Carbon-carbon bond formation in regio- and stereoselective palladium-catalyzed cyclization of allene-substituted conjugated dienes

Article abstract of DOI:10.1021/jo0157324

Regio- and stereoselective palladium-catalyzed reactions of allene-substituted 1,3-dienes 1 in acetic acid at room temperature lead to cyclization with formation of a carbon-carbon bond between the middle carbon of the allene and the terminal carbon of the 1,3-diene. Two different types of reactions, both that constitute 1,4-carboacetoxylations of the 1,3-diene, have been developed. In one of the reactions, Pd(II) catalyzes the oxidation of 1 to bicyclic compounds 2, and in the other, Pd(0) catalyzes the transformation of 1 to bicyclic compounds 3. The products 2 are useful for further synthetic tr0nsformations and undergo Diels-Alder reactions with dienophiles to give polycyclic ring systems.

Full text of DOI:10.1021/jo0157324

J . Org. Chem. 2001, 66, 8015-8025
8015
Ca r bon -Ca r bon Bon d F or m a tion in Regio- a n d Ster eoselective
P a lla d iu m -Ca ta lyzed Cycliza tion of Allen e-Su bstitu ted Con ju ga ted
Dien es
J oakim Lo¨fstedt, J ohan Franze´n, and J an-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received May 4, 2001
Regio- and stereoselective palladium-catalyzed reactions of allene-substituted 1,3-dienes 1 in acetic
acid at room temperature lead to cyclization with formation of a carbon-carbon bond between the
middle carbon of the allene and the terminal carbon of the 1,3-diene. Two different types of reactions,
both that constitute 1,4-carboacetoxylations of the 1,3-diene, have been developed. In one of the
reactions, Pd(II) catalyzes the oxidation of 1 to bicyclic compounds 2, and in the other, Pd(0) catalyzes
the transformation of 1 to bicyclic compounds 3. The products 2 are useful for further synthetic
transformations and undergo Diels-Alder reactions with dienophiles to give polycyclic ring systems.
In tr od u ction
as masked carbon nucleophiles.6 Finally, the use of highly
stabilized carbanions (pKA ≈ 5) led to carbon-carbon
Transition metal-catalyzed reactions of allenes have
attracted increasing interest during the last two decades.1
The majority of these reactions involve palladium(0)-
catalyzed transformations, but recently palladium(II)-
catalyzed oxidations have also been reported.
We have previously been working on palladium(II)-
catalyzed oxidations of 1,3-dienes and developed a num-
ber of regio- and stereoselective inter- and intramolecular
1,4-addition reactions.2,3 These palladium(II)-catalyzed
oxidations were recently extended to 1,2-additions of 1,2-
dienes, that is, allenes.4
Most of the oxidation reactions developed so far for 1,3-
and 1,2-dienes have involved regioselective formation of
new carbon-heteroatom bonds by the use of heteroatom
nucleophiles. A more difficult task is to obtain carbon-
carbon bond formation in these reactions since carbon
nucleophiles are more sensitive to the oxidative reaction
conditions. In the intramolecular palladium(II)-catalyzed
1,4-oxidation of 1,3-dienes, carbon-carbon bond forma-
tion has been achieved in a few instances.5-7 In one
approach, alkynes were used to generate a vinylpalla-
dium intermediate, which subsequently adds to the
diene.5 In another method, allylsilanes were employed
bond formation in the 1,4-oxidation.7
The present work was inspired by the fact that allenes
easily can form a vinylpalladium species,1 which can add
to a double bond. If the allene is the only double bond
species, this leads to a dimerized product.8 In the pres-
ence of carbon monoxide, allenes are carbonylated.9 It is
also reported in the literature that allenes readily insert
into palladium-carbon bonds resulting in the formation
of a new carbon-carbon bond.10
In this paper, we report on palladium-catalyzed reac-
tions in which an allene in the side chain of a cyclic 1,3-
diene is employed to create a carbon-carbon bond via
cyclization. The transformations, which formally consti-
tute 1,4-carboacetoxylations of the 1,3-diene, are highly
stereoselective (Scheme 1).
Resu lts a n d Discu ssion
A. P r ep a r a t ion of St a r t in g Ma t er ia ls. Allene-
substituted dienes 1a -f were obtained from the ketones
(5) (a) Ba¨ckvall, J . E.; Nilsson, Y. I. M.; Andersson, P. G.; Gatti, R.
G. P.; Wu, J . Tetrahedron Lett. 1994, 35, 5713. (b) Nilsson, Y. I. M.;
Andersson, P. G.; Gatti, R. G. P.; Ba¨ckvall, J . E. Tetrahedron 1996,
52, 7511.
(6) (a) Castan˜o, A.; Persson, B. A.; Ba¨ckvall, J . E. Chem. Eur. J .
1997, 3, 482. (b) Castan˜o, A.; Ba¨ckvall, J . E. J . Am. Chem. Soc. 1995,
117, 560.
(7) Ro¨nn, M.; Andersson, P. G.; Ba¨ckvall, J . E. Tetrahedron Lett.
1997, 38, 20.
(8) (a) Shier, G. D. J . Organomet. Chem. 1967, 10, P15-P17. (b)
Hegedus, L. S.; Kambe, N.; Ishii, Y.; Mori, A. J . Org. Chem. 1985, 50,
2240. (c) Deming, T. J .; Novak, B. M.; Ziller, J . W. J . Am. Chem. Soc.
1994, 116, 2366.
(9) (a) Tsuji, J .; Suzuki, T. Tetrahedron Lett. 1965, 6, 3027. (b) Alper,
H.; Hartstock, F. W.; Despeyroux, B. J . Chem. Soc., Chem. Commun.
1984, 905.
(10) (a) Zenner, J . M.; Larock, R. C. J . Org. Chem. 1999, 64, 7312.
(b) Larock, R. C.; He, Y.; Leong, W. W.; Han, X.; Refvik, M. D.; Zenner,
J . M. J . Org. Chem. 1998, 63, 2154. (c) Larock, R. C.; Berrios-Pen˜a, N.
G.; Fried, C. A. J . Org. Chem. 1991, 56, 2615. (d) Desarbre, E.; Me´rour,
J . Y. Tetrahedron Lett. 1996, 37, 43. (e) Diederen, J . H.; Sinkeldam,
R. W.; Fru¨hauf, H. W.; Hiemstra, H.; Vrieze, K. Tetrahedron Lett. 1999,
40, 4255. (f) Grigg, R.; Sridharan, V.; Xu, L. H. J . Chem. Soc., Chem.
Commun. 1995, 1903. (g) Gamez, P.; Ariente, C.; Gore, J .; Cazes, B.
Tetrahedron 1998, 54, 14835. (h) Vicart, N.; Cazes, B.; Gore, J .
Tetrahedron Lett. 1995, 36, 5015. (i) Cazes, B. Pure Appl. Chem. 1990,
62, 1867.
(1) (a) Zimmer, R.; Dinesh, C. U.; Nandanam, E.; Khan, F. A. Chem.
Rev. 2000, 100, 3067. (b) Yamamoto, Y.; Radhakrishnan, U. Chem.
Soc. Rev. 1999, 28, 199. (c) Poli, G.; Giambastiani, G.; Heumann, A.
Tetrahedron 2000, 56, 5959. (d) Barbero, A.; Pulido, F. J . Recent Res.
Dev. Synth. Org. Chem. 1999, 2, 1.
(2) (a) Ba¨ckvall, J . E.; Bystro¨m, S. E.; Nordberg, R. E. J . Org. Chem.
1984, 49, 4619. (b) Ba¨ckvall, J . E.; Nystro¨m, J . E.; Nordberg, R. E. J .
Am. Chem. Soc. 1985, 107, 3676. (c) Ba¨ckvall, J . E. In Metal-Catalyzed
Cross Coupling Reactions; Stang, P., Diederich, F., Eds.; VCH: Wein-
heim, 1998; pp 339-382. (d) Ba¨ckvall, J . E. In The Chemistry of Dienes
and Polyenes; Rappoport, Z., Ed.; Wiley & Sons Ltd.: Chichester, 1997.
(e) Asymmetric version: Itami, K.; Palmgren, A.; Thorarensen, A.;
Ba¨ckvall, J . E. J . Org. Chem. 1998, 63, 6466.
(3) (a) Ba¨ckvall, J . E.; Hopkins, R. B.; Grennberg, H.; Mader, M.
M.; Awasthi, A. K. J . Am. Chem. Soc. 1990, 112, 5160. (b) Grennberg,
H.; Faizon, S.; Ba¨ckvall, J . E. Angew. Chem., Int. Ed. Engl. 1993, 32,
263.
(4) (a) Ba¨ckvall, J . E.; J onasson, C. Tetrahedron Lett. 1997, 38, 291.
(b) J onasson, C.; Ba¨ckvall, J . E. Tetrahedron Lett. 1998, 39, 3601. (c)
J onasson, C.; Karstens, W. F. J .; Hiemstra, H.; Ba¨ckvall, J . E.
Tetrahedron Lett. 2000, 41, 1619. (d) J onasson, C.; Horva´th, A.;
Ba¨ckvall, J . E. J . Am. Chem. Soc. 2000, 122, 9600.
10.1021/jo0157324 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

8016 J . Org. Chem., Vol. 66, No. 24, 2001
Lo¨fstedt et al.
Sch em e 1a
a
Conditions: (a) 0.1 equiv of Pd(OAc)2, 4 equiv of LiOAc, 2 equiv of p-benzoquinone, HOAc, room temperature, 4 h; (b) 0.05 equiv of
Pd(OAc)2, 0.3 equiv of p-benzoquinone, HOAc, 0.02 equiv of iron phthalocyanine, room temperature, 24 h, O2; (c) 0.1 equiv of Pd(OAc)2,
4-50 equiv of LiOAc, 2 equiv of p-benzoquinone, HOAc, room temperature, 14 h; (d) 0.05 equiv of Pd(dba)2, 4 equiv of LiOAc, HOAc, room
temperature, 24 h.
Sch em e 2a
Sch em e 3a
a
Conditions: (a) DHP, PPTS, THF; (b) LiAlH4, Et2O, reflux;
(c) CHBr3, t-BuOK, pentane, 0 °C; (d) MeLi, Et2O, -78 °C; (e)
benzoyl chloride, pyridine, DMAP, CH2Cl2; (f) 7a , NaH, Pd(PPh3)4,
THF.
a
Conditions: (a) lithium acetylide diamine, THF; (b) CuBr,
NH4Br, Cu powder, HBr; (c) 7, NaH, THF.
Sch em e 4
4 according to Scheme 2. Reaction of 4 with lithium
acetylide gave 1,1-disubstituted propargylic alcohols,
which on subsequent treatment with copper bromide in
HBr afforded the corresponding bromoallenes 6 in high
yields.11 Using the method of Landor,12 the latter were
converted to 1a -g by reaction with the sodium salt of
the appropriate diene malonates 7.6a,13
The allene diene homologues 16 were synthesized
either from alkyndiol 8 or from alkenol 12 (Scheme 3).
