Efficient synthesis of 3-substituted coumarins

Article abstract of DOI:10.1081/SCC-200028575

The Mukaiyama's esterification protocol, using 2-chloro-1-methylpyridinium iodide-triethylamine reagent, has been successfully exploited to provide rapid access to a variety of 3-substituted coumarins in satisfactory yields.

Full text of DOI:10.1081/SCC-200028575

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Efficient Synthesis of
3‐Substituted Coumarins
Sabir H. Mashraqui a , Dhaval Vashi a & Hitesh D.
Mistry a
a Department of Chemistry, University of Mumbai,
Vidyanagari, Santacruz (E), Mumbai, 400098, India
Version of record first published: 10 Jan 2011.
To cite this article: Sabir H. Mashraqui , Dhaval Vashi & Hitesh D. Mistry (2004):
Efficient Synthesis of 3‐Substituted Coumarins, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:17, 3129-3134
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3129–3134, 2004
Efficient Synthesis of
3-Substituted Coumarins
*
Sabir H. Mashraqui, Dhaval Vashi, and Hitesh D. Mistry
Department of Chemistry, University of Mumbai, Vidyanagari,
Santacruz (E), Mumbai, India
ABSTRACT
The Mukaiyama’s esterification protocol, using 2-chloro-1-methylpyridinium
iodide-triethylamine reagent, has been successfully exploited to provide rapid
access to a variety of 3-substituted coumarins in satisfactory yields.
Key Words: 3-Substituted coumarins; Synthesis; 2-Chloro-1-methyl-
pyridinium iodide/triethylamine reagent; Coumarin laser dye; Mukaiyama
esterification protocol.
A number of natural products and synthetic analogs featuring coumarin
structural motif display wide-ranging biological properties[1,2] and, in
*
Correspondence: Sabir H. Mashraqui, Department of Chemistry, University of
Mumbai, Vidyanagari, Santacruz (E) Mumbai 400098, India; E-mail:
sh_mashraqui@yahoo.com.
3129
DOI: 10.1081/SCC-200028575
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3130
Mashraqui, Vashi, and Mistry
addition, selected coumarins also find applications as luminescent probes,[3]
fluorescent brightners,[4] laser dyes,[5] and fluoroionophores.[6] Among the
plethora of methods available for coumarin synthesis,[7] viz. lactonizations,
Wittig condensations, and transition metal catalyzed reactions, the classical
Perkin condensation[8] is perhaps the only direct method known for 3-aryl-
coumarins. However, from a practical standpoint, the Perkin method suffers
from the need to use an excess of acetic anhydride/sodium acetate reagent,
harsh conditions, tedious work-up, and unsatisfactory yields. Not surprisingly,
many attempts at improving the Perkin method have been described in the
literature (For attempts at improving the Perkin method, see Ref.[9a–f]). In
particular, the method using PhPOCl2/Et3N as the condensing agent[9f] is
noteworthy in providing 3-substituted coumarins in appreciable yields.
Herein, we describe a convenient, single-step methodology for
3-substituted coumarins by using Mukaiyama esterification conditions.[10]
We envisaged that esterification of appropriate salicaldehyde with arylacetic
would be followed by a Claisen-type condensation under catalysis by Et3N
to provide 3-arylcoumarins, as illustrated in Sch. 1.
To check the validity of Sch. 1, we set up a test reaction between salic-
aldehyde and phenylacetic acid in dry CH3CN containing 2 equivalents of
freshly crystallized 2-chloro-1-methylpyridinium iodide and an excess of tri-
ethylamine. The reaction, after refluxing for 2 hr under N2 was worked-up to
provide the desired product, 3-phenylcoumarin in 81% isolated yield.
Attempts to effect the reaction in other solvents, i.e., dry THF, dioxan, or
DMF or use of less than 2 equivalents of 2-chloro-1-methylpyridinium
iodide, resulted in lower yields of 3-phenylcoumarin. The scope of the
present methodology was found to be general (Table 1), being equally suc-
cessful with either electron-rich or electron-deficient substrates, and the
yields are also in general quite satisfactory.
The reaction was also successfully executed with phenoxyacetic acid and
thiophenoxyacetic acid to afford 3-phenoxy- and 3-thiophenoxycoumarins,
respectively (entries 6 and 7, Table 1). In addition, 2-hydroxy-arylketones
1 and 2 also participated in the reaction with phenylacetic acid to give the
corresponding coumarins[17] 3 and 4 in acceptable yields (Sch. 2). The
Scheme 1. Reagent and condition: (i) 2 equiv of 2-chloro-1-methylpyridinium
iodide/(C2H5)3N in CH3CN, D, N2.

