An efficient route for commercially viable syntheses of furan- and thiophene-anellated β-hydroxychalcones

Article abstract of DOI:10.1016/j.tetlet.2005.06.111

An efficient route for the syntheses of β-hydroxychalcones containing benzofuran and benzothiophene rings is described. Isoxazolines obtained from oxime-olefin cycloadditions were reduced under pressure to a mixture of products. Isoxazoles obtained from C

Full text of DOI:10.1016/j.tetlet.2005.06.111

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5621–5624
An efficient route for commercially viable syntheses of furan-
and thiophene-anellated b-hydroxychalcones I
Prem P. Yadav, Ghufran Ahmad and Rakesh Maurya*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 22 March 2005; revised 16 June 2005; accepted 21 June 2005
Available online 7 July 2005
Abstract—An efficient route for the syntheses of b-hydroxychalcones containing benzofuran and benzothiophene rings is described.
Isoxazolines obtained from oxime–olefin cycloadditions were reduced under pressure to a mixture of products. Isoxazoles obtained
from Claisen aroylation of an ester and subsequent acid cyclization, or from isoxazolines via DDQ-mediated dehydrogenation, were
subjected to catalytic hydrogenation followed by hydrolysis to afford 1-phenyl-3-(benzofuran-5-yl)-1,3-diketone and 1-phenyl-3-
(benzothiophene-5-yl)-1,3-diketones in very good yields.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
their antimicrobial activities.7 We now describe an easy
and efficient approach towards commercially viable syn-
theses of b-hydroxychalcones from isoxazolines and
isoxazoles as masked 1,3-bifunctional compounds.8,9
The development of new methods for the syntheses of
heterocycles is important in organic chemistry. Synthetic
interest in pongamol and its derivatives has increased
due to its antimicrobial,1 quinone reductase,2 soothex
and questice3 activities. It is used commercially in
cosmetic and sun-screen preparations for protection
from UV radiation.4 The active ingredients are usually
obtained from natural sources.3–5 Despite their simple
structural framework they have not been prepared com-
mercially in efficient quantities. As a part of our ongoing
interest in the study of furanoflavonoids6 and their het-
erocyclic analogues, we have previously reported synthe-
ses of nitrogen and sulfur heterocyclic analogues and
2. Results and discussion
A common procedure for the syntheses of furan-anel-
lated b-hydroxychalcones is via condensation of the
karanjic acid ester with the enolate of acetophenone10,11
but the maximum overall yield of the product obtained
was 41%.11 Competing Claisen and aldol condensation
lead to undesired products in these reactions which re-
strict these methods for commercial use. We have tried
these methods but results were inconsistent with the lit-
erature reports and we obtained only poor yields of the
final compounds.7 We now report the use of isoxazolines
derived from oxime–olefin cycloaddition reactions and
their hydrogenolysis to afford b-hydroxyketones which
can be oxidized easily to the b-hydroxychalcones with
mild oxidizing agents (Scheme 1, route 1).
O
OCH3
O
OH
Pongamol
Key ester 1 was obtained from methylation of karanjic
acid (a degradation product of karanjin)12 and also via
a three step sequence starting from cyclohexane-1,3-
dione.11 Ester 2 was obtained from thiophene as de-
scribed previously by us.7 LAH reduction followed by
PCC oxidation of the esters 1 and 2 yielded aldehydes
which were converted to oximes 3 and 4 by heating with
hydroxylamine hydrochloride in aqueous ethanol in
Keywords: Isoxazolines; Isoxazoles; Oxime–olefin cycloaddition; Pon-
gamol; b-Hydroxychalcones.
q CDRI Communication No. 6780.
Corresponding author. Tel.: +91 522 2612411 18x4440; fax: +91 522
2623405/2623938/2629504; e-mail: mauryarakesh@rediffmail.com
*
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.111

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P. P. Yadav et al. / Tetrahedron Letters 46 (2005) 5621–5624
X
X
OCH3
OCH3
N
O
O
OH
route 1
Oxime-Olefin
Cycloaddition
X
OCH3
X
O
OH
OCH3
Li
X= O, S
Corresponding
ester
N
O
O
N
Li
route 2
Scheme 1. Possible routes for the syntheses.