Monoprotection14 of 8 as the THP derivative 9 followed
by reduction with LiAlH4 in ether15 gave the allenic
alcohol 10. The dimethyl analogue of 10, allene alcohol
14, was prepared from 12 by cyclopropanation16 followed
by lithiation of the dibromocyclopropane alcohol 13 and
subsequent rearrangement.17 Allene alcohols 10 and 14
were transformed into the corresponding benzoate esters
11 and 15, respectively, which in turn were allowed to
react with the sodium salt of 7a in a palladium(0)-
catalyzed reaction18 to give 16.
The malonate diene 17 was obtained according to a
literature procedure.19 Reaction of the sodium salt of 17
with 6 gave the allene diene 18 (Scheme 4) in 63% yield
using the method of Landor.12
Allene-substituted dienes 1h -k , without methoxycar-
bonyl groups, were prepared according to Scheme 5. The
malonate diene 7a was transformed to the Weinreb
amide 19 according to a modified literature procedure.5a,20
Subsequent reaction of 19 with the appropriate lithium
acetylide followed by DIBALH-reduction gave alcohols 20
in good to high yields. Mesylation and subsequent copper-
(11) Sigman, S. S.; Eaton, B. E. J . Am. Chem. Soc. 1996, 118, 11783.
(12) Landor, R. S.; Landor, P. D.; Whiter, P. F. J . Chem. Soc., Perkin
Trans. 1 1977, 1710.
(13) Ba¨ckvall, J . E.; Andersson, P. G.; Vågberg, J . O. Tetrahedron
Lett. 1989, 30, 137.
(14) Trost, B. M.; Shi, Y. I. J . Am. Chem. Soc. 1993, 115, 9421.
(15) Masanari, K.; Shuji, T.; Yoshinao, T. Bull. Chem. Soc. J pn.
1995, 68, 1689.
(18) (a) Djahanbini, D.; Cazes, B.; Gore´, B. Tetrahedron Lett. 1984,
25, 203. (b) Djahanbini, D.; Cazes, B.; Gore´, B. Tetrahedron 1987, 43,
3441.
(19) Nilsson, Y.; Anderson, P. G.; Ba¨ckvall, J . E. J . Am. Chem. Soc.
1993, 115, 6609.
(16) Maurin, R.; Bertrand, M. Bull. Soc. Chim. Fr. 1972, 2349.
(17) Richey, H. G.; Moses, L. M. J . Org. Chem. 1983, 48, 4013.
(20) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4174.

Palladium-Catalyzed Cyclization of Dienes
J . Org. Chem., Vol. 66, No. 24, 2001 8017
Sch em e 5a
The starting materials were varied with respect to the
diene ring size and allene substituents. Methyl-substi-
tuted allene 1a gave the product 2a in good yield (Table
1, entry 1). Cyclohexylidene- and cycloheptylidene-
substituted allenes 1c and 1d afforded products 2c and
2d , respectively, in good yields (Table 1, entries 3 and
4). There is a selectivity for the formation of the more
substituted alkyl chain, and this thermodynamically
more stable product is predominantly formed (Table 1,
entries 5-8). The bis-methoxycarbonyl substituents have
only a minor effect on the isolated yields (cf. Table 1,
entries 7 and 8), but without these substituents, a lower
stereoselectivity in the 1,4-carboacetoxylation across the
1,3-diene was obtained (Table 1, entry 8). The size of the
alkyl substituents on the allene seems to have a signifi-
cant effect on the yield with lower yields for larger
substituents (cf. Table 1, entries 1 and 7). In addition, it
seems to be necessary to have three substituents on the
allene. Attempts to use terminal allenes (1j, Figure 1)
or 1-monosubstituted allenes (1k , Figure 1) were unsuc-
cessful and gave complex mixtures of products. Extension
of the allene side chain with an extra methylene group
(16a and 16b, Figure 1) also gave a complex mixture of
products. The acyclic diene (18, Figure 1) gave no
reaction.
a
Conditions: (a) NaCN, H2O, DMSO; (b) AlMe3, HN(OMe)Me,
CH2Cl2; (c) LiCtCR, THF; (d) DIBALH, Et2O; (e) BuLi, MsCl,
THF; (f) R′2CuLi, Et2O; (g) DEAD, PPh3, o-nitrobenzezesulfonyl-
hydrazide,23 THF.
(I)-mediated SN2′ displacement afforded allenes 1h and
1i in 52% and 89% yield, respectively.21 Allenes 1j and
1k were obtained by transformation of the alcohols 20a
and 20b to the corresponding hydrazine derivative under
Mitsunobu conditions, which spontaneously decomposed
to give the allenes in 54% and 60% yield, respectively.22
B1. P a lla d iu m -Ca ta lyzed Oxid a tive Cycliza tion s
of Allen e-Su bstitu ted Con ju ga ted Dien es. Allene-
substituted dienes 1 were transformed into bicyclic
compounds 2 in a palladium-catalyzed oxidation reaction.
In the reaction, two new stereocenters are created with
high stereoselectivity in relation to the stereocenter
already present in the starting material. The relative
stereochemistry between the three stereocenters is com-
pletely controlled in almost all of the cases in this 1,4-
carboacetoxylation of the conjugated diene. The cyclo-
hexadiene-allene derivatives 1a and 1c-i gave a trans-
1,4-carboacetoxylation, whereas the cycloheptadiene-
allene 1b gave the opposite stereochemistry, that is, cis-
1,4-carboacetoxylation. It is known from previous work
that the cycloheptadiene behaves differently under halide-
free conditions2 (see mechanistic discussion). The reac-
tions were carried out at room temperature in acetic acid
with catalytic amounts of palladium acetate and with
p-benzoquinone as the oxidant. For substrates 1a and
1c-i, the amount of lithium acetate has a minor influ-
ence on the outcome of the oxidation. Most reactions were
carried out with 4 equiv of LiOAc (0.3 M LiOAc in HOAc)
relative to the starting material. However, the effect of
LiOAc was large when the cycloheptadiene-allene (1b)
was employed as the starting material. In this case, 1,2-
addition (2b′) and competing 1,4-diacetoxylation were
observed (Table 1, entry 2). It was found that 2 M LiOAc
in HOAc gave the most selective reaction with respect
to formation of 2b (entry 2c). Interestingly, with the use
of 4 M LiOAc in HOAc, formation of the 1,2-addition
product 2b′ was completely depressed (entry 2d). How-
ever, in the latter case the relative amount of the
noncyclized diacetate 2b′′ was 38%.
B2. P a lla d iu m -Ca ta lyzed Non -Oxid a tive Cycliza -
tion s of Allen e-Su bstitu ted Cyclod ien es. In an at-
tempt to isolate a possible (π-allyl)palladium intermedi-
ate in the palladium(II)-catalyzed cyclizations, the reaction
of 1a was carried out without p-benzoquinone. The (π-
allyl)palladium intermediate could not be isolated, but
another product 3a (Table 2) was formed instead, in a
slow reaction. The reaction seems to be catalyzed by
Pd(0). Replacement of Pd(OAc)2 with Pd(dba)2 as the
palladium source went equally well or better. We also
studied the palladium(0)-catalyzed reaction of some
additional allene-substituted dienes (1c, 1e, and 1h ) in
the absence of oxidant, which also gave bicyclic com-
pounds 3 (Table 2). The reactions were performed using
catalytic amounts of palladium dibenzylideneacetone or
palladium acetate in the presence of 0.3 M LiOAc in
acetic acid. When the reaction of 1a was carried out in
deuterated acetic acid, monodeuterated product d1-3a
1
was formed (Scheme 6). H NMR analysis showed that
deuterium had been incorporated at the tertiary carbon
of the isopropyl group with high selectivity (>99%).
C1. Mech a n ism of Oxid a tive Cycliza tion in th e
P r esen ce of p-Ben zoqu in on e (BQ). The mechanism
for the palladium(II)-catalyzed oxidative cyclization of
allene dienes can be explained by Scheme 7a (path A),
where the allene acts as a nucleophile and attacks the
diene in diene complex 21, from the face opposite to that
of palladium, to give π-allyl complexes 22a and 22b. An
intramolecular attack (cis migration), where the acetate
is delivered from palladium in 22a , would explain the
stereochemistry of the product 2a .25 External attack by
acetate on π-allyl complex 22b would give product 2b.
Intramolecular cis migration of acetate is known to be
more difficult from a seven-membered ring than from a
The reaction can also be carried out with a catalytic
amount of p-benzoquinone (30%), palladium acetate (5%),
and iron phthalocyanine (2%) under an oxygen atmo-
sphere.24 Under these conditions, 1a gave product 2a in
good yield (entry 1b).
(23) Myers, A. G.; Zheng, B.; Movassaghi, M. J . Org. Chem. 1997,
62, 7507.
(24) For aerobic palladium-catalyzed 1,4-oxidations using iron ph-
thalocyanine, see ref 3 and see: Wo¨ltinger, J .; Ba¨ckvall, J . E.; Zsigmond
A. Chem.-Eur. J . 1999, 5, 1460.
(25) (a) Ba¨ckvall, J . E.; Nordberg, R. E.; Wilhelm, D. J . Am. Chem.
Soc. 1985, 107, 6892. (b) Grennberg, H.; Langer, V.; Ba¨ckvall, J . E. J .
Chem. Soc., Chem. Commun. 1991, 1190.
(21) Maynard, D. F.; Okamura, W. H. J . Org. Chem. 1995, 60, 1763.
(22) Myers, A. G.; Zheng, B. J . Am. Chem. Soc. 1996, 118, 4492.

8018 J . Org. Chem., Vol. 66, No. 24, 2001
Ta ble 1. P a lla d iu m (II)-Ca ta lyzed Ca r boa cetoxyla tion of Allen e-Su bstitu ted Dien esa
Lo¨fstedt et al.
a
General procedure: To a stirred solution of 10 mol % of palladium acetate were added 2 equiv of p-benzoquinone and 4 equiv of
b
lithium acetate dihydrate in acetic acid (0.3 M) as starting material during 3 h. Total isolated yield after flash chromatography.
c Alternative procedure: To the starting material were added 5 mol % palladium acetate, 2 mol % iron phthalocyanine, and 30 mol %
p-benzoquinone. This was dissolved in acetic acid, and the reaction was run under oxygen atmosphere. The reaction was stirred at room
temperature for 24 h. Alternative procedure: as method in a, but starting material was added during 14 h. e Alternative procedure: as
d
method in a, but starting material was added during 14 h to 16 equiv of lithium acetate dihydrate in acetic acid (1 M). f Alternative
procedure: as method in a, but starting material was added during 14 h to 50 equiv of lithium acetate dihydrate in acetic acid (2 M).
g
Alternative procedure: as method in a, but starting material was added during 14 h to 50 equiv of lithium acetate dihydrate in acetic
acid (4 M).
six-membered ring, and this has been explained by
conformational differences between the two ring sys-
tems.2 In the oxygen-carbon bond-forming process (22a
f 2a and 22b f 2b), palladium(0) is formed, which is
reoxidized to palladium(II) by p-benzoquinone closing the
catalytic cycle.26
Three other possible mechanisms (path B, C, and D)
for the palladium(II)-catalyzed oxidative cyclization of
allene dienes were considered and are discussed below
(Scheme 7b). Path B starts with a nucleophilic attack on
the activated 1,3-diene to give a π-allyl complex which
subsequently would add to the allene to give π-allyl
complex 23. This carbon-carbon bond formation is sim-
ilar to carbopalladation reactions of allenes,10 in which
a vinyl- or arylpalladium species adds to the mid-
dle carbon of the allene.1 Subsequent â-hydride elimina-
tion from the π-allyl complex 23 gives the product 2. In
ongoing work in our group, we are studying related in-
sertions in more detail.27 This route cannot, however,
explain the different stereochemistry of 2a and 2b (Table
1, entry 2), nor the 1,2-products formed (Table 1, entries
2 and 8). Path C would give a vinyl palladium species
from acetoxyoxypalladation of the allene, and subsequent
insertion of the diene would give a π-allyl complex. An
(26) Attempts to reverse the stereochemistry on the six-membered
ring, thus blocking migration with chloride, have so far been unsuc-
cessful. The reaction gives a mixture of products.
