Palladium(0)-catalyzed cyclization of electron-deficient enynes and enediynes

Article abstract of DOI:10.1021/jo049072p

In the presence of a Pd(0) precatalyst, Pd₂(bq) ₂(nbe)₂ or Pd₂(dba)₃, 1,6-enyne esters were heated in refluxing benzene to give cyclodimers as single regioisomers. On the other hand, the combination of the Pd(0) precatalyst and triphenyl phosphite gave rise to various cycloisomerization products depending on the substitution pattern of the enyne esters. Six-membered ring cycloisomerization products were predominantly obtained from enyne esters bearing methallyl or 2-phenyl-2-propenyl moieties, while other enyne esters afforded normal five-membered ring cycloisomerization products. Intramolecular [2 + 2 + 2] cyclocotrimerization of enediyne esters also proceeded in the presence of the Pd(0) precatalyst and triphenylphosphine to give fused cyclohexadienes.

Full text of DOI:10.1021/jo049072p

P a lla d iu m (0)-Ca ta lyzed Cycliza tion of Electr on -Deficien t En yn es
a n d En ed iyn es
Yoshihiko Yamamoto,*,† Shoji Kuwabara,† Yoji Ando,‡ Hitomi Nagata,‡
Hisao Nishiyama,† and Kenji Itoh‡
Department of Applied Chemistry, and Department of Molecular Design and Engineering,
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, J apan
yamamoto@apchem.nagoya-u.ac.jp
Received J une 3, 2004
In the presence of a Pd(0) precatalyst, Pd2(bq)2(nbe)2 or Pd2(dba)3, 1,6-enyne esters were heated in
refluxing benzene to give cyclodimers as single regioisomers. On the other hand, the combination
of the Pd(0) precatalyst and triphenyl phosphite gave rise to various cycloisomerization products
depending on the substitution pattern of the enyne esters. Six-membered ring cycloisomerization
products were predominantly obtained from enyne esters bearing methallyl or 2-phenyl-2-propenyl
moieties, while other enyne esters afforded normal five-membered ring cycloisomerization products.
Intramolecular [2 + 2 + 2] cyclocotrimerization of enediyne esters also proceeded in the presence
of the Pd(0) precatalyst and triphenylphosphine to give fused cyclohexadienes.
In tr od u ction
son-Khand reaction)8 or with organosilicon and tin
compounds (eq 3).9
Transition-metal-catalyzed carbocyclizations are pow-
erful tools for the assembly of carbo- and heterocyclic
frameworks.1 In particular, growing attention is currently
devoted to the environmentally benign catalytic cyclo-
isomerizations of R,ω-enynes.2 For example, the intramo-
lecular alkyne-alkene coupling reaction converts enyne
substrates into 1,3-dienes (eq 1),3 and enyne metathesis
or skeletal reorganization reactions produce vinylcyclo-
pentene derivatives via the carbon-carbon bond fission
(eq 2).4,5 R,ω-Enynes are also attractive substrates for the
catalytic cyclo-coupling with other unsaturated organic
molecules such as alkynes,6 alkenes,7 and CO (the Pau-
Previously, we have developed the palladium(0)-
catalyzed intramolecular cyclotrimerizations of diyne
diesters or triyne diesters in which electron-deficient 1,6-
diyne moieties are essential for the formation of key
† Department of Applied Chemistry.
‡ Department of Molecular Design and Engineering.
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10.1021/jo049072p CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/28/2004
J . Org. Chem. 2004, 69, 6697-6705
6697

Yamamoto et al.
SCHEME 1
SCHEME 2
mixture was further stirred at this temperature for 4 h.
As a result, a complex mixture including a trace amount
of cyclodimer 3a a was obtained instead of the expected
1:1 coupling product of 2a a with 1-octene. Such an enyne
cyclodimerization is very rare, and to the best of our
knowledge, it has been confined to the Rh(I)-catalyzed
reactions of electronically neutral 1,6-enynes.14 Thus, we
tried to optimize the new cyclodimerization of the electron-
deficient enyne 2a a . In the absence of the terminal
alkene, 3a a was obtained as the sole product in 41% yield
(Scheme 2). The yield was improved to 60% by carrying
out the reaction in refluxing benzene. A commercially
available precatalyst, Pd2(dba)3 1b (5 mol % Pd), also
gave 3a a in a slightly higher yield (64%) under the same
conditions (Table 1, run 1).
