Acylation of toluidines with 1,4-dimethylcyclohex-3-enecarbonyl chlorides

Full text of DOI:10.1134/S1070363213010325

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 1, pp. 150–151. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © M.A. Rustamov, N.A. Veisova, Sh.M. Eivazova, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 1, pp. 158–160.
LETTERS
TO THE EDITOR
Acylation of Toluidines
with 1,4-Dimethylcyclohex-3-enecarbonyl Chlorides
M. A. Rustamov, N. A. Veisova, and Sh. M. Eivazova
Institute of Chemical Problems, National Academy of Sciences of Azerbaijan, pr. Dzhavida 29, Baku, AZ 1143 Azerbaijan
e-mail: iradam@rambler.ru
Received June 7, 2012
DOI: 10.1134/S1070363213010325
R1
R2
Amide group is a component of various com-
pounds, which are of great practical importance.
Organic compounds containing the amide groups in
the molecule are obtained mainly by the acylation of
amines with carboxylic acids and their derivatives. In
the literature, there is enough information on the
acylation of amines with aromatic carboxylic acids [1],
their chlorides [2], esters [3], and anhydrides [4].
Among the acylating agents the carboxylic acid
chlorides are the stronger electrophilic reagents.
However, there are no published data on the acylation
of amines with carboxylic acid chlorides of the
cyclohex-3-ene series. We first investigated the acyla-
tion of amines with alicyclic carboxylic acid chlorides.
Recently, the acylation of aromatic mono- and
diamines as well as functionally substituted mono-
amines have been studied [5, 6]. Continuing research
in this area, we studied the acylation of toluidine with
cyclohex-3-enecarbonyl chloride III. 1,4-Dimethyl-
cyclohexenecarboxylic acid I was synthesized by us
via the Diels–Alder condensation of isoprene with
methacrylic acid [7]. The isomers separation was
performed by the method [8].
CH3
CH3
H2N
NH
R3
+
COCl
III
IVа−IVc
R1
R2
CH3
CO
H3C
R3
Vа−Vc
R1 = CH3, R2 = R3 = H (a); R1 = R2 = H, R2 = CH3 (b);
R1 = R2 = H, R3 = CH3 (c).
In contrast to the meta- and para-toluidine, o-
toluidine is a stronger nucleophilic substrate due to the
positive inductive effect (+I) of the methyl group in the
ortho-position with respect to the amine moiety. In this
regard, in the reaction of the acid chloride III with o-
toluidine IVa a part of the liberated HCl reacts with o-
toluidine to form the corresponding ammonium salt.
As a result, the target carboxamide compound Va is
CH3
O
CH3
C
H3C
CH3
COOH
CH3
N
H
OH
I
+
Vа
CH3
CH3
O
H
C
COOH
II
CH3
−H2O
The 1,4-dimethylcyclohex-3-enecarboxylic acid
chloride III was obtained by the reaction of the acid I
with PCl3. The reaction of the acid chloride III with
toluidine proceeds as follows.
H3C
N
H
VI
150

