Reaction of N-(carbamimidoyl)thiourea with 1-benzoyl-2-phenylacetylene

Article abstract of DOI:10.1134/S1070428007010162

1-Benzoyl-2-phenylacetylene reacted with N-(carbamimidoyl)thiourea in glacial acetic acid saturated with 20% HBr to give (4,6-diphenyl-2H-1,3-thazin- 2-ylidene)guanidine hydrobromide. The reaction of the same compounds in anhydrous ethanol in the presence

Full text of DOI:10.1134/S1070428007010162

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 1, pp. 121–125. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © T.E. Glotova, M.Yu. Dvorko, A.I. Albanov, N.I. Protsuk, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 1,
pp. 115–119.
Reaction of N-(Carbamimidoyl)thiourea
with 1-Benzoyl-2-phenylacetylene
T. E. Glotova, M. Yu. Dvorko, A. I. Albanov, and N. I. Protsuk
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: glotova@irioch.irk.ru
Received January 4, 2006
Abstract—1-Benzoyl-2-phenylacetylene reacted with N-(carbamimidoyl)thiourea in glacial acetic acid
saturated with 20% HBr to give (4,6-diphenyl-2H-1,3-thazin-2-ylidene)guanidine hydrobromide. The reaction
of the same compounds in anhydrous ethanol in the presence of sodium ethoxide led to the formation of N-(4,6-
diphenylpyrimidin-2-yl)thiourea. Bis(3-oxo-1,3-diphenylprop-1-en-1-yl) sulfide and 1-benzoyl-2-ethylsulfanyl-
2-phenylethylene were isolated in the reactions of 1-benzoyl-2-phenylacetylene with N-(carbamimidoyl)thio-
urea and N-(carbamimidoyl)-S-ethylisothiuronium bromide, respectively, in anhydrous methanol.
DOI: 10.1134/S1070428007010162
Reactions of sulfur- and nitrogen-containing ambi-
dent nucleophiles, including N-(carbamimidoyl)thio-
urea, with α-acetylenic ketones can take different path-
ways, depending on the conditions and substituents in
the reactants. Therefore, such reactions may be used
for selective synthesis of various heterocycles which
attract interest as potential biologically active sub-
stances, dyes, extractants for noble metals, and rubber
vulcanizing agents. N-(Carbamimidoyl)thiourea is
known to react with α-halo ketones, 2-acylcycloalka-
nones, and thiophosgene to give functionally substitut-
ed derivatives of thiazole [1, 2], pyrimidine [3], and
1,3,5-thiadiazine [4], some of which are important
from the viewpoint of application in medicine and agri-
culture; it also seems to be promising to use N-(car-
bamimidoyl)thiourea as N,N- or S,N-ligand in com-
plex formation with metals [5].
reactions of 1-benzoyl-2-phenylacetylene with N-(car-
bamimidoyl)thiourea and N-(carbamimidoyl)-S-ethyl-
isothiuronium bromide in AcOH, EtOH, MeOH under
acidic (HBr) and basic (EtONa, Et3N) conditions.
1-Benzoyl-2-phenylacetylene (I) reacted with N-(car-
bamimidoyl)thiourea (II) at 20°C in glacial acetic acid
saturated with 20% HBr to give (4,6-diphenyl-2H-1,3-
thia-zin-2-ylidene)guanidine hydrobromide (III) with
high chemoselectivity (yield 91%, Scheme 1). Presum-
ably, the reaction begins with nucleophilic attack by
the sulfur atom of thiourea on the electron-deficient
β-carbon atom in activated acetylene I. The subsequent
attack by the nitrogen atom on the carbonyl carbon
atom in intermediate isothiuronium salt A is accom-
panied by closure of 1,3-thiazine ring and elimination
of water molecule.
Molecule II may be regarded as a composition of
thiourea and guanidine fragments. It is known that
thiourea reacts with α,β-unsaturated carbonyl com-
pounds under acidic conditions to form isothiourea
In continuation of our studies on reactions of
α-acetylenic ketones with S,N-centered ambident nu-
cleophiles [6–9], in the present work we examined
Scheme 1.
