An expeditious coumarin synthesis via a "Pseudocycloaddition" between salicylaldehydes and ketene

Article abstract of DOI:10.1080/00397911.2014.960938

A variety of salicylaldehydes effected tandem nucleophilic addition onto ketene, leading to corresponding coumarins in good yields under mild conditions. This "pseudocycloaddition" represents a very mild variant of the historic Perkin synthesis of coumarin (which remains of key interest in both perfumery and several emerging areas).

Full text of DOI:10.1080/00397911.2014.960938

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An Expeditious Coumarin Synthesis
via a “Pseudocycloaddition” Between
Salicylaldehydes and Ketene
a
a
Sosale Chandrasekhar & Honnaiah Vijay Kumar
a
Department of Organic Chemistry , Indian Institute of Science ,
Bangalore , India
Accepted author version posted online: 25 Sep 2014.Published
online: 26 Nov 2014.
To cite this article: Sosale Chandrasekhar & Honnaiah Vijay Kumar (2015) An Expeditious
Coumarin Synthesis via a “Pseudocycloaddition” Between Salicylaldehydes and Ketene, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
45:2, 232-235, DOI: 10.1080/00397911.2014.960938
To link to this article: http://dx.doi.org/10.1080/00397911.2014.960938
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1
Synthetic Communications , 45: 232–235, 2015
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.960938
AN EXPEDITIOUS COUMARIN SYNTHESIS VIA A
‘PSEUDOCYCLOADDITION’’ BETWEEN
SALICYLALDEHYDES AND KETENE
‘
Sosale Chandrasekhar and Honnaiah Vijay Kumar
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
GRAPHICAL ABSTRACT
Abstract A variety of salicylaldehydes effected tandem nucleophilic addition onto ketene,
leading to corresponding coumarins in good yields under mild conditions. This ‘‘pseudo-
cycloaddition’’ represents a very mild variant of the historic Perkin synthesis of coumarin
(
which remains of key interest in both perfumery and several emerging areas).
Keywords Coumarin; Perkin synthesis; quinodimethane
INTRODUCTION
[
[
1]
2]
Coumarin (2a, Scheme 1) is of both historic and contemporary interest.
Historically, it is of interest with respect to the classical Perkin synthesis (1877),
which defined one of the most important extensions of the Perkin condensation.
3]
Contemporary interest in coumarin derives from its key importance in perfumery,
[
[
apart from sundry applications (in electroplating, etc.). Several modern synthetic
4]
[
5–7]
approaches have been recently reported,
the coumarin nucleus in areas as diverse as medicinal chemistry and molecular
electronics.
as well as fundamental studies on
[
8,9]
The present studies were motivated by the possibility that milder versions of
the original Perkin synthesis could be designed. (This typically involved refluxing
salicylaldehyde and sodium acetate in acetic anhydride.) Also, the classical synthesis
apparently remains mechanistically enigmatic, with several possible routes having
Received May 19, 2014.
Address correspondence to Sosale Chandrasekhar, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560 012, India. E-mail: sosale@orgchem.iisc.ernet.in
2
32

EXPEDITIOUS COUMARIN SYNTHESIS
233
Scheme 1. Synthesis of coumarins 2 from salicylaldehydes 1 and in situ–generated ketene (I).
been considered. These essentially differ in the order of formation of the O -CO and
1
C -C bonds and the identity of the penultimate intermediate prior to the final
3
4
cyclization. It occurred to us that one of these, involving the initial formation of
the O -CO bond followed by rapid cyclization, was susceptible to a novel approach
as described here (cf. Scheme 1).
1
RESULTS AND DISCUSSION
Thus, the reaction of salicylaldehydes (1) with ketene (I) was envisaged to form
the coumarin nucleus in IV, via the tandem nucleophilic addition process shown in
II–III. The immediate product, enolate ion III, was expected to add rapidly to the
aldehyde carbonyl group in its close proximity. Proton transfer in IV generates
enolate V (likely intermolecular, although shown as intramolecular for convenience);
this is followed by elimination of hydroxide ion to form coumarin (2). Interestingly,
this one-pot procedure would represent a ‘‘pseudocycloaddition’’ of I onto 1. [The
putative ortho-quinodimethane tautomer VI of deprotonated 1 may be considered
[10]
as the diene unit in this process. This analogy, however, only indicates the bonding
[
11,12]
changes, ketenes being known to undergo (2 þ 2) cycloadditions preferentially.
]
Indeed, when a mixture of 1a (1.0 equivalent), triethylamine (3.0 equivalents),
˚
and acetyl chloride (2.0 equivalents) in dichloromethane (with added 4 A molecular
sieves) was stirred at 10 C for 9 h, coumarin (2a) was formed in 72% yield (relative
to 1a). The method was extended to include a variety of substituted salicylaldehydes
ꢀ
(
1a–1f), the yields of the corresponding coumarins (2a–2f) being summarized in

