Reaction of N-aryl-3-oxobutanethioamides with bis(guanidinium) carbonate

Article abstract of DOI:10.1134/S1070428007060188

Reactions of N-aryl-3-oxobutanethioamides with bis(guanidinium) carbonate lead to the formation of N-aryl-3-guanidinobut-2-enethioamides, 4-arylamino-6-methylpyrimidin-2-amines, guanidinium acetate, and arylamines, depending on the temperature conditions.

Full text of DOI:10.1134/S1070428007060188

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 6, pp. 907–910. © 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. 6,
pp. 908–911.
Reaction of N-Aryl-3-oxobutanethioamides
with Bis(guanidinium) Carbonate
V. N. Britsun, A. N. Borisevich, 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 March 27, 2006
Abstract—Reactions of N-aryl-3-oxobutanethioamides with bis(guanidinium) carbonate lead to the formation
of N-aryl-3-guanidinobut-2-enethioamides, 4-arylamino-6-methylpyrimidin-2-amines, guanidinium acetate, and
arylamines, depending on the temperature conditions.
DOI: 10.1134/S1070428007060188
Unlike our previous results, no heterocyclic prod-
ucts were isolated in reactions of N-aryl-3-oxobutane-
thioamides Ia–Ie with guanidinium acetate in acetic
acid. Therefore, we applied more severe conditions:
compounds Ia–Ie were fused with bis(guanidinium)
carbonate (II). In this case, the reaction was not selec-
tive, and the products were compounds III, IVa–IVe,
V, and VIa–VIe, whose ratio depended on the tem-
perature and substituent nature in the aryl fragment of
initial thioamide Ia–Ie (Scheme 1). The yields of prod-
ucts III–VI are given in table.
By heating 3-oxo-N-phenylbutanethioamide (Ia)
with guanidinium salt II at 100°C over a period of 1 h
we obtained 32% of 3-guanidino-N-phenylbut-2-ene-
thioamide (III). The latter was also synthesized in 61%
yield by reaction of thioamide Ia with guanidinium
acetate on heating in acetic acid for 2 h. We can con-
clude that the carbonyl group in 3-oxo-N-phenyl-
butanethioamide (Ia) is more reactive than the thiocar-
N-Aryl-3-oxobutanethioamides are polyfunctional
compounds that can be used as starting materials in the
synthesis of various heterocycles, such as 4H-1,3-thia-
zin-4-ones, 4H-thiopiran-4-ones [1], 1,2,5-oxadiazoles
[2], pyrazoles [3], 1,3-thiazolidine-4,5-diones, and
thiophene-2,3-diones [4]. We have recently found that
N-aryl-3-oxobutanethioamides react with 5-substituted
3-amino-1,2,4-triazoles [5], 5-substituted 2-aminopyri-
dines [6], and 2-aminothiazoles [7] in acetic acid to
give fused heterocycles containing a pyrimidine ring.
In continuation of our studies on heterocyclizations of
N-aryl-3-oxobutanethioamides with 1,3-binucleo-
philes, in the present work we examined reactions of
these compounds with guanidinium salts. These reac-
tions can occur at three reaction centers of N-aryl-3-
oxobutanethioamides with elimination of hydrogen
sulfide and arylamines; as a result, 2-amino-4-(aryl-
amino)-6-methylpyrimidines and 2-amino-4-methyl-
pyrimidine-6(1H)-thione can be obtained, respectively.
Scheme 1.
NH2
O
S
NH
Me
S
NH2
NH2
II
N
N
+
2
·CO23–
·H2O +
Ar
Ph
Me
N
H2N
N
N
–CO2, –H2S
NH
H2N
H
H
H
Me
NHAr
Ia–Ie
III
IVa–IVe
+
·AcOH
+
ArNH2
VIa–VIe
H2N
NH2
V
I, IV, VI, Ar = Ph (a), 4-MeOC6H4 (b), 4-MeC6H4 (c), 3-F3CC6H4 (d), 3-ClC6H4 (e).
907

