Cyclocondensation of n-(prop-2-yn-1-yl)- and n-(penta-2,4-diyn-1-yl)- o-phenylenediamines with phenyl isothiocyanate and carbon disulfide

Article abstract of DOI:10.1007/s10593-011-0831-z

The cyclocondensation of N-(prop-2-yn-1-yl)-o-phenylenediamines with phenyl isothiocyanate leads to the formation of 1-(prop-2-yn-1-yl)-1,3-dihydro-2H- benzimidazole-2-thiones irrespective of the substituent nature at the triple bond. Reactions of both mo

Full text of DOI:10.1007/s10593-011-0831-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
CYCLOCONDENSATION OF N-(PROP-2-YN-1-YL)-
AND N-(PENTA-2,4-DIYN-1-YL)-
o-PHENYLENEDIAMINES WITH PHENYL
ISOTHIOCYANATE AND CARBON DISULFIDE
R. V. Novikov1, N. A. Danilkina1, and I. A. Balova1*
The cyclocondensation of N-(prop-2-yn-1-yl)-o-phenylenediamines with phenyl isothiocyanate leads to
the formation of 1-(prop-2-yn-1-yl)-1,3-dihydro-2H-benzimidazole-2-thiones irrespective of the substi-
tuent nature at the triple bond. Reactions of both mono- and diacetylenic derivatives of
o-phenylenediamine with carbon disulfide in the presence of KOH proceed with the formation of two
heterocyclic nuclei simultaneously. From N-(prop-2-yn-1-yl)-o-phenylenediamines containing an aryl
substituent at the triple bond, and N-(penta-2,4-diyn-1-yl)-o-phenylenediamines 2-methylidene-
2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles are formed. The latter are readily isomerized under the
action of base giving thiazolo[3,2-a]benzimidazoles. The cyclocondensation of N-(alk-2-yn-1-yl)-
o-phenylenediamines with CS2 leads to [1,3]thiazino[3,2-a]benzimidazoles.
Keywords: 1-(3-arylprop-2-yn-1-yl)-1,3-dihydro-2H-benzimidazole-2-thiones, N-(penta-2,4-diyn-1-yl)-
o-phenylenediamines, N-(prop-2-yn-1-yl)-o-phenylenediamines, carbon disulfide, [1,3]thiazolo[3,2-a]-
benzimidazoles, phenyl isothiocyanate, cyclocondensation.
Derivatives of [1,3]thiazolo- and 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole possess a broad spec-
trum of biological activity. In experiments in vivo similar compounds display antiulcer action and reduce gastric
hypersecretion [1]. They are inhibitors of collagenase [2], and may be used in the treatment of rheumatoid
arthritis. They also are known to be effective immunomodulators, and display anticancer activity [3–5]. It has
also been discovered that 3-methylthiazolo[3,2-a]benzimidazoles possess antioxidant properties [6].
In spite of the promise of this class of compounds synthetic approaches to them are fairly limited. In the
known methods of constructing this heterocyclic system, a formed benzimidazole fragment is used with
subsequent construction of the 1,3-thiazole ring [7–14]. Typical synthetic precursors of thiazolo[3,2-a]benz-
imidazoles are represented below.
Traditional methods for 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles obtaining are based on reactions
of 2-mercaptobenzimidazoles with 1,2-dihaloethanes [15, 16] or S-ethylenylsulfimines [17]. This enables the
preparation of 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles containing substituents both in the benzene
_______________
*To whom correspondence should be addressed, e-mail: irinabalova@pobox.spbu.ru.
1Saint-Petersburg State University, 26 Universitetskiy Pr., Saint Petersburg 198504, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 917–927, June, 2011. Original
article submitted January 13, 2011.
0009-3122/11/4706-0758©2011 Springer Science+Business Media, Inc.
758
ꢀ

N
N
N
N
N
S
O
Cl
S
N
H
R1
(R)
H
R
R1
R1 = Ar
O
R1 = CH2R2
R = Alk, Ar, Het
N
S
R2
R2 = Ar, H
N
H
nucleus and in the thiazolidine ring. The disadvantage of such an approach is the formation of by-products,
1,2-bis(2-benzimidazolylthio)ethanes.
We discovered previously that the cyclocondensation of N-(penta-2,4-diynyl)-o-phenylenediamines
with phenyl isothiocyanate proceeds with the formation at one stroke of two heterocyclic nuclei, giving
2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles [18]. However in the case of N-(3-phenylprop-2-ynyl)-o-pheny-
lenediamine the reaction led to 1-(3-phenylprop-2-ynyl)-2,3-dihydro-1H-benzimidazole-2-thione, the sub-
sequent cyclization of which into 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole did not occur.
