Cyclocondensation of N-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole

Article abstract of DOI:10.1134/S1070428008080162

Cyclization of N-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole gave 7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-5-thione or 2-methylpyrimido[1,2-a]benzimidazole-4(1H)-thione and 4-(arylamino)-2- methylpyrimido[1,2-a]benzimidazoles whose ratio depends on the nature of aryl substituents in the initial butanethioamides and on the presence of a protic solvent.

Full text of DOI:10.1134/S1070428008080162

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 8, pp. 1200–1204. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © E.I. Maiboroda, V.N. Britsun, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 8, pp. 1213–1217.
Cyclocondensation of N-Aryl-3-oxobutanethioamides
with 2-Aminoimidazole and 2-Aminobenzimidazole
E. I. Maiborodaa and V. N. Britsunb
a Kiev National University of Technology and Design, Kiev, Ukraine
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: bvn1967@rambler.ru
Received January 9, 2008
Abstract—Cyclization of N-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole
gave 7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-5-thione or 2-methylpyrimido[1,2-a]benzimidazole-
4(1H)-thione and 4-(arylamino)-2-methylpyrimido[1,2-a]benzimidazoles whose ratio depends on the nature of
aryl substituents in the initial butanethioamides and on the presence of a protic solvent.
DOI: 10.1134/S1070428008080162
N-Aryl-3-oxobutanethioamides are useful reagents
for the synthesis of various sulfur- and nitrogen-con-
taining heterocycles; they can also be used as com-
plexing agents and model structures for studying keto–
enol–enethiol tautomerism [1]. Increased interest in the
chemistry of N-aryl-3-oxobutanethioamides has stimu-
lated development of preparative procedures for their
synthesis [2, 3].
depended on the nucleophile basicity, acidity of the
medium, and substituent in the benzene ring of the
initial thioamide [4–8].
In the present work we examined heterocyclization
of N-aryl-3-oxobutanethioamides Іa–Ie with such
strongly basic aminoazoles as 2-aminoimidazole (ІІa)
and 2-aminobenzimidazole (ІІb) (pKa 8.35 and 7.39,
respectively [9]). We were interested in regioselectivity
of the process, specifically in the effect of the nature of
substituent in the benzene ring of the initial thioamide
on the reaction direction in protic solvents (acetic or
propionic acid) and in the absence of protic solvent.
Insofar as the process follows the [3+3]-cycloconden-
sation pattern, it may involve three possible reaction
centers in N-aryl-3-oxobutanethioamides Іa–Ie and
We recently published a series of studies on cyclo-
condensation of N-aryl-3-oxobutanethioamides with
nitrogen-containing 1,3-binucleophiles [4–8]. As the
latter we used 2-aminoazoles and 2-aminoazines with
pKa values ranging from 1.82 to 6.86. The products of
these condensations were bicyclic derivatives of aryl-
aminopyrimidines and pyrimidinethiones whose ratio
Scheme 1.
S
NHAr
N
R
R
R
O
S
N
N
+
+
Ar
R
R
Me
N
R
NH2
N
N
N
H
Me
N
H
Me
N
H
Ia–Ie
IIa, IIb
IIIa, IIIb
IVa–IVe
O
S
S
P2S5
(1) KOH; (2) MeI
N
N
N
Me
Me
Me
N
N
N
N
N
N
H
H
Me
V
IIIb
VI
IIa, IIIa, R = H; IIb, IIIb, IV, RR = benzo; I, IV, Ar = Ph (a), 4-MeOC6H4 (b), 4-MeC6H4 (c), 3-ClC6H4 (d), 3-CF3C6H4 (e).
1200

CYCLOCONDENSATION OF N-ARYL-3-OXOBUTANETHIOAMIDES
1201
Reactions of N-aryl-3-oxobutanethioamides Ia–Ie with
2-aminoimidazole (IIa) and 2-aminobenzimidazole (IIb)
two centers in 2-aminoazoles ІІa and IIb; as a result,
the products may be four compounds of the imidazo-
[1,2-a]pyrimidine series.
Yield, %; ratio III:IV
Initial
compounds
Hammett
constant σ
We found that, unlike cyclizations of ethyl aceto-
acetate with 2-aminoimidazole [10] and 2-aminobenz-
imidazole [11], the reaction under study was not selec-
tive: the products were mixtures of fused heterocyclic
compounds IIIa or IIIb and IVa–IVe, whose ratio
depended on the nature of the N-aryl substituent in the
initial thioamide and on the presence of a protic sol-
vent (Scheme 1, see table).