90% and 95% yields, respectively. The oximes thus ob-
tained were subjected to the oxime–olefin cycloaddition
reaction with styrene in ethanol in the presence of chlor-
amine-T13 to produce the reactive dipolar nitrile oxide in
situ and thus the product isoxazolines 5 (94%) and 6
(96%) (Scheme 2).14 Catalytic hydrogenolysis over
Raney-Ni failed under NTP conditions whilst under
pressure (40 psi) a mixture of products due to hydroge-
nation of the furan and thiophene rings along with the
isoxazoline ring was obtained. Various attempts to
hydrogenate the isoxazoline ring selectively failed which
led us to change our strategy to that shown in route 2
(Scheme 1), as isoxazoles are known to undergo hydro-
genolysis under mild conditions.15
X
OCH3
a
b
N
OH
O
N
7. X = O (88%)
8. X = S (92%)
2
3
X
9
OCH3
X
OCH3
4'
8
4
c
10
12
1'
5
6
98%
OH NH
O
OH
11. X = O (pongamol)
12. X = S
9. X = O (90%)
10. X = S (95%)
Scheme 3. Reagents and conditions: (a) n-BuLi (2 equiv), THF, 0 °C,
30 min, added 1/2 in THF, 15 min, then 3 N HCl, reflux, 1 h; (b)
Raney-Ni, H2, rt, THF–H2O (3:1), 12–16 h; (c) silica gel, AcOH few
drops, 18 h.
The isoxazoles 7 and 8 were synthesized from acetophe-
none oxime and esters 1 and 2.11 The acetophenone
oxime was treated with two equivalents of n-BuLi to
afford the dilithium salt of the oxime. Aroylation of
the dianion with the ester was accomplished with
0.5 mol of ester 1 and 2/mol of dianion. Aroylation
occurred at the more nucleophilic carbanion site.16
The presumed intermediate keto-oximes were not iso-
lated but were cyclized directly under acidic conditions
to give the isoxazoles 7 and 8 in 88% and 92% yields,
respectively.17Hydrogenolysis over Raney-Ni at NTP
produced imines 9 (90%) and 10 (95%) and then hydro-
lysis of the imines on silica gel with acetic acid afforded
b-hydroxychalcones 11 (pongamol) and 12 in nearly
quantitative yields (Scheme 3).
After successful completion of the syntheses of the
desired products via isoxazoles, we have further synthe-
sized isoxazoles 13 and 1418 in 90% yields via DDQ-
mediated dehydrogenation of the isoxazolines 5 and 6
in order to avoid the use of butyllithium and render
the process cost effective (Scheme 4). DDQ has not pre-
viously been used for dehydrogenation of isoxazolines.
In conclusion, the work described here demonstrates an
easy, efficient and commercially viable synthesis of pon-
gamol and its sulfur heterocyclic analogue. Further
X
OMe
N
X
OMe
OMe
X
OMe
N
d
a, b, c
OH
O
O
3. X = O (90%)
4. X = S (95%)
5. X = O (94%)
6. X = S (96%)
1. X = O
2. X = S
e
f
No product Mixture of
products
Scheme 2. Reagents and conditions: (a) LAH, THF, 0 °C, rt, 2 h; (b) PCC, dry DCM, rt, 2 h; (c) NH2OHÆHCl, EtOH, 10% aq NaOH, D, 1 h; (d)
styrene, chloramine-T, EtOH, reflux, 9 h; (e) Raney-Ni, H2, rt, THF–H2O (3:1), 48 h; (f) Raney-Ni, H2 40 psi, THF: H2O (3:1), 10 h.