BRITSUN et al.
908
Reactions of N-aryl-3-oxobutanethioamides Ia–Ie with bis-
(guanidinium) carbonate (II)
methyl protons, 2-H, and NH + NH2 + H2O and NH
protons (δ 1.67, 5.18, 6.94, and 14.12 ppm, respec-
tively. Its IR spectrum contained absorption bands at
1560–1600 (C=C), 1650 (C=N), and 3200 cm–1 (NH).
Yield, %
Initial com-
1
pound no.
III
IV
V
VI
In the H NMR spectra of aminopyrimidines IVa–IVe
Iaa
Iab
Ibb
Icb
Idb
Ieb
32
–
–
–
–
we observed singlets at δ 2.06–2.12 (CH3), 5.77–5.91
(5-H), 5.92–6.18 (NH2), and 8.69–9.32 ppm (NH). It is
seen that the chemical shifts vary within a narrow
range (Δδ = 0.26 ppm), except for the NH protons
(Δδ = 0.63 ppm). The reason is that the NH protons
suffer from shielding by the neighboring phenyl ring
(π-electron ring current), whose magnitude depends on
the substituent in the ring. The IR spectra of IVa–IVe
contain characteristic absorption bands belonging to
stretching vibrations of the C=C, C=N, and N–H bonds
(1580–1610, 1640–1650, and 3300–3500 cm–1, respec-
tively). The structure of guanidinium acetate V and
arylamines VIa–VIe was confirmed by the spectral
data and elemental analyses.
28
22
24
40
30
35
34
32
28
33
33
29
30
26
31
–
–
–
–
a
Reaction time 1 h, temperature 100°C.
Reaction time 3 h, temperature 140°C.
b
bonyl group toward guanidinium salts at 100°C (as in
reactions with arylamines [8]).
Fusion of N-aryl-3-oxobutanethioamides Ia–Ie with
bis(guanidinium) carbonate (II) at elevated tempera-
ture (140°C, 3 h) led to the formation of 2-amino-4-
(arylamino)-6-methylpyrimidines IVa–VIe, arylamines
VIa–VIe, and guanidinium acetate (V). Pyrimidine
IVa was also obtained in 41% yield by heating but-2-
enethioamide III for 3 h at 140°C. In the reactions of
salt II with thioamides Id and Ie having electron-
withdrawing substituents in the benzene ring (CF3, Cl),
the yields of pyrimidines IVd and IVe were greater
(30–40%) than in reactions with thioamides Ia–Ic
possessing electron-donor groups (MeO, Me; yield 22–
24%). Presumably, electron-withdrawing groups reduce
the electron density on the thiocarbonyl carbon atom,
so that the rate of nucleophilic attack by the amino
group of guanidine increases. However, the reactions
of thioamides Ia–Ie with guanidinium carbonate at
140°C are generally nonselective.
Our results led us to presume that the examined re-
action involves two concurrent pathways (Scheme 2).
According to the first of these, initial nucleophilic
attack by the amino group of guanidine on the car-
bonyl carbon atom of thioamide I gives enethioamide
III which undergoes thermal intramolecular cycliza-
tion to pyrimidine IV. The presence of an electron-
withdrawing group in the benzene ring of N-aryl-3-
oxobutanethioamide favors this pathway. The second
pathway includes transamination and hydrolysis of
thioamide I by the action of guanidine and water. Here,
a probable intermediate is N-[amino(imino)methyl]-3-
oxobutanamide (VII), and arylamine VI is liberated
during the process. Like other acetoacetamides [9],
butanamide VII readily undergoes hydrolysis at the
C2–C3 bond on heating with water in the presence of
guanidinium carbonate; as a result, guanidinium ace-
tate (V) is formed.
Enethioamide III is a light yellow crystalline sub-
stance, which is very readily soluble in water and polar
organic solvents. Pyrimidines IVa–IVe are colorless
substances; they are sparingly soluble in water and
readily soluble in polar organic solvents. Compound
III showed in the 1H NMR spectrum singlets from the
Thus, unlike 2-aminoazoles [5, 7] and 5-substituted
2-aminopyridines [6], N-aryl-3-oxobutanethioamides
react with bis(guanidinium) carbonate under more
severe conditions, and the reaction leads to the forma-
Scheme 2.
II
III
IV
–CO2, –H2O
–H2S
I
O
O
NH
II
II, H2O
V
–VI, –H2S, –CO2
–CO2
Me
N
NH2
H
VII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 6 2007

