Arylbiguanides in heterocyclization reactions

Article abstract of DOI:10.1007/s11176-005-0218-x

The reactions of arylbiguanides with acetyacetone derivatives were used to obtain N-(pyrimidin-2-yl)-N′-arylguanidines, and the reactions with acetoacetic ester derivatives (depending on the structure of the keto esters), N-aryl-N′-(4-oxo-3,4-dihydropyrim

Full text of DOI:10.1007/s11176-005-0218-x

Russian Journal of General Chemistry, Vol. 75, No. 2, 2005, pp. 303 310. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 2, 2005,
pp. 331 339.
Original Russian Text Copyright
2005 by Kryl’skii, Shikhaliev, Shestakov, Liberman.
Arylbiguanides in Heterocyclization Reactions
D. V. Kryl’skii, Kh. S. Shikhaliev, A. S. Shestakov, and M. M. Liberman
Voronezh State University, Voronezh, Russia
Received April 16, 2003
Abstract The reactions of arylbiguanides with acetyacetone derivatives were used to obtain N-(pyrimidin-
2-yl)-N -arylguanidines, and the reactions with acetoacetic ester derivatives (depending on the structure of the
keto esters), N-aryl-N -(4-oxo-3,4-dihydropyrimidin-2-yl)guanidines or 2-amino-4-arylamino-6-aryl(heteryl)-
sulfanylmethylene-1,3,5-triazines. The N-aryl-N -heterylguanidines formed by the reactions with anhydrides,
acyl halides, and aryl isocyanates give rise to the corresponding triaza derivatives.
Unsubstituted and N-substituted biguanides Ia Ic
are polynucleophiles that may cyclize by fragment A
or by fragment B, depending on the reagent used.
esters IXa IXr. The latter reagents are derivatives of
acetoacetic ester, bearing substituents in the 2 and/or
4 positions.
We found that biguanide Ic with -diketones in
methanol under reflux selectively by the terminal
amidine fragment B to form N-aryl-N -(pyrimidin-2-
yl)guanidines Xa Xe (Tables 1 and 2).
H
N
H
N
NH2
R
N
H
N
H
B
Benzoylacetone fails to react with biguanides in
the above conditions, and the reaction under more
rigid conditions (prolonged refluxing in 1-butanol)
provides a hardly tractable mixture of unidentified
reaction products. Dibenzoylmethane could not be
brought into this reaction. The fact that the reactivity
of -diketones in cyclization of arylbiguanides de-
creases in the order CF3COCH2COMe MeCOCH2
COMe > PhCOCH2COMe > PhCOCH2COPh is prob-
ably associated with increasing content in the corres-
ponding diketone of the enol form which is additional-
ly stabilized by conjugation with the benzene rings.
A
I
R = H (a), Alk (b), Ar (c).
The reactions of unsubstituted biguanide Ia with
ethyl cyanoacetate and ethylmalonamide, leading to
2,4-diamino-1,3,5-triazines II [1], as well as the reac-
tion of comound Ia with benzoin leading to 2-guani-
dinoimidazole III [2] have been described. The reac-
tion of p-tolylbiguanide (Ic, R = p-Tol) with benzil
gives a mixture of regioisomers IVa and IVb [3].
1
The H NMR spectra of solutions of compounds X
The cyclizations of compounds Ic with monochlo-
roacetic esters [4] and oxalic esters (as monopotassiun
salt) [5] have been described. Arylbiguanides Ic, like
N,N-dialkylbiguanides, react with aromatic and ali-
phatic esters [6, 7], give rise to 2-amino-1,3,5-triazi-
nes V. If the ester molecule has a -carbonyl group,
the cyclization takes a different direction: The reaction
product was assigned the structure of 4-hydroxypyri-
midine VI [8]. By reacting ketones with alkoxybi-
guanides, Jensen et al. [9] have prepared 2,4-diamino-
4,6-dihydro-1,3,5-triazines VII.
in DMSO-d6 (Table 2) show a singlet of the pyri-
midine aromatic proton at
6.5 7.4 ppm and two
characteristic broadened two- and one-proton singlets
at 7.59 7.75 and 8.35 9.20 ppm, respectively, from
guanidine protons. The more downfield singlet prob-
ably relates to the NH group adjacent to the pyrimi-
dine ring and possessing a higher acidity.
The structure of compound Xa was confirmed by
independent synthesis via addition of aniline to 2-
cyanamino-4,6-dimethylpyrimidine (XI) in HCl.
The aim of the present work was to study in detail
heterocyclization of arylbiguanides Ic containing
various substituents in the aromatic ring (X = H, Alk,
OAlk, Hlg, OPh, OCH2CH2O, EtOCO, NO2, - and
-naphthyl) with -diketones VIIIa VIIIc and keto
With electrophilic reagents, such as benzoyl chlo-
ride, tosyl chloride, and 3,4-dichlorophenyl isocyanate,
N,N -disubstituted guanidine Xa reacts by the free
imino group of the guanidine fragment, which, as
shown in [10], possesses the highest nucleophilicity.