(27) Lo¨fstedt, J .; Franzen, J . Unpublished results.

Palladium-Catalyzed Cyclization of Dienes
J . Org. Chem., Vol. 66, No. 24, 2001 8019
palladium complex. External attack by acetate on this
π-allyl complex would give the product. Again, this route
implies that the acetate attack would have to be external
for the six-membered ring and intramolecular for the
seven-membered ring, which is less likely.2c However,
mechanism D would be consistent with intramolecular
delivery of acetate in the 1,2- and 1,4-cis-addition prod-
ucts formed as minor products (Table 1, entries 2, 8, and
9). The latter products could also be formed according to
mechanism A via an external attack by acetate.
Path A, where the allene acts as a nucleophile, is the
mechanism that best explains the experimental data and
should be the major pathway. It is consistent with
previous observations that an internal attack by acetate
is usually faster than an external attack by acetate for
six-membered ring π-allyl complexes and that the reac-
tivity order is reversed for the corresponding seven-
membered ring complexes. At present, it is difficult to
completely exclude the involvement of routes B, C, or D
in the palladium(II)-catalyzed oxidative cyclization. In an
attempt to detect possible intermediates from Scheme 7a
F igu r e 1. Unsuccessful starting materials.
Ta ble 2. P a lla d iu m (0)-Ca ta lyzed Ca r boa cetoxyla tion of
Allen e-Su bstitu ted Dien esa
1
and b, H NMR experiments were carried out in deuter-
ated acetic acid. However, no (π-allyl)palladium inter-
mediate could be observed, and the proposed intermedi-
ate diacetate 24 could not be detected. With mechanism
A, this would suggest that an allene attack on the
π-diene-palladium complex is slower than an acetate
attack on the intermediate (π-allyl)palladium complex,
which is reasonable. A control experiment showed that
in the absence of palladium no reaction occurs, and the
starting material was recovered after 48 h.
C2. Mech a n ism of Non -Oxid a tive Cycliza tion in
th e Absen ce of Ben zoqu in on e. The mechanism of the
Pd(0)-catalyzed cyclization can be explained via a palla-
dacycle (Scheme 8) similar to that in a mechanism
proposed by Cazes and Gore.30 In our case, this pallada-
cycle is a bis-allyl complex, and the reactivity of com-
plexes of this type has recently been explored by Szabo31
and Yamamoto.32 It is known that one of the allyls, the
σ-allyl in σ,π-bis-allyl complexes, is quite reactive toward
electrophiles.31-33
a
General procedure: To a mixture of starting material, pal-
ladium catalyst, and lithium acetate dihydrate (4 equiv) was added
acetic acid, and the reaction was stirred at room temperature for
24 h. Total isolated yield after flash chromatography.
b
Sch em e 6
We believe that the metallacycle 25 initially formed
rearranges to σ,π-bis-allyl complex 26 (Scheme 8). The
latter complex will react with a proton in the γ position
of the σ-allyl ligand to give (π-allyl)palladium complex
27. This regioselectivity for electrophilic attack on σ,π-
allyl palladium complexes is now well established.31,33
External attack on π-allyl 27 from the exo side would
give the product 3. It is believed that migration of acetate
from palladium to carbon is disfavored in this case
because palladium is coordinated to the endo face of the
bicyclic system. This would make it difficult to form the
σ-allyl complex required for cis migration of acetate.25
A palladium hydride mechanism for the transformation
of 1 to 3 seems less likely since the hydride would be
expected to attack the middle carbon of the allene.1 An
external acetate attack can now give diacetate 24, which
would undergo 1,4-elimination of AcOH via π-allyl com-
plex 23 to give 2.28 This route implies that the acetate
attack would have to be external for the six-membered
ring and intramolecular for the seven-membered ring,
which is highly unlikely and against previous observa-
tions.2c An intramolecular attack would explain the minor
1,2-cis-addition product (Table 1, entries 2 and 8) and
the 1,4-cis-carboacetoxylation product formed in some
cases (Table 1, entries 8 and 9). Path D involves an allylic
C-H activation29 of the allene to give an alkylidene
π-allyl complex, which should be stabilized in the form
of a dienyl palladium species. This dienyl palladium spe-
cies can in turn add to the diene moiety to give a (π-allyl)-
(30) Besson, L.; Gore, J .; Cazes, B. Tetrahedron Lett. 1995, 36, 3853.
(31) (a) Szabo, K. J . Chem. Eur. J . 2000, 6, 4413. (b) Solin, N.;
Narayan, S.; Szabo, K. J . J . Org. Chem. 2001, 66, 1686. (c) Solin, N.;
Narayan, S.; Szabo, K. J . Org. Lett. 2001, 3, 909.
(32) Nakamura, H.; Aoyagi, K.; Yamamoto, Y. J . Am. Chem. Soc.
2001, 123, 372.
(33) (a) Benn, R.; J olly, P. W.; Mynott, R.; Schenker, G. Organome-
tallics 1985, 4, 1136. (b) Benn, R.; J olly, P. W.; Mynott, R.; Raspel, G.;
Schenker, G.; Schick, K.-P.; Schroth, G. Organometallics 1985, 4, 1945.
(c) J olly, P. W.; Mynott, R.; Raspel, G.; Schick, K.-P. Organometallics
1986, 5, 473.
(28) This elimination should proceed via oxidative addition to give
a π-allyl intermediate, followed by â-elimination. It is likely that the
oxidative addition to 24 would be facilitated by assistance of the double
bond of the cyclohexene ring.
(29) Ba¨ckvall, J . E.; Zetterberg, K.; Åkermark B. π-Allylic Complexes
from Allylic C-H Bond Cleavage in Olefins by Metal Complexes. In
Inorganic Reactions and Methods; Zuckerman, J . J ., Ed.; Verlag
Chemie: Weinheim, Germany, 1991; pp 123-32.

8020 J . Org. Chem., Vol. 66, No. 24, 2001
Lo¨fstedt et al.
Sch em e 7. P a lla d iu m (II)-Ca ta lyzed Oxid a tive Cycliza tion Mech a n ism : (a ) P a th A a n d
(b) P a th s B, C, a n d D
interesting observation is that Pd(PPh3)4 does not cata-
lyze the reaction.
pound 2b, the stereochemistry was assigned using NOE
as indicated in Figure 2. An NOE between the allylic
hydrogen in the ring R to acetate and one of the bridge
hydrogens shows that the acetate and the carbon that
have added are cis to one another (cis-1,4-carboacetoxy-
lation).34
D. Ster eoch em ica l Assign m en t. The stereochemis-
try of 2c was assigned by 1H NMR spectroscopy via
analysis of coupling constants (Figure 2). H-3 shows only
3
small couplings to protons H-4 (3J 3,4a ) J 3,4e ) 4.5 Hz),
and, as a consequence, H-3 must be equatorial. Further-
The coupling constants for compound 3a , given in
Figure 2, confirm the stereochemistry assigned. The
3
more, the large value of J 4a,5 (10.2 Hz) indicates that
H-5 is axial and trans to H-4a. The value of 3J 5,6 (6.8 Hz)
confirms the cis junction between the rings. These data
imply that the carbons that have added to C-6 and the
acetate are trans to one another (trans-1,4-carboacetoxy-
lation). In the corresponding seven-membered ring com-
(34) For 2b′, we were not able to assign the stereochemistry of the
acetate. A significant NOE (11%) was obtained between the CH-OAc
and the vicinal bridge proton for 2b′, but this does not distinguish
between cis and trans stereochemistry since the trans isomer may have
both vicinal hydrogens equatorial.

Palladium-Catalyzed Cyclization of Dienes
J . Org. Chem., Vol. 66, No. 24, 2001 8021
Sch em e 9. Diels-Ald er Rea ction of Com p ou n d s
2a a n d 2c
F igu r e 2.
2c with maleic anhydride in refluxing toluene to give
cycloadducts 28a and 28b, respectively, as a single
diastereoisomer in each case (Scheme 9). The latter
compounds were hydrolyzed and characterized as the
diacids 29a and 29b, respectively. It is interesting to note
that in the two transformations 1c f 2c f 28b, the
relative stereochemistry between seven stereocenters is
completely controlled. NOESY experiments are consis-
tent with the stereochemistry assigned for 29a and 29b
which is in accordance with the stereochemistry of
compounds 2 and the addition of maleic anhydride to the
less-hindered face of compounds 2.
Sch em e 8. P a lla d iu m (0)-Ca ta lyzed Non -Oxid a tive
Cycliza tion s of Allen e-Su bstitu ted Dien es
Con clu sion
A highly stereoselective palladium(II)-catalyzed oxida-
tion of allene-substituted dienes in acetic acid involving
carbon-carbon bond formation has been developed to
give highly substituted bicyclic products. Although the
detailed mechanism of the reaction is not yet established,
a nucleophilic attack by an allene on a diene palladium
complex from the face opposite to that of palladium
(trans-carbopalladation) is a likely pathway for the C-C
bond formation. A palladium(0)-catalyzed reaction of the
same substrates also led to bicyclic products via carbon-
carbon bond formation. The latter reaction is reminiscent
of the reaction of two 1,3-dienes and acetic acid (telom-
erization).36 In our case, a 1,2-diene replaces one 1,3-
diene. The mechanism in our case as well as in telom-
erization is believed to involve a cyclometalation leading
to a bis allyl palladium intermediate.
coupling constants of relevance for the stereochemistry
are in the same range as those of 2c and show that the
acetate is on the exo face of the bicyclic system.
E. Syn th etic Ap p lica tion s. The products 2 obtained
in the palladium(II)-catalyzed oxidative cyclization con-
tain a conjugated diene unit, which can undergo a Diels-
Alder [4 + 2] cycloaddition with an appropriate dieno-
phile.35 This provides a simple, direct route to more
complex polycyclic systems. The latter transformation is
usually stereoselective, and the synthetic utility of com-
pounds 2 was demonstrated by the reaction of 2a and
Exp er im en ta l Section
1H NMR (400 or 300 MHz) and 13C NMR (100 or 75 MHz)
spectra were recorded using chloroform-d1 (7.26 ppm 1H, 77
(35) (a) Paquette, L. A.; Schaefer, A. G.; Blount, J . F. J . Am. Chem.
Soc. 1983, 105, 3642. (b) Nugent, W. A.; Calabrese, J . C. J . Am. Chem.
Soc. 1984, 106, 6422. (c) Trost, B. M.; Lautens, M. J . Am. Chem. Soc.
