Synthesis of isocoumarins and α-pyrones via palladium-catalyzed annulation of internal alkynes

Article abstract of DOI:10.1021/jo9821628

A number of 3,4-disubstituted isocoumarins and polysubstituted α- pyrones have been prepared in good yields by treating halogen- or triflate- containing aromatic and α,β-unsaturated esters, respectively, with internal alkynes in the presence of a palladiu

Full text of DOI:10.1021/jo9821628

8770
J . Org. Chem. 1999, 64, 8770-8779
Syn th esis of Isocou m a r in s a n d r-P yr on es via P a lla d iu m -Ca ta lyzed
An n u la tion of In ter n a l Alk yn es
Richard C. Larock,* Mark J . Doty, and Xiaojun Han
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received October 27, 1998
A number of 3,4-disubstituted isocoumarins and polysubstituted R-pyrones have been prepared in
good yields by treating halogen- or triflate-containing aromatic and R,â-unsaturated esters,
respectively, with internal alkynes in the presence of a palladium catalyst. Synthetically, the
methodology provides an especially simple and convenient, regioselective route to isocoumarins
and R-pyrones containing aryl, silyl, ester, tert-alkyl, and other hindered groups. The reaction is
believed to proceed through a seven-membered palladacyclic complex in which the regiochemistry
of the reaction is controlled by steric factors. A number of 3,4-disubstituted isocoumarins and
polysubstituted R-pyrones have been prepared in good yields by treating halogen- or triflate-
containing aromatic and R,â-unsaturated esters, respectively, with internal alkynes in the presence
of a palladium catalyst. Synthetically, the methodology provides an especially simple and convenient
regioselective route to isocoumarins and R-pyrones containing aryl, silyl, ester, tert-alkyl, and other
hindered groups. The reaction is believed to proceed through a seven-membered palladacyclic
complex in which the regiochemistry of the reaction is controlled by steric factors.
In tr od u ction
marins have been synthesized by the palladium-catalyzed
coupling of 2-(2′,2′-dibromovinyl)benzoates and organo-
stannanes.12 The cross-coupling of o-iodobenzoic acid and
terminal alkynes produces either unsaturated phthal-
ides13 or 3-substituted isocoumarins14 as major products.
Pertinent to the present work, R-pyrones have been
synthesized by the cyclization of open-chain 2,4-penta-
dienoic acids using lithium chloropalladite15 or formed
as unstable multiple-insertion products from the reaction
of palladium complexes with internal alkynes.16
Isocoumarins1 and R-pyrones2 are useful intermediates
in the synthesis of a variety of important hetero- and
carbocyclic molecules, including isocarbostyrils, isoquino-
lines, isochromenes, pyridones, and various aromatic
compounds. These lactones also occur as structural
subunits in numerous natural products that exhibit a
wide range of biological activity.3 Very recently, low
molecular weight R-pyrones have been shown to be potent
HIV-1 protease inhibitors.4
Although traditional approaches to the synthesis of
these ring systems have been diverse,1b,5,6 a number of
organometallic approaches utilizing palladium have been
reported over the past few years. Isocoumarins have been
prepared by the ortho-thallation of benzoic acids and
subsequent palladium-catalyzed olefination using simple
olefins, allylic halides, and vinylic halides or esters.7
Unsubstituted or 3-substituted isocoumarins have been
prepared by the palladium-catalyzed coupling of 2-ha-
lobenzoate esters or 2-halobenzonitriles with alkenes,8
vinylic stannanes,9 or terminal alkynes10 and subsequent
cyclization or π-allylnickel cross-coupling and palladium-
catalyzed cyclization.11 Recently, 3-substituted isocou-
In 1989, Heck reported the direct formation of 3,4-
diphenylisocoumarin in 56% yield from the palladium-
(6) 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.; Keil, E. B.; Sullivan, E. L. J .
Heterocycl. Chem. 1992, 29, 1829. (e) Pavlik, J . W.; Patten, A. D.; Bolin,
D. R.; Bradford, K. C.; Clennan, E. L. J . Org. Chem. 1984, 49, 4523.
(f) Ishibe, N.; Yutaka, S. J . Org. Chem. 1978, 43, 2138. (g) Ishibe, N.;
Sunami, M.; Odani, M. J . Am. Chem. Soc. 1973, 95, 463. Oxidation of
dienones: (h) Takata, T.; Tajima, R.; Ando, W. Chem. Lett. 1985, 665.
(i) Ho, T. L.; Hall, T. W.; Wong, C. M. Synth. Commun. 1973, 3, 79.
