Synthesis and transformations of pyrido[4,3-d]-pyrimidines with N-heterocycles moieties

Article abstract of DOI:10.3987/com-00-9069

ortho-Amino ester (1) was cyclized to fused pyrimidines by reacting with isocyanate, isothiocyanate, or dithioketal reagent. Thioxo compound (2a) was halogenated, methylated and subsequently displaced by amines. ortho-Amino ester (1) was also converted into directly tricyclic azolopyrido[4,3-d]pyrimidines (8-13).

Full text of DOI:10.3987/com-00-9069

HETEROCYCLES, Vol. 55, No. 1, 2001, pp. 115 - 126, Received, 21st September, 2000
SYNTHESIS
AND
TRANSFORMATIONS
OF
PYRIDO[4,3-d]-
PYRIMIDINES WITH N-HETEROCYCLES MOIETIES
A. Z. M. Shaifullah Chowdhury* and Yasuyuki Shibata
Environmental Chemistry Division, National Institute for Environmental Studies,
16-2 Onogawa, Tsukuba, Ibaraki-305-0053, Japan
Abstract - ortho-Amino ester (1) was cyclized to fused pyrimidines by reacting
with isocyanate, isothiocyanate, or dithioketal reagent. Thioxo compound (2a)
was halogenated, methylated and subsequently displaced by amines. ortho-Amino
ester (1) was also converted into directly tricyclic azolopyrido[4,3-d]pyrimidines
(8-13).
Derivatives of pyrido[2,3-d]pyrimidine system are of great interest of its dihydrofolate reductase
inhibiting, antibacterial,1,2 antitumor3 and antiepileptic activities.4 Since the direct introduction of some
substituents into the pyrimidine ring is not easy, syntheses directed to the construction of the ring bearing
useful functional grous in the first step have been well developed.5 Imidazo[1,2-a]pyrido[2,3-d]-
pyrimidine system has already been synthesized earlier in different research group utilizing multi-step
approaches6,7 different to the method reported in this paper. Here, we report a simple, one-pot reaction for
the synthesis of pyrido[4,3-d]pyrimidine, imidazo[1,2-a]pyrido[4,3-d]pyrimidine, pyrimido[1,2-a]-
pyrido[4,3-d]pyrimidine, thiazolo[3,2-a]pyrido[4,3-d]pyrimidine, pyrido[4’,3’:4,5]pyrimido[2,1-b][1,3]-
thiazine and pyrazino[1,2-a]-pyrido[4,3-d]pyrimidine.
Reaction of ortho-amino ester (1) with ethyl isothiocyanatoacetate in pyridine or ethyl N-[bis-
(methylthio)methylene]glycinate (BMMA-reagent) in acetic acid at reflux temperature gave high yields
of monoannelated products (2a, 4) in one-pot reaction.
As the cyclization obviously proceeded via thiourea intermediate, three possible products of the
cyclization had to be considered as shown in Scheme 1. As the undesired but conceivable pathways B and
C (could be formed diazepine derivative or imidazo derivative) could be ruled out by NMR spectroscopy,

the method proved to be useful for giving smooth access via pathway A to pyrido[4,3-d]pyrimidine
system as depicted by the formulas (2a, 4).
O
COOEt
Bn
N
NH
N
R
B
O
COOMe
Bn
COOMe
N
Bn
Bn
SCN
COOEt
COOEt
N
N
COOEt
N
R
COOEt
A
NH2
or
N
R
N
N
N
H
1
C
2a, 4
MeS
SMe
COOMe
R
R = SH, SMe
Bn
N
N
N
O
Scheme 1
Thus, methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1) was converted into ethyl 6-
benzyl-3,4,5,6,7,8-hexahydro-2-methylthio-4-oxopyrido[4,3-d]pyrimidine-3-acetate (4). As depicted in
Scheme 2, the intermediate (4) can be obtained by the following two sequences: 1) preparation of the
thioxopyrimidine (2a) by reaction of 1 with ethyl isothiocyanatoacetate, followed by S-methylation with
methyl iodide, or 2) by the condensation reaction of ethyl N-[bis(methylthio)methylene]glycinate with 1
in the presence of acetic acid. Treatment of ortho-amino ester (1) with ethyl isocyanatoacetate in the
presence of pyridine afforded urethane (3), which was cyclized to 2b with NaOEt.