234
S. CHANDRASEKHAR AND H. V. KUMAR
Table 1. Yields (%) of the various coumarins (2) formed as shown in Scheme 1
2a
2b
2c
2d
2e
2f
72
64
58
70
62
67
Table 1. (The transformation was unsuccessful in the absence of the molecular sieves,
which presumably traps the molecule of water that is a by-product of the process.)
It is highly likely that this reaction occurs via the reaction of 1 and ketene (I),
which is known to be generated by the reaction of acetyl chloride and Et N. Ketenes
3
are also known to add alcohols across the C=C unit to form esters, whether under
[11,12]
basic, neutral, or acidic conditions.
The basic reaction is believed to involve
nucleophilic attack of alkoxide anion at the carbonyl carbon atom leading to the
enolate anion (cf. III). This indicates that the tandem process represented by II is
highly likely.
When the acetate of salicylaldehyde (1a, the acetate is not shown) was treated
with Et N under these conditions, it failed to form coumarin (2a). This strongly
3
indicates that the formation of 2 occurs via the tandem nucleophilic addition protocol
as envisaged and not via the prior formation of the acetate. [Note that Et N (pK ꢁ 10)
3
a
[
13]
can deprotonate 1 (pK < 10) but not an ester (pK ꢁ 25), thus forming II.
]
There have been a few previous reports on the synthesis of coumarins from
a
a
[14,15]
salicylaldehydes and ketene.
However, these employed ketene generated as a
gas, in multistep reactions that generally suffered from poor yields. Recent work
[
16,17]
employs ketene dithioacetals under either electrophilic or nucleophilic activation;
alternatively, malonic half-thioesters have been employed along with an amine
[
18]
catalyst.
simplicity, mildness, and economy of operation.
The method reported herein possesses the relative advantages of
CONCLUSIONS
We have described a novel approach to various coumarins, which remain of
diverse contemporary interest. The route apparently involves a novel pseudocycloaddi-
tion via a tandem nucleophilic addition process. This employs available salicylalde-
hydes as substrates and is characterized by very mild reaction conditions and good
overall yields.
EXPERIMENTAL
A mixture of salicylaldehyde (1a) (1.0 mmol), triethylamine (3.0 mmol), freshly
˚
distilled acetyl chloride (2.0 mmol) and molecular sieves (ꢁ0.25 g, 4 A, as pellets) in
ꢀ
dry CH Cl was stirred for 9 h at 10 C. The insolubles (Et N ꢂ HCl þmolecular sieves)
2
2
3
were filtered off, and the filtrate was worked up with ice cold water. The organic layer
was dried (Na SO ) and concentrated in vacuo to obtain the crude product, which
was chromatographed on silica gel eluting with 20% ethyl acetate–hexane. Coumarin
2a) was thus obtained as a white solid in 72% yield; mp 70–73 C (lit. 68–69 C);
vmax 3058 (b, C-H), 1715 (s, CO); dH 7.26–7.72 (5 H, m, ArH þArCH¼C),
.42 (1 H, d, J 9.5, ArC=CH).
2
4
ꢀ
[19]
ꢀ
(
6

EXPEDITIOUS COUMARIN SYNTHESIS
235
FUNDING
We are grateful to University Grants Commission (New Delhi) for generous
financial support to H. V. K.
SUPPORTING INFORMATION
Detailed procedures and spectral characterization data for all compounds
reported herein can be accessed on the publisher’s website.
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