A novel approach for the synthesis of furopyrimidine and oxobenzofuran derivatives

Article abstract of DOI:10.1002/hlca.201000029

A novel, efficient one-pot approach for the synthesis of furopyrimidine and oxobenzofuran derivatives 4 by a multicomponent reaction of an isocyanide, an aldehyde, and a CH-acid compound in CH₂Cl₂ is reported (Scheme 1 and Table). Th

Full text of DOI:10.1002/hlca.201000029

Helvetica Chimica Acta – Vol. 93 (2010)
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A Novel Approach for the Synthesis of Furopyrimidine and Oxobenzofuran
Derivatives
by Mohammad Bayat*a), Nader Zabarjad Shirazb), and Seyyed Hajar Hosseinia)
a) Chemistry Department, Imam Khomeini International University, Qazvin, Iran
(phone: þ 98-281-3780040; fax: þ 98-281-3780040; e-mail: bayat_mo@yahoo.com)
b) Chemistry Department, Islamic Azad University, Tehran, Iran
A novel, efficient one-pot approach for the synthesis of furopyrimidine and oxobenzofuran
derivatives 4 by a multicomponent reaction of an isocyanide, an aldehyde, and a CH-acid compound in
CH2Cl2 is reported (Scheme 1 and Table). The reactions were completed after 20 h at room temperature.
This method has the advantages of high yields, simple methodology, and easy workup.
Introduction. – The synthetic routes to furopyrimidine and oxobenzofuran
derivatives is not large, and only few procedures have been reported for the synthesis
of furopyrimidines [1 – 4], mostly relying on multi-step reactions giving low yields [1 –
3]. These compounds are an important structural unit in natural products and are
intermediates in drugs and organic synthesis [5][6]. As part of our continuing interest
in the development of new synthetic methods in heterocyclic chemistry and the recent
interest in isocyanide-based multicomponent reactions [7 – 10], we now describe an
efficient synthesis of furopyrimidine and oxobenzofuran derivatives via the reaction of
CH-acids with aldehydes and isocyanides in CH2Cl2 at room temperature.
Results and Discussion. – The reaction of an aldehyde 2, an isocyanide 3, and a
CH-acid compound 1 produces a fused furan 4. The products 4 are derivatives of
dioxofuropyrimidines and 2-amino-oxobenzofuranes (Scheme 1). Cyclohexyl and tert-
butyl isocyanide were used as isocyanide 3, dimedone (¼ 5,5-dimethylcyclohexane-1,3-
Scheme 1
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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dione), N,N’-dimethylbarbituric acid (¼1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-tri-
one), and cyclohexane-1,3-dione as the CH-acid 1, and 4-nitrobenzaldehyde and
glyoxal (¼ethanedial) as the aldehyde 2. Substrates and products are given in the Table.
The structures of the products 4a – 4g were deduced from their elemental analyses, and
IR and 1H- and 13C-NMR spectra. The mass spectra of 4a – 4g displayed the molecular-
ion peak at appropriate m/z values. Initial fragmentations involved the loss of
alkylamino moieties and scission of the heterocycle moieties.
The 1H-NMR spectrum of 4a consisted of a m for the cyclohexyl substituent (d(H)
1.27 – 2.03) and of two single sharp s for Me groups (d(H) 3.41 and 3.54). A m was
observed for the NꢀCH group (d(H) 3.69), a broad signal for the NH group (d(H)
7.88), and a s for the CHO group (d(H) 9.82), in agreement with the suggested
1
structure. The H-decoupled 13C-NMR spectrum of 4a showed 13 sharp signals in
agreement with the proposed structure. The characteristic signal of the CHO C-atom
was discernible (d(C) 183.25), as well as the four signals (d(C) 94.17, 97.59, 148.11, and
150.09) for four C-atoms of the furan moiety. Partial assignments of these resonances
are given in the Exper. Part.
A mechanism for the synthesis of 4a is proposed in Scheme 2. The formation of the
fused structure can be rationalized by initial formation of a conjugated electron-
deficient heterodiene by Knoevenagel condensation of aldehyde 2a and CH-acid 1a,
followed by a [1 þ 4] cycloaddition reaction or a Michael-type addition reaction with
isocyanide 3a to afford an iminofuran derivative, which was then isomerized to product
4.
Scheme 2
In conclusion, we have described a new, general, and successful strategy for the
convenient synthesis of furopyrimidine and oxobenzofuran derivatives. These new one-
pot reactions were performed in CH2Cl2 at room temperature under neutral conditions
and in the absence of any catalyst, the substrates being mixed without any prior
activation or modification. The advantages of the present procedure are experimental
simplicity, easy workup, and high yields (> 70%) of products.

