Synthesis of phthalides and 3,4-dihydroisocoumarins using the palladium-catalyzed intramolecular benzannulation strategy

Article abstract of DOI:10.1021/jo016336o

A novel method for the synthesis of phthalides and 3,4-dihydroisocoumarins via the palladium-catalyzed intramolecular benzannulation of bis-enyne and enyne-diyne systems is described. Various kinds of substituted phthalides 9 and 17 and 3,4-dihydroisocoumarins 19 were synthesized from 8, 16, and 18, respectively, in moderate to excellent yields. The benzannulation reaction proceeded chemoselectively to give the corresponding fused ring compounds A without the formation of the regioisomeric products B (eq 6). Furthermore, this methodology was applied to the synthesis of biologically active 3-n-butylphthalide 23.

Full text of DOI:10.1021/jo016336o

J . Org. Chem. 2002, 67, 2653-2658
2653
Syn th esis of P h th a lid es a n d 3,4-Dih yd r oisocou m a r in s Usin g th e
P a lla d iu m -Ca ta lyzed In tr a m olecu la r Ben za n n u la tion Str a tegy
Taishi Kawasaki, Shinichi Saito, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, J apan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received November 30, 2001
A novel method for the synthesis of phthalides and 3,4-dihydroisocoumarins via the palladium-
catalyzed intramolecular benzannulation of bis-enyne and enyne-diyne systems is described.
Various kinds of substituted phthalides 9 and 17 and 3,4-dihydroisocoumarins 19 were synthesized
from 8, 16, and 18, respectively, in moderate to excellent yields. The benzannulation reaction
proceeded chemoselectively to give the corresponding fused ring compounds A without the formation
of the regioisomeric products B (eq 6). Furthermore, this methodology was applied to the synthesis
of biologically active 3-n-butylphthalide 23.
In tr od u ction
tion,7 nickel-catalyzed8 or mediated9 [2 + 2 + 2] cocy-
clization of alkyne moieties, and rhodium-catalyzed
carbocyclization reaction of diazocarbonyl with tethered
alkynes10 are known as a one-step synthetic procedure.
Recently, we reported an efficient method for the con-
struction of benzene rings using palladium-catalyzed
intermolecular homo-benzannulation reaction of 2-sub-
stituted conjugated enynes (eq 1).11 This reaction was
extended to the intermolecular enyne-diyne [4 + 2] cross-
benzannulation for the synthesis of polysubstituted
benzenes.12 We also found that, in the palladium-
catalyzed benzannulation, electron-deficient enynes bear-
ing an electron-withdrawing group at the C1 or C2
position exhibit higher reactivity than electron-rich
enynes bearing an alkyl or aryl group at the C1 or C2
position, and by applying this finding we were successful
in preparing polysubstituted benzenes easily from 1-sub-
stituted enynes as well as 1,2- and 2,4-disubstituted
enynes.13 Moreover, we reported the synthesis of carbon-
tethered14 exomethylene paracyclophanes and crown-
ether-like cyclophanes15 via an intramolecular palladium-
catalyzed homo-benzannulation of bis-enynes (eq 2).
Synthesis of ortho-, meta-, and paracyclophanes was also
achieved via an intermolecular palladium-catalyzed enyne-
diyne cross-benzannulation approach.16 The palladium-
catalyzed benzannulation methodology was applied fur-
ther to the synthesis of many functionalized benzenes
Phthalides and 3,4-dihydroisocoumarins are a class of
naturally occurring substances exhibiting biological ac-
tivities.1,2 They are also attractive intermediates for the
synthesis of more complex heterocyclic3 and carbocyclic4
compounds, various drugs,5 and naturally occurring
compounds.6 Although various methods have been de-
veloped for the synthesis of phthalides and dihydroiso-
coumarins, only a limited number of papers are known
for the construction of phthalide and dihydroisocoumarin
skeletons from acyclic, acetylenic compounds in a one-
step procedure.7-10 For example, the Alder-Rickert reac-
(1) (a) Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds; Academic Press: New York, 1975; Vol. 1, pp 249-264,
383-384. (b) Inubushi, Y.; Tsuda, Y.; Konita, T.; Matsumoto, S. Chem.
Pharm. Bull. J pn. 1964, 12, 749-750. (c) Inouye, H.; Okuda, T.; Hirata,
Y.; Nagakura, N.; Yoshizaki, M. Chem. Pharm. Bull. J pn. 1967, 15,
786-792. (d) Elander, M.; Leander, K.; Luning, B. Acta Chem. Scand.
1969, 23, 2177-2178. (e) Pushan, W.; Xuanliang, G.; Yixiong, W.;
Fukuyama, Y.; Miura, I.; Sugawara, M. Phytochemistry 1984, 23,
2033-2038.
(2) (a) Hill, R. A. Prog. Chem. Org. Nat. Prods. 1986, 49, 1-78. (b)
Mclnerney, B. V.; Taylor, W. C. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, New York,
1995; Vol. 15, 381.
(3) (a) Snieckus, V. Heterocycles 1980, 14, 1649-1676. (b) Dod-
sworth, D. J .; Caliagno, M. P.; Ehramann, U. E.; Sammes, P. G.
Tetrahedron Lett. 1980, 21, 5075-5078. (c) Hung, T. V.; Mooney, B.
A.; Prager, R. H.; Ward, A. D. Aust. J . Chem. 1981, 34, 151-162. (d)
Hung, T. V.; Mooney, B. A.; Prager, R. H.; Tippett, J . M. Aust. J . Chem.
