Synthesis of isocoumarins and α-pyrones via tandem Stille reaction/heterocyclization

Article abstract of DOI:10.1021/jo050638z

A general route to α-pyrones and 3-substituted isocoumarins from (Z)-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c is described, including compounds bearing a substituent on the aromatic ring. Treatment of (Z)-β-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c with various allenyl-tributyltin reagents in the presence of palladium acetate, triphenylphosphine, and tetrabutylammonium bromide in dimethylformamide provided good yields of the corresponding α-pyrones 3a-k or 3-substituted isocoumarins 5a-g via tandem Stille reaction and 6-endo-dig oxacyclization.

Full text of DOI:10.1021/jo050638z

Synthesis of Isocoumarins and r-Pyrones via Tandem Stille
Reaction/Heterocyclization
Khalil Cherry,† Jean-Luc Parrain,‡ Je´roˆme Thibonnet,†,‡ Alain Ducheˆne,† and
Mohamed Abarbri*,†
Laboratoire de Synthe`se et Physico-Chimie Organique et The´rapeutique, Faculte´ des Sciences de Tours,
Parc de Grandmont, EA 3857, 37200 Tours, France, and Laboratoire Symbio, Equipe Synthe`se par voie
Organome´tallique associe´ au CNRS (UMR 6178), Universite´ Paul Ce´zanne, Aix Marseille III, Campus
Scientifique de Saint Je´roˆme, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
mohamed.abarbri@univ-tours.fr
Received April 1, 2005
A general route to R-pyrones and 3-substituted isocoumarins from (Z)-iodovinylic acids 1a-f or
2-iodobenzoic acids 4a-c is described, including compounds bearing a substituent on the aromatic
ring. Treatment of (Z)-â-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c with various allenyl-
tributyltin reagents in the presence of palladium acetate, triphenylphosphine, and tetrabutylam-
monium bromide in dimethylformamide provided good yields of the corresponding R-pyrones 3a-k
or 3-substituted isocoumarins 5a-g via tandem Stille reaction and 6-endo-dig oxacyclization.
Isocoumarins and R-pyrones are valuable intermedi-
ates in the synthesis of several natural products1,2 and
important hetero- and carbocyclic molecules, including
isocarbostyrils, isoquinolines, isochromenes, and pyri-
dones. These lactones also occur as structural subunits
in numerous natural products that exhibit a wide range
of biological activities,3 including anticancer and HIV-1-
specific reverse transcriptase inhibitor properties,4 and
antiallergic and antimicrobial,5 immunomodulatory,6 cy-
totoxic,7 antifungal,8 and antiinflammatory activities.9
The prominence of coumarins and R-pyrones in natural
products and biologically active molecules3,10 has prompted
considerable interest in their synthesis.11,12
Much attention has been focused on the selective
synthesis of these ring systems by transition metal-
catalyzed heteroannulation reactions.13 In the past de-
* To whom correspondence should be addressed. Fax: 33 (0) 2 47
36 70 73.
(4) (a) Naser-Hijazi, B.; Stolze, B.; Zanker, K. S. Second Proceedings
of the International Society of the Coumarin Investigators; Springer:
Berlin, 1994. (b) Murray, R. D. H.; Me´ndez, J.; Brown, S. A. The
Natural Coumarins: Occurrence, Chemistry, and Biochemistry; J.
Wiley: New York, 1982.
† Laboratoire de Synthe`se et Physico-Chimie Organique et The´ra-
peutique.
‡ Universite´ Paul Ce´zanne.
(1) (a) Barry, R. D. Chem. Rev. 1964, 229. (b) Dickinson, J. Nat.
Prod. Rep. 1993, 10, 71. (c) Kiselyov, A. S. Tetrahedron Lett. 1995, 36,
493. (d) Sugimoto, A.; Shinba-Tanaka, H.; Ishikawa, M. Synthesis 1995,
431. (e) Goff, D. A.; Zuckermann, R. N. J. Org. Chem. 1995, 60, 5748.
(2) (a) Chen, C.-H.; Liao, C.-C. Org. Lett. 2000, 2, 2049. (b) Hsung,
R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L.
J. J. Org. Chem. 1999, 64, 690. (c) Danieli, B.; Lesma, G.; Martinelli,
M.; Passarella, D.; Peretto, I.; Silvani, A. Tetrahedron 1998, 54, 14081.
(d) Jram, V.; Goel, A. J. Chem. Res., Synop. 1997, 460. (e) Liu, Z.;
Meinwald, J. J. Org. Chem. 1996, 61, 6693. (f) Afarinkia, K.; Berna-
Canovas, J. Tetrahedron Lett. 2000, 41, 4955. (g) Stigers, K. D.; Mar-
Tang, R.; Bartlett, P. A. J. Org. Chem. 1999, 64, 8409. (h) Cobas, A.;
Diaz, M. T.; Escudero, S.; Pe´rez, D.; Guitia`n, E.; Castedo, L. In Current
Trends in Organic Synthesis; Scolastico, C., Nicotra, F., Eds.; Kluwer
Academic/Plenum Publishers: New York, 1999; pp 307-314. (i) Ram,
V. J.; Srivastava, P.; Saxena, A. S. J. Org. Chem. 2001, 66, 5333.
(3) (a) Livingstone, R. In Rodd’s Chemistry of carbon compounds;
Caffey, S., Ed.; Elsevier: New York, 1977; vol. IV, Part E, pp 290-
297. (b) Hill, R. A. Progress in the Chemistry of Organic Natural
Products; Springer-Verlag: Weinheim-New York, 1986; Vol. 49, pp
1-78.
(5) (a) Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med. Chem.