To examine the generality of the Pd(0)-catalyzed cy-
clodimerization, other enyne esters were allowed to react
under the same reaction conditions (Table 1). A methallyl
derivative 2a b was similarly converted to 3a b in 69%
yield (Table 1, run 2), whereas cinnamyl and prenyl
derivatives 2a c and 2a d afforded intractable product
mixtures (Figure 1). The ester terminal group on the
alkyne moiety plays an important role. Enyne substrates
bearing a ketone, an amide, or a phenyl terminal group
hardly afforded cyclodimerization products (Figure 1). In
addition to the ether derivatives, tosylamides 2ba and
2bb also furnished the corresponding products 3ba and
3bb in 68 and 58% respective yields (Table 1, runs 3 and
4). It is noteworthy that a much longer reaction time of
18 h was required for the complete conversion of 2bb,
and a small amount of byproduct 4bb was also obtained
(see below).
The cyclodimerization of the enyne esters selectively
gave rise to the single regioisomers. The regiochemistry
of the cyclodimers was unambiguously confirmed by the
X-ray analysis of 3ba (see the Supporting Information,
Figure S1). In its six-membered ring, only the C1-C2
and C7-C8 bonds exhibit typical CdC double bond
lengths of 1.3389(19) and 1.3448(18) Å, respectively. The
C1-C8 bond length of 1.4801(17) Å is very similar with
that of a typical Csp2-Csp2 single bond. The two meth-
oxycarbonyl groups are located at a meta position to each
other. This regioselectivity is opposite to those reported
for the Rh(I)-catalyzed cyclodimerization of enynes.14 The
observed regiochemistry was reasonably explained by the
plausible mechanism outlined in Scheme 3. Dibenzyli-
denacetone ligands might be initially substituted by the
two enyne esters to form a trigonal planar complex I.
Contrary to our assumption, the oxidative cyclization
takes place with the two alkyne terminals to produce a
palladacyclopentadiene II because the electron-deficient
alkynoate moiety is a superior electron acceptor to
unactivated alkenes. In this stage, the palladacycle must
intermediates, palladacyclopentadienes.10 As a continu-
ation of our studies on palladium(0)-catalyzed cyclization,
we turned our attention to 1,6-enynes having an ester
group on the alkyne terminal because such enyne esters
might be attractive precursors for palladacyclopentenes.
The oxidative cyclization giving rise to palladacyclo-
pentenes has been proposed as the key step in the
previously reported linear couplings of highly electron-
deficient dimethyl acetylenedicarboxylate (DMAD) and
electronically neutral terminal alkenes,11a or the three-
component linear coupling of DMAD, terminal alkenes,
and allyl alcohol.11b In this context, we envisaged that
the enyne esters might be entropically more suitable for
the oxidative cyclization leading to palladacyclopentenes.
Here we report the palladium(0)-catalyzed cyclodimer-
ization and cycloisomerizations of enyne esters. As an
extension of the cyclodimerization reaction, we also
present the cyclization of some enediyne esters.
Resu lts a n d Discu ssion
Cyclod im er iza tion of En yn e Ester s. Itoh and co-
workers have previously reported that DMAD reacted
with norbornene in the presence of a tetramethoxycar-
bonyl palladacyclopentadiene to afford a cyclocotrimer-
ization product (Scheme 1).12 On the other hand, a
palladium(0) complex, Pd(mah)2(nbe) (mah ) maleic
anhydride, nbe ) norbornene), selectively catalyzed the
2:1 linear coupling of terminal alkenes with DMAD
(Scheme 1).11a In the latter case, the electron-deficient
olefin ligand, maleic anhydride, was considered to be
essential for the selective oxidative cyclization of DMAD
and an alkene leading to a putative palladacyclopentene
intermediate. Recently, we also reported a new dinuclear
palladium(0) complex, Pd2(bq)2(nbe)2 1a (bq ) p-benzo-
quinone), that catalyzed a similar linear coupling.13
To extend the Pd(0)-catalyzed coupling methodology
through palladacyclopentene intermediates, we attempted
the cyclocoupling of an enyne ester 2a a with excess
1-octene. In a similar manner with the reported linear
coupling,11a a CHCl3 solution of 2a a was added to 10
equiv of 1-octene containing Pd2(bq)2(nbe)2 (5 mol % Pd)
via a syringe pump over 12 h at 50 °C, and the reaction
(10) (a) Yamamoto, Y.; Nagata, A.; Itoh, K. Tetrahedron Lett. 1999,
40, 5035-5038. (b) Yamamoto, Y.; Nagata, A.; Arikawa, Y.; Tatsumi,
K.; Itoh, K. Organometallics 2000, 19, 2403-2405. (c) Yamamoto, Y.;
Nagata, A.; Nagata, H.; Ando, Y.; Arikawa, Y.; Tatsumi, K.; Itoh, K.
