A novel one pot synthesis of γ-butyrolactones

Article abstract of DOI:10.1081/SCC-120006018

α-Arylidene-γ-phenyl-Δ^β,γ-butenolides were converted to the respective γ-butyrolactones in methyl alcohol with sodium borohydride in presence of triethylamine in a single pot.

Full text of DOI:10.1081/SCC-120006018

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A NOVEL ONE POT SYNTHESIS OF γ-BUTYROLACTONES*
G. Sudhakar Reddy a , Parvathi Neelakantan a & D. S. Iyengar b
a Indian Institute of Chemical Technology, Hyderabad, 500 007, India
b Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Published online: 20 Aug 2006.
To cite this article: G. Sudhakar Reddy , Parvathi Neelakantan & D. S. Iyengar (2002): A NOVEL ONE POT SYNTHESIS OF γ-
BUTYROLACTONES*, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:17, 2601-2604
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 17, pp. 2601–2604, 2002
A NOVEL ONE POT SYNTHESIS OF
g-BUTYROLACTONES*
G. Sudhakar Reddy, ParvathiNeelakantan,
and D. S. Iyengary
Indian Institute of Chemical Technology,
Hyderabad-500 007, India
ABSTRACT
a-Arylidene-g-phenyl-Áb,g-butenolides were converted to the
respective g-butyrolactones in methyl alcohol with sodium
borohydride in presence of triethylamine in a single pot.
a-Methylene-g-butyrolactone structural unit, recognized for a variety
of medicinal importance, is present in a wide range of sesquiterpenes and
other natural products.[1] a-Alkylidene and a-arylidene-g-butyrolactones
constitute a functionalised class of g-butyrolactones associated with medic-
inal, agrochemical and other applications.[2] One of the hydroxy substituted
a-arylidene-g-butyrolactones have shown promise in the pharmaceutical
industry as an allergic inhibitor.[2c] A few of the a-arylidene-g-butyrolactones
have been used as intermediates in the synthesis of natural lignans.[3]
Continuing intensive work carried out in this area and the growing impor-
tance of this class of compounds prompted us for newer synthetic approaches.
*IICT communication No. 4391.
yCorresponding author. Fax: (91) 40-7173387, 7173757; E-mail: iyengar@iict.ap.
nic.in
2601
DOI: 10.1081/SCC-120006018
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2602
REDDY, NEELAKANTAN, AND IYENGAR
Synthetic strategies towards a-methylene substituted g-butyrolactones
generally involve either conversion of an existing group at the a-position on
a preformed lactone ring[2b] or utilizing acyclic precursors containing the
desired functional groups. Despite several approaches reported for the con-
struction of a-methylene/alkylidene g-butyrolactones by lactonisation of
acyclic precursors, corresponding parallel approaches for a-arylidene
derivatives are only few.[4,5] One of the latest report is by Liang et al.,[6]
where tungsten alkynols have been employed for the synthesis of these class
of compounds. The above methods reported for a-arylidine derivatives, use
starting materials obtained by multistep synthesis, often involving costly
reagents and controlled conditions.
As a continuing effort to explore the chemistry and synthetic utility of
a-arylidene-g-phenyl-Áb,g-butenolides we report a simple one pot method-
ology for the formation of a-arylidene-g-phenyl-g-butyrolactones directly
from the respective Áb,g-butenolides (Scheme 1).
In a typical reaction a-arylidene g-phenyl Áb,g-butenolide[7] in methyl
alcohol is first treated with triethylamine at room temperature followed by
NaBH4 Work up gives more than 90% yield of the g-butyrolactones.
Formation of the g-butyrolactones proceed via the intermediate g-keto
esters, i.e., a-arylidene-g-keto benzenebutanoic acid methyl ester,[8] followed
by the reduction of the carbonyl group by sodium borohydride to alcohol
with concomitant lactonisation. All the compounds except IIa[6] are new and
1
have been identified on the basis of IR, H NMR and mass spectral data
(Table 1). Compounds are assigned E-isomeric form on the basis of
1H NMR, olefinic proton appearing at d 7.6, characteristic of the E-isomer.
This methodology was also successfully extended to a-[bis(methylthio)-
methylene]-g-phenyl-Áb,g-butenolide (Scheme 2).
The present synthetic strategy is of general applicability to a-ylidene
g-butyrolactones from the respective Áb,g-butenolides. So far no method is
available for the reduction of Áb,g-butenolides to g-lactones.
Scheme 1.