Lett. 1999, 7, 1445. (b) Yoshikawa, M.; Harada, E.; Naitoh, Y.; Inoue,
K.; Matsuda, H.; Shimoda, H.; Yamahara, J.; Murakami, N. Chem.
Pharm. Bull. 1994, 42, 2225.
(6) (a) Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M.
Bioorg. Med. Chem. Lett. 1998, 8, 215. (b) Shimoda, H.; Matsuda, H.;
Yamahara, J.; Yoshikawa, M. Biol. Pharm. Bull. 1988, 21, 809.
(7) Whyte, A. C.; Gloer, J. B.; Scott, J. A.; Mallock, D. J. Nat. Prod.
1996, 59, 765.
(8) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.; Nakajima, S.
Chem. Pharm. Bull. 1981, 29, 2689.
(9) Furuta, T.; Fukuyama, Y.; Asakawa, Y. Phytochemistry 1986,
25, 517.
(10) (a) Khalmuradov, M. A.; Said-Khodzhaev, A. I. Chem. Nat.
Compd. 1999, 35, 364. (b) Murakami, A.; Gao, G.; Omura, M.; Yano,
M.; Ito, C.; Furukawa, H.; Takahashi, D.; Koshimizu, K.; Ohigashi,
H. Bioorg. Med. Chem. Lett. 2000, 10, 59. (c) Maier, W.; Schmidt, J.;
Nimtz, M.; Wray, V.; Strack, D. Phytochemistry 2000, 54, 473. (d)
Garcia-Argaez, A. N.; Ramirez-Apan, T. O.; Delgado, H. P.; Velazquez,
G.; Martinez-Vazquez, M. Planta Med. 2000, 66, 279. (e) Wu, J.; Wang,
L.; Fathi, R.; Yang, Z. Tetrahedron Lett. 2002, 43, 4395.
10.1021/jo050638z CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/27/2005
J. Org. Chem. 2005, 70, 6669-6675
6669

Cherry et al.
SCHEME 1
unsaturated esters with internal alkynes in the presence
of a palladium catalyst.15 Nevertheless, in the case of
nonsymmetric alkynes, two R-pyrone regioisomers were
obtained. More recently, Negishi et al. proposed the
selective conversion of (Z)-2-en-4-ynoic acids into R-py-
rones in the presence of a catalytic amount of ZnBr2 (10%)
or to furanone in the presence of silver salts.16 On the
other hand, we have previously described the synthesis
of dienoic acids and enynes bearing a carboxylic acid
function from â-iodovinylic acids and vinyltin or alkynyl-
zinc reagents.17 This methodology was then applied to
the synthesis of γ-tributyltin methylidenebutenolides.18
We have also described our first results of the synthesis
of the R-pyrones by approaches involving intramolecular
addition of carboxylic acids to allenylstannanes.19 We now
present our full results in this field and their extension
to regioselective synthesis of isocoumarins, and our
investigation of the scope and limitation of the reaction.
To broaden our synthesis strategy and to design a
system suitable for 6-exo lactonization, we planned the
preparation of allenyl-substituted alkenoic acids, which
we believed would exclusively undergo 6-endo mode
cyclization mediated by a palladium complex (Scheme 1).
cade, numerous methods reported for the synthesis of
R-pyrones have utilized halolactonization or transition
metals (Ag, Hg, Rh, Pd) to promote intramolecular
addition of carboxylic acid to alkynes.14 In general, these
reactions of 4-alkynoic acids occur with poor regioselec-
tivity, and in many cases mixtures of γ-alkylidenebuteno-
lides and R-pyrones are obtained (Scheme 1). The prob-
lem of regioselectivity was recently solved by Larock et
al., who demonstrated that substituted isocoumarins or
R-pyrones could be prepared by treating â-halogeno R,â-
(11) (a) Mishra, A.; Dash, B. L.; Behera, R. K. Ind. J. Heterocycl.
Chem. 1996, 6, 149. (b) Nicolaides, D. N.; Fylaktakidou, K.; Litinas,
E. K.; Papageorgiou, G.; Hadjipavlou-Litina, D. J. J. Heterocycl. Chem.
1998, 35, 619. (c) Fall, Y.; Teran, C.; Teijeira, M.; Santana, L.; Uriarte,
E. Synthesis 2000, 643. (d) Larock, R. C.; Varaprath, S.; Lau, H. H.;
Fellows, C. A. J. Am. Chem. Soc. 1984, 106, 5274. (e) Larock, R. C.;
Yum, E. K.; Doty, M. J.; Sham, K. J. Org. Chem. 1995, 60, 3270. (f)
Izumi, T.; Morishita, N. J. Heteroycl. Chem. 1994, 31, 145. (g) Ohta,
S.; Kamata, Y.; Inagaki, T.; Masuda, Y.; Yamamoto, S.; Yamashita,
M.; Kawasaki, I. Chem. Pharm. Bull. 1993, 41, 1188. (h) Yoshikawa,
M.; Harada, E.; Yagi, N.; Okuno, Y.; Muraoka, O.; Aoyama, H.;
Murakami, N. Chem. Pharm. Bull. 1994, 42, 721. (i) Yoshikawa, M.;
Shimada, H.; Yagi, N.; Murakami, N.; Shimoda, H.; Yamahara, J.;
Matsuda, H. Chem. Pharm. Bull. 1996, 44, 1890. (j) Mali, R. S.; Babu,
K. N. J. Org. Chem. 1988, 53, 4676. (k) Rama, N. H.; Iqbal, R.; Zamani,
K.; Saeed, A.; Iqbaql, M. Z.; Choudhary, M. I. Indian J. Chem., Sect.