Chem. Eur. J . 2003, 9, 2469-2483.
(11) (a) Itoh, K.; Hirai, K.; Sasaki, M.; Nakamura, Y.; Nishiyama,
H. Chem. Lett. 1981, 865-868. (b) Munz, C.; Stephan, C.; tom Dieck,
H. J . Organomet. Chem. 1991, 407, 413-420.
(12) (a) Suzuki, H.; Itoh, K.; Ishii, Y.; Simon, K.; Ibers, J . A. J . Am.
Chem. Soc. 1976, 98, 8494-8500. (b) Brown, L. D.; Itoh, K.; Suzuki,
H.; Hirai, K.; Ibers, J . A. J . Am. Chem. Soc. 1978, 100, 8232-8238.
(13) Yamamoto, Y.; Ohno, T.; Itoh, K. Organometallics 2003, 22,
2267-2272.
(14) (a) Grigg, R.; Scott, R.; Stevenson, P. J . Chem. Soc., Perkin
Trans. 1 1988, 1365-1369. (b) Oh, C. H.; Sung, H. R.; J ung, S. H.;
Lim, Y. M. Tetrahedron Lett. 2001, 42, 5493-5495.
6698 J . Org. Chem., Vol. 69, No. 20, 2004

Pd(0)-Catalyzed Cyclization of Enyne and Enediyne Esters
TABLE 1. P d (0)-Ca ta lyzed Cyclod im er iza tion s of En yn e
Ester s (E ) CO2Me)a
F IGURE 1. Enyne substrates which failed to undergo cy-
clodimerization.
SCHEME 3
SCHEME 4
a
A 0.1 M solution of 2 in degassed benzene containing 1b (5
mol % Pd) was refluxed under Ar for the above specified time.b A
cycloisomerization product 4bb was formed in 9% yield.
countered by Trost,4c,15 Mikami,16 and co-workers in their
study on the Pd(II)-catalyzed reactions of enynes. In the
following section, we disclose the selective transformation
of enyne esters into the six-membered ring carbo- and
heterocycles.
be formed in such a way that minimizes the steric
repulsion between the alkenyl side chains. Subsequently,
the pendant alkene is inserted into the Pd-Csp2 bond to
form a palladacycloheptadiene III, which undergoes
reductive elimination to give rise to the final cyclodimer.
Six-Mem ber ed -Rin g F or m a tion s fr om 1,6-En yn e
Ester s. We next examined the effect of ligands and
solvents on the product selectivity with respect to 2bb,
and the results are summarized in Table 2. In our
previous study on the cycloaddition of the diyne diesters,
triphenylphosphine turned out to be an optimal ligand.10
On the contrary, the phosphine suppressed the cy-
clodimerization leading to 3bb but, instead, promoted the
six-membered ring formation yielding 4bb and its isomer
6bb (run 1). In an aprotic polar solvent, 1,2-dichloroeth-
ane (DCE), the cyclodimerization was completely inhib-
ited to afford 4bb and 6bb in 57 and 14% respective
yields (run 2). The replacement of triphenylphosphine by
less electron-donating triphenyl phosphite improved the
selectivity of 4bb over 6bb (run 3), and 2 equiv of P(OPh)3
retarded the reaction (run 4). The combination of the
p-quinone complex 1a and P(OPh)3 gave a similar
selectivity albeit with somewhat lower yield (run 5). More
electron-accepting ligands, tri(pentafluorophenyl)phos-
phine or xylyl isocyanide, afforded considerable amounts
In contrast to the ether and tosylamide substrates,
dimethyl malonate analogues bearing an allyl or a meth-
allyl terminal failed to undergo cyclodimerization under
the same reaction conditions. At higher temperature in
refluxing toluene, 2cb was completely consumed for 24
h, and the inseparable mixture of a cyclohexene 4cb and
a cyclopentene 5 was obtained in 21% combined yield
instead of the expected cyclodimer (Scheme 4). The latter
product 5 was probably formed via enyne metathesis, and
1
the following H NMR data were consistent with those
reported in the literature.4a The absorption of the vinyl
protons were observed at δ 5.54 and 6.26 (each 1 H, d, J
) 1.7 Hz). The two methylenes of the cyclopentene ring
appeared at δ 3.22 and 3.07 as broad peaks, and the
singlet signal corresponding to the allylic methyl protons
was observed at δ 1.66. The methoxy protons resonated
at δ 3.75 and 3.74 with the 1:2 integral ratio.
