New access to thiazolo[4,5-d]pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.5570430527

4-Amino-5-bromo-2-substituted-aminopyrimidines are readily obtained from the newly prepared 5-bromo-2,4-dichloro-6-methylpyrimidine by sequential treatment with ethanolic ammonia and secondary amines. These compounds were successfully reacted with various isothiocyanates in the presence of sodamide in DMF to form the new thiazolo[4,5-d] pyrimidine derivatives.

Full text of DOI:10.1002/jhet.5570430527

Sep-Oct 2006
1327
New Access to Thiazolo[4,5-d]pyrimidine Derivatives
M. Bakavoli*, M. Nikpour and M. Rahimizadeh
Department of Chemistry, School of Sciences, Ferdowsi University, Mashhad, 91775-1436, Iran.
Received June 27, 2005
1 - R2NH, EtOH, heat
2 - NaNH2, DMF, R'NCS
N
N
Cl
R2N
NH2
Br
N
S
R'
N
N
N
H
CH3
CH3
4-Amino-5-bromo-2-substituted-aminopyrimidines are readily obtained from the newly prepared 5-
bromo-2,4-dichloro-6-methylpyrimidine by sequential treatment with ethanolic ammonia and secondary
amines. These compounds were successfully reacted with various isothiocyanates in the presence of
sodamide in DMF to form the new thiazolo[4,5-d] pyrimidine derivatives .
J. Heterocyclic Chem., 43, 1327 (2006).
Introduction.
involve heterocyclization of suitably substituted thiazoles
with carbon disulfide [13], acetic anhydride/trimethy
orthoformate [14,15], and guanidine [16]. The syntheses
from pyrimidines are limited and mostly reported in
patent literature [11,17].
Prompted by these findings and due to our ongoing
studies directed towards the synthesis of fused
heterocycles of biological significance [18], we became
interested in developing an efficient and general route to
derivatives of thiazolo[4,5-d] pyrimidines.
Our synthesis started from 6-methy-pyrimidin-2,4(1H,
3H)-dione 1 which was converted to the new key
intermediate, 5-bromo-6-methy- pyrimidin-2,4(1H,3H)-
dione 2, by treatment with aqueous bromine at room
temperature. The subsequent chlorination of this compound
with phosphorus oxychloride in the presence of DMF
afforded the polyhalogenated derivative 3. The structure of
products 2 and 3 was adequately supported by mass
The growing pharmaceutical and agrochemical interest
for fused pyrimidines has focused the attention of organic
chemists to search for efficient and general routes to these
molecules in synthetically useful yields.
Thiazolo[4,5-d] pyrimidines are a class of fused
heterocycles which have been described as being antiviral
[1-7], antifungal [8], nucleoside analogues [9], agro-
chemicals [10] and enzyme inhibitors [11] agents. Despite
their importance from pharmacological and synthetic
point of views, comparatively few methods for their
preparation have been reported.
Molina's group described the thermal electrocyclic ring
closure of certain carbodiimides and cyclocondensation of
iminophosphoranes with carbon disulfide at room
temperature as the only useful methods for the preparation
of thiazolo[4,5-d]pyrimidines [12]. Other methods mainly
Scheme I
H
N
H
N
N
O
Cl
O
O
Br2, aq
O
Cl
Br
POCl3/DMF
N
HN
HN
Br
CH3
CH3
CH3
3
1
2
NH3, EtOH
rt
N
R2N
N
NH2
Br
NH2
Br
Cl
R2NH, EtOH, heat
N
N
NaNH2, DMF
R'NCS
CH3
CH3
4
5
H
N
R2N
N
N
R2N
N
NR'
NHR'
N
N
S
S
CH3
CH3
6

1328
M. Bakavoli, M. Nikpour and M. Rahimizadeh
Vol 43
5-Bromo-2,4-dichloro-6-methylpyrimidine (3).
spectral and microanalytical data. Selective displacement of
the 4-chlorine atom with ammonia occurred at room
temperature followed by subsequent displacement of the 2-
chlorine atom with secondary amines in ethanol at reflux
temperature to furnish the corresponding diaminopy-
rimidines 5a-b. Treatment of these compounds with
sodamide in DMF which was followed by heterocycli-
zsation with isothiocyanates furnished a host of thiazolo-
[4,5-d] pyrimidines 6 a-f in moderate to high yields .