Ph
Ph
Br–
NH2
NH
Ph
N
S
NH
20% HBr/AcOH
O
HN
S
S
NH2
NH
+
COPh
·HBr
Ph
–H2O
H2N
N
H
NH2
HN
Ph
N
I
II
A
III
121

GLOTOVA et al.
122
derivatives due to the ability of thiourea to undergo
isomerization to isothiuronium salts in acid medium
[10–12]. Therefore, the formation of intermediate A in
the first stage of the acid-catalyzed reaction of 1-ben-
zoyl-2-phenylacetylene (I) with N-(carbamimidoyl)-
thiourea (II) (Scheme 1) seems to be quite reasonable.
The dehydration stage is also catalyzed by acid which
favors formation of mesomeric carbenium–oxonium
ion possessing an enhanced affinity for the nucleo-
philic partner [13].
pyrimidine derivatives VI–VIII, may be expected in
base-catalyzed reactions of thiourea II with unsaturat-
ed ketone I (Scheme 3).
In the reaction of acetylene I with thiourea II in
anhydrous ethanol in the presence of sodium ethoxide
(heating under argon) we isolated 55% of N-(4,6-di-
phenylpyrimidin-2-yl)thiourea (VI) as the only product
(Scheme 3). Its structure was established on the basis
1
of the H, 13C, and 15N NMR data, as well as by
chemical transformation. The 1H NMR spectrum of the
product contained only two multiplet signals belonging
to protons of two phenyl rings in positions 4 and 6 of
the heteroring. The shape of these signals indicated
that both phenyl rings are equivalent and hence that the
pyrimidine ring is substituted in a symmetric mode.
Likewise, only one set of narrow peaks was observed
in the aromatic region of the 13C NMR spectrum. The
signals were assigned using two-dimensional C–H
correlation technique. From the inverse HSQC 15N–1H
spectrum we determined the chemical shifts of the ni-
trogen atoms in the thiourea fragment, for these atoms
are directly linked to protons: δN (relative to MeNO2)
–256.3 (NH2) and –235.3 ppm (NH). The two-dimen-
sional HMBC 15N–1H spectrum contained only one
cross peak between the CH= proton and nitrogen
atoms in the pyrimidine ring (δN –135.6 ppm), which
also confirmed complete equivalence of the ring nitro-
gen atoms.
Scheme 2.
NH
+
2 Ph
COPh
· H2CO3
H2N
NH2
2
I
IV
Ph
EtONa
N
2
–Na2CO3
Ph
N
NH2
V
Baddar et al. [14] reported on the synthesis of pyri-
midine-2-thione derivatives from 1-aroyl-2-phenylace-
tylenes and thiourea or N-monosubstituted thiourea on
heating in ethanol in the presence of sodium ethoxide.
We have found that the reaction of acetylenic ketone I
with diguanidine dihydrogen carbonate (IV) in the
system EtONa–EtOH leads to the formation of 82% of
4,6-diphenylpyrimidin-2-amine (V) (Scheme 2). Thus,
the formation of several alternative products, namely
After isolation of pyrimidine VI, the residue was
a complex mixture of unidentifiable products which
were likely to be formed via polycondensation of the
carbamimidoylthiourea fragments resulting from hy-
drolysis and alkaline cleavage. By heating compound
VI with ethyl bromide in ethanol we obtained the
corresponding S-ethyl derivative IX (Scheme 3); this
result allowed us to rule out alternative structure VII
for the condensation product of compounds I and II.
Scheme 3.
