Synthesis of isocoumarins and α-pyrones via iodocyclization

Article abstract of DOI:10.1016/S0040-4039(02)01731-8

A variety of 3-substituted 4-iodoisocoumarins and 6-substituted 5-iodo-2(2H)-pyranones are readily prepared in excellent yields under mild reaction conditions by the reaction of o-(1-alkynyl)benzoates and (Z)-2-alken-4-ynoates with ICl.

Full text of DOI:10.1016/S0040-4039(02)01731-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7401–7404
Synthesis of isocoumarins and a-pyrones via iodocyclization
Tuanli Yao and Richard C. Larock*
Department of Chemistry, Iowa State University, 2751 Gilman Hall, Ames, IA 50011, USA
Received 8 July 2002; accepted 12 August 2002
Abstract—A variety of 3-substituted 4-iodoisocoumarins and 6-substituted 5-iodo-2(2H)-pyranones are readily prepared in
excellent yields under mild reaction conditions by the reaction of o-(1-alkynyl)benzoates and (Z)-2-alken-4-ynoates with ICl.
© 2002 Published by Elsevier Science Ltd.
Isocoumarins1 and a-pyrones2 are useful intermediates
in the synthesis of a variety of carbocyclic and hetero-
cyclic compounds, including isocarbostyrils, isoquinoli-
nes, isochromenes, pyridones, and various aromatic
compounds. These lactones also occur as structural
subunits in numerous natural products that exhibit a
wide range of biological activities, such as antimicro-
bial,3 androgen-like,4 phytotoxic,5 antifungal6 and
pheromonal7 effects. Very recently, low molecular
weight a-pyrones have been shown to be potent HIV-1
protease inhibitors.8
the synthesis of isocoumarins and a-pyrones (Scheme
3). Herein, we wish to report that electrophilic cycliza-
tion using the corresponding ester-containing alkynes
and ICl provides a very regioselective method for the
synthesis of isocoumarins and a-pyrones.
The o-(1-alkynyl)benzoates and (Z)-2-alken-4-ynoates
required for our approach are readily prepared by
Sonogashira coupling of the corresponding iodo com-
pounds with terminal alkynes (Scheme 4). The yields
from this process range from 90 to 100% and this
procedure
functionality.
readily
accommodates
considerable
Traditional approaches to the synthesis of
isocoumarins9 and pyrones10 have been diverse and a
number of organometallic approaches have been
reported over the past few years.7,11 However, few very
general procedures have thus far been developed. Previ-
ous workers have reported the synthesis of
isocoumarins12 and 5,6-disubstituted 2(2H)-pyranones13
by the iodolactonization of 2-(1-alkynyl)benzoic acids
and 5-substituted (Z)-2-alken-4-ynoic acids, respec-
tively. Unfortunately, they have always obtained mix-
tures of 5- and 6-membered ring products (Scheme 1).
We first examined the reaction of our ester alkynes 1
and 3 (0.3 mmol in 3 ml of CH2Cl2) with ICl (1.2 equiv.
in 0.4 ml of CH2Cl2) (Table 1, entries 1 and 2).17 We
were pleased to see that these substrates reacted in less
than 30 min at room temperature with ICl to afford the
Oliver and Gandour have reported the bromolactoniza-
tion of two alkyl 2-(2-phenylethynyl)benzoates.14
Unfortunately, the scope of this cyclization has not
been further examined (Scheme 2).
Scheme 1.
Recently, efficient syntheses of benzo[b]thiophenes,15
isoquinolines16 and naphthyridines16 by electrophilic
cyclization have been developed. Our interest in extend-
ing this type of cyclization prompted us to reexamine
Keywords: isocoumarins; a-pyrones; iodocyclization.
* Corresponding author. Tel.: +1-515-294-4660; fax: +1-515-294-0105;
e-mail: larock@iastate.edu
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01731-8

