Studies on 6-[(dimethylamino)methylene]aminouracils: A facile one-pot synthesis of pyrimido[4,5-d]pyrimidines and pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1055/s-2001-16036

6-[(Dimethylamino)methylene]amino-1,3-dimethyl uracil 1 undergoes formal [4+2] cycloaddition reaction with non conjugated imines to give pyrimido[4,5-d]pyrimidines 3. When reacted with conjugated imines and α,β-unsaturated nitro compounds cycloaddition al

Full text of DOI:10.1055/s-2001-16036

LETTER
1299
Studies on 6-[(Dimethylamino)methylene]aminouracils: a Facile One-pot
Synthesis of Pyrimido[4,5-d]pyrimidines and Pyrido[2,3-d]pyrimidines.
Ashim J Thakur, Promod Saikia, Dipak Prajapati, Jagir S Sandhu*
Department of Organic Chemistry (Drugs) Regional Research Laboratory, Jorhat 785006, Assam, India
Fax +91 0376 370116 or +91 0376 370011; E-mail: drrljt@csir.res.in
Received 14 May 2001
reactions. Hirota et al synthesised pyrido[2,3-d]pyrim-
idines by the palladium-mediated C-C coupling reaction
of electron-deficient olefins with uracil 1 in refluxing ace-
tic acid,16 but they used a stoichiometric amount of expen-
Abstract: 6-[(Dimethylamino)methylene]amino-1,3-dimethyl ura-
cil 1 undergoes formal [4+2] cycloaddition reaction with non con-
jugated imines to give pyrimido[4,5-d]pyrimidines 3. When reacted
with conjugated imines and
-unsaturated nitro compounds cy-
cloaddition also occurs leading to unexpected pyrido[2,3-d]pyrim- sive Pd(OAc)2 as a coupling reagent. Our synthetic
idines 5 and 9, respectively.
strategy utilising non conjugated and conjugated imines
and -nitro styrenes with 6-[(dimethylamino)methyl-
ene]aminouracil affords an unprecedented one-pot syn-
thesis of pyrimido[4,5-d]pyrimidines and pyrido[2,3-
d]pyrimidines respectively in excellent yields.
Key words: pyrimido[4,5-d]pyrimidines, pyrido[2,3-d]pyrim-
idines, imines,
renes
-unsaturated nitro compounds and
nitrosty-
Pyrimido[4,5-d]pyrimidines and pyrido[2,3-d]pyrim-
idines are an important class of annulated uracils of bio-
logical significances because of their connection with
purine and pteridine systems.1 Several patents have been
reported for the preparation of these fused heterocycles,
derivatives which are useful as bronchodilators,2 vascodi-
lators,2 antiallergic,2,3 antihypertensive4 and anticancer2
agents and recently pyrimido[4,5-d] pyrimidine ana-
logues of folic acid have been screened for antitumor
activity5. Therefore, for the preparation of these complex
molecules, there has been remarkable interest in the syn-
thetic manipulations of uracils.6 Also the synthetic exploi-
tation of the nucleophilic double bond of uracil is an
undeveloped field in view of a great variety of potential
products.7 There have been reports for direct functionali-
sation of uracil using the C5-C6 double bond via
thermolytic8 and photocycloaddition reactions.9 The het-
eroannulation of uracils usually require either forcing
conditions10 or relatively longer synthetic pathways.11 In
continuation of our studies on uracil analogues12 we now
want to present a new, simple and efficient preparation of
novel fused pyrimidines based on [4+2] cycloaddition re-
action by exploiting the 5-6 double bond of uracil in a one-
pot synthesis.