REACTION OF N-ARYL-3-OXOBUTANETHIOAMIDES
909
tion of both heterocyclic products, 4-arylamino-6-
methylpyrimidin-2-amines, and acyclic compounds,
arylamines and guanidinium acetate.
4-(4-Methoxyphenylamino)-6-methylpyrimidin-
2-amine (IVb). mp 220–222°C. IR spectrum, ν, cm–1:
1370, 1410, 1460, 1510, 1580, 1610, 1640, 2940,
1
3100, 3320, 3480. H NMR spectrum, δ, ppm: 2.06 s
EXPERIMENTAL
(3H, 6-CH3), 3.72 (3H, CH3O) 5.77 s (1H, 5-H), 5.92 s
(2H, NH2), 6.81 d (2H, C6H4, J = 8.7 Hz), 7.49 d (2H,
C6H4, J = 8.7 Hz), 8.69 s (1H, NH). Found, %:
C 62.82; H 6.01; N 24.55. C12H14N4O. Calculated, %:
C 62.59; H 6.13; N 24.33.
1
The H NMR spectra were recorded on a Varian-
300 spectrometer (300 MHz) from solutions in
DMSO-d6 using tetramethylsilane as internal refer-
ence. The IR spectra were measured in KBr on a UR-
20 instrument.
6-Methyl-4-(4-methylphenylamino)pyrimidin-2-
amine (IVc). mp 225–227°C. IR spectrum, ν, cm–1:
1370, 1410, 1460, 1510, 1580, 1650, 3000, 3100,
3-Guanidino-N-phenylbut-2-enethioamide (III).
A mixture of 10 mmol of N-aryl-3-oxobutanethioamide
Ia–Ie and 10 mmol of finely ground bis(guanidinium)
carbonate (II) was heated for 1 h at 100°C. The mix-
ture was cooled, treated with 10 ml of isopropyl al-
cohol, and filtered from undissolved material, the fil-
trate was evaporated, and the residue was treated with
10 ml of diethyl ether. The undissolved material was
filtered off, dried, and recrystallized from isopropyl
alcohol. Yield 32%, mp 149–151°C. IR spectrum, ν,
cm–1: 1290, 1370, 1430, 1480, 1500, 1560, 1600, 1650,
1
3200, 3300, 3480. H NMR spectrum, δ, ppm: 2.07 s
(3H, 6-CH3), 2.25 s (3H, CH3), 5.82 s (1H, 5-H), 5.97 s
(2H, NH2), 7.03 d (2H, C6H4, J = 8.1 Hz), 7.50 d (2H,
C6H4, J = 8.1 Hz), 8.79 s (1H, NH). Found, %:
C 66.98; H 6.31; N 25.95. C12H14N4. Calculated, %:
C 67.27; H 6.59; N 26.15.
6-Methyl-4-[3-(trifluoromethyl)phenylamino]-
pyrimidin-2-amine (IVd). mp 95–97°C. IR spectrum,
ν, cm–1: 1330, 1420, 1470, 1590, 1600, 1640, 3100,
1
3300, 3450. H NMR spectrum, δ, ppm: 2.12 s (3H,
1
3000–3200. H NMR spectrum, δ, ppm: 1.67 s (3H,
6-CH3), 5.91 s (1H, 5-H), 6.18 s (2H, NH2), 7.19 d
(1H, C6H4, J = 8.1 Hz), 7.45 m (1H, C6H4), 7.95 s (1H,
C6H4), 8.13 d (1H, C6H4, J = 8.4 Hz), 9.32 s (1H, NH).
Found, %: C 54.01; H 3.85; N 21.05. C12H11F3N4. Cal-
culated, %: C 53.73; H 4.13; N 20.89.
CH3), 5.18 s (1H, 2-H), 6.93 m (1H, C6H5), 6.94 s (6H,
NH, NH2, H2O), 7.17 m (2H, C6H5), 7.84 m (2H,
C6H5), 14.12 s (1H, NH). Found, %: C 52.13; H 6.09;
N 22.48. C11H16N4OS. Calculated, %: C 52.36; H 6.39;
N 22.20.
4-(3-Chlorophenylamino)-6-methylpyrimidin-2-
Reaction of N-aryl-3-oxobutanethioamides Ia–Ie
with bis(guanidinium) carbonate. A mixture of
10 mmol of N-aryl-3-oxobutanethioamide Ia–Ie and
10 mmol of finely ground salt II was heated for 3 h at
140°C. The mixture was cooled and treated with 10 ml
of isopropyl alcohol. The mixture was filtered from
initial guanidinium carbonate, the filtrate was evap-
orated, and the residue was treated with 10 ml of
diethyl ether. The undissolved material (a mixture of
compounds IV and V) was filtered off, dried, and
treated with 5 ml of water. The aqueous phase con-
taining guanidinium acetate V was separated from
crystals of IVa–IVe and evaporated, and salt V was
recrystallized from isopropyl alcohol. The ether solu-
tion was evaporated to isolate arylamines VIa–VIe.
amine (IVe). mp 117–119°C. IR spectrum, ν, cm–1:
1
1410, 1460, 1580, 1640, 3100, 3300, 3450. H NMR
spectrum, δ, ppm: 2.10 s (3H, 6-CH3), 5.87 s (1H,
5-H), 6.13 s (2H, NH2), 6.91 d (1H, C6H4, J = 8.3 Hz),
7.19 m (1H, C6H4), 7.59 d (1H, C6H4, J = 8.5 Hz),
7.87 s (1H, C6H4), 9.16 s (1H, NH). Found, %:
C 56.52; H 5.00; N 24.11. C11H11ClN4. Calculated, %:
C 56.30; H 4.72; N 23.87.
Guanidinium acetate (V). mp 225–227°C; pub-
lished data [10]: mp 227–229°C. 1H NMR spectrum, δ,
ppm: 1.65 s (3H, CH3), 7.73 s (6H, NH2). Found, %:
C 30.39; H 7.41; N 34.98. C3H9N3O2. Calculated, %:
C 30.25; H 7.61; N 35.27.
Aniline (VIa). bp 179–182°C; published data [11]:
bp 183–183.7°C. Found, %: C 77.22; H 7.84; N 14.79.
C6H7N. Calculated, %: C 77.38; H 7.58; N 15.04.
4-Methoxyaniline (VIb). mp 54–57°C; published
data [12]: mp 57.2°C. Found, %: C 67.98; H 7.62;
N 11.51. C7H9NO. Calculated, %: C 68.27; H 7.37;
N 11.37.
6-Methyl-4-phenylaminopyrimidin-2-amine
(IVa). mp 170–172°C. IR spectrum, ν, cm–1: 1365,
1410, 1470, 1500, 1580, 1610, 1650, 2900–3200,
1
3300, 3500. H NMR spectrum, δ, ppm: 2.08 s (3H,
6-CH3), 5.88 s (1H, 5-H), 6.18 s (2H, NH2), 6.92 m
(1H, C6H5), 7.25 m (2H, C6H5), 7.68 m (2H, C6H5),
8.99 s (1H, NH). Found, %: C 66.19; H 5.88; N 28.18.
C11H12N4. Calculated, %: C 65.98; H 6.04; N 27.98.
4-Methylaniline (VIc). mp 40–42°C; published
data [13]: mp 42.5–43°C. Found, %: C 78.22; H 8.25;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 6 2007

