General trends in reaction of N-aryl-3-oxobutanethioamides with 2-aminoazoles(azines)

Article abstract of DOI:10.1134/S1070428007100247

Reaction products obtained from N-aryl-3-oxobutanethioamides and 2-aminoazoles(azines) are derivatives of (arylamino)pyrimidines and pyrimidinethiones. The ratio of the products depends on the basicity of 1,3-binucleophiles, acidity of the medium, and the character of substituents in the phenyl ring of initial thioamides.

Full text of DOI:10.1134/S1070428007100247

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1548−1552. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © V.N. Britsun, A.N. Borisevich, M.O. Lozinskii, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 10,
pp. 1552−1555.
General Trends in Reaction of N-Aryl-3-oxobutanethioamides
with 2-Aminoazoles(Azines)
V. N. Britsun, A. N. Borisevich, and M. O. Lozinskii
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02660 Ukraine
e-mail: bvn1967@rambler.ru
Received July 18, 2006; final version May 30, 2007
Abstract—Reaction products obtained from N-aryl-3-oxobutanethioamides and 2-aminoazoles(azines) are
derivatives of (arylamino)pyrimidines and pyrimidinethiones. The ratio of the products depends on the basicity
of 1,3-binucleophiles, acidity of the medium, and the character of substituents in the phenyl ring of initial
thioamides.
DOI: 10.1134/S1070428007100247
We showed recently that N-aryl-3-oxobutanethio-
amides react with 1,3-binucleophiles like 3-amino-5-R-
1,2,4-triazoles [1], 2-amino-5-R-pyridines [2], 2-amino-
thiazoles [3], and guanidine carbonate [4] to form two
groups of compounds: derivatives of pyrimidine-4-thione
and 4-(arylamino)-pyrimidine, whose ratio is affected by
the basicity of 1,3-binucleophiles and by the character
of substituents in the phenyl ring of initial butane-
thioamides [1–4].
The target of the present study was investigation of
the solvent effect (AcOH and CF3COOH) on the direction
of reaction between N-aryl-3-oxobutanethioamides and
2-aminoazoles(azines), and also analysis and system-
atization of previously obtained results [1–4] and reveal-
ing the general trends in the mentioned transformations.
N-Aryl-3-oxobutanethioamides Ia–Ie at 100–105°C
reacted with 2-amino-5-R-pyridines IIa and IIb,
2-aminobenzothiazole (IV), 3-amino-5-R-1,2,4-triazoles
VIa and VIb, and 5-aminotetrazole (VIII) also in the
absence of the protonic solvents to give 4H-pyrido-
[1,2-a]pyrimidine-4-thiones IIIa and IIIb, 4-arylimino-
4H-benzo[4,5]thiazolo[3,2-a]-pyrimidines Va–Vd, 5-aryl-
amino-1,2,4-triazolo[1,5-a]pyrimidines VIIa–VIIc, and
Although the majority of the reactions save those
described in [4] were carried out in AcOH the role of the
latter was not investigated. Still, the condensations with
an acyclic 1,3-binucleophile, guanidine, occurred also
without a proton-donor solvents [4].
Scheme 1.
Ar
N
S
N
R
N
H2N
R
N
N
H2N
S
IV
IIa, IIb
H3C
N
O
S
H3C
N
S
IIIa, IIIb
Va_Vd
Ph
Ar
HN N
N
HN N
H3C
N
H
H2N
R'
Ar
N
H2N
Ia_Ie
HN
N
NH
VIa, VIb
VIII
Ar = Ph
N
N
N
N
N
N
R'
N
H3C
N
H3C
N
IX
VIIa_VIIc
Ar = Ph (Ia, Va, VIIa, IX), 4-MeOC6H4 (Ib, Vb), 4-MeC6H4 (Ic, Vc), 3-CF3C6H4 (Id, Vd, VIIb), 3-ClC6H4 (Ie, VIIc);
R = H (IIa, IIIa), Me (IIb, IIIb); R’ = H (VIa, VIIa), SMe (VIb, VIIb, VIIc).