(15) Trost, B. M.; Zhi, L.; Imi, K. Tetrahedron Lett. 1994, 35, 1361-
The cycloisomerization converting 1,6-enynes into six-
membered ring products such as 4bb and 4cb has hardly
been explored, although a similar result has been en-
1364.
(16) Mikami, K.; Hatano, M Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5767-5769.
J . Org. Chem, Vol. 69, No. 20, 2004 6699

Yamamoto et al.
TABLE 2. Effects of Ad d itives a n d Solven ts on
P d (0)-Ca ta lyzed Rea ction of En yn e Ester 2bb (E )
CO2Me)
SCHEME 5
yield (%)
4bb
run
catalyst
solvent/time (h) 3bb
6bb
1
2
3
4
5
6
7
1b + 2PPh3
PhH/12
DCE/12
DCE/12
DCE/32
DCE/12
DCE/6
30
0
0
0
0
34
57
64
60
54
20
34
8
14
9
7
4
1b + 2PPh3
1b + 2P(OPh)3
1b + 4P(OPh)3
1a + 2P(OPh)3
1b + 2P(C6F5)3
1b + 2CN(xylyl)
40
25
2
0
DCE/24
57% yield (run 1). In this case, 1a is a preferable catalyst
precursor because of the difficulty in the separation of
4a b from dibenzylideneacetone. In contrast to enyne
esters bearing ether or tosylamide tethers (runs 1-3),
the malonate analogue 2cb failed to undergo cyclo-
isomerization in refluxing DCE. The smooth conversion
of 2cb was observed at 110 °C in chlorobenzene to afford
4cb in 59-64% yields (runs 4 and 5). In the cases of 2a b
and 2cb, 6a b or 6cb were hardly formed. Furthermore,
the cycloisomerization of a 2-phenylallyl analogue 2be
was attempted under the same conditions with 2bb, but
no reaction occurred. Thus, the reaction was conducted
at higher temperature in refluxing chlorobenzene for 8
h to give rise to equal amounts of 4be and 6be as an
inseparable mixture in 53% combined yield (run 6).
Cycloisom er iza tion of Oth er En yn e Ester s. We
further explored the reactivity of other enyne esters
bearing a tosylamide tether under the cycloisomerization
conditions. The allyl analogue 2ba resulted in intractable
products, although it gave the cyclodimer under the
ligand-free conditions (Table 1, run 3). On the other hand,
a cinnamyl derivative 2bc gave rise to a pyrrolidine 7bc
possessing a exo-1,3-diene moiety as a result of the
normal cycloisomerization (Scheme 5).3 The Z,Z-geometry
of the exo-diene moiety was confirmed by X-ray analysis
(see the Supporting Information, Figure S6). Similarly,
a prenyl derivative 2bd underwent the cycloisomerization
to afford an Alder-ene product 8bd selectively in 52-
60% yields (Scheme 5). Only five-membered ring cycliza-
tion was also observed for 2bf (Scheme 5). The obtained
products were a spirocyclic Alder-ene product 8bf and
its isomerized byproduct 9bf.17 A slightly higher isomer
selectivity was obtained with the precatalyst 1b, while
the total yields were similar in either case.
TABLE 3. P d (0)/P (OP h )3-Ca ta lyzed Rea ction of En yn e
Ester s 2 (E ) CO2Me)
run
enynes
X ) O, R ) Me
2a b 1a
Pd(0)
solvent/time (h)
DCE/12
products (yield, %)
1
4a b (57)
X ) NTs, R ) Me
2
3
2bb
2bb
1a
1b
DCE/12
DCE/12
4bb (54) + 6bb (4)
4bb (64) + 6bb (9)
X ) C(CO2Me)2, R ) Me
4
5
2cb
2cb
1a a
1ba
PhClb/1
PhClb/1
4cb (59)
4cb (64)
X ) NTs, R ) Ph
6
2be 1a
PhClb/8
4be/6be (53)c
a
5 mol % Pd(0) complexes (10 mol % Pd) were employed.
Reactions were carried out at 110 °C. c Inseparable 1:1 mixture.
b
of the cyclodimer 3bb (runs 6 and 7). Other ligands such
as triethylphosphine and triethyl phosphite proved to be
entirely inefficient. Therefore, triphenyl phosphite ap-
peared to be the optimal ligand for the six-membered ring
formation.