In the current study we present the results of further investigations on the cyclocondensation of di- and
monoacetylenic derivatives of o-phenylenediamine (OPDA) with varying nature of substituent at the triple bond,
with PhNCS and CS2 with the aim of studying the scope and limitations of this new synthetic approach for the
preparation of 2,3-dihydro[1,3]thiazolo- and [1,3]thiazolo[3,2-a]benzimidazole derivatives.
A series of phenylenediamines 1a–h has been synthesized by the procedure proposed by us previously
[19] with the aim to study the effect of substituents at the triple bond, and of the reaction conditions, on the
structure of the resulting products.
.
NH2
NH2
HCl
NH2
1.
2.
Br
R
HCl (gas)
N
H
R
1a–h
ꢀ R = H, b R = Me, c R = C6H5, d R = 4-BrC6H4, e R = 4-MeOC6H4, f R = 4-O2NC6H4, g R = n-BuCꢀC, h R = PhCꢀC
The first experiments with N-(prop-2-ynyl)-o-phenylenediamine (1a) and N-(3-arylprop-2-yn-1-yl)-
o-phenylenediamines 1d–f, containing substituents with electron-donating and -withdrawing character in the
benzene ring, were carried out under the previously described conditions [18]. Irrespective of the substituent on
the triple bond nature, condensation of monoacetylenic derivatives of OPDA with phenyl isothiocyanate on
boiling in acetonitrile led to the preparation of only N-(prop-2-ynyl)benzimidazole-2-thiones 2a,d–f.
H
H
N
H
N
N
PhNCS
Ph
1a,d–f
S
MeCN, 82oC
S
–PhNH2
N
NH
R
2ꢀ,d–f
R
ꢀ R = H, d R = 4-BrC6H4, e R = 4-MeOC6H4, f R = 4-O2NC6H4
759
ꢀ

Even for compound 2f, the triple bond of which is activated by the electron-withdrawing p-nitrophenyl
substituent, subsequent intramolecular cyclization into 2,3-dihydro[1,3]-thiazolo[3,2-a]benzimidazole did not
occur. The strength of polarization of the triple bond in compound 2f may be judged from the large difference of
13C NMR chemical shifts of the sp-hybridized carbon atoms – 82.8 and 89.1 ppm in comparison with the re-
maining N-(3-arylprop-2-ynyl)benzimidazole-2-thiones 2d–e, for which both acetylenic carbon atoms have
close values of chemical shift, about 82 and 84 ppm.
We then used carbon disulfide in the presence of KOH as cyclocondensing agent. For comparison with
the results obtained previously in [18] we carried out the first experiments with N-(penta-2,4-diynyl)-o-pheny-
lenediamines 1g,h. Their reaction with CS2 in ethanol in the presence of an equivalent amount of KOH led to the
formation of 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles 3g,h. The yield of compound 3g proved to be 15%
higher than on using phenyl isothiocyanate, and compound 3h was obtained in the same yield [18].
H
N
H
N
S
N
N
CS2, KOH
S
S
1g,h
R
H
EtOH, 78oC
– KHS
R
SK
N
N
H
R
2
2
3g,h
g R = n-C4H9 (58%); h R = Ph (47%)
Since amines 1 as free bases have low stability and are isolated as hydrochlorides, we carried out subse-
quent reactions with their hydrochlorides in the presence of 2 equiv. KOH. Under these conditions on interacting
the (bromophenyl)propynyl-o-phenylenediamine hydrochloride 1d with an equimolar quantity of carbon
1
disulfide a mixture of two compounds was obtained. On the basis of H NMR spectrum and data of chromato-
mass-spectrometric analysis it was established that these were the isomeric [1,3]thiazolo[3,2-a]benzimidazoles
with exo- (3d) and endo-cyclic (4d) double bonds in a ratio of 12:1, isolated in a total yield of 60%.
Under these conditions cyclization of the monoacetylenic derivative of OPDA proceeded as a tandem
process with sequential closure of the imidazole and 1,3-thiazolidine rings. This is seemingly caused by the
possibility of a thiolate anion formation from the intermediate benzimidazolethione in the presence of base. Its
subsequent intramolecular attack at the carbon atom of the triple bond is accompanied by the partial
isomerization of the exo double bond into the endo position.
H
N
CS2,
KOH (2 eq.)
N
N
SH
.
