One-pot three component reaction involving cyclohexyl isocyanide for the synthesis of furo[3,4-b]chromenes

Article abstract of DOI:10.3184/174751911X13015945166625

On stirring an equimolar mixture of 4-oxo-4H-chromene-3-carbaldehyde, ninhydrin and cyclohexyl isocyanide in CH₂Cl₂-MeOH (7:1) at room temperature produces 3-cyclohexylimino-1-(2-hydroxy-1,3-dioxo-2,3- dihydro-1H-inden-2-yl)-1,3-dihy

Full text of DOI:10.3184/174751911X13015945166625

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 225
APRIL, 225–228
One-pot three component reaction involving cyclohexyl isocyanide for
the synthesis of furo[3,4-b]chromenes
Suman Kalyan Panjaa, Sourav Maitia, Michael G. B. Drewb and
Chandrakanta Bandyopadhyaya*
aDepartment of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata -700 118, West Bengal, India
bDepartment of Chemistry, The University of Reading, P. O. Box 224, Whiteknights, Reading RG6 6AD, UK
On stirring an equimolar mixture of 4-oxo-4H-chromene-3-carbaldehyde, ninhydrin and cyclohexyl isocyanide in
CH2Cl2-MeOH (7:1) at room temperature produces 3-cyclohexylimino-1-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-
2-yl)-1,3-dihydro-9H-furo[3,4-b]chromen-9-one which on hydrolysis produces 1-(2-hydroxy-1,3-dioxo-2,3-dihydro-
1H-inden-2-yl)-1H-furo[3,4-b]chromene-3,9-dione. The structure of the latter compound was confirmed by single
crystal X-ray diffraction.
Keywords: 3-formylchromone, multicomponent reaction, isocyanide, furo[3,4-b]chromene, atom economy, chromene
Table 1 Crystal data of compound 4a and 12a
Although furo[2,3-b]chromones are well studied with respect
to synthesis and pharmaceutical activities,1 furo[3,4-b]
chromones are very scarce in the literature. This class of
compounds were synthesised (i) by acid-catalysed cyclisation
of α-keto-β-(o-hydroxybenzoyl)butyrolactone;2 (ii) by oxida-
tion of 3-benzoyl-2-benzylchromone with SeO2;3 (iii) by
photolysis of 3-aroyl-2-furylchromone,4,5 which are highly
substituent–dependent; (iv) by heating ethyl 3-bromo-/
acetoxy-methyl-4-oxo-chromene-2-carboxylate in a mixture
of glacial acetic acid and concentrated HCl;6 (v) by lithiation
of the acetal generated from 1, followed by trapping an alde-
hyde and subsequent cyclisation by unmasking the acetal;7 (vi)
by isocyanide-induced 3-component reaction using dibenzo-
ylacetylene and resorcinol8 and (vii) by condensation of ethyl
pentafluorobenzoylpyruvate with aromatic aldehyde in the
presence of piperidine or HCl.9 So, it is of interest to search for
easy route for the synthesis of furo[3,4-b]chromone moieties
in various forms.
Compound 4a
Compound 12a
Chemical formula
Formula weight
Crystal system
C30H27Cl2NO5
552.43
Triclinic
P-1
C21H12O7
376.31
Triclinic
P-1
Space group
Unit cell dimensions
a = 8.9449 (4) Å
a = 11.3453 (6) Å
b = 11.8775 (6) Å b = 12.7065 (9) Å
c = 13.9083 (8) Å c = 13.4497(8) Å
α = 112.523 (5)°
β = 101.640 (4)°
γ = 98.105 (4)°
1297.39 (12) Å 3
2
α = 114.756 (6)°
β = 106.315 (5)°
γ = 93.883 (5)°
1651.16 (18) Å 3
4
Unit cell volume
Formula number, Z
Density (calculated)
Crystal size max (mm)
Crystal size mid (mm)
Crystal size min (mm)
1.414 g cm−3
0.30
1.514 g cm−3
0.24
0.05
0.05
0.03
0.03
Absorption coefficient/µ 0.293
0.115
In connection to our earlier report on the isocyanide-induced
reaction on 4-oxo-4H-chromene-3-carbaldehyde (1),10 there
was a misinterpretation in assigning a structure on the basis
of 1H NMR, 13C NMR and mass spectral analysis. During the
preparation of this manuscript, a report11 on the same reaction
predicted the actual structure without mentioning the previous
report.10 The product from the reaction of 1 and cyclohexyl
isocyanide (2) was reported earlier to be pyrano[3,4-b]
chromones 3.10 But from the single crystal X-ray diffraction
(Table 1), it is confirmed to be furo[3,4-b]chromone 4
(Scheme 1). Structures 3 and 4 having the same molecular for-
mula could not be distinguished on the basis of NMR or mass
F(000)
Data collection in a θ
range
Diffraction refelection
range
576
2.68–30.00°
776
2.83–30.00°
–12<h>=12
–15<h>=11
–14<k>=16
–19<l>=11
–17<k>=17
–18<l>=18
Diffraction reflection
unique:
Reflections collected/
unique
7336/4796
[Rint = 0.0164]
0.925
9214/5350
[Rint = 0.0216]
0.853
Goodness of fit on F2
Reflection threshold
I>2σ(I)
I>2σ(I)
R1 = 0.0436,
wR2 = 0.1022
R1 = 0.0466,
wR2 = 0.0919
1
spectral analysis. From the H NMR spectra, presence of
(R indices defined as R1)
two chromonyl moieties and one N-cyclohexyl moiety were
discernible. A singlet at around δ7.1–7.2 may be assigned to H
at C-1 in 3 or to exocyclic vinyl H in 4. Compound 4a was
crystallised from CH2Cl2 and X-ray crystallography shows the
presence of one solvent molecule in the crystal (Fig. 1).
for 11 protons from cyclohexyl unit and 7 aromatic protons.
IR spectrum of 6a showed signals at 3246 (O-H), 1716 (C=O),
1647 (C=O) cm−1. 13C NMR showed 27 signals having no iso-
chronous carbon atom. The mass spectral data 458 (M+H)+
and 480 (M+Na)+ corroborate the structure. Compound 6b and
6c were also prepared in moderate yields (40–50%) from 1b
and 1c respectively. Many attempts were made to improve the
yield of 6 by changing the solvent. It was observed that a
mixture of dichloromethane and methanol (7:1) gave a better
yield (60–70%).
Formation of 6 may be rationalised as follows: isocyanide
prefers 1,4-addition over 1,2-addition on α, β-unsaturated
carbonyl compounds.12–14 Isocyanide 2 attacks C-2 position
of chromone moiety in 1 to form 7, which intramolecularly
cyclises to 8. It then tautomerises to chromone-fused 2-
aminofuran 9 (Scheme 2). In absence of any other carbonyl
The above reaction involves two molecules of 1 and one
molecule of 2. In order to increase the versatility of this reac-
tion, one molecule of 3-formyl-4-chromone was replaced by
such a carbonyl compound which possesses higher carbonyl
group reactivity than that of 1. On stirring an equimolar
mixture of 1a, ninhydrin (5) and 2 in methanol at room tem-
perature for 12 h, a white precipitate appeared which was
collected by filtration. The structure of the compound was
1
established to be 6a on the basis of IR, H NMR, 13C NMR,
mass spectra and elemental analysis. 1H NMR spectrum
showed three singlets at δ 2.53, 5.85 and 7.32 of which the last
signal was exchangeable with D2O. It also contains signals
* Correspondent. E-mail: kantachandra@rediffmail.com