1070-3632/05/7502-0303 2005 Pleiades Publishing, Inc.

304
KRYL’SKII et al.
H
N
H
N
PhCOCHOHPh
NH2
Ph
Ph
NH
N
III
R2
C6H4Me-4
R2COOEt
N
N
H
R1
NH2
N
H
N
N
N
NH2
Ph
Ph
NH
N
II, V
O
PhCOCOPh
IVa
I
H
N
H
N
H
N
HO
Me
Ph
Ph
H
N
H
N
C6H4Me-4
+
MeCOCH2COOEt
NH
IVb
Me
N
N
O
N
HN
Bu
Me
N
VI
PhO(CH2)nO
H2N
N
MeC(O)Me
NH2
N
VII
II, R1 = H, R2 = CH2CN (a); R1 = H, R2 = CH2CONH2 (c); V, R1 = Ph, R2 = CH2Cl (a); R1 = Ph, R2 = COOK (b); R1 =
Ph, R2 = Py (c); R1 = 4-HO-3,5-t-Bu2C6H2, R2 = Me (d); R1 = 4-HO-3,5-t-Bu2C6H2, R2 = CF3 (e); R1 = 4-HO-3,5-t-
Bu2C6H2, R2 = Ph (f); R1 = 4-HO-3,5-t-Bu2C6H2, R2 = PhCH2CH2 (g); VII, n = 1, 2.
H
N
H
N
H
N
H
N
O
O
R2
NH2
N
R2
R1
+
NH
NH
NH
N
X
X
R1
Ic
VIIIa VIIIc
Xa Xe
Ic, X = H, 4-EtO, 4-PhO, 4-MeO; VIII, R1 = R2 = Me (a), R1 = Me, R2 = CF3 (b), R1 = CF3, R2 = 2-thienyl (c); X, R1 =
R2 = Me, X = H (a); R1 = Me, R2 = CF3, X = 4-EtO (b); R1 = Me, R2 = CF3, X = 4-PhO, (c); R1 = CF3, R2 = 2-thienyl,
X = H (d); R1 = CF3, R2 = 2-thienyl, X = 4-MeO (e).
Table 1. Yields, melting points, TLC data, and elemental analyses Xa Xe, XVa XVn, XVIIIa XVIIId, and XXa XXd
Found, %
H
Calculated, %
M
Comp. Yield,
Rf
mp,
C
Formula
no.
%
C
N
C
H
N
founda calculated
Xa
Xb
Xc
Xd
48
46
57
52
47
42
44
41
52
0.66 205 207 64.50 6.35 29.15 C13H15N5
0.58 150 152 52.92 4.73 20.34 C15H16F3N5O
0.62 156 158 58,93 4.09 18.25 C19H16F3N5O
0.61 204 206 52.80 3.39 19.32 C16H12F3N5S
0.65 211 212 52.09 3.73 17.43 C17H14F3N5OS
0.54 285 287 59.01 5.44 28.66 C12H13N5O
0.62 178 180 63.47 6.59 24.66 C15H19N5O
0.59 250 251 65.11 5.53 19.88 C19H19N5O2
0.55 184 186 55.12 5.76 23.22 C14H17N5O3
64.71 6.27 29.02
53.10 4.75 20.64
58.91 4.16 18.08
52.89 3.33 19.27
51.90 3.59 17.80
59.25 5.39 28.79
63.14 6.71 24.54
65.32 5.48 20.04
55.44 5.65 23.09
241
339
387
363
393
243
285
349
303
241.30
339.33
387.37
363.36
393.40
243.27
285.36
349.41
303.33
Xe
XVa
XVb
XVc
XVd
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

ARYLBIGUANIDES IN HETEROCYCLIZATION REACTIONS
305
Table 1. (Contd.)
Found, %
H
Calculated, %
M
Comp. Yield,
Rf
mp,
C
Formula
no.