HCl
1c–e
S
EtOH, 78oC
N
R
R
N
N
N
KOH
S
S
EtOH, 78oC
N
R
R
3c–e
4c–e
c R = Ph, d R = 4-BrC6H4, e R = 4-MeOC6H4
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The use of CS2 in a 20% excess in the reaction with N-(3-arylprop-2-ynyl)-o-phenylenediamine hydro-
chlorides 1c–e allowed to avoid the formation of a products mixture at the cyclocondensation stage, and 2-aryli-
dene-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles 3c–e were obtained in 59–73% yield. Reaction with the
p-nitrophenyl-substituted amine 1f under these conditions resulted in heavy resinification, and isolation of the
cyclocondensation product was unsuccessful. Subsequent isomerization of compounds 3c–e on heating in the
presence of KOH in ethanol gave 2-benzylthiazolo[3,2-a]benzimidazoles 4c–e in quantitative yield (93–95%).
1
The main difference in the H NMR spectra of compounds 3 and 4 is the position of proton signals of
1
methylene groups and vinylic protons. In the H NMR spectra of arylidene derivatives 3 the signal for the
methylene protons of the thiazolidine ring in the region of ꢁ 5.3 ppm is characteristic and the signal of the proton
at the double bond is observed at ꢁ 7.0 ppm. In the 1H NMR spectra of 2-benzyl-substituted [1,3]thiazolo[3,2-a]-
benzimidazoles 4 the benzylic protons make a signal in the region of ꢁ 4.1 ppm, while the signal of the vinylic
proton is shifted to 8 ppm. The (Z)-configuration of the exocyclic double bond in compound 3 is indicated by
the appearance of a nuclear Overhauser effect (NOE) between the protons of the methylene group and the
vinylic proton. In the spectra of compound 4 the NOE of the methylene group protons is observed involving
both the thiazole proton and the ortho protons of the benzene ring.
CS2,
KOH (2 eq.)
H
N
N
N
N
N
.
S
SH
S
1a,b
HCl
EtOH, 78oC
R
N
R
R
5a,b
a R = H, b R = Me
On condensing carbon disulfide with the hydrochlorides of N-(prop-2-ynyl)-o-phenylenediamine (1a)
and N-(but-2-ynyl)-o-phenylenediamine (1b), having no unsaturated substituent at the triple bond, closure of the
second heterocyclic nucleus involving the triple bond proceeded with a different regiospecificity, giving
4H-[1,3]thiazino[3,2-a]benzimidazoles 5a,b as sole products.
In the NMR spectra of the products of endo (5) and exo (3) cyclization the most characteristic were the
signals for hydrogen and carbon atoms of the methylene group. In the 1H NMR spectra of compounds 5a,b the
protons of the methylene group gave the expected multiplet in the ꢁ 5.0 region, while for the thiazolidine
derivatives 3c–e the corresponding signal was displaced towards low field by 0.3 ppm. In the 13C NMR spectra
of compounds 5a,b the signals of the methylene carbon atoms were found at ꢁ 45 1, but for 2,3-dihydro-
[1,3]thiazolo[3,2-a]benzimidazoles 3 in the region of ꢁ 53 3 ppm.
It was shown previously that for 5-ylidene-4-oxothiazolidines I and 1,3-thiazin-4-ones II derivatives the
3
size of the cis-vicinal coupling constant JCH of the proton at the double bond with the carbon atom of the
2
carbonyl group is always larger than the geminal JCH [20]. This turned out to be useful for identifying a wide
circle of mono- and polycyclic heterocycles formed on cyclization by the endo or the exo type [21–26]. Conse-
quently we thought it expedient to determine the values of the coupling constants for the cyclocondensation pro-
ducts of N-(prop-2-ynyl)-o-phenylenediamine derivatives with carbon disulfide according to the 5-exo-dig and
to 6-endo-dig type using as examples thiazolidine 3c and thiazine 5a.
For the determination of the coupling constants in 5a, we, firstly, carried out the assignment of the pro-
tons signals. For this its NOESY spectrum was recorded in which intense cross peaks were observed between
the signals of the endocyclic methylene group protons and atoms H-3 and H-5. Further, from the 13C NMR
spectrum, with selective decoupling of atoms H-3 and H-2, we established that the C-4 carbon atom in thiazi-
no[3,2-a]benzimidazole 5a had coupling constants 3JCH-2 = 8.1 and 2JCH-3 = 7.2 Hz. The latter surpasses the vici-
761
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RN
N
N
N
H3C
J = 5.7 Hz
H
S
S
S
HO
R
R
Ph
3
O
H
O
H
H
J = 6.6 Hz
J = 6.5 Hz
J = 5–7 Hz
3c
I
III
RN
N
J = 3.6 Hz
S
2
H
R
N
R
N
H
H 5
4
O
H
H3
O
H
J = 8.1 Hz
J = 7.2 Hz
5a
J = 0.6 Hz
J = 1–2 Hz
II
IV
nal constant 3JCH-3 = 6.6 Hz in compound 3c and is significantly greater than analogous constants for 1,3-thiazin-
4-ones II. Such a value for the coupling constant is in good agreement with the above-established (Z)-confi-
3
guration of the exocyclic double bond in compound 3c. At the same time, the coupling constant JCH in com-
pound 3c with an exocyclic double bond is within the limits of values found for 5-ylidene-4-oxothiazolidines I.