226 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1
a Perkin Elmer 240C elemental analyser. Light petroleum refers to the
fraction with distillation range 60–80 °C.
Good quality single crystals of 4a and 12a were obtained from slow
evaporation of solvent (CH2Cl2) at room temperature and they were
used for structural analysis. X-ray data were measured with Mo-Kα
radiation at 150 K using the Oxford Diffraction X-Calibur CCD
System. Data analysis was carried out with the Crysalis program15 and
the structures were solved with the SHELXS-97 program.16 For both
the structures the non-hydrogen atoms were refined with anisotropic
thermal parameters. The hydrogen atoms bonded to carbon and
oxygen were included in geometric positions and given thermal
parameters equivalent to 1.2 times those of the atoms to which they
were attached. Absorption corrections were carried out with the
ABSPACK program.17 The structures were refined on F2 using
the SHELXL-97 program.16 Crystallographic data are collected in
Table 1. CCDC 809699 (for compound 12a) and CCDC 809700 (for
compound 4a) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
Fax: +44 1223 336 033; E-mail: deposit@ccdc.cam.ac.uk).
Fig. 1 ORTEP diagram of 4a with thermal ellipsoids drawn at
Synthesis of 3-cyclohexylimino-1-(2-hydroxy-1,3-dioxo-2,3-dihydro-
1H-inden-2-yl)-1,3-dihydro-9H-furo[3,4-b]chromen-9-ones (6a–c)
Aldehyde 1 (1 mmol) and 5 (1 mmol) were dissolved in a mixture of
dichloromethane (7 mL) and methanol (1 mL). To the resultant mix-
ture, 2 (1 mmol) was added and stirred at room temperature for 12 h.
The reaction mixture on concentration produced 6, which was
crystallised from chloroform-light petroleum (70:30) to afford white
crystalline solids 6a–c.
6a: Yield (285 mg, 62%); m.p. 208–210 °C; IR: νmax 3246,
2930, 1716, 1647 cm−1; 1H NMR: δ(CDCl3) 0.45–0.48 (1H, m,
cyclohexyl-H), 0.73–0.94 (2H, m, cyclohexyl-H), 1.00–1.17 (3H, m,
cyclohexyl-H), 1.23–1.31 (2H, m, cyclohexyl-H), 1.47–1.50 (1H, m,
cyclohexyl-H), 1.55–1.73 (1H, m, cyclohexyl-H), 2.53 (3H, s, CH3),
3.05 (1H, quintet, J = 6.7 Hz, N–CH), 5.85 (1H, s, 1-H), 7.32 (1H, s,
exchangeable, OH), 7.60-7.66 (2H, m, ArH), 7.84-7.87 (2H, m, ArH),
7.89-7.96 (1H, m, ArH), 8.12 (1H, br.d, J = 7.5 Hz, ArH), 8.16 (1H,
br.s, 8-H); 13C NMR: δ 20.9, 24.4, 24.7, 25.2, 31.9, 33.3, 56.6, 76.3,
81.1, 118.8, 123.2, 123.3, 123.7, 125.1, 125.7, 136.3, 136.6, 136.9,
137.0, 140.9, 141.7, 148.6, 153.8, 155.2, 176.1, 196.5, 198.0; MS
(Positive ion electrospray): m/z 458 [M + H]+, 480 [M + Na]+. Anal
Calcd for C27H23NO6: C, 70.89; H, 5.07; N, 3.06. Found: C, 71.10;
H, 4.98; N, 3.00%.
50% probability level.
compound, intermediate 9 attacks a second molecule of
aldehyde 1 to form 10 and finally dehydrates to 4. But in the
presence of 5, which contributes a more reactive carbonyl
function than that of 1, 9 reacts with 5 to form 6.
Unlike the previous report10 for the formation of 4 from 1
and 2, in this case no dehydration takes place on 6 although a
3°-alcohol function is present. On heating 6 with conc. H2SO4
or with KHSO4, the reaction mixture failed to produce the
dehydrated product. Mode of reactions of 4 and 6 also differ
when treated with HCl in methanol. Compound 4 underwent
a rearrangement10 to produce a lactam 11, whereas 6 under
similar condition produced the hydrolysed product lactone 12
(Scheme 3). The structure of 12 was established on the basis of
IR, 1H NMR, 13C NMR and mass spectral analysis. Finally the
structure was confirmed by single crystal X-ray diffraction
(Table 1 and Fig. 2).
6b: Yield (310 mg, 70%); m.p. 198–200 °C; IR: νmax 3300, 2940,
1720, 1650 cm−1; 1H NMR: δ(CDCl3) 0.46–0.50 (1H, m, cyclohexyl-
H), 0.73–0.90 (2H, m, cyclohexyl-H), 1.00–1.17 (2H, m, cyclohexyl-
H), 1.23–1.36 (3H, m, cyclohexyl-H), 1.47–1.51 (1H, m, cyclohexyl-
H), 1.55–1.74 (1H, m, cyclohexyl-H), 3.06 (1H, quintet, J = 6.9 Hz,
N–CH), 5.86 (1H, s, 1-H), 7.23 (1H, s, exchangeable, OH), 7.58
(1H, br.t, J = 7.5 Hz, ArH), 7.73 (1H, br.d, J = 8.4 Hz, 5-H), 7.80–7.86
(3H, m, ArH), 7.89–7.96 (1H, m, ArH), 8.13 (1H, br.d, J = 7.5 Hz,
ArH), 8.38 (1H, br.d, J = 7.8 Hz, 8-H). Anal Calcd for C26H21NO6:
C, 70.42; H, 4.77; N, 3.16. Found: C, 70.11; H, 4.58; N, 3.01%.
In conclusion, we have developed an isocyanide-induced
three component reaction with 100% atom economy involving
3-formyl-4-chromone and ninhydrin to produce hitherto
unreported chromones fused with iminolactones.
Experimental
IR spectra were recorded in KBr on a Beckman IR 20A instrument, 1H
NMR spectra in CDCl3 on a Bruker 300 MHz spectrometer, mass
spectra on a Qtof MicroYA 263 instrument and elemental analysis on