%
C
N
C
H
N
founda calculated
XVe
XVf
XVg
XVh
XVi
XVj
XVk
XVl
65
42
32
29
38
46
62
42
54
51
54
66
61
58
67
74
62
64
0.60 222 224 54.22 5.34 21.08 C17H15N5O4
0.48 217 219 58.44 6.05 24.21 C14H17N5O2
0.52 295 296 64.58 6.57 23.41 C16H19N5O
0.53 321 323 60.05 5.88 23.14 C15H17N5O2
0.58 255 256 63.08 5.14 18.54 C20H20ClN5O
0.60 205 207 58.74 6.68 17.89 C19H25N5O4
0.61 244 246 60.44 4.17 14.88 C24H20ClN5O2S 60.31 4.22 14.65
0.56 243 245 55.95 4.12 20.84 C19H16N6OS2 55.86 3.95 20.57
0.57 220 222 43.95 3.62 23.88 C15H14ClN7OS2 44.17 3.46 24.04
0.56 228 230 54.55 4.84 27.04 C21H21N9O2S
0.75 145 147 62.97 5.34 21.46 C17H17N5S
0.72 153 155 54.25 4.31 21.51 C18H16N6OS2
0.72 195 196 46.74 4.29 26.87 C14H15N7OS2
0.74 180 181 53.54 4.09 31.12 C18H17N9OS
0.52 241 242 63.58 5.32 16.25 C23H23N5O4
54.38 5.17 21.14
58.52 5.96 24.37
64.63 6.44 23.55
60.19 5.72 23.40
62.91 5.28 18.34
58.90 6.50 18.08
353
287
297
299
381
387
478
408
407
463
323
396
361
407
433
512
425
445
353.34
287.33
297.37
299.34
381.92
387.46
478.02
408.50
407.94
463.52
323.42
396.49
361.44
407.46
433.48
512.05
425.93
445.54
XVm
XVn
54.42 4.57 27.20
63.13 5.30 21.65
54.53 4.07 21.20
46.52 4.18 27.13
53.06 4.21 30.94
63.73 5.35 16.16
XVIIIa
XVIIIb
XVIIIc
XVIIId
XXa
XXb
XXc
XXd
0.55 261 263 51.70 3.66 18.96 C22H18ClN7O2S2 51.61 3.54 19.15
0.56 320 322 60.01 7.70 16.68 C21H20ClN5O3
0.54 278 280 67.15 6.24 15.62 C25H27N5O3
59.23 4.73 16.44
67.40 6.11 15.72
a
Found by mass spectrometry.
Table 2. 1H NMR spectra of compounds Xa Xe
Chemical shift, , ppm
pirimid. C5
Comp.
no.
X
R1
R2
2.32 s (6H)
phenyl
(1H),
pirimid. NH
guanid. N
Xa
6.55 s (1H) 6.92
7.24 t (2H),
t
8.35 br.s (1H) 7.75 br.s (2H)
7.48 d (2H)
Xb
Xc
Xd
Xe
1.45 t (3H), 2.26 s (3H)
4.32 q (2H)
7.31 7.65 m 2.32 s (3H)
(9H)
7.24 s (1H) 7.28 7.46 m (4H) 9.03 s (1H) 7.56 br.s (2H)
7.12 s (1H) 7.31 7.65
m
9.24 s (1H) 7.72 br.s (2H)
7.08 t (1H), 7.27 t 7.36 s (1H) 7.55
(1H), 7.36 d (1H)
d
(2H),
9.14 br.s (1H) 7.85 d (1H),
8.19 d (1H)
7.65 7.78 m (3H)
4.25 s (3H)
7.05 t (1H), 7.24 t 7.43 s (1H) 7.52 7.75 m (4H) 9.13 br.s (1H) 7.83 d (1H),
(1H), 7.35 d (1H)
8.14 d (1H)
The reactions lead to Nacyl-N -(4,6-dimethylpyrimi-
din-2-yl)-N -phenylguanidine (XII), N-[(4,6-dimethyl-
pyrimidin-2-ylamino)phenylaminomethylene]-4-tolyl-
sulfonamide (XIII), and 1-(3,4-dichlorophenylphe-
nyl)-3-[(4,6-dimethylpyrimidin-2-ylamino)phenyl-
aminomethylene]urea (XIV).
to form N-aryl-N -(6-oxo-1,6-dihydropyrimidin-2-yl)-
guanidines XVa XVn (Tables 1 and 3). The 6-hydro-
xypyrimidine XVI structure of the heterocyclic frag-
ment is ruled out by the presence in the 1HNMR spec-
trum of the singlet from the olefin proton (R2 = H) at
the C5 atom of the pyrimidine ring at 5.5 6.2 ppm.
Noteworthy is that this signal is lacking in the spectra
of compounds X that contain an aromatic ring and in
those of compounds XV in which the hydrogen atom
The reactions of arylbiguanides Ic with -keto-
esters IXa IXn occur in methanol already at 18 25 C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

306
KRYL’SKII et al.
Me
Me
Me
Me
Ph
O
N
N
H
N
PhCOCl
N
PhNH2 +
N
NH
N
Ph
Ph
Me
N
N
H
N
Me
N
N
H
N
H
N
H
XI
Me
Xa
XII
Cl
Cl
N
Cl
Cl
HN
Me
O
Me
N
O=S=O
N
.
TsCl
N
N
O
N
Ph
Ph
Me
XIV
N
N
H
N
Me
N
H
N
H
H
XIII
at C5 is substituted by another group, like methyl in
compound XVf. The o-quinoid (XV) and p-quinoid
(XVII) structures are difficult to decide between on
the basis of the 1H NMR spectra, but, as shown in a
14.1 14.3 ppm, and the signal of the third proton is
shifted downfield by 3 ppm.
