Synthesis of furan annulated heterocycles via a one-pot three-component reaction

Article abstract of DOI:10.3184/030823409X12510192920315

Three-component reaction between 4-hydroxycoumarin, or 5,5-dimethyl-1,3- cyclohexandione, arylglyoxals, and alkyl isocyanides in acetonitrile afforded furocoumarin or benzofuran derivatives in high yields.

Full text of DOI:10.3184/030823409X12510192920315

JOURNAL OF CHEMICAL RESEARCH 2009
OCTOBER, 599–601
RESEARCH PAPER 599
Synthesis of furan annulated heterocycles via a one-pot
three-component reaction
Mohammad Hossein Mosslemin, Mohammad Anary-Abbasinejad*, Abbas Fazli Nia,
Samaneh Bakhtiari and Hossein Anaraki-Ardakani
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
Three-component reaction between 4-hydroxycoumarin, or 5,5-dimethyl-1,3-cyclohexandione, arylglyoxals, and
alkyl isocyanides in acetonitrile afforded furocoumarin or benzofuran derivatives in high yields.
Keywords: isocyanide, furocoumarin, multi-component reaction, arylglyoxals, 4-hydroxycoumarin
Furocoumarins and benzofurans are an important class of
heterocyclic compounds possessing anticoagulant, insecticide,
anthelminthic, hypnotic, antifungal, and HIV protease
inhibition activity.1-5 They are inherently photosensitive and
found to have therapeutic uses. The photochemotherapeutic
effect relies on their ability to intercalate with the pyrimidine
bases of microorganism DNA.6 Although there are several
methods available for the synthesis of furocoumarins7-10
their application has been limited by difficulties in
controlling the regiochemistry of the linear and angular
adduct.7,8 Some multi-step reactions9,10 have been utilised
for the synthesis of furocumarin derivatives. These methods
usually suffer from drawbacks such as long reaction
times, high temperature and harsh reaction conditions,
which cause decreasing of regiochemistry of the reaction.
Multi-component reactions (MCRs), because of their
productivity, simple procedures, convergence, and facile
execution, are one of the best tools in combinatorial
chemistry.11 A three-component reaction between 4-hydroxy-
coumarin, aromatic aldehydes, and cyclohexyl isocyanide in
benzene under reflux conditions has been recently reported for
the synthesis of furocoumarin derivatives.12 Continuing our
interest in isocyanide-based multicomponent reactions13-16
here we describe an efficient synthesis of 2-alkylamino-3-
(aryl)-furo[3,2-c]chromen-4-ones or 3-(aryl)-2-alkylamino-
6,6-dimethyl-6,7-dihydro-5H-benzofuran-4-one
4 via the
one-pot reaction of 4-hydroxycoumarin or, 5,5-dimethyl-1,3-
cyclohexandione (1) with an arylglyoxal 2 and an isocyanide
3 in high yields without using any catalyst (Scheme 1).
Ar
O
O
z
O
O
H
R
CH3CN
X
Y
H
X
Y
N+
C
+
+
Ar
R
N
O
z
OH
O
1
2
3
4
4
Y-Z
X
O
Ar
R
Yielda/%
91
a
4-NO2C6H4
Cy
b
c
O
O
O
O
C6H5
4-BrC6H4
C6H5
Cy
t-Bu
t-Bu
Cy
89
90
88
89
d
e
4-BrC6H4
f
O
C
C
C
4-NO2C6H4
4-CIC6H4
4-BrC6H4
4-CIC6H4
t-Bu
Cy
92
90
89
91
H3C
H3C
g
h
i
H3C
H3C
t-Bu
t-Bu
H3C
H3C
aIsolated yields.
Scheme 1 Three-component reaction between 4-hydroxycoumarin or 5,5-dimethyl-1,3-cyclohexandione, arylglyoxals and isocyanides.
* Correspondent. E-mail: mohammadanary@yahoo.com

600 JOURNAL OF CHEMICAL RESEARCH 2009
General procedure
solution of 4-hydroxycoumarin or 5,5-dimethyl-1,3-cyclo-
hexandione (1 mmol), arylglyoxal (1 mmol) and alkyl isocyanide
(1 mmol) in acetonitrile (10 mL) was refluxed for 5 h. The solvent
was removed under reduced pressure, and the residue was separated
by column chromatography (silica gel, hexane–EtOAc, 5:1) to afford
the pure title compounds.
