Reaction of N-aryl-3-oxobutanethioamides with 2-amino-1,3-thiazole and 2-amino-1,3-benzothiazole

Article abstract of DOI:10.1134/S1070428007010137

N-Aryl-3-oxobutanethioamides react with 2-amino-1,3-thiazole (2-amino-1,3-benzothiazole) in acetic acid to give mixtures of 7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidine-5-thione (2-methyl-4H-pyrimido-[2,1- b][1,3]benzothiazole-4-thione) and 5-arylimino-7-me

Full text of DOI:10.1134/S1070428007010137

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 1, pp. 103–107. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © V.N. Britsun, A.N. Borisevich, A.N. Esipenko, M.O. Lozinskii, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43,
No. 1, pp. 99–102.
Reaction of N-Aryl-3-oxobutanethioamides
with 2-Amino-1,3-thiazole and 2-Amino-1,3-benzothiazole
V. N. Britsun, A. N. Borisevich, A. N. Esipenko, and M. O. Lozinskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: ioch@bpci.kiev.ua
Received December 20, 2005
Abstract—N-Aryl-3-oxobutanethioamides react with 2-amino-1,3-thiazole (2-amino-1,3-benzothiazole) in
acetic acid to give mixtures of 7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidine-5-thione (2-methyl-4H-pyrimido-
[2,1-b][1,3]benzothiazole-4-thione) and 5-arylimino-7-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidines (4-aryl-
imino-2-methyl-4H-pyrimido[2,1-b][1,3]benzothiazoles), whose ratio depends on the nature of the aryl substit-
uent in the initial butanethioamide.
DOI: 10.1134/S1070428007010137
N-Aryl-3-oxobutanethioamides possess several re-
action centers and are ambident substrates which can
be used as starting materials in synthesis of various
heterocycles [1–4]. These compounds can also act as
efficient complexing agents toward heavy metal ions
[5, 6], herbicides [7], and antitumor agents [8]. In addi-
tion, N-aryl-3-oxobutanethioamides, as well as β-dicar-
bonyl and β-thioxocarbonyl compounds, are capable of
forming strong intramolecular hydrogen bonds, and
they may exist as different tautomers, thus providing
convenient models for studying prototropic tauto-
merism [9–11].
2-amino-1,3-benzothiazole. These reactions may be
considered to follow [3+3]-cyclocondensation pattern
involving three possible reaction centers in N-aryl-3-
oxobutanethioamides and two centers in 2-aminothia-
zole; as a result, the products may be four compounds
of the thiazolo[3,2-a]pyrimidine series.
We found that, unlike reactions of ethyl acetoace-
tate and its derivatives with 2-aminothiazole and
2-aminobenzothiazole [13, 14], N-aryl-3-oxobutane-
thioamides Ia–Ie reacted with the same binucleophiles
IIa and IIb in a nonselective fashion, yielding mix-
tures of compounds IIIa (IIIb) and IVa–IVf whose
ratio depended on the nature of the aryl substituent in
the initial thioamide (Scheme 1, see table).
In continuation of our studies on heterocyclizations
of N-aryl-3-oxobutanethioamides with difunctional
1,3-nucleophiles [12], in the present work we ex-
amined their reactions with 2-amino-1,3-thiazole and
Thiazolo[3,2-a]pyrimidine-5(4)-thiones IIIa and
1
IIIb characteristically showed in the H NMR spectra
Scheme 1.
S
NAr
R
R
R
O
S
AcOH
N
+
+
N
N
Ar
R
R
Me
O
N
H
H2N
R
S
S
S
Me
N
Me
N
Ia–Ie
IIa, IIb
IIIa, IIIb
SMe
IVa–IVf
S
NPh
P2S5
MeI
PhNH2
N
N
N
N
I–
S
S
S
S
Me
N
Me
N
Me
N
Me
N
V
IIIa
VI
IVa
I, Ar = Ph (a), 4-MeOC6H4 (b), 4-EtOC6H4 (c), 4-ClC6H4 (d), 4-O2NC6H4 (e); II, III, R = H (a), RR = CH=CH–CH=CH (b); IV, R =
H, Ar = Ph (a), 4-MeOC6H4 (b), 4-ClC6H4 (c), 4-O2NC6H4 (d); RR = CH=CH–CH=CH, Ph (e), 4-EtOC6H4 (f).