Reaction of sulphonium ylides with diphenylcyclopropenone: (j) Ha-
yasi, Y.; Nozaki, H. Tetrahedron 1971, 27, 3085.
(7) Larock, R. C.; Varaprath, S.; Lau, H. H.; Fellows, C. A. J . Am.
Chem. Soc. 1984, 106, 5274.
(8) (a) Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara, A. J . Hetero-
cycl. Chem. 1990, 27, 1419. (b) Sakamoto, T.; Kondo, Y.; Yamanaka,
H. Heterocycles 1988, 27, 453.
(9) Sakamoto, T.; Kondo, Y.; Yasuhara, A.; Yamanaka, H. Tetrahe-
dron 1991, 47, 1877.
(10) (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988,
27, 2225. (b) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka, H.
Chem. Pharm. Bull. 1986, 34, 2754. (c) Sakamoto, T.; An-naka, M.;
Kondo, Y.; Araki, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1890.
(11) Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J . Org. Chem. 1977,
42, 1329.
(12) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625.
(13) Kundu, N. G.; Pal, M. J . Chem. Soc., Chem. Commun. 1993,
86.
* To whom correspondence should be addressed. Phone: 515-294-
4660. Fax: 515-294-0105. E-mail: larock@iastate.edu
(1) (a) Barry, R. D. Chem. Rev. 1964, 64, 229. (b) Houser, F. M.;
Baghdanov, V. M. J . Org. Chem. 1988, 53, 4676. (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) Hill, R. A. In Progress in the Chemistry of Organic Natural
Products; Springer-Verlag: Weinheim-New York, 1986; Vol. 49, pp
1-78. (b) Dickinson, J . Nat. Prod. Rep. 1993, 10, 71.
(4) Vara Prasad, J . V. N.; Para, K. S.; Lunney, E. A.; Ortwine, D.
F.; Dunbar, J . B.; Ferguson, D.; Tummino, P. J .; Hupe, D.; Tait, B. D.;
Domagala, J . M.; Humblet, C.; Bhat, T. N.; Liu, B.; Guerin, D. A. M.;
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10.1021/jo9821628 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/30/1999

Synthesis of Isocoumarins and R-Pyrones
J . Org. Chem., Vol. 64, No. 24, 1999 8771
catalyzed coupling of methyl 2-iodobenzoate and diphen-
ylacetylene (eq 1).17 Di-p-anisylacetylene and 1-phenyl-
1-hexyne afforded only 38% and 29% yields, respectively,
of the corresponding isocoumarins. Because of our own
interest in this type of annulation process,18 we have
extended this annulation methodology to a general
synthesis of isocoumarins19 and R-pyrones20 and report
those results here.
very little effect on the reaction rate or product yield as
shown in eq 3. Even the neopentyl, phenyl, and tert-butyl
o-iodobenzoate esters cyclized in approximately the same
time and yield as the corresponding methyl ester. It is
necessary to use an ester in this annulation process, as
attempted annulation using the parent carboxylic acid,
o-iodobenzoic acid, resulted in disappearance of the
starting material and formation of only a trace amount
of the desired product.
Resu lts a n d Discu ssion
We have developed a simple procedure for the annu-
lation of internal alkynes by appropriate halogen- or
triflate substituted esters (eq 2). Our results using this
procedure for the synthesis of isocoumarins are sum-
marized in Table 1, entries 1-12.
This annulation process is highly regioselective for
alkynes containing tertiary alkyl, aryl, trialkylsilyl, or
other hindered groups, with the only product having the
more sterically demanding group in the position adjacent
to the heteroatom (Table 1, entries 4-12). However, high-
yielding, clean reactions are generally limited to these
types of alkynes. Attempted annulation of less substi-
tuted alkynes, such as 4-octyne, lead to complex reaction
mixtures. Highly substituted naphthalene derivatives
were also formed in some cases, as in the reaction of
1-phenyl-1-propyne and methyl 2-iodobenzoate under
slightly different reaction conditions (eq 4). The regio-
chemical assignment of the naphthalene isomers is based
1
on H NMR deshielding of the methyl group by the ester
carbonyl group in the major isomer and the assumption
that the second alkyne insertion proceeds regioselectively
as described in our recent analogous polycyclic aromatic
hydrocarbon chemistry.18g
Isocoumarins can be prepared from either o-iodo- or
o-bromobenzoate esters, although the o-iodobenzoate
esters generally afford shorter reaction times and higher
yields (Table 1, entries 1 and 2). The corresponding aryl
triflate was also treated with internal alkynes under
these same conditions, but failed to produce any isocou-
marin product, even after 6 days (Table 1, entry 3).