P. P. Yadav et al. / Tetrahedron Letters 46 (2005) 5621–5624
5623
X
OMe
N
X
OMe
X
OMe
O
a
b, c
90%
98%
O
N
O
OH
13. X = O
14. X = S
5. X = O
6. X = S
11. X = O (pongamol)
12. X = S
Scheme 4. Reagents and conditions: (a) DDQ, dioxane, reflux, 6–8 h; (b) Raney-Ni, H2, rt, THF–H2O (3:1), 12–16 h, (c) silica gel, AcOH few drops,
18 h.
14. Compound 5: white crystals, mp 85 °C; IR (KBr) mmax
2902, 1593, 1468, 1354, 1244, 1156, 1060, 808, 977, 897,
763 cmꢀ1 1H NMR (CDCl3, 200 MHz) d: 7.74 (1H, d,
:
studies on the syntheses and pharmacological potential
of functionalized isoxazolines, isoxazoles and b-
hydroxychalcones are in progress.
;
J = 8.6 Hz, H-6), 7.57 (1H, d, J = 1.4 Hz, H-2), 7.41–7.31
(5H, m, H-20–H-60), 7.23 (1H, dd, J = 8.6, 0.6 Hz, H-7),
6.92 (1H, d, J = 1.4 Hz, H-3), 5.69 (1H, dd, J = 10.6, 8.5,
H-12), 4.04 (3H, s, –OCH3), 3.93 (1H, dd, J = 17.2,
10.7 Hz, H-11a), 3.48 (1H, dd, J = 17.2, 8.4 Hz, H-11b);
13C NMR (CDCl3, 50 MHz) d: 158.2 (C-10), 156.1 (C-8),
152.5 (C-4), 144.8 (C-2), 141.6 (C-10), 129.0 (C-30, 50),
128.4 (C-40), 126.3 (C-20, 60), 125.9 (C-6), 119.2 (C-9),
115.5 (C-5), 107.3 (C-7), 105.3 (C-3), 82.9 (C-12), 60.9
(OCH3), 46.2 (C-11); FAB MS (+ve): m/z 294 [M+H]+.
Elemental analysis calcd for C18H15NO3: C, 73.71; H,
5.15; N, 4.78%. Found: C, 73.54; H, 5.26; N, 4.59%.
Compound 6: oil; IR (KBr) mmax: 2928, 1638, 1493,
Acknowledgements
Two of the authors (P.P.Y and G.A.) acknowledge
CSIR and MOH, respectively, for fellowships.
References and notes
1. Murty, M. S. R.; Rao, E. V. Indian Drugs 1985, 22, 462–
464.
2. Chang, L. C.; Gerhaeuser, C.; Song, L.; Farnsworth, N.
R.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 1997,
60, 869–873.
1
1453, 1364, 1331, 1216, 1047, 1013, 770 cmꢀ1; H NMR
(CDCl3, 200 MHz) d: 7.78 (1H, d, J = 8.4 Hz, H-6), 7.64
(1H, d, J = 8.5 Hz, H-7), 7.41–7.49 (6H, m, H-2, H-20–H-
60), 7.36 (1H, br d, J = 6.9 Hz, H-3), 5.74 (1H, dd,
J = 10.7, 8.3 Hz, H-12), 3.94 (1H, dd, J = 17.2, 10.7 Hz,
H-11a), 3.91 (3H, s, –OCH3), 3.53 (1H, dd, J = 17.2,
8.2 Hz, H-11b); 13C NMR (CDCl3, 50 MHz) d: 155.6
(C-10), 154.2 (C-4), 143.8 (C-8), 141.5 (C-10), 134.5 (C-9),
129.1 (C-30, 50), 128.5 (C-40), 127.1 (C-2), 126.3 (C-20, 60),
125.6 (C-3), 121.1 (C-6), 119.0 (C-7), 118.3 (C-5), 83.0
(C-12), 62.9 (OCH3), 45.8 (C-11); FAB MS (+ve): m/z 310
[M+H]+. Elemental analysis calcd for C18H15NO2S: C,
69.88; H, 4.89; N, 4.53; S, 10.36%. Found: C, 70.14; H,
4.73; N, 4.62; S, 10.49%.