Another key intermediate, chloropyrido[4,3-d]pyrimidine derivative (5), was obtained from
thioxopyrimidine (2a) and POCl . A substitution reaction of chloro derivative (5) with pyrrolidine or
3
morpholine furnished pyrido[4,3-d]pyrimidine derivatives (6). On reaction with hydrazine hydrate,
chloropyrido[4,3-d]pyrimidine derivative (5) or the methyl thioester (4) afforded the N-aminolactam,
imidazo[1,2-a]pyrido[4,3-d]pyrimidine (7).

Bn
COOMe
NH2
Bn
COOMe
N
N
NHCONHCH2COOEt
1
3
O
O
Bn
Bn
N
N
COOEt
N
N
COOEt
N
H
X
N
SMe
4
2a, X = S
2b, X = O
O
N
O
Bn
Bn
N
N
N
N
COOEt
N
O
N
Cl
NH2
5
7
O
Bn
N
N
COOEt
N
NR
N
6a, NR=
6b, NR=
N
O
Scheme 2
A series of imino thioacetals: 2-methylthio-2-thiazoline, 5,6-dihydro-2-methylthio-4H-1,3-thiazine, 2-
methylthio-2-imidazoline, 2-methylthio-1,4,5,6-tetrahydropyrimidine and 2-methylthio-2-pyrazine,
reacted readily with ortho-amino ester (1) to give the tricyclic fused products, thiazolo[3,2-a]pyrido[4,3-
d]pyrimidine derivative (8), pyrido[4’,3’:4,5]pyrimido[2,1-b][1,3]thiazine derivative (9), imidazo[1,2-a]-
pyrido[4,3-d]pyrimidine derivative (10), pyrido[4,3-d]pyrimido[1,2-a]pyrimidine derivative (11) and
pyrazino[1,2-a]pyrido[4,3-d]pyrimidine derivative (13) respectively by an one-step reaction. 2-

Chloropyrimidine also reacted with 1 in one-pot reaction to afford 8-benzyl-7,8,9,10-tetrahydro-6H-
pyrido[4,3-d]pyrimido[1,2-a]pyrimidine-6-one (12) (Scheme 3).
O
O
Bn
Bn
N
N
(CH2)n
N
N
(CH2)n
N
N
H
N
S
8, n = 1
9, n = 2
10, n = 1
11, n = 2
Bn
COOMe
NH2
N
1
O
O
N
Bn
Bn
N
N
N
N
N
N
N
12
13
Scheme 3
EXPERIMENTAL
1
Melting points were determined on a Yanaco hot stage apparatus and are uncorrected. H and 13C NMR
spectra were recorded on a JNM - ALPHA 500 (500 MHz) spectrometer in CDCl3 or DMSO-d6 using
TMS as internal standard and the chemical shifts are expressed in d ppm. Elemental analyses were
performed on a EA 1108 (Fisons Instruments) Elemental Analyzer.
Using same methods of Sauter et al. ethyl N-[bis(methylthio)methylene]glycinate8 and ethyl isothio-
cyanatoacetate9 were obtained both as a syrup. 2-Methylthio-2-thiazoline10,11 and 5,6-dihydro-2-
methylthio-4H-1,3-thiazine10,12 were synthesized via a two-step procedure from 2 - aminoethanol or 3 -
aminopropanol and CS2 and subsequent methylation with methyl iodide. 2-Methylthio-2-imidazoline and
2-methylthio-1,4,5,6-tetrahydropyrimidine were prepared according to literature procedures.13,14 Methyl
4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate was purchased from Kanto Chemicals. Ethyl
isocyanatoacetate, 2-chloropyrimidine and 2-methylthio-2-pyrazine were purchased from Aldrich.