The structures of 4bb and 6bb were clearly determined
by X-ray analyses (see the Supporting Information,
Figures S2 and S3). They are inner-ring double-bond
isomers. While a conjugated s-trans diene is found in
4bb, the exocyclic olefin is isolated from the inner-ring
double bond in 6bb. The vinyl protons of 4bb resonated
at δ 5.48 and 7.24, while those of 6bb were observed at
δ 5.57 and 6.45. It is noteworthy that the exocyclic
alkenes have an E geometry as a result of the net trans-
addition of the alkene C-H bond onto the electron-
deficient alkyne. This observation is inconsistent with the
cis-addition mechanism proposed by Trost and co-workers
(see below).4c
Cycloisom er iza tion Mech a n ism s. The five-mem-
bered ring cycloisomerization catalyzed by a low-valent
transition metal is expected to proceed via oxidative
cyclization followed by â-H elimination of the resultant
palladacyclopentene intermediate. On the other hand, a
Table 3 summarizes the results of the cycloisomeriza-
tion of various methallyl enyne esters. In a similar
manner using 1a as a precatalyst, the ether enyne 2a b
(X ) O) was selectively converted to the expected 4a b in
(17) Asymmetric Alder-ene cycloisomerization of 2bf has been
reported; see: Hatano, M.; Mikami, K. Org. Biomol. Chem. 2003, 1,
3871-3873.
6700 J . Org. Chem., Vol. 69, No. 20, 2004

Pd(0)-Catalyzed Cyclization of Enyne and Enediyne Esters
SCHEME 6
SCHEME 8
SCHEME 7
reorganization and related reactions.4d-k,19 The pal-
ladium(0)-catalyzed skeletal reorganization, however, is
unprecedented, whereas pallada(II)cyclopentadiene com-
plexes have been reported as efficient catalysts for enyne
skeletal reorganization.4a-c Oi, Inoue, and their co-
workers have found that highly electrophilic dicationic
species, [Pd(dppp)(PhCN)2](BF4)2 and [Pd(PPh3)(PhCN)2]-
(BF4)2, were totally ineffective toward this type of
cyclization.4i In addition, almost exclusive formation of
the cyclohexene derivatives 4 under the present pal-
ladium(0) catalysis is inconsistent with the typical ex-
amples using [RuCl2(CO)3]2,4d PtCl2,4e and [IrCl(CO)3]n,4f
which uniformly produced five-membered ring products.
With these facts in mind, we postulated another mech-
anism, which involves a palladacyclopentene intermedi-
ate (Scheme 8). The new mechanism starts with the
oxidative cyclization of an enyne ester leading to the
palladacyclopentene intermediate IV. Its subsequent
isomerization would afford the cyclopropyl carbene spe-
cies V. This type of isomerization was proposed for the
palladacycle-catalyzed reactions of enynes4a-c,20 and the
titanium(II)-mediated cyclization of enyne esters.21 If the
fused bond in V is cleaved, a zwitterionic intermediate
VI would be produced. In this stage, the coordinated
palladium carbene moiety must be oriented to minimize
the unfavorable steric interaction between the P(OPh)3-
coordinated palladium center and the cyclopropane ring
moiety, resulting in the E geometry of the exocyclic
alkene. Subsequent proton transfer and reductive elimi-
palladium(II) hydride might be a catalytically active
species, when Pd(II) catalyst is used with a hydride donor
such as carboxylic acids or hydrosilanes. In this case, the
catalytic cycle starts with hydropalladation of an alkyne,
and subsequent insertion of a pendant alkene into the
resultant Pd-Csp2 bond is followed by the â-H elimina-
tion, which affords the final product as well as Pd-H
species. To obtain further information with respect to the
mechanism, we carried out some D-labeling studies. As
depicted in Scheme 6, 2bd -d6 was subjected to the
cycloisomerization under identical conditions with 2bd
to afford 8bd in 55% yield with ca. 70% D content (8bd -
d6/8bd -d5 ) 7:3). The D content was slightly reduced to
63% in the presence of 600 mol % H2O, while the
deuterated ligand, P(OC6D6)3, never affected the D
content. Similarly, 2bd underwent cycloisomerization
with 600 mol % D2O to obtain 8bd in 58% yield with ca.
20% D content (8bd /8bd -d1 ) 80:20). On the other hand,
no deuterium incorporation was detected when the same
cycloisomerization was carried out in benzene-d6 or DCE-
d4. These data suggest that most of the D-labels were
transferred in an intramolecular fashion via a pallada-
cyclopentene intermediate, but some of them were lost
probably via D-H exchange with water from the solvent.
