Cyclocondensation of N-prop-2-ynyl-and N-pentadiynyl-o-phenylenediamines with phenyl isothiocyanate

Article abstract of DOI:10.1007/s10593-008-0068-7

Cyclocondensation of N-prop-2-ynyl-o-phenylenediamine with phenyl isothiocyanate leads to the formation of 1-(3-arylprop-2-ynyl)-2,3-dihydro-1H- benzimidazole-2-thiones. In the reactions of diacetylene derivatives - N-penta-2,4-diynyl-o-phenylenediamine - with phenyl isothiocyanate the formation of two heterocyclic nuclei occurs simultaneously to form [1,3]thiazolidino[3,2- a]benzimidazoles.

Full text of DOI:10.1007/s10593-008-0068-7

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
CYCLOCONDENSATION OF N-PROP-2-YNYL-
AND N-PENTADIYNYL-o-PHENYLENEDIAMINES
WITH PHENYL ISOTHIOCYANATE
R. V. Novikov, M. E. Borovitov, and I. A. Balova
Cyclocondensation of N-prop-2-ynyl-o-phenylenediamine with phenyl isothiocyanate leads to the
formation of 1-(3-arylprop-2-ynyl)-2,3-dihydro-1H-benzimidazole-2-thiones. In the reactions of
diacetylene derivatives − N-penta-2,4-diynyl-o-phenylenediamine - with phenyl isothiocyanate the
formation of two heterocyclic nuclei occurs simultaneously to form [1,3]thiazolidino[3,2-a]benz-
imidazoles.
Keywords: 1-(3-arylprop-2-ynyl)-2,3-dihydro-1H-benzimidazol-2-thiones, N-penta-2,4-diynyl-
o-phenylenediamine, phenyl isothiocyanate, N-prop-2-ynyl-o-phenylenediamines, [1,3]thiazo-
lidino[3,2]benzimidazoles, cyclocondensation.
Derivatives of [1,3]thiazolo[3,2-a]benzimidazole are of interest as a result of their wide range of
biological activity. The known methods for the synthesis of [1,3]thiazolo[3,2-a]benzimidazole heterocyclic
system are based on the use of derivatives of benzimidazole and further conversions directed at creation of the
1,3-thiazole ring [1-6]. In the literature there are also examples of cyclization of acetylenic derivatives, namely
2-(prop-1-ynylthio)benzimidazoles, to obtain [1,3]thiazolo[3,2-a]benzimidazoles [5, 6].
We have observed previously that the reaction of N-penta-2,5-diynylamines with phenyl isothiocyanate
led to the formation of 5-(prop-2-ynylidene)-2-phenyliminothiazolidines as a result of cyclization of the
intermediately formed thiourea [7].
In the present paper results are presented of the reaction of N-prop-2-ynyl- and N-penta-2,4-diynyl-
substituted o-phenylenediamines with phenyl isothiocyanate, the objective of which was to examine the
possibility of forming two heterocyclic rings simultaneously for the synthesis of thiazolo[3,2-a]benzimidazole
system. The synthesis of the initial acetylenic and diacetylenic derivatives of o-phenylenediamine was carried
out according to previously developed method [8].
The reactions of 1-prop-2-ynyl-o-phenylenediamines 1a,b with phenyl isothiocyanate in boiling
acetonitrile led to the formation of 1-(3-arylprop-2-ynyl)benzimidazole-2-thiones 2a,b, isolated in yields of
about 50%.
The 1H NMR spectra of compounds 2a,b contain signals of an NH proton at ~ 12 ppm. In the 13C NMR
spectra two signals at 80-90 ppm are present characteristic of carbon atoms of an acetylenic bond. So we have
observed the formation of a benzimidazole ring, but subsequent nucleophilic attack of the mercapto group on the
triple bond, which might lead to the formation of a 1,3-thiazolidine ring, did not occur.
__________________________________________________________________________________________
Chemistry Faculty, St. Petersburg State University, St. Petersburg 198504, Russia; e-mail:
irinabalova@vandexl.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 627-631, April,
2007. Original article received April 30, 2007.
494
0009-3122/08/4404-0494©2008 Springer Science+Business Media, Inc.

H
H
N
N
Ph
R
NH2
PhNCS
S
MeCN, boiling
–PhNH2
N
H
NH
R
1a,b
H
N
S
N
R
2a,b
a R = Ph, 45% , b R = 4-BrC6H4, 46%
In contrast to the monoacetylenic derivatives of o-phenylenediamine the reactions of N-penta-
2,4-diynyl-o-phenylenediamines 3a,b with phenyl isothiocyanate in analogous conditions led to the formation of
[1,3]thiazolidino[3,2-a]benzimidazoles 4a,b in 43 and 47% yields respectively.
The intermediate compounds in the first stage of the reaction are the corresponding thioureas 5, which
was shown with the example of N-5-phenylpenta-2,4-diynyl-o-phenylenediamine 3b. Its reaction with phenyl
isothiocyanate at room temperature gives the thiourea 5b, isolated in 75% yield.
H
H
N
N
Ph
NH2
PhNCS
S
–PhNH2
R
MeCN, boiling
N
H
NH
R
3a,b
5a,b
H
N
N
S
S
R
N
N
H
6a,b
4a,b
R
a R = n-Bu, 43%, b R1 = Ph, 47%
In the cases of the derivatives of o-phenylenediamine 3a,b carrying out the reaction in boiling
acetonitrile lead to cascading cyclization and fixation of the benzimidazole-2-thiones 6a,b formed was not
successful.
The 1H NMR spectra of compounds 4a,b are characterized by doublets of the protons of the methylene
group at about 5 ppm and triplet of the vinyl proton in the region of 6 ppm with 4J ~ 2 Hz. The configuration of
the exo-double bond was shown on the basis of the existence of NOE between the protons of the methylene
group and the proton at the exo-double bond.
495