1985, 107, 1781. (d) Trost, B. M.; Tanoury, G. J .; Lautens, M.; Chan,
C.; MacPherson, D. T. J . Am. Chem. Soc. 1994, 116, 4255. (e) Trost,
B. M.; Romero, D. L.; Rise, F. J . Am. Chem. Soc. 1994, 116, 4268.
(36) (a) Tsuji, J . Palladium Reagents and Catalysts: Innovations
in Organic Synthesis; Wiley: Chichester, 1995. (b) Takacs J . M. In
Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, G.
A., Wilkinson, G., Eds.; Pergamon: Elmsford, 1995; Vol. 12 (Hegedus,
L. S., Vol. Ed.), p 785. (c) Takacs, J . M.; Chandramouli, S. V. J . Org.
Chem. 1993, 58, 7315.

8022 J . Org. Chem., Vol. 66, No. 24, 2001
Lo¨fstedt et al.
ppm 13C) as an internal standard. GC-MS (EI) was measured
using a Thermo Quest GCQ plus. Elemental analyses were
performed by Analytische laboratorien, Lindlar, Germany. All
reactions were performed under argon atmosphere, unless
otherwise stated.
3.20-3.10 (m, 1H), 2.30-2.10 (m, 2H), 1.95-1.78 (m, 2H), 1.59
(br s, 3H), 1.35-1.17 (m, 4H), 0.85-0.79 (m, 3H). 13C NMR
(CDCl3, 100 MHz): δ 201.1 [diastereomer 201.0], 170.0 [dst
170.0], 169.9 [dst 169.8], 126.8 [dst 126.7], 125.8 [dst 125.7],
124.4 [dst 124.4], 123.4 [dst 123.3], 104.0 [dst 104.0], 89.1 [dst
89.0], 61.3 [dst 61.3], 52.1 [dst 52.1], 52.1 [dst 52.1], 38.9 [dst
38.7], 33.2 [dst 33.2], 29.3 [dst 29.3], 24.5 [dst 24.5], 22.2 [dst
22.2], 18.2 [dst 18.1], 13.7 [dst 13.7]. MS (EI) m/z: 318 (22)
[M+], 258 (50), 198 (87), 157 (75), 143 (100).
Gen er a l P r oced u r e for th e P r ep a r a tion of Dien e
Allen es 1. Allen e 1a . The dienemalonate 7a (0.25 g, 1.2
mmol) was dissolved in dry THF (6 mL) and cooled to 0 °C.
NaH (60% in mineral oil) (0.06 g, 1.5 mmol) was added, and
the solution was stirred for 5 min. The cooling bath was then
removed, and the slurry was stirred for an additional 60 min.
The bromoallene 1a (0.8 g, 2.4 mmol) was added dropwise as
a solution in THF (3 mL). The reaction was followed by GC-
MS and stirred until the dienemalonate had disappeared (3
h). Water (30 mL) was added, the aqueous phase was extracted
with Et2O (3 × 30 mL), and the combined organic layers were
dried (Na2SO4). Careful evaporation (water bath at room
temperature) followed by flash chromatography (pentane:Et2O,
90:10) gave 0.24 g (72% yield) of 1a . 1H NMR (CDCl3, 400
MHz): δ 5.94-5.81 (m, 2H), 5.76-5.68 (m, 2H), 5.50 (septet,
J ) 2.9 Hz, 1H), 3.69 (two s, 6H), 3.29-3.21 (m, 1H), 2.28-
2.18 (m, 2H), 1.64 (br s, 6H). 13C NMR (CDCl3, 100 MHz): δ
201.8, 170.2, 170.1, 126.8, 125.9, 124.5, 123.5, 99.4, 87.8, 61.6,
52.4, 52.3, 38.8, 24.6, 19.8, 19.7. MS (EI) m/z: 276 (9) [M+],
216 (44), 157 (100).
Allen e 1b. This was prepared as above in 80% yield.
Contains a byproduct that was effectively removed by HPLC
purification. 1H NMR (CDCl3, 400 MHz): δ 5.90-5.65 (m, 4H),
5.50 (septet, J ) 2.7 Hz, 1H), 3.69 (s, 6H), 3.06 (br d, J ) 9.3
Hz, 1H), 2.5-2.3 (m, 2H), 2.02 (m, 1H), 1.8-1.5 (m, 7H). 13C
NMR (CDCl3, 100 MHz): δ 202.3, 170.6, 170.5, 134.1, 133.9,
124.6, 123.9, 99.4, 87.8, 62.6, 52.5, 52.4, 45.5, 32.2, 29.8, 20.0,
19.9. MS (EI) m/z: 290 (5) [M+], 231 (64), 230 (100).
Allen e 1c. This was prepared as above in 55% yield. 1H
NMR (CDCl3, 400 MHz): δ 5.94-5.81 (m, 2H), 5.77-5.69 (m,
2H), 5.50 (quintet, J ) 2.9 Hz, 1H), 3.72 (two s, 6H), 3.32-
3.21 (m, 1H), 2.30-2.21 (m, 2H), 2.13-2.05 (m, 4H), 1.66-
1.44 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 198.5, 170.3 (2C),
127.0, 126.0, 124.6, 123.6, 106.6, 87.7, 61.6, 52.5, 52.4, 38.9,
30.8 (2C), 27.1 (2C), 25.9, 24.7. MS (EI) m/z: 316 (14) [M+],
257 (50), 256 (72), 197 (100).
P r ep a r a tion of Allen e Ester 11. Compound 10 was
obtained according to literature procedures14,15 and benzoy-
lated by dissolving the allene alcohol (0.5 g, 7.1 mmol) in CH2-
Cl2 (7 mL). The solution was cooled to 0 °C, and pyridine (0.85
mL, 8.6 mmol) and DMAP (0.09 g, 0.7 mmol) were then added.
Finally, benzoyl chloride was added dropwise, and the reaction
was stirred for 3 h (not full conversion). The organic layer was
washed with HCl (2 M) and saturated NaHCO3 and finally
dried (Na2SO4). Evaporation followed by flash chromatography
(pentane:Et2O, 75:25) gave 0.17 g (48% yield based on recov-
1
ered starting material) of 11. H NMR (CDCl3, 400 MHz): δ
8.05 (m, 2H, Ph), 7.53 (m, 1H, Ph), 7.40 (m, 2H, Ph), 5.40
(quintet, J ) 6.7 Hz, 1H), 4.82 (m, 4H). 13C NMR (CDCl3, 100
MHz): δ 209.5, 166.0, 132.8, 130.0, 129.5, 128.2, 86.4, 76.6,
62.6.
Allen e Ester 15. This was prepared as above in 30% yield.
1H NMR (CDCl3, 400 MHz): δ 8.05 (m, 2H, Ph), 7.55 (m, 1H,
Ph), 7.42 (m, 2H, Ph), 5.22 (tsept, J ) 6.5, 2.7 Hz, 1H), 4.75
(d, J ) 6.5 Hz, 2H), 1.70 (d, J ) 2.7 Hz, 6H). 13C NMR (CDCl3,
100 MHz): δ 203.5, 166.6, 130.1, 130.7, 129.8, 128.5, 97.7, 85.1,
63.9, 20.5.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dien e-
Allen es 16. Dien e-Allen e 16a . The diene malonate 7a (0.38
g, 1.8 mmol) was dissolved in dry THF (2 mL) and cooled to 0
°C. NaH (60% in mineral oil) (0.1 g, 2.4 mmol) was added to
the solution and stirred for 5 min; the cooling bath was then
removed, and the slurry was stirred for additional 30 min. This
was added to Pd(PPh3)4 (0.05 g, 0.04 mmol) in THF (5 mL)
via cannula. Finally, a solution of 11 (0.17 g, 0.91 mmol) was
added dropwise as a solution in THF (0.5 mL). The reaction
was followed by GC-MS and stirred overnight. Water was
added, the aqueous phase was extracted with Et2O (3 × 30
mL), and the combined organic layers were dried (Na2SO4).
Careful evaporation (water bath at room temperature) followed
by flash chromatography (pentane:Et2O, 90:10) gave 0.08 g
(33% yield) of 16a . 1H NMR (CDCl3, 400 MHz): δ 5.95 (m,
1H), 5.91 (m, 1H), 5.85 (m, 2H), 4.97 (quint, J ) 7.3 Hz, 1H),
4.63 (m, 2H), 3.70 (s, 3H), 3.68 (s, 3H), 3.15 (ddt, J ) 12.6,
9.8, 3.6 Hz, 1H), 2.63 (m, 2H), 2.35 (ddd, J ) 17.5, 8.9, 4.9 Hz,
1H), 2.19 (dddd, J ) 17.5, 13.4, 3.6, 2.5 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): δ 209.8, 170.7 (2C), 126.1, 125.9, 124.9,
123.5, 84.5, 74.6, 60.7, 52.3, 52.2, 36.2, 32.2, 24.4. MS (EI)
m/z: 262 (5) [M+], 230 (100), 198 (95), 145 (100).
Dien e-Allen e 16b. This was prepared as above in 36%
yield. 1H NMR (CDCl3, 400 MHz): δ 5.93 (m, 1H), 5.85 (m,
1H), 5.75 (m, 2H), 4.78 (tseptet, J ) 7.5, 2.9 Hz, 1H), 3.71 (s,
3H), 3.70 (s, 3H), 3.18 (dddd, J ) 12.1, 9.1, 6.3, 3.3 Hz, 1H),
2.64 (dd, J ) 14.4, 7.5 Hz, 1H), 2.58 (dd, J ) 14.4, 7.5 Hz,
1H), 2.34 (dddd, J ) 17.3, 8.8, 5.2, 1.4 Hz, 1H), 2.20 (dddd, J
) 17.3, 13.8, 4.0, 2.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ
203.9, 171.2 (2C), 126.8, 126.3, 125.1, 123.9, 95.5, 83.1, 60.7,
52.5, 52.4, 36.1, 33.3, 24.5, 20.6 (2C). MS (EI) m/z: 290 (70)
[M+], 230 (48), 226 (56), 133 (68), 132 (100).
Dien e-Allen e 18. This was prepared as for 1a in 63% yield.
1H NMR (CDCl3, 300 MHz): δ 5.98 (m, 2H), 5.60 (m, 1H), 5.48
(quintet, J ) 2.0 Hz, 1H), 5.37 (m, 1H), 3.71 (s, 6H), 2.74 (d,
J ) 7.4 Hz, 2H), 2.10 (m, 4H), 1.71 (d, J ) 7.1 Hz, 3H), 1.65-
1.45 (m, 6H). 13C NMR (CDCl3, 75 MHz): δ 198.3, 170.7 (2C),
134.1, 131.3, 128.3, 125.0, 107.1, 88.1, 58.5, 52.6 (2C), 37.7,
32.8, 31.0, 27.3, 25.9, 23.0, 18.0. MS (EI) m/z: 318 (16) [M+],
259 (44), 258 (100).
P r ep a r a tion of Wein r eb Am id e 19. Water (3.0 mL, 166
mmol) was added at room temperature via a cannula to a
solution of 7a (7.0 g, 33.3 mmol) and NaCN (8.2 g, 166 mmol)
in DMSO (98 mL). The reaction mixture was stirred at 75 °C
for 30 h. Water was added, followed by extraction of the water
Allen e 1d . This was prepared as above in 40% yield (based
1
on recovered starting material). H NMR (CDCl3, 400 MHz):
δ 5.96-5.81 (m, 2H), 5.77-5.69 (m, 2H), 5.50 (quintet, J )
2.9 Hz, 1H), 3.72 (two s, 6H), 3.32-3.21 (m, 1H), 2.40-2.20
(m, 6H), 1.70-1.50 (m, 8H). 13C NMR (CDCl3, 100 MHz): δ
201.6, 170.3, 170.2, 126.9, 125.9, 124.5, 123.5, 108.6, 87.5, 61.5,
52.4, 52.3, 38.8, 31.7 (2C), 29.2 (2C), 28.0 (2C), 24.6. MS (EI)
m/z: 330 (18) [M+], 270 (68), 211 (100).
