A facile one-pot synthesis of novel substituted 1,2,3,4- tetrahydropyrimidines part 5 [1]: Synthesis of bis[(1-alkyl/aralkyl)-5-benzoyl- 6-methylthio-1,2,3,4-tetrahydropyrimidinyl]alkane and benzene, bis[3-phenyl-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-d]

Article abstract of DOI:10.1002/jhet.5570420535

Bis-1,2,3,4-tetrahydropyrimidinylalkanes/benzenes 2a-f have been synthesized by the reaction of N,S-acetals with formaldehyde and diamines. Reaction of pyrazoles 3a and 3b with diamines and formaldehyde yield bis-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin

Full text of DOI:10.1002/jhet.5570420535

A Facile One-pot Synthesis of Novel Substituted 1,2,3,4-
Tetrahydropyrimidines Part 5 [1]: Synthesis of Bis[(1-alkyl/aralkyl)-
5-benzoyl-6-methylthio-1,2,3,4-tetrahydropyrimidinyl]alkane and
Benzene, Bis[3-phenyl-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-d]-
pyrimidinyl]alkane and Bis[1-benzyl-7-phenyl-1,2,3,4-tetrahydro-
pyrazolo[1,5-a]triazinyl]alkane and Benzene
Jul-Aug 2005
975
a
a
b
a*
Milan Ch. Dutta , Kaushik Chanda , Philippe Helissey and Jai N. Vishwakarma
a
Organic Research Lab., Department of Chemistry, St Anthony’s College, Shillong-793001, India.
E-mail: jnvishwakarma@rediffmail.com.
Laboratoire de Chimie Therapeutique, UNR CNRS-Universite Rene Descartes No 8638,
b
Faculte des Sciences Pharmaceutiques et Biologiques 4-Avenue de l'Observatoire, 75270 Paris Cedex 06, France.
Received November 10, 2004
Bis-1,2,3,4-tetrahydropyrimidinylalkanes/benzenes 2a-f have been synthesized by the reaction of N,S-
acetals with formaldehyde and diamines. Reaction of pyrazoles 3a and 3b with diamines and formaldehyde
yield bis-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidinylalkanes 4a-b and bis-1,2,3,4-tetrahydropyrazolo[1,5-
a]triazinylalkanes and benzene 5a-c respectively in good yields.
J. Heterocyclic Chem., 42, 975 (2005).
Several pyrazolo[3,4-d]pyrimidines and their mercapto
analogues are known to possess important biological prop-
erties [2-6]. In view of this, we reported the synthesis of
4,5,6,7-tetrahydro derivatives [7]. However, to the best of
our knowledge, bis-pyrazolotetrahydropyrimidines are
unknown in the literature and hence their biological prop-
erties remain unexplored. Prompted by the above observa-
tions and in continuation with our on-going program on
the development of novel synthetic strategies for tetrahy-
dropyrimidines [1, 8-10], we undertook the present inves-
tigation and the results of our studies are reported herein.
Thus, when a mixture of N,S-acetal 1a [11], ethylenedi-
amine and formaldehyde (2:1:4) in methanol was stirred at
room temperature, work up of the reaction mixture yielded
an off white solid in 72% yield, which was characterized
as 1,2-bis(1-methyl-5-benzoyl-6-methylthio-1,2,3,4-
tetrahydropyrimidinyl)ethane (2a). The reaction was
found to be general with other diamines and with corre-
sponding 1 to give the respective 2b-f in 52-72% overall
yields. The structures of these products were confirmed on
the basis of analytical and spectral data. Thus, the ir spec-
tra of 2a-f showed strong absorption bands in the range
observed as multiplets resonating between δ 1.40-1.62
ppm. The singlets due to protons of methylthio group
appeared between δ 1.90-1.98, while the aromatic protons
gave multiplets in the usual range.
Further reaction of 2 with hydrazine hydrate to achieve
the synthesis of 4 resulted in the formation of a complex
reaction mixture from which isolation of the desired prod-
uct was unsuccessful. This is probably due to the cleavage
of the tetrahydropyrimidine ring in the presence of this
nucleophilic reagent under experimental conditions. We
then turned our attention to another strategy involving the
conversion of 1 into pyrazole 3 [12] and then 3 into the
desired bis-pyrazolotetrahydropyrimidines 4 (Scheme).