Ethyl 6-benzyl-1,2,3,4,5,6,7,8-octahydro-4-oxo-2-thioxopyrido[4,3-d]pyrimidine-3-acetate (2a): A
solution of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1) (0.98 g, 4 mmol) and
ethyl isothiocyanatoacetate (0.58 g, 4 mmol) in pyridine (7 mL) was refluxed for 4 h. The reaction
mixture was diluted with ethanol and cooled. The resulting crystals were collected by filtration and
0
recrystallized from ethanol to give 2a as brown needles. Yield: 1.17 g (82%); mp 188-189 C. 1H NMR
(CDCl3): dH 1.19-1.21 (t, J = 7.10 Hz, 3H, Me), 2.46 (t, 2H, J = 5.19 Hz, 8-H), 2.61 (t, J = 5.49 Hz, 2H,
7-H), 3.27 (s, 2H, 5-H), 3.61 (s, 2H, Ph -CH2), 4.12-4.16 (q, J = 7.02 Hz, 2H, OCH2), 5.07 (s, 2H, CH2),
7.18-7.35 (m, 5H, Ar-H), 10.80 (s, 1H, NH). 13C NMR (CDCl3): dC 14.04 (q, Me), 26.38 (t, C-8), 47.07
(t, C-7), 47.63 (t, C-5), 48.56 (t, CH2), 61.62 (t, Ph-CH2), 61.88 (t, OCH2), 110.87 (s, C-4a), 127.37 (d, C-
4’), 128.92 (d, C-3’ and C-5’), 129.69 (d, C-2’ and C-6’), 137.25 (s, C-1’), 146.48 (s, C-8a), 159.19 (s,
C=O), 167.06 (s, C=O), 175.51 (s, C=S). Anal. Calcd for C H21N3O3S: C, 60.14; H, 5.88; N, 11.69.
18
Found: C, 60.01; H, 5.96; N, 11.67.
Methyl 1-benzyl-4-(3-ethoxycarbonylmethylureido)-1,2,5,6-tetrahydropyridine-3-carboxylate (3):
The title compound was prepared in the same manner as 2a from methyl 4-amino-1-benzyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (1) (0.98 g, 4 mmol) and ethyl isocyanatoacetate (0.52 g, 4 mmol),
0
1
reaction time 5 h and recrystallized from ethanol as yellow needles. Yield: 0.94 g (63%); mp 104 C. H
NMR (CDCl3): dH 1.40 (t, J = 7.63 Hz, 3H, Me), 2.31 (t, J = 5.50 Hz, 2H, 5-H), 2.52 (t, J = 6.61 Hz, 2H,
6-H), 3.26 (s, 2H, 2-H), 3.56 (s, 2H, Ph -CH2), 3.63 (s, 3H, Me), 4.37 (s, 2H, CH2), 4.40 (q, J = 7.20 Hz,
2H, OCH2), 7.25-7.40 (m, 5H, Ar-H), 8.36 (s, 1H, NH), 9.82 (s, 1H, NH). 13C NMR (CDCl3): dC 14.01
(q, Me), 39.51 (t, C-5), 48.45 (t, CH2), 49.77 (t, C-6), 50.62 (q, Me), 54.86 (t, C-2), 61.38 (t, Ph-CH2),
61.60 (t, OCH2), 101.87 (s, C-3), 127.65 (d, C-4’), 128.92 (d, C-3’ and C-5’), 129.20 (d, C-2’ and C-6’),
137.59 (s, C-1’), 145.47 (s, C-4), 157.29 (s, C=O), 167.07 (s, C=O), 169.15 (s, C=O). Anal. Calcd for
C19H25N3O5: C, 60.78; H, 6.71; N, 11.19. Found: C, 60.66; H, 6.82; N, 11.08.
Ethyl 6-benzyl-1,2,3,4,5,6,7,8-octahydro-2,4-dioxopyrido[4,3-d]pyrimidine-3-acetate (2b): A solution
of urea derivative (3) (0.75 g, 2 mmol) and sodium ethoxide (0.14 g, 2 mmol) in absolute ethanol (10 mL)
was stirred for 1 h at rt. The solvent was removed in vacuo and the obtained solid was recrystallized from
0
ethanol to give crystals (2b). Yield: 0.50 g (74%); mp 210-211 C. 1H NMR (DMSO-d6): dH 1.18 (t, J =
7.02 Hz, 3H, Me), 2.49 (t, J = 5.19 Hz, 2H, 8-H), 2.62 (t, J = 5.48 Hz, 2H, 7-H), 3.32 (s, 2H, 5-H), 3.61
(s, 2H, Ph -CH2), 4.17 (q, J = 7.03 Hz, 2H, OCH2), 5.10 (s, 2H, CH2), 7.20-7.32 (m, 5H, Ar-H), 8.98 (s,
1H, NH). 13C NMR (CDCl3): dC 13.91 (q, Me), 30.91 (t, C-8), 47.611 (t, C-7), 48.08 (t, C-5), 50.09 (t,
CH2), 61.22 (t, Ph-CH2), 60.68 (t, OCH2), 114.45 (s, C-4a), 127.21 (d, C-4’), 128.65 (d, C-3’ and C-5’),

129.48 (d, C-2’ and C-6’), 139.85 (s, C-1’), 146.21 (s, C-8a), 153.91 (s, C=O), 166.29 (s, C=O), 169.08
(s, C=O). Anal. Calcd for C18H21N3O4: C, 62.95; H, 6.16; N, 12.23. Found: C, 62.06; H, 6.23; N, 12.16.
