Studies on 6-[(dimethylamino)methylene]aminouracil: A facile one-pot synthesis of novel pyrimido[4,5-d]pyrimidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.01.047

The reactions of 6-[(dimethylamino)methylene]aminouracil 1, with various heterocumulenes such as aryl isocyanates and isothiocyanates give rise to novel pyrimido[4,5-d]pyrimidines in excellent yields, after elimination of dimethylamine from the (1:1) cycl

Full text of DOI:10.1016/j.tetlet.2005.01.047

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1433–1436
Studies on 6-[(dimethylamino)methylene]aminouracil: a facile
one-pot synthesis of novel pyrimido[4,5-d]pyrimidine derivatives
Dipak Prajapatia,* and Ashim J. Thakurb
aDepartment of Medicinal Chemistry, Regional Research Laboratory, Jorhat 785 006, Assam, India
bDepartment of Chemical Sciences, Central University, Tezpur 784028, India
Received 26 October 2004; revised 11 January 2005; accepted 11 January 2005
Available online 25 January 2005
Abstract—The reactions of 6-[(dimethylamino)methylene]aminouracil 1, with various heterocumulenes such as aryl isocyanates and
isothiocyanates give rise to novel pyrimido[4,5-d]pyrimidines in excellent yields, after elimination of dimethylamine from the (1:1)
cycloadducts and tautomerisation. This procedure provides a convenient method for direct synthesis of pyrimido[4,5-d]pyrimidine
derivatives under thermal conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Pyrimidines and fused pyrimidines represent a broad
class of compounds, which have received considerable
attention due to their wide range of biological activi-
ties.1–4 Among them, the pyrimido[4,5-d]pyrimidines
and pyrido[2,3-d]pyrimidines are an important class of
annulated uracils with biological significance because
of their connection with purine pteridine systems.5 Sev-
eral patents have been reported for the preparation of
these fused heterocycles, derivatives of which are useful
as bronchodilators,6 vasodilators,2 antiallergic,6,7 anti-
hypertensive8 and anticancer6 agents. Most of these
preparations rely on cyclocondensation reactions from
pyrimidine or pyridine intermediates. However this type
of stepwise synthetic strategy limits the synthetic flexibil-
ity. Recently pyrimido[4,5-d]pyrimidine analogues of
folic acid have been screened for antitumour activity.9
Therefore, with the aim of the preparation of these com-
plex molecules, there has been remarkable interest in the
synthetic manipulations of uracils,10 although the syn-
thetic exploitation of the nucleophilic double bond of
uracil is an undeveloped field in view of a great variety
of potential products.11 An approach to the synthesis
of pyrimido[4,5-d]pyrimidines reported by Wamhoff
and Muhr12 is the aza-Wittig type reaction of imino-
phosphoranes of 5-aminouracils leading to functional-
ised pyrimido[4,5-d]pyrimidines. Our synthetic strategy
utilizing aromatic isocyanates and isothiocyanates with
6-[(dimethylamino)methylene]aminouracil affords an
unprecedented one-pot synthesis of novel pyrim-
ido[4,5-d]pyrimidines in excellent yields in refluxing
nitrobenzene in 45–70 min based on a [4+2] cycloaddi-
tion strategy. In the past a cycloaddition approach has
had little appeal since the dienophilic nature of the
pyrimidine ring is rather limited, and the diene proper-
ties of vinylpyrimidines had not been established.13 It
was postulated that if a vinylpyrimidine system were
appropriately substituted with strongly electron-donat-
ing groups, cycloaddition might occur with electron defi-
cient dienophiles. It has been reported that the dienyl-
character of furan is enhanced by incorporation of a
dimethylhydrazino group14 and as 1-(dimethylamino)-
3-methyl-2-azabutadiene15 functions as an azadiene,
perhaps the dienic character of vinylpyrimidines would
be increased by similar substituents. This is also sup-
ported by HOMO calculations.16 It is notable that
although the chemistry of isothiocyanates greatly resem-
bles that of isocyanates, the cycloaddition reactions of
isothiocyanates have received little attention. In addi-
tion to their widely known nucleophilic substitution
reactions, isothiocyanates react with suitable substrates
to form 1,2-, 1,3- and 1,4-cycloadducts.17a With isocya-
nates, reactions occur almost exclusively across the
C@N bond, while with the isothiocyanates, the C@S
bond often participates in the cycloaddition reactions.
Perhaps the best example of the interaction across the
C@S bond is the dimerisation of sulfonyl isothio-
cyanates to afford the symmetric dimers.17b In a
recent report18 various isocyanates were reacted with
Keywords: Amidines; Pyrimido[4,5-d]pyrimidines; Aryl isothiocya-
nates; Aryl isocyanates.
