Enaminouraciles as precursors for synthesis of pyrimido[4,5-d]pyrimidme-2,4-diones

Article abstract of DOI:10.1515/znb-2000-0515

The reaction of 6-aminouracil 1 with formaldehyde and secondary amines in ethanol at room temperature gave the corresponding 5-alkylaminomethyl derivatives (2a-c) and bis(4-pyrimidyl)methane (4). Also, Mannich reaction with primary aliphatic and aromatic

Full text of DOI:10.1515/znb-2000-0515

Enaminouraciles as Precursors for Synthesis of Pyrimido[4,5-a]pyrimidine-
,4-diones
2
W. S. Hamama
Chemistry D epartm ent, Faculty of Science, M ansoura University, Mansoura, Egypt
Reprint requests to Dr. W. S. Hamama. E-mail: Sinfac@mum.mans.eun.eg
Z. Naturforsch. 55b, 443-447 (2000); received January 25, 2000
6-Aminouracil, Mannich Reaction, Pyrimido[4,5-d]pyrimidine
The reaction of 6-aminouracil 1 with formaldehyde and secondary amines in ethanol at
room tem perature gave the corresponding 5-alkylaminomethyl derivatives (2a-c) and bis(4-
pyrimidyl)methane (4). Also, Mannich reaction with primary aliphatic and aromatic amines
at room tem perature afforded pyrimido[4,5-rf]pyrimidine (5 and 6).
Treatment of 1 with o-phenylenediam ine through transamination gave compound 7 which
cyclized through intram olecular Mannich reaction with formalin to yield pyrimido[4,5-el-
[
l,4]diazepine (8).
Introduction
the C-5 center is more nucleophilic than the amino
group at C-6 [8]. The IR spectra of 2a-c displayed
the N H 2 stretching bands at 3484-3152 cm -1. The
The importance of uracile and its annelated sub-
strates is well recognized by synthetic [1] as well
as biological chemists [2]. With the development
of clinically useful anticancer [3], antiviral [4], an-
tiallergic [5], and antitum or [6] drugs, there has
recently been rem arkable interest in the synthetic
manipulations of enamino amide in which the 6-
amino-l,3-dimethyluracil is considered to be a het-
erocyclic enamino amide [7,8]. Chem otherapeuti-
cally valuable compounds in this class such as pyri-
midopyrimidinedione derivatives are reported in
the patent literature [5]. Recently, the synthesis of
pyrimidine Mannich bases has been reported [9].
Although, the Mannich of 3(5)-arylaminopyra-
zoles with primary amines has been reported [10]
as a route to pyrazolo[3,4-rf]pyrimidine, no atten-
tion has been paid to the similar reaction with 6-
amino-l,3-dimethyluracil, which can be used as a
key intermediates for the synthesis of pyri-
mido[3,4-rf]pyrimidine-2,4-dione derivatives.
!
H NM R spectra of 2a-c lacked the 5-H proton (at
(3 4.76 ppm) [8]; however, compound 4 was iso-
lated as the main product on heating the reaction
mixture for a short time (30 min) due to the con-
densation of 1 with formalin. The structure of 4
was established by its analytical and spectral data.
On using dimethylamine in the Mannich reaction
with compound 1, compound 4 was isolated as a
sole product instead of the expected Mannich base
3
. The formation of 4, may be rationalized in terms
of the formation [11,12] of 3 as an interm ediate
which undergoes deamination to give 4. On the
other hand, treatm ent of 1 with primary aliphatic
and aromatic amines and formalin in a molar ratio
(
1:1:2) gave the pyrimido[4,5-d]pyrimidine ring
systems (5 and 6) via a double Mannich reaction.
The involvement of both C-5 and amino group in
this reaction is in line with our work [13,14] and
the work of Roth and Hagen [15].
Furtherm ore, the interesting psychopharmaco-
logical activity of benzodiazepine [16,17], pursued
Results and Discussion
The objective of the present work was to investi- us to synthesize the pyrimido[4,5-e][l,4]diazepine
gate the behaviour of the Mannich reaction derivative 8. Compound 8 has been obtained
towards 6-amino-l,3-dimethyluracile (1) as a bi- through transamination of 1 with o-phenylenedia-
functional nucleophile with both secondary and
primary amines.
The Mannich reaction of 1 with morpholine, N-
mine to give 7 followed by intramolecular M an-
nich type cyclization with formalin to afford 8. The
above reaction sequence is similar to some re-
methylpiperazine or piperazine and formalin af- ported cases [18,19] in which the diazepine ring
forded the Mannich bases 2a-c which revealed that system has been obtained.