Products
EtCOOH no solvent
Іa + IІa
IIIa
42
–
–0.000
–0.000
–0.268
–0.170
+0.373
+0.430
Іa + IІb IIIb, IVa
Іb + IІb IIIb, IVb
20:28
31:10
36:17
15:28
10:38
28:26
00:49
22:33
31:25
27:20
Іc + IІb
Іd + IІb IIIb, IVd
Іe + IІb IIIb, IVe
IIIb, IVc
2-Methyl-4-(4-tolylamino)pyrimido[1,2-a]benz-
imidazole (IVc) was synthesized previously from
4-chloro-2-methylpyrimido[1,2-a]benzimidazole and
4-toluidine and was patented as antihypertensive agent
[12]. Therefore, we presumed that all compounds IVa–
IVe have the structure of 4-(arylamino)-2-methylpyri-
generation of the corresponding anion by the action of
bases. The negative charge in that anion is delocalized
over the thiolic sulfur atom and N1 atom in the pyri-
midine ring. In addition, the formation of carbon–
nitrogen bond is more favorable than the formation of
carbon–sulfur bond for energy reasons (the energies
of formation of the C–N and C–S bonds are 285 and
272 kJ/mol, respectively) [14]. Thus, S- and N-alkyla-
tion are, respectively, the kinetically and thermody-
namically controlled processes.
1
mido[1,2-a]benzimidazoles. However, the H NMR
data did not allow us to unambiguously identify prod-
ucts ІІІa and IIIb as 2-methylimidazo[1,2-a]pyrimi-
dine-4-thiones or 4-methylimidazo[1,2-a]pyrimidine-
2-thiones. To determine their structure, we synthesized
2-methylpyrimido[1,2-a]benzimidazol-4(1H)-one (V)
according to the procedure described in [11], and com-
pound V was treated with tetraphosphorus decasulfide
in pyridine to obtain 2-methylpyrimido[1,2-a]benz-
imidazole-4(1H)-thione (IIIb). The 1H NMR spectra of
samples of IIIb synthesized by reaction of thioamide
Ia with 2-aminobenzimidazole (IIb) and by sulfuriza-
tion of compound V were fully identical, and their
mixture showed no depression of the melting point.
Unlike 7-methyl-5,8-dihydro[1,2,4]triazolo[1,5-a]pyri-
midine-5-thiones [4], alkylation of 2-methylpyrimido-
[1,2-a]benzimidazole-4(1H)-thione (IIIb) with methyl
iodide occurred at the N1 rather than sulfur atom to
give 1,2-dimethylpyrimido[1,2-a]benzimidazole-
4(1H)-thione (VI). Presumably, the different regiose-
lectivity in the alkylation of IIIb is determined by the
effect of the fused benzene ring [13], which reduces
π-electron density on the azole ring and thus facilitates
1
In the H NMR spectra of imidazo[1,2-a]pyrimi-
dinethiones IIIa, IIIb, and VI characteristic are sing-
lets from the 2(7)-CH3, 3-H, and 6-H protons (δ 2.33–
2.36, 6.95–7.02, and 9.72–9.76 ppm, respectively),
while 4-(arylamino)pyrimido[1,2-a]benzimidazole-
4(1H)-thiones IVa–IVe displayed singlets from the
2-CH3, 3-H, and 6-H protons at δ 2.15–2.18, 5.52–
5.55, and 8.58–8.62 ppm, respectively. It is seen that
the chemical shifts of protons in the imidazole and
pyrimidine rings of compounds IVa–IVe are lower by
1.10–1.47 ppm than the corresponding values for
compounds IIIa, IIIb, and VI; presumably, increased
shielding of the above protons in IVa–IVe is related to
conjugation between the lone electron pair on the ni-
trogen atom in the arylamino group and bicyclic pyri-
mido[1,2-a]benzimidazole system.
Scheme 2.
Me
H
N
Me
N
N
IIa, IIb
R
R
Ia–Ie
NH
HN
N
S
HS
NHAr
R
R
Ar
A
B
X = H, 4-MeO, 4-Me, 3-Cl, 3-F3C; R = H; RR = benzo.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

MAIBORODA, BRITSUN
1202
Scheme 3.