B 1998, 37, 365. (l) Bovicelli, P.; Lupattelli, P.; Crescenzi, B.; Sanetti,
A.; Bernini, R. Tetrahedron 1999, 55, 14719. (m) Mal, D.; Bandyo-
padhyay, M.; Ghorai, S. K.; Datta, K. Tetrahedron Lett. 2000, 41, 3677.
(n) Hussain, M. T.; Rama, N. H.; Malik, A. Indian J. Chem., Sect. B
2001, 40, 372. (o) Natsugari, H.; Ikeura, Y.; Kiyota, Y.; Ishichi, Y.;
Ishimaru, T.; Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, T.; Doi, T.;
Otsuka, M. J. Med. Chem. 1995, 38, 3106. (p) Rossi, R.; Carpita, A.;
Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003, 59, 2067. (q)
An, Z.; Catellani, M.; Chiusoli, G. P. Gazz. Chim. Ital. 1990, 120, 383.
(r) Catellani, M.; Chiusoli, G. P.; Solari, G. Tetrahedron Lett. 1994,
35, 5919. (s) Catellani, M.; Chiusoli, G. P.; Fagnola, M. C.; Solari, G.
Tetrahedron Lett. 1994, 35, 5923. (t) Johnson, J. R. Org. React. 1942,
1, 210. (u) Sethna, S.; Phadke, R. Org. React. 1953, 7, 1.
(12) (a) Vara Prasad, J. V. N.; Para, K. S.; Lunney, E. A.; Ortwine,
D. F.; Dunbar, J. B., Jr.; 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. (b) Tuanli, Y.; Larock, R. C. J. Org. Chem. 2003,
68, 5936.
(13) (a) Ogawa, Y.; Maruno, M.; Wakamatsu, T. Heterocycles 1995,
41, 2587. (b) Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron
2000, 56, 2533. (c) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.;
Mannina, L. Tetrahedron Lett. 2000, 41, 5281. (d) Minami, T.;
Nishimoto, A.; Nakamura, M. Chem. Pharm. Bull. 1994, 42, 170. (e)
Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron Lett. 2001,
42, 2852. (f) Kvita, V.; Fischer, W. Chimica 1992, 45, 457. (g) Kadnikov,
D. V.; Larock, R. C. J. Org. Chem. 2003, 68, 9423.
Results and Discussion
Synthesis of r-Pyrones. Our investigation began
with the coupling of tributylstannylallene20 with (Z)-3-
iodoprop-2-enoic acid17 under conditions identical to those
used for the synthesis of γ-tributyltin methylidene-
butenolides [Pd(PPh3)4 (1%), DMF, 25 °C].18,21 Unfortu-
nately, neither allenyl-substituted propenoic acid nor
cyclized products (five- or six-membered ring lactones)
were detected. Only a large amount of tin byproducts
were recovered, among them the tributylstannyl ester of
the starting iodovinylic acid. To avoid the proteolysis of
allenylstannane and to promote the cross-coupling reac-
tion, we examined the reaction under various conditions
(solvent, catalyst, presence of additives, ...). The influence
of the nature of the carboxylic acid derivative on conver-
sion rates was examined first. In DMF and in the
presence of 1% of tetrakis(triphenylphosphine)palladium,
the ethyl ester of 1a yielded exclusively ethyl hex-2-en-
4-ynoate in 75% yield. The use of tributyltin carboxylate
under conditions identical to those used for the synthesis
of tributyltin methylidenebutenolides provided 52% yield
of 6-methylpyran-2-one 3a, without any trace of hexa-
2,4,5-trienoic acid or hex-2-en-4-ynoic acid.
Next, the natures of the solvent and palladium com-
plexes were examined. THF was found to be ineffective,
whereas acetonitrile afforded a very poor yield (<25%)
(15) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
(16) Anastasia, L.; Xu, C.; Negishi, E. Tetrahedron Lett. 2002, 43,
5673.
(17) (a) Ducheˆne, A.; Abarbri, M.; Parrain, J.-L.; Kitamura, M.;
Noyori, R. Synlett 1994, 524. (b) Abarbri, M.; Parrain, J.-L.; Cintrat,
J. C.; Ducheˆne, A. Synthesis 1996, 82.
(14) For a recent synthesis using Pd or Ag catalysts, see: (a) Xu,
C.; Negishi, E. Tetrahedron Lett. 1999, 40, 431. (b) Ma, S.; Shi, Z. J.
Org. Chem. 1998, 63, 6387. (c) Rossi, R.; Bellina, F.; Biagetti, M.;
Mannina, L. Tetrahedron Lett. 1998, 39, 7799. (d) Rossi, R.; Bellina,
F.; Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998, 39, 7599. (e)
Rossi, R.; Bellina, F.; Mannina, L. Tetrahedron Lett. 1998, 39, 3017.
(f) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini, P.
Tetrahedron 1998, 54, 135. (g) Marshall, J. A.; Wolf, M. A.; Wallace,
E. M. J. Org. Chem. 1997, 62, 367. (h) Marshall, J. A.; Wolf, M. A.;
Wallace, E. M. J. Org. Chem. 1995, 60, 796. (i) Marshall, J. A.; Wolf,
M. A.; Wallace, E. M. J. Org. Chem. 1996, 61, 3238. (j) Ogawa, Y.;
Maruno, M.; Wakamatsu, T. Synlett 1995, 871.
(18) Rousset, S.; Abarbri, M.; Thibonnet, J.; Ducheˆne, A.; Parrain,
J.-L. Org. Lett. 1999, 1, 701.
(19) Rousset, S.; Abarbri, M.; Thibonnet, J.; Ducheˆne, A.; Parrain,
J.-L. Chem. Commun. 2000, 1987.