Surprisingly, the nature of the R group on the ester had
(17) Tao, W.; Silverberg, L. J .; Rheingold, A. L.; Heck, R. F.
Organometallics 1989, 8, 2550.
(18) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K. Synlett 1990, 529. (c) Larock, R. C.;
Berrios-Pen˜a, N. G.; Fried, C. A. J . Org. Chem. 1991, 56, 2615. (d)
Larock, R. C.; Berrios-Pen˜a, N. G.; Narayanan, K. J . Org. Chem. 1990,
55, 3447. (e) Larock, R. C.; Fried, C. A. J . Am. Chem. Soc. 1990, 112,
5882. (f) Roesch, K. R.; Larock, R. C. J . Org. Chem. 1998, 63, 5306. (g)
Larock, R. C.; Tian, Q. J . Org. Chem. 1998, 63, 2002. (h) Larock, R.
C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org. Chem. 1997, 62, 7536.
(i) Larock, R. C.; Berrios-Pen˜a, N. G.; Fried, C. A.; Yum, E. K.; Tu, C.;
Leong, W. J . Org. Chem. 1993, 58, 4509. (j) Larock, R. C.; Doty, M. J .;
Cacchi, S. J . Org. Chem. 1993, 58, 4579. (k) Larock, R. C.; Zenner, J .
M. J . Org. Chem. 1995, 60, 482. (l) Larock, R. C.; Guo, L. Synlett 1995,
465. (m) Larock, R. C.; Yum, E. K. Tetrahedron 1996, 52, 2743. (n)
Larock, R. C.; He, Y.; Leong, W. W.; Han, X.; Refvik, M. D.; Zenner, J .
M. J . Org. Chem. 1998, 63, 2154. (o) Larock, R. C.; Doty, M. J .; Han,
X. Tetrahedron Lett. 1998, 39, 5143. (p) Larock, R. C.; Yum, E. K.;
Refvik, M. D. J . Org. Chem. 1998, 63, 7652. (q) Larock, R. C.; Tian,
Q.; Pletnev, A. A. J . Am. Chem. Soc. 1999, 121, 3238. (r) Larock, R. C.
J . Organomet. Chem. 1999, 576, 111.
Alkynes containing a terminal trimethylsilyl group can
be annulated in good yield, albeit at a slower rate, by
changing the solvent from dimethylformamide to aceto-
nitrile, if the alkyne has a large group, such as a phenyl
or 1-cyclohexenyl group, on the other end of the triple
bond (Table 1, entries 7 and 8). Gas chromatographic
analysis indicated that acetonitrile prevented desilylation
of the alkyne under the reaction conditions. However, for
similar alkynes having smaller alkyl groups on the
opposite side of the triple bond, such as 1-(trimethylsilyl)-
propyne, acetonitrile failed to prevent desilylation of the
(19) For a preliminary communication on isocoumarin synthesis,
see: Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. C. J . Org. Chem.
1995, 60, 3270.
(20) For a preliminary communication on R-pyrone synthesis, see:
Larock, R. C.; Han, X.; Doty, M. J ., Tetrahedron Lett. 1998, 39, 5713.

8772 J . Org. Chem., Vol. 64, No. 24, 1999
Larock et al.
Ta ble 1. Syn th esis of Isocou m a r in s a n d r-P yr on es Via An n u la tion of In ter n a l Alk yn es (Eqs 2 a n d 8)a

Synthesis of Isocoumarins and R-Pyrones
J . Org. Chem., Vol. 64, No. 24, 1999 8773
Ta ble 1 (Con tin u ed )

8774 J . Org. Chem., Vol. 64, No. 24, 1999
Larock et al.
Ta ble 1 (Con tin u ed )

Synthesis of Isocoumarins and R-Pyrones
J . Org. Chem., Vol. 64, No. 24, 1999 8775
Ta ble 1 (Con tin u ed )
a
All of the reactions were run in the presence of 5 mol % of Pd(OAc)2 (except entry 12, 10 mol % Pd(OAc)2), 1 equiv of Na2CO3, 1 equiv
b
of LiCl, 5 ml of DMF (except entries 6-8, 5 mL of CH3CN) at 100 °C. A colon (:) indicates that the products were inseparable, and a plus
sign (+) indicates that they were separated. c Yields refer to isolated compounds purified by chromatography. All of these compounds
gave satisfactory 1H NMR, 13C NMR, HRMS, and IR spectra. This reaction was run in the presence of 2.5 equiv of LiCl. e This reaction
d
was run in the presence of 3.0 equiv of LiCl. f This reaction was run in the presence of 2.0 equiv of Na2CO3.