0
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4
44
W. S. Ham am a • Pyrimido(4.5-^)pyrim idine-2,4-diones
Experimental
(6.5 mmol) or piperazine (3.25 mmol) and formalin
(
6.5 mmol, 40% solution) in ethanol (20 ml). The
Melting points (uncorrected) were taken in an
open capillary tubes by the use of a Gallenkamp
electric melting points apparatus. Infrared spectra
were recorded on a M attson 500 FTIR spectrometer
using KBr wafer technique. !H NMR spectra were
measured on Varian-Gemini 200 MHz in CDC13 or
DM SO-d6 as solvent unless stated otherwise and
with TMS as internal standard. Mass spectra were
determ ined on GC-MSHP Model 5988.
reaction mixture was stirred for 2 h then left at
room tem perature for 3 days. The resulting precipi-
tate was collected by filtration and crystallized from
ethanol to give the corresponding Mannich bases
2
a-c in m oderate yield (Table I).
Bis-(4-amino-l,3-dimethyl-2,6-dioxopyrimidine)-
methane (4)
A
mixture of
1
(3.3 mmol) and formalin
4
2
4
-Amino-1,3-dimethy1-5-(N-morpholinomethyl)-
,6-dioxo-l,2,3,4-tetrahydro-pyrimidine (2a),
-amino-l ,3-dimethyl-5-(N-methylpiperazino-
(3.3 mmol, 40% solution) was heated in ethanol
(25 ml) at 80 °C for 30 min. The resulting precipi-
tate was collected by filtration and crystallized
from acetic acid to give 4 in good yield (Table I).
methyl)-2,6-dioxo-l,2,3,4-tetrahydropyrimidine
2b) and N ,N ’-bis(4-amino-l,3-dimethyl-2,6-
(
dioxo-pyrimidin-5-ylmethyl)-piperazine (2c)
l,3,6,8-Tetrasubstituted-4,5,6,7-tetrahydro-2,4-
dioxopyrimido[4,5-d]pyrimidine 5a,b and 6a,b
A solution of the enaminone (1) (6.5 mmol) in
ethanol (30 ml) was added to a stirred solution
of morpholine (6.5 mmol), methylpiperazine
A solution of 1 (6.5 mmol) in ethanol (30 ml)
was added to
a
solution of primaryamines
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W. S. Hamama • Pyrimido(4,5-öf)pyrimidine-2,4-diones
445
Table I. Analytical data of the compounds 2,4,5,6,7, and 8.
Compound
Yield
M.p
(°C)
Solvent of
cryst.
Molecular
Microanalysis Calcd/Found
(
% )
56
52
41
70
75
60
73
80
30
80
Formula, (g/mol)
C
H
N
2
a
104
128
231
320
170
116
196
158
205
235
E tO H
E tO H
E tO H
AcOH
EtO H
EtO H
EtO H
EtO H
EtO H
E tO H
c 11H18N4o 3
51.96
51.89
53.91
53.84
51.42
51.31
48.44
48.22
51.42
51.29
62.92
62.81
59.59
59.64
57.82
57.76
58.52
58.60
60.45
60.36
7.13
7.06
7.92
7.84
6.71
6.65
5.63
5.58
6.71
6.59
6.34
6.22
6.00
6.02
6.07
6.01
5.73
5.79
5.46
5.40
22.04
22.00
26.20
26.12
26.65
26.59
26.08
26.01
26.65
26.71
19.57
19.63
18.53
18.50
16.86
16.80
22.75
22.78
21.69
21.59
(
254.3)
2b
c 12h 21n 5o 2
267.3)
c 18h 28n 8o 4
420.5)
c 13h 18n 6o 4
322.3)
c 9h 14n 4o 2
210.2)
CisH 18N40 2
286.3)
C i5H 18N40 3
302.3)
(
2c
(
4
(
5a
(
5b
(
6a
(
6b
Ci6H2()N40 4
(
332.4)
c 12h 14n 4o 2
246.3)
c 13h 14n 4o 2
258.3)
7
(
8
(
Table II. Mass spectra and IR spectra of compounds 2,4,5,6,7, and 8.
Compound
IR (KBr) (cm ”1)
MS, m/e (% )
2a
3484, 3188 (N H 2); 2958, 2803 (CH aliph.); 1702
255 (M ++ l)(l); 207(2); 185(3); 166(7); 149(21);
111(14); 81(44); 69(100); 56(55)
(
CO lactam)
2b
3407, 3152 (N H 2); 2950, 2810 (CH aliph), 1702
269 (M ++2)(3); 264(14); 252(8); 239(19); 205(10);
164(17); 159(13); 129(16); 98(31); 97(85); 83(100);
(
CO lactam)
6
9(48)
2c
3305, 3149 (N H 2); 2940, 2816 (CH aliph); 1695
CO lactam)
420(M+)(1); 411(2); 407(29); 368(9); 285(6);
238(28); 196(100); 169(55); 98(45); 83(75); 67(25)
(
4
3395, 3127 (N H 2); 2944 (CH aliph); 1661 (CO
lactam)
323(M++1)(37); 209(M+-1)(36); 167(37); 149(100);
105(41); 82(42); 57(75).