1548

GENERAL TRENDS IN REACTION OF N-ARYL-3-OXOBUTANETHIOAMIDES
1549
Table 1. Ratio of products of reaction between N-phenyl-3-
oxobutanethioamide (Ia) and 2-aminoazoles(azines) at 100–
105°C
5-phenylaminotetrazolo[1,5-a]pyrimidine (IX), whose
structure and composition were proved by H NMR
spectra and elemental analyses (Scheme 1).
1
Ratio (%)
arylimine:thione
(without
The variation of the ratio of the reaction products as
a function of aminoazoles(azines) basicity, solvent
acidity, and the character of the substituents in the phenyl
ring of oxobutanethioamides is presented in Tables 1
and 2.
Ratio (%)
arylimine:thione
(AcOH)
pKα
[9, 10]
Compound
solvent)
Guanidine
13.71
−
28:0 [1–4]
0:47
2-Amino-
pyridine
(pyridine)
6.86
(5.23)
0:65
In contrast to reactions in acetic acid the cyclo-
condensations in the absence of the protonizing solvents
occurred selectively giving as a rule fused derivatives of
4-(arylimino)pyrimidinre.
3-Amino-1,2,4-
triazole 1,2,4-
triazole)
2-Aminothi-
azole(thiazole)
2-Aminobenzo-
thiazole(benzoth
iazole)
4.17
(2.55)
8:50
62:0
As expected no dependence existed of the ratio
4-(arylamino)pyrimidine:pyrimidine-4-thione on pKα of
initial 2-aminoazoles(azines) (Table 1). However the
variation in the ratio of the products correlates not with
pKα of 2-aminoazoles(azines) but with those of the
corresponding unsubstituted azoles(azines). This fact is
due to reaction of N-aryl-3-oxobutanethioamides with
1,3-binucleophiles proceeding through enthioamide A [4]
(Scheme 2) where the basicity of the enamine nitrogen
is diminished and therefore the intramolecular cyclization
is governed by the basicity of the endocyclic nitrogen.
5.39
(2.53)
4.51
35:30
62:16
−
59:0a
(1.2)
1.82
(–2.68)
a The ratio in toluene was 64:0.
−
56:0
5-Aminotetra-
zole (tetrazole)
Table 2. Ratio of products of condensation of N-aryl-3-
oxobutanethioamides Ia, Ib, and Id with 2-aminobenzothiazole
(IV) at 100–105°C
The data of Tables 1 and 2 unambiguously show that
the protonizing solvent (AcOH) also significantly affects
the reaction direction. At the use of CF3COOH no cyclo-
condensation occurred of N-aryl-3-oxobutanethioamides
with 2-aminoazoles. Apparently this is due to the fact
that CF3COOH being a strong acid (pKα 0.23 [5])
completely protonates the amino group of 2-aminoazoles
Ratio
(arylimino)pyrimidine:pyrimidinethione (%)
Solvent
Ar = Ph Ar = 4-MeOC6H4 Ar = 3-CF3C6H4
ACOH
62:16
59:0
32:34
48:0
59:0
55:0
Without
solvent
Scheme 2.
NH Ar
H3C
H3C
N
H3C
H
S
H+
SH
NH
S
H
+
N
H
Ar
N
_ArNH2,
_H+
N
N
N
H3C
N
H
Ar
N
S
B
C
А
N
_H2S
NH2
NH2
H3C
N
III
_ArNH2
H
S
HN
H
H3C
N
H3C
N
S
H
N
N
N Ar
Ar
H
_H2S
N
N
N
Ar
D
V
E
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

BRITSUN et al.
1550
thus preventing their reaction with 3-oxobutanethio-
amides.