Thus, when a mixture of 3(5)-methylaminopyrazole 3a,
ethylenediamine and formaldehyde (2:1:4) was stirred at
room temperature in methanol for 5 hours, work up of the
reaction mixture yielded 4a in 53% yields, the structure of
which was proposed to be 1,2-bis(3-phenyl-7-methyl-
4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidinyl)ethane on
the basis of analytical and spectral data. Similarly, 3a
reacted with butylenediamine and formaldehyde under
identical conditions to give 4b in 55% yield. However, the
reaction of 3a with p-phenylenediamine and formaldehyde
gave an intractable reaction mixture from which no prod-
uct could be isolated. Interestingly, when 3(5)-benzy-
laminopyrazole 3b was reacted with ethylenediamine and
formaldehyde under identical conditions, the product iso-
lated (51%) was characterized as 1,2-bis(1-benzyl-7-
phenyl-1,2,3,4-tetrahydropyrazolo[1,5-a]triazinyl)ethane
(5a) instead of the corresponding bis-pyrazolopyrim-
idinylethane. The reaction of 3b was found to follow a
similar course of reaction with other diamines giving 5b
and 5c in 50 and 55% yields respectively. The bis-pyra-
zolotriazinyl derivatives 5 were distinguished from the
corresponding bis-pyrazolopyrimidinyl derivatives by the
-1
1603-1639 cm due to carbonyl group stretching frequen-
1
cies. The H nmr spectra showed singlets due to methylene
protons at C and C of the tetrahydropyrimidine ring in
2
4
the range of δ 3.80-4.55 and δ 3.40-4.12 respectively. The
singlets due to NMe protons in 2a-c appeared in the range
of δ 3.00-3.10 while the benzylic methylene protons in 2d-
f gave singlets in the range of δ 3.65-4.30. In the spectra of
2a and 2d, the signals due to the protons of ethylene chain
appeared as singlets at 2.80 and 2.56 ppm respectively,
whereas the NCH protons of butylene chain in com-
2
pounds 2b and 2e gave multiplets in the range of δ 2.35-
2.52. The signals corresponding to the methylene protons
at C and C of the butylene chain of 2b and 2e are
2
3

976
M. Ch. Dutta, K. Chanda, P. Helissey and J. N. Vishwakarma
Vol. 42
EXPERIMENTAL
presence of a signal due to H-8 between δ 5.72-6.05 (2 s,
1
2x1H) in their H nmr spectra. In addition, the band due to
Melting points were recorded by open capillary method and
are uncorrected. The infrared spectra were recorded on a Perkin-
NH in the ir spectra of 4a-b was found absent in those of
5a-c. The difference in the reactivities of 3(5)-methy-
laminopyrazole 3a and the corresponding benzylaminopy-
razole 3b to give 4 and 5 respectively could be explained
1
Elmer 983 spectrometer. H nmr (90 MHz) spectra were recorded
1
13
on Varian EM-390 spectrometer. High-resolution H nmr and
C
nmr (300 MHz) spectra were recorded on Bruker ACF-300 spec-
trometer. The chemical shifts (δ ppm) and the coupling constants
(Hz) are reported in the standard fashion with reference to TMS
as internal reference. FAB-mass spectra (MS) were measured on
JEOL 3SX 102/DA-6000 Mass spectrometer using Argon as the
FAB gas and m-nitrobenzylalcohol as the matrix. Elemental
analyses were performed on a Vario-EL III instrument.
in terms of decreased nucleophilicity of C position in 3b
4
because of reduced delocalization of the lone pair of elec-
trons of the benzylamino nitrogen due to hyperconjugation
of CH of benzyl group, while the nitrogen lone pair in
2
methylamino group of 3a is completely delocalized over
pyrazole ring, thus facilitating ring closure through C
position.
4
Bis[(1-Alkyl/aralkyl)-5-benzoyl-6-methylthio-1,2,3,4-tetrahy-
dropyrimidinyl]alkanes/benzenes (2a-f).