Ph
N
NH2
I
+
II
Ph
Ph
N
N
H
S
VI
When the reaction of benzoylacetylene I with
an equimolar amount of thiourea II was performed in
anhydrous methanol at 20°C, the major product was
(E,Z)-3,3'-thiobis(1,3-diphenylprop-2-en-1-one) (X); it
was isolated in 50% yield (Scheme 4). The process is
likely to include nucleophilic addition to give interme-
diate sulfide B, and dissociation of the C–S bond in the
latter leads to thiol C and cyanoguanidine XI; thiol C
then reacts with another molecule of acetylene I,
yielding sulfide X. The 13C NMR spectrum of the
reaction mixture after separation of sulfide X showed
the presence of only unreacted initial thiourea II and
cyanoguanidine XI in approximately equal amounts.
EtBr
N
NH
·HBr
Ph
N
N
H
SEt
Ph
IX
Ph
N
NH2
NH
NH2
N
N
S
Ph
S
Ph
N
NH
VII
VIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 1 2007

REACTION OF N-(CARBAMIMIDOYL)THIOUREA
123
Scheme 4.
H
H
N
Ph
S
N
NH2
Ph
SH
NH2
MeOH, 20°C
NC
I
+
II
+
O
Ph
NH
NH
O
Ph
NH
XI
B
C
Ph
S
Ph
I
C
COPh COPh
X
With a view to obtain heterocyclization products at
the amidine fragment, we tried to react compound I
with N-(carbamimidoyl)-S-ethylisothiuronium bromide
(XII) in anhydrous methanol. However, no reaction
occurred even at the boiling point, whereas the reac-
tion performed in the presence of an equimolar amount
of triethylamine on heating led to the formation of
3-ethylsulfanyl-1,3-diphenylprop-2-en-1-one (XIII)
(yield 61%) and cyanoguanidine (XI) (Scheme 5). This
result may be rationalized assuming facile base-cata-
lyzed decomposition of isothiuronium salt XII to
cyanoguanidine and ethanethiol which adds to acety-
lene I to give compound XIII.
(4,6-Diphenyl-2H-1,3-thiazin-2-ylidene)guani-
dine hydrobromide (III). N-(Carbamimidoyl)thiourea
(II), 1.18 g (10 mmol), was added in portions under
stirring to a solution of 2.06 g (10 mmol) of 1-benzoyl-
2-phenylacetylene (I) in 30 ml of glacial acetic acid
saturated with 20% HBr. The mixture was stirred for
1 h at 20°C, the precipitate was filtered off and dis-
persed in a mixture of 20 ml of ethanol and 10 ml of
diethyl ether, the suspension was stirred for 1 h, and
the precipitate was filtered off, washed with 20 ml of
diethyl ether, and dried under reduced pressure. Yield
3.53 g (91%), yellow crystals, mp 232–234°C. IR spec-
trum, ν, cm–1: 3110, 3300, 3405 (NH2, H2N+); 1630
(C=Nguan); 1460–1550 (C=C, C=N), 680 (C–S).
1H NMR spectrum, δ, ppm: 7.62–7.73 m (6H, m-H,
p-H), 8.01 d (2H, o-H), 8.32 d (2H, o-H), 8.08 s (1H,
5-H), 8.34 br.s (2H, NH2), 8.58 br.s (2H, H2N+).
13C NMR spectrum, δC, ppm: 110.44 (C5); 127.30,
129.17, 129.35, 129.73, 133.03, 133.83, 134.02, 136.20
(Carom); 160.35 (C6); 162.87 (Cguan); 165.90 (C4); 169.41
(C2). Found, %: C 52.91; H 3.76; Br 20.32; N 14.49;
S 7.95. C17H14N4S·HBr. Calculated, %: C 52.72;
H 3.90; Br 20.63; N 14.46; S 8.28.
Scheme 5.