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Table. Synthesis of Furopyrimidine and Oxobenzofuran Derivatives
RꢀNC 3
CH-Acid 1
Aldehyde 2
Product 4

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Helvetica Chimica Acta – Vol. 93 (2010)
Experimental Part
General. Glyoxal, N,N’-dimethylbarbituric acid, alkyl isocyanides, and other reagents and solvents
used in this work were obtained from Fluka (Buchs, Switzerland) and used without further purification.
M.p.: Gallenkamp electrothermal 9100 apparatus; uncorrected. IR Spectra: Bruker-Tensor-27 spec-
.
trometer; KBr pellets; ˜n in cmꢀ1 1H- and 13C-NMR Spectra: Bruker-DRX-300-Avance instrument;
CDCl3 as solvent; d in ppm rel. to Me4Si as internal standard, J in Hz. MS: Shimadzu-QP-GC-Mass-1100-
EX spectrometer operating at an ionization potential of 70 eV; in m/z (rel. %). Elemental analyses:
Heraeus-CHN-O-Rapid analyzer; exper. values in agreement with calc. values.
General Procedure, Exemplified for 4a. A mixture of glyoxal (2a; 0.058 g, 1 mmol) and cyclohexyl
isocyanide (3a; 0.111 g, 1 mmol) in CH2Cl2 (8 ml) was stirred at r.t. Then, a soln. of N,N’-
dimethylbarbituric acid (1a; 0.156 g, 1 mmol) in CH2Cl2 (2 ml) was added to the mixture during
10 min. The mixture was stirred for 20 h at r.t. (TLC monitoring). After completion of the reaction, the
solvent was evaporated and the residue purified by column chromatography (silica gel 60 (70 – 230 mesh;
Merck), hexane/AcOEt 4 :1): product 4a.
6-(Cyclohexylamino)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxofuro[2,3-d]pyrimidine-5-carboxalde-
hyde (4a): Yield 0.259 g (85%). Pale yellow crystals. M.p. 197 – 1998. IR: 3320 (NꢀH), 1685 and 1577
(C¼O), 1048 (CꢀN). 1H-NMR: 1.27 – 2.03 (m, 10 H of cHex); 3.41 (s, MeN); 3.54 (s, MeN); 3.66 – 3.71
(br. m, CHꢀN); 7.88 (br. s, NH); 9.82 (s, CHO). 13C-NMR: 24.43, 25.12, 28.38 (5 C of cHex); 29.73, 33.38
(2 MeN); 52.14 (CHNH); 94.17 (C(4a)); 97.59 (C(5)); 148.11 (C(6)); 150.09 (C(7a)); 157.13, 159.16
(2 C¼O); 183.25 (CHO). EI-MS: 305 (23, Mþ), 223 (100), 166 (37), 138 (29), 83 (31), 55 (51). Anal.
calc. for C15H19N3O4 (305.33): C 59.01, H 6.27, N 13.76; found: C 58.9, H 6.3, N 13.7.
6-[(tert-Butyl)amino]-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxofuro[2,3-d]pyrimidine-5-carboxalde-
hyde (4b): Yield 0.223 g (80%). Orange solid. M.p. 135 – 1378. IR: 3323 (NꢀH), 2973 (CꢀH), 1681, 1575
1
(C¼O), 1038 (CꢀN). H-NMR: 1.46 (s, t-Bu); 3.36 (s, MeN); 3.52 (s, MeN); 8.12 (br. s, NH); 9.77 (s,
CHO). 13C-NMR: 28.07, 29.73 (2 MeN); 29.88 (Me3C); 53.84 (Me3C); 93.74 (C(4a)); 94.85 (C(5));
148.37 (C(6)); 150.01 (C(7a)); 157.67, 159.40 (2 C¼O); 183.17 (CHO). EI-MS: 279 (21, Mþ), 222 (100),
106 (61), 137 (70), 119 (19), 109 (29), 57 (60). Anal. calc. for C13H17N3O4 (279.29): C 55.91, H 6.14, N
15.05; found: C 56.1, H 6.2, N 15.1.
2-[(tert-Butyl)amino]-4,5,6,7-tetrahydro-6,6-dimethyl-4-oxobenzofuran-3-carboxaldehyde (4c):
Yield 0.195 g (74%). Orange oil. IR: 3300 (NꢀH), 2962 (CꢀH), 1650, 1575 (C¼O), 1014 (CꢀN).
1H-NMR: 1.45 (s, t-Bu); 2.37 (s, CH2); 2.67 (s, CH2); 8.17 (br. s, NH); 9.84 (s, CHO). 13C-NMR: 28.70,
28.53 (2 Me); 29.73 (Me3C); 35.44 (Me2C); 35.44, 36.73 (2 CH2); 53.12 (Me3C); 95.28, 99.10, 157.47,
162.94 (furan ring); 183.25 (CHO); 193.90 (C¼O). EI-MS: 263 (21, Mþ), 247 (31), 206 (100), 192 (17),
150 (37), 123 (37), 95 (20), 83 (24), 57 (98). Anal. calc. for C15H12NO3 (263.33): C 68.42, H 8.04, N 5.32;
found: C 68.4, H 8.1, N 5.2.
2-(Cyclohexylamino)-4,5,6,7-tetrahydro-6,6-dimethyl-4-oxobenzofuran-3-carboxaldehyde (4d):
Yield 0.260 g (90%). Orange solid. M.p. 126 – 1288. IR: 3247 (NꢀH), 2924 (CꢀH), 1656, 1588
(C¼O), 1077 (CꢀN). 1H-NMR: 1.20 – 1.93 (m, 10 H of cHex); 2.41 (s, CH2); 2.68 (s, CH2); 3.71 (br. s,
CHN); 7.8 (br. s, NH); 9.88 (s, CHO). 13C-NMR: 24.59, 25.23, 33.40 (5 C of cHex); 28.50, 28.67 (2 Me);
35.42 (Me2C); 35.45, 36.70 (2 CH2); 57.21 (CHNH); 93.01, 98.50, 157.51, 161.50 (furan ring); 183.72
(CHO); 196.50 (C¼O). EI-MS: 289 (24, Mþ), 207 (73), 12 (26), 151 (96), 122 (100), 95 (27), 83 (29), 55
(47). Anal. calc. for C17H23NO3 (289.37): C 70.56, H 8.01, N 4.84; found: C 70.6, H 7.9, N 4.8.
6-(Cyclohexylamino)-1,3-dimethyl-5-(4-nitrophenyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (4e):
Yield 0.310 g (78%). Orange solid. M.p. 108 – 1108. IR: 3300 (NꢀH), 1673 (C¼O), 1521, 1347 (NO2),
1110 (CꢀO). 1H-NMR: 1.24 – 1.78 (m, 10 H of cHex); 3.37 (s, MeN); 3.48 (s, MeN); 3.72 – 3.79 (br. m,
CHN); 6.32 (br. s, NH); 7.65 (d, 3J ¼ 8.7, 2 arom. H); 7.91 (d, 3J ¼ 8.7, 2 arom. H). 13C-NMR: 24.77, 25.32,
28.38 (5 C of cHex); 28.24, 29.52 (2 MeN); 57.19 (CHNH); 945.47 (C(4a)); 101.35 (C(5)); 123.47, 129.48,
138.10, 145.87 (arom. C); 148.64 (C(6)); 150.30 (C(7a)); 160.55, 162.02 (2 C¼O). EI-MS: 398 (10, Mþ),
304 (19), 277 (10), 151 (50), 126 (24), 83 (100), 55 (34). Anal. calc. for C20H22N4O5 (398.41): C 60.29, H
5.57, N 14.06; found: C 60.3, H 5.6, N 14.1.
2-(Cyclohexylamino)-6,7-dihydro-6,6-dimethyl-3-(4-nitrophenyl)benzofuran-4(5H)-one (4f): Yield
0.313 g (82%). Pale yellow oil. IR: 3400 (NꢀH), 1672, 1597 (C¼O), 1522, 1346 (NO2), 1108 (CꢀO).