Ethyl 6-benzyl-3,4,5,6,7,8-hexahydro-2-methylthio-4-oxopyrido[4,3-d]pyrimidine-3-acetate (4):
Method-A: To a solution of sodium methoxide (0.53 g, 10 mmol) in dry methanol (75 mL) was added
0
thioxo compound (2a) (3.59 g, 10 mmol) and the mixture was stirred as the temperature raised to 60 C.
Methyl iodide (1.42 g, 10 mmol) was added while the mixture was refluxed under nitrogen for 2 h and
then the mixture was cooled to give a solid. The solid was collected and recrystallized from ethanol.
Yield: 2.57 g (69%).
Method B: A solution of methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1) (0.98 g, 4
mmol) and ethyl N-[bis(methylthio)methylene]glycinate (0.82 g, 4 mmol) in 8 mL of dry acetic acid was
heated under reflux for 8 h. The solution was poured into an ice - water. The mixture was stirred for 1 h.
The precipitated was collected by filtration and recrystallized from ethanol. Yield 0.86 g (58%). The
0
compound is identical with the compound obtained by method A. mp 145-146 C. 1H NMR (CDCl3): dH
1.15 (t, J = 7.10 Hz, 3H, Me), 2.49 (t, J = 5.19 Hz, 2H, 8-H), 2.60 (s, 3H, SMe), 2.64 (t, J = 5.49 Hz, 2H,
7-H), 3.30 (s, 2H, 5-H), 3.60 (s, 2H, Ph -CH2), 4.25 (q, J = 7.00 Hz, 2H, OCH2), 4.85 (s, 2H, CH2), 7.22-
7.40 (m, 5H, Ar-H). 13C NMR (CDCl3): dC 14.03 (q, SMe), 14.86 (q, Me), 27.26 (t, C-8), 47.06 (t, C-7),
47.60 (t, C-5), 44.20 (t, CH ), 60.75 (t, Ph-CH2), 61.73 (t, OCH2), 111.26 (s, C-4a), 127.49 (d, C-4’),
2
128.36 (d, C-3’ and C-5’), 129.13 (d, C-2’ and C-6’), 134.89 (s, C-1’), 144.21 (s, C-8a), 157.80 (s, C-2),
162.20 (s, C=O), 166.88 (s, C=O). Anal. Calcd for C19H23N3O3S: C, 61.10; H, 6.20; N, 11.25. Found: C,
61.01; H, 6.26; N, 11.18.
Ethyl
6-benzyl-3,4,5,6,7,8-hexahydro-2-(1-pyrrolidinyl)-4-oxopyrido[4,3-d]pyrimidine-3-acetate
(6a): A suspension of the thioxo product (2a) (5.74 g, 16 mmol) in phosphoryl chloride (100 mL, 1080
mmol) was refluxed at 120 0C for 22 h. Excess phosphoryl chloride was distilled off under vacuum. Ether
(100 mL) was added and the mixture was stirred for 2 h. The solid was collected by filtration and washed
with ether to afford chloro product (5), mp 102 0C (air sensitive).
A solution of the crude chloro product (5) (0.36 g) and pyrrolidine (0.49 g, 1.5 mmol) in triethylamine (5
mL) was refluxed for 4 h. The solvent was evaporated in vacuo. The obtained solid was recrystallized
from ethanol and ethyl acetate (3:1) to give 6a as white crystals. Yield: 0.24 g (62%), mp 160-161 0C. 1H
NMR (CDCl3): dH 1.27 (t, J = 7.10 Hz, 3H, Me), 1.70-1.90 (m, 4H, -CH2-CH2-), 2.54 (t, J = 5.20 Hz, 2H,

8-H), 2.78 (t, J = 5.50 Hz, 2H, 7-H), 3.35 (s, 2H, 5-H), 3.30-3.50 (m, 4H, H C-N-CH2), 3.61 (s, 2H, Ph-
2
CH2), 4.30 (q, J = 7.00 Hz, 2H, CH2O), 4.70 (s, 2H, CH2), 7.25-7.40 (m, 5H, Ar-H). 13C NMR (DMSO-
d6): dC 14.20 (q, Me), 25.40 (t, CH2-CH2), 26.54 (t, C-8), 46.09 (t, C-7), 47.20 (t, CH ), 47.77 (t, C-5),
2
50.50 (t, H2C-N-CH2), 61.62 (t, Ph-CH2), 61.88 (t, OCH2), 111.04 (s, C-4a), 127.56 (d, C-4’), 128.71 (d,
C-3’ and C-5’), 129.64 (d, C-2’ and C-6’), 136.98 (s, C-1’), 150.78 (s, C-8a), 159.70 (s, C-2), 162.13 (s,
C=O), 167.32 (s, C=O). Anal. Calcd for C22H28N4O3: C, 66.64; H, 7.11; N, 14.13. Found: C, 66.69; H,
7.22; N, 14.19.