SEt
NH
Et3N, MeOH, Δ
·HBr
[EtSH]
HN
N
NH2
Ph
H
XII
H
N
SEt
NH2
I
NC
+
–Et3N·HBr
O
Ph
XIII
NH
XI
4,6-Diphenylpyrimidin-2-amine (V). A mixture of
1.03 g (5 mmol) of 1-benzoyl-2-phenylacetylene (I)
and 0.34 g (5 mmol) of sodium ethoxide in 20 ml of
anhydrous ethanol was added while stirring under
argon to a suspension of 0.45 g (2.5 mmol) of diguani-
dine dihydrogen carbonate (IV) in 5 ml of anhydrous
ethanol. The mixture was heated to the boiling point,
stirred for 4 h at that temperature under argon, cooled,
poured into 100 ml of water, and acidified with acetic
acid to pH 6–7. The precipitate was filtered off and
dried under reduced pressure. Yield 1.01 g (82%),
colorless needles, mp 133–134°C (from MeCN); pub-
lished data [16]: mp 135–137°C (from toluene). IR
spectrum, ν, cm–1: 3430, 3290 (NH2); 1500–1620
Taking into account the available published data,
we can conclude that the behavior of N-(carbam-
imidoyl)thiourea and N-(carbamimidoyl)-S-ethyliso-
thiourea in reactions with 1-benzoyl-2-phenylacetylene
under the above conditions is similar to the behavior of
thiourea [15] and S-benzylisothiourea [14] in reactions
with aroyl(phenyl)acetylenes, where products of sulfur
addition to the latter were also formed.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Bruker
1
13
IFS-25 instrument. The H, C, and 15N NMR spectra
were obtained on a Bruker DPX-400 spectrometer at
400.13 (1H) and 100.61 MHz (13C) using DMSO-d6 as
solvent.
1
(C=C, C=N). H NMR spectrum, δ, ppm: 6.76 s (2H,
NH2), 7.51–8.22 m (10H, Harom), 7.70 s (1H, 5-H).
13C NMR spectrum, δC, ppm: 101.96 (C5); 127.07,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 1 2007

GLOTOVA et al.
124
128.69, 130.51, 137.46 (Carom); 164.14 (C2); 164.99
(C4, C6). Found, %: C 77.56; H 5.56; N 17.23.
C16H13N3. Calculated, %: C 77.71; H 5.30; N 16.99.
[17]. 13C NMR spectrum, δC, ppm: 125.79, 125.95
(CH=); 128.33–139.78 (Carom); 153.56, 154.38 (S–C=);
189.07, 189.24 (C=O). Found, %: C 80.42; H 4.86;
S 7.16. C30H22O2S. Calculated, %: C 80.69; N 4.96;
S 7.18.
N-(4,6-Diphenylpyrimidin-2-yl)thiourea (VI).
A mixture of 1.03 g (5 mmol) of 1-benzoyl-2-phenyl-
acetylene (I) and 0.34 g (5 mmol) of sodium ethoxide
in 20 ml of anhydrous ethanol was added while stirring
under argon to a suspension of 0.59 g (5 mmol) of
compound II in 5 ml of anhydrous ethanol. The mix-
ture was heated to the boiling point, stirred for 4 h at
that temperatue under argon, and kept for 12 h at 5–
8°C. The precipitate was filtered off, washed with 5 ml
of cold ethanol, and dried under reduced pressure.
Yield 0.84 g (55%), colorless crystals, mp 222–224°C
(from EtOH). IR spectrum, ν, cm–1: 3150, 3300, 3390
The filtrate was evaporated to dryness, the residue
was ground with diethyl ether, and the precipitate was
filtered off to isolate 0.42 g of a colorless crystalline
13
substance which (according to the C NMR data) was
an approximately equimolar mixture of initial N-(car-
bamimidoyl)thiourea (II) and cyanoguanidine (XI).
13C NMR spectrum, δC, ppm: II: 188.11 (C=S), 161.90
(C=NH); XI: 118.89 (C≡N), 163.08 (C=NH).
3-Ethylsulfanyl-1,3-diphenylprop-2-en-1-one
(XIII). 1-Benzoyl-2-phenylacetylene (I), 1.03 g
(5 mmol), was dissolved in 20 ml of anhydrous metha-
nol, 1.14 g (5 mmol) of N-(carbamimidoyl)-S-ethyliso-
thiuronium bromide (XII) and 0.505 g (5 mmol) of
triethylamine were added, and the mixture was stirred
for 3 h under reflux. The solvent was distilled off, the
residue was ground with 40 ml of diethyl ether, and the
precipitate was filtered off. The ether extract was evap-
orated to dryness to obtain 0.82 g (61%) of compound
XIII as a thick oily substance which crystallized on
storage, mp 92°C (bright yellow crystals from EtOH).