Allen e 1e. This was prepared as above in 68% yield (two
diastereomers 50:50). 1H NMR (CDCl3, 400 MHz): δ 5.96-
5.79 (m, 2H), 5.77-5.69 (m, 2H), 5.59 (two overlapping sextets,
J ) 2.9 Hz, 1H), 3.68 (two s, 6H), 3.28-3.13 (m, 1H), 2.33-
2.18 (m, 2H), 1.96-1.88 (m, 2H), 1.65 (m, 3H), 0.98 (m, 3H).
13C NMR (CDCl3, 100 MHz): δ 200.7 [diastereomer 200.7],
170.0 [dst 170.0], 169.9 [dst 169.9], 126.8 [dst 126.7], 125.9
[dst 125.8], 124.5 [dst 124.4], 123.4 [dst 123.4], 105.8 [dst
105.8], 89.8 [dst 89.7], 61.5 [dst 61.5], 52.3 [dst 52.3] (2C), 39.1
[dst 38.9], 26.9 [dst 26.8], 24.8 [dst 24.7], 18.4 [dst 18.3], 11.9
[dst 11.9]. MS (EI) m/z: 290 (12) [M+], 230 (55), 197 (60), 169
(85), 143 (100).
Allen e 1f. This was prepared as above in 50% yield (two
diasteromers 50:50). 1H NMR (CDCl3, 400 MHz): δ 5.94-5.81
(m, 2H), 5.77-5.69 (m, 2H), 5.60 (m, 1H), 3.72 (two s, 6H),
3.28-3.13 (m, 1H), 2.40-2.18 (m, 2H), 2.17-2.06 (m, 1H),
1.67-1.64 (m, 3H), 0.98-0.95 (m, 6H). 13C NMR (CDCl3, 100
MHz): δ 200.3 [diastereomer 200.1], 170.3 [dst 170.3], 170.2
[dst 170.2], 127.1 [dst 126.9], 126.1 [dst 125.9], 124.7 [dst
124.7], 123.6 [dst 123.5], 110.2 [dst 110.2], 90.1 [dst 90.0], 61.6
[dst 61.5], 52.3 [dst 52.3] (2C), 39.2 [dst 38.9], 32.1 [dst 32.1],
24.8 [dst 24.7], 22.2 [dst 22.2] (2C), 16.2 [dst 18.1]. MS (EI)
m/z: 304 (18) [M+], 229 (58), 201 (100), 183 (80).
Allen e 1g. This was prepared as above in 73% yield (two
diasteromers 50:50). 1H NMR (CDCl3, 400 MHz): δ 5.94-5.81
(m, 2H), 5.77-5.69 (m, 2H), 5.50 (m, 1H), 3.63 (two s, 6H),

Palladium-Catalyzed Cyclization of Dienes
J . Org. Chem., Vol. 66, No. 24, 2001 8023
phase with Et2O (6 × 40 mL). The combined organic phases
were washed with water and brine followed by drying
(Na2SO4). The solvent was removed by distillation at ambient
pressure, and the residue was purified by column chromatog-
raphy (pentane:Et2O, 90:10). The solvent was again removed
by distillation at ambient pressure to give 4.6 g (91%) of the
ester.
Trimethylaluminum (2 M in hexane, 13.9 mL, 27.8 mmol)
was added dropwise to a solution of N,O-dimethylhydroxy-
lamine hydrochloride (2.7 g, 27.8 mmol) in CH2Cl2 (35 mL) at
room temperature. The solution was stirred for 15 min followed
by addition of the neat ester (2.1 g, 13.9 mmol) and stirred
overnight. The reaction was quenched by very slow addi-
tion of 1 M HCl followed by extraction of the water phase with
CH2Cl2 (3 × 30 mL) and drying of the combined organic phases
(Na2SO4). The solvent was removed under reduced pressure
to give the product (2.3 g, 90%), which was used without
further purification. Spectral data were in accordance with
those previously reported.5b
distillation at ambient pressure, and the residue was column-
chromatographed (pentane, 100%). The solvent was again
removed by distillation at ambient pressure to give 295 mg
(54%) of 1j as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ
5.92-5.85 (m, 2H), 5.79-5.70 (m, 2H), 5.07 (quintet, J ) 6.9
Hz, 1H), 4.67 (dt, J ) 6.6, 2.9 Hz, 2H), 2.45-2.35 (m, 1H),
2.29 (dddd, J ) 17.2, 8.6, 4.8, 1.5 Hz, 1H), 2.13-2.00 (m, 3H).
13C NMR (CDCl3, 400 MHz): δ 209.4, 130.9, 126.0, 124.2 (2
C), 88.1, 74.7, 33.3, 33.2, 28.4. MS (EI) m/z: 132 (9) [M+], 117
(73), 77 (100).
Allen e 1k . Diethyl azodicarboxylate (0.28 mL, 1.76 mmol)
was added to a solution of PPh3 (462 mg, 1.76 mmol) in THF
(5 mL) at -15 °C. After 10 min, a solution of the acetylene
alcohol 20b (257 mg, 1.26 mmol) in THF (4 mL) was added to
the solution. The mixture was stirred for an additional 10 min
at ambient temperature before a solution of o-nitrobenzene-
sulfonylhydrazine (387 mg, 1.76 mmol) in THF (5 mL) was
added. After 1 h at -15 °C, the mixture was warmed to room
temperature and stirred overnight. The solvent was removed
under reduced pressure, and the residue was column-chro-
matographed (pentane, 100%) to give 143 mg (60%) of 1k as a
mixture of diastereomers (50:50). 1H NMR (CDCl3, 400 MHz):
δ 5.88 (m, 2H), 5.75 (m, 2H), 5.11-4.99 (m, 2H), 2.38 (m, 1H),
2.28 (m, 1H), 2.08 (m, 3H), 1.99 (m, 2H), 1.37 (m, 4H), 0.91 (t,
J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 400 MHz): δ 204.9 [dst
204.8], 131.2 [dst 131.2], 126.0 [dst 126.0], 124.2 (2C) [dst 124.1
(2C)], 91.0, 88.9, 34.1 [dst 34.1], 33.3 [dst 33.3], 31.6, 28.9, 28.5
[dst 28.4], 22.4, 14.1. MS (EI) m/z: 188 (22) [M+], 145 (70),
117 (66).
P r ep a r a t ion of Lit h iu m Dia lk ylcu p r a t es, Gen er a l
P r oced u r e. MeLi or BuLi (2.05 equiv) in hexane was added
dropwise to a slurry of CuI (1.0 equiv) in Et2O (7.5 mL/mmol)
at 0 °C and then cooled to -78 °C for immediate use.
Allen e 1h . n-BuLi (1.6 M in hexane, 1.9 mL, 3.09 mmol)
was added dropwise to a solution of acetylene alcohol 20a (600
mg, 2.9 mmol) in THF (3 mL) at -78 °C and after 5 min was
followed by addition of mesyl chloride (0.25 mL, 3.19 mmol).
After an additional 5 min at ambient temperature, the mixture
was transferred via cannula to a Et2O solution of Me2CuLi
(4.35 mmol, prepared as above) at -78 °C. The resulting
suspension was stirred at ambient temperature for 0.5 h and
then warmed to 0 °C for 10 min and quenched with saturated
NH4Cl (30 mL). Et2O (20 mL) was added, and the mixture was
filtered through Celite. The water phase was extracted with
Et2O (3 × 30 mL), the combined organic phases were dried
(MgSO4), and the solvent was removed under reduced pres-
sure. The residue was column-chromatographed (pentane,
100%) to afford 521 mg (89%) of 1h as a mixture of diastere-
omers (50:50). 1H NMR (CDCl3, 400 MHz): δ 5.88 (m, 2H),
5.75 (m, 2H), 4.95 (m, 1H), 2.37 (m, 1H), 2.28 (apparent dddd,
Acetylen e Alcoh ol 20a . Trimethylsilyl acetylene alcohol
was prepared from Weinreb amide 19 (1.20 g, 6.6 mmol) and
trimethylsilyl acetylene as described for butyl acetylene alcohol
20b below. The crude trimethylsilyl acetylene alcohol (1.43 g)
was dissolved in MeOH (40 mL), KF (1.50 g, 26.0 mmol) was
added, and the mixture was stirred overnight. CH2Cl2 (50 mL)
and H2O (50 mL) were added followed by extraction of the
water phase with CH2Cl2 (3 × 30 mL) and drying of the
combined organic phases (Na2SO4). The solvent was removed
under reduced pressure, and the residue was column-chro-
matographed (pentane:Et2O, 80:20) to give 608 mg (62%) of
20a (diastereomeric mixture (50:50)) as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ 5.90 (m, 2H), 5.75 (m, 2H), 4.46 (m, 1H),
2.57 (m, 1H), 2.48 (apparent dd, J ) 4.7, 2.2 Hz, 1H), 2.35 (m,
1H), 2.10-1.70 (m, 4H). 13C NMR (CDCl3, 400 MHz): δ 130.4
[dst 130.3], 125.8 [dst 125.7], 124.5 [dst 124.5], 124.3 [dst
124.3], 85.1, 73.4 [dst 73.3], 60.6 [dst 61.0], 42.2 [dst 42.1],
29.5 [dst 29.4], 28.8 [dst 28.5].
Acetylen e Alcoh ol 20b. n-BuLi (1.6 M in hexane, 2.76 mL,
4.42 mmol) was added dropwise to a solution of 1-hexyne (0.63
mL, 5.52 mmol) in THF (2.5 mL) at -78 °C. The mixture was
stirred at -78 °C for 20 min and then at 0 °C for 1 h. The
lithium-hexyne reagent was transferred via cannula to the
Weinreb amide 19 (466 mg, 2.57 mmol) in THF (2.5 mL) at
-40 °C. The reaction mixture was warmed to 0 °C for 20 min
and then to room temperature for an additional 30 min and
poured into ice-cooled 1 M HCl (30 mL). Et2O (30 mL) and
brine were added, and the water phase was extracted with
Et2O:CH2Cl2 1:1 (3 × 30 mL). The combined organic phases
were dried (MgSO4), and the solvent was removed under
reduced pressure. The crude product was dissolved in Et2O
(10 mL) and cooled to -78 °C. DIBALH (1.5 M in toluene, 2.40
mL, 3.60 mmol) was added dropwise to the solution. After 15
min, H2O (10 mL) was added at ambient temperature, and
the mixture was warmed to room temperature and partitioned
between Et2O (10 mL) and 2 M HCl (10 mL). The water phase
was extracted with Et2O (4 × 20 mL), and then the combined
organic phases were washed with water and brine followed
by drying (MgSO4) and removal of the solvent under reduced
pressure. The residue was column-chromatographed (pentane:
Et2O, 85:15) to afford 474 mg (90%) of 20b (diastereomeric
mixture (50:50)) as a colorless oil. 1H NMR (CDCl3, 400 MHz):
δ 5.87 (m, 2H), 5.74 (m, 2H), 4.42 (m, 1H), 2.54 (m, 1H), 2.32
(m, 1H), 2.19 (m, 2H), 2.01 (m, 1H), 1.91-1.63 (m, 3H), 1.47
(m, 2H), 1.39 (m, 2H), 0.89 (apparent t, J ) 7.3 Hz, 3H). 13C
NMR (CDCl3, 400 MHz): δ 130.9 [dst 130.8], 125.8 [dst 125.8],
124.3 [dst 124.2] (2C), 86.0 [dst 85.9], 81.4 [dst 81.3], 61.0 [dst
61.0], 42.9 [dst 42.7], 30.9, 29.7 [dst 29.6], 28.8 [dst 28.6], 22.1,
18.6, 13.8.