(20) (a) Tanaka, H.; Hai, A. K.; Ogawa, A. H.; Torii, S. Synlett 1993,
835. (b) Brandsma, L. Synthesis of Acetylenes, Allenes, and Cumu-
lenes: a laboratory manual; Elsevier Scientific Pub. Co.: New York,
1981.
(21) Rousset, S.; Abarbri, M.; Thibonnet, J.; Parrain, J.-L.; Ducheˆne,
A. Tetrahedron Lett. 2003, 44, 7633.
6670 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Isocoumarins and R-Pyrones
SCHEME 2
addition of carboxylic acids to allenylstannanes, we next
examined the possibility of regioselectively preparing
isocoumarins by this same methodology and report our
results here.
Synthesis of Isocoumarins. 3-Substituted isocou-
marins are attractive synthesis targets because of their
biological and pharmacological activities. These hetero-
cycles have been prepared by the palladium-catalyzed
coupling of 2-halobenzoate esters or 2-halobenzonitriles
with alkenes,24 vinylic stannanes,25 or terminal alkynes,26
with subsequent cyclization or π-allylnickel cross-cou-
pling and palladium-catalyzed cyclization,27 itself by
coupling of 2-(2,2-dibromovinyl) benzoates and orga-
nostannanes,28 or by palladium-catalyzed annulation of
terminal alkynes and 2-iodophenols.29 The cross-coupling
of o-iodobenzoic acid and terminal alkynes produces
either unsaturated phthalides30,31 or 3-substituted iso-
coumarins32 as major products. In our case, the reaction
conditions chosen were those used for the synthesis of
R-pyrones. Thus, the coupling of 2-iodo benzoic acids
4a-c with tributylstannylallene at 80 °C under identical
conditions provided a highly regioselective method for the
synthesis of isocoumarins (Scheme 3). It should be noted
that the reaction requires heating because no reaction
occurred at room temperature. The results are sum-
marized in Table 2.
Both 2-iodo benzoic acids 4a-c and a variety of
allenyltributyltins were successfully utilized. This process
afforded reasonable yields of substituted isocoumarins
5a-g, including compounds bearing a substituent group
on the aromatic ring (5c-g). Thus, the cyclization of
2-iodo benzoic acid bearing an electron-withdrawing
group ortho to the hydroxycarbonyl group proved to be
nearly as successful as 2-iodobenzoic acid itself (entries
3, 5, and 7, Table 2). In addition, the yield was compa-
rable to the yield obtained with the parent 2-iodo benzoic
acid. These results are important, because isocoumarins
possessing an electron-withdrawing group such as fluo-
rine, and an electron-donating group such as methoxy
group, have been synthesized.
of cyclized product. We also observed that phosphine-
ligated palladium appeared to be more efficient than
other palladium salts such as palladium acetate (without
additional triphenylphosphine) or bis(acetonitrile)palla-
dium chloride. Tetrakis(triphenylphosphine)palladium
gave approximately identical yields to the Pd(OAc)2/PPh3
couple. The use of an excess (1.5 equiv) of allenyltribu-
tyltin was essential to obtain good yields of these pyra-
nones 3a-k, and a stoichiometric quantity of allenyl-
tributyltin provides the desired pyranones, but in poor
yields (<40%). The use of sodium carbonate as base is
not necessary in these heterocyclization reactions as we
previously mentioned.19 In the absence of a palladium
complex, no reaction occurred between the (Z)-iodovinylic
acids 1a-f and the allenyltributyltins, the starting
materials are recovered. After experimentation with a
variety of conditions and methods, it was found that the
best result for the final cyclization step was obtained
using 5% palladium acetate, 10% triphenylphosphine,
and tetrabutylammonium bromide in DMF at room
temperature, providing an 83% yield of R-pyrone 3a
(Scheme 2). The results are summarized in Table 1.
The reaction of tributylstannylallene with a range of
(Z)-3-substituted 3-iodoprop-2-enoic acids under regio-
and stereocontrol gave good yields of 4-substituted-6-
methyl-2-pyranones 3a-f as the sole products (entries
1-6, Table 1). The scope and limitations of this annula-
tion reaction were studied by allowing a wide variety of
allenyltributyltins to react with various â-iodo propenoic
acids under our optimized reaction conditions. High
regioselectivity was observed in each case. The use of
3-alkylallenylstannanes (entries 7-10, Table 1) showed
that the regioselective heteroannulation reaction oc-
curred only on carbons 1 and 2 of the allenyltin reagent.
The methodology also proved to be very convenient and
general for the synthesis of various 4,6-disubstituted
2-pyranones. The reaction temperature does not have any
effect on the regioselectivity. The annulation reactions
performed at 80 °C afforded 2-pyranones with compa-
rable results. The R-pyrones were obtained without any
trace of 3-allenyl or 3-alkynyl propenoic acids. On the
other hand, the γ-alkylidenepyranones previously ob-
tained by Larock et al. from a reaction of allenes with
(Z)-3-iodopropenoic acids were not observed. This almost
certainly indicates a mechanism different from those
proposed by Larock and Yamamoto, respectively.22,23 In
our case, the regioselectivity of this process would arise
from the nucleophilic attack of the carboxylate function
on the central carbon of the allenyl moiety.
When 2-iodo-4-methoxybenzoic acid was allowed to
react with allenylstannane (entries 4 and 6, Table 2), the
desired isocoumarins 5d and 5f were produced at 65%
and 61% yield, respectively. The starting materials for
our synthesis of isocoumarins, 2-iodo benzoic acid 4a and
2-fluoro-6-iodo benzoic acid 4b, were commercially avail-
able. 2-Iodo-4-methoxybenzoic acid 4c was synthesized
from 4-methoxybenzoic acid by a known procedure.33
(24) (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.
