Synthesis of isocoumarins and α-pyrones via electrophilic cyclization

Article abstract of DOI:10.1021/jo034308v

A variety of substituted isocoumarins and α-pyrones are readily prepared in excellent yields under very mild reaction conditions by the reaction of o-(1-alkynyl)benzoates and (Z)-2-alken-4-ynoates with ICl, I₂, PhSeCl, p-O₂NC₆

Full text of DOI:10.1021/jo034308v

Syn th esis of Isocou m a r in s a n d r-P yr on es via
Electr op h ilic Cycliza tion
Tuanli Yao and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received March 8, 2003
A variety of substituted isocoumarins and R-pyrones are readily prepared in excellent yields under
very mild reaction conditions by the reaction of o-(1-alkynyl)benzoates and (Z)-2-alken-4-ynoates
with ICl, I2, PhSeCl, p-O2NC6H4SCl, and HI. This methodology accommodates various alkynyl esters
and has been successfully extended to the synthesis of polycyclic aromatic and biaryl compounds.
In tr od u ction
olefination by using simple olefins, as well as allylic and
vinylic halides or esters.9c Unsubstituted or 3-substituted
isocoumarins and pyrones have been prepared by the
palladium-catalyzed coupling of 2-halobenzoate esters,
2-halobenzoic acids or 2-halobenzonitriles with alkenes,11
vinylic stannanes12 or terminal alkynes13 and subsequent
cyclization, or π-allylnickel cross-coupling and palladium-
catalyzed cyclization.9a Isocoumarins and R-pyrones have
also been prepared by the palladium-catalyzed annula-
tion of internal alkynes.14
Isocoumarins1 and R-pyrones2 represent two important
classes of naturally occurring lactones, which are struc-
tural subunits in numerous natural products that exhibit
a wide range of biological activities, such as antimicro-
bial,3 androgen-like,4 phytotoxic,5 antifungal,6 and phero-
monal7 effects. Recently, low molecular weight R-pyrones
have been shown to be potent HIV-1 protease inhibitors.8
Considerable efforts have been directed toward the
synthesis of isocoumarins9 and R-pyrones10 either by
traditional approaches or by organometallic approaches.
Isocoumarins have been prepared by the ortho-thallation
of benzoic acids and subsequent palladium-catalyzed
Previous workers have reported the synthesis of iso-
coumarins15 and 5,6-disubstituted 2(2H)-pyranones16 by
the iodolactonization of 2-(1-alkynyl)benzoic acids and
5-substituted (Z)-2-alken-4-ynoic acids, respectively (eq
* Corresponding author.
(10) Synthesis of alkyl- and/or aryl-substituted R-pyrones. Cocata-
lyzed incorporation of two CO molecules into cyclopropenyl cations:
(a) Henry, W.; Hughes, R. P. J . Am. Chem. Soc. 1986, 108, 7876. Ni-
catalyzed incorporation of CO2 into dialkyl-substituted alkyne
dimers: (b) Inoue, Y.; Itoh, Y.; Kazama, H.; Hashimoto, H. Bull. Chem.
Soc. J pn. 1980, 53, 3329. Photoisomerization of 4-pyrones: (c) West,
F. G.; Hartke-Karger, C.; Koch, D. J .; Kuehn, C. E.; Arif, A. M. J . Org.
Chem. 1993, 58, 6795. (d) Pavlik, J . W.; Patten, A. D.; Bolin, D. R.;
Bradford, K. C.; Clennan, E. L. J . Org. Chem. 1984, 49, 4523. (e) Ishibe,
N.; Yutaka, S. J . Org. Chem. 1978, 43, 2138. (f) Ishibe, N.; Sunami,
M.; Odani, M. J . Am. Chem. Soc. 1973, 95, 463. Oxidation of
dienones: (g) Takata, T.; Tajima, R.; Ando, W. Chem. Lett. 1985, 665.
(h) Ho, T. L.; Hall, T. W.; Wong, C. M. Synth. Commun. 1973, 3, 79.