1981, 34, 383-395. (e) Prager, R. H.; Tipett, J . M.; Ward, A. D. Aust.
J . Chem. 1981, 34, 1085-1093.
(4) (a) Newman, M. S.; Kumar, S. J . Org. Chem. 1978, 43, 370-
371. (b) de Silva, S. O.; Watanabe, M.; Snieckus, V. J . Org. Chem. 1979,
44, 4802-2808. (c) Ciufolini, M. A.; Browne, M. E. Tetrahedron Lett.
1987, 27, 171-174. (d) Aidhen, I. S.; Narasimhan, N. S. Tetrahedron
Lett. 1989, 30, 5323-5324.
(5) Kubota, K.; Ogawa, Y.; Hosaka, K.; Chin, M. J pn Kokai Tokkyo
Koho J P01, 50,818 [89 50,818]; Chem. Abstr. 1990, 112, 76923e.
(6) (a) Cundasawmy, N. E.; Mclean, D. B. Can. J . Chem. 1972, 50,
3028-3036. (b) de Silva, S. O.; Ahmad, I.; Snieckus, V. Can. J . Chem.
1979, 57, 1598-1605. (c) Broadhurst, M. J .; Hassall, C. H. J . Chem.
Soc., Perkin Trans. 1 1982, 2227-2238. (d) Clarke, S. I.; Kusum, B.;
Prager, R. H.; Ward, A. D. Aust. J . Chem. 1983, 36, 2493-2498. (e)
Bates, M. A.; Sammes, P. G.; Thomson, G. A. J . Chem. Soc., Perkin
Trans. 1 1988, 3037-3045.
(7) (a) Harland, P. A.; Hodge, P. Synthesis 1982, 3, 223-225. (b)
Kanakam, C. C.; Mani, N. S.; Ramanathan, H.; Rao, G. S. R. S. J .
Chem. Soc., Perkin Trans. 1 1989, 11, 1907-1913.
(8) (a) Sambaiah, T.; Li, L.-P.; Huang, D.-J .; Lin, C.-H.; Rayabarapu,
D. K.; Cheng, C.-H. J . Org. Chem. 1999, 64, 3663-3670. (b) Sato, Y.;
Ohashi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5231-5234.
(9) (a) Bhatarah, P.; Smith, E. H. J . Chem. Soc., Chem. Commun.
1991, 277-278. (b) Bhatarah, P.; Smith, E. H. J . Chem. Soc., Perkin
Trans. 1 1992, 2163-2168.
(10) Padwa, A.; Weingarten, M. D. J . Org. Chem. 2000, 65, 3722-
3732.
(11) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.; Tando,
K.; Yamamoto, Y. J . Am. Chem. Soc. 1996, 118, 3970-3971.
(12) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.;
Radhakrishnan, U.; Yamamoto, Y. J . Am. Chem. Soc. 1999, 121, 6391-
6402.
(13) Saito, S.; Chounan, Y.; Nogami, T.; Fukushi, T.; Tsuboya, N.;
Yamada, Y.; Kitahara, H.; Yamamoto, Y. J . Org. Chem. 2000, 65,
5350-5354.
(14) Saito, S.; Tsuboya, N.; Yamamoto, Y. J . Org. Chem. 1997, 62,
5042-5047.
(15) Weibel, D.; Gevorgyan, V.; Yamamoto, Y. J . Org. Chem. 1998,
63, 1217-1220.
(16) Gevorgyan, V.; Tsuboya, N.; Yamamoto, Y. J . Org. Chem. 2001,
66, 2743-2746.
10.1021/jo016336o CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/22/2002

2654 J . Org. Chem., Vol. 67, No. 8, 2002
Kawasaki et al.
such as phenols17 and polysubstituted alkoxycarbonyl- or
cyanostyrenes.18 A not only synthetically important but
also mechanistically interesting aspect of the [4 + 2]
benzannulation reaction lies in the high regio- and
chemoselectivity for the annulation.19
Sch em e 1. Rep r esen ta tive P r oced u r e for th e
Syn th esis of Bis-en yn e Ester s
similar to that shown in Scheme 1, and detailed proce-
dures are mentioned in the Supporting Information.
Syn th esis of P h th a lid es. The unsubstituted bis-
enyne 8a reacted in the presence of a catalytic amount
of Pd(PPh3)4 (40 mol %) and DPPF (80 mol %) to give
4-vinylphthalide 9a in a moderate yield (Table 1, entry
1). The reaction proceeded smoothly, and no trace amount
of regioisomeric fused ring was detected in the reaction
mixture. However, a trace amount of 4-phenylfuran-
2(5H)-one 10a was obtained as a byproduct.22 When the
reaction of 8a was carried out under more concentrated
conditions (toluene, 30 mM), the intermolecular dimer-
ization was accompanied by the desired intramolecular
annulation. As mentioned above, usually high catalyst
loading (40 mol %) was employed to obtain a higher yield
of 9a . When 5 mol % or 10 mol % of Pd(PPh3)4 was used,
9a was obtained in 14% or 43% yield, respectively. To
obtain the phthalide 9a efficiently, it was necessary to
carry out the reaction of the bis-enyne 8a under a highly
diluted condition (toluene, 2.5 mM), and the bis-enyne
should be added slowly (over a period of 3 h) to a toluene
solution containing palladium catalyst. The reaction of
the alkyl- and aryl-substituted bis-enynes 8b and 8c gave
the corresponding phthalides 9b and 9c, respectively, in
high to acceptable yields, though a higher temperature
(100 °C) was needed in the reaction of the phenyl-
substituted bis-enyne 8c (Table 1, entries 2 and 3). The
bis-enyne 8d with propargyl alcohol moiety underwent
the benzannulation reaction in a manner similar to give
the hydroxy-substituted phthalide 9d in 49% yield (Table
1, entry 4). The bis-enynes 8e and 8f, substituted with a
methyl group at the R2 position, reacted smoothly (Table
1, entries 5 and 6). Since electron-deficient enynes are
more reactive than alkyl-substituted enynes in the [4 +
2] benzannulation,13 we also carried out the reaction of
the bis-enynes substituted by an electron-withdrawing
group (Table 1, entries 7-9). The bis-enynes 8g and 8h
substituted by (Z)-ester at the R3 position gave the
phthalides 9g and 9h , respectively, irrespective of the
presence or absence of propyl group at R1 position (Table
1, entries 7 and 8). The bis-enyne 8i substituted by (E)-
C6F13 group at the R4 position also gave the corresponding
As a further development of these benzannulation
reactions, we attempted to synthesize fused rings using
the intramolecular benzannulation strategy. In this
paper, we report a new route for the synthesis of fused
rings 2, such as phthalides and dihydroisocoumarins, via
the palladium-catalyzed one-step benzannulation reac-
tion of enyne esters 1, in which ester group is attached
at the C1 position of enyne functionality (eq 3).
