InCl3-catalyzed three-component reaction: A novel synthesis of dihydropyrano[3,2-b]chromenediones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2010.08.044

Three-component coupling (3CC) of kojic acid, aldehyde and 1,3-dione has been achieved in the presence of 10 mol % InCl₃ under solvent-free conditions to afford the corresponding dihydropyrano[3,2-b]chromenedione derivatives in good yields. This is the first example of the condensation of kojic acid, aldehyde and 1,3-diones to provide a novel series of kojic acid derivatives.

Full text of DOI:10.1016/j.tetlet.2010.08.044

Tetrahedron Letters 51 (2010) 5677–5679
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
InCl3-catalyzed three-component reaction: a novel synthesis of
dihydropyrano[3,2-b]chromenediones under solvent-free conditions
⇑
B. V. Subba Reddy , M. Ramana Reddy, G. Narasimhulu, J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component coupling (3CC) of kojic acid, aldehyde and 1,3-dione has been achieved in the presence
of 10 mol % InCl3 under solvent-free conditions to afford the corresponding dihydropyrano[3,2-
b]chromenedione derivatives in good yields. This is the first example of the condensation of kojic acid,
aldehyde and 1,3-diones to provide a novel series of kojic acid derivatives.
Received 20 May 2010
Revised 9 August 2010
Accepted 13 August 2010
Available online 18 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Kojic acid
Indium trichloride
Aldehyde
1,3-Diones
Chromenedione
Multi-component, one-pot synthesis has received considerable
attention because of its wide range of applications in pharmaceuti-
cal chemistry for the creation of structural diversity and combinato-
rial libraries for drug discovery.1 MCRs are extremely convergent,
producing a remarkably high increase of molecular complexity in
just one step.2 The ready availability, potential biological activity
and high reactivity of kojic acid makes it an attractive molecule in
pharmaceutical chemistry.3,4 Consequently, a large number of kojic
acid derivatives have been prepared for biological evaluation.5,6
Recently, indium trichloride has evolved as a mild and water-toler-
ant Lewis acid imparting high regio-, chemo- and diastereoselectiv-
ity in various organic transformations.7 Compared to conventional
Lewis acids, indium trichloride in particular has advantages of low
catalyst loading, moisture stability and catalyst recycling. However,
to the best of our knowledge, there are no reports on three-compo-
nent coupling of aldehyde, kojic acid and 1,3-diketone to produce a
new class of kojic acid derivatives.
In continuation of our interest in exploring the synthetic utility of
indium(III) chloride,8 we herein disclose a novel three-component
reaction for the direct synthesis of dihydropyrano[3,2-b]chromen-
edione derivatives from kojic acid, 1,3-diones and aldehydes. We
initially attempted a three-component reaction of kojic acid (1),
dimedone (2) and benzaldehyde (3) in the presence of 10 mol %
InCl3. The reaction proceeded well under neat conditions at 120 °C
and the corresponding product, 2-(hydroxymethyl-7,7-dimethyl-
10-phenyl-7,8-di-hydroxypyrano[3,2-b]chromene-4,9-(6H,10H)-
dione 4a was obtained in 90% yield (Scheme 1).
This result provided the incentive for further study of the reac-
tion with various aldehydes and 1,3-dikeones. Interestingly, a vari-
ety of aldehydes including ortho-, meta-, and para-substituted aryl
aldehydes participated well in this reaction (Table 1). As seen from
Table 1, halo-substituted aromatic aldehydes gave comparatively
higher yields than methoxy and methyl-substituted aromatic alde-
hydes (Table 1, entries b–d, and j). Aliphatic aldehyde, for example,
n-propanaldehyde also participated in this reaction under similar
conditions (Table 1, entry l). Both cyclic and acyclic 1,3-diketones
worked well in this reaction. Interestingly, curcumin was also
effective for this three-component reaction (Table 1, entry h).
However, the reaction did not proceed with b-ketoesters such as
ethyl or methyl acetoacetate under similar conditions due to the
transesterification of b-ketoester with the primary hydroxyl group
of kojic acid.
Mechanistically, we suggest that the reaction proceeds through
a domino Knoevenagel-hetero Diels–Alder reaction to give a
tricyclic intermediate which on dehydration leads to the desired
product (Scheme 2).
O
O
CHO
O
O
O
3
10 mol% InCl3
120 ºC
HO
HO
+
OH
O
O
O
1
4a
2
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Scheme 1. Reaction between kojic acid, dimedone and benzaldehyde.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.044