The structures of compounds 4a-i were deduced from their
elemental analyses and their IR, 1H NMR, 13C NMR spectra.
The mass spectra of these compounds displayed molecular ion
A
1
peaks at the appropriate m/z values. The H NMR spectrum
of 4a consisted of multiplet signals for the cyclohexyl ring
(d = 1.25–2.18 ppm) and a multiplet for N–CH of cyclohexyl
ring (d = 3.98 ppm). Aromatic protons resonated at d = 7.26–
8.29 ppm and a fairly broad doublet (d = 8.89 ppm,
3JHH = 8.2 Hz) was observed for the NH proton. The presence
of an amine proton is confirmed by exchange with D2O
indicating an exchangeable proton. The 1H-decoupled 13C
NMR spectrum of 4a showed 20 distinct resonances, partial
assignment of these resonances is given in the Experimental
section. The IR spectrum of compound 4a exhibited an
absorption band at 3245 cm-1 for NH group and strong broad
absorptions about 1739 and 1644 cm-1 for carbonyl groups.
A reasonable mechanism for the formation of compounds
4 is presented in Scheme 2. The first step may involve adduct
formation by Knoevenagel condensation of 4-hydroxy-
2-Cyclohexylamino-3-(4-nitro-benzoyl)-furo[3,2-c]chromen-4-
one (4a): Yellow crystals, (0.39 g, 91%). M.p. 208–210°C. IR (KBr)
(nmax, cm-1): 3245 (N–H), 1739, 1644 (C=O). MS (m/z,%): 432 (M+,
10). Anal. Calcd for C24H20N2O6 (432) C, 66.66; H, 4.66; N, 6.48.
Found: C, 66.54; H, 4.62; N, 6.37%. 1H NMR (300.1 MHz, CDCl3):
d = 1.25–2.18 (10 H, m, 5 CH2), 3.98 (1 H, m, N–CH), 7.26–8.29
3
(8 H, m, arom), 8.89 (1 H, d, JHH = 8.2 Hz, NH…O=C), ppm. 13C
NMR (75.46 MHz, CDCl3): d = 23.32, 24.13 and 32.12 (5 CH2),
50.99 (N–CH), 92.48, 107.01, 110.60, 115.83, 119.14, 121.83, 123.57,
128.06, 129.85, 145.10, 147.92, 148.63, 150.76 and 155.13 (arom. and
2 C=C), 163.92, 186.11(C=O) ppm.
3-Benzoyl-2-cyclohexylamino-furo[3,2-c]chromen-4-one
(4b):
Yellowcrystals,(0.34g,89%).M.p.165–167°C.IR(KBr)(nmax,cm-1):
3270 (N–H), 1676, 1604 (C=O). MS (m/z,%): 387 (M+, 5). Anal.
Calcd for C24H21NO4 (387) C, 74.40; H, 5.46; N, 3.62. Found: C,
74.32; H, 5.40; N, 3.51%. 1H NMR (300.1 MHz, CDCl3): d = 1.25–
2.16 (10 H, m, 5 CH2), 3.93 (1 H, m, N–CH), 7.25–7.80 (9 H, m,
coumarin
or
5,5-dimethyl-1,3-cyclohexandione
with
arylglyoxal to give the intermediate 5. The next step of this
mechanism could involve the [4 + 1] cycloaddition reaction
of the electron-deficient heterodiene moiety of adduct 5 with
the isocyanide to afford an iminolactone intermediate 6 which
then undergoes a [1, 3]-H shift to yield the furocoumarin or
benzofuran as the end product.
In summary, we report a simple and efficient one-pot
synthesis of 2-alkylamino-3-(aryl)-furo[3,2-c]chromen-4-
one or 3-(aryl)-2-alkylamino-6,6-dimethyl-6,7-dihydro-5H-
benzofuran-4-one derivatives by three-component reaction
between 4-hydroxycoumarin or 5,5-dimethyl-1,3-cyclo-
hexandione, arylglyoxals, and alkyl isocyanides. The
advantage of this method is that the reaction is carried
out under neutral conditions and simply available starting
materials are used without any purification or modification.