103

BRITSUN et al.
104
Yields of compounds III and IV in the reactions of N-aryl-
3-oxobutanethioamides Ia–Ie with 2-amino-1,3-thiazole
(IIa) and 2-amino-1,3-benzothiazole (IIb)
ing reduced electron density in the thiazolopyrimidine
ring system of VI. Heating of a solution of iodide VI
in aniline at 150°C resulted in nucleophilic replace-
ment of the methylsulfanyl group by phenylimino with
liberation of methanethiol and formation of thiazolo-
[3,2-a]pyrimidine IVa (Scheme 1). The 1H NMR spec-
tra of samples of IVa obtained by aminolysis of iodide
VI and by reaction of thioamide Ia with aminothiazole
IIa were identical, and their mixture showed no
depression of the melting point. Thus the structure of
compounds IIIa, IIIb, and IVa–IVf was unambigu-
ously proved by independent syntheses.
Yield, %
Initial reactants
III
30
52
15
–
IV
35
20
69
70
62
33
Ia + IIa
Ib + IIa
Id + IIa
Ie + IIa
Ia + IIb
Ic + IIb
16
31
The results of our study show that, unlike 5-substi-
tuted 3-amino-1,2,4-triazoles [12], the exocyclic amino
group in aminothiazoles IIa and IIb is more reactive
than the endocyclic imino group N3H (in the 2-imino
tautomer) toward N-aryl-3-oxobutanethioamides Ia–Ie.
The carbonyl group in N-aryl-3-oxobutanethioamides
Ia–Ie is more reactive than the C=S group in reactions
with 2-aminothiazoles IIa and IIb, as in reactions with
arylamines [15].
singlets from protons in the 7(2)-Me group and 6(3)-H
at δ 2.32–2.35 and 7.23–7.32 ppm, respectively. The
spectra of 5(4)-aryliminothiazolopyrimidines IVa–IVf
contained signals from the 7(2)-Me group and 6(3)-H
at δ 2.08–2.17 and 5.90–6.10 ppm. In the IR spectra of
IIIa and IIIb we observed absorption bands belonging
to stretching vibrations of the C=N and =C–H bonds at
1570–1580 and 3100 cm–1, respectively, while the cor-
responding absorption bands in the spectra of IVa–IVf
were located at 1590–1610, 1630–1650, and 2900–
3100 cm–1. However, the IR and 1H NMR data did not
allow us to distinguish between 7-methyl-5H-[1,3]thia-
zolo[3,2-a]pyrimidine-5-thiones and 5-arylimino-7-
methyl-5H-[1,3]thiazolo[3,2-a]pyrimidines, on the one
hand, and isomeric 5-methyl-7H-[1,3]thiazolo[3,2-a]-
pyrimidine-7-thiones and 7-arylimino-5-methyl-7H-
[1,3]thiazolo[3,2-a]pyrimidines. Therefore, we per-
formed a series of chemical transformations to deter-
mine the structure of compounds III and IV.
By reaction of 2-amino-1,3-thiazole with ethyl
acetoacetate according to the procedure described in
[13] we synthesized 7-methyl-5H-[1,3]thiazolo[3,2-a]-
pyrimidin-5-one (V), and treatment of the latter with
P2S5 in pyridine gave thiazolo[3,2-a]pyrimidine IIIa.
The 1H NMR spectra of samples of IIIa prepared from
thioamide Ia and 2-amino-1,3-thiazole (IIa) and by
sulfurization of known thiazolopyrimidinone V [13]
were fully identical, and their mixture showed no
depression of the melting point.