The synthetic potential of the reaction in study can
be much extended by the use of the available 4-chloro-
acetoacetic ester. By substitution of the chlorine in
the latter by its reaction with appropriate nucleophile,
such as arene- or heterenethiols, we could prepare
acetoacetic ester derivatives IXk IXn [R1 = p-chloro-
phenylsulfanylmethyl (k), 1,3-benzothiazol-2-ylsul-
fanylmethyl (l), 5-methyl-1,3,4-thiadiazol-2-ylsul-
fanylmethyl (m), and 1-phenyl-1H-1,2,3,4-tetrazol-5-
ylsulfanylmethyl (n); R2 = H]. These products could
be brought in heterocyclization with arylbiguanides to
obtain compounds XVk XVn.
detailed research on the N3 H
N1 H amide
amide tautomerism of 4-pyrimidones [11], the prefer-
red structure is XV. The same tautomeric form we
assigned to the products of cyclization of hetaryl-
guanidines with acetoacetic ester derivatives [12].
The broadened singlet at 11.0 11.3 ppm relates
to the pyrimidine N1H group. This signal remains un-
changed after acylation of guanidines XV. At the
same time, the guanidine proton signals change:
Instead of the broadened signal corresponding to two
NH groups we now observe a one-proton singlet at
H
N
H
N
H
N
H
N
H
N
H
N
O
O
O
O
R1
N
O
R2
R2
NH
NH
HN
R2
IXa IXn
X
X
R1
R1
XVa XVn
XVII
H
N
H
N
N
OH
R2
NH
N
X
R1
XVI
IX, XV, R1 = Me, R2 = H, X = H (a); R1 = Pr, R2 = H, X = 3-Me (b); R1 = Ph, R2 = H, X = 4-EtO (c); R1 = MeOCH2,
R2 = H, X = 4-MeO (d); R1 = MeOCOCH2, R2 = H, X = 2-MeO (e); R1 = R2 = Me, X = 4-MeO (f); R1 + R2 = (CH2)4,
X = 3-Me (g); R1 + R2 = (CH2)3, X = 4-MeO (h); R1 = Me, R2 = PhCH2, X = (2-Me, 3-Cl) (i); R1 = Me, R2 =
(CH2)2CO2Et, X = 4-EtO (j); R1 = 4-ClC6H4SCH2, R2 = H, X = 4-PhO (k); R1 = Ht1SCH2, R2 = H, X = H (l); R1 =
Ht2SCH2, R2 = H, X = 3-Cl (m); R1 = Ht3SCH2, R2 = H, X = 4-EtO (n); Ht1 = 1,3-benzothiazol-2-yl, Ht2 = 5-methyl-
1,3,4-thiadiazol-2-yl, Ht3 = 1-phenyl-1H-1,2,3,4-tetrazol-5-yl.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

ARYLBIGUANIDES IN HETEROCYCLIZATION REACTIONS
Table 3. 1H NMR spectra of compounds XVa XVn
307
Chemical shift, , ppm
pirimid. C5
Comp.
no.
X
R1
R2
phenyl
pirimid. NH
guanid. N
XVa
XVb
2.10 s (3H)
5.50 s (1H) 6.88 7.34 m (5H) 11.12 br.s (1H) 8.14 br.s (2H),
9.76 br.s (1H)
1.93 s (3H) 1.00 t (3H),
1.62 m (2H),
5.60 s (1H) 6.78 s (1H),
7.27 7.44 m (3H)
11.22 br.s (1H) 8.14 br.s (2H),
9.70 br.s (1H)
2.48 t (2H)
XVc
XVd
XVe
XVf
XVg
1.33 t (3H), 7.24
3.78 q (2H) 7.53 m (9H)
3.39 s (3H) 3.78 s (3H),
4.15 s (2H)
3.70 s (3H) 3.48 s (2H),
4.11 s (3H)
5.57 s (1H) 7.24 7.53
5.69 s (1H) 6.87
m
11.15 br.s (1H) 8.15 br.s (2H),
9.62 br.s (1H)
11.14 br.s (1H) 8.00 br.s (2H),
9.65 br.s (1H)
d
(2H),
7.40 d (2H)
5.72 s (1H) 7.67 7.74 m (4H) 11.20 br.s (1H) 8.11 br.s (2H),
9.07 br.s (1H)
3.78 s (3H) 1.88 s (3H) 2.17 s (3H)
6.86
d
(2H),
11.04 br.s (1H) 7.98 br.s (2H),
9.58 br.s (1H)
11.20 br.s (1H) 8.08 br.s (2H),
8.90 br.s (1H)
7.41 d (2H)
6.82 d (1H),
7.14 t (1H),
7.38 d (1H),
7.50 s (1H)
2.22 2.48 m
1.69 m (4H),
2.22 2.48 m (7H, aliph. Me)
XVh
XVi
XVj
3.73 s (3H) 1.95 m (2H),2.52 2.71 m (4H)
1.72 s (3H) 2.21 s (3H) 2.40 s (2H),