The reactions with low-basic aminoazoles IV, VIa,
VIb, and VIII (pKα 1.82–4.51, pKα of the corresponding
unsubstituted azoles 1.2–2.55) in the absence of protonic
solvents evidently proceed through intermediate C and
consequently lead to the formation of (arylimino)-
pyrimidines V.
The data of Tables 1 and 2 suggest that two groups of
competing reactions occur. The reactions should be
regarded both from the thermodynamic and from
electronic viewpoints. It is known [6] that C–N bond is
by 13 kJ mol−1 more stable than C−S bond (energies of
formation are respectively 285 and 272 kJ mol−1). How-
ever to estimate the possibility of a certain process to
occur it is necessary to take into account the energy
effects of all accompanying phenomena. In the case in
question the reaction products and the solvent possess
either basic or acidic properties, and therefore the
neutralization (protonation) enthalpy also should be
considered; it amounts to 13.3 kJ mol−1 [7]. Inasmuch as
the nucleo-philic substitution at a carbon bonded with a
double bond to oxygen or sulfur proceeds by a tetrahedral
mechanism [8] the neutralization processes should favor
those reactions of highly basic 2-aminoazoles(azines) in
acetic acid which involve the elimination of arylamines
and the formation of pyrimidinethiones. Actually, the
higher the basicity of the initial heterocycle, the higher
was the yield of thione in cyclocondensations performed
in AcOH (Table 1). In all likelihood pyrimidinethiones
III formation occurred via intermediate B where the
arylamine elimination was easy.
The “abnormal” reactivity of 2-amino-5-R-pyridines
probably originates from the fact that they are bases of
moderate strength (pKα of pyridine 5.23) and in inter-
mediate D the hydrogen of mercapto group is likely
coordinated to the exocyclic nitrogen atom; the latter
facilitates arylamine elimination and leads to the
formation of pyrimidinethiones III.
The reaction products obtained from N-aryl-3-oxo-
butanethioamides with guanidine carbonate as seen from
Table 1 were solely (4-arylimino)pyrimidines V. Inas-
much as guanidine is a strong base (pKα 13.71 [5]), the
reaction apparently proceeded through intermediate E
where the guanidine served as a proton-acceptor. Thus
the acid medium favors the arylamines elimination and
the pyrimidinethiones formation whereas the presence
of strong bases facilitates the ejection of hydrogen sulfide
and the generation of (arylimino)pyrimidines.
The effect of the character of substituents in the
phenyl ring of N-aryl-3-oxobutanethioamide is well
consistent with the above rules: in reactions proceeding
in AcOH the yield of pyrimidinethione is the greater the
higher is the electron-donor effect of the substituent
whereas in the absence of the protonizing solvent the
thione is not formed (Table 2). Evidently the
condensation in AcOH proceeds through intermediate
B, and in the second case, via intermediate C.
Since intermediate B contained three nitrogen atoms
it should be revealed which among them suffered
protonation more likely. It should be also kept in mind
that in intermediates B–E the nitrogen of the arylamino
group is outside the pyrimidine ring plane, i.e., it is not
in conjugation with the ring. Therefore the pyrimidine
ring decreases the electron density on the N atom of the
arylamino group only by the inductive effect. The basicity
of arylamino group is likely to be comparable with the
basicity of the corresponding arylamines (pKα of p-nitro-
aniline 1.02, of aniline, 4.58, of p-anisidine, 5.29 [5]),
whereas the basicity of the pyrimidine ring apparently is
close to the value established for pyrimidine (pKα 1.3
[5]). These data show the direction of intermediate B
protonation and consequently the readiness of arylamine
elimination.
Thus the reaction of N-aryl-3-oxobutanethioamides
with 2-aminoazoles(azines) results in formation of deriv-
atives of (arylimino)pyrimidines or pyrimidinethiones
whose ratio depends on the heterocycle basicity in the
initial 2-aminoazoles(azines), on the character of the
substituent in the phenyl ring of thioamide, and on the
protonating capability of the solvent.