(25) Sakamoto, T.; Kondo, Y.; Yasuhara, A.; Yamanaka, H. Tetra-
hedron 1991, 47, 1877.
(26) (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.
(27) Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J. Org. Chem. 1977,
42, 1329.
(28) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625.
(29) Kadnikov, D. V.; Larock, R. C. J. Organomet. Chem. 2003, 687,
425.
In continuation of our studies on the synthesis of
R-pyrones by approaches that involve intramolecular
(30) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin Trans.
1 1998, 561.
(22) Larock, R. C.; He, Y.; Leon, W. W.; Han, X.; Refvik, M. D.;
Zenner, M. J. J. Org. Chem. 1998, 63, 2154.
(23) Yamamoto, Y.; Al-Masum, M.; Fujiwara, N. J. Chem. Soc.,
Chem. Commun. 1996, 381.
(31) Kundu, N. G.; Pal, M. J. Chem. Soc., Chem. Commun. 1993,
86.
(32) (a) Liao, H.-Y.; Cheng, C.-H. J. Org. Chem. 1995, 60, 3711. (b)
Sashida, H.; Kawamukai, A. Synthesis 1999, 1145.
J. Org. Chem, Vol. 70, No. 17, 2005 6671

Cherry et al.
TABLE 1. Synthesis of Substituted r-Pyrones 3a-k
a Isolated yield of analytically pure products.
SCHEME 3
illustrated in Tables 1 and 2, better yields were obtained
in the case of R-pyrones as compared to the isocoumarins.
On the basis of the above results, we believe that this
isocoumarin synthesis proceeds by the same mechanism
as that proposed for the synthesis of R-pyrones.
All of the isocoumarins 5a-g and R-pyrones 3a-k
were well characterized by satisfactory spectroscopic (MS,
IR, H NMR, and 13C NMR) and analytical data.
1
Isocoumarins 5a-g were obtained without any trace
of 2-allenyl benzoic acids, and without any trace of five-
membered ring products, giving a regioselective character
to the cyclization process where only 6-endo mode cy-
clization was observed (Scheme 3 and Table 2). As
(33) (a) Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich, E.
D. J. Org. Chem. 1974, 39, 2787. (b) Meyers, A. I.; Mihelich, E. D. J.
Org. Chem. 1975, 40, 3158. (c) Liang, P.-H.; Hsin, L.-W.; Pong, S.-L.;
Hsu, C.-H.; Cheng, C.-Y. J. Chin. Chem. Soc. 2003, 50, 449.
6672 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Isocoumarins and R-Pyrones
TABLE 2. Synthesis of 3-Substituted Isocoumarins 5a-g
a Isolated yield of analytically pure product.
SCHEME 4. Proposed Mechanism of the Formation of Isocoumarin and r-Pyrone
Mechanism. Based on the above observations and the
known palladium chemistry, a possible mechanism for
the formation of R-pyrones and isocoumarins by a single-
step palladium-catalyzed reaction of (Z)-3-iodopropenoic
acid or 2-iodobenzoic acid derivatives with allenylstan-
nanes is shown in Scheme 4. First, Pd(OAc)2 is reduced
to a Pd(0) complex, which is the actual catalyst in the
process, followed by an oxidative addition of the vinylic
(or aromatic) iodide to palladium (0). A Stille mecha-
nism34 would yield 3-allenylpropenoic acid (or 2-allenyl-
benzoic acid) by transmetalation and reductive elimina-
tion. After activation by complexation with palladium,
the allene undergoes intramolecular 6-exo-dig nucleo-
philic attack by the carboxylate function, the catalytic
cycle being completed by protonolysis, and affords R-py-
rone or isocoumarin as the final product.
J. Org. Chem, Vol. 70, No. 17, 2005 6673

Cherry et al.
2H), 2.21 (s, 3H), 2.33 (t, J ) 7.3 Hz, 2H), 5.87 (s, 1H), 5.92 (s,
1H); 13C NMR (50 MHz, CDCl3) δ 13.5, 19.7, 21.3, 37.8, 105.6,
109.6, 161.0, 161.9, 164.1; MS (EI) m/z (%) 152 (M•+, 36), 124
(24), 96 (100), 95 (43), 43 (83). Anal. Calcd for C9H12O2: C,
71.03; H, 7.95. Found: C, 71.09; H, 8.0.
An alternative pathway involving the vinylic palladium
addition to the central carbon atom of the stannylallene
could be excluded on the basis of the experiments
conducted with 1- or 3-substituted allenylstannanes
because other regioisomers should have been obtained
rather than 3a-k or 5a-g.22
On the other hand, an isomerization of allene to alkyne
prior to nucleophilic attack of the carboxylate function
is also excluded, because, in this case, a probable mixture
of five- and six-membered ring products will be formed.30-32
6-Methyl-4-phenyl-2H-pyran-2-one (3d).37 IR (neat) 2960,
2926, 2855, 1741, 1725, 1642, 1552; 1H NMR (200 MHz, CDCl3)
δ 2.35 (bs, 3H), 6.35 (bs, 1H), 6.38 (s, 1H), 7.31-7.62 (m, 5H);
13C NMR (50 MHz, CDCl3) δ 20.7, 104, 108.8, 127.3, 129.7,
131, 137, 157, 162.7, 163; MS (EI) m/z (%) 186 (M•+, 53), 158
(100), 129 (40), 115 (69), 51 (15), 43 (39). Anal. Calcd for
C12H10O2: C, 77.40; H, 5.41. Found: C, 77.36; H, 5.36.
