One-pot three component condensation reaction in water: An efficient and improved procedure for the synthesis of furo[2,3-d]pyrimidine-2,4(1H,3H)-diones

Article abstract of DOI:10.1016/S0040-4039(02)02260-8

The environment-friendly three component condensation reactions of N,N^′-dimethylbarbituric acid, 4-nitrobenzaldehyde and alkyl or aryl isocyanides to afford the corresponding furo[2,3-d]pyrimidine-2,4(1H,3H)-diones, in water, in high yields aft

Full text of DOI:10.1016/S0040-4039(02)02260-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9151–9154
One-pot three component condensation reaction in water: an
efficient and improved procedure for the synthesis of
furo[2,3-d]pyrimidine-2,4(1H,3H)-diones
Ahmad Shaabani,a,* Mohammad Bagher Teimouria and Hamid Reza Bijanzadehb
aDepartment of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
bDepartment of Chemistry, Tarbiat Modarres University, PO Box 14155-4838, Tehran, Iran
Received 9 September 2002; revised 25 September 2002; accepted 4 October 2002
Abstract—The environment-friendly three component condensation reactions of N,N%-dimethylbarbituric acid, 4-nitrobenzalde-
hyde and alkyl or aryl isocyanides to afford the corresponding furo[2,3-d]pyrimidine-2,4(1H,3H)-diones, in water, in high yields
after several minutes are reported. © 2002 Elsevier Science Ltd. All rights reserved.
1
1. Introduction
elemental analyses and IR, H NMR and 13C NMR
spectra. The mass spectra of these compounds dis-
played molecular ion peaks at the appropriate m/z
values.
It is well known that pyrimidine systems as purine
analogues exhibit a wide range of biological activities.1–4
Among them, the furo[2,3-d]pyrimidine derivatives act
as sedatives, antihistamines, diuretics, muscle relaxants
and antiulcer agents.
The formation of these heterocycles can be rationalized
by initial formation of a conjugated electron-deficient
heterodiene by standard Knoevenagel condensation of
the aldehyde 2 and the N,N%-dimethylbarbituric acid
1,15,16 followed by a [1+4] cycloaddition reaction10–14,17–20
or a Michael-type16,21 addition reaction with isocyanide
3 to afford an iminolactone 5, which then isomerizes to
yield the furo[2,3-d]pyrimidines (4a–e) (Scheme 2).
The synthesis of furopyrimidines has received little
attention and only few procedures have been reported
in the literature,2,5–9 most of which rely on multi-step
reactions with yields being low2,5,6 (Scheme 1).
In connection with our previous work on the reaction
of isocyanides with electron-deficient heterodienes,10–14
we wish to report a facile and rapid protocol for the
three component condensation reactions of N,N%-
dimethylbarbituric acid 1, 4-nitrobenzaldehyde 2 and
alkyl or aryl isocyanides 3 in water at 75°C (Scheme 1).
In conclusion, we have shown that the three component
condensation reactions of N,N%-dimethylbarbituric acid
1, 4-nitrobenzaldehyde 2 and an alkyl or aryl isocya-
nide 3 efficiently occurs in water without needing a
catalyst at 75°C in a few minutes, providing a conve-
nient and efficient synthesis of furo[2,3-d]pyrimidine-
2,4(1H,3H)-diones. The one-pot nature and the use of
the water as an eco-compatible reaction solvent makes
it an interesting alternative to multi-step approaches.2
The one-pot three component condensation reactions
of N,N%-dimethylbarbituric acid 1, 4-nitrobenzaldehyde
2 and alkyl or aryl isocyanides 3 proceeded sponta-
neously at 75°C in water and were complete after
1
several minutes. H and 13C NMR spectra of the crude
products clearly indicated the formation of furo[2,3-
d]pyrimidine-2,4(1H,3H)-diones 4. Any product other
than 4 could not be detected by NMR spectroscopy.
The structure of compounds 4a–e was deduced from
2. Experimental
2.1. Typical procedure for the preparation of 5-p-
nitrophenyl-6-tert-butylamino-1,3-dimethylfuro[2,3-d]-
pyrimidine-2,4(1H,3H)-dione (4a)
To a magnetically stirred mixture of N,N%-dimethylbar-
bituric acid (0.172 g, 1.1 mmol) and 4-nitrobenzalde-
* Corresponding author. Fax: +98-21-2403041; e-mail: a-shaabani@
cc.sbu.ac.ir
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02260-8