Reaction of sulfonium ylides with diphenylcyclopropenone: (i) Hayasi,
Y.; Nozaki, H. Tetrahedron 1971, 27, 3085. (j) Kotrestou, S. I.;
Georgiadis, M. P. Org. Prep. Proced. Int. 2000, 32, 161. (k) Tsuda, T.;
Morikawa, S.; Saegusa, T. J . Chem. Soc., Chem. Commun. 1989, 9. (l)
Liebeskind, L. S.; Wang, J . Tetrahedron 1993, 49, 5461. (m) Cerezo,
S.; Moreno-Man˜as, M.; Pleixats, R. Tetrahedron Lett. 1998, 54, 7813.
(n) Fringuelli, F.; Piermatt, O.; Pizzo, F. Heterocycles 1999, 50, 611.
(o) Tominaga, Y. Yuki Gosei Kagaku Kyokaishi 1989, 47, 413.
(11) (a) Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara, A. J .
Heterocycl. Chem. 1990, 27, 1419. (b) Sakamoto, T.; Kondo, Y.;
Yamanaka, H. Heterocycles 1988, 27, 453.
(12) (a) Sakamoto, T.; Kondo, Y.; Yasuhara, A.; Yamanaka, H.
Tetrahedron 1991, 47, 1877. (b) Rossi, R.; Bellina, F.; Biagetti, M.;
Catanese, A.; Mannina, L. Tetrahedron Lett. 2001, 41, 5281. (c) Bellina,
F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron 2000, 56, 2533.
(13) (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988,
27, 2225. (b) Sakamoto, T.; Annaka, M.; Kondo, Y.; Yamanaka, H.
Chem. Pharm. Bull. 1986, 34, 2754.
(14) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(15) Nagarajan, A.; Balasubramanian, T. R. Indian J . Chem. Sect.
B 1988, 27, 380.
(1) (a) Barry, R. D. Chem. Rev. 1964, 64, 229. (b) Houser, F. M.;
Baghdanov, V. M. J . Org. Chem. 1988, 53, 4647. (c) Mali, R. S.; Babu,
K. N. J . Org. Chem. 1998, 63, 2488 and references therein.
(2) (a) Kvita, V.; Fischer, W. Chimia 1992, 46, 457. (b) Kvita, V.;
Fischer, W. Chimia 1993, 47, 3. (c) Posner, G. H.; Nelson, T.; Kinter,
C.; J ohnson, N. J . Org. Chem. 1992, 57, 4083.
(3) (a) Barrero, A. F.; Oltra, J . E.; Herrador, M. M.; Sanchez, J . F.;
Quilez, J . F.; Rojas, F. J .; Reyes, J . F. Tetrahedron 1993, 49, 141. (b)
Abraham, W. R.; Arfmann, H. A. Phytochemistry 1988, 27, 3310.
(4) Schlingmann, G.; Milne, L.; Carter, G. T. Tetrahedron 1998, 54,
13013.
(5) Sato, H.; Konoma, K.; Sakamura, S. Agric. Biol. Chem. 1981,
45, 1675.
(6) (a) Simon, A.; Dunlop, R. W.; Ghisalberti, E. L.; Sivasitham-
param, K. Soil Biol. Biochem. 1988, 20, 263. (b) Claydon, N.; Asllan,
M.; Hanson, J . R.; Avent, A. G. Trans. Br. Mycol. Soc. 1987, 88, 503.
(c) Culter, H. G.; Cox, R. H.; Crumley, F. G.; Cole, P. O. Agric. Biol.
Chem. 1986, 50, 2943.
(7) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.; Meinwald, J . Tetra-
hedron Lett. 1995, 36, 71.
(8) Vara Prasad, J . V. N.; Para, K. S.; Lunney, E. A.; Ortwine, D.
F.; Dunbar, J . B.; Fergunson, D.; Tummino, P. J .; Hupe, D.; Tait, B.
D.; Domagala, J . M.; Humblet, C.; Bhat, T. N.; Liu, B.; Guerin, D. A.
M.; Baldwin, E. T.; Erickson, J . W.; Sawyer, T. K. J . Am. Chem. Soc.