5a
3436 (NH); 2934 (CH aliph); 1705 (CO lac-
tam)
210(M+)(37); 209(M+-1)(36); 167(37); 149(100);
105(41); 82(42); 57(75)
5b
3289 (NH); 3090 (CH arom ); 2984 (CH aliph);
286(M+)(9); 285 (M +-l)(17); 237(20); 180(15);
165(16); 124(29); 96(37); 72(19); 57(100)
1
692 (CO lactam)
6a
3510 (O H); 3298 (NH); 3120 (CH arom ); 2943
305(M++2) (33); 304 (M ++ l) (14); 303 (M +)(13);
273(33); 180(26); 157(35); 118(38); 106(64);
(
CH aliph); 1684 (CO lactam)
7
2(46); 59(100)
6b
3504 (O H); 3294 (NH); 3120 (CH arom); 2965
332(M+) (8); 275 (23); 184(21); 152(32); 115(35);
101(60); 71(22); 57(100)
(
CH aliph); 1690 (CO lactam)
7
8
3400 (N H 2); 3254 (NH); 3150 (CH arom); 2984
CH aliph); 1665 (CO lactam)
243(M+-3) (3); 239(12); 236(19); 215(23); 183(17);
165(18); 130(39); 111(48); 97(100); 57(88)
(
3259 (NH); 3059 (CH arom ); 2910 (CH aliph);
655 (CO lactam)
257(M+-1)(4); 256(M+-2) (5); 250 (15); 247(19);
237(24); 209(16); 183(24); 161(36); 147(39);
1
1
04(30); 97(36); 84(39); 68(31); 57(100)
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46
W. S. Hamama ■Pyrimido(4,5-d)pyrim idine-2,4-diones
Table III. !H NMR of the compounds 2a, 2c, 4, 5a, 6a (6.5 mmol) and formalin (13 mmol, 40% solution)
and 8.
in ethanol (20 ml) and the reaction mixture was
stirred for 2 h, then left at room tem perature for
Com-
pound
3
days. The resulting precipitate was collected by
'H NMR (solvent) ö ppm
filtration, then purified by crystallization from eth-
anol to give the corresponding pyrimido[4,5-d]pyr-
imidine derivatives in good yield.
2a
(CDC13): d = 2.4 [t, 4H, -N(CH,)-,]; 3.2 [s, 3H,
CONCH,]; 3.3[s, 3H. (CO)2N-CH,]: 4.3 [s, 2H.
C=C-CH2-N]; 3.6[q, 6H (4H, 0(C H 2)2 and 2H,
NH2), became triplet after deuteration]
4
-(o-AminoaniIino)-l ,3-dimethyl-2,6-dioxo-l,2,3,4-
2c
(DMSO-d6): (3 = 2.3 [m, 8H, N(CH2)4], 3.10 [s,
tetrahydropyrimidine (7)
6
3
H, (CONCH3)2]; 3.14 [s, 4H, (C=C-CH2N)2];
.2[s, 6H, ((CO)2NCH3)2]; 3.7[s, 4H. (NH2)2,
A mixture of 1 (6.5 mmol) and o-phenylenedia-
mine (6.5 mmol) in glacial acetic acid (20 ml), was
heated for 2 h on a steam bath, kept overnight at
exchangeable with D20]
4
(DMSO-d6): (3= 3.1 [s. 6H, (CO-NCH,)2]; 3.2 [s,
8
3
H (6H, ((CO)2NCH3)2 and 2H, CH2-(C=C)2]; room tem perature, diluted with water then basi-
.3 [s, 4H, (NH2)2, exchangeable with D20]
fied to pH 8 by ammonia. The precipitated pro-
duct was crystallized from ethanol to give 7 in low
yield (Table I).
5a
(DMSO-d6): ö = 2.8 [s, 3H, N-CH,]; 3.1 [s, 3H,
CON-CH3]; 3.3 [(s, 3H, (CO)2N-CH3]; 3.4 [brs,
1
H. NH, exchangeable with D?0]; 3.9 [s, 2H,
CH2-N]; 4.5 [d, 2H. N-CH2-N] “
6
,10-Dihydro-l,3-dimethyl-2,4-dioxopyrimido-
6a
(CDC13): <5 = 3.2 [s, 3H, CON-CH,]; 3.3 [s, 3H.
[4,5-e][1,4]diazepine (8)
(
2
CO)2NCH3]; 4.2 [s. 2H, N-CH2-C=C]; 4.7 [s,
H. NCH2N], 4.8 [s, 2H, NCH2Ö]; 5.4 [s, 1H.
To a solution of (4 mmol) of 7 in ethanol (10 ml)
was added formalin (6 mmol, 40% solution), and
the mixture was refluxed for 0.5 h. The deposited
crystals were collected by filtration and crystal-
lized from ethanol to give 8 in good yield (Table I).
OH, exchangeable with D20]; 6.8-7.2 [m, 5H,
arom-H]
8
(DMSO-d6): 3.2[s, 3H, CON-CH3]; 3.3 [s, 3H,
(
1
CO)2NCH3]; 3.5 [s, 2H, N-CH2-C=C]; 4.4 [s,
H, NH, exchangeable with D2OJ; 5.2 [s, 1H
C=C-NH-C=C, exchangeable with D20]; 7.1-
.5 [m, 4H,arom-H]
7
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W. S. Hamama • Pyrimido(4,5-d)pyrim idine-2,4-diones
447
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(
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