Scheme 1
6-[(Dimethylamino)methylene]amino-1,3-dimethyl urac-
il 1 was readily obtained by the reaction of 6-amino-1,3-
dimethylbarbituric acid with (DMF-DMA) under thermal
condition in the solid state. The reaction proceeds more
efficiently when carried out under microwave irradiation
and takes only 3 min to complete the reaction in 90%
yield. The arylidene-N-arylamines 2 and cinnamaldehyde
imines 4 used were prepared from the corresponding alde-
hydes and amines by a published procedure.17 Treatment
of 1 with an equimolar amount of benzylidene aniline 2a
(Ar = Ph, Ar’ = Ph) under reflux condition gave after
elimination of dimethylamine from the 1:1 cycloadduct
and tautomerisation, the pyrimido[4,5-d]pyrimidine 3a as
the only product in 95% yield19 and there was no evidence
for the formation of any other products. The structure of
the compound 3a was assigned on the basis of its spectral
data and elemental analysis. The diagnostic signal for the
azomethine proton at 8.20 was absent in the cycload-
duct, whilst upfield shift of this from 8.20 to 6.08
A new approach to the synthesis of pyrimido[4,5-d]pyri-
midines reported by Wamhoff et.al.13 is the aza-Wittig-
type reaction of iminophosphoranes of 5-aminouracils
with aromatic isocyanates which leads to functionalised
pyrimido[4,5-d]pyrimidines. Broom et al.14 synthesised
pyrido[2,3-d]pyrimidine from the reaction of DMAD and
6-aminouracil in protic solvent but obtained uncyclised
condensed acetylenic adduct when the reaction was car-
ried out in DMF. Also Wamhoff’s group reported substi-
tuted pyrido[2,3-d]pyrimidines from 6-substituted uracil
via [4+2] cycloaddition with electron-deficient olefins.15
The main disadvantages in this method are the limitation
to electron-deficient olefins and the low yield due to side
Synlett 2001, No. 8, 1299–1301 ISSN 0936-5214 © Thieme Stuttgart · New York

1300
A. J. Thakur et al.
LETTER
showed that cycloaddition had occurred at the azomethine To further investigate the synthetic scope of this cycload-
function. Also the 1H NMR spectrum showed the absence dition reaction, we also reacted various
unsaturated
of H-5 proton of the uracil 1 and two methyl groups from nitro compounds 7 with amidine 1 and isolated the corre-
the cycloadduct 3a and other signals appeared at 3.29 sponding dihydropyrido[2,3-d]pyrimidines 8, which were
(s,3H, NCH3), 3.55 (s, 3H, NCH3), 6.08 (s, 1H, H-5), readily converted into their aromatic analogues 9, by oxi-
7.07-7.79 (m, 10H, ArH), 8.12 (s, 1H, CH=N-). The mass dative aromatization in refluxing nitrobenzene.18 The
spectrum of 3a revealed a strong molecular ion peak at m/ structure of product as pyrido[2,3-d]pyrimidine was as-
z 346. Similarly other pyrimido[4,5-d]pyrimidines 3b-f signed on the basis of its elemental and spectral analysis.
were prepared in 70-95% yields and their characteristics This is in contrast to our earlier report20 where we ob-
are recorded in the Table. Interestingly, when the above tained the simple Michael adduct and failed to prepare
reaction was carried out with a conjugated imine such as fused pyrimidines from the reaction of
-unsaturated ni-
cinnamylidine aniline and refluxed in dry DMF for 6 h we tro compounds with 6-amino, 6-hydroxylamino and 6-hy-
obtained the pyrido[2,3-d]pyrimidine 5a in 90% yield in- drazino 1,3-dimethyluracils. However, with amidine 1
stead of the expected pyrimido[4,5-d]pyrimidine deriva- and -nitrostyrene we successfully synthesised fused py-
tive 6a. Here, the carbon-carbon double bond of rimidines in excellent yields. The 1H NMR spectrum of 9a
conjugated imine reacted and the carbon-nitrogen double shows the absence of the methylene protons on the -car-
bond remained intact. The structure of the fused pyrimi- bon atoms (characteristic peak for Michael adduct) and in-
dine 5a thus obtained is confirmed on the basis of its spec- dicates the presence of CH=N proton at 8.73 which
tral analysis.The 1H NMR spectra 5a showed the presence rules out the formation of Michael adduct 10. In addition
of typical azomethine proton at 8.27 along with the N- to this signal, the two N-methyl protons of the uracil
methyls of the uracils (Scheme 1).