It is known that thioamide Ia reacts with aniline
and other aromatic amines in acetic acid to give en-
aminothioamides [15]. Therefore, we expected initial
formation of enaminothioamides VII by reaction of
thioamides Ia–Ie with aminothiazoles IIa and IIb
(Scheme 2). As follows from the data in table, the
mode of cyclization of enaminothioamides VII de-
pends on the nature of the substituent in the benzene
ring of N-aryl-3-oxobutanethioamide Ia–Ie. Electron-
donor substituents favor formation of the correspond-
ing thiazolo[3,2-a]pyrimidine-5-thione III. For ex-
ample, in going from thioamide Ia (Ar = Ph) to Ib
(Ar = 4-MeOC6H4), the yield of compound IIIa in-
creases from 30 to 52%, while the yield of alternative
product IV decreases from 35 (IVa) to 20% (IVb). By
contrast, in the reaction with p-nitrophenyl derivative
Ie, the yield of IVd reached 70%, while thazolopyrimi-
dinethione IIIa was not formed at all.
Taking into account that nucleophilic substitution at
a carbon atom linked to oxygen or sulfur by a double
bond involves formation of a tetrahedral intermediate
[16], there are reasons to believe that intramolecular
cyclization of enaminothioamides VII follows two
concurrent pathways: (1) through intermediate VIIIa
with elimination of substituted aniline and formation
of thiazolo[3,2-a]pyrimidine-5(4)-thione IIIa or IIIb
and (2) through intermediate VIIIb which loses hydro-
gen sulfide molecule to give 5(4)-aryliminothiazolo-
[3,2-a]pyrimidines IVa–IVf. Presumably, interme-
The structure of aryliminothiazolo[3,2-a]pyrimi-
dines IVa–IVf was confirmed as follows. Alkylation of
IIIa with methyl iodide gave 7-methyl-5-methylsul-
fanyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-4-ium iodide
(VI). Unlike initial compound IIIa, all signals in the
1H NMR spectrum of VI were displaced downfield by
0.35–0.76 ppm (except for the 3-H proton which is also
strongly deshielded in the initial compound), indicat-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 1 2007

REACTION OF N-ARYL-3-OXOBUTANETHIOAMIDES
105
Scheme 2.
N
S
Me
R
N
IIIa, IIIb
–ArNH2
H
N
S
R
Me
NH
H
R
R
Ar
S
N
IIa or IIb, AcOH
Ia–Ie
VIIIa
NHAr
S
N
Me
H
S
VII
R
N
IVa–IVf
–H2S
N
S
R
Ar
H
VIIIb
diates VIIIa and VIIIb are transformed via four-
membered cyclic transition states in which a weak
hydrogen bond (coordination) exists between the SH
proton (NH proton of the N-arylamino group) and
nitrogen atom of N-arylamino group (sulfur atom),
depending on the basicity of the N-aryl group. The
proposed scheme is consistent with the data given in
table, which illustrate the effect of the substituent
nature in initial thioamides Ia–Ie on the ratio of prod-
ucts III and IV.
precipitate of compound IIIa or IIIb was filtered off.
The filtrate was treated with 50 ml of 25% aqueous
Na2CO3, the mixture was left to stand for 12 h, and the
precipitate of 5-arylimino-7-methyl-5H-[1,3]thiazolo-
[3,2-a]pyrimidine IVa–IVd or 4-arylimino-2-methyl-
4H-pyrimido[2,1-b][1,3]benzothiazole IVe or IVf was
filtered off. The yields of compounds IIIa, IIIb, and
IVa–IVf are given in table.
7-Methyl-5H-[1,3]thiazolo[3,2-a]pyrimidine-5-
thione (IIIa). mp 142–143°C (from ethanol). IR spec-
trum, ν, cm–1: 1210, 1310, 1370, 1460, 1580, 3100.