A mixture of 5-bromo-6-methyl-pyrimidine-2,4(1H,3H)-dione 2
(2.05 g, 10 mmoles) and dimethylformamide (0.5 mL) in
phosphoroxychloride (10 mL) was heated under reflux for 3 hours.
The solvent was removed in vacuo and the residue was added to
ice. The precipitate was collected by filtration and crystallized from
petroleum ether (40-60 °C) as pale green crystals (2.06 g, 85%
1
yield, mp 44-46 °C); H NMR ( CDCl3): ꢀ, 2.75 (s, 3H, CH3);
13CNMR (CDCl3): ꢀ, 25.64, 119.24, 157.64, 161.6, 171.2; ms: m/z,
240 (55%), 242 (90%), 244 (43%), 246 (6%).
The structural assignments of compounds 6a-f are
based upon spectral and microanalytical data. The IR
spectra did not exhibit the stretching vibration bands at
3450 and 3300 cm-1 (broad, NH2) due to precursors but
showed a sharp band at 3380 cm-1 for the NH absorption.
Anal. Calcd. for C5H3BrCl2N2: C, 24.83; H, 1.25; N, 11.58.
Found: C, 24.9; H, 1.23; N, 11.65.
5-Bromo-2-chloro-6-methylpyrimidin-4-amine (4).
A
solution of 5-bromo-2,4-dichloro-6-methylpyrimidine
(2.42 g, 10 mmoles) in ethanol (25 mL) and concentrated
ammonia (2 mL) was stirred in a closed flask at room
temperature for 12 hours. The creamy like precipitate was
collected by filtration ,washed with warm water and dried at
80 °C (2.0 g, 90% yield, mp 172-174 °C); 1H NMR ( CDCl3):
ꢀ, 2.51 (s, 3H, CH3), 6.08 (s, 2H, NH2); 13CNMR ( CDCl3): ꢀ,
24.25, 101.86, 157.96, 161.47, 166.5; ms: m/z, 221 (78%),
223 (100%), 225(25%).
1
Further proof came from the H NMR spectra, which
showed the disappearance of a broad 2H signal belonging
to NH2 moiety of compounds 5a-b and the appearance of
two sharp 1H (NH) signals with different chemical shifts
indicating the construction of a thiazole ring around the
pyrimidine nucleous.
It is notworthy that the presence of these two NH
signals clearly demonstrate the tautomeric equilibrium
which exists between amine and iminie forms of the
thiazolo[4,5-d] pyrimidines. The ratio between these two
tautomers is nearly 1: 1.
In conclusion, the sequential treatment of the newly
prepared 5-bromo-2,4-dichloro-6-methylpyrimidine with
ethanolic ammonia and secondary amines which was
followed by interaction with sodamide in DMF and
subsequent heterocyclization with isothiocyanates is a
new, efficient and general access to thiazolo[4,5-d]-
pyrimidine derivatives.
General Procedure for the Reaction of 5-Bromo-2-chloro-6-
methylpyrimidin-4-amine (4) with Morpholine or Pyrrolidine.
5-Bromo-2-chloro-6-methylpyrimidin-4-amine (4) (2.22 g, 10
mmoles) in ethanol (25 mL) was heated under reflux with either
morpholine (2.0 g) or pyrrolidine (1.8 g) for 4 hours. Then water
(20 mL) was added and the solution was kept over night , the
precipitate was collected by filtration and washed with warm
water and dried at 80 °C to give 5a and 5b respectively.
5-Bromo-6-methyl-2-morpholin-4-ylpyrimidin-4-amine (5a).
This compound was obtained as a creamy powder in 70%
yield , mp 123-126 °C; IR: 3300 and 3450 cm-1 (NH2) ;1H NMR
(CDCl3): ꢀ, 2.49 (s, 3H, CH3), 3.55 (m, 8H, CH2-(O&N)), 5.2
(s, 2H, NH2); 13CNMR (CDCl3): ꢀ, 24.42, 44.28, 48.86, 66.62,
91.39, 159.87, 164.19, 166.35; ms: m/z, 272 (90%), 274 (90%).
Anal. Calcd. for C9H13BrN4O: C, 39.58; H, 4.8; N, 20.51.