Previously in [27], it was shown that the size of the cis-vicinal constant (3JCH) in similar systems depends little
on the structure and lies within 5.0–7.0 Hz limits for both cyclic and acyclic compounds such as methacrylic
acid III. But, unlike the vicinal, the geminal coupling constants may vary within wide limits [28]. In particular it
was discovered that the geminal constant (2JCH) increased appreciably on changing the hybridization of the
considered carbon atom from sp or sp2 to sp3, which is evidently seen in the example of cyclohexenone IV [28],
and also on comparing 2JCH in 1,3-thiazin-4-ones II and in compound 5a.
The obtained results confirm once more that inclusion of a triple bond in the conjugated diacetylene
system increases its electrophilicity. Unlike N-(penta-2,4-diynyl)-o-phenylenediamines, which on interaction
with PhNCS form 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles [18], N-(prop-2-ynyl)-o-phenylenediamines
1a,d–f independent of the nature of the substituent on the triple bond give only 1-(prop-2-ynyl)-1,3-dihydro-2H-
benzimidazole-2-thiones 2a,d–f. Carrying out the cyclocondensation with carbon disulfide in the presence of
base for both mono- and diacetylenic derivatives of OPDA leads to a tandem conversion with formation directly
of the two heterocyclic fragments. Closure of the second ring in the intermediately formed 1-(prop-
2-ynyl)benzimidazole-2-thiones, as a result of nucleophilic addition to the triple bond, may proceed according to
the 5-exo-dig and to the 6-endo-dig type. On conjugation of the triple bond with the aromatic nucleus or a
second triple bond and stabilization of the intermediate anion by a benzyl or propargyl type, exo cyclization
occurs which enables the formation of 2-(prop-2-ynylidene)-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazoles, and
also of 2-benzylthiazolo[3,2-a]benzimidazoles. In the absence of conjugation cyclization proceeds with the
formation of a six-membered ring and gives the corresponding 4H-[1,3]thiazino[3,2-a]benzimidazoles.
These tandem conversions are a new approach to the construction of the given condensed heterocyclic
systems. The special features, mentioned by us, of the formed products NMR spectra on endo or exo cyclization,
may be useful when establishing the structures of similar compounds.
EXPERIMENTAL
The IR spectra were recorded on a Specord IR 75 instrument in KBr disks. The 1H and 13C NMR spectra
were obtained on a Bruker DPX 300 spectrometer (at 300 and 75 MHz respectively) of CDCl3 solutions (com-
pounds 3g,h, 5b), or DMSO-d6 solutions (compounds 2a, 3c–e, 4e, 5a), and of DMSO-d6–CCl4 1:4 mixture
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solutions (compounds 2d–f, 4c,d). Chemical shifts are given relative to the signals of the residual protons
(CDCl3 ꢁ 7.28 and DMSO-d6, ꢁ 2.50 ppm) or carbon atoms (CDCl3 ꢁ 77.16 and DMSO-d6 ꢁ 39.52 ppm
respectively) of the solvents. For the identification of the carbon atoms signals in compounds 3c and 5a, and
also for the determination of the JC-H constant, 13C NMR spectra of solutions of these compounds in DMSO-d6
were recorded without broad band decoupling from hydrogen atoms and with selective decoupling from atoms
H-2 and H-3 for compound 5a. The precision of coupling constants measuring was 0.5 Hz. Low-resolution
mass spectra were recorded on a MX-1321 instrument using direct insertion (temperature of ionization chamber
200oC), energy of ionizing electrons 70 eV. High-resolution mass spectra were obtained on a Bruker MicrOTOF
mass spectrometer with a time of flight mass analyzer on ionization by the method of electrodiffusion in the
detection of positive ions mode. Chromatomass-spectrometric analysis was carried out on an Agilent 6890
instrument with an Agilent 5973 mass detector (ionization energy 70 eV). Elemental analysis was carried out on
a Hewlett-Packard 185 B instrument. Solvents (chemically pure) (Vekton) were first redistilled. Analysis of
reaction mixtures was effected by TLC on silica gel plates of type Kieselgel 60 F254 (Merck).
