Novel method for synthesis of pyrido[4,3-d]pyrimidines

Full text of DOI:10.1007/s10593-005-0142-3

Chemistry of Heterocyclic Compounds, Vol. 41, No. 2, 2005
NOVEL METHOD FOR SYNTHESIS
OF PYRIDO[4,3-d]PYRIMIDINES
I. Susvilo, R. Palskyte, S. Tumkevicius, and A. Brukstus
Keywords: arylethynylpyrimidines, palladium, pyrido[4,3-d]pyrimidines, cross coupling, cyclization.
Recently we synthesized some alkynyl derivatives of pyrimidine and pyrrolo[2,3-d]pyrimidine, and we
showed that they can be used to obtain pyrrolo[3,2-d]pyrimidine 7-oxides [1, 2] and pyrrolo[2,3,4-de]-
pyrimido[5',4':5,6][1,3]diazepino[1,7-a]indoles [3] respectively. Continuing our research in this direction, in this
report we present a novel route for synthesis of a pyrido[4,3-d]pyrimidine heterocyclic system using 4-amino-6-
chloro-2-methylthiopyrimidine-5-carbaldehyde (1) as the starting compound. Interest in methods for synthesis of
pyrido[4,3-d]pyrimidine derivatives to a significant extent is due to the biological activity of these compounds
[4-6].
We synthesized phenylethynylpyrimidine 2 by means of the palladium-catalyzed reaction of cross
coupling compound 1 with phenylacetylene. The reaction was carried out under an argon atmosphere at a
temperature of 50-60°C, using 4 mol % PdCl (PPh ) , 2 mol % CuI, and a 3-fold molar excess of
2
3 2
phenylacetylene.
NH2
NH2
CHO
Cl
CHO
Ph, PdCl (PPh )
N
2
3 2
N
CuI, Et N, DMF
3
MeS
N
MeS
N
Ph
1
2
H NBu-t
2
NH2
NH2
Bu-t
N
N
AgNO3
N
N
CHCl3
Ph
MeS
N
MeS
N
4
3
Ph
Heating aldehyde 2 with excess tert-butylamine in an autoclave at 100°C leads to formation of imine 3
in 93% yield. Preliminary study of the reaction of cyclization of compound 3 to form the corresponding
pyrido[4,3-d]pyrimidine 4 in the presence of Cu(I) or Ag(I) salts showed that AgNO is an effective catalyst for
3
this conversion. Compound 4 was synthesized in 79% yield by heating phenylethynylpyrimidine 3 in chloroform
in the presence of 10 mol % AgNO3.
_
_________________________________________________________________________________________
Vilnius University, Department of Organic Chemistry, Vilnius LT-03225, Lithuania; e-mail:
sigitas.tumkevicius@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 298-300,
February, 2005. Original article submitted September 10, 2004.
2
68
0009-3122/05/4102-0268©2005 Springer Science+Business Media, Inc.

The IR spectra were taken in vaseline oil on an FT-IR Spectrum BX II (Perkin-Elmer)
1
spectrophotometer. The H NMR spectra were obtained on a Varian INOVA (300 MHz) spectrometer using
TMS as an internal standard. The course of the reactions and the purity of the compounds obtained were
followed by TLC on Alufol Silica Gel 60 F254 plates (Merck).
The starting 4-amino-6-chloro-2-methylthiopyrimidine-5-carbaldehyde (1) was synthesized according to
the method in [7].
4
-Amino-2-methylthio-6-(phenylethynyl)pyrimidine-5-carbaldehyde (2). Yield 42%; mp 178-179°C
-
1
1
(
(
octane). IR spectrum (vaseline oil), ν, cm : 3381, 3277 (NH ), 2214 (C≡C), 1765 (CHO). H NMR spectrum
2
300 MHz, CDCl ), δ, ppm: 2.59 (3H, s, SCH ); 5.84 (1H, br. s, NH); 7.43-7.67 (5H, m, ArH); 8.60 (1H, br. s,
3
3
1
3
NH); 10.49 (1H, s, CHO). C NMR spectrum (75 MHz, CDCl ), δ, ppm: 14.6, 98.4, 108.8, 120.9, 130.6, 132.8,
1
3
+
55.1, 160.9, 177.6, 191.7. Mass spectrum, m/z (%): 269 [M] (100). Found, %: C 62.69; H 4.15; N 15.75.
C H N OS. Calculated, %: C 62.43; H 4.12; N 15.60.
1
4
11
3
4
-Amino-5-tert-butyliminomethyl-2-methylthio-6-(phenylethynyl)pyrimidine (3). Yield 93%;
-
1
1
mp 109-110°C (2-PrOH–H O). IR spectrum (vaseline oil), ν, cm : 3445, 3269 (NH ), 2214 (C≡C). H NMR
2
2
spectrum (300 MHz, (CD ) CO), δ, ppm: 1.36 (9H, s, 3CH ); 2.58 (3H, s, SCH ); 5.70 (1H, br. s, NH); 7.53-7.71
3
2
3
3
(
5H, m, ArH); 8.94 (1H, s, CH); 10.06 (1H, br. s, NH). Found, %: C 66.71; H 6.28; N 17.23. C H N S.
18 20 4
Calculated, %: C 66.64; H 6.21; N 17.27.
4
-Amino-2-methylthio-7-phenylpyrido[4,3-d]pyrimidine (4). Yield 79%; mp 144-145°C
-
1
1
(
toluene–octane). IR spectrum (vaseline oil), ν, cm : 3402, 3388 (NH ). H NMR spectrum (300 MHz, CD Cl ),
2
2
2
δ, ppm: 2.58 (3H, s, SCH ); 6.73 (2H, br. s, NH ); 7.27 (1H, s, CH); 7.37-7.67 (5H, m, ArH); 8.89 (1H, s, CH).
3
2
Found, %: C 62.69; H 4.58; N 20.79. C H N S. Calculated, %: C 62.66; H 4.51; N 20.88.
1
4
12
4
This research was performed with the financial support of the Lithuanian Foundation for Science and
Education (project No. T-04220).
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