The present investigation describes facile syntheses of
hitherto unreported bis-tetrahydropyrimidines, bis-pyra-
zolotetrahydropyrimidines and bis-pyrazolotetrahydro-
triazines.
General Procedure.
A mixture of diamine (1 mmol) and formaldehyde (4 mmol,
40% solution) in 2 ml methanol was stirred at room temperature

Jul-Aug 2005
A Facile One-pot Synthesis of Novel Substituted 1,2,3,4- Tetrahydropyrimidines Part 5
977
for 10 minutes. To this was added a solution of enaminone 1 (2
mmol) in 5-6 ml methanol and the resulting mixture stirred for 3-
8 hours in case of 2b, 2c, 2e, 2f and 22-30 hours in case of 2a and
2d. After completion of the reaction (monitored by tlc), the reac-
tion mixture was cooled in ice water and the precipitated product
was collected by filtration, washed with cold methanol (3 x 1 ml)
and dried to give pure 2a-2f, which were recrystallized from
methanol.
13
CH ) 7.25-7.41 (m, 16H), 7.69-7.72 (m, 4H); C nmr (CDCl ): δ
2
3
16.66, 25.21, 53.89, 54.32, 55.19, 69.46, 117.86, 127.69, 127.87,
128.51, 128.70, 131.05, 138.13, 141.42, 151.60, 195.96; ms: m/z
+
703 (MH ).
Anal. Calcd. for C
H N O S (702.97): C, 71.76; H, 6.60;
42 46 4 2 2
N, 7.97. Found: C, 72.02; H, 6.64; N, 8.04.
1,4-Bis (1-Benzyl-5-benzoyl-6-methylthio-1,2,3,4-tetrahydro-
pyrimidinyl)benzene (2f).
1,2-Bis (1-methyl-5-benzoyl-6-methylthio-1,2,3,4-tetrahydro-
pyrimidinyl)ethane (2a).
The compound was obtained as a white solid in 70% yield, mp
-1
1
197-198 °C; ir (KBr): 1516, 1568, 1629 cm ; H nmr (CDCl ): δ
3
The compound was obtained as a white solid in 72% yield, mp
1.95 (s, 6H, 2 CH ), 4.00 (s, 4H, 2 CH ), 4.30 (s, 4H, 2 CH ),
3
2
2
C
1 1
159-160° C; ir (KBr): 1455, 1554, 1625 cm- ; H nmr (CDCl ): δ
13
3
4.52 (s, 4H, 2 CH ), 7.28-7.45 (m, 20H), 7.75-7.79 (m, 4H);
nmr (CDCl ): δ 16.37, 50.49, 54.91, 67.00, 117.40, 126.94,
127.54, 127.97, 128.29, 128.59, 128.83, 131.37, 137.71, 140.92,
2
1.98 (s, 6H, 2 CH ), 2.80 (s, 4H, 2 CH ), 3.10 (s, 6H, 2 CH ),
3
2
3
3
3.58 (s, 4H, 2 CH ), 3.98 (s, 4H, 2 CH ), 7.35-7.48 (m, 6H),
2
2
13
7.68-7.72 (m, 4H); C nmr (CDCl ): δ 16.61, 40.04, 52.16,
53.74, 72.94, 115.28, 127.76, 128.33, 130.66, 142.04, 152.71,
195.73; ms: m/z 523 (MH ).
+
3
141.94, 152.63, 195.84; ms: m/z 723 (MH ).
Anal. Calcd. for C
H N O S (722.96): C, 73.10; H, 5.86;
44 42 4 2 2
+
N, 7.75. Found: C, 73.31; H, 5.90; N, 7.69.
Anal. Calcd. for C
H N O S (522.73): C, 64.34; H, 6.56;
28 34 4 2 2
Bis (3-Phenyl-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-d]pyrim-
idinyl)alkanes (4a-b).
N, 10.72. Found: C, 64.11; H, 6.51; N, 10.79.
1,4-Bis (1-Methyl-5-benzoyl-6-methylthio-1,2,3,4-tetrahydro-
pyrimidinyl)butane (2b).
General Procedure.