The 20% deuterium incorporation from excess D2O sup-
ports such a D-H exchange (Scheme 7), which is,
however, less pronounced than that of the recently
reported Pd(II)-catalyzed asymmetric cycloisomerization
of a related enyne ester.18
(19) (a) Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.; Seki,
Y. J . Am. Chem. Soc. 1998, 120, 9104-9105. (b) Mainetti, E.; Mourie`s,
V.; Fensterbank, L.; Malacria, M.; Marco-Contelles, J . Angew. Chem.,
Int. Ed. 2002, 41, 2132-2135. (c) Mart´ın-Matute, B.; Ceardenas, D.
J .; Echavarren, A. M. Angew. Chem., Int. Ed. 2001, 40, 4754-4757.
(d) Me´ndez, M.; Mun˜oz, M. P.; Nevado, C.; Ca´rdenas, D. J .; Echavarren,
A. M. J . Am. Chem. Soc. 2001, 123, 10511-10520. (e) Ferna´ndez-Rivas,
C.; Meendez, M.; Nieto-Oberhuber, C.; Echavarren, A. M. J . Org. Chem.
2002, 67, 5197-5201. (f) Nevado, C.; Charruault, L.; Michelet, V.;
Nieto-Oberhuber, C.; Munoz, M. P.; Me´ndez, M.; Rager, M.-N.; Geneˆt,
J .-P.; Echavarren, A. M. Eur. J . Org. Chem. 2003, 706-713. (g) Nevado,
C.; Ca´rdenas, D. J .; Echavarren, A. M. Chem. Eur. J . 2003, 9, 2627-
2635. (h) Martin-Matute, B.; Nevado, C.; Ca´rdenas, D. J .; Echavarren,
A. M. J . Am. Chem. Soc. 2003, 125, 5757-5766.
(20) (a) Trost, B. M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl.
1993, 32, 1085-1087. (b) Trost, B. M.; Hashmi, A. S. K. J . Am. Chem.
Soc. 1994, 116, 2183-2184. (c) Trost, B. M.; Hashmi, A. S. K.; Ball, R.
G. Adv. Synth. Catal. 2001, 343, 490-494.
(21) (a) Suzuki, K.; Urabe, H.; Sato, F. J . Am. Chem. Soc. 1996, 118,
8729-8730. (b) Urabe, H.; Suzuki, K.; Sato, F. J . Am. Chem. Soc. 1997,
119, 10014-10027.
The six-membered ring cyclization might proceed via
a polarized η1-alkyne complex as proposed in the skeletal
(18) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed.
2001, 40, 249-253.
J . Org. Chem, Vol. 69, No. 20, 2004 6701

Yamamoto et al.
SCHEME 9
Previously, Trost and Tanoury reported the pallada-
cycle-catalyzed reaction of a 1,6-enyne and DMAD af-
fording the corresponding 1:1 cycloadduct and metathesis
product.6 In this paper, they proposed a pallada(IV)-
cyclopentene as a common intermediate. For our case, it
might be reasonable to consider that the metathesis
product 10 and the cycloadduct 11 were formed from a
pallada(II)cyclopentene-DMAD complex 13 because the
palladacycle 1c itself never gave 10 and 11 in the absence
of DMAD (Scheme 11). In addition, the in-situ-formed
palladacyclopentadiene species was readily trapped with
DMAD to form considerable amounts of hexamethyl
mellitate. The reductive elimination from 13 would give
rise to an elusive cyclobutene intermediate 14, which
undergoes electrocyclic ring opening to afford 10. DMAD
is considered to facilitate the reductive elimination of 14
as a highly electron-accepting ligand. Alternatively, the
insertion of the coordinated DMAD into the Pd-Csp2
bond is followed by reductive elimination to furnish 11.