Ethyl
6-benzyl-3,4,5,6,7,8-hexahydro-2-(4-morpholinyl)-4-oxopyrido[4,3-d]pyrimidine-3-acetate
(6b): The chloro derivative (5) was prepared by the method described above. A solution of the crude
chloro product (5) (0.36 g) and morpholine (0.13 g, 1.5 mmol) in triethylamine (5 mL) was refluxed for 2
h. The solvent was evaporated in vacuo. The obtained solid was recrystallized from a mixture of ethanol
and ethyl acetate (3:1) to give 6b as white crystals. Yield: 0.26 g (65%); mp 135 0C. 1H NMR (CDCl3): dH
1.25 (t, J = 7.10 Hz, 3H, Me), 2.50 (t, J = 5.15 Hz, 2H, 8-H), 2.67 (t, J = 5.50 Hz, 2H, 7-H), 3.10 (m, 4H,
-H2C-N-CH2-), 3.25 (s, 2H, 5-H), 3.59 (s, 2H, Ph-CH2), 3.80 (m, 4H, -H2C-O-CH2-), 4.25 (q, J = 7.10 Hz,
2H, CH2O), 4.65 (s, 2H, CH2), 7.20-7.40 (m, 5H, Ar-H). 13C NMR (DMSO-d6): dC 13.97 (q, Me), 26.50
(t, C-8), 47.10 (t, C-7), 45.45 (t, CH2), 47.60 (t, C-5), 50.47 (t, -H2C-N-CH2-), 61.50 (t, Ph-CH2), 61.60 (t,
OCH2), 66.14 (t, -H2C-O-CH2-), 110.87 (s, C-4a), 137.25 (s, C-1’), 127.37 (d, C-4’), 128.92 (d, C-3’ and
C-5’), 129.69 (d, C-2’ and C-6’), 150.56 (s, C-8a), 159.12 (s, C-2), 162.01 (s, C=O), 167.07 (s, C=O).
Anal. Calcd for C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.17; H, 6.95; N, 13.48.
1-Amino-7-benzyl-1,2,3,5,6,7,8,9-octahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidine-2,5-dione
(7):
Method A: A solution of the crude chloro product (5) (0.72 g) and 99% of hydrazine hydrate (0.10 g, 3
mmol) in triethylamine (5 mL) was refluxed for 5 h. The solvent was evaporated in vacuo. The obtained
solid was recrystallized from a mixture of ethanol and ethyl acetate (3:1) to give 7 as white crystals.
Yield: 0.44 g (70%).
Method B: A solution of the methylthio derivative (4) (0.74g, 2 mmol) and 99% of hydrazine hydrate (5
mL, 102.87 mmol) in 8 mL of ethanol was heated under reflux for 8 h with stirring. The solvent was
evaporated under reduced pressure. The solid was washed with water and recrystallized from isopropanol
1
to give white crystals. Yield: 0.68 g (61%); mp 268 0C. H NMR (CDCl3): dH 2.48 (t, J = 4.88 Hz, 2H, 9-
H), 2.62 (t, J = 5.49 Hz, 2H, 8-H), 3.30 (s, 2H, 6-H), 3.65 (s, 2H, Ph-CH2), 4.40 (s, 2H, 3-H), 5.25 (s, 2H,
NH2), 7.20-7.40 (m, 5H, Ar-H). 13C NMR (DMSO-d6): dC 26.47 (t, C-9), 49.82 (t, C-3), 47.24 (t, C-8),

47.30 (t, C-6), 60.20 (t, Ph-CH2), 111.09 (s, C-5a), 127.55 (d, C-4’), 128.45 (d, C-3’ and C-5’), 129.56 (d,
C-2’ and C-6’), 136.67 (s, C-1’), 150.80 (s, C-9a), 154.75 (s, C-10a), 162.84 (s, C=O), 166.08 (s, C=O).