3. Anon, U. K. Res. Disclosure 1999, 422, P776; Chem.
Abstr. 1999, 131, 276845k.
4. (a) Oka, N.; Ishigami, M.; Okada, M. Japanese Patent, JP
2001064294 A2, 2001; Chem. Abstr. 2001, 134, P227118d;
(b) Natraj, C. V.; Nambudiry, M. E. N. Indian Patent, IN
171,532, 1992. Chem. Abstr. 1996, 125, P95574b.
5. (a) Ogawa, K.; Takata, S.; Nanba, T.; Yoshino, K. PCT
Int. Appl. WO 9809610 A1, 1998; Chem. Abstr. 1998, 128,
234995s; (b) Gregory, M. F.; Morris, C. Eur. Pat. Appl.
EP 521651 A2, 1993; Chem. Abstr. 1993, 118, 66621q; (c)
Carr, S. W.; Franklin, K. R.; Nunn, C. C.; Pasternak, J. J.;
Scott, I. R. Eur. Pat. Appl. EP 557089 A1, 1993; Chem.
Abstr. 1993, 119, 233704y; (d) Nambudiry, M. E.; Natraj,
C. V. Can. Pat. Appl. CA 2029263 AA, 1991. Chem. Abstr.
1991, 115, 142032d.
6. (a) Yadav, P. P.; Ahmad, G.; Maurya, R. Phytochemistry
2004, 65, 439–443; (b) Ahmad, G.; Yadav, P. P.; Maurya,
R. Phytochemistry 2004, 65, 921–924.
7. Yadav, P. P.; Gupta, P.; Chaturvedi, A. K.; Shukla, P. K.;
Maurya, R. Bioorg. Med. Chem. 2005, 13, 1497–1505.
8. (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416;
(b) Hassner, A.; Murthy, K. S. K. Tetrahedron Lett. 1986,
27, 1407–1410; (c) Curran, D. P. J. Am. Chem. Soc. 1982,
104, 4024–4026.
9. (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.;
Simoni, D. Synthesis 1987, 857–869; (b) McGregor, D. N.;
Corbin, U.; Swigor, J. E.; Cheney, L. C. Tetrahedron 1969,
25, 389–395; (c) Bianchi, G.; DeAmici, M. J. Chem. Soc.,
Chem. Commun. 1978, 962–963.
10. Mukerjee, S. K.; Seshadri, T. R. J. Chem. Soc. 1955, 2048–
2049.
11. (a) Lee, Y. R.; Morehead, A. T., Jr. Tetrahedron 1995, 51,
4909–4922; (b) Pirrung, M. C.; Lee, Y. R. Tetrahedron
Lett. 1994, 35, 6231–6234.
15. Sainsbury, M. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: New York, 1991; Vol. 8, pp 644–
646.