1994, 116, 6989.
(9) (a) Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J . Org. Chem. 1977,
42, 1329. (b) Batu, G.; Stevenson, R. J . Org. Chem. 1980, 45, 1532. (c)
Larock, R. C.; Varaprath, S.; Lau, H. H.; Fellows, C. A. J . Am. Chem.
Soc. 1984, 106, 5274. (d) Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara,
A. J . Heterocycl. Chem. 1997, 27, 1783. (e) Liao, H.-Y.; Cheng, C.-H.
J . Org. Chem. 1995, 60, 3711. (f) Sashida, H.; Kawamukai, A. Synthesis
1999, 1145. (g) Sashida, H.; Kawamukai, A. Tetrahedron 2000, 56,
4777. (h) Napolitano, E. Org. Prep. Proced. Int. 1997, 29, 631. (i) Rossi,
R.; Bellina, F.; Biagetti, M.; Catanese, A.; Mannina, L. Tetrahedron
Lett. 2000, 41, 5281.
(16) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron
2001, 57, 2857.
10.1021/jo034308v CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003
5936
J . Org. Chem. 2003, 68, 5936-5942

Synthesis of Isocoumarins and R-Pyrones
SCHEME 1
1). These acids have always produced a mixture of five-
and six-membered-ring products.
CuI in Et3N solvent at 55 °C. The yields of this process
range from 80% to 100% and this procedure should
readily accommodate considerable functionality.
Oliver and Gandour have reported the bromolacton-
ization of alkyl 2-(2-phenylethynyl)benzoates (eq 2).17
Unfortunately, only two examples were reported and the
scope of this cyclization has not been examined.
To explore the scope of this electrophilic cyclization
strategy, the reactions of alkynyl ester 1 with different
electrophiles (ICl, I2, p-O2NC6H4SCl, PhSeCl, and HI) in
CH2Cl2 at room temperature have been studied (Table
1, entries 1-5). Excellent g90% yields of a single regio-
isomeric isocoumarin have been obtained in all cases. Of
all of the electrophilic reagents examined, ICl gave the
fastest reaction, followed by I2, p-O2NC6H4SCl, and
PhSeCl, while the reaction of HI took 96 h.
During the course of our investigation of the electro-
philic cyclization of analogous esters,18 Rossi et al.
reported the synthesis of isocoumarins and R-pyrones by
iodocyclization of the corresponding acetylenic esters.19
They report that the reactions of four 2-alken-4-ynoate
methyl esters with I2 in CH2Cl2 generally afford mixtures
of the corresponding iodo-pyrones and -furanones, but
that the reaction with ICl in CH2Cl2 produces predomi-
nantly the six-membered-ring lactones, albeit in only 51-
72% yields. Analogous reactions of four methyl 2-(aryl-
ethynyl)benzoates with I2 in MeCN produce excellent
yields of pure 4-iodoisocoumarins in two cases, but
mixtures of five- and six-membered-ring lactones in 26%
and 83% overall yields in the other two cases. The use of
ICl in CH2Cl2 afforded an 81% yield of an essentially pure
isocoumarin in one example, but only a 47% yield of a
55:45 mixture of six- and five-membered-ring products
in another. Herein, we wish to report the successful
electrophilic cyclization of analogous esters for the syn-
thesis of isocoumarins and R-pyrones. This chemistry
generally produces excellent yields of a single regioiso-
meric six-membered-ring lactone and can be extended to
electrophiles other than I2 and ICl. In a couple of cases,
five-membered-ring lactones are cleanly produced.
Both ICl and I2 are efficient and quite general for the
preparation of isocoumarins. Most of the functional
groups that we have studied so far have tolerated the
reaction conditions, and yields above 90% have been
obtained in most cases (entries 1, 2, 6-8, 10, 13, and 14).