6.85
7.51
d
d
(2H),
(2H)
10.92 br.s (1H) 7.90 br.s (2H),
8.92 br.s (1H)
6.78 7.35 m (8H) 11.13 br.s (1H) 8.01 br.s (2H),
9.53 br.s (1H)
6.84
6.78 7.35
m
1.22 t (3H), 2.20 s (3H) 1.41 t (3H),
d
(2H),
11.36 br.s (1H) 8.02 br.s (2H),
10.23 br.s (1H)
4.07 m (4H)
2.41 t (2H),
2.62 t (2H),
4.07 m (4H)
7.32 d (2H)
XVk
XVl
6.72 7.44 m 4.35 s (2H),
6.72 7.44 m
5.72 s (1H) 6.72 7.44 m
(13H)
5.97 s (1H) 6.67 7.12 m (9H) 11.30 br.s (1H) 8.21 br.s (2H),
9.32 br.s (1H)
11.33 br.s (1H) 8.01 br.s (2H),
9.22 br.s (1H)
4.02 s (2H),
6.67 7.12 m
XVm
XVn
2.69 s (3H),
4.37 s (2H)
1.33 t (3H), 4.32 s (2H),
3.78 q (2H) 7.24 7.53 m
6.09 s (1H) 7.22 7.44 m (3H), 11.21 br.s (1H) 8.21 br.s (2H),
7.85 s (1H)
9.24 br.s (1H)
5.87 s (1H) 7.24 7.53 m (9H) 11.15 br.s (1H) 8.14 br.s (2H),
9.62 br.s (1H)
With acetoacetic ester derivatives IXo IXr contain-
ing 2 arylsulfanyl(heterylsulfanyl) substituents [Ar =
4-MePh (o), Ht = Ht1 (p), Ht2 (q), Ht3 (r)], we failed
to obtain expected guanidines XV. Instead of them,
2-amino-4-arylamino-6-aryl(heteryl)sulfanylmethyl-
1,3,5-triazines XVIIIa XVIIId were isolated in all
the cases (Tables 1 and 4). The same compounds were
obtained by independent synthesis from 2-amino-4-
arylamino-6-chloromethyl-1,3,5-triazines V (R1 = Ar,
R2 = CH2Cl) (prepared, in their turn, by cyclization of
arylbiguanides with methyl chloroacetate) and the
corresponding arene(heterene)thiols in the presence of
1,6-dihydropyrimidin-2-yl)guanidines XV is probably
explained by the fact that keto esters IXo IXr that are
additionally stabilized by the acceptor 2-sulfanyl
group in a solution of such a strong base as biguanide
undergo acidic cleavage with subsequent cyclization
of the resulting aryl(heteryl)thioacetic acid with bi-
guanide. To verify this suggestion, we effected one
more independent synthesis of compound XVIIIb by
reaction of arylbiguanide (Ic, X = 4-MeO) with methyl
(1,3-benzothiazol-2-ylsulfanyl)acetate (XIX).
Guanidines XV are smoothly acylated by the free
imino group with anhydrides or acyl halides (in the
latter case, in the presence of pyridine) in dry di-
triethylamine.
Apparently, the formation of com-
pounds XVIII instead of expected N-aryl-N -(6-oxo-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

308
KRYL’SKII et al.
S
Ar(Ht)
NH2
IXo IXr
XVa XVn IXo IXr Ic
N
N
XC6H4
N
N
H
XVIIIa XVIIId
S
Ar(Ht)SH
NEt3
Ic + Ht1SCH2CO2Me
N
N
XC6H4
XIX
NH2
N
H
N
V
XVIII, X = H, Ar = 4-MeC6H4 (a); X = 4-MeO, Ht = Ht1 (b); X = 4-MeO, Ht = Ht2 (c); X = 4-MeO, Ht = Ht3 (d).
Table 4. 1H NMR spectra of compounds XVIIIa XVIIId
Chemical shift, , ppm
Comp.
no.
X
NH
NH2
CH2
phenyl
Ar (Ht)
XVIIIa
9.24 s (1H) 6.97 s (2H) 4.30 s (2H) 7.56 7.80 m (7H)
2.08 s (3H), 6.82 d (2H),
7.56 7.80 m
XVIIIb 3.72 s (3H) 9.28 s (1H) 6.98 s (2H) 4.45 s (2H) 6.79 d (2H)
7.34 7.66 m (4H), 7.86 d
(1H), 8.02 d (1H)
2.68 s (3H)
XVIIIc 3.72 s (3H) 9.29 s (1H) 6.99 s (2H) 4.30 s (2H) 6.84 d (2H), 7.61 d (2H)
XVIIId 3.71 s (3H) 9.41 s (1H) 7.14 s (2H) 4.44 s (2H) 6.81 d (2H), 7.51 7.71 m (7H) 7.51 7.71 m
Table 5. 1H NMR spectrum XXa XXd
Chemical shift, , ppm
Comp.
no.
