Synthesis of 3-(4-chlorophenyl)oxirane-2,2-dicarboxamide

Article abstract of DOI:10.1007/s11172-007-0225-7

Oxidation of (E)-3-(4-chlorophenyl)-2-cyanoprop-2-enethioamide with hydrogen peroxide or the H₂O₂-KOH system gave 3-(4-chlorophenyl)oxirane-2,2-dicarboxamide. This compound was also obtained by an independent "one pot" synthesis from

Full text of DOI:10.1007/s11172-007-0225-7

Russian Chemical Bulletin, International Edition, Vol. 56, No. 7, pp. 1470—1473, July, 2007
1470
Synthesis of 3ꢀ(4ꢀchlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide
V. V. Dotsenko,aꢀ S. G. Krivokolysko,a E. B. Rusanov,b A. V. Gutov,b and V. P. Litvinovc†
aChemEx Laboratory, V. Dal´ EastꢀUkrainian National University,
20a Molodyozhny kv., 91034 Lugansk, Ukraine.
Fax: + 380 (0642) 41 9151. Eꢀmail: ksg@lep.lg.ua
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine,
5 ul. Murmanskaya, 02094 Kiev, Ukraine.
Fax: + 380 (044) 573 2643. Eꢀmail: iochkiev@ukrpack.net
cN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 8837
Oxidation of (E)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ2ꢀcyanopropꢀ2ꢀenethioamide with hydrogen perꢀ
oxide or the H2O2—KOH system gave 3ꢀ(4ꢀchlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide. This
compound was also obtained by an independent "one pot" synthesis from pꢀchlorobenzaldehyde
and 2ꢀcyanoacetamide through in situ oxidation of their adduct (E)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ
cyanopropꢀ2ꢀeneamide with the H2O2—KOH system. The structure of 3ꢀ(4ꢀchloropheꢀ
nyl)oxiraneꢀ2,2ꢀdicarboxamide was confirmed by Xꢀray diffraction and spectroscopic data.
Key words: arylmethylidene(cyano)thioacetamides, oxidation, the Radziszewski reaction,
3ꢀ(4ꢀchlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide, Xꢀray diffraction analysis.
It is known that oxidation of thioamides gives, deꢀ
pending on the structures of the substrate and the oxiꢀ
dant, the corresponding amides,1,2 benzothiazole1,3
or thiadiazole derivatives,4 nitriles,1,5 and thioamide
Sꢀoxides.6 Proceeding further in our investigations of the
chemistry of cyanothioacetamide,7 we studied peroxidaꢀ
tion of arylmethylidene(cyano)thioacetamides. These
easily accessible compounds are of interest because of the
presence of several oxidizable fragments: the thioamide
group, the cyano group, and the activated double bond.
In addition, the vicinity of the cyano and thioamide groups
allows oxidative closure of an isothiazole ring, which has
been illustrated8,9 with a number of cyclic cyanothioacetꢀ
amide derivatives, 3ꢀcyanopyridineꢀ2(1H )ꢀthiones, as exꢀ
amples.
We found that oxidation of (E)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ
2ꢀcyanopropꢀ2ꢀenethioamide (1) with an excess of
30% H2O2 in hot EtOH both in the presence (method A)
and in the absence of an alkali (method B) is a nonꢀ
regioselective process that involves both the functional
groups and the double bond and leads to earlier unꢀ
known 3ꢀ(4ꢀchlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide (2)
(Scheme 1). The structure of compound 2 was confirmed
by Xꢀray diffraction and spectroscopic data and an indeꢀ
pendent synthesis from (E)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ2ꢀcyanoꢀ
acrylamide (3). For the latter reaction, we developed a
convenient "one pot" synthesis via the Knoevenagel conꢀ
densation of aldehyde 4 with 2ꢀcyanoacetamide (5) folꢀ
lowed by the in situ Radziszewski oxidation10,11 of the
resulting cyanoacrylamide 3 (method C) (see Scheme 1).
It should be noted that methods A and B provide comꢀ
parable results (the yields of compound 2 are low
(23—29%)), while method C is simpler and more efficient.
1
The H NMR spectrum of diamide 2 shows a singlet
at δ 4.27 for the sole proton of the oxirane ring, which
is characteristic of the oxirane protons in 2,3ꢀepoxy
dicarboxylic acid derivatives: 2ꢀalkoxycarbonylꢀ2ꢀ
cyanooxiranes (δ 4.11—4.50)12 and 2,2ꢀdicyanooxiranes
(δ 4.48—5.20).12—14 At the same time, the signal for
the olefinic proton in the starting thioamide 1 appears
at δ 8.10.15 In addition, the spectrum of compound 2
contains a quadruplet for the protons of the aryl substituꢀ
ent and two broadened singlets for the protons of the
diastereotopic carbamoyl groups. The IR spectrum of
compound 2 shows no absorption bands due to the cyano
group but contains bands at 3450, 3370, and 3150 cm–1
(NH2 stretching vibrations) and a broadened band at
1675 cm–1 (C=O).
Xꢀray diffraction analysis unambiguously proved the
structure of compound 2, which crystallizes in a cenꢀ
trosymmetric space group. The general view of its molꢀ
ecule is shown in Fig. 1 (for selected geometrical paramꢀ
eters, see the figure caption). The angle between the planes
of the phenyl and oxirane rings is 121.2°; the carbamoyl
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1417—1419, July, 2007.
1066ꢀ5285/07/5607ꢀ1470 © 2007 Springer Science+Business Media, Inc.