The starting acetylene and diacetylene OPDA derivatives 1a–g were synthesized by the method of [19],
1-bromobuta-2,4-diynes and 3-arylpropargyl bromides were obtained from the corresponding alcohols according
to [29]. To obtain the hydrochlorides, which are more stable on storage, the isolation procedure was modified.
After processing the reaction mixture the organic solvent was removed at reduced pressure, the residue was
dissolved in dry ether and gaseous HCl was passed through. The precipitated salt was filtered off, washed with a
small amount of ether, and dried in a vacuum desiccator.
Reaction of N-(Prop-2-yn-1-yl)-o-phenylenediamines 1a,d–f with Phenyl Isothiocyanate (General
Method). A solution of the corresponding diamine 1 (5 mmol) in acetonitrile (10 ml) and a solution of phenyl
isothiocyanate (0.57 g, 5 mmol) in acetonitrile (10 ml) were placed in a flask fitted with a reflux condenser. The
reaction mixture was boiled with stirring until complete disappearance of the starting amine (TLC, hexane–ethyl
acetate, 2:1). The reaction as a rule was completed after 1 h. At the end of the reaction the solvent was removed
under reduced pressure, the precipitated solid was filtered off, washed with a small amount of acetonitrile, and
recrystallized from an ethanol—hexane mixture.
1-(Prop-2-yn-1-yl)-1,3-dihydro-2H-benzimidazole-2-thione (2a). Yield 0.58 g (62%); needle-like
crystals; mp 184–185oC. IR spectrum, ꢂ, cm–1: 3295, 3141, 3110, 3069, 3033, 2992, 2939, 2911, 2856, 2123,
1620, 1563, 1481, 1464, 1419, 1387, 1371, 1274, 1138, 1104, 1015, 988, 942, 920, 899, 834, 761, 746, 701,
1
663, 631, 600. H NMR spectrum, ꢁ, ppm (J, Hz): 3.34 (1H, t, J = 2.4, CH); 5.15 (2H, d, J = 2.4, CH2); 7.23
(2H, m, H Ar); 7.34 (2H, m, H Ar); 12.93 (1H, s, NH). 13C NMR spectrum, ꢁ, ppm: 33.6 (CH2); 76.1 (Cß); 78.6
(Cß); 110.7, 110.7, 123.3, 124.1, 131.6, 132.5, 168.9 (C-2). Found: m/z 189.0560 [M+H]+. C10H9N2S.
Calculated: [M+H] 189.0486.
1-[3-(4-Bromophenyl)prop-2-yn-1-yl]-1,3-dihydro-2H-benzimidazole-2-thione (2d) [18]. Mass
spectrum, m/z (Irel, %): 346 [M+4]+ (6), 345 [M+3]+ (24), 344 [M+2]+ (100), 343 [M+1]+ (53), 342 [M]+ (98),
341 [M–H]+ (32), 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.
1-[3-(4-Methoxyphenyl)prop-2-yn-1-yl]-1,3-dihydro-2H-benzimidazole-2-thione (2e). Yield 0.56 g
(38%); colorless needle-like crystals; mp 196–197oC. IR spectrum, ꢂ, cm–1: 3140, 3098, 3065, 2989, 2835, 2215,
1
1608, 1505, 1462, 1342, 1253, 1198, 1031, 733. H NMR spectrum, ꢁ, ppm: 3.77 (3H, s, CH3); 5.30 (2H, s,
CH2); 6.79 (2H, m, H Ar); 7.10–7.25 (3H, m, H Ar); 7.31 (2H, m, H Ar); 7.35–7.45 (1H, m, H Ar); 12.79 (1H, s,
NH). 13C NMR spectrum, ꢁ, ppm: 33.6 (CH2); 54.9 (CH3O); 81.2, 84.1 (Cꢀ); 109.3, 110.0, 113.7, 114.0, 121.9,
122.6, 131.3, 132.0, 133.0, 159.5, 168.4. Mass spectrum, m/z (Irel, %): 295 [M+1]+ (18), 294 [M]+ (77), 293
[M–H]+ (20), 279 (23), 145 (100), 102 (14). Found, %: C 69.29; H 4.83; N 9.42. C17H14N2OS. Calculated, %:
C 69.36; H 4.79; N 9.52.