Anal. Calcd for C16H17N5O2: C, 61.72; H, 5.50; N, 22.49. Found: C, 61.83; H, 5.56; N, 22.61.
7-Benzyl-2,3,6,7,8,9-hexahydro-5H-thiazolo[3,2-a]pyrido[4,3-d]pyrimidin-5-one (8): A solution of
methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1) (0.98 g, 4 mmol) and 2-
0
methylthio-2-thiazoline (0.66 g, 5 mmol) in dry acetic acid (6 mL) was heated to 100 C for 5 h. After
cooling to rt, crushed ice (100 g) was added and the mixture was stirred for 1 h. The separated product
was collected and recrystallized from ethyl acetate to give 8 as red crystals. Yield: 0.71 g (60%); mp 98-
99 0C. 1H NMR (CDCl3): dH 2.51 (t, J = 5.00 Hz, 2H, 9-H), 2.64 (t, J = 5.50 Hz, 2H, 8-H), 3.30 (s, 2H, 6-
H), 3.58 (t, J = 7.50 Hz, 2H, 2-H), 3.68 (s, 2H, Ph-CH2), 4.33 (t, J = 7.50 Hz, 2H, 3-H), 7.20-7.35 (m, 5H,
Ar-H). 13C NMR (CDCl3): dC 26.82 (t, C-9), 28.46 (s, C-2), 44.10 (t, C-8), 45.93 (t, C-6), 49.52 (t, C-3),
60.94 (t, Ph-CH2), 99.51 (s, C-5a), 127.41 (d, C-4’), 128.45 (d, C-3’ and C-5’), 129.17 (d, C-2’ and C-6’),
136.41 (s, C-1’), 148.35 (s, C-9a), 156.97 (s, C-10a), 162.89 (s, C=O). Anal. Calcd for C16H17N3OS: C,
64.18; H, 5.72; N, 14.03. Found: C, 64.24; H, 5.79; N, 14.05.
8-Benzyl-3,4,7,8,9,10-hexahydro-2H,6H-pyrido[4',3':4,5]pyrimido[2,1-b][1,3]thiazin-6-one (9): The
title compound was prepared in the same manner as 8 from methyl 4-amino-1-benzyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (1) (0.98 g, 4 mmol) and 5,6-dihydro-2-methylthio-4H-1,3-thiazine
(0.73 g, 5 mmol). An analytical sample was recrystallized from a mixture of ethyl acetate and ether (3:1)
to afford 9 as red crystals. Yield: 0.58 g (47%); mp 73-74 0C. 1H NMR (CDCl3): dH 2.50 (t, 2H, J = 4.90
Hz, 10-H), 2.30 (m, 2H, 3-H), 2.58 (t, J = 5.50 Hz, 2H, 9-H), 3.20 (t, J = 7.50 Hz, 2H, 2-H), 3.28 (s, 2H,
7-H), 3.60 (s, 2H, Ph-CH2), 4.20 (t, 2H, J = 6.50 Hz, 4-H), 7.28-7.35 (m, 5H, Ar-H). 13C NMR (CDCl3):
dC 22.93 (t, C-3), 26.64 (t, C-10), 27.72 (s, C-2), 46.01 (t, C-9), 40.88 (t, C-4), 46.92 (t, C-7), 60.42 (t, Ph-
CH2), 99.69 (s, C-5a), 127.33 (d, C-4’), 128.43 (d, C-3’ and C-5’), 128.76 (d, C-2’ and C-6’), 136.02 (s,
C-1’), 147.82 (s, C-10a), 153.65 (s, C-11a), 161.90 (s, C=O). Anal. Calcd for C17H19N3OS: C, 65.14; H,
6.11; N, 13.40. Found: C, 65.24; H, 6.03; N, 13.48.
General Procedure for the Cyclization Reaction: Synthesis of Compounds (10-13). A solution of
methyl 4-amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate (1) (0.98 g, 4 mmol) and appropriate
reagent (6 mmol) in hexamethylphosphoric triamide (HMPA, 5 mL) was heated to 160 0C for an
appropriate period of time. After cooling to rt, crushed ice (70 g) was added and the mixture was stirred

for 1 h. The resulting crystals were collected by filtration and were purified by recrystallization from an
appropriate solvent.