Found: C, 39.24; H, 4.61; N, 20.31.
EXPERIMENTAL
The melting points were recorded on an Electrothermal type
9100 melting point apparatus. The IR spectra were obtained on a
4300 Shimadzu Spectrometer. The 13C NMR spectra were
recorded on a Bruker BRX 500 AVANCE spectrometer. The
1HNMR (100 MHz) spectra were recorded on a Bruker AC 100
spectrometer. The mass spectra were scanned on a Varian Mat
CH-7 instrument at 70 eV. Elemental analysis was obtained on
a Thermo Finnigan Flash EA microanalyzer.
5-Bromo-6-methyl-2-pyrrolidin-1-ylpyrimidin-4-amine (5b).
This compound was obtained as a creamy powder in 77%
yield, mp 199-202 °C, IR: 3320 and 3460 cm-1 (NH2) ; 1H NMR
(CDCl3): ꢀ, 1.94 (t, 4H, 2 ((CH2)-CH2N), 2.51 (s, 3H, CH3), 3.5
(t, 4H, 2(CH2N)), 5.1 (s, 2H, NH2); 13C NMR (CDCl3): ꢀ,
24.55, 25.57, 50.7, 90.6, 158.58, 159.8, 164.1; ms: m/z, 256
(80%), 258 (80%).
5-Bromo-6-methyl-pyrimidine-2,4(1H,3H)-dione (2).
Anal. Calcd. for C9H13BrN4: C, 42.04; H, 5.10; N, 21.79.
Found: C, 42.18; H, 5.02; N, 21.89.
To a suspension of 6-methyl-pyrimidine-2,4(1H,3H)-dione
(2.52 g, 20 mmoles) in water (40 mL), bromine (3.2 g, 20
mmoles) was added dropwise with vigorous stirring over a
period of 1 minute. Stirring was continued for further 30
minutes. The mixture was heated to boil and then cooled to
room temperature to give a white residue which was collected
by filtration, washed with warm water and dried at 80 °C (3.28
g, 80% yield, mp 260 °C (dec). IR: 3200 cm-1 (NH), 1550 cm-1
(C=O) ; 1H NMR ( d6-DMSO): ꢀ, 2.13 (s, 3H,CH3),11.24 (s, 1H,
N1H), 11.37 (s, 1H, N3H); 13C NMR (d6-DMSO): ꢀ, 19.52,
95.05, 150.27, 151.38, 160; ms: m/z, 204 (90%), 206 (90%).
General Procedure for Preparation of Thiazolo[4,5-d]-
pyrimidines.
To a solution of the foregoing compounds (5a and 5b) (1
mmol) in dimethylformamide (2 mL) sodium amide (0.078 g, 2
mmoles) was added on stirring . The stirring was continued for
5 minutes, then an appropriate isothiocyanate (3 mmoles) was
added. The solution was heated at 130 °C for 1 hour, then
poured into a solution of water (10 mL) and acetic acid (1 mL).
The mixture was extracted with chloroform (3x5mL), dried at

Sep-Oct 2006
New Access to Thiazolo[4,5-d]pyrimidine Derivatives
1329
reduced pressure, then crystallized from absolute ethanol to give
compounds 6a-f .
7-Methyl-N-phenyl-5-pyrrolidin-1-yl[1,3]thiazolo[4,5-d]pyrimidin-
2-amine(6f)
This compound was obtained as a brown powder in 40%
N-Ethyl-7-methyl-5-morpholin-4-yl[1,3]thiazolo[4,5-d]pyrimidin-
2-amine (6a).
1
yield, mp 150-153, IR: 3380 cm-1 (NH).; HNMR: (CDCl3) ꢀ,
1.95 (m, 4H, 2(CH2)-CH2N), 2.41 (s, 3H, CH3), 3.5 (t, 4H,
2(CH2N)), 7.2-7.6 (m, 5H, aromatic), 8.6&13.36 (s, 1H, two
NH); ms: m/z , 311, 313.