JOURNAL OF CHEMICAL RESEARCH 2011 227
Scheme 2
Scheme 3
6c: Yield (285 mg, 60%); m.p. 212–214 °C; IR: νmax 3250, 2980,
1710, 1640 cm−1; 1H NMR: δ(CDCl3) 0.46–0.49 (1H, m, cyclohexyl-
H), 0.69–0.90 (2H, m, cyclohexyl-H), 1.00–1.17 (2H, m, cyclohexyl-
H), 1.22–1.36 (3H, m, cyclohexyl-H), 1.47–1.51 (1H, m, cyclohexyl-
H), 1.55–1.72 (1H, m, cyclohexyl-H), 3.06 (1H, quintet, J = 6.6 Hz,
N–CH), 5.86 (1H, s, 1-H), 6.97 (1H, s, exchangeable, OH), 7.69 (1H,
d, J = 9.0 Hz, 5-H), 7.77 (1H, dd, J = 9.0, 2.1 Hz, 6-H), 7.83–7.91
(2H, m, ArH), 7.93–7.98 (1H, m, ArH), 8.13 (1H, br.d, J = 7.5 Hz,
ArH), 8.34 (1H, br.d, J = 2.1 Hz, 8-H). Anal Calcd for C26H20NClO6:
C, 65.35; H, 4.22; N, 2.93. Found: C, 65.11; H, 4.06; N, 3.02%.
concentrate to afford a white solid, which was filtered, washed with
water, dried in air and crystallised from chloroform-light petroleum
to afford 1-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-1H-
furo[3,4-b]chromene-3,9-dione 12.
12a: Yield (225 mg, 60%); m.p. 262–264 °C; IR: νmax 3250, 2950,
1
1730, 1710, 1650 cm−1; H NMR: δ(CDCl3) 2.56 (3H, s, CH3), 5.93
(1H, s, 1-H), 7.22 (1H, s, exchangeable, OH), 7.63 (1H, d, J = 8.4 Hz,
5-H), 7.73 (1H, br.d, J = 8.4 Hz, 6-H), 7.88–7.98 (3H, m, ArH),
8.13 (1H, br.d, J = 7.5 Hz, ArH), 8.20 (1H, br.s, 8-H); 13C NMR:
δ 21.1, 74.2, 78.1, 118.9, 123.3, 123.9, 124.4, 126.0, 131.2, 136.9,
137.2, 137.8, 137.9, 140.6, 141.4, 148.9, 155.1, 161.7, 176.1, 195.0,
197.3; MS (Positive ion electrospray): m/z 377 [M + H]+, 399 [M +
Na]+. Anal Calcd for C21H12O7: C, 67.03; H, 3.21. Found: C, 66.92;
H, 3.11%.
Hydrolysis of iminolactone 6
Iminolactone 6 (1 mmol) was dissolved in methanol (10 mL) and
concentrated HCl (two drops) was added. The resultant mixture was
heated under reflux for 1 h. Solvent was removed from the reaction
mixture under reduced pressure. Ice water (10 g) was added to the
12b: Yield (200 mg, 55%); m.p. 234–236 °C; IR: νmax 3290, 2960,
1
1735, 1710, 1660 cm−1; H NMR: δ(CDCl3) 5.95 (1H, s, 1-H), 7.15