Resu lts a n d Discu ssion
P r ep a r a tion of Bis-en yn es a n d En yn e-Diyn es.
The bis-enyne 8k was prepared in four steps from
commercially available 1-heptyn-3-ol 3 (Scheme 1). The
enyne 4 was synthesized by the Sonogashira coupling of
3 with vinyl bromide.20 Treatment of 4 with (Z)-3-bromo-
2-propenoic acid 521 in the presence of DCC-DMAP gave
the ester 6 in 84% yield. The Sonogashira coupling of this
ester with (trimethylsilyl)acetylene gave the protected
bis-enyne 7. Deprotection with KF-MeOH/THF produced
the bis-enyne 8k . Other bis-enynes 8a -j, 18a -d , and 20
and enyne-diynes 16a ,b were prepared by a method
(17) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. J . Org. Chem. 1998,
63, 1244-1247.
(18) Saito, S.; Ohmori, O.; Yamamoto, Y. Org. Lett. 2000, 2, 3853-
3855.
(19) Reviews: (a) Gevorgyan, V.; Yamamoto, Y. J . Organomet. Chem.
1999, 576, 232-247. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,
2901-2915.
(20) (a) Sonogashira, K.; Tohada, Y,; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470. (b) For the coupling of vinylbromide and propargyl
alcohol, see: Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D.
Application of Transition Metal Catalysts in Organic Synthesis;
Springer: Berlin, 1998; pp 201-204.
(21) Weir, J . R.; Patal, B. A.; Heck, R. F. J . Org. Chem. 1980, 45,
4926-4931.
(22) The spectral data of 10a were identical to those reported in
the literature: Mabon, R.; Richecoeur, A. M. E.; Sweeney, J . B. J . Org.
Chem. 1999, 64, 328-329.

Synthesis of Phthalides and 3,4-Dihydroisocoumarins
Ta ble 1. Syn th esis of P h th a lid es
J . Org. Chem., Vol. 67, No. 8, 2002 2655
entry
enyne
R1
R2
R3
R4
R5
reaction timea (h)
product
yieldb (%)
1c
2
8a
8b
8c
8d
8e
8f
8g
8h
8i
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.5
1.0
18
0.5
0.5
7
0.5
0.5
1.5
0.5
0.5
9a
9b
9c
9d
9e
9f
9g
9h
9i
53
81
38
49
67
43
57
79
46
47
54
n-C6H13
Ph
CH2OH
H
n-C3H7
H
n-C3H7
n-C3H7
H
3d
4
5
6
7c
8
CO2CH3
CO2CH3
H
H
H
9e
10c
11c
n-C6F13
H
H
8j
8k
H
H
Ph
n-C4H9
9j
9k
H
a
Bis-enynes 8 were added to a toluene solution containing palladium catalyst over a period of 3 h, and then the mixture was stirred
at 80 °C for the indicated time. Isolated yields. c A trace amount of the rearranged product 10 was obtained. The bis-enyne 8c was
added to a toluene solution of palladium catalyst over a period of 1 h. e The bis-enyne 8i was added over a period of 1 h, and the reaction
was carried out at 100 °C.
b
d
Sch em e 2. P r op osed Mech a n ism for th e
F or m a tion of 10
worth mentioning. A proposed mechanism is shown in
Scheme 2. The coordination of Pd(0) to alkyne moiety of
the bis-enyne 8a would give the palladacycle 12 through
11.12 The reductive elimination of Pd(0) from this com-
plex, as usually observed in the previous benzannulation
reactions,19 must give the phthalide 9a . Actually, this was
observed as apparent from the results of Table 1. On the
other hand, the propargylpalladium complex 14 would
be formed through the bond reorganization from 12. To
better understand this process, arrows for bond migration
are shown in 14′. Further migration from 14 would lead
the formation of the allenylpalladium complex 15, which
would give 4-phenylfuran-2(5H)-one 10a upon reductive
elimination of Pd(0).
To extend this intramolecular benzannulation protocol
for the synthesis of fused rings, we investigated the
reaction of the enyne-diyne system as shown in eq 4.