Sch em e 1
alkyne and hence resulted in low product yields. There-
fore, progressively more steric hindrance had to be
introduced into the silyl moiety of these alkynes in order
to maintain clean, high-yielding reactions (Table 1,
entries 9 and 10). While the majority of the isocoumarin
reactions have been run on only a 0.5 mmol scale, the
transformation depicted in entry 10 of Table 1 was
increased to 5.0 mmol, which resulted in an almost
identical yield (72% versus 76%).
The regiochemistry has been established for the prod-
ucts of entries 721 and 107 of Table 1 by comparison with
known compounds following desilylation (see below). On
the basis of these results, the regiochemistry indicated
in Table 1 is assumed for all other products containing a
tertiary center.
The annulation of 4,4-dimethyl-2-pentyne by â-naph-
thyl 2-iodobenzoate resulted in a 73% yield of 3-tert-butyl-
4-methylisocoumarin and recovery of 53% of â-naphthol.
On the basis of these results, we believe that this
annulation process proceeds as shown in Scheme 1 by a
sequence involving (1) reduction of Pd(OAc)2 to the actual
catalyst Pd(0), (2) oxidative addition of the starting halide
or triflate to Pd(0), (3) aryl- or vinylpalladium coordina-
tion to the alkyne and subsequent insertion to form a
vinylpalladium intermediate, (4) attack of the carbonyl
oxygen on the vinylpalladium intermediate to form a
seven-membered palladacyclic complex, and (5) regenera-
tion of the Pd(0) catalyst by reductive elimination and
formation of the salt. Loss of the R group of the ester is
thought to occur either during the reaction by either an
SN1 or SN2 process or during the aqueous workup, but
the real path for this step is unclear.
(21) Beautement, K.; Clough, J . M. Tetrahedron Lett. 1984, 25, 3025.

8776 J . Org. Chem., Vol. 64, No. 24, 1999
Larock et al.
Sch em e 2
Although the process is limited to the annulation of
hindered internal alkynes, the methodology proves to be
very convenient and general for the synthesis of 4-sub-
stituted isocoumarins as well, via the silylated products,
since the silyl moiety can readily be cleaved at room
temperature in the presence of potassium fluoride dihy-
drate and tetra-n-butylammonium chloride (eq 5).22
equiv of NaCN, and 1.5 equiv of AcOH in MeOH at room
temperature to provide the desired (Z)-methyl â-iodo-
substituted 2-propenoates 14-19.25 The triflates 20 and
21 were synthesized from the corresponding â-keto ester
(eq 6).26 The stereochemistry of the triflates 20 and 21
1
was assigned by H NMR spectral analysis based on the
fact that the chemical shift of a methyl group cis to an
ester group appears further downfield due to the deshield-
ing effect of an ester group.27
We next examined the possibility of preparing R-py-
rones by this same methodology. The starting materials
for our R-pyrone synthesis, â-iodo-substituted prope-
noates, were synthesized by the reactions shown in
Scheme 2. (Z)-â-Iodo-substituted 2-propenols 2-6 were
synthesized by the CuI-catalyzed Grignard addition
across the triple bond of an appropriate propargylic
alcohol and subsequent quenching by I2.23 Alcohol 7 was
prepared by the reaction of 3-phenyl-2-propyn-1-ol with
Red-Al [NaAlH2(OCH2CH2OMe)2], followed by quenching
with I2.24 Oxidation of the (·)-â-iodo-substituted 2-pro-
penols with 20 equiv of MnO2 in CH2Cl2 at room tem-
perature afforded the corresponding aldehydes 8-13.25
The resulting (Z)-â-iodo-substituted 2-propenals were
subjected to a second oxidation by 20 equiv of MnO2, 5.2
The diiodide 22 was synthesized in 88% yield according
to a literature procedure (eq 7).28
Methyl (Z)-3-bromo-3-iodo-2-phenyl-propenoate (23)
was prepared according to the reactions shown in Scheme
3.25,29
The palladium-catalyzed annulation of a variety of
internal alkynes using the above-mentioned vinylic io-
dides and triflates has been carried out as shown in eq
8. The reaction conditions chosen are those used for the
(22) Carpino, L. A.; Sau, A. C. J . Chem. Soc., Chem. Commun. 1979,
514.
(23) Duboudin, J . G.; J ousseaume, B. J . Organomet. Chem. 1979,
168, 1.
(24) Marshall, J . A.; Shearer, B. G.; Crooks, S. L. J . Org. Chem.
1987, 52, 1236.
(25) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616.
(26) Crisp, G.; Meyer, A. J . Org. Chem. 1992, 57, 6972.