16. Beam, C. F.; Dyer, M. C. D.; Schwarz, R. A.; Hauser, C.
R. J. Org. Chem. 1970, 35, 1806–1810.
17. Compound 7: colourless needles, mp 102–103 °C; IR
(KBr) mmax: 2993, 1590, 1477, 1454, 1390, 1186, 1107, 941,
1
904, 845, 764 cmꢀ1; H NMR (CDCl3, 200 MHz) d: 7.86
(1H, d, J = 8.5 Hz, H-6), 7.83 (2H, m, H-20–H-60), 7.59
(1H, br s, H-2), 7.43–7.47 (3H, m, H-30, 40, 50), 7.30 (1H,
d, J = 8.6 Hz, H-7), 7.05 (1H, s, H-11), 6.97 (1H, br s,
H-3), 4.07 (3H, s, OCH3); 13C NMR (CDCl3, 50 MHz) d:
172.3 (C-10), 161.2 (C-8), 159.0 (C-4), 154.6 (C-12), 144.9
(C-2), 130.3 (C-40), 129.3 (C-30, 50), 128.2 (C-10), 126.2
(C-20, 60), 126.0 (C-6), 119.6 (C-5), 115.0 (C-9), 107.4
(C-7), 105.3 (C-3), 101.0 (C-11), 60.9 (OCH3); FAB MS
(+ve): 292 [M+H]+. Elemental analysis calcd for
C18H13NO3: C, 74.22; H, 4.50; N, 4.81%. Found: C,
74.08; H, 4.36; N, 4.69%. Compound 8: white plates, mp
138–139 °C; IR (KBr) mmax: 3104, 2942, 1595, 1573, 1459,
1
1394, 1327, 1213, 1009, 939, 761 cmꢀ1; H NMR (CDCl3,
300 MHz) d: 7.97 (1H, d, J = 8.7 Hz, H-6), 7.93 (2H, dd,
J = 7.8, 2.1 Hz, H-20, 60), 7.76 (1H, d, J = 8.7 Hz, H-7),
7.58 (1H, d, J = 6.0 Hz, H-2), 7.48–7.54 (4H, m, H-30, 40,
50, 3), 7.18 (1H, s, H-11), 4.04 (3H, s, OCH3); 13C NMR
(CDCl3, 50 MHz) d: 167.3 (C-10), 163.7 (C-12), 153.1
12. Kawase, Y.; Matsumoto, T.; Fukui, K. Bull. Chem. Soc.
Jpn. 1955, 28, 273–275.
13. Hassner, A.; Lokanath Rai, K. M. Synthesis 1989, 57–59.

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P. P. Yadav et al. / Tetrahedron Letters 46 (2005) 5621–5624
(C-4), 143.9 (C-8), 134.4 (C-10), 130.3 (C-40), 129.8 (C-9),
100.7 (C-11), 60.3 (OMe-4); FAB MS (+ve): m/z 292
[M+H]+. Elemental analysis calcd for C18H13NO3: C,
74.22; H, 4.50; N, 4.81%. Found: C, 74.39; H, 4.59; N, 4.73%.
Compound 14: colourless needles, mp 141–143 °C; IR,
1H and 13C NMR are nearly similar to compound 8,
except for the 13C NMR values for the three carbons C-4,
C-10 and C-12; 13C NMR (CDCl3, 50 MHz) d: 170.3
(C-12), 160.9 (C-10), 154.1 (C-4), 143.6 (C-8), 134.8 (C-10),
130.3 (C-40), 129.4 (C-30, 50), 128.1 (C-9), 127.1 (C-2),
126.2 (C-20, 60), 125.7 (C-6), 121.1 (C-3), 119.2 (C-7), 117.7
(C-5), 100.8 (C-11), 62.6 (OCH3); FAB MS (+ve): m/z 308
[M+H]+. Elemental analysis calcd for C18H13NO2S: C,
70.34; H, 4.26; N, 4.56; S, 10.43%; Found: C, 70.50; H,
4.41; N, 4.63; S, 10.57%.
129.3 (C-30, 50), 127.5 (C-2), 127.3 (C-20, 60), 124.0 (C-6),
121.5 (C-3), 119.3 (C-7), 116.3 (C-5), 101.1 (C-11), 61.8
(OCH3); FAB MS (pos.): m/z 308 [M+H]+, 615
[2M+H]+. Elemental analysis calcd for C18H13NO2S: C,
70.34; H, 4.26; N, 4.56; S, 10.43%. Found: C, 70.48; H,
4.36; N, 4.41; S, 10.54%.
18. Compound 13: colourless needles, mp 104–105 °C; IR,
1H and 13C NMR are nearly similar to compound 7, except
for the 13C NMR values for the three carbons C-12, C-10
and C-4; 13C NMR (CDCl3, 50 MHz) d: 169.8 (C-12),
162.5 (C-8), 158.1 (C-4), 152.3 (C-10), 145.2 (C-2), 130.2
(C-40), 130.0 (C-30, 50), 129.0 (C-10), 126.8 (C-20, 60), 126.2
(C-6), 118.8 (C-9), 114.6 (C-5), 107.4 (C-7), 105.6 (C-3),