IR spectrum, ν, cm–1: 1620 (C=O), 1480–1510 (C=C),
1
(NH, NH2); 1490–1585 (C=C, C=N). H NMR spec-
trum, δ, ppm: 8.22 s (1H, 5-H), 8.27 d (4H, o-H),
7.55–7.59 m (6H, m-H, p-H), 9.22 and 10.39 (2H,
NH2), 10.56 (1H, NH). 13C NMR spectrum, δC, ppm:
107.46 (C5); 127.59, 129.20, 131.75, 135.96 (Carom);
158.11 (C2); 165.24 (C4, C6); 181.18 (C=S). Found, %:
C 66.45; H 4.48; N 18.35; S 10.24. C17H14N4S. Cal-
culated, %: C 66.64; H 4.60; N 18.28; S 10.46.
N-(4,6-Diphenylpyrimidin-2-yl)-S-ethylisothiuro-
nium bromide (IX). A mixture of 0.306 g (1 mmol) of
compound VI and 5 ml of ethyl bromide in 20 ml of
anhydrous ethanol was stirred for 12 h at 40°C. The
solution was evaporated under reduced pressure, the
residue was ground with 20 ml of water, and the pre-
cipitate was filtered off and dried under reduced pres-
sure over CaCl2. Yield 0.3 g (72%), colorless powder,
mp 169–170°C. IR spectrum, ν, cm–1: 2800–3100 (HN,
H2N+), 1500–1600 (C=C, C=N). 1H NMR spectrum, δ,
ppm: 1.36 t (3H, CH3), 3.34 q (2H, CH2), 7.58–8.28 m
(10H, Harom), 8.41 s (1H, 5-H), 11.5 br.s (2H, HN,
HN=). 13C NMR spectrum, δC, ppm: 13.99 (CH3);
25.79 (CH2); 110.24 (C5); 128.09, 129.56, 132.46,
135.51 (Carom); 157.89 (C2); 165.91 (C4, C6); 170.19
(C–S). Found, %: C 55.12; H 4.48; Br 19.01; N 13.35;
S 7.58. C19H18N4S·HBr. Calculated, %: C54.94; H 4.61;
Br 19.23; N 13.48; S 7.72.
1
700 (C–S). H NMR spectrum, δ, ppm: 0.95 t (3H,
CH3), 2.38 q (2H, CH2), 7.10 s (1H, CH=), 7.46–
7.91 m (10H, Harom). 13C NMR spectrum, δC, ppm:
13.89 (CH3); 26.08 (CH2); 120.22 (C2); 127.49,
127.64, 128.18, 128.27, 128.53, 131.92, 138.02, 138.28
(Carom); 160.94 (C3); 187.32 (C=O). Found, %:
C 76.27; H 5.86; S 12.12. C17H16OS. Calculated, %:
C 76.08; H 6.00; S 11.95.
The material insoluble in ether was recrystallized
from 20 ml of water to obtain 0.13 g (31%) of cyano-
guanidine (XI) as colorless crystals with mp 201–
202°C; published data [18]: mp 206–208°C. IR spec-
trum, ν, cm–1: 3151–3427 (NH, NH2), 2162–2207
(C≡N). 13C NMR spectrum, δC, ppm: 118.91 (C≡N),
163.10 (C=NH). Found, %: C 28.59; H 5.03; N 66.83.
C2H4N4. Calculated, %: C 28.57; H 4.76; N 66.67.
3,3'-Thiobis(1,3-diphenylprop-2-en-1-one) (X).