1-[3-(4-Nitrophenyl)prop-2-yn-1-yl]-1,3-dihydro-2H-benzimidazole-2-thione (2f). Yield 0.74 g
1
(48%), yellow needle-like crystals; mp 188–189oC. H NMR spectrum, ꢁ, ppm: 5.40 (2H, s, CH2); 7.10–7.30
(3H, m, H Ar); 7.35–7.45 (1H, m, H Ar); 7.62 (2H, m, H Ar); 8.16 (2H, m, H Ar); 12.87 (1H, s, NH). 13C NMR
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spectrum, ꢁ, ppm: 34.2 (CH2); 82.8, 89.1 (Cß); 109.9, 110.8, 122.8, 123.5, 124.1, 129.5, 132.0, 132.6, 133.3,
147.8, 169.3. Mass spectrum, m/z (Irel, %): 311 [M+2]+ (6), 310 [M+1]+ (19), 309 [M]+ (100), 262 (28), 261 (19),
187 (17), 134 (11), 103 (12), 89 (10), 77 (10). Found, %: C 62.11; H 3.64; N 13.41. C16H11N3O2S. Calcu-
lated, %: C 62.12; H 3.58; N 13.58.
Reaction of N-(Penta-2,4-diynyl)-o-phenylenediamines 1g,h with Carbon Disulfide (General Me-
hod). A solution of KOH (0.28 g, 5 mmol) in a mixture of ethanol (15 ml) and water (0.5 ml), and carbon
disulfide (0.4 ml, 6 mmol) were placed in a flask fitted with a reflux condenser. The mixture was stirred for
5 min, after which the corresponding N-(penta-2,4-diynyl)-o-phenylenediamine 1 (5 mmol) was added. The
reaction mixture was boiled until disappearance of the starting amine (TLC), poured into water, the precipitated
solid was filtered off, washed with water, dried, and recrystallized from an ethanol–hexane mixture.
(2Z)-2-(Hept-2-yn-1-ylidene)-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole (3g) and (2Z)-2-(3-phenyl-
prop-2-yn-1-ylidene)-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole (3h) were obtained as described in [18].
Reaction of N-(Prop-2-yn-1-yl)-o-phenylenediamine Hydrochlorides 1c–e with Carbon Disulfide
(General Mehod). A solution of KOH (0.28 g, 5 mmol) in a mixture of ethanol (15 ml) and water (0.5 ml), and
the corresponding N-(prop-2-yn-1-yl)-o-phenylenediamine hydrochloride 1 was placed in a flask fitted with a
reflux condenser. The mixture was heated at 40–50oC for 20 min. After cooling to room temperature KOH
(0.28 g, 5 mmol) and carbon disulfide (0.4 ml, 6 mmol) were added to the reaction mixture which was then
stirred for 5 min at room temperature, and boiled for 2 h, checking the progress of the reaction by TLC. At the
end of the reaction the solvent was removed under reduced pressure to 1/5 of the initial volume. The precipitated
solid was filtered off, washed with a small amount of alcohol, with water, dried, and recrystallized from a
mixture of 1,4-dioxane–water.
(2Z)-2-Benzylidene-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole (3c). Yield 0.77 g (59%); colorless
crystals; mp 250–251oC. IR spectrum, ꢂ, cm–1: 3051, 1612, 1474, 1443, 1390, 1255, 1148, 1088, 850, 737, 688.
1H NMR spectrum, ꢁ, ppm (J, Hz): 5.35 (2H, d, J = 2.0, CH2); 7.07 (1H, t, J = 2.0, CH); 7.15–7.25 (2H, m,
H Ar); 7.35 (1H, t, J = 6.7, H Ar); 7.40–7.60 (6H, m, H Ar). 13C NMR spectrum, ꢁ, ppm: 51.1; 110.9; 119.2;
122.6; 122.8; 124.2; 128.5; 128.6; 129.8; 133.4; 134.2; 135.9; 136.0; 148.6. Mass spectrum, m/z (Irel, %): 265
[M+1]+ (29), 264 [M]+ (100), 263 [M–H]+ (69), 231 (13), 204 (16), 187 (11), 134 (11), 132 (16), 102 (10).
Found, %: C 72.77; H 4.51; N 10.51. C16H12N2S. Calculated, %: C 72.70; H 4.58; N 10.60.