On the basis of these results, we can conclude that the
Pd(0)-catalyzed cycloisomerizations of the enyne esters
proceed via the palladacycle mechanism.23
Cycloisom er iza tion of Ar en e-Yn e Ester . Recently,
the cyclizations of a variety of arene-ynes have been
accomplished by means of ruthenium, platinum, and
gallium catalyses.24 With our catalytic system, a N-
benzyltosylamide 2bg failed to undergo cycloisomeriza-
tion even at 110 °C in chlorobenzene for 24 h (Scheme
12). This indicates that the arene-yne ester cannot
undergo oxidative cyclization. In contrast, a furan deriva-
tive 2bh was cyclized in the presence of 1a /2P(OPh)3 (30
mol % Pd) in refluxing DCE to give a furopiperidine 16bh
albeit in low yield (Scheme 12). With reduced catalyst
loadings, the longer reaction gave rise to intractable
product mixture, probably due to the decomposition of
the starting material or the product. The structure of
16bh was confirmed by X-ray analysis (see the Support-
ing Information, Figure S7). The exo-alkylidenepiperidine
core is very similar to that of 4bb except for the exocyclic
alkene geometry.
nation give rise to 4 and 6 from the common intermediate
VI. The cyclization of 2bb was reexamined in the
presence of excess D2O (Scheme 9). Unfortunately, the
reaction was deteriorated by D2O addition, resulting in
the low-yield formation of 4bb/4bb-d 1 (40%). In contrast
to the Alder-ene type cycloisomerization of 2bd , signifi-
cant deuterium incorporation was observed (62%), in-
dicative of the hydrogen-atom transfer taking place in
an intermolecular fashion as outlined in Scheme 8.
The observed deuterium incorporation and the E
geometry of the exocyclic alkene moiety can also be
explained by an alternative mechanism proposed by
Mikami and Hatano.16 They considered that the hydro-
palladation of the alkyne followed by subsequent two
alkene insertions might produce a cyclopropane inter-
mediate, and its ring opening via the fused C-C bond
fission finally gives rise to the six-membered ring product.
To confirm the palladacycle mechanism, we further
carried out the PD(0)-catalyzed reaction of 2bb in the
presence of DMAD, in which the palladacyclopentene
intermediate such as IV might be trapped as the cycload-
duct with DMAD. As outlined in Scheme 10, 2bb and 2
equiv of DMAD were heated in a DCE solution containing
a catalyst (10 mol % Pd) for 24 h. When 1a was used as
a precatalyst, two new products 10 and 11 were formed
in 15 and 25% respective yields together with 4bb. The
1
structure of 10 was deduced from the H NMR analysis
as follows. The methylene protons on its five-membered
pyrroline ring appeared as two multiplets at lower field
(δ 4.08 and 4.27) than those of the six-membered ring
compound 4bb (δ 3.69 and 3.78).22 The vinyl protons were
observed as a couple of doublets with a small coupling
constant (δ 5.55 and 6.32, J ) 1.4 Hz). These data allowed
us to assign 10 as an enyne metathesis product similar
to 5. The other product 11 is the 1:1 cycloadduct of 2bb
Cycliza tion of En ed iyn e Ester s. We have previously
found that a triyne diester 17 was cyclized upon treat-
ment with a catalytic amounts of 1b/2PPh3 in refluxing
toluene to afford a tricyclic product 18 via intramolecular
[2 + 2 + 2] cyclotrimerization (Figure 2).10 A palladium-
(0) trialkyne complex 19 was also obtained from the
stoichiometric reaction of 1b with 17 at ambient tem-
perature and fully characterized by NMR spectroscopy
and X-ray diffraction study.10b,c
As a part of the present palladium(0)-catalyzed cy-
clization of enyne esters, we briefly explored the cycliza-
tion of enediyne diesters 20 and 21 and enediyne esters
22. First, the cis-enediyne diester 20 was subjected to
the reaction under the same conditions as with that for
17. However, an intractable product mixture was ob-
1
and DMAD. Its H NMR showed the absorptions of the
methoxy groups as three singlets with an equal intensity
(δ 3.74, 3.75, and 3.79) and the methylene protons as
three sets of doublets (δ 2.36 and 2.59, J ) 16.8 Hz; δ
2.79 and 3.62, J ) 9.2 Hz; δ 4.08 and 4.64, J ) 19.8 Hz).
During the reaction, a palladacyclopentadiene 1c must
be generated from 1a and DMAD.12 In fact, hexamethyl
mellitate 12, which was formed via 1c, was obtained in
40% yields based on DMAD. With this fact in mind, the
reaction was also conducted using 1c as a precatalyst.
As a result, a similar product distribution was observed,
although the sluggish reaction reduced the total isolated
yield (Scheme 10, run 2). On the contrary, 1c/P(OPh)3
gave rise to only the six-membered ring products 4bb
and 6bb in the absence of DMAD (Scheme 10, run 3).
These results indicate that the formation of 10 and 11
requires a [Pd(0)-P(OPh)3] species and DMAD.
(23) The alternative palladium(II) hydride mechanism was proposed;
see ref 16.