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NOVEL ONE POT SYNTHESIS OF g-BUTYROLACTONES
2603
Table 1.
Entry
II, R
H (a)
2,6-di. Cl (b)
p-F (c)
p-CH3 (d)
m-OC6H5 (e)
p-OCH3 (f)
p-OH (g)
M.P. (ꢀC)
Yield (%)
1
2
3
4
5
6
7
119
125
74
124
146
94
98
93
95
98
95
96
92
197
Scheme 2.
In conclusion we present a very simple and practical method for the
synthesis of a-arylidene-g-butyrolactones, which are themselves active and
also serve as important building blocks for bioactive molecules,[9] with readily
available starting materials under mild reaction conditions with excellent
yields.
Typical procedure: The synthesis of a-(4-methylphenyl)-g-phenyl-g-
butyrolactone (Entry 4) is representative. To a solution of a-(4-methylphe-
nyl)-g-phenyl-Áb,g-butenolide (0.262 g, 1 mmol) in methyl alcohol (25 mL),
triethyl amine (0.101 g, 1 mmol) was added and the contents stirred at room
temperature (28ꢀC) for 0.5 h. Sodium borohydride (0.057 g, 1.5 mmol) was
added to it and the mixture was stirred at room temperature for additional
0.5 h and finally refluxed for 1 h. Solvent was removed under reduced pressure
and the residue was taken in ethyl acetate (25 mL). The ethyl acetate layer was
successfully washed with dilute hydrochloric acid (10%, 20 mL), followed
by water (2 ꢁ 25 mL). The organic layer was dried over anhydrous sodium
sulfate, concentrated and the product (IId) was isolated by column chro-
matography [silica gel/ethyl acetate : Hexane (5 : 95)] in 98% yield (0.258 g).[10]
ACKNOWLEDGMENT
One of the author (GSR) acknowledges UGC, New Delhi for financial
assistance.

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2604
REDDY, NEELAKANTAN, AND IYENGAR
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1. (a) Devon, T.K.; Scott, A.I. Hand Book of Naturally Occurring
Compounds; Academic Press: New York, 1972; Vol. 2, 79–175; (b)
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Hoffmann, H.M.R.; Rabe, J. Angew. Chem. Int. Ed. Engl. 1985, 24, 94.
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1976, 84, 116942x; Niwa, M.; Iguchi, M.; Yamamura, S. Chem. Lett.
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8. The intermediate ester was fully characterized on the basis of spectral
1
data: IR, H NMR, MS and HRMS.
9. Matsuda, I.; Murata, S.; Izumi, Y. Bull. Chem. Soc. Jpn. 1979, 52,
2389–2393.
10. IId. m.p. 124ꢀC; IR (CHCl3) cmꢂ1 : 1730 (C¼O, s); 1640 (C¼C, w).
1H NMR (200 MHz, CDCl3): d 3.02–3.19 (1H, dm, J ¼ 17.6 Hz),
3.6–3.75 (1H, ddd, J ¼ 17.6, 8.9, 2.3), 5.58 (1H, dd, J ¼ 8.8 and 6 Hz),
7.6 (1H, s), 7.2–7.45 (9H, m). MS : m/e 264 (Mþ). HRMS for
C18H16O2 : calcd, 264.115; found, 264.115. 1H NMR of all g-butyrolac-
tones exhibited similar pattern. Compound IIb exhibited the C-4 methy-
lene protons between 3.15–3.3 as ddd and between 2.7–2.8 as dm, a clean
upfield shift due to the chlorine atoms in the phenyl ring, confirming the
E-isomeric form of the product.
Received in the Netherlands August 24, 2001