(2Z)-2-(4-Bromobenzylidene)-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole (3d). Yield 1.24 g
(73%); light-yellow crystals; mp 237–238oC. IR spectrum, ꢂ, cm–1: 3052, 2916, 1615, 1583, 1476, 1440, 1391,
1255, 1150, 857, 742. 1H NMR spectrum, ꢁ, ppm, (J, Hz): 5.35 (2H, d, J = 1.7, CH2); 7.04 (1H, br. s, CH); 7.15–
7.27 (2H, m, H Ar); 7.40 (2H, d, J = 8.4, H Ar); 7.46 (1H, dd, 3J = 7.6, 4J = 1.7, H Ar); 7.56 (1H, dd, 3J = 8.0,
4J = 2.5, H Ar); 7.67 (2H, d, J = 8.4, H Ar). 13C NMR spectrum, ꢁ, ppm; 51.2; 110.9; 119.2; 121.5; 122.6; 122.8;
123.1; 130.6; 132.7; 134.3; 134.8; 135.3; 148.7; 155.8. Mass spectrum, m/z (Irel, %): 345 [M+3]+ (20), 344
[M+2]+ (100), 343 [M+1]+ (84), 342 [M]+ (98), 341 [M–H]+ (68), 311 (10), 309 (10), 284 (12), 282 (12), 263
(18), 204 (18), 187 (13), 131 (22), 115 (18), 102 (16). Found, %: C 55.82; H 3.27; N 7.71. C16H11BrN2S.
Calculated, %: C 55.99; H 3.23; N 8.16.
(2Z)-2-(4-Methoxybenzylidene)-2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole (3e). Yield 1.00 g
(69%); light-yellow crystals; mp 254–255oC. IR spectrum, ꢂ, cm–1: 3051, 3006, 2969, 2837, 1605, 1507, 1475,
1
1438, 1390, 1245, 1033, 854, 732. H NMR spectrum, ꢁ, ppm (J, Hz): 3.83 (3H, s, CH3); 5.31 (2H, d, J = 1.7,
CH2); 6.99 (1H, br. s, CH); 7.05 (2H, d, J = 8.4, H Ar); 7.15–7.25 (2H, m, H Ar); 7.38 (2H, d, J = 8.4, H Ar);
13
7.43 (1H, d, J = 6.8, H Ar); 7.55 (1H, d, J = 6.8, H Ar). C NMR spectrum, ꢁ, ppm: 55.8; 65.6; 111.9; 115.2;
121.6; 122.2; 123.1; 123.4; 129.8; 131.3; 131.9; 139.5; 143.0; 154.6; 157.2. Mass spectrum, m/z (Irel, %): 295
[M+1]+ (25), 294 [M]+ (100), 293 [M–H]+ (68), 279 (21), 147 (13), 145 (17), 134 (11), 103 (11), 77 (14).
Found, %: C 69.40; H 4.89; N 9.41. C17H14N2OS. Calculated, %: C 69.36; H 4.79; N 9.52.
Isomerization of 2,3-Dihydro]1,3]thiazolo[3,2-a]benzimidazoles 3c–e into Thiazolo[3,2-a]benzimid-
azoles 4c–e. Compound 3 (5 mmol) was dissolved in ethanol (10 ml), KOH (0.28 g, 5 mmol) was added and the
764
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mixture heated to boiling for 30 min, after which the solvent was removed under reduced pressure, and the
reaction product was recrystallized from a 1,4-dioxane–water mixture.
2-Benzyl[1,3]thiazolo[3,2-a]benzimidazole (4c). Yield 1.2 g (93%); colorless crystals; mp 222–224oC.
IR spectrum, ꢂ, cm–1: 3027, 2920, 1592, 1453, 1321, 1275, 1240, 737, 705. 1H NMR spectrum, ꢁ, ppm (J, Hz):
4.18 (2H, s, CH2); 7.22–7.40 (7H, m, H Ar); 7.64 (1H, d, J = 7.9, H Ar); 7.94 (1H, d, J = 7.9, H Ar); 8.28 (1H, s,
H-3). 13C NMR spectrum, ꢁ, ppm: 33.9; 111.3; 116.1; 118.4; 120.7; 122.9; 128.5; 128.6; 128.7; 129.5; 129.9;
138.5; 146.9; 155.5. Found, %: C 72.54; H 4.69; N 10.41. C16H12N2S. Calculated, %: C 72.70; H 4.58; N 10.60.
2-(4-Bromobenzyl)[1,3]thiazolo[3,2-a]benzimidazole (4d). Yield 1.6 g (93%); light-yellow needle-
1
like crystals; mp 235–236oC. IR spectrum, ꢂ, cm–1: 3090, 2919, 1615, 1590, 1456, 1322, 1275, 1235, 738. H
NMR spectrum, ꢁ, ppm (J, Hz): 4.10 (2H, s, CH2); 7.10–7.20 (2H, m, H Ar); 7.25 (2H, d, J = 8.0, H Ar); 7.44
(2H, d, J = 8.0, H Ar); 7.59 (1H, d, J = 8.0, H Ar); 7.75 (1H, d, J = 8.0, H Ar); 7.99 (1H, s, CH). 13C NMR
spectrum, ꢁ, ppm: 33.9; 110.70; 115.9; 118.6; 120.3; 120.5; 122.6; 127.4; 129.6; 130.5; 131.5; 137.3; 147.2;
155.4. Mass spectrum, m/z (Irel, %): 345 [M+3]+ (21), 344 [M+2]+ (100), 343 [M+1]+ (53), 342 [M]+ (98), 341
[M–H]+ (35), 263 (18), 204 (11), 187 (19), 131 (22), 102 (17). Found, %: C 55.87; H 3.45; N 7.89.