5678
B.V.S. Reddy et al. / Tetrahedron Letters 51 (2010) 5677–5679
Table 1
Three-component reaction for the synthesis of dihydropyrano[3,2-b]chromenediones
Entry
Kojic acid
Diketone
Aldehyde
Producta
Time (min)
90
Yieldb (%)
90
O
O
CHO
Ar
O
O
O
O
O
O
O
O
HO
O
HO
HO
HO
HO
HO
HO
OH
OH
a
O
O
O
O
O
O
O
CHO
Ar
HO
b
c
d
e
f
95
90
95
80
80
85
85
95
85
95
95
95
O
O
O
OMe
CHO
O
O
O
O
Ar
HO
OH
OH
OH
OH
OH
OH
O
OPh
O
O
O
O
O
O
CHO
Ar
HO
O
O
O
O
O
O
O
CHO
Ar
HO
O
O
O
Cl
O
O
O
O
CHO
Ar
HO
O
O
O
F
CHO
O
O
O
O
Ar
HO
HO
HO
g
O
Cl
O
O
O
O
O
OMe
OH
CHO
Ar
O
HO
O
O
O
OH
OMe
h
120
65
O
OH
OMe
OH
OMe
O
O
CHO
CHO
Ar
O
O
O
O
HO
O
HO
HO
HO
HO
OH
OH
OH
OH
i
85
75
70
70
85
85
90
85
O
O
O
O
O
O
O
Ar
HO
j
O
O
O
O
OMe
CHO
O
O
O
Ar
HO
k
l
O
O
O
O
O
Cl
O
O
O
CHO
HO
O
O
O
a
All products were characterized by 1H NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
b
The effects of various indium(III) reagents such as InF3, InCl3,
ethanol and 1,2-dichloroethane were used. The best results were
obtained under solvent-free conditions. The scope and generality
of this process is illustrated with respect to various aldehydes
and 1,3-diones and the results are presented in Table 1.9
In summary, we have developed a novel method for the synthe-
sis of dihydropyrano[3,2-b]chromenedione derivatives by means of
a three-component reaction between kojic acid, aldehyde and 1,3-
dione using a catalytic amount of InCl3 under neat conditions. This
In(ClO4)3 and In(OTf)3 were tested. Of these, indium trichloride
was found to be an effective catalyst in terms of conversion.
Though, the reaction proceeds even with 10 mol % of p-TSA, the
products were obtained in low yields (30–40% over 6–8 h). Next,
we have studied the effect of the solvent for this conversion. The
reactions were sluggish and the corresponding products were ob-
tained in low yields when solvents such as toluene, acetonitrile,