The reaction of 16a and 16b proceeded smoothly under
the similar conditions as above to give the corresponding
phthalides 17a and 17b, respectively, in moderate yields.
phthalide 9i in 46% yield, though a rather higher
temperature (100 °C) was needed (Table 1, entry 9). This
observation is in agreement with the previous finding
that (Z)-substituted enynes are in general more reactive
than (E)-isomers in the palladium-catalyzed benzannu-
lation of enynes.13 3-Phenyl- and n-butyl-substituted
phthalides 9j and 9k were prepared from the bis-enynes
8j and 8k , respectively, in a similar manner (Table 1,
entries 10 and 11). It should be noted that, in entries 1,
7, 10, and 11, trace amounts of the rearranged products
10a ,g,j,k were observed, although in entries 7 and 10
the structural identification of 10g and 10j was not
unambiguous due to very trace amounts of formation of
those products.
Syn th esis of 3,4-Dih yd r oisocou m a r in s. The syn-
thesis of 3,4-dihydroisocoumarins 19 was accomplished
by the use of 18 as a starting substrate (Table 2).
5-Hexen-3-ynyl (Z)-2-buten-4-ynoate 18a was trans-
formed into 5-vinyl-3,4-dihydroisocoumarin 19a ; a small
amount of dimeric aromatic product, which was formed
via the intermolecular benzannulation reaction, was also
obtained (Table 2, entry 1). Here also, the benzannulation
reaction proceeded chemoselectively as observed in the
formation of phthalides. n-Propyl- and phenyl-substituted
bis-enynes at R1 position 18b and 18c gave the corre-
Although the rearranged products 10 were obtained
only in trace amounts, a mechanistic consideration on
the formation of this interesting product seems to be

2656 J . Org. Chem., Vol. 67, No. 8, 2002
Kawasaki et al.
Ta ble 2. Syn th esis of 3,4-Dih yd r oisocou m a r in s
Sch em e 3. Syn th esis of 3-n -Bu tylp h th a lid e 23
reaction
yieldb
(%)
entry bis-enyne
R1
R2
timea (h) product
1c
2
18a
18b
18c
18d
H
H
H
H
0.5
17
4.0
0.5
19a
19b
19c
19d
65
83
90
46
n-C3H7
Ph
H
3d
4
CO2CH3
of this compound via the palladium-catalyzed benzan-
nulation reaction. As mentioned in Table 1, entry 11,
3-butyl-4-vinylphthalide 9k was obtained in a moderate
yield. Starting from 3-butyl-4-vinylphthalide 9k , 3-n-
butylphthalide 23 could be synthesized in two steps
(Scheme 3). The ozonolysis of 9k followed by the decar-
bonylation of the product 22 with RhCl(PPh3)3 gave 23
in 75% yield in two steps.
a
Bis-enynes 18 were added to a toluene solution containing
palladium catalyst over a period of 3 h, and then the mixture was
stirred at 80 °C for the indicated time. Isolated yields. c A trace
b
d
amount of dimeric product was obtained. The bis-enyne 18c was
added to a toluene solution of palladium catalyst over a period of
1 h, and the reaction was carried out at 100 °C.
sponding 3,4-dihydroisocoumarins 19b and 19c, respec-
tively, in good yields (Table 2, entries 2 and 3). The ester-
substituted bis-enyne 18d also reacted smoothly under
similar reaction conditions to give 19d in 46% yield
(Table 2, entry 4).
Con clu sion s
We have accomplished a new synthetic route for the
construction of fused rings such as phthalides and 3,4-
dihydroisocoumarins via the palladium-catalyzed ben-
zannulation of bis-enyne and enyne-diyne systems. It
should be noted that the fused ring formation proceeds
in completely chemoselective manner. That is, the enyne
attached to the ester-carbonyl group reacted as a four-
carbon unit and the enyne (or diyne) attached to ester-
oxygen group reacted as a two carbon unit in the [4 + 2]
benzannulation reaction, and in all cases the type A fused
ring was obtained (eq 6). No trace amount of the type B
fused ring, arising from the reaction between the alkyne
moiety attached to ester-carbonyl group as a two-carbon
unit and the enyne moiety attached to ester-oxygen group
as a four-carbon unit, was detected (eq 6).
Syn th esis of Seven -Mem ber ed Rin g Sk eleton .
Since we were successful in synthesizing five- and six-
membered ring skeletons, we next attempted to synthe-
size a seven-membered fused ring. The reaction of
6-hepten-4-ynyl (Z)-2-buten-4-ynoate 20 with Pd(PPh3)4
catalyst was carried out under similar conditions, Pd-
(PPh3)4 (40 mol %) and DPPF (80 mol %) in toluene (2.5
mM). However, only a trace amount of the desired seven-
membered ring product 21 was obtained, and the dimeric
benzannulation adduct was obtained as a major product.
After many optimizations, we could synthesize the seven-
membered ring product 21 in 22% yield under highly
diluted conditions (0.5 mM) at 100 °C (eq 5). However,
even under these conditions, the dimeric product was
obtained in 19% yield.
Ap p lica tion to th e Syn th esis of Biologica lly Ac-
tive 3-n -Bu tylp h th a lid e. Phthalides possess a wide
range of biological activity. For instance, 3-n-butylphtha-
lide, which is a constituent of celery seed oil,23 is used
for seasoning and flavoring purposes, shows anticonvul-
sant action,24 increases the duration of anesthesia,25 and
exhibits cerebral antiischemic action.26 Since both chiral
and racemic 3-n-butylphthalide have many kinds of
biological activity, we became interested in the synthesis
Exp er im en ta l Section
P a lla d iu m -Ca ta lyzed Ben za n n u la tion of Bis-En yn es
8. A Rep r esen ta tive P r oced u r e. A mixture of Pd(PPh3)4
(230 mg, 0.20 mmol) and DPPF (220 mg, 0.40 mmol) in dry
toluene (195 mL) in a 300 mL flask was kept at 80 °C. To this
mixture was slowly added a toluene (5 mL) solution of 8a (80
mg, 0.50 mmol) for 3 h with a syringe pump. After the mixture
was stirred for an additional 30 min, toluene was evaporated
and the resulting mixture was passed through a short silica
gel column chromatography (hexane and Et2O). The residue
was further purified by silica gel column chromatography
(hexane/AcOEt ) 10:1) to give 9a (42 mg, 53%).