The difference in the behavior of the mono- and diacetylenic derivatives of o-phenylenediamine in the
cyclocondensation reactions with phenyl isothiocyanate is explained by the greater reactivity of the conjugated
systems of the triple bonds with respect to nucleophilic attack of the mercapto group which occur trans-
stereospecifically. The reaction of N-penta-2,4-diynyl-o-phenylenediamines with phenyl isothiocyanate is the
first example of the synthesis of [1,3]thiazolidino[3,2-a]benzimidazoles in which two heterocyclic nuclei are
formed simultaneously.
EXPERIMENTAL
Elemental analyses were obtained with a Hewlett-Packard 185B. IR spectra of KBr disks
1
13
(4000-400 cm-1) were recorded with a Specord IR-75 instrument. H and C NMR spectra were recorded on a
Bruker DRX 300 (300 and 75 MHz respectively). Chemical shifts were measured relative to the residual signals
of the solvent (1H/13C: 7.28/77.16; 2.50/39.52 ppm respectively). Mass spectra were measured on a CPX-1321
(EI) instrument with direct injection, ionization energy 70 eV (temperature of the ionization chamber 200°C).
Chem. pure solvents (Vekton) were redistilled before use. TLC analysis was carried out on Kieselgel 60 F254
(Merck) aluminum plates. The acetylene and diacetylene derivatives of o-phenylenediamine 1a,b and 3a,b
starting materials were made by method [8], 1-bromo-2,4-diynes and 3-arylpropargyl bromides were prepared
from the corresponding alcohols by method [9].
N-Phenyl-N'-[2-(5-phenylpenta-2,4-diynyl)aminophenyl]thiourea (5b). A solution of PhNCS
(570 mg, 5 mmol) in MeCN (10 ml) was added to amine 3b (1.23 g, 5 mmol) in acetonitrile (10 ml). The
reaction mixture was stirred at room temperature until the initial amine had completely disappeared (TLC
monitoring, ~3 h). At the end of the reaction the solvent was evaporated, the residue was filtered off, washed
with a small amount of acetonitrile to give the thiourea 5b (1.43 g, 75%) as light-yellow crystals;
mp 178-180°C. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 4.20 (2H, d, J = 5.7, CH2); 5.63 (1H, t, J = 5.7,
NH); 6.7 (1H, t, J = 7.5, Ar-H); 6.81 (1H, d, J = 8, Ar-H); 7.08-7.6 (12H, m, Ar-H); 9.01 (1H, s, NH); 9.67 (1H,
s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 32.9, 66.1, 73.7, 76.3, 83.0, 111.8, 116.9, 120.4, 123.5, 124.3,
125.2, 127.4, 128.3, 128.7, 128.8, 129.8, 132.4, 139.6, 142.9, 180.6. Found, %: C 75.40; H 5.14; N 11.08.
C24H19N3S. Calculated, %: C 75.56; H 5.02; N 11.01.
Reaction of N-Prop-2ynyl- (1a,b) and N-Pent-2,4-diynyl-o-phenylenediamines 3a,b with Phenyl
Isothiocyanate (General Method). Compounds 1 or 3 (5 mmol) in acetonitrile (10 ml) were placed in a flask
fitted with a reflux condenser and PhNCS (0.57 g, 5 mmol) in MeCN (10 ml) was added with stirring. The
mixture was heated to boiling while stirring for 1 h until the starting amine had completely disappeared (TLC
monitoring). At the end of the reaction the solvent was evaporated, the residue was filtered off, washed with a
small amount of acetonitrile and recrystallized from an ethanol–hexane mixture.
1-(3-Phenylprop-2-ynyl)-1,3-dihydro-2H-benzimidazole-2-thione (2a) was obtained as white needles
(590 mg, 45%); mp 166-167°C. IR spectrum, ν, cm-1: 3137, 3058, 2983, 2930, 1621, 1598, 1505, 1461, 1388,
1
1339, 1230, 1201, 1136, 988, 756, 735, 690. H NMR spectrum (DMSO-d6–CCl4, 1:4), δ, ppm (J, Hz): 5.33
(2H, s, CH2); 7.10-7.32 (6H, m, Ar-H); 7.34-7.44 (3H, m, Ar-H); 12.82 (1H, s, NH). 13C NMR spectrum
(DMSO-d6–CCl4, 1:4), δ, ppm: 33.6, 82.8, 84.0, 109.3, 110.0, 122.0, 122.1, 122.7, 128.1, 128.3, 131.3, 131.5,
132.0, 168.5. Mass spectrum, m/z (Irel, %): 266 [M +2]+(6), 264 [M]+ (100), 263 (60), 262 (12), 231 (22), 115
(86), 90 (12). Found, %: C 72.64; H 4.62; N 10.54. C16H12N2S. Calculated, %: C 72.70; H 4.58; N 10.60.
1-[3-(4-Bromophenyl)prop-2-ynyl]1,3-dihydro-2H-benzimidazole-2-thione (2b) was obtained as
colorless needles (780 mg, 46%); mp 212-213°C. IR spectrum, ν, cm-1: 3139, 3061, 2983, 2920, 1621, 1505,
1460, 1427, 1339, 1229, 1193, 1136, 1072, 987, 822, 736. 1H NMR spectrum (DMSO-d6–CCl4, 1:4), δ, ppm (J,
Hz): 5.32 (2H, s, CH2); 7.1-7.26 (3H, m, Ar-H); 7.31 (2H, d, J = 8.4, Ar-H); 7.34-7.40 (1H, m, Ar-H); 7.43 (2H,
d, J =8.4, Ar-H); 12.82 (1H, s, NH). 13C NMR spectrum (DMSO-d6–CCl4, 1:4), δ, ppm: 33.5, 82.9, 84.2, 109.2,
496