228 JOURNAL OF CHEMICAL RESEARCH 2011
for spectral analysis, Dr T. Ghosh for helpful discussion and
finally the college authority for providing research facilities.
Received 29 January 2011; accepted 23 March 2011
Paper 1100555 doi: 10.3184/174751911X13015945166625
Published online: 3 May 2011
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Fig. 2 ORTEP diagram of 12a with thermal ellipsoids drawn at
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8
9
(1H, s, exchangeable, OH), 7.68 (1H, br.dd, J = 7.8, 7.5 Hz, 7-H), 7.74
(1H, br.d, J = 8.4 Hz, 5-H), 7.86-7.99 (4H, m, ArH), 8.13 (1H, br.d,
J = 7.2 Hz, ArH), 8.42 (1H, br.d, J = 7.8 Hz, 8-H). Anal Calcd for
C20H10O7: C, 66.31; H, 2.78. Found: C, 66.40; H, 2.69%.
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12c: Yield (235 mg, 58%); m.p. 240–242 °C; IR: νmax 3250, 2970,
1
1730, 1705, 1655 cm−1; H NMR: δ(CDCl3) 5.94 (1H, s, 1-H), 6.87
(1H, s, exchangeable, OH), 7.70 (1H, d, J = 9.0 Hz, 5-H), 7.84–7.91
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17 ABSPACK Program, Oxford Diffraction Ltd., 2005.

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