154 JOURNAL OF CHEMICAL RESEARCH 2018
NaBH4
SOCl2
O
OH
Cl
1
2
3
KOH/EtOH
AgCN
CONH2
CN
CYT
4
Scheme 1
order to remove traces of water as a benzene–water azeotrope
(cloudy distillate). After 10 mL had been collected, the distillate
was clear and the homogeneous mixture was cooled to room
temperature, resulting in deposition of some crystalline alcohol.
Redistilled thionyl chloride (6.5 g, 1.1 equiv.) was added portion-
wise to the stirred mixture during 0.25 h, after which time all of
the solid alcohol had disappeared, despite there being little heat of
reaction. The mixture was heated to reflux for 0.5 h and then set
for distillation. A distillate of 60 mL was collected and then the
cooled mixture was evaporated in vacuo at 40 °C to remove all of
the volatile components (which were collected in a trap immersed
in a dry-ice bath). The pinkish solid residue of the chloro compound
(3) 11.34 g (100%) was used at once in the next step of the synthesis.
In an earlier run, a sample recrystallised from CCl4 had a m.p. in
the range 123–124 °C [lit.4 123–125 °C]; 1H NMR (CDCl3): δ (ppm)
6.89 (s, 5H), 7.18 (s, 10(11)H2), 7.39–7.49 (m, ArH6), 7.68 (sbr,
ArH2); 13C NMR (CDCl3): δ (ppm) 67.9 (CHCl), 128.4, 128.6, 128.7,
130.6, 131.6, 134.7, 136.9.
traces of water. The synthesis was therefore continued with
the unpurified compound. The indications were that it had
been produced in essentially quantitative yield, and, using a
1994 recipe,6 it was treated with CuCN in toluene (rather than
AgCN in benzene3) and refluxed for 2 h. This generated the
corresponding nitrile, which was purified by recrystallisation
to give an 84% yield. For the conversion of the nitrile (3) to
cytenamide (CYT), the original 1964 hydrolysis conditions
(KOH/EtOH)3 were employed; again purification was effected
by recrystallisation to give a 76% yield.
In this way, 58 g of cytenamide (CYT) was prepared, in
several batches, for deployment in an automated polymorph
screen. This process yielded seven polymorphs of cytenamide,
and a report of the structures of two of them, CYT I and CYT
II, which exhibit the same two-dimensional similarity that
exists between two analogous structures of carbamazepine
(CBZ), appeared as a short communication.1 In addition, the
crystal structures of five solvates of cytenamide (CYT) with
acetic acid,7 trifluoroacetic acid,8 butyric acid,9 dioxane10 and
formic acid11 have been published online.
5H-5-Cyanodibenzo[a,d]cycloheptene (4)
Dry toluene (110 mL) and CuCN (67.2 g, 75 mmol) were added to
solid 5H-5-chlorodibenzo[a,d]cycloheptene (3) (11.34 g, 50 mmol)
and the mixture was refluxed for 2 h. The mixture was filtered
while hot through a pad of Celite, and the pale yellow filtrate was
evaporated in vacuo to yield the crude nitrile as an off-white solid
(10.53 g). Recrystallisation from ethanol gave the nitrile (4): White
crystals; yield 9.10 g (84%); m.p. 96–98 °C [lit.3 99–100 °C]; IR
(νmax/cm−1): 2243 (C≡N); 1H NMR (CDCl3): δ (ppm) 4.76 (s, 5H),
5.01 (brs, NH), 5.93 (brs, NH), 7.16 (s, 1H2), 7.33–7.47 (m, ArH6),
7.71 (sbr, ArH2); 13C NMR (CDCl3): δ (ppm) 41.1 (CHCN), 118.3,
125.6, 127.8, 128.6, 129.2, 131.3, 132.4, 133.9.
Experimental
Solvents (which were redistilled before use), reagents and
dibenzosuberenone (1) were obtained from Sigma-Aldrich, Dorset,
UK. Petroleum ether had a b.p. of 60–80 °C. IR spectra were obtained
on a Shimadzu 8700 spectrometer. NMR spectra were obtained on a
Bruker AMX 300 spectrometer (1H NMR at 300 MHz, 13C NMR
at 75 MHz) in CDCl3 using TMS as internal standard. Chemical
shifts (δ) are given in parts per million (ppm) and coupling constants
(J) are given in hertz (Hz). Reactions were monitored by thin layer
chromatography (TLC) using 0.25 mm pre-coated silica gel UV-
sensitive plates (Merck) and developing solvents of EtAc/petroleum
ether (1:4; v/v) or EtOH/toluene (1:4; v/v).
5H-Dibenzo[a,d]cycloheptene-5-carboxamide
(CYT)
(cytenamide)
A solution of 5H-5-cyano-dibenz[a,d]cycloheptene (4) (8.70 g,
40 mmol) and KOH (24 g) in ethanol (400 mL) was refluxed (16
h). The solvent was removed in vacuo at 40 °C, water was added
and the precipitate collected and dried. Recrystallisation from ethyl
acetate, after decolourisation with charcoal, yielded cytenamide
(CYT): White crystals; yield 7.16 g (76%); m.p. 217–219 °C [lit.3
217–219 °C]; 1H NMR: δ (ppm) 4.81 (s, 5H), 6.98 (s, 10(11)H2),
7.24–7.39 (m, ArH8); 13C NMR (CDCl3): δ (ppm) 59.5 (CHC=O),
127.5, 128.9, 129.3, 130.0, 130.9, 134.4, 136.7, 173.6 (C=O).
5H-Dibenzo[a,d]cyclohepten-5-ol (2)
Dibenzosuberenone (5H-dibenzo[a,d]cyclohepten-5-one) (1) (12.37 g,
60 mmol) would only partly dissolve in MeOH (200 mL) at room
temperature, but upon treatment with sodium borohydride (1.70 g,
3 equiv.) and manual swirling, the mixture warmed up to give a
homogeneous solution within 0.25 h. After 1 h, acetone (4 mL) was
added to destroy the excess borohydride. Most of the solvent was then
evaporated off under suction and water (100 mL) was then added to
the residue (30 mL). The precipitate so formed was isolated, dried and
recrystallised from petroleum ether–CH2Cl2 to yield the alcohol (2):
yield 10.5 g (84%); m.p. 120–122 °C [lit.4 120 °C]; 1H NMR (CDCl3):
δ (ppm) 2.62 (brs, OH), 5.38 (s, 5H), 7.11 (s, 10(11)H2), 7.26–7.46
(m, ArH6), 7.67 (d, ArH2); 13C NMR (CDCl3): δ (ppm) 74.6 (CHOH),
124.8, 126.8, 128.6, 128.7, 130.9, 132.6, 140.6.
Received 10 March 2018; accepted 20 March 2018
Paper 1805309
Published online: 28 March 2018
References
5H-5-Chlorodibenzo[a,d]cycloheptene (3)
1
A.J. Florence, C.T. Bedford, F.B.A. Fabbiani, K. Shankland, T. Gelbrich,
M.B. Hursthouse, N. Shankland, A. Johnston and P. Fernandes,
CrystEngComm, 2008, 10, 811.
Dry benzene (100 mL) was added to 5H-dibenzo[a,d]cyclohepten-
5-ol (2) (10.41 g, 50 mmol) and the suspension was boiled in