(23) Barton, D. H. R.; de Vries, J . X. J . Chem. Soc. 1963, 1916-
1919.
(24) Yu, S.; You, S.; Chen, H. Yaoxue Xuebao 1984, 19, 486-490;
Chem. Abstr. 1984, 101, 222490c.
4-Vin ylp h th a lid e (9a ): yellow solid; mp 54.3-55.4 °C; 1H
NMR (300 MHz, CDCl3) δ 7.81 (d, J ) 7.6 Hz, 1H), 7.69 (d, J
) 7.8 Hz, 1H), 7.51 (dd, J ) 7.6, 7.6 Hz, 1H), 6.69 (dd, J )
(25) Sato, H.; Yorozu, H.; Yamaoka, S. Biomed. Res. 1993, 14, 385-
390.
(26) Wang, X. W. Drugs Future 2000, 25, 16-23.

Synthesis of Phthalides and 3,4-Dihydroisocoumarins
J . Org. Chem., Vol. 67, No. 8, 2002 2657
17.7, 11.3 Hz, 1H), 5.66 (d, J ) 17.8 Hz, 1H), 5.50 (d, J ) 11.4
Hz, 1H), 5.38 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 171.0, 143.7,
132.6, 132.5, 131.7, 129.5, 126.1, 124.9, 118.3, 69.5; IR (KBr)
3090, 2976, 2957, 2926, 1753, 1655, 1630, 1483, 1364, 1315,
1254, 1061, 1016 cm-1; HRMS calcd for C10H8O2 160.0524,
found 160.0511.
1639, 1601, 1456, 1439, 1396, 1358, 1294, 1265, 1221, 1205,
1175, 1090, 1059, 1022 cm-1; HRMS calcd for C15H16O4
260.1048, found 260.1056.
4-((E)-3,3,4,4,5,5,6,6,7,7,8,8,8-Tr id eca flu or o-2-octen yl)-
1
5-p r op ylp h th a lid e (9i): brown solid; mp 27.8-28.9 °C; H
NMR (300 MHz, CDCl3) δ 7.85 (d, J ) 7.9 Hz, 1H), 7.42 (d, J
) 7.7 Hz, 1H), 7.39 (ddd, J ) 16.5, 2.3, 2.3 Hz, 1H), 5.90 (ddd,
J ) 16.3, 11.4, 11.4 Hz, 1H), 5.33 (s, 2H), 2.76 (dd, J ) 7.8,
7.8 Hz, 2H), 1.62 (ddddd, J ) 7.6, 7.6, 7.6, 7.6, 7.6 Hz, 2H),
0.97 (dd, J ) 7.4, 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
5-Hexyl-4-vin ylp h th a lid e (9b): yellow oil; 1H NMR (300
MHz, CDCl3) δ 7.73 (d, J ) 7.7 Hz, 1H), 7.34 (d, J ) 7.9 Hz,
1H), 6.89 (dd, J ) 17.8, 11.6 Hz, 1H), 5.59 (d, J ) 11.5 Hz,
1H), 5.39 (d, J ) 18.1 Hz, 1H), 5.34 (s, 2H), 2.74 (dd, J ) 7.9,
7.9 Hz, 2H), 1.61-1.50 (m, 2H), 1.37-1.24 (m, 6H), 0.87 (dd,
J ) 6.8, 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.2, 147.7,
144.9, 131.9, 131.6, 130.9, 124.4, 124.0, 119.7, 70.0, 33.7, 31.6,
30.8, 29.2, 22.5, 14.0; IR (neat) 3096, 3018, 2955, 2930, 2856,
1771, 1676, 1630, 1595, 1468, 1433, 1358, 1321, 1267, 1238,
1084, 1055, 1016 cm-1; HRMS calcd for C16H20O2 244.1462,
found 244.1454.
5-P h en yl-4-vin ylp h th a lid e (9c): yellow solid; mp 83.8-
84.7 °C; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J ) 7.9 Hz,
1H), 7.49 (d, J ) 7.7 Hz, 1H), 7.45-7.40 (m, 3H), 7.36-7.33
(m, 2H), 6.61 (dd, J ) 18.0, 11.8 Hz, 1H), 5.49-5.45 (m, 3H),
5.38 (d, J ) 18.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 171.0,
147.0, 144.9, 139.4, 133.5, 131.6, 131.0, 129.7, 128.4, 128.1,
125.2, 124.4, 119.0, 70.3; IR (neat) 3105, 3061, 3020, 2957,
2928, 2856, 1763, 1655, 1626, 1593, 1460, 1448, 1425, 1362,
1267, 1072, 1045, 1011 cm-1; HRMS calcd for C16H12O2
236.0837, found 236.0812.