Anal. Calcd. for C16H17N5S: C, 61.71; H, 5.50; N, 22.49; S,
10.30 Found : C, 61.6; H, 5.54; N, 22.55; S, 10.12.
This compound was obtained as a green powder in 56%
yield, mp 170-171 °C, IR: 3380 cm-1 (NH); 1H NMR (CDCl3):
ꢀ, 1.35 (t,3H, (CH3)-CH2), 2.43 (s, 3H, CH3), 3.4-3.7 (m, 10H,
CH2-(O&N&NH)), 8.50&11.09(s, 1H, two NH); ms: m/z,
279, 281.
Anal. Calcd. for C12H17N5OS: C, 51.59; H, 6.13; N, 25.07; S,
11.48. Found : C, 51.7; H, 6.08; N, 25.1; S, 11.25.
REFRENCES
N-Butyl-7-methyl-5-morpholin-4-yl[1,3]thiazolo[4,5-d]pyrimidin-
2-amine (6b).
*
Corresponding author: email:mbakavoli@yahoo.com
[1] G. R. Revankar, T. S. Rao, K. Ramasamy and D. F. Smee,
NucleosidesNucleotides, 14, 671 (1995).
[2] F. D. Smee, H. A. Alaghmandan, K. Ramasamy and G. R.
Revankar, Antiviral Res. 26, 203 (1995).
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Smee, G. R. Revankar, R. K. Robins, K. Ronald and H. B. Cottam, J.
Med. Chem. 34, 3006 (1991).
This compound was obtained as a green powder in 60% yield,
1
mp 138-140, IR: 3370 cm-1 (NH); H NMR (CDCl3): ꢀ, 0.95
(t,3H, (CH3)-CH2), 1.45-1.65 (m, 4H, (CH2)-CH2&(CH2)-CH3),
2.45 (s, 3H, CH3), 3.6-3.8 m, 10H, CH2-(O&N&NH)),
8.50&11.09 (s, 1H, two NH); ms: m/z, 307, 309.
[4] E. S. A. M. Badawey, S. M. Rida, A. A. Huzza, H. T. Y.
Fahmy and Y. M. Gohar, Eur. J. Med. Chem., 28, 91 (1993).
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Fahmy and Y. M. Gohar, Eur. J. Med. Chem. 28, 97 (1993).
[6] P. G. Higgins, G. I. Barrow, D. A. J. Tyrrel, N. J. C. Snell,
K. Jones and W. B. Jolley, Antiviral Chem., 2, 61 (1991).
[7] D. F. Smee, J. H. Huffman, A. C. Gessman, J. W. Huggins
and R. W. Sidwell, Antiviral Res., 15, 229 (1991).
Anal. Calcd. for C14H21N5OS: C, 54.70; H, 6.89; N, 22.78; S,
10.43. Found: C, 54.82; H, 6.81; N, 22.86; S, 10.25.
7-Methyl-5-morpholin-4-yl-N-phenyl[1,3]thiazolo[4,5-d]pyrim-
idin-2-amine (6c).
This compound was obtained as a brown powder in 38%
1
yield, mp 166-169, IR: 3390 cm-1 (NH); H NMR (CDCl3): ꢀ,
2.45 (s, 3H, CH3), 3.8 (m, 8H, CH2-(O&N)), 7.2-7.7 (m, 5H,
aromatic), 8.7&13.05 (s, 1H, two NH); 13C NMR (CDCl3): ꢀ,
24.95, 44.34, 66, 91.96, 123.67, 126.24, 128.62, 137.69, 153.88,
157.16, 166.76, 178.23; ms: m/z , 327,329.
Anal. Calcd. for C16H17N5OS: C, 58.70; H, 5.23; N, 21.39; S,
9.79. Found: C, 58.55; H, 5.15; N, 21.45; S, 9.6.
[8] T. S. Rao, G. R. Revankar, R. S. Vinayak and R. K. Robins,
J. Heterocyclic Chem., 28, 1779 (1991).
[9] S. Kato, M. Ishazaki and S. Sada, Jpn. Kokai Tokyo Koho JP
63,250,385[88,250,-385](Cl. C07D/00521) 18 Oct 1988, Appl. 87/82,
207, 04 Apr 1987; 10pp [C. A., 111, 153776]
[10] R. L. Miller, G. A. Ramsey, T. A. Krenitsky and G. B. Elion,
Biochemstry, 11, 4723 (1972).