*
Corresponding author. Tel.: +91 376 2370356; fax: +91 376
2370011; e-mail: dr_dprajapati2003@yahoo.co.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.047

1434
D. Prajapati, A. J. Thakur / Tetrahedron Letters 46 (2005) 1433–1436
at the C@N bond of the isocyanate. Also, the 1H
O
NMR spectrum showed the absence of the H-5 proton
of the uracil 1 and the presence of two methyl groups
from the cycloadduct 4a at d 3.35 (s, 3H, CH3) and at
3.68 (s, 3H, NCH3), and other peaks at 6.98–7.54(m,
5H, ArH) and 8.62 (s, 1H, CH@N–). Similarly, other
pyrimido[4,5-d]pyrimidines 4b–d were prepared in 80–
86% yields (Table 1). To investigate further the synthetic
scope of this cycloaddition reaction, we reacted various
aromatic isothiocyanates 2e–i with amidine 1 in reflux-
ing nitrobenzene (45–70 min) and isolated the corre-
sponding pyrimido[4,5-d]pyrimidine derivatives, after
elimination of dimethylamine from the 1:1 cycloadducts.
Me
O
O
N
X
Ar
Me
N
N
Me
N
N
Me
N
2
(-)
PhNO2
N
N
Me
O
2
N
Me
1
(+)
+
N
Ar
X
C
3
2
X
X
O
O
Me
Me
Ar
NHAr
Me
N
N
N
O
O
N
Me
N
N
Me
N
N
2
1
The H NMR spectrum showed the absence of the H-5
4
proton of the uracil 1 and the presence of two methyl
groups for the cycloadduct 3e at d 3.32 (s, 3H, NCH3)
and 3.60 (s, 3H, NCH3). Also, the characteristic isothi-
ocyanate peak at 2120 cmꢀ1 was absent in the IR spec-
trum of the cycloadduct whilst the appearance of peak
at 1600 cmꢀ1 showed that the cycloaddition had
occurred at the C@N bond of the isothiocyanate. How-
ever, we did not observe the formation of any Michael
type products 5. This finding is in contrast to an earlier
report20 where Sandhu et al. have obtained simple
Michael adducts and failed to prepare fused pyrimidines
from the reactions of a,b-unsaturated nitro compounds
with 6-amino, 6-hydroxylamino and 6-hydrazino-1,3-
dimethyluracils. However, with amidine 1 and aryl iso-
cyanates or aryl isothiocyanates, we successfully syn-
thesised fused pyrimidines in excellent yields. The high
regiospecificity observed in these reactions is consistent
with the electron donating effect of the dimethylamino
substituent increasing the nucleophilicity of the C-5
position. Although, we could not isolate any intermedi-
ates from the reaction mixture, a reasonable mechanism
for the formation of the product would involve initial
electrophilic attack of the aryl isocyanate at the C-5
position of the amidine 1 to give the Michael adduct
3, which suffers a subsequent nucleophilic attack on
the imino carbon atom eliminating dimethylamine to
give product 4. However further work is in progress to
understand the mechanism in detail.
5
Ar = C6H5, p-ClC6H4, p-FC6H4, p-BrC6H4,
C6H5CH2, p-C6H4SO2
X = O, S
Scheme 1.
6-hydrazino-uracils in refluxing ethanol and the corres-
ponding pyrazolo[3,4-d]pyrimidines were obtained in
excellent yields. We have now found that the C@N bond
of isocyanates and isothiocyanates react with uracil
amidine 1, yielding novel pyrimido[4,5-d]pyrimidine
derivatives in excellent yields, leaving the C@S bond of
isothiocyanates intact (Scheme 1).
Treatment of 6-[(dimethylamino)methylene]amino-1,3-
dimethyl uracil 1, with an equimolar amount of aryl iso-
cyanate 2a (Ar = C6 H5, X = O) in nitrobenzene (10 mL)
under reflux conditions gave, after elimination of dim-
ethylamine from the 1:1 cycloadduct, the pyrimido[4,5-
d]pyrimidine 4a as the only product (yellowish solid)
mp 209–210 °C in an 86% yield.19 The 6-[(dimethyla-
mino)methylene]amino-1,3-dimethyl uracil 1, was read-
ily obtained by the reaction of 6-amino-1,3-dimethyl
barbituric acid with (DMF–DMA) under thermal con-
ditions in the solid state. The reaction proceeds more
efficiently when carried out under microwave irradiation
and it takes only 3 min to complete the reaction in 90%
yield. The structure of product 4a as a pyrimido[4,5-
d]pyrimidine derivative was assigned on the basis of its
elemental and spectral analyses. The diagnostic signal
for the isocyanate at 2275 cmꢀ1 in the IR was absent
in the cycloadduct whilst the appearance of peak at
1610 cmꢀ1 showed that the cycloaddition had occurred
In conclusion, our results demonstrate a new, simple
and efficient synthesis of novel complex pyrimido[4,5-
d]pyrimidine derivatives of biological significance in
almost quantitative yields. These results also illustrate
that the title compound 1 is a useful substrate for the
generation of an array of fused nitrogen heterocycles.