3ꢀ(4ꢀChlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1471
Scheme 1
B is morpholine
Table 1. Selected geometrical parameters of the hydrogen bonds
in the crystal of compound 2
C(2)
C(3)
C(4)
O(3)
D—H...A
d/Å
D—H—A angle
/deg
C(7)
Cl(1)
C(10)
N(2)
O(2)
D—H
H...A
D...A
C(1)
O(1)
C(8)
N(1)—H(3)...O(1)#1 0.94(3) 2.16(3) 2.952(2)
N(1)—H(9)...O(2)#2 0.92(3) 1.98(3) 2.896(3)
N(2)—H(5)...O(3)#3 0.86(3) 2.11(3) 2.934(3)
N(2)—H(6)...O(2)#4 0.86(3) 2.43(3) 3.031(3)
141(2)
171(3)
161(3)
127(2)
C(5)
C(6)
C(9)
N(1)
Note. The symmetry operation codes for generation of equivaꢀ
#1
#2
lent atoms are –x – 1/2, y – 1/2, z; –x + 1/2, y – 1/2, z;
#3 –x, –y + 1, –z + 1; and #4 x + 1/2, –y + 1/2, –z + 1.
Fig. 1. General view of structure 2. Selected bond lengths:
C(7)—C(8) 1.483(3) Å, C(7)—O(1) 1.445(2) Å, C(8)—O(1)
1.439(2) Å, C(8)—C(9) 1.501(3) Å, C(8)—C(10) 1.524(3) Å,
C(9)—N(1) 1.312(3) Å, and C(10)—N(2) 1.320(3) Å; and bond
angles: O(1)—C(7)—C(8) 58.9(1)°, O(1)—C(8)—C(7) 59.2(1)°,
and C(8)—O(1)—C(7) 61.9(1)°.
inhibitors.18 The reactions described in the present work
and the properties of the products will be a subject of our
future investigations.
Experimental
C(9)N(1)O(2) and C(10)N(2)O(3) groups make angles of
120.6° and 83.4°, respectively, with the oxirane ring.
The C(9)—N(1) (1.312(3) Å) and C(10)—N(2) bonds
(1.320(3) Å) are substantially shorter than a standard single
C—N bond (1.45 Å) because of strong conjugation of the
lone electron pairs of the N atoms with the πꢀsystems of
the carbonyl groups. In the crystal, a branched system of
NH...O hydrogen bonds was detected; their selected paꢀ
rameters are given in Table 1.
In conclusion, it should be noted that 2,3ꢀepoxy
amides show antiinflammatory and hypotensive effects,16
inhibit calciumꢀactivated neutral thiol protease,17 and can
act as tranquillizers, antibiotics, and peptide hydrolase
1
H NMR spectra were recorded on a Varian Gemini 200
instrument (200 MHz) in DMSOꢀd6 with Me4Si as the internal
standard. IR spectra were recorded on an IKSꢀ29 spectrophoꢀ
tometer (in Nujol). Elemental analysis was carried out on a
Perkin—Elmer C,H,NꢀAnalyser instrument. The purity of the
compounds obtained was checked by TLC on Silufol UV 254
plates in acetone—heptane (1 : 1). Spots were visualized in
the iodine vapor or under UV light. Melting points were deꢀ
termined on a Kofler hot stage and are given uncorrected.
(E)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ2ꢀcyanopropꢀ2ꢀenethioamide (1) was
prepared according to a known procedure.15
3ꢀ(4ꢀChlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide
Method A. 35% Hydrogen peroxide (d = 1.1 g cm–3; 4 mL,
(2).