1-Benzoyl-2-phenylacetylene (I), 1.03 g (5 mmol),
was added in small portions under stirring to a suspen-
sion of 0.59 g (5 mmol) of thiourea II in 20 ml of
anhydrous methanol. The mixture was stirred for 3 h at
20°C, and the precipitate was filtered off, washed with
methanol, and dried under reduced pressure. Yield
0.56 g (50%), yellow crystals, mp 134–136°C (E,Z-
isomer); published data: mp 139°C [15], 135–136°C
REFERENCES
1. Katsura, Y., Nishino, S., Tomishi, T., Sakane, K., Matsu-
moto, Y., Ishikawa, H., and Takasugi, H., Bioorg. Med.
Chem. Lett., 1998, vol. 8, p. 1307.
2. Srimanth, K. and Rajesuwar Rao, V., Indian J. Chem.,
Sect. B, 1999, vol. 38, p. 473.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 1 2007

REACTION OF N-(CARBAMIMIDOYL)THIOUREA
125
11. Kataev, E.G., Konovalova, L.K., and Yarkova, E.G.,
Zh. Org. Khim., 1969, vol. 5, p. 621.
12. Konovalov, A.I., Konovalova, L.K., and Kataev, E.G.,
Zh. Org. Khim., 1974, vol. 10, p. 1580.
3. Sevenard, D.M., Khomutov, O.G., Koryakova, O.V.,
Sattarova, V.V., Kodess, M.I., Stelten, J., Loop, I.,
Lork, E., Pashkevich, K.I., and Roschenthaler, G.V.,
Synthesis, 2000, vol. 12, p. 1738.
13. Becker, H., Einführung in die Elektronentheorie orga-
nisch–chemischer Reaktionen, Berlin: Wissenschaften,
1974, 3rd ed. Translated under the title Vvedenie v
elektronnuyu teoriyu organicheskikh reaktsii, Moscow:
Mir, 1977, p. 291.
14. Baddar, F.G., Al-Hajjar, F.H., and El-Rayyes, N.R.,
J. Heterocycl. Chem., 1978, vol. 15, p. 105.
15. Basyouni, M.N. and Omar, M.T., Aust. J. Chem., 1974,
4. Oliver, J.E. and DeMilo, A.B., J. Heterocycl. Chem.,
1971, vol. 8, p. 1087.
5. Cheng San-Ting, Doxiadi, E., Vilar, R., White, A.J.P.,
and Williams, D.J., J. Chem. Soc., Dalton Trans., 2001,
p. 2239.
6. Glotova, T.E., Protsuk, N.I., Kanitskaya, L.V., Dolgu-
shin, G.V., and Lopyrev, V.A., Khim. Geterotsikl. Soe-
din., 2004, p. 1848.
vol. 27, p. 1585.
7. Glotova, T.E., Protsuk, N.I., Albanov, A.I., Lopy-
rev, V.A., and Dolgushin, G.V., Cent. Europ. J. Chem.,
2003, vol. 3, p. 222.
16. Clark, J.H., English, J.P., Winnek, P.S., Marson, H.W.,
Cole, Q.P., and Clapp, J.W., J. Am. Chem. Soc., 1946,
vol. 68, p. 96.
8. Glotova, T.E., Protsuk, N.I., Dvorko, M.Yu., and Alba-
17. Baddar, F.G., Al-Hajjar, F.H., and El-Rayyes, N.R.,
nov, A.I., Russ. J. Org. Chem., 2004, vol. 40, p. 1222.
J. Heterocycl Chem., 1976, vol. 13, p. 691.
9. Glotova, T.E., Dvorko, M.Yu., and Albanov, A.I., Russ.
J. Org. Chem., 2005, vol. 41, p. 629.
18. Inorganic Syntheses, Audrieth, L.F., Ed., New York:
McGraw-Hill, 1950. vol. 3. Translated under the title
Neorganicheskie sintezy, Moscow: Inostrannaya Litera-
tura, 1952, vol. 3, p. 44.
10. Cavallito, C.J., Martini, C.M., and Nachod, F.C., J. Am.
Chem. Soc., 1951, vol. 73, p. 2544.
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