(27) Gibbs, R.; Krishnan, U.; Dolence, J .; Poulter, C. J . Org. Chem.
1995, 60, 7821.
(28) Bonnet, B.; Gallic, Y.; Ple, G.; Duhamel, L. Synthesis 1993,
1071.
(29) Bovonsombat, P.; McNelis, E. Tetrahedron Lett. 1992, 33, 7705.

Synthesis of Isocoumarins and R-Pyrones
J . Org. Chem., Vol. 64, No. 24, 1999 8777
Sch em e 3
synthesis of isocoumarins. The results are summarized
in Table 1, entries 13-40.
retards the oxidative addition reaction and subsequent
insertion of the internal alkynes. It should be pointed out
that we did not observe any methyl 3-phenylpropynoate,
the â-hydride elimination product of the vinylic pal-
ladium intermediate from ester 19, despite careful chro-
matography of the products from the reactions of ester
19 and diphenylacetylene or 4,4-dimethyl-2-pentyne.
However, ester 16, which has a phenyl group adjacent
to the iodo group, gave R-pyrones in good yields, perhaps
due to activation by the phenyl group in the 2-position
during the oxidative addition step. Fourth, an alkyl or
aryl substituent in the 3-position increases the regiose-
lectivity during the carbopalladation step, resulting, in
most cases, in the formation of just one regioisomer
(Table 1, entries 22-25, 30, and 32). Finally, in contrast
to acyclic vinylic triflates (Table 1, entry 33), cyclic vinylic
triflates and even analogous bromides can be used to
annulate onto internal alkynes to afford bicyclic R-py-
rones in good yields as a single regioisomer (Table 1,
entries 34-40).
From the results, we can make the following observa-
tions. (1) Methyl (Z)-3-iodo-2-methyl-2-propenoate (Table
1, entries 13-15) gives slightly lower yields than methyl
(Z)-3-iodo-2-phenyl-2-propenoate (Table 1, entries 16-
20). Both give a mixture of regioisomers when 4,4-
dimethyl-2-pentyne or 2-methyl-4-phenyl-3-butyn-2-ol
are employed as the alkyne. (2) Methyl (Z)-3-iodo-2,3-
diphenyl-2-propenoate (Table 1, entries 21-25) generally
gives good yields of just one regioisomer. (3) Ethyl (Z)-
3-iodo-2-propenoate (Table 1, entries 26-28) gives only
very low yields of products. (4) Methyl (Z)-3-iodo-2-
methyl-3-phenyl-2-propenoate (Table 1, entries 29 and
30) gives lower yields of products and a slower reaction
rate compared with the first two esters mentioned above.
(5) Trialkylsilyl-substituted R-pyrones in which C-Si
bonds are available for further functionalization can be
obtained in modest yields from the corresponding silyl-
alkynes (Table 1, entries 20, 24, and 25). (6) The triflate
20, which is easily prepared, gives the desired product
in only a very low yield (Table 1, entry 33). (7) Cyclic
vinylic bromides and triflates afford the desired bicyclic
R-pyrones in very good yields (Table 1, entries 34-40).
From the above findings, we conclude that vinylic
substrates with an organic substituent in the 2-position
generally give R-pyrones in good yields (Table 1, entries
13-25). Second, the presence of a hydrogen â to the
iodide in the starting material lowers the yields of the
palladium reactions, presumably due to â-hydride elimi-
nation in the vinylic palladium intermediate, although
we have no solid evidence that this is the source of the
problem. For example, three of the esters used in this
study, which have a â-hydrogen, namely ethyl (Z)-3-iodo-
2-propenoate and esters 18 and 20, usually gave R-py-
rones in low yields (Table 1, entries 26-28 and 31-33).
Third, esters with a phenyl group adjacent to the iodo
group gave R-pyrones in poor yields. For example, ester
17 gave only low yields of products (Table 1, entries 29
and 30) and ester 19 failed to give any R-pyrones at all.
These observations might be explained by the above-
mentioned â-hydride elimination reaction (for ester 19)
and/or steric hindrance about the C-I bond, which
Once again, the silyl-substituted pyrones provide a
novel route to other highly substituted pyrones by simple
desilylation (eq 9).
The regiochemistry was established for the products
of entries 16 and 17 of Table 1 by NOESY spectroscopy.
For the minor product of entry 16, there was an NOE
interaction between C4-H and C5-C(CH3)3 and no
interaction between C4-H and C6-CH3. This compound
was therefore assigned the structure shown in Table 1.