[11] K. Grohe, Ger. Offen. 2,223,421 (Cl. C07d), 22 Nov 1973,
appl. P22 23 421. 5, 13 May 1972; 12pp [C. A. 80, 37148].
[12] P. Molina, A. Arques, M. V. Vinader, J. Becher and K.
Brondum, J. Org. Chem., 53, 4654 (1988).
[13] R. Evers and G. Faix, Ger.(East) DD 248, 595 (Cl.
C07D513/04), 12 Aug 1987, Appl. 289, 582, 24 Apr 1986; 3pp [C. A.
108, 112494].
N-ethyl-7-methyl-5-pyrrolidin-1-yl[1,3]thiazolo[4,5-d]pyrimidin-2-
amine (6d)
This compound was obtained as a green powder in 65% yield,
1
mp 159-160, IR: 3380 cm-1 (NH); HNMR: ( CDCl3) ꢀ, 1.32
(t,3H, (CH3)-CH2), 2.01 (m, 4H, 2(CH2)-CH2N), 2.43 (s, 3H,
CH3), 3.5 (t, 4H, 2(CH2N)), 3.7 (q, 2H, (NH-CH2)-CH3),
8.42&11.42(s, 1H, two NH); ms: m/z , 263, 265.
Anal. Calcd. for C12H17N5S: C, 54.73; H, 6.51; N, 26.59; S,
12.18 Found : C, 54.6; H, 6.55; N, 26.65; S, 12.02.
[14] K. J. Gewald , Prakt. Chem., 304, 26 (1966).
[15] W. Ried and D. Kuhurt, Liebigs. Ann.Chem., 4, 780 (1986).
[16] A. Singh, A. S. Uppal, T. K. Bindal and M. Singh,. Indian. J.
Chem., 19B, 37 (1980).
[17] A. B. Berger, E. Edeltrant, U. S. 3, 772, 290 (Cl. 260-256.
5R; C07d), 13 Nov 1973, Appl. 849, 899, 13 Apr 1969; 4pp [C. A. 80,
48027].
N-buthyl-7-methyl-5-pyrrolidin-1-yl[1,3]thiazolo[4,5-d]pyrimidin-
2-amine (6e)
[18] M. Rahimizadeh, Z. Tavallai and M. Bakavoli, Indian J Chem.,
43B, 679 (2004); M. M. Heravi, A. Kivanloo, M. Rahimizadeh, M.
Bakavoli and M. Ghassemzadeh, Tetrahedron Lett., 45, 5747 (2004); M.
M. Heravi, A. Kivanloo, M. Rahimizadeh, M. Bakavoli, B. Neumuller and
M. Ghassemzadeh, Tetrahedron Lett., 46,1607 (2005); M. Bakavoli, G.
Bagherzadeh and M. Rahimizadeh, Mendeleev Commun.,4, 145 ( 2005);
M. M. Heravi, M. Bakherad, M. Rahimizadeh, M. Bakavoli and M.
Ghassemzadeh, Heterocyclic Commun., 10, 335 (2004); M. Bakavoli, M.
Nikpour and M. Rahimizadeh , Phosphorus Sulfur and Silicon and the
Related Elements, 180(10),2265 (2005); ibid, M. Bakavoli, B. Reihani, M.
Rahimizadeh and M. Nikpour 181(1), 99 (2006).
This compound was obtained as a green powder in 58% yield,
1
mp 151-154, IR: 3370 cm-1 (NH); HNMR: ( CDCl3) ꢀ, 0.95
(t,3H, (CH3)-CH2), 1.3-1.7 (m, 4H, (CH2)-CH2&(CH2)-CH3),
2.01 (m, 4H, 2(CH2)-CH2N), 2.42 (s, 3H, CH3), 3.5 (t,
4H,2(CH2N)), 3.7 (q, 2H, (NH-CH2)-CH3), 8.45&11.4(s, 1H,
two NH); 13CNMR: ( CDCl3) ꢀ, 13.63, 20.2, 25.22, 25.36, 30.67,
45.76, 46.76, 90.68, 154.17, 156.2, 166.5, 179.73; ms: m/z,
291,293.
Anal. Calcd. for C14H21N5S: C, 57.70; H, 7.26; N, 24.03; S,
11.00 Found : C, 57.76; H, 7.2; N, 24.11; S, 10.81.