BRITSUN et al.
910
5. Britsun, V.N., Borisevich, A.N., Samoilenko, L.S., Cher-
nega, A.N., and Lozinskii, M.O., Russ. J. Org. Chem.,
2006, vol. 42, p. 1516.
N 12.82. C7H9N. Calculated, %: C 78.46; H 8.47;
N 13.07.
3-(Trifluoromethyl)aniline (VId). bp 182–185°C;
published data [14]: bp 187.5°C. Found, %: C 51.93;
H 4.03; N 8.88. C7H6F3N. Calculated, %: C 52.18;
H 3.75; N 8.69.
6. Britsun, V.N., Borisevich, A.N., Pirozhenko, V.V., and
Lozinskii, M.O., Russ. J. Org. Chem., 2007, vol. 43,
p. 276.
7. Britsun, V.N., Borisevich, A.N., Esipenko, A.N., and
Lozinskii, M.O., Russ. J. Org. Chem., 2007, vol. 43,
p. 103.
3-Chloroaniline (VIe). bp 231–234°C; published
data [15]: bp 236.5°C. Found, %: C 56.61; H 5.02;
N 11.14. C6H6ClN. Calculated, %: C 56.49; H 4.74;
N 10.98.
8. Borisevich, A.N. and Pel’kis, P.S., Zh. Org. Khim.,
1967, vol. 3, p. 1339.
9. Knorr, L., Justus Liebigs Ann. Chem., 1886, vol. 236,
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