110.0, 121.1, 122.0, 122.4, 122.7, 126.5, 131.3, 131.9, 133.2, 168.5. Mass spectrum, m/z (Irel, %): 346 [M + 4]+
(6), 81Br; 345 [M+3]+ (24), 81Br; 344 [M+2]+ (100), 81Br; 343 [M+1]+ (53), 79Br; 342 [M]* (98), 81Br; 341 [M-H]+
79
79
(98), Br; 341 [M]+(32), Br; 263 (23); 262 (11); 195 (61); 193 (64); 131 (14); 122 (11); 114 (30); 113 (18);
103 (18); 88 (10). Found, %: C 55.97, H 3.34, N 7.95. C16H11BrN2S. Calculated, %: C 55.99; H 3.23; N 8.16.
(Z)-2-Hept-2-ynylidene[1,3]thiazolidino[3,2-a]benzimidazole (4a) was obtained as light-yellow
crystals (570 mg, 43%); mp 154-155°C. IR spectrum, ν, cm-1: 3047, 3022, 2954, 2931, 2869, 2860, 2208, 1612,
1
1583, 1481, 1446, 1388, 1375, 1282, 790, 759, 746. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.95 (3H, t,
J = 7.1, CH3); 1.42-1.63 (4H, m, 2CH2); 2.44 (2H, t, J = 5.1, CH2); 5.03 (2H, t, J = 2.2, CH2); 5.87 (1H, t,
J =2.2, CH); 7.18-7.23 (3H, m, Ar-H); 7.63-7.65 (1H, m Ar-H). 13C NMR spectrum (CDCl3), δ, ppm: 14.0, 19.8,
22.4, 49.0, 76.8, 101.0, 104.6, 109.1, 119.6, 122.6, 122.7, 133.8, 145.6, 148.5, 155.8. Mass spectrum, m/z (Irel,
%): 270 [M+2]+ (5), 268 [M]+ (100), 239 (14), 229 (53), 211 (14), 206 (10), 167 (14). Found, %: C 71.63,
H 6.03, N 10.18. Calculated for C16H16N2S, %: C71.61, H 6.01, N 10.44.
(Z)-2-(3-Phenylprop-2-ynylidene)[1,3]thiazolidino[3,2-a]benzimidazole (4b) was obtained as
colorless crystals (670 mg, 47%); mp 219-220.5°C. IR spectrum, ν, cm-1: 3049, 3008, 2920, 2850, 2191, 1608,
1
1583, 1479, 1436, 1388, 1377, 1334, 1309, 1282, 1249, 1203, 1147, 1068, 690, 657. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 5.11 (2H, d, J = 2.2, CH2); 6.08 (3H, t, J = 2.2, CH); 7.18-7.25 (3H, m, Ar-H);
13
7.33-7.40 (3H, m, Ar-H); 7.48-7.55 (2H, m, Ar-H); 7.65-7.72 (1H, m, Ar-H). C NMR spectrum (CDCl3), δ,
ppm : 49.3, 85.12, 99.3, 104.0, 109.1, 119.7, 122.7, 122.8, 122.9, 128.9, 131.9, 133.9, 138.3, 147.3, 155.5. Mass
spectrum, m/z (Irel, %): 290 [M+2]+ (4), 288 [M]+ (100), 287 [M-1]+ (58), 256 (23), 255 (16), 230 (18), 139 (12),
114 (9), 102 (8). Found, %: C 74.76; H 4.2; N 9.63. C18H12N2S. Calculated, %: C 74.97; H 4.19; N 9.71.
This work was carried out with financial support from grant RFFI No. 05-03-32504.
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