B.V.S. Reddy et al. / Tetrahedron Letters 51 (2010) 5677–5679
5679
Shestopalov, A. A.; Rodinovskaya, L. A.; Shestopalov, A. M.; Litvinov, V. P. Russian
Chem. Bulletin. 2004, 53, 724.
O
O
O
O
H
7. (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149; (b) Babu, G.; Perumal, P. T.
Aldrichim. Acta 2000, 33, 16; (c) Ghosh, R. Indian J. Chem. 2001, 40B, 550.
8. (a) Yadav, J. S.; Sunny, A.; Reddy, B. V. S.; Sabitha, G. Tetrahedron Lett. 2001, 42,
8063; (b) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M. Synlett 2001, 1781; (c) Yadav,
J. S.; Reddy, B. V. S.; Sabitha, G.; Prabhakar, A.; Kunwar, A. C. Tetrahedron Lett.
2003, 44, 2221; (d) Yadav, J. S.; Reddy, B. V. S.; Reddy, Ch. S. Tetrahedron Lett.
2004, 45, 4583.
OH
InCl3
-H2O
O
HO
+
+
O
O
[4+2]
9. General procedure: A mixture of aldehyde (1 mmol), kojic acid (1.0 mmol), 1,3-
dicarbonyl compound (1.1 mmol) and InCl3 (10 mol %) was stirred at 120 °C for
a specified time (Table 1). After complete conversion, as indicated by TLC, the
reaction mixture was diluted with water and extracted with ethyl acetate
(2 Â 10 mL). The combined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo and purified by column chromatography on silica gel
(Merck, 60–120 mesh, ethyl acetate–hexane, 7:3) to afford the pure substituted
dihydropyrano[3,2-b]chromenedione. Compound 4a: Solid, mp 186–188 °C; IR
(KBr): mmax 3361, 3081, 2955, 2892, 1669, 1624, 1443, 1377, 1284, 1219, 1147,
O
O
O
O
O
O
OH
OH
-H2O
O
O
HO
1076, 991, 953, 712 cmÀ1
(m, 5H), 6.37 (s, 1H), 5.48–5.38 (br s, 1H), 4.82 (s, 1H), 4.20 (dd, J = 5.8, 11.7 Hz,
2H), 2.64 (d, J = 5.2 Hz, 2H), 2.20 (d, J = 6.0 Hz, 2H), 1.14 (s, 3H), 1.06 (s, 3H); 13
;
1H NMR (300 MHz, CDCl3 + DMSO-d6): d 7.33–7.16
Scheme 2. A plausible reaction mechanism.
C
NMR (75 MHz, DMSO-d6): d 195.4, 169.6, 168.3, 163.6, 150.9, 140.9, 136.5,
128.5, 127.8, 127.3, 111.4, 111.2, 59.0, 49.6, 37.7, 31.8, 28.2, 26.7; ESI-MS: m/z:
352 (M+). HRMS calcd for C21H20O5: 352.1388, found: 352.1399. Compound 4b:
method is simple and is convenient to prepare a wide range of kojic
acid derivatives in a single-step operation.
Solid, mp 180–182 °C; IR (KBr):
m
max 3361, 2955, 1670, 1628, 1512, 1445, 1376,
1261, 1219, 1183, 1075, 952, 824, 777 cmÀ1
;
1H NMR (300 MHz, CDCl3 + DMSO-
Acknowledgement
d6): d 7.14 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 5.57–5.48 (m,
1H), 4.75 (s, 1H), 4.29–4.11 (m, 2H), 3.74 (s, 3H), 2.63 (d, J = 3.4 Hz, 2H), 2.19 (d,
J = 10.0 Hz, 2H), 1.13 (s, 3H), 1.05 (s, 3H). 13C NMR (75 MHz, DMSO-d6): d 195.9,
170.2, 168.8, 163.9, 158.9, 151.7, 136.9, 133.5, 129.4, 114.4, 111.8, 59.6, 55.5,
50.2, 37.3, 32.3, 28.8, 27.2. ESI-MS: m/z: 382 (M+). HRMS calcd for C22H22O6:
382.1414, found: 382.1419. Compound 4f: Solid, mp 160–164 °C; IR (KBr): mmax
M.R.R., S.J. and G.N. thank the CSIR, New Delhi for the award of
fellowships.
3363, 2960, 2927, 1639, 1600, 1507, 1376, 1221, 1191, 1073, 955, 844 cmÀ1 1H
;
References and notes
NMR (500 MHz, CDCl3 + DMSO-d6): d 7.28–7.20 (m, 2H), 7.03–6.94 (m, 2H), 6.37
(s, 1H), 5.51–5.39 (br s, 1H), 4.29–4.12 (m, 2H), 2.64 (q, J = 17.8 Hz, 2H), 2.20 (q,
J = 16.7 Hz, 2H), 1.14 (s, 3H), 1.06 (s, 3H). 13C NMR (75 MHz, DMSO-d6): d 195.4,
169.6, 168.3, 163.6, 162.8, 159.6, 150.5, 136.5, 137.1, 137.0, 129.8, 129.7, 115.4,
115.1, 111.4, 111.1, 59.0, 49.6, 37.0, 31.8, 26.8. ESI-MS: m/z: 370 (M+). HRMS
calcd for C21H19O5F: 370.1214, found: 370.1208. Compound 4g: Solid, mp 198–
200 °C; IR (KBr): mmax 3282, 2954, 2871, 1668, 1633, 1595, 1443, 1376, 1221,
1. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123; (b) Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki,
R. J.; Steel, J. Tetrahedron 1995, 51, 8135; (c) Domling, A. Chem. Rev. 2006, 106,
17.
2. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley: Weinheim, 2005; (b)
Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660.
3. Zhu, M. P.; Kimiaki, I. Tetrahedron Lett. 1997, 38, 5301.
4. Xiong, X.; Pirrung, M. C. Org. Lett. 2008, 10, 1151.
5. (a) Sefkow, M.; Kaatz, H. Tetrahedron Lett. 1999, 40, 6561; (b) Barham, H. N.;
Reed, G. N. J. Am. Chem. Soc. 1938, 60, 1541.
1193, 1145, 1039, 952, 753 cmÀ1 1H NMR (500 MHz, CDCl3 + DMSO-d6): d 7.35
;
(d, J = 7.3 Hz, 1H), 7.24–7.15 (m, 3H), 6.38 (s, 1H), 5.36 (s, 1H), 4.30–4.12 (m, 2H),
2.66 (q, J = 17.8 Hz, 2H), 2.20 (q, J = 15.7 Hz, 2H), 1.14 (s, 3H), 1.10 (s, 3H); 13C
NMR (75 MHz, DMSO-d6): d 195.2, 169.5, 168.3, 164.2, 150.0, 138.1, 136.7,
132.7, 130.2, 129.5, 129.0, 127.5, 111.4, 110.6, 59.0, 49.6, 35.1, 31.7, 28.2, 26.8.
ESI-MS: m/z: 386 (M+). HRMS calcd for C21H19O5Cl: 386.0999, found: 386.1005.
6. (a) Kobayashi, Y.; Kayahara, H.; Tadasa, K.; Tanaka, H. Bioorg. Med. Chem. Lett.
1996, 6, 1303; (b) Fox, R. C.; Taylor, P. D. Synth. Commun. 1998, 28, 1575; (c)