6-Methyl-4-trimethylsilyl-2H-pyran-2-one (3e). IR (neat)
2960, 1764, 1730, 1624, 1523, 1253; 1H NMR (200 MHz, CDCl3)
δ 0.23 (s, 9H), 2.23 (bs, 3H), 5.97-6.0 (m, 1H), 6.28 (bs, 1H);
13C NMR (50 MHz, CDCl3) δ -0.8, 14, 105.7, 118, 160.3, 160.4,
161.6; MS (EI) m/z (%) 182 (M•+, 19), 154 (27), 139 (100), 73
(49), 43 (60). Anal. Calcd for C9H14O2Si: C, 59.30; H, 7.74.
Found: C, 59.35; H, 7.80.
Conclusion
In summary, we have developed a general and conve-
nient regioselective method for the preparation of 3-sub-
stituted isocoumarins and substituted R-pyrones via the
palladium-catalyzed coupling of 2-iodobenzoic acid de-
rivatives or vinylic acids and allenyltributyltins. The
heteroannulation reaction proceeded selectively and pro-
vided good isolated yields of a variety of 3-substituted
isocoumarins and substituted R-pyrones.
4-Methoxymethyl-6-methyl-2H-pyran-2-one (3f). IR
(neat) 2995, 2928, 2824, 1738, 1715, 1645, 1568, 1449, 1308,
1
1199; H NMR (200 MHz, CDCl3) δ 2.2 (s, 3H), 3.38 (s, 3H),
4.18 (bs, 2H), 5.92 (bs, 1H), 6.08 (bs, 1H); 13C NMR (50 MHz,
CDCl3) δ 20.5, 59.4, 72.5, 103, 109, 156.7, 162.7, 163.5; MS
(EI) m/z (%) 154 (M•+, 22), 122 (21), 95 (28), 45 (19), 43 (100).
Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C, 62.28;
H, 6.48.
Experimental Section
6-Ethyl-4-methyl-2H-pyran-2-one (3g).38 IR (neat) 2981,
2977, 2968, 1713, 1644; 1H NMR (CDCl3, 200 MHz) δ 1.05 (t,
J ) 7.5 Hz, 3H), 1.97 (s, 3H), 2.33 (t, J ) 7.5 Hz, 2H), 5.73
(bs, 1H), 5.77 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 11.3, 22.9,
27.1, 105.2, 110.7, 156.9, 163.6, 166.3; MS (EI) m/z (%) 138
(M•+, 53), 111 (51), 109 (100), 95 (63), 53 (92). Anal. Calcd for
C8H10O2: C, 69.54; H, 7.30. Found: C, 69.49; H, 7.27.
6-Ethyl-4-trimethylsilyl-2H-pyran-2-one (3h). IR (neat)
2960, 1745, 1727, 1622, 1523, 1255; 1H NMR (200 MHz, CDCl3)
δ 0.17 (s, 9H), 1.15 (t, J ) 7.5 Hz, 3H), 2.41 (q, J ) 7.5 Hz,
2H), 5.90 (s, 1H), 6.19 (s, 1H); 13C NMR (CDCl3, 50 MHz) δ
-2.1, 11.7, 27.3, 104.6, 118.6, 162.2, 163.1, 165.5; MS (EI) m/z
(%) 196 (M•+, 22), 168 (30), 153 (100), 75 (15), 57 (17). Anal.
Calcd for C10H16O2Si: C, 61.18; H, 8.21. Found: C, 61.13; H,
8.13.
General Procedure for the Preparation of r-Pyrones
3a-k. Palladium acetate (112 mg, 0.5 mmol), triphenylphos-
phine (262 mg, 1 mmol), and tetrabutylammonium bromide
(3.2 g, 10 mmol) were progressively added to a degassed
solution of 3-substituted-3-iodopropenoic acids 1a-f (10 mmol)
in anhydrous DMF (40 mL). The mixture was stirred at room
temperature for 10 min, and allenylstannane (15 mmol) was
then added. The reaction mixture was stirred for 4h after
conversion was complete (checked by TLC), and the reaction
was quenched with aqueous NH4Cl solution. After ether
extraction (3 × 20 mL) and usual treatments, the crude
products were chromatographed on silica gel (hexane/ether )
80/20) to obtain compounds 3a-k.
6-Methyl-2H-pyran-2-one (3a).35 IR (neat) 2960, 2926,
2856, 1732, 1713, 1636, 1559, 1341, 1099; 1H NMR (200 MHz,
CDCl3) δ 2.24 (s, 3H), 5.96 (dd, J ) 6.5 Hz, J ) 0.7 Hz, 1H),
6.1 (dd, J ) 9.4 Hz, J ) 0.7 Hz, 1H), 7.23 (dd, J ) 9.4 Hz, J
) 6.5 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 20.5, 103.8, 113.5,
144.3, 163.3, 163.5; MS (EI) m/z (%) 110 (M•+, 40), 95 (39), 82
(50), 43 (50), 39 (100). Anal. Calcd for C6H6O2: C, 65.45; H,
5.49. Found: C, 65.40; H, 5.42.
6-Ethyl-4-methoxymethyl-2H-pyran-2-one (3i). IR (neat)
3084, 2995, 2928, 2844, 1738, 1714, 1645, 1568, 1199; 1H NMR
(200 MHz, CDCl3) δ 1.12 (t, J ) 7.5 Hz, 3H), 2.46 (q, J ) 7.5
Hz, 2H), 3.33 (s, 3H), 4.14 (s, 2H), 5.87 (s, 1H), 6.04 (s, 1H);
13C NMR (50 MHz, CDCl3) δ 11.4, 27.3, 59.3, 72.4, 101.1, 108.9,
156.7, 163.5, 167.4; MS (EI) m/z (%) 168 (M•+, 71), 139 (100),
111 (54), 57 (71), 45 (35). Anal. Calcd for C9H12O3: C, 64.27;
H, 7.19. Found: C, 64.20; H, 7.14.