Table 1. Characteristics of pyrimido[4,5-d]pyrimidines 4a–i
Product
Ar
X
Reaction time (min)
Yielda (%)
Mp (°C)
4a
4b
4c
4d
4e
4f
C6H5
O
O
O
O
S
45
60
50
70
65
70
60
65
50
86
82
209–210
171–173
300–302
335–337
279–281
176–178
271–272
273–275
p-BrC6H4ꢀ
p-ClC6H4ꢀ
p-MeC6H4SO2ꢀ
C6H5
83
80
85
80
p-BrC6H4ꢀ
p-FC6H4ꢀ
p-ClC6H4ꢀ
C6H5CH2ꢀ
S
4g
4h
4i
S
81
85
S
S
84191–192
a Yields refer to the isolated pure compounds.

D. Prajapati, A. J. Thakur / Tetrahedron Letters 46 (2005) 1433–1436
1435
19. Typical reaction of uracil amidine 1 with aromatic isocya-
nates and isothiocyanates: To a solution of 6-[(dimethyla-
mino)methylene]-1,3-dimethyl uracil 1 (0.210 g, 1 mmol)
in redistilled nitrobenzene (10 mL), phenyl isocyanate 2a
(Ar = C6H5, X = O, 0.12 g, 1 mmol) was added and the
resulting mixture allowed to reflux for 45 min (monitored
by TLC). After completion of the reaction, the nitroben-
zene was distilled off from the reaction mixture under
reduced procedure. The crude, so obtained, was subjected
to column chromatography to afford the corresponding
pyrimido[4,5-d]pyrimidine 4a in 86% yield, mp 209–
210 °C, recrystallised from chloroform–petroleum ether
(40–60) (3:1). To generalize this reaction we reacted
various aryl isocyanates and isothiocyanates 2 with uracil
amidine 1 and isolated the corresponding pyrimido[4,5-
d]pyrimidines in 80–86% yields. The structure of the fused
pyrimidines 4 thus obtained were confirmed on the basis
of their spectral and elemental analyses. Compound 4a:
(yellowish solid), IR mmax/KBr/cmꢀ1: 1660, 1720 (C@O),
Acknowledgements
We thank the Department of Science and Technology
(DST), New Delhi for financial support and Dr. P. G.
Rao, Director, Regional Research Laboratory, Jorhat
for his keen interest and constant encouragement.
References and notes
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1
1610 (C@N); H NMR (CDCl3) at d 3.35 (s, 3H, CH3),
3.68 (s, 3H, NCH3), 6.98–7.54(m, 5H, ArH), 8.62 (s, 1H,
CH@N–); dc 28.0 (NMe), 29.6 (NMe), 90.9 (C-4a), 127.6
0
(C-20), 129.2 (C-40), 130.4(C-3 ), 139.9 (C-10), 151.6 (C-
8a), 157.4(C-2), 158.0 (C-7), 158.3 (C-4), 158.6 (C-5). MS
m/z 284(M +). Anal. Calcd for C14H12N4O3: C, 59.15; H,
4.23; N, 19.72. Found: C, 59.22; H, 4.28; N, 19.65%.
Compound 4b: (yellowish solid), IR mmax/KBr/cmꢀ1: 1674,
1719 (C@O), 1608 (C@N); 1H NMR (CDCl3) d 3.22 (s,
3H, NMe), 3.42 (s, 3H, NMe), 7.02-7.70 (m, 4H, ArH),
8.12 (s, 1H, CH@N–); dc 27.7 (NMe), 29.4(NMe), 90.9
0
(C-4a), 126.9 (C-20), 127.4(C-6 ), 128.8 (C-40), 129.8 (C-
50), 133.3 (C-30), 133.9 (C-40), 150.4(C-8a), 157.5 (C-2),
158.0 (C-7, C-4), 158.6 (C-5). MS m/z 363 (M+). Anal.
Calcd for C14H11N4O3Br: C, 46.28; H, 3.03; N, 15.43.
