A single-step assembly of coumarin ring skeleton from oxygenated phenols and acetylenic esters by catalytic indium chloride in the absence of solvent

Article abstract of DOI:10.1081/SCC-120034175

Ring oxygenated coumarins were obtained in a single-step by condensation of appropriately substituted phenols with acetylenic esters by catalytic amounts of indium chloride in the absence of solvent.

Full text of DOI:10.1081/SCC-120034175

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A Single‐Step Assembly of Coumarin Ring Skeleton
from Oxygenated Phenols and Acetylenic Esters by
Catalytic Indium Chloride in the Absence of Solvent
N. Kalyanam a , A. Nagarajan a & M. Majeed a
a Research and Development, Sabinsa Corporation , 1 Deerpark Drive, Suite D, Monmouth
Junction, New Jersey, 08852, USA
Published online: 20 Aug 2006.
To cite this article: N. Kalyanam , A. Nagarajan & M. Majeed (2004) A Single‐Step Assembly of Coumarin Ring Skeleton
from Oxygenated Phenols and Acetylenic Esters by Catalytic Indium Chloride in the Absence of Solvent, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:10, 1909-1914,
DOI: 10.1081/SCC-120034175
To link to this article: http://dx.doi.org/10.1081/SCC-120034175
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 10, pp. 1909–1914, 2004
A Single-Step Assembly of Coumarin Ring
Skeleton from Oxygenated Phenols and
Acetylenic Esters by Catalytic Indium
Chloride in the Absence of Solvent
*
N. Kalyanam, A. Nagarajan, and M. Majeed
Research and Development, Sabinsa Corporation,
Monmouth Junction, New Jersey, USA
ABSTRACT
Ring oxygenated coumarins were obtained in a single-step by conden-
sation of appropriately substituted phenols with acetylenic esters by
catalytic amounts of indium chloride in the absence of solvent.
Key Words: Coumarins; Indium chloride.
INTRODUCTION
Coumarins are ubiquitous compounds occurring naturally and they find
various uses in fragrance, pharmaceutical, and agrochemical areas.[1] Several
*
Correspondence: N. Kalyanam, Research and Development, Sabinsa Corporation,
1 Deerpark Drive, Suite D, Monmouth Junction, NJ 08852, USA; Fax: 732-438-
1105; E-mail: kalyanam@sabinsa.com.
1909
DOI: 10.1081/SCC-120034175
0039-7911 (Print); 1532-2432 (Online)
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Copyright # 2004 by Marcel Dekker, Inc.

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1910
Kalyanam, Nagarajan, and Majeed
methods have been developed for the synthesis of coumarin skeletons.[2]
Especially interesting is the recent Trost’s Pd-catalyzed method for the
synthesis of several oxygenated coumarins in a single-step from polyhydroxy-
phenols derivatives and acetylenic esters.[3] This palladium-catalyzed method
constitutes an easy entry into certain coumarin structures otherwise accessible
only multistep sequence. Trost et al. also evaluated other catalysts for this
transformation. They also found that indium triflate was ineffective for
this transformation. This prompts us to report our use of indium trichloride
as an effective catalyst for this transformation.
Indium trichloride has been used as a Lewis acid catalyst in several syn-
thetic transformations (for reviews of recent applications of InCl3 see Ref.[4]).
We report herein a single-step entry into coumarins using a tandem Michael
addition and cyclization sequence of substituted phenols with acetylenic esters
using indium chloride in catalytic (ꢀ10–12 mol%) quantities.
Thus, phloroglucinol reacts with ethyl propiolate in the presence of
indium chloride (11 mol% of phloroglucinol) to give 5,7-dihydroxycoumarin
(entry 2, Table 1) in 32% isolated yield (Sch. 1). Dimethylation of 5,7-dihy-
droxycoumarin is known to give 5,7-dimethoxycoumarin, a naturally occur-
ring coumarin isolated from Citrus aurantifolia (Limettin).[5] Thus, we have
a simple two-step sequence to Limettin from readily available starting
materials, which was otherwise obtainable only by a lengthy route.[6] Reaction
of phloroglucinol with a substituted acetylenic ester such as ethyl phenyl-
propiolate proceeds in better yield (55% after crystallization) to give the
corresponding coumarin (entry 3, Table 1).
Another coumarin, namely 4-phenyl ayapin, is obtained under similar
conditions in a single-step from Sesamol and ethyl phenylpropynoate
under these indium chloride catalyzed conditions (entry 5, Table 1). Longer
sequences for synthesizing ayapin related coumarins have been reported.[7]
It was found that the phenol itself failed to react with acetylenic esters by
the present method. Only more reactive phenols such as hydroxy/methylene
dioxy substituted phenols reacted smoothly. Also the reaction failed with
phenolic substrate containing an amine function (e.g., m-dimethyl amino phenol).
Even though the yields are in the moderate to good range, this very simple
entry into substituted coumarin skeletons should render this method worthy of
further exploration and adoption.
REPRESENTATIVE EXPERIMENTAL PROCEDURE
7-Hydroxycoumarin (entry 1, Table 1): a mixture of resorcinol (0.330 g,
3 mmol), ethyl propiolate (0.400 g, 4.1 mmol), and indium chloride (0.078 g,
0.35mmol) in a round-bottomed flask was stirred at 908C for 2 hr. The reaction