1H NMR spectrum, δ, ppm: 2.35 s (3H, 7-CH3), 7.23 s
(1H, 6-H), 7.84 d (1H, 2-H, J = 4.8 Hz), 8.66 d (1H,
3-H, J = 4.8 Hz). Found, %: C 45.86; H 3.03; N 15.18;
S 35.30. C7H6N2S2. Calculated, %: C 46.13; H 3.32;
N 15.37; S 35.18.
Thus 2-amino-1,3-thiazole and 2-amino-1,3-benzo-
thiazole react with N-aryl-3-oxobutanethioamides to
give mixtures of 7-methyl-5H-[1,3]thiazolo[3,2-a]pyri-
midine-5-thione (2-methyl-4H-pyrimido[2,1-b][1,3]-
benzothiazole-4-thione) and 5-arylimino-7-methyl-5H-
[1,3]thiazolo[3,2-a]pyrimidines (4-arylimino-2-meth-
yl-4H-pyrimido[2,1-b][1,3]benzothiazoles), whose
ratio depends on the nature of the aryl substituent in
the initial butanethioamide.
2-Methyl-4H-pyrimido[2,1-b][1,3]benzothiazole-
4-thione (IIIb). mp 181–183°C (from nitromethane).
IR spectrum, ν, cm–1: 1320, 1360, 1450, 1530, 1570,
1
3100. H NMR spectrum, δ, ppm: 2.32 s (3H, 2-CH3),
7.32 s (1H, 3-H), 7.52–7.69 m (2H, Harom), 8.11 d (1H,
9-H, J = 7.8 Hz), 10.45 d (1H, 6-H, J = 8.7 Hz).
Found, %: C 57.02; H 3.70; N 11.79. C11H8N2S2. Cal-
culated, %: C 56.87; H 3.47; N 12.06.
EXPERIMENTAL
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Varian-300 spectrometer (300 MHz)
using tetramethylsilane as internal reference. The IR
spectra were recorded in KBr on a UR-20 instrument.
7-Methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (V)
was synthesized by the procedure reported in [13].
N-(7-Methyl[1,3]thiazolo[3,2-a]pyrimidin-5-
ylidene)aniline (IVa). mp 150–153°C (from nitro-
methane). IR spectrum, ν, cm–1: 1350, 1370, 1400,
1
1490, 1510, 1580, 1600, 1650, 3100. H NMR spec-
trum, δ, ppm: 2.10 s (3H, 7-CH3), 5.91 s (1H, 6-H),
6.87 m (2H, Harom), 7.00 m (1H, Harom), 7.31 m (2H,
Harom), 7.42 d (1H, 2-H, J = 4.5 Hz), 8.12 d (1H, 3-H,
J = 4.5 Hz). Found, %: C 64.89; H 4.32; N 17.19.
C13H11N3S. Calculated, %: C 64.71; H 4.59; N 17.41.
Reactions of N-aryl-3-oxobutanethioamides Ia–
Ie with 2-amino-1,3-thiazole (IIa) and 2-amino-1,3-
benzothiazole (IIb) (general procedure). A solution of
10 mmol of N-aryl-3-oxobutanethioamide Ia–Ie and
10 mmol of 2-amino-1,3-thiazole (IIa) or 2-amino-1,3-
benzothiazole (IIb) in 8 ml of acetic acid was heated
for 4 h at 100°C. The mixture was cooled, and the
4-Methoxy-N-(7-methyl[1,3]thiazolo[3,2-a]pyri-
midin-5-ylidene)aniline (IVb). mp 146–148°C (from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 1 2007

BRITSUN et al.
106
ethanol). IR spectrum, ν, cm–1: 1350, 1370, 1400,
1440, 1510, 1560, 1610, 1630, 2900–3100. H NMR
reflux. The mixture was cooled, diluted with 30 ml of
water, and extracted with chloroform (2×10 ml). The
extract was dried over MgSO4 and evaporated under
reduced pressure (water-jet pump), and the residue was
recrystallized from ethanol. Yield of compound IIIa
0.783 g (43%), mp 142–143°C.