ACYLATION OF TOLUIDINES
151
obtained in a low yield. To prevent this disadvantage,
the starting amine IVa was taken in excess. The yield
of carboxamide Va increases to 90–93% as the
reagents ratio III:IVa equals 1:1.3.
Increasing the reaction temperature also increases
the yield of the desired product. Under the Madelung
reaction conditions the carboxamide Va undergoes the
intramolecular cyclization to form the corresponding
indole VI.
mp 75–76°C (EtOH–H2O), Rf 0.38. IR spectrum, ν,
cm–1: 3320 (N–H), 1675 (CO–NH), 1640 (С=Сcycle),
1580, 1500 (С=СAr), 870 (С=СAr).
1,4-Dimethyl-N-p-tolylcyclohex-3-enecarboxamide
(IVc) was obtained similarly in a p-xylene medium
(70 ml) from 11 g (0.064 mol) of the acid chloride III
and 6.8 g (0.064 mol) of p-toluidine. Yield 14.38 g
(92.50%), mp 95–97°C (EtOH–H2O), Rf 0.38. IR
spectrum, ν, cm–1: 3320 (N–H), 1675 (CO–NH), 1640
(С=Сcycle), 1580, 1500 (С=СAr), 870 (С=СAr).
2-(1,4-Dimethylcyclohex-3-enyl)-1H-indole (V).
A mixture of 24.3 g of carboxamide IVa, 6.07 g of
sodium n-butoxide and 80 ml of n-butanol was placed
into a three-neck flask equipped with a mechanical
stirrer, a thermometer, and a reflux condenser with a
trap. The reaction mixture was heated with stirring at a
temperature of 135–140°C for 6 h and kept overnight.
The precipitate was filtered off and washed several
times with water. Yield 19.50 g (86.70%), mp 58–59°C,
Rf 0.26. IR spectrum, ν, cm–1: 3070 (N–H), 1635
(С=Сcycle), 1580, 1490 (С=СAr), 750 (С=СAr). 1H NMR
spectrum, δ, ppm: 1.25 s (3Н, СН3), 1.65 s (3Н, = С–
СН3), 1.95–2.15 m (4Н, 2СН2), 2.50–2.60 m (2Н,
СН2), 5.48 s (1Н, =СН), 5.80 s (1Н, =СН), 7.20–7.30
m (4Н, С6Н4), 9.5 s (1Н, NH).
The structure of the obtained compounds was con-
firmed by the IR and NMR spectroscopy.
1,4(1,3)-3-Dimethylcyclohex-3-enecarboxylic acids
(III). A mixture of 258 g (3 mol) of methacrylic acid,
184 g (3 mol) of isoprene, and 200 ml of toluene was
heated in the presence of 2 g of hydroquinone for 2 h
in a rotating pressure reactor at a temperature of 180–
200°C. After the usual treatment of the reaction
mixture 452.64 g (92%) of the adduct was obtained as
a mixture of isomers, which were separated by the
known method [8] to afford 398.32 g (88%) of 1,4-
dimethylcyclohex-3-enecarboxylic acid I (mp 62–63°C)
and 54.3 g (12%) of 1,3-dimethylcyclohex-3-enecar-
boxylic acid II [mp 131.5–133°C (10 mm Hg), nD20
1.4741]. Physico-chemical constants of the obtained
acids were identical to the published data [7].
The IR spectra were recorded on a UR-20 instru-
1,4-Dimethyl-N-o-tolylcyclohex-3-enecarboxamide
(IVa). A three-neck flask equipped with a mechanical
stirrer, a reflux condenser, and a dropping funnel was
charged with 100 ml of p-xylene and 13.92 ml
(0.13 mol) of o-toluidine. Then to a mixture was added
17.25 g (0.1 mol) of 1,4-dimethylcyclohex-3-enecar-
bonyl chloride III under stirring. The temperature of
the reaction mixture rose to 55°C. After the addition of
acid chloride III the reaction mixture was heated at
125–130°C for 5 h and left overnight. The crystals
precipitated on cooling were filtered off and washed
with water. Then the obtained crystals were recrys-
tallized from aqueous ethanol. Yield 3.22 g (90.67%),
mp 70–72°C, Rf 0.34. IR spectrum, ν, cm–1: 3330 (N–H),
1670 (CO–NH), 1630 (С=Сcycle), 1600, 1520, 1480
1
ment for suspensions in liquid paraffin. The H NMR
spectra were taken on a Bruker 300 spectrometer
(300 MHz) from 5–15% solutions in CCl4, internal re-
ference HMDS. The TLC was performed on a silica
gel eluting with a petroleum ether–diethyl ether–acetic
acid system (90:10:4.5).
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medium (80 ml) from 8.60 g (0.05 mol) of 1,4-
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 1 2013