Aryl-substituted (entries 1 and 2) and long-chain alkyl-
substituted alkynes (entries 6 and 7) are readily accom-
modated, and the presence of an olefin (entry 8) or an
alcohol group (entry 10) presents no difficulties. However,
alkynes bearing a H or Si(i-Pr)3 group (entries 11 and
12) have afforded exclusively the five-membered-ring
products as determined by the carbonyl stretch in their
IR spectra.9i Compound 14 has also been reported earlier
by Rossi.9b This is apparently due to the limited stability
of the resulting cationic intermediate19b (entry 11) and
the steric bulk of the Si(i-Pr)3 group (entry 12), respec-
tively (see the later mechanistic discussion). Isocou-
marins bearing electron-donating or electron-withdraw-
ing substituents in the 4- and/or 5-positions of the
aromatic ring have also been synthesized in excellent
yields (entries 13 and 14). These cyclizations are not
limited to simple methyl esters. The corresponding tert-
butyl ester 22 has been cyclized by ICl in a quantitative
yield (entry 16).
Resu lts a n d Discu ssion
We next examined the possibility of preparing R-py-
rones by this same methodology. (Z)-2-Alken-4-ynoates
bearing both an aryl group (23) and an alkyl group (27)
on the acetylene moiety have reacted with ICl, p-O2-
NC6H4SCl, or PhSeCl to produce the corresponding
R-pyrones 24, 25, 26, and 28 in excellent yields (entries
17-20). Ethyl (Z)-2-methyl-5-phenyl-2-alken-4-ynoate
(29) reacts with ICl to afford a 59% yield of the desired
5-iodo-R-pyrone 30, along with an inseparable byproduct
(entry 21). Fortunately, when using I2, the iodocyclization
product 30 is obtained as the only product in an 84% yield
(entry 22). Ethyl (Z)-3,5-diphenyl-2-alken-4-ynoate (31)
also gives a single pyrone product 32 in an 84% yield
(entry 23). However, when 2,3-disubstituted (Z)-2-alken-
4-ynoates are employed, mixtures of five- and six-
membered-ring products are obtained no matter whether
I2, ICl, or PhSeCl is employed as the electrophile (entries
24-27). Thus, it appears that steric effects play an
important role in the regioselectivity of cyclization. The
more bulky the substituents are in positions 2 and 3 of
A two-step approach to isocoumarins and R-pyrones
has been examined involving (i) preparation of o-(1-
alkynyl)benzoates and (Z)-2-alken-4-ynoates by a Son-
agashira coupling reaction20 and (ii) electrophilic cycliza-
tion (Scheme 1).
The o-(1-alkynyl)benzoates and (Z)-2-alken-4-ynoates
required for our approach are readily prepared by Sono-
gashira coupling20 of the corresponding iodo compounds
with terminal alkynes, using 2% PdCl2(PPh3)2 and 1%
(17) Oliver, M. A.; Gandour, R. D. J . Org. Chem. 1984, 49, 558.
(18) For a preliminary communication, see: Yao, T.; Larock, R. C.
Tetrahedron Lett. 2002, 43, 7401.
(19) (a) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R.
Tetrahedron 2002, 58, 5023. (b) Rossi, R.; Carpita, A.; Bellina, F.;
Stabile, P.; Mannina, L. Tetrahedron 2003, 59, 2067.
(20) For reviews, see: (a) Campbell, I. B. The Sonogashira Cu-Pd-
Catalyzed Alkyne Coupling Reaction. Organocopper Reagents; Tayler,
R. T. K., Ed.; IRL Press: Oxford, UK, 1994, pp 217-235. (b) Sono-
gashira, K.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi 1993, 51,
1053. (c) Sonogashira, K. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, UK, 1991; Vol. 3, pp 521-549.