A mixture of diamine (1 mmol) and formaldehyde (4 mmol,
40% solution) in 2 ml methanol was stirred at room temperature
for 10 minutes. To this was added a solution of aminopyrazole 3a
(2 mmol) in 5-6 ml methanol and the resulting mixture stirred for
3-8 hours. After the completion of the reaction (monitored by tlc),
the solvent was distilled off, the residue dissolved in chloroform
(5 ml), the solution washed with water (3 x 3 ml), dried over anhy-
The compound was obtained as a white solid in 66% yield, mp
-1
1
116-118 °C; ir (KBr): 1542, 1603 cm ; H nmr (CDCl ): δ 1.58-
3
1.62 (m, 4H), 1.90 (m, 6H, 2 CH ), 2.42-2.52 (m, 4H), 3.05 (s,
3
6H, 2 CH ), 3.45 (s, 4H, 2 CH ), 3.80 (s, 4H, 2 CH ), 7.28-7.40
3
2
2
13
(m, 6H), 7.59-7.64 (m, 4H); C nmr (CDCl ): δ 16.47, 25.49,
40.09, 53.65, 53.86, 72.50, 115.83, 127.75, 128.35, 130.66,
142.02, 152.71, 195.82; ms: m/z 551 (MH ).
3
+
drous Na SO and the solvent evaporated to give crude bis-pyra-
2
4
Anal. Calcd. for C
H N O S (550.78): C, 65.42; H, 6.95;
30 38 4 2 2
zolotetrahydropyrimidines 4a-b, which were purified by passing
through neutral alumina column using ethylacetate as eluant.
N, 10.17. Found: C, 65.63; H, 6.89; N, 10.22.
1,4-Bis (1-Methyl-5-benzoyl-6-methylthio-1,2,3,4-tetrahydro-
pyrimidinyl)benzene (2c).
1,2-Bis (3-Phenyl-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-d]-
pyrimidinyl)ethane (4a).
The compound was obtained as a white solid in 56% yield, mp
This compound was obtained as a white solid in 53% yield, mp
1 1
210-211 °C; ir (KBr): 1510, 1555, 1625 cm- ; H nmr (CDCl ): δ
3
-1 1
248-250 °C: ir (KBr): 1445, 3170 cm ; H nmr(CDCl ): δ 2.50 (s,
3
1.90 (s, 6H, 2 CH ), 3.00 (s, 6H, 2 CH ), 4.12 (s, 4H, 2 CH ),
3
3
2
4H, 2 CH ), 2.73 (s, 6H, 2 CH ), 3.75 (s, 4H, 2 CH ), 3.90 (s, 4H,
2
3
2
4.45 (s, 4H, 2 CH ), 7.19-7.29 (m, 3H), 7.30-7.43 (m, 7H), 7.65-
2
2 CH ), 7.25-7.65 (m, 10H), 12.05 (broad multiplet 2H, 2 NH):
+
2
7.70 (m, 4H); ms: m/z 571 (MH ).
13
C nmr (CDCl ): δ 36.79, 49.34, 52.11, 71.69, 98.65, 125.35,
3
Anal. Calcd. for C
H N O S (570.77): C, 67.34; H, 6.00;
32 34 4 2 2
+
126.40, 127.45, 128.81, 129.90; ms: m/z 455 (MH ).
N, 9.82. Found: C, 67.08; H, 6.04; N, 9.76.
Anal. Calcd. for C
H N (454.57): C, 68.70; H, 6.65; N,
26 30 8
1,2-Bis (1-Benzyl-5-benzoyl-6-methylthio-1,2,3,4-tetrahydro-
pyrimidinyl)ethane (2d).
24.65. Found: C, 68.95; H, 6.70; N, 24.53.
1,4-Bis (3-Phenyl-7-methyl-4,5,6,7-tetrahydropyrazolo[3,4-d]-
pyrimidinyl)butane (4b).