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A. Shaabani et al. / Tetrahedron Letters 43 (2002) 9151–9154
Scheme 1.
3
hyde (0.151 g, 1 mmol) in water (20 mL) was added
tert-butyl isocyanide (0.084 g, 1 mmol) via a syringe
and heated for 30 min at 75°C. After cooling to room
temperature, the resulting red precipitate was filtered
and washed with water (50 mL).
3.85 (1 H, d, JHH=6.9 Hz, NH), 7.78 and 8.20 (4 H, 2
d, JHH=8.7 Hz, arom.). 13C NMR (CDCl3, Me4Si): lC
3
24.71, 25.44 and 33.98 (5 CH2), 28.39 and 29.52 (2
NCH3), 55.06 (NꢀCH), 95.47 (C4a), 101.36 (C5), 123.47
(Cmeta-NO2), 129.47 (Cortho-NO2), 138.04 (Cpara-NO2),
145.87 (C-NO2), 149.93 (C6), 150.14 (C7a), 150.96 (C2),
158.07 (C4). MS (m/z,%) 398 (M+, 100), 316 (38), 288
(47), 259 (42), 187 (50), 141 (26), 110 (25), 83 (65), 67
(68), 55 (98). Anal. calcd for C20H22N4O5 (398.45): C,
60.28; H, 5.56; N, 14.06%. Found: C, 60.36; H, 5.49; N,
14.19%.
The solid residue was dried and crystallized from
CH2Cl2–EtOH (1:2) to yield 4a as red crystals (0.286 g,
77%). Mp 179–181°C. IR (KBr) (wmax, cm−1): 3360
(NꢀH), 1708 and 1653 (CꢁO). 1H NMR (CDCl3,
Me4Si): lH 1.19 (9 H, s, C(CH3)3), 3.38 and 3.57 (6 H,
2 s, 2 NCH3), 3.51 (1 H, s, NH), 7.84 and 8.21 (4 H, 2
3
d, JHH=8.7 Hz, arom.). 13C NMR (CDCl3, Me4Si): lC
2.3. 5-p-Nitrophenyl-6-benzylamino-1,3-dimethylfuro-
[2,3-d]pyrimidine-2,4(1H,3H)-dione (4c)
28.35 and 29.49 (2 NCH3), 30.24 (CMe3), 54.83
(CMe3), 95.01 (C4a), 109.37 (C5), 123.24 (Cmeta-NO2),
130.20 (Cortho-NO2), 137.81 (Cpara-NO2), 146.43 (C-
NO2), 148.94 (C6), 150.30 (C7a), 151.90 (C2), 158.10
(C4). MS (m/z,%) 372 (M+, 72), 316 (98), 295 (83), 231
(24), 187 (90), 141 (29), 57 (100). Anal. calcd for
C18H20N4O5 (372.41): C, 58.05; H, 5.41; N, 15.04%.
Found: C, 57.90; H, 5.46; N, 14.92%.
Orange crystals (0.329 g, 81%). Mp 201–202°C. IR
(KBr) (wmax, cm−1): 3280 (NꢀH), 1706 and 1664 (CꢁO).
1H NMR (CDCl3, Me4Si): lH 3.37 and 3.52 (6 H, 2 s,
3
2 NCH3), 4.36 (1 H, t, JHH=4.9 Hz, NH), 4.37 (2 H,
3
d, JHH=4.9 Hz, CH2), 7.27–7.32 (5 H, m, C6H5), 7.67
and 8.15 (4 H, 2 d, JHH=8.4 Hz, arom.). 13C NMR
3
(CDCl3, Me4Si): lC 28.41 and 29.46 (2 NCH3), 50.22
(CH2), 95.60 (C4a), 100.62 (C5), 123.52, 127.73, 128.06,
128.91, 129.45, 137.67, 137.91 and 146.00 (arom.),
149.92 (C6), 150.10 (C7a), 150.86 (C2), 158.07 (C4). MS
(m/z,%) 406 (M+, 54), 315 (95), 258 (53), 187 (15), 141
(13), 91 (100). Anal. calcd for C21H18N4O5 (406.43): C,
62.06; H, 4.46; N, 13.78%. Found: C, 62.19; H, 4.51; N,
13.93%.
2.2. 5-p-Nitrophenyl-6-cyclohexylamino-1,3-dimethyl-
furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (4b)
Red crystals (0.355 g, 89%). Mp 180–181°C. IR (KBr)
(wmax, cm−1): 3255 (NꢀH), 1708 and 1661 (CꢁO). 1H
NMR (CDCl3, Me4Si): lH 1.18–1.96 (10 H, m, 5 CH2),
3.26 (1 H, m, NꢀCH), 3.38 and 3.56 (6 H, 2 s, 2 NCH3),