J . Org. Chem, Vol. 68, No. 15, 2003 5937

Yao and Larock
TABLE 1. Syn th esis of Su bstitu ted Isocou m a r in s a n d r-P yr on es (Sch em e 1)a
5938 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Isocoumarins and R-Pyrones
Ta ble 1 (Con tin u ed )
J . Org. Chem, Vol. 68, No. 15, 2003 5939

Yao and Larock
Ta ble 1 (Con tin u ed )
a
All reactions were run under the following conditions, unless otherwise specified: 0.30 mmol of the o-(1-alkynyl)benzoate or (Z)-2-
alken-4-ynoate in 3 mL of CH2Cl2 was placed in a 4-dram vial under N2 and 1.2 equiv of electrophile in 0.4 mL of CH2Cl2 was added at
b
room temperature. The reaction was run at -78 °C. c This product could not be obtained completely pure.
the (Z)-2-alken-4-ynoates, the lower the yield of the six-
membered-ring product (compare entries 23 and 26, and
24 and 25). The bulkier substituents on the (Z)-2-alken-
4-ynoates apparently force the oxygen of the carbonyl
group closer to C-4 of the alkenynoate ester resulting in
the five-membered-ring product (see the later mechanis-
tic discussion). The nature of the electrophile plays an
important role in these cyclization reactions. Compared
5940 J . Org. Chem., Vol. 68, No. 15, 2003

Synthesis of Isocoumarins and R-Pyrones
SCHEME 2
with I2, the stronger electrophilic reagent ICl affords a
higher yield of the six-membered-ring product (compare
entries 25 and 26), although the five-membered-ring
lactone still predominates.
Ring-containing esters can also be used in this iodocy-
clization process (entries 28-33). The six-membered-ring
ester 41 gives a 55% yield of the five-membered-ring
product 42 with ICl (entry 28), and a 60% yield of the
five-membered-ring product 43 with PhSeCl (entry 29).
We believe that the six-membered cyclohexenyl ring in
41 forces the oxygen of the carbonyl group closer to C-4
of the alkenynoate ester resulting in five-membered ring
formation (see the later mechanistic discussion). Inter-
estingly, the five-membered-ring-containing esters 44
and 46 give only products of addition of ICl across the
carbon-carbon triple bond. However, by using I2 instead
of ICl, both substrates 44 and 46 afford the desired
bicyclic R-pyrones 45 and 47 respectively as the only
products in excellent yields (entries 31 and 33). Note that
these two iodocyclization reactions take a much longer
time to reach completion. A reasonable explanation is
that the reaction is slowed because the oxygen of the
carbonyl group is oriented away from the carbon-carbon
triple bond (see the later mechanistic discussion).
A biisocoumarin has also been prepared by this cy-
clization methodology as shown in entry 34. When ICl
or I2 is used at room temperature, a mixture of the
desired biisocoumarin 49 and an inseparable byproduct
were obtained. However, ICl at -78 °C afforded the
biisocoumarin 49 as the only product in a 90% yield.
Our iodocyclization results are generally consistent
with those reported by Rossi.19 For instance, in our work,
with ICl or I2 as the electrophile and CH2Cl2 as the
solvent, the reactions generally afford six-membered-ring
lactones, except for alkynes 13, 15, and 41, where five-
membered-ring lactones are formed exclusively, and
alkynes 33 and 36, where mixtures of five- and six-
membered-ring lactones are produced. Rossi has usually
obtained a mixture of five- and six-membered-ring prod-
ucts from the cyclization of esters when using solvents
other than CH2Cl2 and claimed that the solvent employed
effects the regioselectivity of iodocyclization.19a With ICl
and CH2Cl2, Rossi obtained almost exclusively the six-
membered-ring lactone from the cyclization of ester 1,
and in some other cases, small amounts of five-membered-
ring lactones were detected. Rossi obtained a mixture of
(E)- and (Z)-five-membered-ring lactone 14 when using
alkyne 13.19b However, in our case, only (E)-14 was
obtained. We would like to point out that our reaction
times (0.5-1 h) are much shorter than Rossi’s (3-3.5 h),
which might be the reason we get higher yields and better
stereoselectivity.
An interesting feature of this process is the fact that
the iodoisocoumarins and iodo-2(2H)-pyrones generated
can be further elaborated by using various palladium-
catalyzed processes. For example, the Sonagashira (eq
3),20 Heck (eq 4),21 and Suzuki reactions (eqs 5 and 6)22
afford the corresponding products 50-53, respectively,
in good yields.