The compound was obtained as a white solid in 52% yield, mp
-1
1
101-102 °C; ir (KBr): 1522, 1634 cm ; H nmr (CDCl ): δ 1.90
3
This compound was obtained as a white solid in 55% yield, mp
(s, 6H, 2 CH ), 2.56 (s, 4H, 2 CH ), 3.45 (s, 4H, 2 CH ), 3.75 (s,
3
2
2
-1
1
214-216 °C ir (KBr): 1363, 3416 cm ; H nmr (CDCl ): δ 1.41-
3
4H, 2 CH ), 4.55 (s, 4H, 2 CH ), 7.22-7.45 (m, 16H), 7.68-7.72
2
2
1.55 (m, 4H, 2 CH ), 2.41-2.55 (m, 4H, 2 CH ), 2.73 (s, 6H, 2
13
2
2
(m, 4H); C nmr (CDCl ): δ 16.79, 52.14, 54.48, 55.12, 69.57,
117.36, 127.37, 127.66, 127.89, 128.52, 128.76, 131.08, 141.41,
151.64, 195.84; ms: m/z 675 (MH ).
3
CH ), 3.65 (s, 4H, 2 CH ), 3.85 (s, 4H, 2 CH ), 7.25-7.55 (m,
3
2
2
+
10H), 12.00 (broad multiplet, 2H, 2 NH); ms: m/z 483 (MH ).
+
Anal. Calcd. for C (482.62): C, 69.68; H, 7.10; N,
H
N
8
28 34
Anal. Calcd. for C
H N O S (674.92): C, 71.18; H, 6.27;
40 42 4 2 2
23.22. Found: C, 69.42; H, 7.16; N, 23.33.
N, 8.30. Found: C, 71.42; H, 6.22; N, 8.36.
Bis(1-Benzyl-7-phenyl-1,2,3,4-tetrahydropyrazolo[1,5-a]tria-
zinyl)alkanes/benzene (5a-c).
1,4-Bis (1-Benzyl-5-benzoyl-6-methylthio-1,2,3,4-tetrahydropy-
rimidinyl)butane (2e).
General Procedure.
The compound was obtained as a white solid in 60% yield, mp
-1
1
A mixture of diamine (1 mmol) and formaldehyde (4 mmol,
40% solution) in 2 ml methanol was stirred at room temperature
for 10 minutes. To this was added a solution of aminopyrazole 3b
149-159 °C; ir (KBr): 1562, 1639 cm ; H nmr (CDCl ): δ 1.40-
3
1.50 (m, 4H, 2 CH ), 1.90 (s, 6H, 2 CH ), 2.35-2.40 (m, 4H, 2
2
3
CH ), 3.40 (s, 4H, 2 CH ), 3.65 (s, 4H, 2 CH ), 4.55 (s, 4H, 2
2
2
2

978
M. Ch. Dutta, K. Chanda, P. Helissey and J. N. Vishwakarma
Vol. 42
(2 mmol) in 5-6 ml methanol and the resulting mixture stirred for
3-8 hours. After the completion of the reaction (monitored by
tlc), the reaction mixture was cooled in ice water and the precipi-
tated product was collected by filtration, washed with cold
methanol (3 x1 ml) and dried to give pure 5a-c, which were
recrystallized from methanol.
Acknowledgement.
The authors thank the Principal Rev. Fr Ioannis Warpakma,
SDB for the facilities and Rev. Fr. Stephen Mavely, SDB and Rev
Fr. Joseph Nellanatt, SDB for their encouragement during the
course of this investigation. The financial support from ICAR-
NATP-PIU is gratefully acknowledged. Authors (KC and MCD)
thank ICAR for Senior Research Fellowships. Thanks are also
due to the Heads of RSIC-CDRI (Lucknow) and RSIC-NEHU
(Shillong) for recording spectra. The authors also wish to express
their gratitude to Dr A. Das of ICAR for his keen interest in this
investigation.
1,2-Bis (1-Benzyl-7-phenyl-1,2,3,4-tetrahydropyrazolo[1,5-a]-
triazinyl)ethane (5a).
This compound was obtained as a white solid in 51% yield, mp
-1
1
225-226 °C; ir (KBr): 1399, 1634 cm ; H nmr (CDCl ): δ 2.90
3
(s, 4H, 2 CH ), 3.98 (s, 4H, 2 CH ), 4.25 (s, 4H, 2 CH ), 4.99(s,
2
2
2
4H, 2 CH ), 5.72 (s, 2H, 2 C -H), 7.24-7.37 (m, 16H), 7.70-7.73
2
8
+
(m, 4H); ms: m/z 607 (MH ).