EXPERIMENTAL
1H NMR spectra were recorded on a spectrometer
Varian 300 (300 MHz) from solutions in DMSO-d6 using
TMS as internal reference.
In reactions carried out without solvent or in aprotic
solvent (toluene) no correlation was observed between
pKα of azoles(azines) and the products ratio due to the
difference in the interaction mechanisms. Therefore to
understand the results all the possible routes of these
reactions should be considered (Scheme 2).
2-Methyl-7-R-4H-pyrido[1,2-a]pyrimidine-4-
thiones IIIa and IIIb, 4-arylimino-2-methyl-4H-
benzo-[4,5]thiazolo[3,2-a]pyrimidines Va–Vd, 5-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

GENERAL TRENDS IN REACTION OF N-ARYL-3-OXOBUTANETHIOAMIDES
1551
arylimino-7-methyl-2-R-[1,2,4]triazolo[1,5-
a]pyrimidines VIIa–VIIc, and 7-methyl-5-phenyl-
iminotetrazolo[1,5-a]pyrimidine (IX). General
procedure.Amixture of 5 mmol of N-aryl-3-oxobutane-
thioamide Ia–Ie and 5 mmol of 2-amino-5-R-pyridine
(2-aminoazole) IIa, IIb, IV, VIa, VIb, and VIII was
heated for 1–2 h at 120°C (bath temperature), cooled,
diluted with 8 ml of ethyl ether, and the precipitate was
filtered off.
7.17 m (2Harom), 7.34 m (1Harom), 7.51–7.58 m (3Harom),
7.95 m (1Harom), 9.33 m (1Harom). Found, %: C 59.89;
H 3.48; N 11.77. C18H12F3N3S. Calculated, %: C 60.16;
H 3.37; N 11.69.
7-Methyl-5-phenylamino[1,2,4]triazolo[1,5-a]-
pyrimidine (VIIa). Yield 0.698 g (62%), mp 183–185°C
(from 2-propanol) (183–185°C [1]). 1H NMR spectrum
is identical to that published in [1]. Found, %: C 64.20;
H 5.11; N 31.29. C12H11N5. Calculated, %: C 63.99;
H 4.92; N 31.09.
2-Methyl-4H-pyrido[1,2-a]pyrimidine-4-thione
(IIIa). Yield 0.414 g (47%), mp 156–158°C (from
7-Methyl-2-methylsulfanyl-5-[3-(trifluoromethyl)-
phenyl]amino[1,2,4]triazolo[1,5-a]pyrimidine (VIIb).
Yield 0.898 g (53%), mp 198–200°C (from CH3NO2).
1H NMR spectrum, δ, ppm: 2.42 s (3H, 7-CH3), 2.68 s
(3H, SMe), 6.42 s (1H, H6), 7.60 m (1Harom), 7.69 m
(1Harom), 7.75 m (2Harom), 10.22 s (1H, NH). Found, %:
C 49.72; H 3.81; N 20.42. C14H12F3N5S. Calculated, %:
C 49.55; H 3.56; N 20.64.
1
ACOH) (156–158°C [2]). H NMR and IR spectra are
identical to those published in [2]. Found, %: C 61.18;
H 4.83; N 15.71. C9H8N2S. Calculated, %: C 61.34;
H 4.58; N 15.90.
2,7-Dimethyl-4H-pyrido[1,2-a]pyrimidine-4-
thione (IIIb). Yield 0.409 g (43%), mp 140–142°C (from
1
ethanol) (140–142°C [2]). H NMR and IR spectra are
identical to those published in [2]. Found, %: C 63.40;
H 5.11; N 14.88. C10H10N2S. Calculated, %: C 63.13;
H 5.30; N 14.72.