7-Benzyl-2,3,6,7,8,9-hexahydro-1H,5H-imidazo[1,2-a]pyrido[4,3-d]pyrimidin-5-one
(10):
This
compound was obtained from 2-methylthio-2-imidazoline, reaction time 5 h and recrystallized from
0
1
methanol to give 10 as yellow crystals. Yield: 62%; mp 230-231 C. H NMR (CDCl3): dH 2.42 (t, J =
4.88 Hz, 2H, 9-H), 2.71 (t, J = 5.49 Hz, 2H, 8-H), 3.25 (s, 2H, 6-H), 3.30 (t, J = 6.70 Hz, 2H, 2-H), 3.60
(s, 2H, Ph -CH2), 4.70 (t, J = 6.70 Hz, 2H, 3-H), 7.23-7.32 (m, 5H, Ar-H), 8.14 (s, 1H, NH). 13C NMR
(CDCl ): dC 26.80 (t, C-9), 47.25 (t, C-8), 43.34 (t, C-2), 44.80 (t, C-3), 47.44 (t, C-6), 60.49 (t, Ph-CH2),
3
111.10 (s, C-5a), 127.40 (d, C-4’), 128.43 (d, C-3’ and C-5’), 128.69 (d, C-2’ and C-6’), 134.21 (s, C-1’),
150.91 (s, C-9a), 155.30 (s, C-10a), 166.04 (s, C=O). Anal. Calcd for C16H18N4O: C, 68.06; H, 6.42; N,
19.84. Found: 67.92; C, H, 6.21; N, 19.97.
8-Benzyl-1,2,3,4,7,8,9,10-octahydro-6H-pyrido[4,3-d]pyrimido[1,2-a]pyrimidin-6-one (11): This
compound was obtained from 2-methylthio-1,4,5,6-tetrahydropyrimidine, reaction time 3 h and
0
1
recrystallized from methanol to give 11 as yellow crystals. Yield: 68%; mp 168-169 C. H NMR
(CDCl3): dH 1.90 (m, 2H, 3-H), 2.49 (t, J = 4.88 Hz, 2H, 10-H), 2.60 (t, J = 5.49 Hz, 2H, 9-H), 3.20 (t, J =
5.19 Hz, 2H, 2-H), 3.30 (s, 2H, 7-H), 3.60 (s, 2H, Ph-CH2), 3.91 (t, J = 5.49 Hz, 2H, 4-H), 7.21-7.29 (m,
5H, Ar-H), 8.10 (s, 1H, NH). 13C NMR (CDCl3): dC 21.01 (s, C-3), 26.71 (t, C-10), 37.89 (s, C-2), 38.35
(s, C-4), 47.20 (t, C-9), 47.52 (t, C-7), 61.71 (t, Ph-CH2), 105.54 (s, C-6a), 127.68 (d, C-4’), 128.32 (d, C-
3’ and C-5’), 128.83 (d, C-2’ and C-6’), 136.57 (s, C-1’), 150.25 (s, C-10a), 157.08 (s, C-11a), 165.58 (s,
C=O). Anal. Calcd for C17H20N4O: C, 68.89; H, 6.80; N, 18.90 Found: C, 68.97; H, 6.84; N, 19.03.
8-Benzyl-7,8,9,10-tetrahydro-6H-pyrido[4,3-d]pyrimido[1,2-a]pyrimidin-6-one (12): This compound
was obtained from 2-chloropyrimidine, reaction time 8 h and recrystallized from methanol to give 12 as
0
yellow crystals. Yield: 48%; mp 280-281 C. 1H NMR (CDCl3): dH 2.50 (t, J = 4.88 Hz, 2H, 10-H), 2.62
(t, J = 5.50 Hz, 2H, 9-H), 3.24 (s, 2H, 7-H), 3.60 (s, 2H, Ph-CH2), 7.21-7.30 (m, 5H, Ar-H), 8.29-8.42 (m,
3H, 2-H, 3-H and 4-H). 13C NMR (CDCl3): dC 29.62 (t, C-10), 48.89 (t, C-9), 50.35 (t, C-7), 61.26 (t, Ph-
CH2), 109.26 (s, C-6a), 127.70 (d, C-4’), 128.33 (d, C-3’ and C-5’), 129.05 (d, C-2’ and C-6’), 132.7 7 (s,
C-3), 136.90 (s, C-1’), 138.27 (s, C-2), 142.10 (s, C-4), 157.66 (s, C-10a), 158.02 (s, C-11a), 162.14 (s,
C=O). Anal. Calcd for C17H16N4O: C, 69.84; H, 5.51; N, 19.16. Found: C, 69.96; H, 5.63; N, 19.07.