X
R1
R2 pirimid. C5
phenyl
acyl
pirimid. N1
guanid. N
XXa
4.27 s (4H) 1.00 t (3H),
1.65 m (2H),
5.69 s (1H) 6.85 d (1H), 7.21 8.11
m
m
11.21 s (1H) 12.18 s (1H),
14.51 s (1H)
7.21 8.11 m
(7H)
2.46 m (2H)
2.68 s (3H),
4.36 s (2H)
3.40 s (3H),
XXb
XXc
XXd
6.06 s (1H) 7.19 8.12 m 7.19 8.12
(9H)
5.96 s (1H) 7.19 8.02 m 2.44 s (3H), 11.30 s (1H) 12.28 s (1H),
11.21 s (1H) 12.23 s (1H),
14.09 s (1H)
4.29 s (2H)
(8H)
7.19 8.02 m
14.32 s (1H)
11.14 s (1H) 12.02 s (1H),
14.36 s (1H)
1.71 2.68 m (14H)
6.92 8.28 m 6.92 8.28 m
(7H)
methylacetamide to give N-acyl-N -aryl-N -(6-oxo-
1,6-dihydropyrimidin-2-yl)guanidines XXa XXd
(Tables 1 and 5).
pounds can be ranked as follows: acetoacetic ester and
its derivatives [except for those containing 2-aryl-
(heteryl)sulfanyl substituent], acetylacetone, 1,1,1-tri-
fluoro-2,4-pentanedione, 1,1,1-trifluoro-4-(2-thie-
enyl)-2,4-butanedione, benzoylacetone, and dibenzoyl-
methane. The tendency of the carbonyl compounds
Thus, in terms of decreasing reactivity in hetero-
cyclization with arylbiguanides, -dicarbonyl com-
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ARYLBIGUANIDES IN HETEROCYCLIZATION REACTIONS
309
for enolization increases in the same order. The reac-
tion products are N-aryl-N -(pyrimidin-2-yl)guanidines
X and N-aryl-N -(6-oxo-1,6-dihydropyrimidin-2-yl)-
guanidines XV.
s (1H, pyrimid.), 7.21 t (1H, arom.), 7.37 7.56 m (5H,
arom.), 7.79 d (2H, arom.), 8.16 d (2H, arom.), 12.31
s (1H, NH), 13.20 s (1H, NH). Found, %: C 69.47; H
5.64; N 20.48. C20H20N5O. Calculated, %: C 69.36;
H 5.78; N 20.23. M 346.28.
2-Aryl(heteryl)sulfanyl-substituted derivatives of
acetoacetic ester undergo acidic cleavage uder the
reaction conditions, which changes the reaction direc-
tion and results in formation of 2-amino-4-arylamino-
6-aryl(heteryl)sulfanylmethyl-1,3,5-triazines XVIII.
N-[(4,6-Dimethylpyrimidin-2-ylamino)phenyl-
aminomethylene]-4-methylbenzenesulfonamide
(XIII). p-Toluenesulfonyl chloride, 1.00 g, was added
to a stirred solution of 1.21 g of guanidine Xa in a
mixture of 15 ml of dry dioxane with 2 ml of dry tri-
ethylamine. The mixture was heated at 80 C for 2 h
and poured into 100 ml of distilled water. The
medium of the suspension formed was made weakly
acidic with HCl. The precipitate was filtered off,
washed with water, and recrystallized from dioxane.
EXPERIMENTAL
1
The H NMR spectra in DMSO-d6 or DMSO-d6 +
CCl4 were measured on a Bruker AC-300 instrument
(300 MHz) relative to TMS. The mass spectra were
obtained on an LKB-9000 instrument, ionizing energy
70 eV. Reaction progress and product purity were
controlled by TLC on Merck UV-254 plates, eluent
ethyl acetate.
1
Yield 0.89 g (45%), colorless crystals, mp 208 C. H
NMR spectrum (DMSO-d6 + CCl4), , ppm: 2.41 s
(3H, Ar CH3), 2.50 s (6H, pyrimid. CH3), 7.00 s (1H,
pyrimid.), 7.05 7.26 m (5H, arom.), 7.30 d (2H,
arom.), 7.70 d (2H, arom.), 10.45 s (1H, NH), 11.72 s
(1H, NH). Found, %: C 60.58; H 5.35; N 17.84.
C20H21N5O2S. Calculated, %: C 60.76; H 5.32; N
17.72. M 395.31.
N-(4,6-Dimethylpyrimidin-2-yl)-N -phenylguani-
dine (Xa). a. A mixture of 1.77 g of phenylbiguanide
Ic (X = H) and 0.98 ml of acetylacetone (VIIIa) in
20 ml of methanol was refluxed for 2 h. After cooling,
colorless crystals precipitated and were filtered off and
recrystallized from dioxane.
1-(3,4-Dichlorophenyl)-3-[(4,6-dimethylpyrimi-
din-2-ylamino)phenylaminomethylene]urea (XIV).
3,4-Dichlorophenyl isocyanate, 0.9 g, was added to a
stirred solution of 1.21 g of guanidine Xa in 15 ml of
dry dioxane. The precipitate that formed was filtered
off and recrystallized from dioxane. Yield 1.88 g
b. Concentrated HCl, 0.93 ml, was added to a mix-
ture of 1.48 g of pyrimidine XI and 0.93 g of aniline
in 15 ml of 2-propanol. The mixture was refluxed for
1 h and treated with a solution of 0.5 g of NaOH in
100 ml of distilled water. The precipitate that formed
was filtered off and recrystallized from dioxane. Yield
1.33 g (55%), colorless crystals, mp 207 C.