showed as singlets. The IR spectrum of this compound in-
dicated a strong band at 1575 cm-1 which is the character-
istic absorption of the NO2 group and other bands at 1660
and 1705 cm-1 characteristic absorption of the uracil sys-
tems. The molecular ion peak M+ in 9a is at m/z 312. Sim-
ilarly other -nitrostyrenes were reacted with uracil 1 and
the corresponding pyrido[2,3-d]pyrimidines 9b-f were
isolated in 85-92% yields. The high regiospecificity ob-
served in these reactions is consistent with the electron
donating effect of the dimethylamine substituent increas-
ing the nucleophilicity of the C-5 position and the estab-
lished reactivity of the olefins.
Table Characteristics for Pyrimido[4,5-d] and Pyrido[2,3-d]-pyri-
midines.
In conclusion, our results demonstrate a new, simple and
efficient synthesis of novel complex pyrimido[4,5-d]pyri-
midines and pyrido[2,3-d]pyrimidines of biological sig-
nificance 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.
Acknowledgement
aYields refer to the isolated pure compounds.
We thank the Department of Science of Technology, New Delhi for
financial support and RSIC, Shillong for recording 300 MHz NMR
spectra of some of our samples and one of us (AJT) thanks CSIR
New Delhi for the award of a research fellowship to him.
References and Notes
(1) a) Lunt, E., Comprehensive Organic Chemistry, Barton, D.,
Ollis, W. D., eds. Pergamon press, Oxford 1974, Vol. 4, p 493;
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(2) Coates, W. J., Eur. Pat. 1990, 351058; Chem. Abstr. 1990,
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Abstr. 1984, 104, 186439.
(4) Raddatz, P., and Bergmann, R., Ger. Pat. 1988, 3601731;
Chem. Abstr. 1988, 109, 54786.
Scheme 2
Synlett 2001, No. 8, 1299–1301 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Studies on 6-[(Dimethylamino)methylene]aminouracils
1301
(5) Delia, T. J., Baumann, M., Bunker, A., Heterocycles 1993, 35,
1397.
Recrystallised from CHCl3: pet.ether (40-60) (1:2), yield
95%, mp 156-158 °C (whitish solid). 3a (Ar = Ph, Ar’ = Ph):
max (KBr)/cm-1 1690 and 1650 (C=O); H (300 MHz, CDCl3)
3.29 (s, 3H, NCH3), 3.55 (s, 3H, NCH3), 6.08 (s, 1H, H-5),
7.07-7.79 (m, 10H, ArH), 8.12 (s, 1H, -CH=N); c 160.17 ((C-
2), 151.48 (C-4) 151.12(C-8a), 121.72, 125.43, 126.69,
127.64, 128.03, 140.76, 140.89, 148.11 (C-7 and C-Ph), 90.16
(C-4a), 57.96 (C-5), 28.55 (C-9), 27.08 (C-10). m/z 346 (M+);
(Found: C, 69.47; H, 5.28; N, 16.29, C20H18N4O2 requires C,
69.36; H, 5.20; N, 16.18%). Similarly pyrido[2,3-
(6) a) Hirota, K., Kitade, Y., Senda, S., Halat, M. J., Watanabe, K.
A., Fox, J. J., J. Org. Chem. 1981, 46, 846; (b) Su, T. L.,
Huang, J. T., Burchanal, J. H., Watanabe, K. A., Fox, J. J., J.
Med. Chem. 1986, 29, 709; (c) Prajapati, D., Sandhu, J. S.,
Synthesis 1988, 342.
(7) a) Taylor, E. C., Sawinski, F., J. Org. Chem. 1974, 39, 907;
(b) Wamhoff, H., Winfried, S., J. Org. Chem. 1986, 51, 2787;
(c) Hirota, K., Benno, K., Yumuda, Y., Senda, S., J. Chem.