Helvetica Chimica Acta – Vol. 93 (2010)
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1H-NMR (500 MHz): 1.13 – 1.75 (m, 10 H of cHex); 2.61 (s, CH2); 2.75 (s, CH2); 3.81 – 3.90 (br. m, CHN),
5.62 (d, 3J ¼ 8.1, NH); 7.60 (d, 3J ¼ 8.0, 2 arom. H); 8.25 (d, 3J ¼ 8.0, 2 arom. H). 13C-NMR: 24.71, 25.34,
32.64 (5 C of cHex); 27.45, 29.26 (2 Me); 31.48 (Me2C); 35.45, 36.75 (2 CH2); 56.06 (CHNH); 92.50,
98.15, 156.95, 160.50 (furan ring); 123.44, 132.36, 137.80, 146.10 (arom. C); 186.47 (CHO); 193.85
(C¼O). EI-MS: 382 (13, Mþ), 324 (12), 299 (24), 283 (45), 167 (30), 150 (46), 128 (31), 104 (19), 83
(100), 55 (67). Anal. calc. for C22H26N2O4 (382.45): C 69.09, H 6.85, N 7.32; found: C 69.1, H 6.8, N 7.4.
2-(Cyclohexylamino)-4,5,6,7-tetrahydro-4-oxobenzofuran-3-carboxaldehyde (4g): Yield 0.195 g
1
(75%). Yellow oil. IR: 3242 (NꢀH), 2930 (CꢀH), 1660, 1592 (C¼O). H-NMR (500 MHz): 1.09 –
2.05 (m, 10 H of cHex); 2.16 – 2.25 (m, CH2CH2CO); 2.43 – 2.51 (m, CH2C¼C); 2.78 (AB q,
CH2CH2CO); 3.69 – 3.77 (m, CHN), 7.82 (br. s, NH); 9.85 (s, CHO). 13C-NMR: 24.59, 25.23, 33.40
(5 C of cHex); 25.50, 35.45, 36.70 (3 CH2); 56.85 (CHNH); 93.58, 99.10, 157.25, 162.48 (furan ring);
183.41 (CHO); 193.68 (C¼O). EI-MS: 261 (16, Mþ), 178 (60), 163 (27), 150 (100), 121 (95), 98 (24), 83
(30). Anal. calc. for C15H19NO3 (261.32): C 68.94, H 7.33, N 5.36; found: C 68.9, H 7.3, N 5.4.
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Received January 22, 2010