1
spectrum, δ, ppm: 2.08 s (3H, 7-CH3), 3.73 s (3H,
CH3O), 5.90 s (1H, 6-H), 6.78 d (2H, Harom, J =
8.6 Hz), 6.85 d (2H, Harom, J = 8.6 Hz), 7.37 d (1H,
2-H, J = 4.3 Hz), 8.08 d (1H, 3-H, J = 4.3 Hz). Found,
%: C 61.75; H 5.02; N 15.21. C14H13N3OS. Calculated,
%: C 61.97; H 4.83; N 15.49.
7-Methyl-5-methylsulfanyl-5H-[1,3]thiazolo-
[3,2-a]pyrimidin-4-ium iodide (VI). A solution of
0.91 g (5 mmol) of compound IIIa and 1.14 g
(8 mmol) of methyl iodide in 10 ml of benzene was
heated for 8 h at 50°C. The mixture was cooled, and
the precipitate was filtered off. Yield 1.085 g (67%),
mp 215–216°C. IR spectrum, ν, cm–1: 1310, 1340,
4-Chloro-N-(7-methyl[1,3]thiazolo[3,2-a]pyrimi-
din-5-ylidene)aniline (IVc). mp 183–185°C (from
nitromethane). IR spectrum, ν, cm–1: 1340, 1370, 1410,
1
1505, 1570, 1590, 1640, 3000–3100. H NMR spec-
trum, δ, ppm: 2.12 s (3H, 7-CH3), 5.91 s (1H, 6-H),
6.79–6.87 m (2H, Harom), 7.03 m (1H, Harom), 7.31 m
(1H, Harom), 7.43 d (1H, 2-H, J = 4.6 Hz), 8.08 d (1H,
3-H, J = 4.6 Hz). Found, %: C 56.45; H 3.37; N 15.49.
C13H10ClN3S. Calculated, %: C 56.62; H 3.66; N 15.24.
1
1370, 1430, 1490, 1560, 1585, 2900–3100. H NMR
spectrum, δ, ppm: 2.77 s (3H, 7-CH3), 2.97 s (3H,
SCH3), 7.99 s (1H, 6-H), 8.46 d (1H, 2-H, J = 4.0 Hz),
8.65 d (1H, 3-H, J = 4.0 Hz). Found, %: C 29.92;
H 2.52; N 8.47. C8H9IN2S2. Calculated, %: C 29.64;
H 2.80; N 8.64.
N-(7-Methyl[1,3]thiazolo[3,2-a]pyrimidin-5-
ylidene)-4-nitroaniline (IVd). mp 215–217°C (from
DMSO). IR spectrum, ν, cm–1: 1250, 1320, 1410,
A solution of 0.81 g (2.5 mmol) of iodide VI in
3 ml of aniline was heated for 0.5 h at 150°C. The
mixture was cooled, and the precipitate was filtered
off, washed in succession with diethyl ether (2×5 ml),
20% aqueous Na2CO3 (2×10 ml), and water, and dried.
Yield of thiazolopyrimidine IVa 0.374 g (62%),
mp 150–153°C (from nitromethane).
1
1500, 1560, 1590, 1640, 3100. H NMR spectrum, δ,
ppm: 2.17 s (3H, 7-CH3), 6.10 s (1H, 6-H), 7.08 d (2H,
Harom, J = 8.4 Hz), 7.52 d (1H, 2-H, J = 4.0 Hz), 8.16–
8.19 m (3H, Harom, 3-H). Found, %: C 54.35; H 3.31;
N 19.69. C13H10N4O2S. Calculated, %: C 54.54;
H 3.52; N 19.57.
N-(2-Methyl-4H-pyrimido[2,1-b][1,3]benzothia-
zol-4-ylidene)aniline (IVe). mp 198–199°C (from
DMSO). IR spectrum, ν, cm–1: 1360, 1390, 1460,
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