7402
T. Yao, R. C. Larock / Tetrahedron Letters 43 (2002) 7401–7404
Scheme 3.
Scheme 5.
tion to I+ is followed by either SN2 attack of the
chloride on the R1 group when R1=Me or perhaps SN1
cleavage of the R1 group in the case of the t-butyl ester.
Scheme 4.
An interesting feature of this chemistry is the fact that
the iodoisocoumarins and iodo-2(2H)-pyranones can be
further elaborated using a variety of palladium-cata-
lyzed processes. For example, the Sonogashira coupling
reaction,19 Heck reaction,20 and Suzuki reaction21
afforded the corresponding products 18, 19 and 20 in
73%, 60% and 58% yields, respectively (Scheme 6).
desired isocoumarins 2 and 4 in 90% and 85% isolated
yields, respectively. The corresponding five-membered
ring lactones were not observed in either case. Virtually
no difference in the rate of reaction or the overall yield
was observed using an alkyne bearing an aryl group (1)
or a long chain alkyl group (3).
In conclusion, efficient syntheses of 3-substituted 4-
iodoisocoumarins and 6-substituted 5-iodo-2(2H)-pyra-
nones under very mild reaction conditions have been
developed. This methodology is successful with a vari-
ety of ester alkynes and affords the anticipated substi-
tuted isocoumarins and a-pyrones in excellent yields,
free of the corresponding 5-membered ring lactones.
Further investigation into the scope and limitations of
this novel electrophilic cyclization is underway.
To further test the scope of this electrophilic cycliza-
tion, alkynes bearing functional groups, including silyl
(5), vinylic (7), and hydroxy (9) groups, have been
allowed to react with ICl. We were pleased to find that
the alkyne bearing a Si(i-Pr)3 group (5) reacted with ICl
at room temperature to afford the corresponding 4-
iodoisocoumarin 618 in 96% yield. However, a mixture
of the desired isocoumarin 8 and an unidentified
byproduct was observed when the alkyne bearing a
vinylic group (7) was allowed to react with ICl at room
temperature. Interestingly, when the same reaction was
carried out at −78°C, the desired 4-iodoisocoumarin 8
was the only product formed in 98% yield. The alkyne
9 bearing a hydroxy group also afforded the corre-
sponding 4-iodoisocoumarin 10, but only in moderate
yield. Although no major sideproducts were obtained in
this later reaction, it is possible that cyclization of the
alcohol onto the carbon–carbon triple bond may be
lowering our overall yield. We also have examined the
reaction of the substituted o-(1-alkynyl)benzoate 11
with ICl (entry 6). Since electron-rich aryl groups might
potentially react with ICl, we carried out this reaction
at −78°C and were pleased to find that the desired
4-iodoisocoumarin 12 was the only product formed in a
99% isolated yield.
Surprisingly, the nature of the R1 group of the ester
had very little effect on the reaction rate or product
yield. Even a tert-butyl ester (13) cyclized in approxi-
mately the same time and yield as the corresponding
methyl ester (1) (compare entries 1 and 7). Based on
this observation, we propose the following mechanism
for this electrophilic cyclization (Scheme 5). Nucle-
ophilic attack of the oxygen of the carbonyl group on
the carbon–carbon triple bond activated by coordina-
Scheme 6.

T. Yao, R. C. Larock / Tetrahedron Letters 43 (2002) 7401–7404
Table 1. Synthesis of substituted isocoumarins and a-pyronesa
7403
Acknowledgements
References
We gratefully acknowledge the donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society, for partial support of this research and
Johnson Matthey, Inc. and Kawaken Fine Chemicals
Co., Ltd. for donations of palladium catalysts.
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17. A representative procedure for synthesis of the isocou-
marins and a-pyrones follows: the ester alkyne (0.30
mmol) in 3 ml of CH2Cl2 was placed in a 4 dram vial and
flushed with N2. The ICl (1.2 equiv.) in 0.5 ml of CH2Cl2
was added dropwise to the vial by a syringe. The reaction
was stirred at room temperature for 30 min. The reaction
mixture was then diluted with 50 ml of ether, washed
with 25 ml of satd Na2S2O3, dried (MgSO4) and filtered.
The solvent was evaporated under reduced pressure and
the product was isolated by chromatography on a silica
gel column. See Ref. 18 for representative spectral data.
18. Isocoumarin 6: purification by flash chromatography
(20:1 hexane/EtOAc) afforded 123.6 mg (96%) of the
product as a white solid: mp 117–120°C; 1H NMR
(CDCl3) l 1.13–1.23 (m, 18H), 1.63–1.74 (m, 3H), 7.65
(dt, J=0.9, 7.5 Hz, 1H), 7.79 (dt, J=1.2, 8.1 Hz, 1H),
7.95 (d, J=7.5 Hz, 1H), 9.18 (d, J=8.1 Hz, 1H); 13C
NMR (CDCl3) l 13.6, 18.9, 84.8, 125.8, 126.5, 127.1,
131.1, 134.3, 139.2, 153.1, 165.9; IR (neat, cm−1) 2946,
2866, 1784; HRMS calcd for C18H25IO2Si: 428.0668.
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