J
) 17.0, 8.5, 4.8, 1.3 Hz, 1H), 2.10-2.01 (m, 3H), 1.93
(apparent td, J ) 7.0, 2.9 Hz, 2H), 1.67 (d, J ) 2.9 Hz, 3H),
1.37 (m, 4H), 0.91 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 400
MHz): δ 202.3, 131.5 [dst 131.4], 126.0, 124.2, 123.9 [dst
123.9], 99.4, 88.1 [dst 88.0], 34.5, 34.0 [dst 34.0], 33.3 [dst 33.3],
30.0 [dst 30.0], 28.5 [dst 28.5], 22.6, 19.4 [dst 19.4], 14.2. MS
(EI) m/z: 202 (100) [M+], 145 (46).
Allen e 1i. This was prepared from butylacetylene alcohol
20b as described for methylbutyl allene 1h above in 52% yield
(diastereomeric mixture (50:50)). 1H NMR (CDCl3, 400 MHz):
δ 5.88 (m, 2H), 5.75 (m, 2H), 5.01 (t quintet, J ) 6.9, 2.9 Hz,
1H), 2.36 (m, 1H), 2.28 (dddd, J ) 17, 8.5, 4.8, 1.3 Hz, 1H),
2.07 (m, 3H), 1.92 (td, J ) 6.9, 2.8 Hz, 4H), 1.34 (m, 8H), 0.90
(t, J ) 7.1 Hz, 6H). 13C NMR (CDCl3, 400 MHz): δ 201.8, 131.5,
126.0, 124.2, 123.9, 104.2, 89.6, 34.7, 33.5, 32.7, 32.6, 30.2 (2
C), 28.5, 22.7 (2 C),14.2 (2 C). MS (EI) m/z: 244 (100) [M+],
187 (54), 131 (68), 117 (50).
Gen er a l P r oced u r e for th e P r ep a r a tion of 2. Com -
p ou n d 2c. To a stirred solution of palladium acetate 0.033 g
(0.14 mmol), benzoquinone 0.31 g (2.9 mmol), and lithium
acetate dihydrate 0.59 g (5.8 mmol) in acetic acid (15 mL) at
room temperature was added 0.46 g (1.46 mmol) of 1c
dissolved in acetic acid (4 mL) during 3 h. The reaction was
stirred an additional hour, water was added, and the water
layer was extracted with Et2O (3 × 30 mL). The combined
Allen e 1j. This was prepared from acetylene alcohol 20a
as described for butyl allene 1k below except for the workup
which was done as follows. The reaction mixture was parti-
tioned between pentane and water. The water phase was
extracted with pentane (3 × 30 mL), and the combined organic
phases were washed with water (2 × 30 mL) and brine (30
mL) followed by drying (MgSO4). The solvent was removed by

8024 J . Org. Chem., Vol. 66, No. 24, 2001
Lo¨fstedt et al.
organic layers were washed with NaOH (2 M) and brine and
finally dried (Na2SO4). Evaporation followed by flash chroma-
tography (pentane:Et2O, 75:25) gave 0.42 g (77% yield) of 2c.
1H NMR (CDCl3, 300 MHz): δ 6.15 (ddd, J ) 0.9, 3.9, 10.1
Hz, 1H), 5.85 (m, 1H), 5.80 (ddd, J ) 2.3, 4.5, 10.1 Hz, 1H),
5.65 (d, J ) 2.3 Hz, 1H) 5.06 (q, J ) 4.5 Hz, 1H, CHOAc),
3.8-3.7 (overlapping peaks including s at 3.74 and 3.69, total
7H), 3.50 (ddd, J ) 10.2, 6.8, 5.0 Hz, 1H), 2.3-2.0 (m, 4H),
2.01 (s, 3H), 1.84 (ddd, J ) 14.5, 10.2, 4.5 Hz, 1H), 1.7-1.5
(m, 5H). 13C NMR (CDCl3, 75 MHz): δ 170.6, 170.4, 170.2,
131.9, 131.6, 127.3, 125.0, 120.6, 67.8, 65.2, 52.8, 52.6, 43.8,
38.7, 27.1, 26.7, 25.6, 22.1, 21.3. MS (EI) m/z: 374 (1) [M+],
254 (90), 196 (100). Anal. Calcd for C21H26O6: C, 67.36; H, 7.00.
Found: C, 67.24; H, 7.06.
Com p ou n d 2a . This was prepared as above in 67% yield.
1H NMR (CDCl3, 400 MHz): δ 6.19 (ddd, J ) 10.3, 3.8, 0.9
Hz, 1H), 5.84 (ddd, J ) 10.0, 4.4, 2.3 Hz, 1H), 5.73 (d, J ) 2.6
Hz, 1H), 5.13-5.04 (m, 3H), 3.8-3.7 (overlapping peaks
including s at 3.77 and 3.72, total 7H), 3.56 (ddd, J ) 12.0,
7.0, 5.3 Hz, 1H), 2.15 (s, 3H), 1.93 (br s, 3H), 1.84 (ddd, J )
13.8, 10.3, 4.4 Hz, 1H), 1.65 (dt, J ) 13.8, 5.0 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ 170.6, 170.5, 170.1, 148.7, 138.3,
131.3, 125.3, 124.0, 115.2, 68.0, 65.1, 52.8, 52.6, 43.9, 38.7, 27.0,
21.5, 21.2. MS (EI) m/z: 276 (9), 216 (44), 157 (100). Anal.
Calcd for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.92; H,
6.50.
at 3.76 and 3.71, total 7H), 3.51 (ddd, J ) 12.3, 11.9, 6.4 Hz,
1H), 2.05 (s, 3H), 1.75 (br s, 3H), 1.62-1.54 (m, 5H). 13C NMR
(CDCl3, 100 MHz): δ 170.7, 170.3, 170.3, 148.2, 131.5, 130.9,
125.0, 123.9, 123.5, 68.5, 65.0, 52.7, 52.4, 45.7, 38.1, 26.9, 23.1,
21.3, 14.6. MS (EI) m/z: 306 (3) [M+], 228 (100).
1
2e′. H NMR (CDCl3, 400 MHz): δ 6.15 (ddd, J ) 10.3, 4.1,
1.0 Hz, 1H), 5.83 (ddd, J ) 10.3, 4.7, 2.5 Hz, 1H), 5.67 (qq, J
) 6.8, 1.4 Hz, 1H), 5.62 (d, J ) 2.5 Hz, 1H, olefin), 5.09 (q, J
) 4.7 Hz, 1H), 3.80-3.65 (overlapping peaks including s at
3.77 and 3.72, total 7H), 3.53 (dddd, J ) 11.8, 10.4, 6.9, 4.9
Hz, 1H), 2.03 (s, 3H), 1.95-1.60 (m including s at 1.81 and d
at 1.73, total 8H). 13C NMR (CDCl3, 100 MHz): δ 170.8-170.6
(2C), 150.3, 131.7, 125.1, 124.7, 121.4, 100.0, 68.2, 65.2, 52.8,
52.6, 43.8, 38.6, 27.1, 21.3, 14.7, 13.9. MS (EI) m/z: 306 (3)
[M+], 228 (90), 169 (100).
1
2e′′. H NMR (CDCl3, 400 MHz): δ 6.14 (ddd, J ) 0.7, 4.0,
10.1 Hz, 1H), 5.85 (ddd, J ) 2.4, 4.8, 10.1 Hz, 1H), 5.72 (d, J
) 2.6 Hz, 1H), 5.1-5.0 (m, including s at 5.07 and 5.03, 3H),
3.80-3.45 (overlapping peaks including s at 3.77 and 3.72,
total 7H), 2.25 (br q, J ) 7.4 Hz, 2H), 2.05 (s, 3H), 1.62-1.54
(m, 2H), 1.05 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz):
δ 170.7-170.3 (3C), 144.2, 131.4, 125.2, 123.2, 123.2, 112.8,
68.0, 65.1, 52.8, 52.6, 44.2, 38.5, 27.6, 27.0, 12.5. MS (EI) m/z:
306 (3) [M+], 228 (80), 169 (100).
Com p ou n d s 2f. These were prepared as above in 60% total
yield. The reaction gave two isomers (Table 1), which were
not possible to separate by HPLC. 1H NMR (CDCl3, 400
MHz): δ 6.09 (dd, J ) 10.3, 4.3 Hz, 1H), 5.90 (m, 2H + 1H),
5.70 (d, J ) 2.6 Hz, 1H), 5.13 (m, 1H + 1H, CHOAc), 5.05 (br
s, 1H), 4.98 (br s, 1H), 3.80-3.65 (overlapping peaks including
s at 3.77, 3.76 and 3.72, 3.71, total 7H + 7H), 3.50 (m, 1H +
1H), 2.53 (septet, J ) 7.0 Hz, 1H), 2.05 (s, 3H + 3H), 1.8-1.5
(m including d at 1.69, J ) 4.4 Hz, and s at 1.65 and 1.55, 2H
+ 11H), 1.09 (d, J ) 7.0 Hz, 3H), 0.98 (d, J ) 7.0 Hz, 3H). 13C
NMR (CDCl3, 100 MHz): δ 170.7-170.2 (3C + 3C), 150.9,
149.7, 149.1, 132.2, 131.7, 130.0, 125.3, 124.9, 123.1, 122.8,
111.0, 68.8, 65.4, 65.3, 53.0, 52.9, 52.8, 52.6, 46.2, 45.0, 38.6,
38.2, 32.1, 29.9, 27.2, 27.1, 22.7, 21.9, 21.5, 21.2, 20.4, 18.2.
MS (EI) m/z (major): 362 (1) [M+], 330 (10), 183 (100).
(minor): 330 (6), 242 (60), 228 (80), 183 (100).
Com p ou n d s 2b. These were prepared as above in 71-87%
total yield. The reaction gave two to three isomers depending
on LiOAc concentration (Table 1), which were separated by
flash chromatograhy or HPLC.
1
2b (m a jor p r od u ct). H NMR (CDCl3, 400 MHz): δ 6.12
(dd, J ) 11.3, 3.8 Hz, 1H), 5.77 (d, J ) 2.5 Hz, 1H), 5.70 (ddd,
J ) 11.0, 4.7, 2.7 Hz, 1H), 5.36 (m, 1H), 5.10 (br s, 1H), 4.94
(br s, 1H), 3.90 (m, 1H), 3.80-3.65 (overlapping peaks includ-
ing s at 3.77 and 3.72, total 7H), 2.68 (ddd, J ) 11.8, 9.9, 4.4
Hz, 1H), 2.15 (m, 1H), 2.06 (s, 3H), 1.92 (br s, 3H), 1.84 (m,
2H). 13C NMR (CDCl3, 100 MHz): δ 171.0, 170.2, 170.1, 150.3,
137.6, 136.5, 129.5, 124.9, 115.6, 71.2, 68.2, 52.6, 52.3, 51.1,
47.4, 30.2, 25.0, 21.2, 21.0. MS (EI) m/z: 288 (15), 229 (100).