7-Methyl-2-methylsulfanyl-5-(3-chlorophenyl)-
amino[1,2,4]triazolo[1,5-a]pyrimidine (VIIc). Yield
1
0.905 g (57%), mp 191–193°C (from CH3NO2). H NMR
spectrum, δ, ppm: 2.41 s (3H, 7-CH3), 2.67 s (3H, SMe),
6.41 s (1H, H6), 7.31 m (1Harom), 7.37–7.49 m (3Harom),
10.12 s (1H, NH). Found, %: C 50.93; H 4.09; N 23.15.
C13H12ClN5S. Calculated, %: C 51.06; H 3.96; N 22.90.
2-Methyl-4-phenylimino-4H-benzo[4,5]thiazolo-
[3,2-a]pyrimidine (Va). Yield 0.858 g (59%), mp 198–
199°C (from DMSO) (198–199°C [3]). 1H NMR and IR
spectra are identical to those published in [3]. Found,
%: C 70.30; H 4.76; N 14.21. C17H13N3S. Calculated,
%: C 70.08; H 4.50; N 14.42.
7-Methyl-5-phenylaminotetrazolo[1,5-a]pyrimi-
dine (IX). Yield 0.633 g (56%), mp 223–226°C (from
CH3NO2). 1H NMR spectrum, δ, ppm: 2.76 s (3H, 7-CH3),
6.70 s (1H, H6), 7.11 m (1Harom), 7.39 m (2Harom), 7.83 m
(2Harom), 10.28 s (1H, NH). Found, %: C 58.64; H 4.19;
N 36.94. C11H10N6. Calculated, %: C 58.40; H 4.45; N 37.15.
2-Methyl-4-(4-methoxyphenyl)imino-4H-benzo-
[4,5]thiazolo[3,2-a]pyrimidine (Vb). Yield 0.770 g
(48%), mp 186–187°C (from CH3NO2). 1H NMR spec-
trum, δ, ppm: 2.08 s (3H, 2-CH3), 3.82 s (3H, CH3O),
6.03 s (1H, H3), 6.77 d (2H, p-C6H4, J 8.7 Hz), 6.90 d
(2H, p-C6H4, J 8.7 Hz), 7.45 m (2Harom), 7.90 m (1Harom),
9.36 m (1Harom). Found, %: C 67.49; H 4.56; N 12.81.
C18H15N3OS. Calculated, %: C 67.27; H 4.70; N 13.07.
Reactions of N-aryl-3-oxobutanethioamides Ia, Ib, and
Id with 2-aminobenzothiazole (IV) in AcOH and isola-
tion of the products were performed by procedure [3].
REFERENCES
2-Methyl-4-(4-methylphenyl)imino-4H-benzo-
[4,5]thiazolo[3,2-a]pyrimidine (Vc). Yield 0.793 g
(52%), mp 177–179°C (from CH3NO2). 1H NMR spec-
trum, δ, ppm: 2.08 s (3H, 2-CH3), 2.31 s (3H, CH3),
5.99 s (1H, H3), 6.76 d (2H, p-C6H4, J 8.1 Hz), 7.14 d
(2H, p-C6H4, J 8.1 Hz), 7.46 m (2Harom), 7.91 m (1Harom),
9.34 m (1Harom). Found, %: C 71.02; H 5.17; N 13.89.
C18H15N3S. Calculated, %: C 70.79; H 4.95; N 13.76.
1. Britsun, V.N., Borisevich, A.N., Samoilenko, L.S.,
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3. Britsun, V.N., Borisevich, A.N., Esipenko,A.N., Lozinskii,
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2-Methyl-4-[3-(trifluoromethyl)phenyl]imino-
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4H-benzo[4,5]thiazolo[3,2-a]pyrimidine (Vd). Yield
1
0.987 g (55%), mp 189–191°C (from CH3NO2). H NMR
spectrum, δ, ppm: 2.13 s (3H, 2-CH3), 6.00 s (1H, H3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

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