The major product of entry 17 was assigned the structure
shown due to the lack of an observable NOE interaction
between C4-H and the methyl hydrogens. The above
assignments are consistent with our previous work, i.e.,
the bulkier group of the alkyne ends up bonded to the
carbon atom attached to the oxygen in the pyrone
product, which was also presumably the carbon to which
the palladium species was originally attached.18 The rest
of the products in Table 1 have been assigned by analogy
with the above observations.
On the basis of the above results, we believe that this
R-pyrone synthesis proceeds by the same mechanism as
that proposed for the synthesis of isocoumarins (Scheme
1).
To extend the above chemistry to a double annulation
process, dihalo-substituted esters 22 and 23 were pre-
pared (eq 7 and Scheme 3). When compounds 22 or 23

8778 J . Org. Chem., Vol. 64, No. 24, 1999
Larock et al.
and 2 equiv of LiCl at 75 °C for 22-32 h, the double
annulation products 24-26 were formed in 17-19%
yields (eqs 10-12) with the formation of four new
carbon-carbon and/or carbon-oxygen bonds.30
The formation of compounds 24-26 can be explained
by the reactions shown in Scheme 4. The oxidative
addition of Pd(0) to compound 22 or 23 affords vinylpal-
ladium intermediate 27 in which the halogen trans to
the carbonyl group undergoes preferential insertion. This
is consistent with the known reactivity of such halogens
toward Pd oxidative addition.31 Vinylpalladium interme-
diate 27 undergoes insertion of a molecule of internal
alkyne and subsequent substitution onto the adjacent
phenyl ring to form intermediate 28.18g,h Vinylpalladium
intermediate 29 is then formed by oxidative addition of
Pd(0) to compound 28 and subsequent insertion of a
second molecule of internal alkyne. When diphenylacety-
lene is employed, compound 24 or 26 is obtained. When
4,4-dimethyl-2-pentyne is used, compound 25 is produced.
The formation of compounds 24 and 26 indicates that the
production of aromatic rings is easier than that of
R-pyrones.
In conclusion, a useful synthesis of 3,4-disubstituted
isocoumarins and a variety of 3,4,6-tri- and 3,4,5,6-
tetrasubstituted R-pyrones has been developed using the
palladium-catalyzed annulation of internal alkynes via
appropriate halogen- and/or triflate-substituted esters.
The procedure utilizes readily available starting materi-
als. The reactions proceed under relatively mild condi-
tions and give good yields. Although the reaction is
somewhat limited in scope synthetically, it is suited for
the synthesis of the 4-substituted ring systems via the
corresponding silyl alkynes. The above chemistry has also
been extended to the synthesis of polycyclic aromatic
compounds by employing geminal dihalo-substituted
esters.
were reacted with diphenylacetylene or 4,4-dimethyl-2-
pentyne in the presence of 10% Pd(OAc)2, 2 equiv of Et3N
Sch em e 4

Synthesis of Isocoumarins and R-Pyrones
J . Org. Chem., Vol. 64, No. 24, 1999 8779
δ 1.30 (s, 9H), 2.39 (s, 3H), 2.70 (d, J ) 1.0 Hz, 3H), 7.25 (d, J
) 1.2 Hz, 1H). Compound 31 (minor isomer): 1H NMR (CDCl3)
δ 1.35 (s, 9H), 2.13 (s, 3H), 2.50 (d, J ) 1.0 Hz, 3H), 6.91 (d, J
) 1.2 Hz, 1H). Additional spectral data for the product
mixture: 13C NMR (CDCl3) δ 15.9, 16.4, 17.2, 20.4, 28.9, 30.8,
32.3, 37.4, 104.1, 109.7, 121.4, 121.9, 123.3, 141.5, 147.0, 156.3,
163.8, 164.2; IR (CHCl3) 1699 cm-1; HRMS 180.1147 (calcd
for C11H16O2 180.1150).
Exp er im en ta l Section
Gen er a l Meth od s. All 1H and 13C NMR spectra were
recorded at 300 and 75.5 MHz, respectively. Thin-layer chro-
matography (TLC) was performed using commercially pre-
pared 60 mesh silica gel plates (Whatman K6F) and visualized
with short wavelength UV light (254 nm) and basic KMnO4
solution [3 g of KMnO4 + 20 g of K2CO3 + 5 mL of NaOH (5%)
+ 300 mL of H2O].