2-Benzyl-1,2,3,4-tetrahydro-11H-pyrazino[1,2-a]pyrido[4,3-d]pyrimidin-11-one
(13):
This
compound was obtained from 2-methylthio-2-pyrazine, reaction time 11 h and recrystallized from
0
methanol to give 13 as colourless crystals. Yield: 32%; mp >300 C. 1H NMR (CDCl3): dH 2.54 (t, J =
4.54 Hz, 2H, 4-H), 2.60 (t, 2H, J = 5.61 Hz, 3-H), 3.43 (s, 2H, 1-H), 3.62 (s, 2H, Ph-CH2), 7.24-7.30 (m,
5H, Ar-H), 8.32 (d, J = 1.95 Hz, 1H, 8-H), 8.57 (d, J = 1.95 Hz, 1H, 9-H), 9.05 (s, 1H, 6-H). 13C NMR
(CDCl ): dC 27.94 (t, C-4), 49.85 (t, C-3), 50.06 (t, C-1), 60.32 (t, Ph-CH2), 124.80 (s, C-6a), 127.68 (d,
3
C-4’), 128.13 (d, C-3’ and C-5’), 128.74 (d, C-2’ and C-6’), 136.80 (s, C-1’), 145.70 (s, C-8), 148.20 (s,
C-9), 149.10 (s, C-6), 1565.24 (s, C-4a), 159.20 (s, C-5a), 162.90 (s, C=O). Anal. Calcd for C17H16N4O: C,
69.84; H, 5.51; N, 19.16. Found: C, 69.70; H, 5.66; N, 19.24.
ACKNOWLEDGEMENTS
The authors wish to express their gratitude to the Japan Science and Technology Agency (JST) and Japan
International Science Technology Exchange Centre (JISTEC) for their financial support. The authors are
indebted to Dr. K. Kaya, Dr. T. Sano and Ms. C. Suzuki for recording the NMR spectra and also grateful
to Dr. M. Nishikawa and Ms. Y. Amano for elemental analyses at the Microanalytical Laboratory, at the
National Institute for Environmental Studies, Tsukuba, Japan.
REFERENCES
1.
2.
3.
B. S. Hurlbert and B. F. Valenti, J. Med. Chem., 1968, 11, 708.
J. Matsumoto and S. Minami, J. Med. Chem., 1975, 18, 74.
E. M. Griwsky, S. Lee, C. W. Sigel, D. S. Duch, and C. A. Nickol, J. Med. Chem., 1980, 23,
327.
4.
L. Bornschein, R. Kraft, S. Pfeifer, M. Ullmann, and H. Longer, Pharmazie, 1979, 34, 732.
5.
F. Sauter, J. Fröhlich, and A. Z. M. S. Chowdhury, Sci. Pharm., 1996, 64, 647; F. Sauter, J.
Fröhlich, A. Z. M. S. Chowdhury, and C. Hametner, Monatsh. Chem., 1997, 128, 503.
U. Urleb, B. Stanovnik, and M. Tisler, J. Heterocycl. Chem., 1990, 27, 643.
G. M. Coppola, J. D. Fraser, G. E. Hardtmann, and M. J. Shapiro, J. Heterocycl. Chem., 1985, 22,
193.
6.
7.
8.
9.
F. Sauter, J. Fröhlich, K. Blasl, and K. Gewald, Heterocycles, 1995, 40, 851.
F. Sauter, J. Fröhlich, A. Z. M. S. Chowdhury, and C. Hametner, Acta Chimica Slovenica, 1996,
43, 365.
10. J. E. Jansen, US Patent, 1942, 18th August, 2,293,465 [Chem. Abstr., 1943, 37, 1300].
11. A. K. Bose, J. L. Fahey, and M. S. Manhas, J. Heterocycl. Chem., 1973, 10, 791.

12. J. L. Fahey, B. C. Lange, J. M. Van der Veen, G. R. Young, and A. K. Bose, J. Chem. Soc., Perkin
Trans. 1, 1977, 1117.
13. C. F. H. Allen, C. O. Edens, and J. VanAllan, Org. Syn., Coll. Vol., 1955, 3, 394.
14. A. M. Dave, K. N. Bhatt, N. K. Undavia, and P. B. Trivedi, J. Indian Chem. Soc., 1988, 75, 296.