3
arom), 8.71 (1 H, d, JHH = 8.2 Hz, NH…O=C), ppm. 13C NMR
(75.46 MHz, CDCl3): d = 24.45, 25.32 and 33.30 (5 CH2), 51.86
(N-CH), 93.42, 108.91, 111.92, 116.80, 120.03, 124.36, 127.62,
128.56, 129.63, 131.36, 140.58, 149.13, 151.79 and 156.11 (arom.
and 2 C=C), 164.74, 189.62 (C=O) ppm.
3-(4-Bromo-benzoyl)-2-tert-butylamino-furo[3,2-c]chromen-4-
one (4c): Red crystals, (0.39 g, 90%). M.p. 145–146°C. IR (KBr)
(nmax, cm-1): 3420 (N–H), 1742, 1640 (C=O). MS (m/z,%): 439 (M+,
11). Anal. Calcd for C22H18BrNO4 (439) C, 60.01; H, 4.12; N, 3.18.
Found: C, 60.22; H, 4.11; N, 3.12%. 1H NMR (300.1 MHz, CDCl3):
d = 1.61 (9 H, s, CMe3), 7.33–7.78 (8 H, m, arom), 9.03 (1 H, br,
NH…O=C), ppm. 13C NMR (75.46 MHz, CDCl3): d = 30.22 (CMe3),
53.87 (CMe3), 93.92, 108.91, 111.86, 116.91, 124.51, 125.92, 129.92,
130.13, 130.85, 132.55, 139.26, 149.68, 151.76 and 156.31 (arom.
and 2 C=C), 165.12, 188.32 (C=O) ppm.
3-Benzoyl-2-tert-butylamino-furo[3,2-c]chromen-4-one(4d):Yellow
oil, (0.31 g, 88%). IR (KBr) (nmax, cm-1): 3315 (N–H), 1688, 1618
(C=O). MS (m/z,%): 361 (M+, 6). Anal. Calcd for C22H19NO4 (361)
C, 73.12; H, 5.30; N, 3.88. Found: C, 73.08; H, 5.36; N, 3.82%.
1H NMR (300.1 MHz, CDCl3): d = 1.62 (9 H, s, CMe3), 7.26–7.66
(9 H, m, arom), 9.06 (1 H, br, NH…O=C), ppm. 13C NMR (75.46
MHz, CDCl3): d = 29.83 (CMe3), 53.76 (CMe3), 94.83, 111.92,
116.83, 119.92, 124.45, 127.64, 128.43, 128.82, 129.66, 133.46,
135.20, 140.42, 149.86, 151.72 and 156.11 (arom. and 2 C=C),
165.08, 189.86 (C=O) ppm.
3-(4-Bromo-benzoyl)-2-cyclohexylamino-furo[3,2-c]chromen-4-
one (4e): Yellow crystals, (0.41 g, 89%). M.p. 120–122°C. IR (KBr)
(nmax, cm-1): 3485 (N–H), 1739, 1642 (C=O). MS (m/z,%): 465 (M+, 9).
Anal. Calcd for C24H20BrNO4 (465) C, 61.81; H, 4.32; N, 3.00.
Found: C, 61.78; H, 4.35; N, 3.09%.1H NMR (300.1 MHz, CDCl3):
Experimental
Melting points were determined with an electrothermal 9100
apparatus. Elemental analyses were performed at analytical laboratory
of Islamic Azad University, Yazd branch using a Costech ECS 4010
CHNS-O analyser. Mass spectra were recorded on a FINNIGAN-
MAT 8430 mass spectrometer operating at an ionisation potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer.
1H and 13C NMR spectra were recorded on Bruker DRX-300 Avance
spectrometer at solution in CDCl3 using TMS as internal standard.
The chemicals used in this work purchased from Fluka (Buchs,
Switzerland) were used without further purification.
O
O Ar
O
O
H
R
N+
C
- H2O
X
z
X
+
OH
Ar
Y
[4+1] Cycloaddition
Y
z
H
O
O
O
1
2
5
Ar
O
X
[1,3]-H Shift
H
4
Y
z
N
O
R
6
Scheme 2 Suggested mechanism for formation of compounds 4a–i.