Rea gen ts. All reagents were used directly as obtained
commercially unless otherwise noted. Anhydrous Na2CO3 and
LiCl were purchased from Fisher Scientific. Pd(OAc)2 was
donated by J ohnson Matthey, Inc., and Kawaken Fine Chemi-
cals Co., Ltd. The following starting materials for the annu-
lation reactions were made according to literature proce-
dures: 1-(tert-butyldimethylsilyl)-1-hexyne,32 ethyl (Z)-3-iodo-
2-propenoate,33 methyl (Z)-2-bromocyclohex-1-ene-1-carboxy-
late,34 methyl (Z)-2-bromocyclohept-1-ene-1-carboxylate,34 meth-
yl 2-trifluoromethanesulfonyloxy-1-cyclohexene-1-carboxy-
late,35 ethyl 2-trifluoromethanesulfonyloxy-1-cyclopentene-1-
carboxylate,35 and methyl 2-(trifluoromethanesulfonyloxy)-
benzoate.36 The preparation and characterization of the other
aryl and vinylic esters used in this study are included in the
Supporting Information.
The physical characterization data for all other R-pyrones
prepared appear in the Supporting Information.
Gen er al P r ocedu r e for th e P alladiu m -Catalyzed Dou ble
An n u la tion Rea ction s. Pd(OAc)2 (6 mg, 0.026 mmol), Et3N
(53 mg, 0.50 mmol), DMF (5 mL), LiCl (21.2 mg, 0.50 mmol),
the alkyne (1 mmol for diphenylacetylene and 2.5 mmol for
4,4-dimethyl-2-pentyne), and the dihaloalkene (0.25 mmol)
were placed in a 2 dram vial. The vial was heated in an oil
bath at 75 °C for the necessary period of time. The reaction
was monitored by TLC to establish completion. The reaction
mixture was cooled, diluted with ether, washed with saturated
NH4Cl, dried over anhydrous Na2SO4, and decanted. The
solvent was evaporated under reduced pressure, and the
product was isolated by chromatography (EtOAc/hexanes) on
a silica gel column. The following compounds were prepared
by the above procedure.
Gen er a l P r oced u r e for th e Syn th esis of Isocou m a r in s
a n d r-P yr on es. Pd(OAc)2 (3 mg, 0.013 mmol), Na2CO3 (26.5
mg, 0.25 mmol), DMF (5 mL), LiCl (10.6 mg, 0.25 mmol), the
alkyne (0.5 mmol), and the ester (0.25 mmol) were placed in a
2 dram vial (the isocoumarins and bicyclic pyrones were
prepared on twice this scale). The vial was heated in an oil
bath at 100 °C for the necessary period of time. The reaction
was monitored by TLC to establish completion. The reaction
mixture was cooled, diluted with ether, washed with saturated
NH4Cl, dried over anhydrous Na2SO4, and filtered. The solvent
was evaporated under reduced pressure, and the product was
isolated by chromatography (EtOAc/hexanes) on a silica gel
column.
3-ter t-Bu tyl-4-m eth ylisocou m a r in (En tr ies 1-3, Ta ble
1). The reaction mixture was chromatographed using 15:1
n-hexane/EtOAc to yield a white solid: mp 94-96 °C (hex-
anes); 1H NMR (CDCl3) δ 1.46 (s, 9H), 2.34 (s, 3H), 7.45 (dt, J
) 0.9, 7.8 Hz, 1H), 7.56 (d, J ) 8.1 Hz, 1H), 7.73 (dt, J ) 1.2,
8.1 Hz, 1H), 8.10 (dd, J ) 0.9, 7.8 Hz, 1H); 13C NMR (CDCl3)
δ 12.9, 29.6, 37.2, 107.3, 120.1, 122.4, 127.0, 129.1, 134.3, 139.8,
159.2, 162.5; IR (CHCl3) 1720 cm-1; HRMS m/z 216.1150 (calcd
for C14H16O2, 216.1150).
7-E t h oxyc a r b on yl-5,6,12-t r ip h e n ylb e n z[a ]a n t h r a -
cen e (24, Eq 10). The reaction mixture was chromatographed
using 1:15 EtOAc/hexanes to yield a brown solid: mp 193-
195 °C (hexanes); 1H NMR (CDCl3) δ 1.00 (t, J ) 7.2 Hz, 3H),
3.31 (q, J ) 7.2 Hz, 2H), 6.66-7.27 (m, 23H); 13C NMR (CDCl3)
δ 13.6, 61.3, 125.1, 126.36, 126.40, 126.46, 126.54, 126.9, 127.0,
127.06, 127.14, 127.2 (2C), 127.4, 127.5, 128.3, 130.1, 130.3,
130.5 (2C), 130.9, 131.5, 133.6, 134.8, 134.9, 135.5, 135.6,
136.3, 143.5, 144.2, 145.6, 146.7, 168.4; IR (CHCl3) 1720 cm-1
HRMS 528.2084 (calcd for C39H28O2 528.2089).