170.4, 148.8, 145.2 (dd, J C-F ) 1.2, 1.2 Hz), 134.9 (dd, J C-F
)
9.7, 9.7 Hz), 131.5, 127.6, 126.5, 124.6, 122.8-106.6 (m), 120.2
(dd, J C-F ) 23.4, 23.4 Hz), 69.3, 35.7, 24.2, 13.7; IR (KBr) 2968,
2941, 2880, 1759, 1366, 1321, 1302, 1271, 1238, 1200, 1144,
1111, 1067, 1026 cm-1; HRMS calcd for C19H13F13O2 520.0707,
found 520.0734.
3-P h en yl-4-vin ylp h th a lid e (9j): white solid; mp 83.7-
84.8 °C; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J ) 7.5 Hz,
1H), 7.80 (d, J ) 7.7 Hz, 1H), 7.57 (dd, J ) 7.7, 7.7 Hz, 1H),
7.36-7.31 (m, 3H), 7.19-7.16 (m, 2H), 6.43 (s, 1H), 6.37 (dd,
J ) 17.5, 11.1 Hz, 1H), 5.68 (d, J ) 17.5 Hz, 1H), 5.22 (d, J )
10.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 170.2, 145.7, 135.5,
133.4, 131.0, 130.5, 130.0, 129.6, 129.0, 128.2, 126.8, 124.7,
117.9, 83.0; IR (KBr) 3099, 3088, 3059, 3032, 1753, 1634, 1479,
1456, 1410, 1296, 1271, 1261, 1250, 1082 cm-1. Anal. Calcd
for C16H12O2: C, 81.34; H, 5.12. Found: C, 81.32; H, 5.23.
1
3-Bu tyl-4-vin ylp h th a lid e (9k ): yellow oil; H NMR (300
5-Hyd r oxym eth yl-4-vin ylp h th a lid e (9d ): brown solid;
mp 139.5-141.5 °C; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J )
7.9 Hz, 1H), 7.66 (d, J ) 7.9 Hz, 1H), 6.90 (dd, J ) 18.0, 11.6
Hz, 1H), 5.65 (d, J ) 11.7 Hz, 1H), 5.47 (d, J ) 17.9 Hz, 1H),
5.37 (s, 2H), 4.86 (d, J ) 5.8 Hz, 2H), 1.80 (dd, J ) 5.7, 5.7
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 171.0, 144.7, 144.4,
131.4, 130.8, 129.0, 125.4, 124.7, 120.9, 69.9, 62.7; IR (KBr)
3433, 3076, 3018, 2943, 2924, 2878, 2812, 1742, 1597, 1452,
1435, 1364, 1265, 1084, 1059, 1007 cm-1; HRMS calcd for
MHz, CDCl3) δ 7.78 (d, J ) 7.7 Hz, 1H), 7.74 (d, J ) 7.7 Hz,
1H), 7.48 (dd, J ) 7.7, 7.7 Hz, 1H), 6.75 (dd, J ) 17.4, 11.0
Hz, 1h), 5.79 (d, J ) 17.5 Hz, 1H), 5.62 (dd, J ) 8.0, 2.7 Hz,
1H), 5.47 (d, J ) 11.1 Hz, 1H), 2.22-2.13 (m, 1H), 1.73-1.52
(m, 1H), 1.46-1.19 (m, 4H), 0.86 (dd, J ) 7.0, 7.0 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 170.5, 146.8, 132.7, 131.5, 130.5,
129.3, 126.5, 124.7, 118.0, 81.2, 33.5, 26.7, 22.2, 13.7; IR (neat)
3088, 3017, 2957, 2930, 2872, 1767, 1483, 1354, 1300, 1252,
1078 cm-1; HRMS calcd for C14H16O2 216.1149, found 216.1152.
C
11H10O3 190.0630, found 190.0621.
5-Bu tyl-4-p h en ylfu r a n -2(5H)-on e (10k ): pale yellow oil;
1H NMR (300 MHz, CDCl3) δ 7.48-7.43 (m, 5H), 6.25 (d, J )
1.4 Hz, 1H), 5.48 (ddd, J ) 7.7, 2.9, 1.5 Hz, 1H), 2.04-1.93
4-(1-Meth ylvin yl)p h th a lid e (9e): brown solid; mp 52.1-
52.6 °C; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J ) 7.3 Hz,
1H), 7.61 (dd, J ) 7.6, 0.9 Hz, 1H), 7.51 (dd, J ) 7.6, 7.6 Hz,
1H), 5.37 (s, 2H), 5.33 (m, 1H), 5.10 (s, 1H), 2.15 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.1, 143.5, 141.1, 137.5, 132.0,
129.3, 126.1, 124.5, 116.4, 70.1, 22.8; IR (KBr) 3123, 3080,
3065, 2986, 2953, 2926, 1771, 1655, 1624, 1578, 1541, 1522,
1487, 1447, 1431, 1377, 1356, 1317, 1288, 1258, 1207, 1175,
1144, 1061, 1022 cm-1; HRMS calcd for C11H10O2 174.0680,
found 174.0662.
(m, 1H), 1.63-1.16 (m, 5H), 0.83 (dd, J ) 7.2, 7.2 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 172.9, 167.8, 131.2, 130.2, 129.2,
127.1, 114.3, 82.2, 33.2, 26.5, 22.3, 13.8; IR (neat) 3099, 3065,
3030, 2957, 2930, 2860, 1747, 1622, 1456, 1448, 1171 cm-1
HRMS calcd for C14H16O2 216.1149, found 216.1149.