1
(88%), colorless crystals, mp 212 C. H NMR spec-
trum (DMSO-d6 + CCl4), , ppm: 2.49 s (6H, pyrimid.
CH3), 6.91 s (1H, pyrimid.), 6.91 7.08 m (5H, arom.),
7.36 d (1H, arom.), 7.59 s (1H, arom.), 8.05 s (1H,
arom.), 9.32 s (1H, NH), 11.82 s (1H, NH), 12.62 s
(1H, NH). Found, %: C 56.05; H 4.18; N 19.44.
C20H18Cl2N6O. Calculated, %: C 55.92; H 4.19; N
19.57. M 429.34.
N-(4-Ethoxyphenyl)-N -[4-methyl-6-(trifluoro-
methyl)pyrimidin-2-yl)guanidine (Xb), N-[4-me-
thyl-6-(trifluoromethyl)pyrimidin-2-yl)-N -(4-phe-
noxyphenyl)guanidine (Xc), N-phenyl-N -[4-thi-
enyl-6-(trifluoromethyl)pyrimidin-2-yl)guanidine
(Xd), N-(4-methoxyphenyl)-N -[4-thienyl-6-(tri-
fluoromethyl)pyrimidin-2-yl)guanidine (Xd) were
prepared by procedure a.
N-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-
N -phenylguanidine (XVa). a. A solution of 1.77 g
of phenylbiguanide and 1.52 ml of acetoacetic ester
(IXa) in 20 ml of methanol was left to stand at 18
25 C for 30 h. The precipitate that formed was filtered
off and recrystallized from dioxane, yield 1.02 g
(42%), colorless crystals, mp 285 287 C.
N-Benzoyl-N -(4,6-dimethylpyrimidin-2-yl)-N -
phenylguanidine (XII). Benzoyl chloride, 0.77 g,
was added dropwise to a stirred solution of 1.21 g of
guanidine Xa in a mixture of 15 ml of dry dioxane
and 2 ml of dry triethylamine. The reaction mixture
was stirred for 1 h at 18 25 C and poured into 100
ml of distilled water. The medium of the suspension
formed was made weakly acidic with HCl. The pre-
cipitate was filtered off, washed with water, and re-
crystallized from dioxane, yield 1.07 g (62%), color-
N-(3-Methylphenyl)-N -(4-propyl-6-oxo-1,6-di-
hydropyrimidin-2-yl)guanidine (XVb), N-(4-ethoxy-
phenyl)-N -(4-phenyl-6-oxo-1,6-dihydropyrimidin-
2-yl)guanidine (XVc), N-[4-(methoxymethyl)-6-
oxo-1,6-dihydropyrimidin-2-yl]-N -(4-methoxyphe-
nyl)guanidine (XVd), N-[4-(methoxycarbonylme-
thyl)-6-oxo-1,6-dihydropyrimidin-2-yl)-N -(2-me-
thoxyphenyl)guanidine (XVe), N-(4-methoxyphe-
nyl)-N -(4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-
1
less crystals, mp 176 C. H NMR spectrum (DMSO-
d6 + CCl4), , ppm: 2.52 s (6H, pyrimid. CH3), 7.00
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005

310
KRYL’SKII et al.
2-yl)guanidine (XVf), N-(3,4,5,6,7,8-hexahydro-4-
oxoquinazolin-2-yl)-N -(3-methylphenyl)guanidine
(XVg), N-(4-methoxyphenyl)-N -(4-oxo-4,5,6,7-
tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl)guani-
dine (XVh), N-(5-benzyl-4-methyl-6-oxo-1,6-dihyd-
ropyrimidin-2-yl)-N -(3-chloro-2-methylphenyl)-
guanidine (XVi), N-[5-(2-ethoxycarbonylethyl)-4-
methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-N -(4-
ethoxyphenyl)guanidine (XVj), N-[4-(4-chloro-
phenylsulfanylmethyl)- 6-oxo-1,6-dihydropyrimi-
din-2-yl]-N -(4-phenoxyphenyl)guanidine (XVk),
N-[4-(1,3-benzothiazol-2-ylsulfanylmethyl)-6-oxo-
1,6-dihydropyrimidin-2-yl]-N -phenylguanidine
(XVl), N-(3-chlorophenyl)- N -[4-(5-methyl-1,3,4-
thiadiazol-2-ylsulfanylmethyl)-6-oxo-1,6-dihydro-
pyrimidin-2-yl]guanidine (XVm), N-(4-ethoxy-
phenyl)-N -[4-(1-phenyl-1H-1,2,3,4-tetrazol-5-ylsul-
fanylmethyl)-6-oxo-1,6-dihydropyrimidin-2-yl]-
guanidine (XVn) were prepared similarly to XVa.
yl)-N -(4-propyl-6-oxo-1,6-dihydropyrimidin-2-yl)-
guanidine (XXa) was prepared in a similar way.