JOURNAL OF CHEMICAL RESEARCH 2009 601
d = 1.26–2.17 (10 H, m, 5 CH2), 3.95 (1 H, m, N–CH), 7.26–7.80
102°C. IR (KBr) (nmax, cm-1): 3345 (N–H), 1680, 1633 (C=O).
MS (m/z,%): 373 (M+, 6). Anal. Calcd for C21H24ClNO3 (373) C,
67.46; H, 6.47; N, 3.75. Found: C, 67.42; H, 6.31; N, 3.71%. 1H NMR
(300.1 MHz, CDCl3) d = 1.14 (6 H, s, 2CH3), 1.49 (9 H, s, CMe3),
2.31 (2H, s, CH2), 2.73 (2H, s, CH2), 7.27–7.47 (4 H, m, arom), 8.79
(1 H, br, NH…O=C), ppm. 13C NMR (75.46 MHz, CDCl3): d = 27.36
(2CH3), 28.77 (CMe3), 34.06, 36.07 (2CH2), 51.70 (C(CH3)2), 51.98
(CMe3), 92.75, 116.55, 126.65, 128.52, 135.42, 138.72, 156.92 and
163.63 (arom. and 2 C=C), 187.07, 190.62 (C=O) ppm.
3
(8 H, m, arom), 8.73 (1 H, d, JHH = 8.2 Hz, NH…O=C), ppm. 13C
NMR (75.46 MHz, CDCl3): d = 24.68, 25.24 and 33.21 (5 CH2), 51.86
(N–CH), 93.11, 108.54, 111.74, 116.70, 120.06, 124.42, 125.85,
129.71, 130.12, 130.70, 139.21, 149.22, 151.67 and 156.12 (arom.
and 2 C=C), 164.85, 188.16(C=O) ppm.
2-t-Butylamino-3-(4-nitro-benzoyl)-furo[3,2-c]chromen-4-one
(4f): Yellow crystals, (0.37 g, 92%). M.p. 150–151°C. IR (KBr)
(nmax, cm-1): 3325 (N–H), 1680, 1623 (C=O). MS (m/z,%): 406 (M+,
6). Anal. Calcd for C22H18N2O6 (406) C, 65.02; H, 4.46; N, 6.89.
Found: C, 65.11; H, 4.39; N, 6.85%. 1H NMR (300.1 MHz, CDCl3):
d = 1.64 (9 H, s, CMe3), 7.26–8.37 (9 H, m, arom), 9.19 (1 H, br,
NH…O=C), ppm. 13C NMR (75.46 MHz, CDCl3): d = 30.34 (CMe3),
54.14 (CMe3), 94.11, 111.76, 117.05, 120.08, 123.03, 124.62, 128.82,
129.06, 130.22, 138.93, 146.28, 149.06, 150.07 and 151.83 (arom.
and 2 C=C), 165.32, 187.33 (C=O) ppm.
Received 13 July 2009; accepted 15 August 2009
Paper 09/0682 doi: 10.3184/030823409X12510192920315
Published online: 8 October 2009
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3-(4-Chloro-benzoyl)-2-cyclohexylamino-6,6-dimethyl-6,7-dihydro-
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93°C. IR (KBr) (nmax, cm-1): 3275 (N–H), 1724, 1678 (C=O).
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H, 5.78; N, 3.35. Found: C, 60.41; H, 5.61; N, 3.33%. 1H NMR
(300.1 MHz, CDCl3): d = 1.14 (6 H, s, 2CH3), 1.48 (9 H, s, CMe3),
2.30 (2H, s, CH2), 2.73 (2H, s, CH2), 7.26–7.49 (4 H, m, arom), 8.80
(1 H, br, NH…O=C), ppm. 13C NMR (75.46 MHz, CDCl3): d = 27.44
(2CH3), 28.76 (CMe3), 34.05, 36.04 (2CH2), 51.67 (C(CH3)2), 51.99
(CMe3), 92.73, 116.53, 124.45, 128.74, 129.52, 139.1, 156.94, and
163.65 (arom. and 2 C=C), 187.12, 190.75 (C=O) ppm.
9
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