;
P a lla d iu m -Ca ta lyzed Ben za n n u la tion of En yn e-
Diyn es 16. Rep r esen ta tive P r oced u r e. A mixture of Pd-
(PPh3)4 (58 mg, 0.05 mmol) and DPPF (55 mg, 0.10 mmol) in
dry toluene (45 mL) in a 100 mL flask was kept at 80 °C. To
this mixture was slowly added a toluene (5 mL) solution of
16a (29 mg, 0.13 mmol) for 3 h via a syringe pump. After the
mixture was stirred for an additional 30 min, toluene was
evaporated, and the resulting mixture was passed through a
short silica gel column (hexane and Et2O). The residue was
further purified by silica gel column chromatography (hexane/
AcOEt ) 10:1) to give 17a (15 mg, 52%).
4-(1-Meth ylvin yl)-5-p r op ylp h th a lid e (9f): colorless oil;
1H NMR (300 MHz, CDCl3) 7.73 (d, J ) 7.9 Hz, 1H), 7.36 (d,
J ) 7.9 Hz, 1H), 5.34 (dd, J ) 1.5, 1.5 Hz, 1H), 5.16 (s, 2H),
4.89 (s, 1H), 2.66-2.61 (m, 2H), 1.68-1.58 (m, 2H), 1.55 (s,
3H), 0.95 (dd, J ) 7.4, 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
171.5, 146.4, 145.0, 141.0, 137.8, 130.3, 124.0, 123.3, 116.9,
69.1, 34.8, 24.9, 23.6, 14.1; IR (neat) 3080, 3028, 2963, 2934,
2872, 1771, 1682, 1643, 1599, 1456, 1377, 1356, 1304, 1258,
1240, 1167, 1142, 1086, 1055, 1018 cm-1; HRMS calcd for
4-(2-P h en yla cetylen yl)p h th a lid e (17a ): yellow solid; mp
124.7-126.0 °C; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J ) 7.7
Hz, 1H), 7.79 (dd, J ) 7.7, 0.8 Hz, 1H), 7.56-7.51 (m, 3H),
7.39-7.35 (m, 3H), 5.40 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
170.6, 148.4, 136.4, 131.7, 129.3, 129.2, 128.5, 126.2, 125.3,
122.0, 118.5, 95.5, 83.8, 69.5; IR (KBr) 3071, 3047, 2922, 2208,
1759, 1686, 1659, 1611, 1597, 1572, 1541, 1522, 1510, 1497,
1475, 1443, 1397, 1364, 1308, 1261, 1177, 1151, 1061, 1013
cm-1; HRMS calcd for C16H10O2 234.0680, found 234.0684.
C
14H16O2 216.1149, found 216.1156.
4-((Z)-2-Meth oxycar bon yl-1-vin yl)ph th alide (9g): white
1
solid; mp 107.5-108.5 °C; H NMR (300 MHz, CDCl3) δ 7.88
(d, J ) 7.9 Hz, 1H), 7.82 (d, J ) 7.7 Hz, 1H), 7.53 (dd, J ) 7.6,
7.6 H, 1H), 6.95 (d, J ) 12.1 Hz, 1H), 6.17 (d, J ) 12.3 Hz,
1H), 5.25 (s, 2H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.8, 165.4, 145.3, 138.0, 133.9, 130.3, 128.9, 125.7, 125.5,
123.2, 69.1, 51.7; IR (KBr) 3258, 3009, 2955, 2924, 2851, 1771,
1753, 1724, 1645, 1458, 1431, 1416, 1265, 1232, 1194, 1165,
1067, 1015 cm-1. Anal. Calcd for C12H10O4: C, 66.05; H, 4.62.
Found: C, 65.95; H, 4.64.
4-(2-P h en yla cetylen yl)-5-p r op ylp h th a lid e (17b): white
1
solid; mp 101.7-102.5 °C; H NMR (300 MHz, CDCl3) δ 7.77
4-((Z)-2-Meth oxyca r bon yl-1-vin yl)-5-p r op ylp h th a lid e
(9h ): red solid; mp 62.3-63.8 °C; 1H NMR (300 MHz, CDCl3)
δ 7.78 (d, J ) 7.7 Hz, 1H), 7.36 (d, J ) 7.7 Hz, 1H), 7.09 (d, J
) 11.9 Hz, 1H), 6.23 (d, J ) 11.9 Hz, 1H), 5.10 (s, 2H), 3.60 (s,
3H), 2.61 (dd, J ) 7.8, 7.8 Hz, 2H), 1.64-1.51 (m, 2H), 0.92
(dd, J ) 7.4, 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.2,
165.1, 146.4, 145.4, 139.6, 130.1, 124.8, 124.2, 123.1, 69.3, 51.6,
35.6, 23.4, 13.8; IR (neat) 3067, 3030, 2961, 2874, 1771, 1728,
(d, J ) 7.9 Hz, 1H), 7.53-7.49 (m, 2H), 7.41-7.36 (m, 4H),
5.37 (s, 2H), 2.93 (dd, J ) 7.7, 7.7 Hz, 2H), 1.76 (ddddd, J )
7.5, 7.5, 7.5, 7.5, 7.5 Hz, 2H), 1.00 (dd, J ) 7.4, 7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 170.8, 151.3, 149.3, 131.6, 130.1,
129.1, 128.6, 124.9, 123.8, 122.3, 117.5, 98.7, 82.7, 69.5, 36.7,
23.8, 13.9; IR (KBr) 3059, 3020, 2951, 2926, 2866, 1753, 1593,
1493, 1450, 1362, 1315, 1055, 1009 cm-1; HRMS calcd for
C
19H16O2 276.1149, found 276.1143.

2658 J . Org. Chem., Vol. 67, No. 8, 2002
Kawasaki et al.