N-(3-Chlorophenyl)-N -[4-(methoxymethyl)-6-
oxo-1,6-dihydropyrimidin-2-yl]-N -(4-methylbenz-
oyl)guanidine (XXc). 4-Methylbenzoyl chloride,
1.55 g, and 2 ml of pyridine were added to a solution
of 3.08 g of guanidine XVm in 15 ml of dry dime-
thylacetamide, and the mixture was heated for 30 min
at 70 C. After cooling, the reaction mixture was
poured into water, and the precipitate that formed was
filtered off, dried, and recrystallized from DMF to
obtain colorless crystals.
N-(4-Oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-
N -(4-methoxybenzoyl)-N -(2,4-dimethylphenyl)-
guanidine (XXg) was synthesized in a similar way.
REFERENCES
1. Chance, L.H., J. Chem. Eng. Data, 1980, vol. 25,
6-(1,3-Benzothiazol-2-ylsulfanylmethyl)-2-(4-
methoxyphenyl)-1,3,5-triazine-2,4-diamine
(XVIIIb). a. A solution of 2.07 g of (4-methoxyphe-
nyl)biguanide (Ic) and 3.55 g of ester IXp in 20 ml
of methanol was refluxed for 3 h. The precipitate that
formed was filtered off and recrystallized from
dioxane.
no. 4, p. 402.
2. Burmistrov, K., Fleck, A., Schramm, H.W., and
Schubert-Zsilavecz, M., Sci. Pharm., 1994, vol. 62,
no. 2, p. 172
3. Schramm, H.W., Sci. Pharm., 1991, vol. 59, no. 4,
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4. Sintezy organicheskih preparatov (Organic Syntheses),
b. Triethylamine, 2 ml, was added to a solution of
2.66 g of triazine V and 1.67 g of 1,3- benzothiazol-2-
thiol in 15 ml of DMF. The mixture was heated at 60
65 C for 2 h and then poured into 200 ml of cold
water. The precipitate that formed was filtered off and
recrystallized from dioxane.
Moscow: Inostrannaya Literatura, 1960, vol. 10, p. 5.
5. Sokolovskaya, S.V., Sokolova, V.N., and Magid-
son, O.Yu., Zh. Obshch. Khim., 1957, vol. 27, no. 3,
p. 765.
6. Kelarev, V.I., Karahanov, R.A., Bellul’, M., Ushako-
va, L., and Mikaya, A.I., Khim. Geterotsikl. Soedin.,
1988, no. 5, p. 674.
c. A solution of 2.07 g of biguanide Ic and 2.39 g
of ester XIX in 20 ml of methanol was left to stand at
18 25 C for 20 h. The precipitate that formed was
recrystallized from dioxane.
7. Kelarev, V.I., Remizov, A.S., Karahanov, R.A., Po-
livin, Yu.N., and Oietaio, D., Khim. Geterotsikl.
Soedin., 1992, no. 10, p. 1395.
6-(4-Methylphenylsulfanylmethyl)-1,3,5-triazine-
2,4-diamine (XVIIIa), 2-(4-methoxyphenyl)-6-(5-
methyl-1,3,4-thiadiazol-2-ylsulfanylmethyl)-1,3,5-
triazine-2,4-diamine (XVIIIc), and 2-(4-methoxy=
phenyl)-6-(1-phenyl-1H-1,2,3,4-tetrazol-5-ylsulfa-
nylmethyl)-1,3,5-triazine-2,4-diamine (XVIIId)
were prepared by procedure a.
8. Shuto, Y., Taniguchi, E., and Maekawa, K., J. Fac.
Agr. Kyushu Univ., 1974, vol. 18, no. 4, p. 221.
9. Jensen, N.P., Ager, A.R., Bliss, R.A., Canfield, C.J.,
Kotecka, B.M., Rieckmann, K.H., Terpinski, J., and
Jacobus, D.P., J. Med. Chem., 2001, vol. 44, no. 23,
p. 3925.
10. Shikhaliev, Kh.S., Ermolova, G.I., Falaleev, A.V.,
and Solov’ev, A.S., Izv. Vyssh. Uchebn. Zaved., Khim.
Khim. Tekhnol., 1998, vol. 41, no. 2, p. 45.
N-Benzoyl-N -(3-chlorophenyl)-N -[4-(5-methyl-
1,3,4-thiadiazol-2-ylsulfanylmethyl)-6-oxo-1,6-di-
hydropyrimidin-2-yl]guanidine (XXb). Benzoic an-
hydride, 2.26 g, was added to a solution of 4.08 g of
compound XVm, and the mixture was heated for
40 min at 80 C. After cooling, a precipitate formed
and was recrystallized from DMF to obtain pale
brown crystals.
11. Kheifetz, G.M., Kol’tsov, A.I., Khachaturov, A.S.,
and Gindin, V.A., Zh. Org. Khim., 2000, vol. 36,
no. 9, p. 1411.
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and Solov’ev, A.S., Khim. Geterotsikl. Soedin., 2002,
no. 2, p. 232.
N-Benzoyl-N -(2,3-dihydro-1,4-benzodioxan-6-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 2 2005