Anal. Calcd for C19H24O6: C, 65.50; H, 6.94. Found: C, 65.29;
H, 6.88.
Com p ou n d s 2g. These were prepared as above in 49% total
yield. The reaction gave two isomers (Table 1), which were
separated by HPLC.
2b′. 1H NMR (CDCl3, 400 MHz): δ 5.87 (dd, J ) 7.2, 4.7
Hz, 1H), 5.84 (dd, J ) 5.8, 1.6 Hz, 1H), 5.78 (d, J ) 2.2 Hz,
1H), 5.71 (dd, J ) 5.8, 2.5 Hz, 1H, CHOAc), 5.03 (br s, 1H),
4.91 (br s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.25 (dt, J ) 9.6, 2.5
Hz, 1H), 3.17 (td, J ) 10.7, 3.0 Hz, 1H), 2.42-2.10 (m, 3H),
1.93 (s, 3H), 1.87 (br s, 3H), 1.50 (m, 1H). 13C NMR (CDCl3,
100 MHz): δ 171.4, 170.5, 170.3, 149.9, 138.4, 134.2, 127.6,
125.7, 113.9, 71.2, 69.1, 68.1, 52.6, 52.4, 52.3, 46.4, 27.9, 27.3,
21.8, 20.9. MS (EI) m/z: 348 (2) [M+], 229 (100), 228 (60), 169
(70).
Ma jor 2g. 1H NMR (CDCl3, 400 MHz): δ 5.92 (m, 2H), 5.48
(dd, J ) 2.9, 0.7 Hz, 1H), 5.34 (tt, J ) 7.6, 1.5 Hz, 1H), 5.12
(m, 1H), 3.80-3.65 (overlapping peaks including s at 3.76 and
3.71, total 7H), 3.50 (ddd, J ) 12.0, 6.2, 5.5 Hz, 1H), 2.05 (s,
3H), 1.93 (br q, J ) 8.0 Hz, 1H), 1.75 (br s, 3H), 1.60 (m, 2H),
1.30 (m, 2H), 0.83 (br t, J ) 8.0 Hz, 3H). 13C NMR (CDCl3,
100 MHz): δ 170.7, 170.3, 170.2, 148.4, 131.6, 130.2, 129.9,
124.9, 123.1, 68.5, 65.0, 52.7, 52.4, 45.8, 38.1, 30.9, 26.8, 23.1,
21.3, 13.8. MS (EI) m/z: 376 (3) [M+], 317 (20), 256 (100), 197
(70).
Min or 2g′. 1H NMR (CDCl3, 400 MHz): δ 6.14 (ddd, J )
10.2, 4.1, 0.8 Hz, 1H), 5.86 (ddd, J ) 10.2, 4.9, 2.5 Hz, 1H),
5.71 (d, J ) 2.5 Hz, 1H), 5.10 (q, J ) 4.5 Hz, 1H, CHOAc),
5.06 (br s, 1H), 5.03 (br s, 1H), 3.80-3.65 (overlapping peaks
including s at 3.77 and 3.72, total 7H), 3.53 (m, 1H), 2.3-0.8
including s at 2.05 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
170.6, 170.5 (2C), 148.3, 143.1, 131.4, 125.1, 123.4, 113.7, 68.1,
65.1, 52.8, 52.6, 44.2, 38.5, 34.6, 30.2, 29.7, 27.0, 22.3, 13.9.
MS (EI) m/z: 376 (3) [M+], 316 (20), 256 (100).
2b′′. 1H NMR (CDCl3, 300 MHz): δ 5.64-5.54 (m, 4H, 2
olefinic + 2 CHOAc), 5.42 (sept, J ) 2.9 Hz, 1H), 3.71 (s, 6H),
2.84 (tt, J ) 9.5, 5.1 Hz, 1H), 2.07 (s, 6H), 2.00 (m, 4H), 1.68
(s, 3H), 1.67 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 202.3, 170.3
(2C), 170.1 (2C), 130.3 (2C), 99.2, 86.8, 70.5 (2C, CHOAc), 63.1,
52.5 (2C), 33.7 (CH), 32.6 (2CH2), 21.2 (2C, AcO), 19.8 (2C,
Me). MS (EI) m/z: 349 (25), 197 (100).
Com p ou n d 2d . This was prepared as above in 60% yield.
1H NMR (CDCl3, 400 MHz): δ 6.15 (ddd, J ) 7.4, 4.4, 0.7 Hz,
1H), 5.97 (t, J ) 7.1 Hz, 1H), 5.80 (dddd, J ) 7.4, 5.0, 2.5, 0.7
Hz, 1H), 5.58 (d, J ) 2.5, 1H), 5.09 (q, J ) 4.5 Hz, 1H, CHOAc),
3.8-3.7 (overlapping peaks including s at 3.77 and 3.72, total
7H), 3.52 (ddd, J ) 11.5, 6.6, 5.0 Hz, 1H), 2.33 (m, 2H), 2.21
(m, 2H), 2.06 (s, 3H), 1.8-1.2 (m, 8H). 13C NMR (CDCl3, 75
MHz): δ 170.7 (2C), 170.4, 150.7, 139.4, 131.9, 131.6, 124.9,
120.8, 67.9, 65.2, 52.8, 52.5, 44.1, 38.4, 32.1, 31.4, 29.7, 28.6,
27.0, 26.6, 26.5, 21.3. MS (EI) m/z: 388 (10), 268 (100), 209
(75).
Com p ou n d s 2h . These were prepared as above in 48% total
1
yield. H NMR (CDCl3, 400 MHz): δ 5.88 (ddd, J ) 10.1, 3.8,
1.1 Hz, 1H), 5.78 (ddd, J ) 10.1, 4.0, 2.3 Hz, 1H), 5.38 (dd, J
) 2.4, 4.8 Hz, 1H), 5.29 (tq, J ) 7.3, 1.5 Hz, 1H), 5.24 (br dd,
J ) 9.9, 4.6 Hz, 1H), 3.36-3.32 (m, 1H), 2.74-2.66 (m, 1H),
2.54 (ddt, J ) 16.3, 8.1, 2.3 Hz, 1H), 2.10 (ddt, J ) 16.3, 4.8,
2.4 Hz, 1H), 2.05 (s, 3H), 1.96 (qq, 7.3, 1.1 Hz, 2H), 1.87 (ddd,
J ) 13.4, 8.8, 4.5 Hz, 1H), 1.78-1.71 (m, 4 H), 1.30 (m, 2H),
0.85 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3, 400 MHz): δ 171.1,
144.6, 132.5, 131.7, 129.0, 126.0, 125.4, 66.9, 46.3, 37.1, 32.7,
31.4, 31.3, 23.9, 23.6, 21.6, 14.1. MS (EI) m/z: 260 (5) [M+],
218 (51), 200 (87), 171 (100), 157 (67), 143 (50), 129 (47).
Com p ou n d s 2e. These were prepared as above in 67% total
yield. The reaction gave three isomers (Table 1), which were
separated by HPLC as 2e + 2e′′ and 2e′.
2e (m a jor ). 1H NMR (CDCl3, 400 MHz): δ 5.92 (app d, J )
2.7 Hz, 2H), 5.51 (d, J ) 2.9 Hz, 1H), 5.43 (qq, J ) 6.8, 1.5 Hz,
1H), 5.12 (m, 1H), 3.80-3.69 (overlapping peaks including s

Palladium-Catalyzed Cyclization of Dienes
J . Org. Chem., Vol. 66, No. 24, 2001 8025
2h ′. 1H NMR (CDCl3, 400 MHz): δ 5.79 (ddd, J ) 10.3, 3.7,
2.2 Hz, 1H), 5.66 (dtd, J ) 10.2, 2.2, 1.2 Hz, 1H), 5.35 (dd, J
) 5.0, 2.65 Hz, 1H), 5.32-5.25 (m, 2H), 3.28 (m, 1H), 2.65-
2.56 (m, 2H), 2.09 (dt, J ) 16.8, 2.5 Hz, 1H), 2.05 (s, 3H), 1.98
(qt, J ) 7.4, 1.2 Hz, 2H), 1.90 (m, 1H), 1.77 (dd, J ) 2.8, 1.3
Hz, 3H), 1.53 (m, 1H), 1.32 (qd, J ) 7.5, 1.5 Hz, 2H), 0.87 (t,
J ) 7.4 Hz, 3H). 13C NMR (CDCl3, 400 MHz): δ 171.1, 144.5,
131.8, 130.3, 128.7, 128.2, 125.0, 69.7, 46.4, 38.1, 34.2, 32.7,
31.4, 23.8, 23.6, 21.6, 14.1. MS (EI) m/z: 260 (5) [M+], 218 (50),
200 (82), 171 (100).
6H), 1.53 (m, 2H), 1.40-0.92 (m, 5H). 13C NMR (CDCl3, 100
MHz): δ 170.7, 170.6, 170.5, 155.7, 131.6, 125.2 118.8, 67.9,
65.2, 52.7, 52.3, 44.9, 38.3, 37.7, 32.1, 31.1, 26.6, 26.4, 26.1,
21.3. MS (EI) m/z: 284 (24) [M+], 252 (100). Anal. Calcd for
C
21H28O6: C, 67.00; H, 7.50. Found: C, 67.22; H, 7.34.
Com p ou n d 3c. This was prepared as above in 52% yield
(diastereomeric mixture (50:50)) using 5 mol % Pd(dba)2 and
1
stirred for 48 h. H NMR (CDCl3, 300 MHz): δ 6.07 (dd, J )
10.2, 4.4 Hz, 1H), 5.96 (m, 1H), 5.45 (br s, 1H), 5.12 (m, 1H),
3.74 (s, 3H), 3.70 (s, 3H), 3.55 (m, 1H), 3.43 (dt, J ) 11.0, 6.6
Hz, 1H), 2.21 (q, J ) 6.8 Hz, 0.5H), 2.07 (m overlapping a s at
2.05, 3.5H), 1.7-1.4 (m, 3H), 1.35 (m, 1H), 1.07 (d, J ) 6.9
Hz, 1.5H), 1.01 (d, J ) 6.9 Hz, 1.5H), 0.88 (t, J ) 7.4 Hz, 1.5H),
0.78 (t, J ) 7.2 Hz, 1.5H). 13C NMR (CDCl3, 75 MHz): δ 170.9
[2 dst], 170.7 (2C) [2 dst], 154.6 [dst 154.2], 131.8 [2 dst], 125.5
[dst 125.3], 120.3 [dst 119.7], 68.1 [2 dst], 65.4 [dst 65.4], 52.9
[dst 52.9], 52.6 [2 dst], 45.5 [dst 45.4], 38.6 [2 dst], 35.3 [dst
34.1], 27.8 [dst 27.6], 27.0 [dst 26.9], 21.5 [2 dst], 19.3 [17.6
dst], 12.1 [10.5 dst]. MS (EI) m/z: 290 (3) [M+], 229 (100). Anal.
Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C, 64.86; H,
7.40.
2h ′′. 1H NMR (CDCl3, 400 MHz): δ 5.96 (dddd, J ) 10.0,
5.0, 3.7, 1.3 Hz, 1H), 5.79 (ddt, J ) 9.9, 3.85, 2.0 Hz, 1H,
olefinic), 5.43 (q, J ) 2.2 Hz, 1H), 5.30 (tq, J ) 7.2, 1.4 Hz,
1H), 5.08 (m, 1H, CHOAc), 3.01 (m, 1H), 2.56 (m, 1H), 2.50
(dt, J ) 7.5, 2.4, 1H), 2.28 (br dt, J ) 17.5, 5.7 Hz, 1H), 2.07
(dt, J ) 17.5, 2.3 Hz, 1H), 2.01 (s, 3H), 1.93 (overlapping peaks
including a br q, J ) 7.2 Hz, total 3H), 1.78 (q, J ) 1.3 Hz,
3H), 1.29 (m, 2H), 0.85 (t, J ) 7.5 Hz, 3H). MS (EI) m/z: 200
(22), 171 (100).
Com p ou n d s 2i. These were prepared as above in 44% total
1
yield. H NMR (CDCl3, 400 MHz): δ 5.87 (ddd, J ) 10.1, 3.6,
0.9 Hz, 1H), 5.78 (ddd, J ) 10.1, 4.2, 2.2 Hz, 1H), 5.34 (dd, J
) 2.4, 4.8 Hz, 1H), 5.26 (tt, J ) 7.3, 1.3 Hz, 1H), 5.23 (br q, J
) 4.4 Hz, 1H), 3.30-3.26 (m, 1H), 2.74-2.65 (m, 1H), 2.57 (ddt,
J ) 16.1, 8.0, 2.4 Hz, 1H), 2.13-1.91 (m, 8H), 1.84 (ddd, J )
13.6, 9.4, 4.4 Hz, 1H), 1.75 (dt, 13.6, 5.1 Hz, 1H), 1.33-1.18
(m, 6H), 0.84 (t, J ) 7.32 Hz, 6H). 13C NMR (CDCl3, 400
MHz): δ 171.1, 143.4, 136.6, 132.8, 128.3, 126.6, 125.2, 66.9,
46.5, 37.3, 36.9, 32.5, 31.5, 31.2, 30.9, 23.6, 22.4, 21.6, 14.2,
14.1. MS (EI) m/z: 302 (12) [M+], 260 (65), 242 (100).
Com p ou n d 3d . This was prepared as above in 44% yield
(diastereomeric mixture (50:50)) using 5 mol % Pd(OAc)2 and
1
stirred for 48 h. H NMR (CDCl3, 400 MHz): δ 6.04 (m, 1H),
5.80 (m, 1H), 5.28 (m, 1H), 5.21 (m, 1H), 3.14 (m, 1H), 2.63
(m, 1H), 2.44 (m, 1H), 2.20-2.12 (m, 1H), 2.05 (s, 3H), 1.98
(m, 1H), 1.82 (m, 1H), 1.69 (apparent dt, J ) 13.5, 5.1 Hz,
1H), 1.49 (m, 1H), 1.26 (m, 5H), 1.02 (apparent dd, J ) 12.5,
6.8 Hz, 3H), 0.88 (apparent td, J ) 7.0, 1.4 Hz, 3H). 13C NMR
(CDCl3, 400 MHz): δ 171.1, 150.5, 132.7, 125.6, 121.6 [dst
121.2], 67.0 [dst 66.9], 45.9 [dst 45.8], 36.6 [dst 36.6], 35.5 [dst
35.2], 33.6 [dst 33.2], 33.0 [dst 32.9], 31.3 [dst 31.3], 30.0 [dst
29.2], 23.1 [dst 23.1], 21.6 [dst 20.4], 18.8, 14.3. MS (EI) m/z:
203 (13), 202 (42), 146 (100).
1
2i′. H NMR (CDCl3, 400 MHz): δ 5.77 (ddd, J ) 10.3, 3.7,
2.0 Hz, 1H), 5.64 (ddd, J ) 10.3, 3.5, 2.0 Hz, 1H), 5.32-5.25
(m, 3H), 3.26-3.20 (m, 1H), 2.66-2.55 (m, 2H), 2.13-2.01 (m,
8H), 1.89 (dddd, J ) 11.8, 5.3, 4.4, 1.3 Hz, 1H), 1.53 (td, J )
12.0, 9.7 Hz, 1H), 1.37-1.21 (m, 6H), 0.86 (t, J ) 7.3 Hz, 6H).
13C NMR (CDCl3, 400 MHz): δ 171.3, 143.4, 136.6, 130.4,
128.2, 128.1, 125.7, 69.8, 46.6, 38.2, 36.8, 34.3, 32.8, 31.2, 30.8,
23.6, 22.4, 21.6, 14.2, 14.1. MS (EI) m/z: 302 (2) [M+], 242 (91),
199 (86), 143 (100).
Gen er a l P r oced u r e for th e P r ep a r a tion of 28. Com -
p ou n d 28a . To 0.32 g (0.96 mmol) of 2a dissolved in 12 mL of
dry toluene were added maleic anhydride 0.47 g (4.8 mmol)
and two crystals of butylated hydroxytoluene (BHT). The
reaction was refluxed for 24 h. Evaporation followed by flash
chromatography (pentane:Et2O, 50:50 to 0:100) gave 28a (0.37
g) in 85% yield. The solid diacid 29a was formed in the freezer.
This solid was washed with CH2Cl2 and pentane, and the
Alter n a tive P r oced u r e for th e P r ep a r a tion of 2. To 1a
(90 mg, 0.33 mmol) were added palladium acetate (4 mg, 0.016
mmol), iron phthalocyanine (4 mg, 0.007 mmol), and benzo-
quinone (10 mg, 0.10 mmol). This was dissolved in acetic acid,
and a balloon filled with oxygen was applied. The reaction was
stirred at room temperature for 24 h. Water was added and
extracted with Et2O (3 × 30 mL). The combined organic layers
were dried (Na2SO4); evaporation followed by flash chroma-
tography (pentane:Et2O, 75:25) gave 73 mg (67% yield) of 2a .
Gen er a l P r oced u r e for th e P r ep a r a tion of 3. Com -
p ou n d 3a . To 1a (0.11 g, 0.41 mmol) were added lithium
acetate dihydrate (0.17 g, 1.6 mmol) and Pd(dba)2 (0.023 g,
0.04 mmol), and the mixture was dissolved in 6 mL of HOAc.
The reaction mixture was stirred at room temperature for 24
h. H2O was added, and the water layer was extracted with
Et2O (3 × 30 mL). The combined organic layers were dried
(Na2SO4), concentrated in vacuo, and subsequent flash chro-
matography (pentane:Et2O, 75:25) of the residue gave 0.09 g
(65% yield) of 3a . 1H NMR (CDCl3, 300 MHz): δ 6.09 (dd, J )
9.1, 4.4 Hz, 1H), 5.96 (ddd, J ) 10.2, 5.5, 2.2 Hz, 1H), 5.44
(dd, J ) 3.0, 1.6 Hz, 1H), 5.11 (td, J ) 5.5, 3.3 Hz, 1H), 3.74
(s, 3H), 3.70 (s, 3H), 3.57 (m, 1H), 3.44 (dt, J ) 11.0, 6.6, Hz,
1H), 2.31 (tpent, J ) 7.1, 1.3), 2.05 (s, 3H), 1.52 (m, including
J ) 3.3 Hz, 2H), 1.10 (d, J ) 6.6 Hz, 3H), 1.02 (d, J ) 6.9 Hz,
3H). 13C NMR (CDCl3, 75 MHz): δ 170.9, 170.7 (2C), 131.7,
125.5, 118.9, 68.1, 65.4, 52.9, 52.6, 45.3, 38.7, 28.1, 26.9, 21.6,
21.5, 20.9. MS (EI) m/z: 294 (2) [M+], 212 (100).
1
purified solid was not soluble in CDCl3. H NMR (CO(CD3)2,
400 MHz): δ 6.34 (dd, J ) 10.1, 4.8 Hz, 1H), 5.85 (ddd, J )
10.1, 5.3, 2.2 Hz, 1H), 5.11 (dt, J ) 5.8, 3.2 Hz, 1H), 3.73 (s,
3H), 3.70-3.56 (m, 3H), 3.53 (s, 3H), 3.06 (m, 2H), 2.30 (m,
1H), 2.17-2.05 (m, 1H), 1.99 (s, 3H), 1.69 (br s, 3H), 1.57 (br
td, J ) 13.5, 3.1 Hz, 1H), 1.48 (dt, J ) 13.5, 3.9 Hz, 1H). 13C
NMR (CO(CD3)2, 75 MHz): δ 173.2, 171.1, 170.4, 169.9, 169.8,
133.1, 130.8, 124.8, 123.4, 65.2, 63.9, 52.2, 50.9, 48.7, 43.6, 41.7,
41.3, 38.5, 31.6, 27.4, 20.4, 19.0.
Com p ou n d 28b. This was prepared as above in 82% yield
and purified to form the solid diacid 29b. 1H NMR (CO(CD3)2,
400 MHz): δ 6.12 (ddd, J ) 10.1, 4.4, 1.1 Hz, 1H), 5.68 (ddd,
J ) 10.1, 3.7, 2.0 Hz, 1H), 5.11 (m, 1H), 4.18 (dd, J ) 8.8, 4.1
Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.58 (t, J ) 8.8 Hz, 1H),
3.49 (m, 2H), 3.33 (m, 1H), 2.61 (m, 1H), 2.39 (m, 1H), 2.28
(m, 1H), 1.99 (s, 3H), 1.95 (m, 1H), 1.88 (m, 1H), 1.76 (m, 1H),
1.69 (m, 2H), 1.56 (m, 2H), 1.43 (m, 1H). 13C NMR (CO(CD3)2,
75 MHz): δ 173.4, 171.5, 171.4, 170.0, 169.8, 138.2, 131.2,
131.1, 124.8, 65.2, 63.6, 52.7, 52.3, 46.5, 44.9, 44.7, 42.2, 41.6,
36.8, 27.6, 25.6, 24.7, 21.8, 21.7, 20.4.
Su p p or tin g In for m a tion Ava ila ble: Characterization
spectra for compounds 1a -k , 2d , 2e + 2e′′, 2e′, 2f + 2f′, 2g,
2g′, 2h , 2h ′, 2h ′′, 2i, 2i′, 3a , 3d , 11, 15a ,b, 16a ,b, 20a ,b, 28a ,b,
29a ,b. This material is available free of charge via the Internet
at http://pubs.acs.org.
Com p ou n d 3b. This was prepared as above in 84% yield.
1H NMR (CDCl3, 400 MHz): δ 6.08 (dd, J ) 10.0, 4.4 Hz, 1H),
5.96 (ddd, J ) 10.0, 5.4, 2.2 Hz, 1H), 5.41 (br s, 1H), 5.11 (dt,
J ) 5.4, 3.4 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.57 (m, 1H),
3.42 (dt, J ) 11.7, 6.3, Hz, 1H), 2.05 (s, 3H), 2.00-1.64 (m,
J O0157324