C16H11BrN2S. Calculated, %: C 55.99; H 3.23; N 8.16.
2-(4-Methoxybenzyl)[1,3]thiazolo[3,2-a]benzimidazole (4e). Yield 1.39 g (95%); light-yellow needle-
like crystals; mp 198–199oC. IR spectrum, ꢃ, cm–1: 3092, 2931, 2837, 1609, 1510, 1456, 1303, 1276, 1242,
1
1209, 1035, 744. H NMR spectrum, ꢁ, ppm (J, Hz): 3.79 (3H, s, CH3); 4.07 (2H, s, CH2); 6.84 (2H, d,
J = 8.0, H Ar); 7.13–7.18 (2H, m, H Ar); 7.20 (2H, d, J = 8.0, H Ar); 7.56 (1H, d, J = 8.0, H Ar); 7.74 (1H, d,
J = 8.0, H Ar); 7.93 (1H, s, CH). 13C NMR spectrum, ꢁ, ppm: 34.0; 55.9; 112.1; 115.0; 116.6; 119.2; 121.6;
123.8; 126.2; 130.2; 130.5; 131.2; 134.6; 159.1; 159.2. Mass spectrum, m/z (Irel, %): 295 [M+1]+ (23), 294 [M]+
(100), 293 [M–H]+ (50), 279 (14), 263 (17), 147 (11), 134 (10), 102 (11). Found, %: C 69.45; H 4.71; N 9.43.
C17H14N2OS. Calculated, %: C 69.36; H 4.79; N 9.52.
4H-[1,3]Thiazino[3,2-a]benzimidazole (5a). Yield 0.64 g (68%); colorless needle-like crystals; mp
151–153oC. IR spectrum, ꢂ, cm–1: 3061, 3049, 2953, 2925, 2830, 1614, 1478, 1464, 1454, 1446, 1407, 1272,
1262, 1255, 1154, 1143, 1000, 959, 867, 857, 809, 774, 747, 738, 668, 625. 1H NMR spectrum, ꢁ, ppm (J, Hz):
3
4
3
3
4
4.95 (2H, dd, J = 3.6, J = 2.2, CH2); 6.21 (1H, dt, 3J = 10.3, J = 3.6, H-3); 6.64 (1H, d t, J = 10.3, J = 2.2,
H-2); 7.23 (2H, m, H Ar); 7.44–7.55 (2H, m, H Ar). 13C NMR spectrum, ꢁ, ppm 43.9 (CH2); 110.4 (CH); 115.6
(CH); 117.2 (CH); 118.3 (CH); 122.6 (CH); 123.2 (CH); 135.3; 143.3; 143.6. Found: m/z: 189.0560 [M+H]+.
C10H9N2S. Calculated: [M+H]+ 189.0486.
2-Methyl-4H-[1,3]thiazino[3,2-a]benzimidazole (5b). Yield 0.65 g (65%); light-beige laminar crys-
tals; mp 252–253oC. IR spectrum, ꢂ, cm–1: 3144, 3104, 3071, 2987, 2949, 2917, 2830, 1611, 1502, 1478, 1426,
1
1363, 1338, 1233, 1193, 1114, 998, 774, 738, 611, 557, 421. H NMR spectrum, ꢁ, ppm (J, Hz): 2.34 (3H, s,
CH3); 5.07 (2H, d, J = 5.8, CH2); 5.86 (1H, t, J = 5.8, H-3); 7.15–7.30 (4H, m, H Ar). 13C NMR spectrum, ꢁ,
ppm: 29.2 (CH3); 46.0 (CH2); 110.2; 110.7; 123.3; 123.4; 124.0; 126.6; 131.0; 132.9; 168.2. Found: m/z
203.0690 [M+H]+. C11H11N2S. Calculated: [M+H]+ 203.0643. Found, %: C 65.26; H 4.87; N 13.74. C11H10N2S.
Calculated, %: C 65.32; H 4.98; N 13.85.
The authors are deeply grateful to associate professor S. I. Selivanova for recording the NMR spectra.
The authors thank the Saint-Petersburg State University for financial support (Research grant 12.38.14.2011).
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