4,6-Dimethyl-2H-pyran-2-one (3b).36 IR (neat) 2959, 2926,
1
1736, 1704, 1651; H NMR (200 MHz, CDCl3) δ 2.14 (s, 3H),
2.24 (s, 3H), 5.87 (s, 1H), 5.97 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 19.6, 21.2, 106.2, 110.3, 156, 161, 163; MS (EI) m/z
(%) 124 (M•+, 42), 96 (70), 95 (21), 53 (100), 43 (61). Anal. Calcd
for C7H8O2: C, 67.73; H, 6.50. Found: C, 67.68; H, 6.45.
6-Methyl-4-propyl-2H-pyran-2-one (3c). IR (neat) 3071,
2963, 2875, 1770, 1731, 1644, 1562, 1463, 1231; 1H NMR (200
MHz, CDCl3) δ 0.86 (t, J ) 7.3 Hz, 3H), 1.17 (sext, J ) 7.3 Hz,
6-Hexyl-4-methyl-2H-pyran-2-one (3j).21,39 IR (neat) 2958,
1
2930, 2860, 1736, 1647, 1564; H NMR (200 MHz, CDCl3) δ
0.76 (t, J ) 6.3 Hz, 3H), 1.15-1.18 (m, 6H), 1.53 (m, 2H), 2.0
(s, 3H), 2.33 (t, J ) 7.3 Hz, 2H), 5.75 (s, 1H), 5.82 (s, 1H); 13
C
NMR (50 MHz, CDCl3) δ 14.4, 21.8, 22.8, 27.2, 29.0, 31.8, 33.9,
106.1, 110.8, 156.8, 163.8, 165.3; MS (EI) m/z (%) 194 (M•+,
26), 124 (33), 109 (100), 96 (48), 95 (76). Anal. Calcd for
C12H18O2: C, 74.19; H, 9.34. Found: C, 74.13; H, 9.29.
5-Methoxy-4-methoxymehyl-6-methyl-2H-pyran-2-
one (3k). IR (neat) 2994, 2938, 2826, 1738, 1642, 1558, 1230,
(34) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813. (c) Mitchell,
T. N. Synthesis 1992, 803. (d) Farina, V. In Comprehensive Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G., Wilkinson, G., Eds.;
Elsevier: Oxford, 1995; Vol. 12, Chapter 3.4, pp 161-241. (e) Farina,
V.; Roth, G. P. In Advances in Metal-Organic Chemistry; Liebeskind,
L. S., Ed.; JAI Press: New York, 1996; Vol. 5, pp 1-53. (f) Farina, V.;
Krishnamurthy, V.; Scott, W. J. In Org. React.; Paquette, L. A., Ed.;
John Wiley & Sons: New York, 1997; Vol. 50, Chapter 1, pp 1-652.
(g) Farina, V.; Krishnamurthy, V. The Stille Reaction; Wiley: New
York, 1999.
1
1122; H NMR (200 MHz, CDCl3) δ 2.18 (s, 3H), 3.40 (s, 3H),
3.59 (s, 3H), 4.27 (s, 2H), 6.15 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 15.3, 59.7, 62.5, 68.9, 109.7, 138.5, 154.2, 154.6, 162.4;
MS (EI) m/z (%) 184 (M•+, 23), 169 (22), 141 (22), 43 (100), 39
(14). Anal. Calcd for C9H12O4: C, 58.69; H, 6.57. Found: C,
58.66; H, 6.49.
(35) (a) Kotretsou, S. I.; Georgiadis, M. P. Org. Prep. Proced. Int.
2000, 32, 161. (b) Izumi, T.; Kasahara, A. Bull. Chem. Soc. Jpn. 1975,
48, 1673.
(36) (a) Zhou, M.; Yoshida, Y.; Ishii, S.; Noguchi, H. Synth. Commun.
1999, 29, 2241. (b) Dieter, R. K.; Fishpaugh, J. R. J. Org. Chem. 1988,
53, 2031.
(37) (a) Kalinin, V. N.; Shilova, O. S.; Okladnoi, D. S.; Schmidham-
mer, H. Dokl. Akad. Nauk 1996, 351, 67. (b) Fairlamb, I. J. S.;
Marrison, L. R.; Dickinson, J. M.; Lu, F. J.; Schmidt, J. P. Bioorg. Med.
Chem. 2004, 12, 4285.
(38) Dieter, R. K.; Fishpaugh, J. R. J. Org. Chem. 1987, 52, 923.
(39) Pittet, A. O.; Klaiber, E. M. J. Agric. Food Chem. 1975, 23, 1189.
6674 J. Org. Chem., Vol. 70, No. 17, 2005

Synthesis of Isocoumarins and R-Pyrones
General Procedure for the Preparation of Isocou-
marins 5a-g. Palladium acetate (112 mg, 0.5 mmol), tri-
phenylphosphine (262 mg, 1 mmol), and tetrabutylammonium
bromide (3.2 g, 10 mmol) were progressively added to a
degassed solution of 2-iodobenzoic acids 4a-c (10 mmol) in
anhydrous dimethylformamide (40 mL). The mixture was
stirred at room temperature for 10 min, and allenylstannane
(15 mmol) was then added. The reaction mixture was heated
in an oil bath at 80 °C for the necessary period of time. After
conversion was complete (checked by TLC, reaction time < 10
h), the reaction mixture was cooled, diluted with diethyl ether,
and quenched with aqueous NH4Cl solution. After ether
extraction (3 × 20 mL) and usual treatments, the products
5a-g were isolated by chromatography (hexane/ether: 70/30)
on silica gel column or by crystallization in diethyl ether.