Anal. Calcd. for C N (606.76): C, 75.22; H, 6.31; N,
8
REFERENCES AND NOTES
H
38 38
18.47. Found: C, 75.48; H, 6.26; N, 18.56.
*
To whom correspondence should be addressed.
[1] Part 4 of the series: K. Chanda, M. Ch. Dutta and J. N.
Vishwakarma, Ind. J. Chem., Section B, (2004), communicated.
[2] S. Kobayashi, Chem. Pharm. Bull., 21, 941 (1973).
[3] Y. V. Dobrynin, T. A. Bektemirov, T. P. Ivanova, E. V.
Chekunova, O. G. Andzhaparidze, I. A. Korbukh, Y. N. Bulychev, N. G.
Yakunina and M. N. Preobrazhenskaya, Kim. –Farm. Zh., 14, 10 (1980);
Chem. Abstr., 93, 88460d (1980).
1,4-Bis (1-Benzyl-7-phenyl-1,2,3,4-tetrahydropyrazolo[1,5-a]-
triazinyl)butane (5b).
This compound was obtained as white solid in 50% yield, mp
-1
1
132-133 °C; ir (KBr): 1576, 1637 cm ; H nmr (CDCl ): δ
3
1.35-1.45 (m, 4H, 2 CH ), 2.69-2.82 (m, 4H, 2 CH ), 4.05 (s,
2
2
4H, 2 CH ), 4.33 (s, 4H, 2 CH ), 5.03 (s, 4H, 2 CH ), 5.75 (s,
2
2
2
[4] B. R. Baker, W. F. Wood and J. A. Kozma, J. Med. Chem., 11,
661(1968).
2H, 2 C -H), 7.23-7.45 (m, 16H), 7.70-7.80 (m, 4H); ms: m/z
8
+
635 (MH ).
[5] F. Delbarre, C. Auscher, A. Degery, H. Brovilhet, J. L. Oliver,
Presse Med., 76, 2329 (1968); Chem. Abstr., 70, 86172n (1969).
[6] J. Riviere, F. M. 5,816; Chem. Abstr., 70, 118170p (1969).
[7] J. N. Vishwakarma, M. Mofizuddin, H. Ila and H. Junjappa, J.
Heterocyclic Chem., 25, 1387 (1988).
Anal. Calcd. for C
17.65. Found: C, 75.40; H, 6.73; N, 17.54.
H N (634.82): C, 75.68; H, 6.67; N,
40 42 8
1,4-Bis (1-Benzyl-7-phenyl-1,2,3,4-tetrahydropyrazolo[1,5-a]-
triazinyl)benzene (5c).
[8] E. Karim, K. Kishore and J. N. Vishwakarma, J. Heterocyclic
Chem., 40, 901 (2003).
[9] K. Chanda, M. Ch. Dutta, E. Karim and J. N. Vishwakarma, J.
Heterocyclic Chem., 41, 627 (2004).
[10] M. Ch. Dutta, K. Chanda, and J. N. Vishwakarma, J.
Heterocyclic Chem., 42, 121 (2005).
[11] A. Kumar, V. Aggarwal, H. Ila and H. Junjappa, Synthesis,
247 (1984).
This compound was obtained as white solid in 55% yield, mp
-1
1
154-156 °C ir (KBr): 1454, 1515, 1576 cm ; H nmr (CDCl ): δ
3
4.59 (s, 4H, 2 CH ), 4.83 (s, 4H, 2 CH ), 5.85 (s, 4H, 2 CH ),
2
2
2
C
13
6.05 (s, 2H, 2 C -H), 7.45–7.80 (m, 21H), 8.09-8.12 (m, 3H);
8
nmr (CDCl ): δ 53.93, 65.06, 65.67, 83.75, 120.59, 125.40,
3
127.55, 128.47, 128.64, 133.71, 136.45, 143.21, 148.49, 150.49;
+
ms: m/z: 655 (MH ).
Anal. Calcd. for C
17.11. Found: C, 77.30; H, 5.80; N, 17.21.
H N (654.81): C, 77.04; H, 5.85; N,
42 38 8
[12] J.N. Vishwakarma, B. K. Roychowdhury, H. Ila and H.
Junjappa, Ind. J. Chem., 24B, 472 (1985).