 8.04 d (4H, Harom, J =
8.6 Hz). Mass spectrum: m/z 370 (Irel 100%) [M – 1]+.
Found, %: C 61.32; H 3.14; N 7.40. C19H12Cl2N2O2.
Calculated, %: C 61.48; H 3.26; N 7.55. M 371.226.
EXPERIMENTAL
N-(4-Bromophenyl)-3,3-dicyano-3-(cyclohex-1-
en-1-yl)propanamide (7). Yield 2.72 g (76%), color-
less powder, mp 142–143°C (from EtOH). IR spec-
trum, ν, cm–1: 3313 (NH), 2246 (C≡N), 1666 (C=O).
1H NMR spectrum, δ, ppm: 1.34–1.65 m (4H, CH2),
1.76‒2.19 m (4H, CH2), 3.14 d and 3.48 d (1H each,
The IR spectra were recorded in KBr on a Perkin
1
Elmer Spectrum One spectrometer. The H and 13C
NMR spectra were measured on a Varian-400 instru-
ment at 400.13 and 100 MHz, respectively, from
solutions in DMSO-d6 containing tetramethylsilane as
internal standard. The mass spectra were obtained on
an Agilent 1100 LC/MSD SL instrument; samples
were introduced in a CF3COOH matrix. The elemental
compositions were determined on a Perkin Elmer CHN
analyzer. The melting points were measured on
a Kofler hot stage. The progress of reactions was
monitored, and the purity of the isolated compounds
was checked, by TLC on Silufol UV-254 plates using
acetone–hexane (3:5) as eluent; spots were visualized
under UV light or by treatment with iodine vapor.
2
CH2CO, J = 16.8 Hz), 6.10 br.s (1H, =CH), 7.28 d
(2H, Harom, J = 7.1 Hz), 7.70 d (2H, Harom, J = 7.1 Hz),
9.27 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
22.11, 22.19, 22.02, 22.10, 23.27, 24.74, 47.94, 48.69,
126.86, 131.35 (2C), 132.25 (2C), 133.00, 158.37,
161.22, 171.64. Mass spectrum: m/z 357 (Irel 100%)
[M – 1]+. Found, %: C 56.91; H 4.42; N 11.60.
C17H16BrN3O. Calculated, %: C 57.00; H 4.50;
N 11.73. M 358.241.
2-(2-Oxo-2-phenylethyl)propanedinitrile (9a).
Yield 1.45 g (79%), colorless powder, mp 148‒149°C
(from EtOH). IR spectrum, ν, cm–1: 2252 (C≡N), 1711
Typical procedure for the alkylation of CH acids
1‒3, 8, 10a, 10b, and 13‒15. To a solution of 10 mmol
of CH acid 1‒3, 8, 10a, 10b, or 13‒15 in 20 ml of
DMF we added under stirring at 20°C 5.6 mL
(10 mmol) of 10% aqueous potassium hydroxide and
then 10 mmol of alkylating agent 4a‒4c or 5. The
mixture was stirred for 2 h and diluted with an equal
volume of water, and the precipitate was filtered off
and washed with water, ethanol, and hexane. In the
synthesis of 6a, 6b, 11, 16a, and 16b, 11.2 mL
(20 mmol) of 10% aqueous potassium hydroxide and
20 mmol of phenacyl bromide 4a or 4b were used.
1
(C=O). H NMR spectrum, δ, ppm: 3.99 d (2H, CH2,
J = 6.0 Hz), 5.01 t (1H, CHCN, J = 6.0 Hz), 7.54 t
(2H, Harom, J = 7.5 Hz), 7.67 t (1H, Harom, J = 7.5 Hz),
8.00 d (2H, Harom, J = 7.6 Hz). Mass spectrum: m/z 183
(Irel 100%) [M – 1]+. Found, %: C 71.62; H 4.29;
N 15.14. C11H8N2O. Calculated, %: C 71.73; H 4.38; N
15.21. M 181.199.
2-[2-(4-Bromophenyl)-2-oxoethyl]propanedi-
nitrile (9b). Yield 2.16 g (82%), colorless powder,
mp 99‒100°C (from EtOH). IR spectrum, ν, cm–1:
1
2249 (C≡N), 1698 (C=O). H NMR spectrum, δ, ppm:
2,2-Bis(2-oxo-2-phenylethyl)propanedinitrile
(6a) was synthesized from CH acid 1, 2, or 3 and
phenacyl bromide (4a). Yield 78, 80, and 74%, respec-
tively; yellow powder, mp 203‒205°C (from EtOH).
IR spectrum, ν, cm–1: 2248 (C≡N), 1693 (C=O).
1H NMR spectrum, δ, ppm: 4.23 s (4H, CH2), 7.57 t
(4H, Harom, J = 7.6 Hz), 7.68 t (2H, Harom, J = 7.6 Hz),
8.02 d (4H, Harom, J = 7.8 Hz). 13C NMR spectrum, δC,
ppm: 28.85, 44.55 (2C), 116.30 (2C), 128.54 (4C),
129.50 (4C), 134.82 (2C), 135.39 (2C), 194.40 (2C).