A. Shaabani et al. / Tetrahedron Letters 43 (2002) 9151–9154
9153
Scheme 2.
2.4. 5-p-Nitrophenyl-6-(2,6-dimethylphenylamino)-1,3-
dimethylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (4d)
1H NMR (CDCl3, Me4Si): lH 2.46 (4 H, m,
3
CH2NCH2), 2.58 (2 H, t, JHH=5.7 Hz, NCH2), 3.30 (2
3
3
H, d of t, JHH=5.7 Hz, JHH=5.5 Hz, NHCH2), 3.39
Orange crystals (0.307 g, 73%). Mp 200–201°C. IR
(KBr) (wmax, cm−1): 3270 (NꢀH), 1701 and 1658 (CꢁO).
1H NMR (CDCl3, Me4Si): lH 2.16 (6 H, s, 2 CH3), 3.37
and 3.44 (6 H, 2 s, 2 NCH3), 5.76 (1 H, s, NH),
6.93–6.98 (3 H, m, C6H3Me2), 7.75 and 8.08 (4 H, 2 d,
3JHH=8.6 Hz, C6H4NO2). 13C NMR (CDCl3, Me4Si):
lC 18.36 (2 CH3), 28.44 and 29.53 (2 NCH3), 95.47
(C4a), 103.30 (C5), 123.01, 124.85, 129.13, 129.63,
130.76, 136.83, 136.96 and 146.05 (arom.), 146.16 (C6),
150.11 (C7a), 151.19 (C2), 158.08 (C4). MS (m/z,%) 420
(M+, 100), 348 (24), 320 (15), 288 (23), 131 (55), 77 (47).
Anal. calcd for C22H20N4O5 (420.45): C, 62.84; H, 4.79;
N, 13.32%. Found: C, 62.70; H, 4.88; N, 13.47%.
and 3.57 (6 H, 2 s, 2 NCH3), 3.66 (4 H, m, CH2OCH2),
4.95 (1 H, t, JHH=4.8 Hz, NH), 7.80 and 8.23 (4 H, 2
3
d, 3JHH=8.7 Hz, C6H4NO2). 13C NMR (CDCl3,
Me4Si): lC 28.45 and 29.49 (2 NCH3), 41.70 (NHCH2),
53.31 (CH2NCH2), 57.12 (NCH2), 66.98 (CH2OCH2),
95.66 (C4a), 98.33 (C5), 123.57 (Cmeta-NO2), 129.15
(Cortho-NO2), 138.14 (Cpara-NO2), 145.74 (C-NO2),
150.10 (C6), 150.66 (C7a), 150.97 (C2), 158.09 (C4). MS
(m/z,%) 429 (M+, 16), 288 (10), 114 (33), 100 (98), 87
(100), 70 (26), 42 (88). Anal. calcd for C20H22N5O6
(429.47): C, 55.93; H, 5.39; N, 16.30%. Found: C,
55.81; H, 5.48; N, 16.38%.
2.5. 5-p-Nitrophenyl-6-(2-morpholinoethylamino)-1,3-
dimethylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (4e)
Acknowledgements
Deep violet crystals (0.318 g, 74%). Mp 186–187°C. IR
(KBr) (wmax, cm−1): 3275 (NꢀH), 1704 and 1671 (CꢁO).
We gratefully acknowledge the financial support from
the Research Council of Shahid Beheshti University.

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11. Shaabani, A.; Ajabi, S.; Farrokhzad, F.; Bijanzadeh, H.
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