Con clu sion s
Efficient syntheses of a wide variety of substituted
isocoumarins and R-pyrones have been developed under
very mild reaction conditions. This methodology accom-
modates a variety of alkynyl esters with various func-
tional groups and affords the anticipated substituted
isocoumarins and R-pyrones in excellent yields. In a few
cases, five-membered-ring lactones or mixtures of five-
and six-membered-ring lactones are formed. The result-
ing iodine-containing products are readily elaborated to
Surprisingly, the nature of the R1 group on the ester
had very little effect on the reaction rate or the product
yield. Even a tert-butyl ester 22 cyclized in approximately
the same time and yield as the corresponding methyl
ester 1 (compare entries 1 and 16). On the basis of this
observation, we propose the following mechanism for this
electrophilic cyclization (Scheme 2). Nucleophilic attack
by the oxygen of the carbonyl group on the carbon-
carbon triple bond activated by coordination 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 tert-butyl ester.
(21) For leading reviews of the Heck reaction, see: (a) de Meijere,
A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (b)
Shibasaki, M.; Boden, C. D. J .; Kojima, A. Tetrahedron 1997, 53, 7371.
(c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d) Overman,
L. E. Pure Appl. Chem. 1994, 66, 1423
J . Org. Chem, Vol. 68, No. 15, 2003 5941

Yao and Larock
evaporated under reduced pressure and the product was
isolated by chromatography on a silica gel column.
more complex products by using known organopalladium
chemistry. Although Rossi et al.19 have reported several
reactions of alkynyl esters with ICl or I2, we have
extended the above chemistry to the synthesis of poly-
cyclic aromatic and biisocoumarins and generally ob-
tained cleaner reactions. We have also shown that
electrophiles other than I2 and ICl, namely HI, PhSeCl,
and p-O2NC6H4SCl, can be used in this chemistry.
4-Iod o-3-p h en yl-6,7-d ih yd r ocyclop en t a [c]p yr a n -1-5-
(H)-on e (45). Purification by flash chromatography (5:1 hex-
ane/EtOAc) afforded 86 mg (85%) of the product as a white
solid: mp 134-135 °C; 1H NMR (CDCl3) δ 2.07-2.18 (m, 2H),
2.92-3.05 (m, 4H), 7.42-7.47 (m, 3H), 7.68-7.72 (m, 2H); 13
C
NMR (CDCl3) δ 21.7, 31.7, 40.7, 70.3, 125.6, 128.3, 129.8, 130.6,
134.0, 159.8, 160.6, 163.1; IR (neat, cm-1) 1723; HRMS calcd
for
C14H11O2I 337.9804, found 337.9808. Anal. Calcd for
C
14H11O2I: C, 49.73; H, 3.28. Found: C, 49.62; H, 2.81.
Gen er a l P r oced u r e for th e Electr op h ilic Cycliza tion
Exp er im en ta l Section
of Ester Alk yn es by P h SeCl or p-O2NC6H4SCl. The ester
alkyne (0.30 mmol), PhSeCl or p-O2NC6H4SCl (1.5 equiv), and
CH2Cl2 (3 mL) were placed in a 4-dram vial and flushed with
N2. The reaction mixture was stirred at room temperature for
1 h unless otherwise indicated. The solvent was evaporated
under reduced pressure and the product was isolated by
chromatography on a silica gel column.
Gen er a l P r oced u r e for P r ep a r a t ion of t h e E st er
Alk yn es. To a solution of the corresponding organic iodide or
triflate (1.0 mmol) and the terminal alkyne (1.2 mmol, 1.2
equiv) in Et3N (4 mL) were added PdCl2(PPh3)2 (1.4 mg, 2 mol
%) and CuI (2.0 mg, 1 mol %). The resulting mixture was then
heated under an N2 atm at 55 °C. The reaction was monitored
by TLC to establish completion. When the reaction was
complete, the mixture was allowed to cool to room temperature,
and the ammonium salt was removed by filtration. The solvent
was removed under reduced pressure and the residue was
purified by column chromatography on silica gel to afford the
corresponding ester alkyne.