H
Me
Me
N
N
2H+
R
R
N
N
IIIa, IIIb
IVa–IVe
–ArNH2
–2H+
a
b
–H2S
X
X
HS
N
HS
N
R
R
H
H
H
C
D
B
H
Me
Me
N
N
H+
R
R
N
N
IVa–IVe
IIIa, IIIb
–H2S, –H+
c
d
–ArNH2
X
X
HS
N
HS
N
R
R
H
H
E
F
There are reasons to believe [7, 15] that the reaction
of thioamides Ia–Ie with aminoimidazoles IIa and IIb
involves initial formation of enaminothioamide A
which is converted into tetrahedral intermediate B and
that these processes are reversible (Scheme 2). The
data given in table show that the direction of the sub-
sequent decomposition of intermediate B depends on
both substituent nature in the benzene ring and the
presence of protic solvent (AcOH, EtCOOH). In most
cases, the reaction in the absence of acid is not selec-
tive, and the products are mixtures of imidazo[1,2-a]-
pyrimidines IIIb and IVa and IVc–IVe. Only the con-
densation of N-(4-methoxyphenyl)-3-oxobutanethio-
amide (Ib) selectively gives pyrimidobenzimidazole
IVb (see table). On the whole, the ratio of compounds
IIIb and IVa–IVe changes in parallel with the Ham-
mett constants σ of the corresponding substituents: the
stronger the electron-donating power of the substit-
uent, the lesser the fraction of imidazo[1,2-a]pyrimi-
dine-4-thione (III) and vise versa (the stronger the
electron-withdrawing power of the substituent, the
larger the ratio III:IV).
(Іa) gave 7-methyl-5,8-dihydroimidazo[1,2-a]pyrimi-
dine-5(8H)-thione (IIIa) as the only product. Presum-
ably, the reason is high basicity of initial 2-amino-
imidazole (imidazole), pKa 8.35 (6.99) [9], and easy
formation and subsequent decomposition of interme-
diate C (path a). In going to acid medium, the sub-
stituent effect changes to the opposite. Electron-donat-
ing substituent X favors protonation of the exocyclic
nitrogen atom (intermediate C), which facilitates elim-
ination of aromatic amine and formation of thiones
IIIa and IIIb (path a).
Elimination of hydrogen sulfide from intermediate
B having electron-withdrawing substituent X is likely
to involve formation of structure E protonated at the
N8 atom (path c). Since the energy of the S–C bond is
higher than the energy of the C–N bond, rise in tem-
perature favors the transformation of intermediate E
into compounds IVa–IVe. This assumption is sup-
ported by the fact that thioamides Іd and Ie react with
2-aminobenzimidazole (ІIb) only in propionic acid at
135–140°C, while no reaction occurs in acetic acid at
100–110°C. It is known that less basic 2-amino-4-R-5-
R′-thiazoles (pKa 4.51–5.39) react with N-(4-nitro-
phenyl)-3-oxobutanethioamide in acetic acid at 100–
110°C [6]. Probably, protonation of intermediate E at
the sulfur atom favors formation of arylaminopyrim-
idine derivatives IVa–IVe.
These results may be interpreted as shown in
Scheme 3. If the X substituent is an electron-donating
group (path b, intermediate D), the electron density on
the N–C4 bond increases (the N–C4 bond becomes
stronger), and hydrogen sulfide is released. If the X
substituent is an electron-withdrawing group (path d,
intermediate F), the electron density on the N–C4 bond
decreases, so that its dissociation with elimination of
aromatic amine is favored.
Thus the cyclocondensation of N-aryl-3-oxobutane-
thioamides with 2-aminoimidazoles is generally nonse-
lective, and it gives mixtures of two different products.
On the other hand, the reaction direction may be con-
trolled by using protic solvent, as well as by selecting
appropriate substituent in the benzene ring of the initial
thioamide.
The reactions in acetic or propionic acid were gen-
erally nonselective; only the cyclization of 2-amino-
imidazole (ІІa) with N-phenyl-3-oxobutanethioamide
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

CYCLOCONDENSATION OF N-ARYL-3-OXOBUTANETHIOAMIDES
1203
EXPERIMENTAL
2-Methyl-N-phenylpyrimido[1,2-a]benzimidazol-
4-amine (IVa). mp 311–313°C. H NMR spectrum, δ,
1
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Varian Unity 300 spectrometer
(300 MHz); the chemical shifts were measured relative
to tetramethylsilane as internal reference. 2-Methyl-
pyrimido[1,2-a]benzimidazol-4(1H)-one (V) was syn-
thesized according to the procedure reported in [11].
ppm: 2.17 s (3H, CH3), 5.53 s (1H, 3-H), 6.98 m (2H,
Harom), 7.03 m (1H, 8-H), 7.37 m (4H, Harom, NH),
7.55 m (2H, Harom), 8.60 d (1H, 6-H, J = 7.5 Hz).