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Single-Step Synthesis of Coumarin Ring Skeleton
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Kalyanam, Nagarajan, and Majeed

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Single-Step Synthesis of Coumarin Ring Skeleton
1913
Scheme 1. InCl3 catalyzed synthesis of coumarins.
mixture was allowed to cool to room temperature, diluted with 10 mL water
and extracted with ethyl acetate (3 Â 10 mL). The combined organic layers
were dried over anhydrous sodium sulfate; solvent removed on a rotary evap-
orator to give the crude product. This was dissolved in minimum amount of
ethyl acetate under warm conditions and hexane was added drop-wise to
induce crystallization to afford 0.256 g (52%) of the product. M.P.: 230–
2328C dec (Ref.[8] 2308C).
An identical procedure was followed for 5,7-dihydroxycoumarin (entry 2,
Table 1)
For the coumarins (entries 3 and 4, Table 1), the crude product was given
a toluene wash (2 Â 20 mL) to remove any excess unreacted acetylenic ester.
The product thus obtained was triturated with ether, filtered and dried.
For the coumarin (entry 5, Table 1), the product was isolated by prepara-
tive silica gel TLC (ethyl acetate : hexane ¼ 50 : 50).
All the reactions were run on a 3 mmol scale based on the phenolic
substrates.
REFERENCES
1. Murray, R.D.H.; Mendez, J.; Brown, S.A. The Natural Coumarins:
Occurrence, Chemistry and Biochemistry; John Wiley & Sons:
New York, 1982.
2. (a) Hepworth, J.D.; Heron, B.M. Prog. Heterocycl. Chem. 2002, 14, 332;
(b) Chavan, S.P.; Shivasankar, K.; Sivappa, R.; Kale, R. Tetrahedron Lett.
2002, 43, 8583 (and references cited therein).
3. (a) Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 1996, 118, 6305;
(b) Trost, B.M.; Toste, F.D.; Greenman, K. J. Am. Chem. Soc. 2003,
125, 4518.
4. (a) Babu, S.A. Synlett. 2002, 531; (b) Ranu, B.C. Eur. J. Org. Chem. 2000,
2347; (c) Chauhan, K.K.; Frost, C.G. J. Chem. Soc. Perkin Trans. 1 2000,
3015; (d) Babu, G.; Perumal, P.T. Aldrichim. Acta 2000, 33, 16.

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Kalyanam, Nagarajan, and Majeed
5. Stanley, W.L.; Vannier, S.H. Phytochemistry 1967, 6, 585.
6. Hassan, M.A.; Shiba, S.A.; Harb, N.S.; Abou-El-Regal, M.K.; El
Metwally, S.A. Synth. Commun. 2002, 32, 679.
7. Fukui, K.; Mitsuru Nakayama, M. Bull. Chem. Soc. Jpn 1962, 35, 1321.
8. Aldrich Chemical Catalogue; Aldrich Chemical Company: 2000–2001; 920.
9. Kaufman, K.D.; Kelly, R.C. J. Heterocycl. Chem. 1965, 2, 91.
10. Iinuma, M.; Tanaka, T.; Hamada, K.; Mizuno, M.; Asai, F. Chem. Pharm.
Bull. 1987, 35, 3909.
11. Ahluwalia, V.K.; Seshadri, T.R. J. Chem. Soc. 1957, 970.
Received in the USA January 6, 2004

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