3.98 d (2H, CH2, J = 6.1 Hz), 5.01 t (1H, CHCN, J =
6.1 Hz), 7.71 d (2H, Harom, J = 7.6 Hz), 7.93 d (2H,
H
arom, J = 7.6 Hz). Mass spectrum: m/z 262 (Irel 100%)
[M – 1]+. Found, %: C 50.14; H 2.55; N 10.58.
C11H7BrN2O. Calculated, %: C 50.22; H 2.68; N 10.65.
M 263.095.
4-(4-Chlorophenyl)-2-[2-(4-chlorophenyl)-2-oxo-
ethyl]-4-oxo-2-(4-phenyl-1,3-thiazol-2-yl)butane-
nitrile (11). Yield 2.5 g (70%), colorless powder,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015

DYACHENKO, PAVLOVA
1696
mp 255‒257°C (from BuOH). IR spectrum, ν, cm–1:
18.2 Hz), 4.22 q (2H, OCH2, J = 7.0 Hz), 7.54 t (4H,
Ph, J = 7.6 Hz), 7.66 t (2H, Ph, J = 7.2 Hz), 7.99 d
(4H, Ph, J = 7.6 Hz). 13C NMR spectrum, δC, ppm:
14.16, 41.91, 44.35 (2C), 62.88, 119.18, 128.55 (4C),
129.35 (4C), 134.47 (2C), 135.89 (2C), 168.57, 195.75
(2C). Mass spectrum: m/z 348 (Irel 100%) [M – 1]+.
Found, %: C 72.01; H 5.30; N 3.95. C21H19NO4. Cal-
culated, %: C 72.19; H 5.48; N 4.01. M 349.390.
1
2245 (C≡N), 1691 (C=O). H NMR spectrum, δ, ppm:
2
4.19 d and 4.33 d (2H each, CH2CO, J = 18.2 Hz),
7.30 t (1H, Ph, J = 7.2 Hz), 7.34 t (2H, Ph, J = 7.5 Hz),
7.60 d (4H, Harom, J = 8.2 Hz), 7.73 d (2H, Ph, J =
7.5 Hz), 7.99 d (4H, Harom, J = 8.2 Hz), 8.09 s (1H,
5′-H). 13C NMR spectrum, δC, ppm: 46.46 (2C), 50.11,
115.53, 118.14, 121.02, 125.98 (2C), 128.26 (2C),
128.73 (2C), 129.03 (2C), 130.06 (2C), 133.61 (2C),
134.59, 138.84, 147.12, 153.50, 160.11, 167.67,
182.08, 194.40 (2C). Mass spectrum, m/z 504
(Irel 100%) [M – 1]+. Found, %: C 64.02; H 3.44;
N 5.47. C27H18Cl2N2O2S. Calculated, %: C 64.16;
H 3.59; N 5.54. M 505.426.
Ethyl 4-(4-chlorophenyl)-2-[2-(4-chlorophenyl)-
2-oxoethyl]-2-cyano 4-oxobutanoate (16b). Yield
2.93 g (70%, from 13), colorless powder, mp 148‒
150°C (from EtOH). IR spectrum, ν, cm–1: 2249 (C≡N);
1
1705, 1694 (C=O). H NMR spectrum, δ, ppm: 1.19 t
(3H, Me, J = 6.8 Hz), 3.89 d and 4.01 d (2H each,
CH2CO, 2J = 18.2 Hz), 4.18 q (2H, OCH2, J = 6.8 Hz),
7.64 d (4H, Harom, J = 8.2 Hz), 8.10 d (4H, Harom, J =
8.2 Hz). Mass spectrum: m/z 417 (Irel 100%) [M – 1]+.
Found, %: C 60.18; H 3.96; N 3.22. C21H17Cl2NO4.
Calculated, %: C 60.30; H 4.10; N 3.35. M 418.280.
2-(Cyclohex-1-en-1-yl)-2-[4-(4-nitrophenyl)-1,3-
thiazol-2-yl]-4-oxo-4-phenylbutanenitrile (12a).
Yield 3.23 g (73%), colorless powder, mp 160‒162°C
(from BuOH). IR spectrum, ν, cm–1: 2235 (C≡N), 1689
1
(C=O). H NMR spectrum, δ, ppm: 1.51‒1.72 m (4H,
CH2), 1.96‒2.22 m (4H, CH2), 4.05 d and 4.40 d
(1H each, CH2CO, 2J = 18.2 Hz), 6.11 br.s (1H, =CH),
7.54 t (2H, Ph, J = 7.5 Hz), 7.65 t (1H, Ph, J = 7.1 Hz),
8.03 d (2H, Ph, J = 7.5 Hz), 8.10 d (2H, Harom, J =
8.3 Hz), 8.19 d (2H, Harom, J = 8.3 Hz), 8.46 s (1H,
5′-H). 13C NMR spectrum, δC, ppm: 21.19, 22.03,
24.18, 24.31, 37.22, 44.18, 46.02, 48.11, 121.02 (2C),
124.11 (2C), 127.15, 128.02 (2C), 128.93 (2C), 129.18
(2C), 133.18, 134.01, 140.00, 146.95, 168.30. Mass
spectrum: m/z 442 (Irel 100%) [M – 1]+. Found, %:
C 67.60; H 4.35; N 9.32. C25H21N3O3S. Calculated, %:
C 67.70; H 4.47; N 9.47. M 443.528.
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colorless crystals, mp 134‒136°C (from EtOH). IR
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015