Found, %: C 74.66; H 5.24; N 20.57. C17H14N4. Cal-
culated, %: C 74.43; H 5.14; N 20.42.
N-(4-Methoxyphenyl)-2-methylpyrimido[1,2-a]-
benzimidazol-4-amine (IVb). mp 303–305°C.
1H NMR spectrum, δ, ppm: 2.15 s (3H, CH3), 3.76 s
(3H, CH3O), 5.55 s (1H, 3-H), 6.88 d (2H, C6H4, J =
8.5 Hz), 6.94 d (2H, C6H4, J = 8.5 Hz), 7.21 m (1H,
8-H), 7.34 m (1H, 7-H), 7.52 d (1H, 9-H, J = 5.7 Hz),
7.57 br.s (1H, NH), 8.61 d (1H, 6-H, J = 7.8 Hz).
Found, %: C 70.78; H 5.42; N 18.64. C18H16N4O. Cal-
culated, %: C 71.04; H 5.30; N 18.41.
2-Methyl-N-(4-methylphenyl)pyrimido[1,2-a]-
benzimidazol-4-amine (IVc). mp 310–312°C; pub-
lished data [12]: mp 312–313°C. 1H NMR spectrum, δ,
ppm: 2.15 s (3H, 2-CH3), 2.31 s (3H, CH3C6H4), 5.52 s
(1H, 3-H), 6.83 d (2H, C6H4, J = 7.9 Hz), 7.16 m (3H,
C6H4, 8-H), 7.35 m (1H, 7-H), 7.56 d (1H, 9-H, J =
6.3 Hz), 7.63 br.s (1H, NH), 8.60 d (1H, 6-H, J =
7.5 Hz). Found, %: C 75.14; H 5.73; N 19.62.
C18H16N4. Calculated, %: C 74.98; H 5.59; N 19.43.
N-(3-Chlorophenyl)-2-methylpyrimido[1,2-a]-
benzimidazol-4-amine (IVd). mp 323–325°C.
1H NMR spectrum, δ, ppm: 2.18 s (3H, CH3), 5.54 s
(1H, 3-H), 6.89 d (1H, 4′-H, J = 7.2 Hz), 6.95 s (1H,
2′-H), 7.07 m (1H, Harom), 7.20 m (1H, Harom), 7.35 m
(2H, Harom), 7.52 d (1H, 9-H, J = 6.6 Hz), 7.56 br.s
(1H, NH), 8.58 d (1H, 6-H, J = 7.9 Hz). Found, %:
C 66.29; H 4.03; N 18.35. C17H13ClN4. Calculated, %:
C 66.13; H 4.24; N 18.15.
7-Methylimidazo[1,2-a]pyrimidine-5(8H)-thione
(IIIa). A solution of 0.386 g (2 mmol) of 3-oxo-N-
phenylbutanethioamide (Ia), 0.264 g (1 mmol) of
2-aminoimidazole (IІa) sulfate, and 0.164 g of sodium
acetate in 3 ml of acetic acid was heated for 8 h at
110°C. The mixture was cooled, and the precipitate
was filtered off. Yield 0.139 g (42%), mp 330–333°C.
1H NMR spectrum, δ, ppm: 2.33 s (3H, CH3), 6.95 s
(1H, 6-H), 7.80 d (1H, 2-H, J = 2.7 Hz), 8.04 d (1H,
3-H, J = 2.7 Hz), 13.40 br.s (1H, NH). Found, %:
C 51.12; H 3.99; N 25.40. C7H7N3S. Calculated, %:
C 50.89; H 4.27; N 25.43.
4-Arylamino-2-methylpyrimido[1,2-a]benzimid-
azoles IVa–IVe (general procedure). a. A solution of
2 mmol of N-aryl-3-oxobutanethioamide Ia–Ie and
2 mmol of 2-aminobenzimidazole (IІb) in 5 ml of pro-
pionic acid was heated for 7 h at 135°C. The mixture
was cooled, and the precipitate of 2-methylpyrimido-
[1,2-a]benzimidazole-4(1H)-thione (IIIb) was filtered
off. The yields of IIIb are given in table. mp 340–
1
343°C. H NMR spectrum, δ, ppm: 2.34 s (3H, CH3),
6.99 s (1H, 3-H), 7.35 m (1H, 8-H), 7.58 m (2H, 7-H,
9-H), 9.72 d (1H, 6-H, J = 7.8 Hz), 13.30 br.s (1H,
NH). Found, %: C 61.15; H 3.94; N 19.61. C11H9N3S.