3-Methylisocoumarin (5a).40 Isolated as colorless prisms
with mp 71-73 °C (lit.S6(b) mp 71 °C).
J ) 2.5 Hz, 1H), 7.02 (dd, J ) 8.8 Hz, J ) 2.5 Hz, 1H), 8.21 (d,
J ) 8.8 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 20.1, 56, 104,
107.3, 113.4, 116.3, 132.1, 140.4, 155.6, 163.2, 165.1; MS (EI)
m/z (%) 190 (M•+, 100), 175 (49), 148 (18), 119 (54), 43 (28).
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.44;
H, 5.25.
3-Ethyl-8-fluoro-isocoumarin (5e). IR (neat) 3083, 2973,
1
1743, 1661, 1614; H NMR (200 MHz, CDCl3) δ 1.29 (t, J )
7.5 Hz, 3H), 2.58 (qd, J ) 7.5 Hz, J ) 1.2 Hz, 2H), 6.26 (t, J
) 1.2 Hz, 1H), 7.07-7.18 (m, 2H), 7.60-7.70 (m, 1H); 13C NMR
(50 MHz, CDCl3) δ 11.5, 27, 102 (d, JC-F ) 3 Hz), 109.4 (d,
JC-F ) 7 Hz), 115 (d, JC-F ) 21 Hz), 121.3 (d, JC-F ) 4 Hz),
136.5 (d, JC-F ) 10 Hz), 140.6, 159 (d, JC-F ) 5.5 Hz), 161,
163 (d, JC-F ) 265 Hz); 19F NMR (188 MHz, CDCl3,) δ -108;
MS (EI) m/z (%) 192 (M•+, 100), 163 (63), 136 (28), 107 (96),
57 (33). Anal. Calcd for C11H9FO2: C, 68.74; H, 4.72. Found:
C, 68.79; H, 4.76.
3-Ethylisocoumarin (5b).11j,41 Isolated as a pale yellow
3-Ethyl-6-methoxyisocoumarin (5f). Mp 93-95 °C; IR
(KBr) 3088, 2990, 1725, 1650, 1606, 1160; 1H NMR (200 MHz,
CDCl3) δ 1.31 (t, J ) 7.5 Hz, 3H), 2.60 (q, J ) 7.5 Hz, 2H),
3.94 (s, 3H), 6.23 (s, 1H), 6.78 (d, J ) 2.4 Hz, 1H), 7.02 (dd, J
) 8.8 Hz, J ) 2.4 Hz, 1H), 8.21 (d, J ) 8.8 Hz, 1H); 13C NMR
(50 MHz, CDCl3) δ 11.6, 27.1, 56, 102.4, 107.6, 113.7, 116.3,
132.2, 140.4, 160.6, 163.2, 165.1; MS (EI) m/z (%) 204 (M•+,
94), 175 (82), 148 (34), 119 (100), 65 (22). Anal. Calcd for
C12H12O3: C, 70.57; H, 5.92. Found: C, 70.54; H, 5.94.
solid with mp 72-74 °C (lit.S7(a) mp 72-73 °C).
8-Fluoro-3-methylisocoumarin (5c). Mp 110-112 °C; IR
(KBr) 3083, 2973, 1743, 1661, 1614; 1H NMR (200 MHz,
CDCl3) δ 2.28 (d, J ) 1.0 Hz, 3H), 6.26 (q, J ) 1.0 Hz, 1H),
7.06-7.16 (m, 2H), 7.59-7.70 (m, 1H); 13C NMR (50 MHz,
CDCl3) δ 20, 103.5, 109.4 (d, JC-F ) 7 Hz), 115 (d, JC-F ) 21
Hz), 121.3 (d, JC-F ) 4 Hz), 136.5 (d, JC-F ) 10 Hz), 140.6,
156, 159 (d, JC-F ) 5.5 Hz), 163 (d, JC-F ) 266 Hz); 19F NMR
(188 MHz, CDCl3) δ -108.5; MS (EI) m/z (%)178 (M•+, 100),
163 (38), 107 (65), 43 (79). Anal. Calcd for C10H7FO2: C, 67.42;
H, 3.96. Found: C, 67.38; H, 3.95.
Acknowledgment. We thank MESR and CNRS for
providing financial support and the “Service d’analyse
chimique du vivant de Tours” for recording NMR and
mass spectra.
6-Methoxy-3-methylisocoumarin (5d).42 Mp 86-88 °C;
IR (KBr) 3079, 2992, 1726, 1648, 1610, 1150; 1H NMR (200
MHz, CDCl3) δ 2.31 (s, 3H), 3.94 (s, 3H), 6.23 (s, 1H), 6.75 (d,
Supporting Information Available: Lists of the 1H and/
or 13C chemical shifts of the compounds 3c-f, 3i, 3k, and 5c-
f. This material is available free of charge via the Internet at
http://pubs.acs.org.
(40) (a) Sashida, H.; Kawamukai, A. Synthesis 1999, 1145. (b)
Larock, R. C.; Varaprath, S.; Lau, H. H.; Fellows, C. A. J. Am. Chem.
Soc. 1984, 106, 5274.
(41) Tirodkar, R. B.; Vsgaonkar, R. N. Indian J. Chem. 1970, 8, 123.
(42) Hauser, F. M.; Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237.
JO050638Z
J. Org. Chem, Vol. 70, No. 17, 2005 6675