P a lla d iu m -Ca t a lyzed Ben za n n u la t ion of Bis-en yn es
18. Rep r esen ta tive P r oced u r e. A mixture of Pd(PPh3)4 (230
mg, 0.20 mmol) and DPPF (220 mg, 0.40 mmol) in dry toluene
(195 mL) in a 300 mL flask was kept at 80 °C. To this mixture
was slowly added a toluene (5 mL) solution of 18a (87 mg,
0.50 mmol) for 3 h via a syringe pump. After the mixture was
stirred for an additional 30 min, toluene was evaporated, and
the resulting mixture was passed through a short silica gel
column (hexane and Et2O). The residue was further purified
by silica gel column chromatography (hexane/AcOEt ) 10:1)
to give 19a (57 mg, 65%).
1713, 1587, 1460, 1391, 1288, 1277, 1246, 1123, 1057, 1040
cm-1. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C,
77.61; H, 7.59.
6-P h en yl-5-vin yl-3,4-d ih yd r oisocou m a r in (19c): white
oil; 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J ) 8.1 Hz, 1H),
7.43-7.30 (m, 6H), 6.48 (dd, J ) 18.0, 11.6 Hz, 1H), 5.50 (dd,
J ) 11.5, 1.4 Hz, 1H), 5.20 (dd, J ) 17.9, 1.4 Hz, 1H), 4.48
(dd, J ) 5.9, 5.9 Hz, 2H), 3.17 (dd, J ) 5.8, 5.8 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 165.6, 146.4, 140.3, 137.7, 135.0,
133.5, 129.6, 129.2, 129.1, 128.1, 127.6, 124.7, 121.7, 67.1, 26.9;
IR (neat) 3084, 3059, 3030, 2984, 2955, 2899, 1717, 1653, 1628,
1587, 1566, 1522, 1497, 1472, 1447, 1394, 1337, 1285, 1259,
1205, 1180, 1157, 1126, 1074, 1057, 1040, 1024 cm-1; HRMS
calcd for C17H14O2 250.0993, found 250.1014.
5-Vin yl-3,4-d ih yd r oisocou m a r in (19a ): white solid; mp
1
78.0-79.5 °C; H NMR (300 MHz, CDCl3) δ 8.05 (d, J ) 7.9
Hz, 1H), 7.69 (d, J ) 7.7 Hz, 1H), 7.37 (dd, J ) 7.8, 7.8 Hz,
1H), 6.85 (dd, J ) 17.4, 11.0 Hz, 1H), 5.69 (d, J ) 17.3 Hz,
1H), 5.43 (d, J ) 10.9 Hz, 1H), 4.51 (dd, J ) 6.0, 6.0 Hz, 2H),
3.06 (dd, J ) 6.0, 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
165.2, 136.8, 135.6, 132.5, 130.8, 129.9, 127.3, 125.6, 118.0,
66.6, 24.8; IR (KBr) 3069, 2982, 2955, 2914, 1717, 1628, 1591,
1472, 1412, 1396, 1300, 1277, 1256, 1240, 1119, 1088, 1067,
1038 cm-1; HRMS calcd for C11H10O2 174.0680, found 174.0709.
Anal. Calcd for C11H10O2: C, 75.84; H, 5.79. Found: C, 75.54;
H, 6.05.
5-((Z)-2-Meth oxyca r bon yl-1-vin yl)-3,4-d ih yd r oisocou -
m a r in (19d ): white solid; mp 88.5-89.2 °C; 1H NMR (300
MHz, CDCl3) δ 8.09 (d, J ) 7.7 Hz, 1H), 7.52 (d, J ) 7.7 Hz,
1H), 7.37 (dd, J ) 7.8, 7.8 Hz, 1H), 7.06 (d, J ) 12.1 Hz, 1H),
6.16 (d, J ) 12.1 Hz, 1H), 4.50 (dd, J ) 6.0, 6.0 Hz, 2H), 3.63
(s, 3H), 2.95 (dd, J ) 6.0, 6.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 165.5, 164.9, 140.8, 137.4, 133.7, 133.6, 130.4, 126.7,
125.2, 123.0, 66.7, 51.5, 25.4; IR (KBr) 3049, 2993, 2955, 2924,
1719, 1638, 1437, 1400, 1296, 1271, 1232, 1190, 1115, 1036
cm-1; HRMS calcd for C13H12O4 232.0735, found 232.0738.
6-P r op yl-5-vin yl-3,4-d ih yd r oisocou m a r in (19b): white
solid; mp 95.5-96.5 °C; 1H NMR (300 MHz, CDCl3) δ 7.96 (d,
J ) 8.1 Hz, 1H), 7.21 (d, J ) 8.1 Hz, 1H), 6.70 (dd, J ) 18.0,
11.6 Hz, 1H), 5.63 (dd, J ) 11.4, 1.7 Hz, 1H), 5.24 (dd, J )
17.9, 1.8 Hz, 1H), 4.43 (dd, J ) 6.0, 6.0 Hz, 2H), 3.05 (dd, J )
5.9, 5.9 Hz, 2H), 2.66-2.60 (m, 2H), 1.64-1.52 (m, 2H), 0.94
(dd, J ) 7.3, 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.7,
147.0, 137.4, 136.0, 132.8, 129.1, 128.1, 123.3, 121.5, 67.0, 36.0,
26.7, 23.5, 14.0; IR (KBr) 3090, 2999, 2963, 2928, 2905, 2868,
Su p p or tin g In for m a tion Ava ila ble: Details for the
preparation and spectroscopic data for compounds 4-8, 16,
18, and 20-23. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O016336O