;
3,6-Di-ter t-bu tyl-4,5-d im eth yl-1H-n a p h th o[1,2-c]p yr a n -
1-on e (25, Eq 11). The reaction mixture was chromatographed
using 1:20 EtOAc/hexanes to yield a light yellow solid: mp
1
140-142 °C (hexanes); H NMR (CDCl3) δ 1.48 (s, 9H), 1.77
(s, 9H), 2.36 (s, 3H), 2.48 (s, 3H), 7.48 (t, J ) 7.7 Hz, 1H), 7.57
(t, J ) 7.7 Hz, 1H), 8.42 (d, J ) 8.4 Hz, 1H), 9.74 (d, J ) 8.7
Hz, 1H); 13C NMR (CDCl3) δ 19.2, 26.8, 29.1, 33.6, 37.6, 39.6,
107.6, 113.1, 124.5, 126.3, 126.4, 126.8, 128.5, 130.2, 132.0,
147.0, 155.0, 161.6, 162.1; IR (CHCl3) 1706 cm-1; HRMS
336.2094 (calcd for C23H28O2 336.2089).
7-Me t h oxyca r b on yl-5,6,12-t r ip h e n ylb e n z[a ]a n t h r a -
cen e (26, Eq 12). The reaction mixture was chromatographed
using 1:15 EtOAc/hexanes to yield a brown solid: mp 217-
The product characterization data for all other isocoumarins
prepared appears in the Supporting Information.
1
219 °C (hexanes); H NMR (CDCl3) δ 3.02 (s, 3H), 6.66-6.75
(m, 8H), 6.84-7.03 (m, 11H), 7.22-7.25 (m, 4H); 13C NMR
(CDCl3) δ 52.0, 125.1, 126.40, 126.46, 126.48, 126.88, 126.97
(2C), 127.1, 127.2, 127.4, 128.2, 128.3, 128.4, 130.1, 130.3,
130.6, 130.9, 131.3, 131.6, 133.5, 133.6, 134.76, 134.84, 135.3,
135.6, 136.2, 143.1, 144.8, 145.8, 146.9, 168.8; IR (CHCl3) 1715
cm-1; HRMS 514.1936 (calcd for C38H26O2 514.1933).
6-ter t-Bu tyl-3,5-dim eth yl-2H-pyr an -2-on e (30) an d 5-ter t-
Bu tyl-3,6-d im eth yl-2H-p yr a n -2-on e (31) (En tr y 13, Ta ble
1). The reaction mixture was chromatographed using 1:15
EtOAc/hexanes to yield a light yellow inseparable liquid (30:
31 ) 69:31). Compound 30 (major isomer): 1H NMR (CDCl3)
(30) The following dihalides failed to give any double annulation
products: Br2CdCPhCO2Et, Br2CdC(CO2Et)2, and I2CdC(CO2Et)2.
(31) (a) Nuss, J . M.; Rennels, R. A.; Levine, B. H. J . Am. Chem. Soc.
1993, 115, 6991. (b) Torii, S.; Okumoto, H.; Tadokoro, T.; Nishimura,
A.; Rashid, M. A. Tetrahedron Lett. 1993, 34, 2139.
(32) Buchwald, S. L.; Watson, B. T.; Wannamaker, M. W.; Dewan,
J . C. J . Am. Chem. Soc. 1989, 111, 4486.
(33) Ma, S.; Lu, X. J . Chem. Soc., Chem. Commun. 1990, 1643.
(34) Abad, A.; Arno, M.; Pedro, J . R.; Seoane, E. J . Chem. Soc.,
Perkin Trans. 1 1983, 2471.
(35) Keenan, R. M.; Weinstock, J .; Finkelstein, J . A.; Franz, R. G.;
Gaitanopoulos, D. E.; Girard, G. R.; Hill, D. T.; Morgan, T. M.;
Samanen, J . M.; Hempel, J .; Eggleston, D. S.; Aiyar, N.; Griffin, E.;
Ohlstein, E. H.; Stack, E. J .; Weidley, E. F.; Edwards, R. J . Med. Chem.
1992, 35, 3858.
(36) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110,
1557.
Ack n ow led gm en t. We gratefully acknowledge par-
tial financial support from the Petroleum Research
Fund, administered by the American Chemical Society;
J ohnson Matthey, Inc. and Kawaken Fine Chemicals
Co., Ltd. for the palladium compounds; and Merck for
Academic Development Awards in 1997 and 1998.
Su p p or tin g In for m a tion Ava ila ble: The preparation of
the starting materials, product characterization data for the
isocoumarin and R-pyrone products, and 1H and 13C NMR
spectra for all new compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9821628