Efficient Synthesis of 3-Substituted Coumarins
Table 1. Synthesis of 3-substituted coumarins.
3131
Entry
Producta
R
R0
% Yieldb
Lit.c
1
2
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
C6H5
81
78
91
75
68
25
75
89
72
75
80
91
80
63
11
11
11
9b
9f
4-MeOC6H4
4-NO2C6H4
3,4-(MeO)2C6H3
2-thienyl
3
4
5
6
-OC6H5
-SC6H5
9f
7
1g
1h
1i
12
13
14
15
16
8
6-NO2
6-Br
C6H5
C6H5
C6H5
9
10
11
12
13
14
1j
7-NMe2
7-NEt2
6-NO2
6-CHO
6-NO2
1k
1l
4-NO2C6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3-indolyl
d
–
d
1m
1n
–
d
–
aReactions refluxed for 2 hr, unless mentioned otherwise; for 1c and 1h, reflux time is
1 hr, for 1f reflux time is 8 hr.
bAll yields are isolated yields.
cPhysical and spectral data agree with those reported in the literature.
dSelected characterizations of unknown coumarins: Product 1l; mp 2628C–638C. IR
(KBr): 1740, 1612, 1522, 1350, 1245, 1100, 1035 cm21 1H NMR (300 MHz,
;
CDCl3): d 3.82 (s, 6H), 7.08 (d, 1H, J ¼ 8 Hz), 7.34–7.38 (m, 2H), 7.64 (d, 1H,
J ¼ 8 Hz), 8.4 (dd, 1H, J ¼ 8 and 1.5 Hz), 8.42 (s, 1H), 8.74 (s, 1H); Anal. Calcd.
for C17H13NO6: C, 62.38; H, 3.97; N, 4.28. Found: C, 62.70; H, 4.25; N, 4.47.
Product 1m; mp 1658C–1678C. IR (KBr): 1738, 1697, 1609, 1521, 1360, 1150 cm21
;
1H NMR (300 MHz, CDCl3): d 3.84 (s, 6H), 6.7 (d, 1H, J ¼ 8.5 Hz), 7.15–7.3
(m, 2H), 7.66 (s, 1H), 7.7–7.85 (m, 2H), 7.9 (s, 1H), 9.9 (s, 1H); Anal. Calcd. for
C18H14O5: C, 69.67; H, 4.51. Found: C, 69.89; H, 4.33. Product 1n; mp 3008C–
3048C; IR (KBr): 3325, 1710, 1505, 1435, 1340, 1250, 1070, 970 cm21 1H NMR
;
(300 MHz, CDCl3): d 7.05 (bs, 1H), 7.15–7.30 (m, 2H), 7.5 (d, 1H, J ¼ 8 Hz), 7.63
(d, 1H, J ¼ 8 Hz), 8.20 (d, 1H, J ¼ 7 Hz), 8.25 (s, 1H), 8.32 (d, 1H, J ¼ 7 Hz), 8.60
(s, 1H), 8.95 (s, 1H); Anal. Calcd. for C17H10N2O4: C, 66.66; H, 3.26; N, 9.15.
Found: C, 66.49; H, 3.47; N, 9.41.
present procedure has also been successfully extended toward the synthesis of
a commercially important laser dye 7[18] in good yield by reacting 5-diethyl-
amino salicaldehyde 5 with 2-benzothiazolylacetic acid 6.
In conclusion, we have described a new application of the Mukaiyama
esterification protocol as an efficient, metal-free alternative to the classical
Perkin condensation to provide rapid entry into a variety of 3-substituted

3132
Mashraqui, Vashi, and Mistry
Scheme 2. Reagent and condition: (i) 2-chloro-1-methylpyridinium iodide/(C2H5)3N
in CH3CN, D/N2.
coumarin systems. Unlike other Perkin modifications,[9] the present
method obviates the need to prepare unstable arylacetic chloride/anhydride
or the application of corrosive PhPOCl2 as the condensing agent.[9f]
Thus, given the ever-rising importance of coumarins in diverse fields,
the reported method appears to be an attractive approach toward these
molecules.
TYPICAL PROCEDURE
To a solution of freshly crystallized 2-chloro-1-methylpyridinium
iodide (4.0 mmol) in dry CH3CN (distilled over P2O5; 20 mL) were added
phenylacetic acid (2.2 mmol), salicaldehyde (2.0 mmol), and triethylamine
(5 mmol). The reaction was gently refluxed under N2 for 2 hr. The
reaction mixture was concentrated under reduced pressure and the semi-
solid residue was treated with diluted hydrochloric acid. The solid
product obtained was filtered, dried, and purified by a short SiO2 column
chromatography (elution with petroleum ether-CHCl3 2 : 1) to give 3-phenyl-
coumarin (1a) as a colorless solid in 81% yield, mp 1408C–1428C (Lit.[9a] mp
1428C).

Efficient Synthesis of 3-Substituted Coumarins
ACKNOWLEDGMENT
3133
Thanks are due to the C.S.I.R., New Delhi, India, for financial support and
Professor R.M. Kellogg, University of Groningen, and Professor V.K. Singh,
I.I.T., Mumbai, for providing high-resolution NMR spectra.
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Received in India May 17, 2004