Soc., Perkin Trans 1. 1985, 1137; (d) Sasaki, T., Minamoto,
T., Suzuki, T., Suguira, T., J. Am. Chem. Soc. 1978, 100, 2248.
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(9) a) Wexlar, A., Swenton, J. S., J. Am. Chem. Soc. 1976, 98,
1602; (b) Hyatt, J. A., Swenton, J. S., J. Am. Chem. Soc. 1972,
94, 7605.
(10) a) Yoneda, F., Higuichi, M., Nagamatsu, T., J. Am. Chem.
Soc. 1974, 96, 5607; (b) Yoneda, F., Nagamatsu, T., Senga,
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J. S., J. Org. Chem. 1990, 55, 568; Baruah, B., Prajapati, D.,
Sandhu, J. S., Ghosh, A. C., J. Chem. Soc., Perkin Trans 1.
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1969, 585.
(18) In a typical case, to a solution of 6-[(Dimethylamino)methyl-
ene]amino-1,3-dimethyluracil (0.210 g, 1 mmol) in dry DMF
(15 mL), was added benzylidine aniline (0.207 g, 1 mmol) and
the mixture allowed to reflux for 6 h (monitored via TLC).
After completion of the reaction, the DMF was distilled off
from the reaction mixture under reduced pressure. Then it was
extracted with chloroform, washed with water (3 20 mL).
The organic layer was dried over anhydrous Na2SO4 and
column chromatographed to give the pure product.
d]pyrimidines 3b-f and 5b-d were prepared and characterised.
5a m.p. 243-244 °C; max (KBr)/cm-1 1690 and 1660 (C=O);
H (300 MHz, CDCl3) 3.35 (s, 3H, NCH3), 3.83 (s, 3H, NCH3),
6.68-7.82 (m, 10H, ArH), 8.27 (s, 1H, CH=N), 9.52 (s, 1H).
(19) In a typical procedure, to a solution of 1 (0.21 g, 1 mmol) in
dry CHCl3 (10 mL) at 0 °C, was added -nitrostyrene (0.15 g,
1 mmol) slowly and stirred for 5 min. It was then removed
from the ice bath and the reaction was allowed to stir at room
temperature. The reaction immediately took a red colour, and
the stiring was continued for another 1 h. A red solid was
obtained which was removed and washed with chloroformand
hexane repeatedly several times and a yellow solid was
obtained. This was then taken in nitrobenzene (20 mL) and
refluxed for 5 h. The nitrobenzene was then removed under
reduced pressure and the solid thus obtained was extracted
with chloroform and washed with sodium bicarbonate
solution (3 20 mL). The organic layer was dried, distilled
and purified through column chromatography to give the
corresponding pyrido[2,3-d]pyrimidine 9a in 91% yield. 9a
(R = C6H5): mp 197-198 °C; max (KBr)/cm-1 1575, 1705 and
1660 (NO2, C=O). H (300MHz, CDCl3) 3.36 (s, 3H, NCH3),
3.82 (s, 3H, NCH3), 7.02-7.63 (m, 5H, ArH), 8.73 (s, 1H, -
CH=N); m/z 312 (M+) (Found: C, 57.76; H, 3.88; N, 17.80.
C15H12N4O4 requires C, 57.69; H, 3.84; N, 17.94%). c 158.27
(C-2), 152.22 (C-4), 149.73 (C-8a), 147.75 (C-5), 147.02,
142.61 (C-6, C-7), 128.65, 128.14, 125.85, 124.99 (C-Ph),
107.38 (C-4a), 28.55 (C-9), 27.08 (C-10).
(20) Prasad, A. S., Sandhu, J. S., Baruah, J. N., J. Heterocycl.
Chem. 1984, 21, 1657.
Article Identifier:
1437-2096,E;2001,0,08,1299,1301,ftx,en;D06701ST.pdf
Synlett 2001, No. 8, 1299–1301 ISSN 0936-5214 © Thieme Stuttgart · New York