3-P h en yl-4-(p h en ylselen yl)isocou m a r in (4). Purification
by flash chromatography (7:1 hexane/EtOAc) afforded 124 mg
(95%) of the product as a white solid: mp 137-139 °C; 1H NMR
(CDCl3) δ 7.12-7.22 (m, 5H), 7.38-7.48 (m, 3H), 7.54 (t, J )
7.5 Hz, 1H), 7.65-7.74 (m, 3H), 8.05 (d, J ) 8.1 Hz, 1H), 8.37
(dd, J ) 8.1, 1.2 Hz, 1H); 13C NMR (CDCl3) δ 105.0, 121.1,
126.7, 128.1, 128.5, 129.0, 129.1, 129.7, 129.9, 130.0, 130.4,
132.1, 134.3, 135.6, 138.7, 159.8, 162.0; IR (neat, cm-1) 1739;
HRMS calcd for C21H14O2Se 378.0160, found 378.0167.
Gen er a l P r oced u r e for th e Electr op h ilic Cycliza tion
of Ester Alk yn e 1 by HI. The ester alkyne 1 (0.30 mmol),
40% HI (2.0 equiv), and CH2Cl2 (3 mL) were placed in a 4-dram
vial and flushed with N2. The reaction mixture was stirred at
room temperature for 96 h. The reaction mixture was then
diluted with 50 mL of ether, washed with 25 mL of satd aq
NaHCO3 and 25 mL of H2O, dried (MgSO4), and filtered. The
solvent was evaporated under reduced pressure and the
product was isolated by chromatography on a silica gel column.
3-P h en ylisocou m a r in (5). Purification by flash chroma-
tography (20:1 hexane/EtOAc) afforded 63 mg (92%) of the
product as a white solid with spectral properties identical with
those previously reported: mp 87-89 °C (lit.24 mp 90-91 °C).
Meth yl 2-(P h en yleth yn yl)ben zoa te (1). Purification by
flash chromatography (10:1 hexane/EtOAc) afforded 235 mg
(99%) of the product as a yellow liquid with spectral properties
identical with those previously reported.23
Gen er a l P r oced u r e for th e Electr op h ilic Cycliza tion
of Ester Alk yn es by ICl. 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 with a syringe. The reaction was stirred at room
temperature for 30 min unless otherwise indicated. The
reaction mixture was then diluted with 50 mL of ether, washed
with 25 mL of satd aq Na2S2O3, dried (MgSO4), and filtered.
The solvent was evaporated under reduced pressure and the
product was isolated by chromatography on a silica gel column.
4-Iod o-3-p h en ylisocou m a r in (2). Purification by flash
chromatography (10:1 hexane/EtOAc) afforded 94.6 mg (90%)
of the product as a white solid with spectral properties
identical with those previously reported: mp 137-138 °C
(lit.19a mp 136-138 °C).
Gen er a l P r oced u r e for th e Electr op h ilic Cycliza tion
of Ester Alk yn es by I2. The ester alkyne (0.30 mmol), I2 (1.2
equiv), and 3 mL of CH2Cl2 were placed in a 4-dram vial and
flushed with N2. The reaction was stirred at room temperature
for 60 min unless otherwise indicated. The reaction mixture
was then diluted with 50 mL of ether, washed with 25 mL of
satd aq Na2S2O3, dried (MgSO4), and filtered. The solvent was
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, and the National
Science Foundation for partial support of this research,
and J ohnson Matthey, Inc. and Kawaken Fine Chemi-
cals Co., Ltd. for donations of palladium catalysts.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for the compounds listed in Table 1 and experimental
procedures and characterization data for the reactions sum-
marized in eqs 3-6. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457. (b) Suzuki, A. J . Organomet. Chem. 1999, 576, 147. Suzuki,
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J ., Eds.; Wiley-VCH: New York, 1998; Chapter 2.
J O034308V
(23) Shi, C.; Zhang, Q.; Wang, K. K. J . Org. Chem. 1999, 64, 925.
(24) Gray, T. I.; Pelter, A.; Ward, R. S. Tetrahedron 1979, 35, 2539.
5942 J . Org. Chem., Vol. 68, No. 15, 2003