Calculated, %: C 61.37; H 4.21; N 19.52.
The filtrate was evaporated, the residue was ground
with diethyl ether, and the precipitate of compound
IVa–IVe was filtered off. The yields of IVa–IVe are
given in table.
2-Methyl-N-(3-trifluoromethylphenyl)pyrimido-
[1,2-a]benzimidazol-4-amine (IVe). mp 293–295°C.
1H NMR spectrum, δ, ppm: 2.18 s (3H, CH3), 5.53 s
(1H, 3-H), 7.21 m (3H, Harom), 7.37 m (2H, Harom),
7.56 m (3H, Harom, NH), 8.62 d (1H, 6-H, J = 7.1 Hz).
Found, %: C 63.01; H 4.05; N 16.11. C18H13F3N4. Cal-
culated, %: C 63.16; H 3.83; N 16.37.
b. A mixture of finely powdered N-aryl-3-oxobu-
tanethioamide Ia–Ie, 2 mmol, and 2-aminobenzimid-
azole (IІb), 2 mmol, was heated for 0.5 h at 130–
140°C. The mixture was cooled to 70°C, treated with
3 ml of boiling isopropyl alcohol, and cooled to 5°C,
and the precipitate (a mixture of compounds IIІb and
IVa–IVe) was filtered off. The ratio IIIb :IV was
Sulfurization of 2-methylpyrimido[1,2-a]benz-
imidazole-4(1H)-thione (V). A solution of 1.99 g
(10 mmol) of compound V and 2.22 g (10 mmol) of
P2S5 in 10 ml of pyridine was heated for 10 h under
reflux. The mixture was cooled, diluted with 30 ml of
water, and extracted with chloroform (2×10 ml). The
extract was dried over magnesium sulfate and evapo-
rated, and the residue was recrystallized from DMSO.
Yield of thione IIIb 0.667 g (31%). The product was
1
determined by H NMR spectroscopy. The product
mixture was treated with a 10% aqueous solution of
potassium hydroxide, the undissolved material (com-
pound IVa–IVe) was filtered off, the filtrate was acid-
ified with acetic acid, and the precipitate of IIIb was
filtered off.
1
identical in the melting point and H NMR data to
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 8 2008

MAIBORODA, BRITSUN
1204
5. Britsun, V.N., Borisevich, A.N., Pirozhenko, V.V., and
Lozinskii, M.O., Russ. J. Org. Chem., 2007, vol. 43,
p. 276.
a sample of IIIb prepared from N-phenyl-3-oxobu-
tanethioamide (Ia) and 2-aminobenzimidazole (IІb).
1,2-Dimethylpyrimido[1,2-a]benzimidazole-
4(1H)-thione (VI). A solution of 0.056 g (1 mmol) of
potassium hydroxide, 0.215 g (1 mmol) of thione IIIb,
and 0.213 g (1.5 mmol) of methyl iodide in 5 ml of
ethanol was heated for 4 h under reflux. The mixture
was cooled, and the precipitate was filtered off. Yield
6. Britsun, V.N., Borisevich, A.N., Esipenko, A.N., and
Lozinskii, M.O., Russ. J. Org. Chem., 2007, vol. 43,
p. 103.
7. Britsun, V.N., Borisevich, A.N., and Lozinskii, M.O.,
Russ. J. Org. Chem., 2007, vol. 43, p. 907.
8. Britsun, V.N., Borisevich, A.N., and Lozinskii, M.O.,
1
0.142 g (62%), mp 269–271°C. H NMR spectrum, δ,
Russ. J. Org. Chem., 2007, vol. 43, p. 1548.
ppm: 2.36 s (3H, 2-CH3), 3.83 s (3H, 1-CH3), 7.02 s
(1H, 3-H), 7.40 m (1H, 8-H), 7.65 m (1H, 7-H), 7.78 d
(1H, 9-H, J = 5.4 Hz), 9.76 d (1H, 6-H, J = 7.5 Hz).
Found, %: C 63.02; H 5.05; N 18.47. C12H11N3S. Cal-
culated, %: C 62.86; H 4.84; N 18.33.
9. Catalan, J., Abboud, J.L., and Elguero, J., Adv. Hetero-
cycl. Chem., 1987, vol. 41, p. 248.
10. Badawey, E.S. and Kappe, T., J. Heterocycl. Chem.,
1995, vol. 32, p. 1003.
11. Hermecz, I., Horvath, A., and Valsvari-Debreczy, L.,
Synthesis, 1984, no. 2, p. 152.
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