Found: C, 55.22; H, 4.28; N, 19.65%. Compound 4c:
(whitish solid), IR mmax/KBr/cmꢀ1: 1680, 1736 (C@O),
1605 (C@N); 1H NMR (CDCl3) d 3.32 (s, 3H, NMe), 3.63
(s, 3H, NMe), 7.06–7.66 (m, 4H, ArH), 8.10 (s, 1H,
CH@N–); dc 27.6 (NMe), 29.9 (NMe), 91.3 (C-4a), 121.7,
126.1, 128.0, 130.1, 133.9, 134.3, 150.7, 156.7, 157.7, 158.6.
MS m/z 318 (M+). Anal. Calcd for C14H11N4O3Cl: C,
52.83; H, 3.46; N, 17.61. Found: C, 52.89; H, 3.53; N,
17.53%. Compound 4d: (yellowish solid), IR mmax/KBr/
cmꢀ1: 1660, 1722 (C@O), 1610 (C@N); 1H NMR (CDCl3)
d 2.28 (C–Me), 3.25 (s, 3H, NMe), 3.46 (s, 3H, NMe), 6.98
(d, 2H, J = 9, ArH), 7.48 (d, 2H, J = 9, ArH), 8.22 (s, 1H,
CH@N–); dc 21.4(PhCH 2), 28.0 (NMe), 30.1 (NMe), 91.8
(C-4a), 127.6, 130.0, 130.8, 139.4, 151.8, 157.1, 158.4,
158.9. MS m/z 362 (M+). Anal. Calcd for C15H14N4O5S:
C, 49.72; H, 3.87; N, 15.47. Found: C, 49.81; H, 3.92; N,
15.39%. Compound 4e: IR mmax/KBr/cmꢀ1: 1663, 1713
(C@O), 1600 (C@N); 1H NMR (CDCl3) d 3.46 (s, 3H,
NMe), 3.69 (s, 3H, NMe), 7.27–7.30 (m, 2H, ArH), 7.53–
7.57 (m, 3H, ArH), 8.32 (s, 1H, CH@N–); dc 28.8 (NMe),
30.5 (NMe), 91.3 (C-4a), 127.6, 128.1, 130.0, 140.2, 151.7,
157.5, 1580, 159.2. MS m/z 300 (M+). Anal. Calcd for
C14H12N4O2S: C, 56.00; H, 4.00; N, 18.67. Found: C,
56.10; H, 4.06; N, 18.59%. Compound 4f: IR mmax/KBr/
cmꢀ1: 1680, 1710 (C@O), 1599 (C@N); 1H NMR (CDCl3)
d 3.20 (s, 3H, NMe), 3.38 (s, 3H, NMe), 7.10–7.75 (m, 4H,
ArH), 8.12 (s, 1H, CH@N–); MS m/z 379 (M+). Anal.
Calcd for C14H11N4O2SBr: C, 44.33; H, 2.90; N, 14.78.
Found: C, 44.40; H, 2.98; N, 14.69%. Compound 4g: IR
8. Raddatz, P.; Bergmann, R. Ger. Pat. 360731, 1988; Chem.
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m
max/KBr/cmꢀ1: 1670, 1715 (C@O), 1596 (C@N); 1H
NMR (CDCl3) d 3.34(s, 3H, NMe), 3.54(s, 3H, NMe),
7.12–7.76 (m, 4H, ArH), 8.10 (s, 1H, CH@N–); MS m/z
318 (M+). Anal. Calcd for C14H11N4O2SF: C, 52.83; H,
3.46; N, 17.61. Found: C, 52.89; H, 3.52; N, 17.53%.
Compound 4h: IR mmax/KBr/cmꢀ1: 1675, 1712 (C@O),
18. Bhuyan, P. J.; Borah, H. N.; Sandhu, J. S. Tetrahedron
Lett. 2002, 43, 895.

1436
D. Prajapati, A. J. Thakur / Tetrahedron Letters 46 (2005) 1433–1436
1598 (C@N); 1H NMR (CDCl3) d 3.16 (s, 3H, NMe), 3.32
1715 (C@O), 1600 (C@N); 1H NMR (CDCl3). MS m/z 298
(M+). Anal. Calcd for C15H14N4O2S: C, 60.40; H, 4.70; N,
18.79. Found: C, 60.48; H, 4.80; N, 18.68%.
(s, 3H, NMe), 7.06–7.71 (m, 4H, ArH), 8.16 (s, 1H,
CH@N–); MS m/z 334(M +). Anal. Calcd for C14H11
N4O2SCl: C, 50.30; H, 3.29; N, 1677. Found: C, 50.24; H,
3.36; N, 16.86%. Compound 4i: IRmmax/KBr/cmꢀ1: 1670,
20. Prasad, A. S.; Sandhu, J. S.; Baruah, J. N. J. Heterocycl.
Chem. 1984, 21, 1657.