1472
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Dotsenko et al.
45 mmol) was added at 0 °C to a suspension of thioamide 1 (1 g,
4.5 mmol) in EtOH (5 mL). Then 10% KOH (2.5 mL, 4.5 mmol)
was added dropwise with cooling and stirring. The observed
exothermic reaction was accompanied by dissolution of thioꢀ
amide 1 and evolution of oxygen. After the reaction was comꢀ
pleted, the mixture was filtered through a paper filter and kept at
~20 °C for several days. The colorless crystalline precipitate that
formed was filtered off, washed with EtOH, and recrystalꢀ
lized from EtOH—Me2CO (1 : 1). The yield was 29%, m.p.
225—227 °C. The crystals obtained were used for Xꢀray difꢀ
fraction analysis. Found (%): C, 50.29; H, 3.76; N, 11.60.
C10H9ClN2O3. Calculated (%): C, 49.91; H, 3.77; N, 11.64. IR,
and refined isotropically. At the final step of refinement, an
isotropic extinction correction was applied (extinction coeffiꢀ
cient 0.0026(3)). Final residuals were R1(F 2) = 0.0393 and
Rw(F 2) = 0.1081, GOF = 1.035 for reflections with I > 2σ(I )
and R1(F ) = 0.0477 and Rw(F 2) = 0.1144, GOF = 1.035 for all
reflections. The residual electron densities in the final refineꢀ
ment cycle were 0.20 and –0.26 e Å–3. Comprehensive Xꢀray
diffraction data for compound 2 have been deposited with the
Cambridge Crystallographic Data Center (CCDC 605743).
References
1
ν/cm–1: 3450, 3370, 3150 (2 NH2); 1675 (C=O). H NMR, δ:
4.27 (s, 1 H, CH, oxirane); 7.36 (q, 4 H, 4ꢀClC6H4, 2J = 8.5 Hz);
7.40, 7.58 (both br.s, 2 H each, 2 C(O)NH2).
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Method B. 35% Hydrogen peroxide (2 mL, 2.26 mmol) was
added to a suspension of thioamide 1 (0.5 g, 2.25 mmol) in
EtOH (5 mL) and the mixture was brought to boiling. The
observed exothermic reaction was accompanied by dissolution
of thioamide 1 and evolution of oxygen. On reflux with stirꢀ
ring for 3 min, the dark red solution turned pale yellow. The
reaction mixture was kept for 5 days. The white resinous preꢀ
cipitate that formed was treated with EtOH and filtered off.
The yield of compound 2 was 23%, colorless crystals, m.p.
223—225 °C. On recrystallization from Me2CO, m.p.
225—227 °C. The product was identical with that obtained acꢀ
cording to method A.
Method C. Three drops of morpholine were added to a mixꢀ
ture of 2ꢀcyanoacetamide 5 (0.5 g, 6 mmol) and 4ꢀchloroꢀ
benzaldehyde 4 (0.84 g, 6 mmol) in EtOH (8 mL). The mixture
was brought to boiling and then stirred at ~50 °C for 3 min to
give a suspension of (E)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ2ꢀcyanoacrylamide
3 as colorless crystals. 35% Addition of H2O2 (5 mL, 57 mmol)
and 10% KOH (0.5 mL, 0.9 mmol) to the suspension initiated a
highly exothermic reaction resulting in a pale yellow solution.
The mixture was kept at ~20 °C for 24 h and colorless crystals of
oxiranedicarboxamide 2 were filtered off and washed with EtOH.
The yield was 60%, m.p. 225—227 °C. In terms of spectroscopic
characteristics, the product was identical with those obtained
according to methods A and B.
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at ~20 °C for a single crystal (0.26×0.21×0.19 mm) on an
Enraf—Nonius CADꢀ4 automatic fourꢀcircle diffractometer
(λꢀCuKα radiation, graphite monochromator, ω/2θ scan mode,
θ
max = 65°, sphere segment –1 < h < 9, –1 < k < 8, –1 < l < 45).
The total number of reflections was 2373. Crystals of comꢀ
pound 2 are orthorhombic: a = 7.693(2) Å, b = 7.390(2) Å, c =
38.641(7) Å, V = 2196.7(9) Å3, Z = 8, dcalc = 1.552 g cm–3, µ =
4.759 cm–1, F(000) = 1056, space group Pbca (No. 61). The
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tions with I > 2σ(I )); the number of parameters refined was 182;
the number of reflections per parameter was 8.4; the weighting
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2
2
scheme was ω = 1/[σ (F0 ) + (0.0640P)2 + 0.933P], where
2
2
P = (F0 + 2Fc )/3; max. (mean) shift/esd in the final cycle
was 0.018 (0.002). Calculations were corrected for anomaꢀ
lous scattering; PSI scan semiempirical absorption correction
was applied (Tmin = 0.32, Tmax = 0.46). All hydrogen atoms were
objectively located from the electron density difference map

3ꢀ(4ꢀChlorophenyl)oxiraneꢀ2,2ꢀdicarboxamide
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1473
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Received July 3, 2006;
in revised form April 27, 2007