(24) (a) Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J . Org. Chem.
2000, 65, 4913-4918. (b) Inoue, H.; Chatani, N.; Murai, S. J . Org.
Chem. 2002, 67, 1414-1417. (c) Fu¨rstner, A.; Mamane, V. J . Org.
Chem. 2002, 67, 6264-6267. (d) Fu¨rstner, A.; Mamane, V. Chem.
Commun. 2003, 2112-2113. (e) Pastine, S. J .; Youn, S. W.; Sames, D.
Org. Lett. 2003, 5, 1055-1058. (f) Pastine, S. J .; Sames, D. Org. Lett.
2003, 5, 4053-4055. (g) Pastine, S. J .; Youn, S. W.; Sames, D.
Tetrahedron 2003, 59, 8859-8868.
(22) It was reported for the related enyne metathesis that the
methylene protons of five-membered ring products generally appeared
at lower fields than those of six-membered ring products (Kitamura,
T.; Sato, Y.; Mori, M. Adv. Synth. Catal. 2002, 344, 678-693.).
6702 J . Org. Chem., Vol. 69, No. 20, 2004

Pd(0)-Catalyzed Cyclization of Enyne and Enediyne Esters
SCHEME 10
SCHEME 11
F IGURE 2. Triyne diester 17 and its Pd(0) complex 19,
cyclization product 18, and enediyne esters 20-22 (E ) CO2-
Me).
SCHEME 13
SCHEME 12
SCHEME 14
tained. In contrast, the trans-isomer 21 was similarly
heated in the refluxing toluene containing 1b/2PPh3 (5
mol % Pd) for 2.5 h to give nearly equal amounts of
cyclized products 23 and 24 as an inseparable mixture
in 36% combined yield (Scheme 13). The stoichiometric
reaction of 1b with 1.4 equiv of 21 was also carried out
in acetone at room temperature to obtain 23 in 12% yield
together with trace amounts of white solid (Scheme 14).
allows us to assign 23 to the symmetrical 1,3-cyclohexa-
diene, which is directly formed via [2 + 2 + 2] cyclization
of 21. Although the spectral data of the pure 24 were not
available, its unsymmetrical structure is deduced from
the 13C NMR measurement of the mixture of 23 and 24.
Total fourteen signals were observed for 24. The conju-
gated and nonconjugated carbonyl signals appeared at δ
165.54 and 171.10, respectively. The olefinic carbons
conjugated with the methoxycarbonyl group were ob-
served at δ 117.14 and 156.10, while the isolated alkene
carbons resonated at δ 129.47 and 129.50. These data
suggested that 24 has a 1,4-cyclohexadiene ring with one
enoate moiety.
The cyclization products were characterized as follows.
The 1H NMR spectrum of 23 shows only one singlet peak
of the methoxy group as well as a pair of doublets and
three broad multiplet peaks, indicative of its highly
symmetrical structure. This was also supported by its 13
C
NMR data. One carbonyl (δ 165.20) and two olefinic (δ
155.58 and 120.34) signals are observed with four upfield
peaks (δ 45.34, 51.81, 70.20, and 72.73). These data
J . Org. Chem, Vol. 69, No. 20, 2004 6703

Yamamoto et al.
TABLE 4. Com p a r ison of Sp ectr a l Da ta for 17, 19, 21, a n d 25
17
19
21
22
IR (cm-1
13C NMR δ (ppm)
)
2239 (CtC)
78.03 (CtC)
82.02 (CtC)
82.45 (CtC)
153.13 (CdO)
1977 (CtC)
72.90 (CtC)
75.75 (CtC)
89.69 (CtC)
160.80 (CdO)
2251 (CtC)
77.74 (CtC)
83.36 (CtC)
129.06 (CdC)
153.24 (CdO)
1970 (CtC)
77.21 (CtC)
88.22 (CtC)
94.08 (CdC)
160.66 (CdO)
SCHEME 15
cycloisomerizations to furnish five-membered ring prod-
ucts. As an extension of these enyne ester cyclizations,
we also examined the palladium(0)-catalyzed reactions
of some enediyne esters to obtain intramolecular [2 + 2
+ 2] cyclocotrimerization products.
Exp er im en ta l Section
Typ ica l P r oced u r e for Cyclod im er iza tion of En yn e
E st er s: Cyclod im er iza t ion of 2a a Usin g P d 2(d b a )3 a s
P r eca ta lyst. A solution of 2a a (77 mg, 0.50 mmol) and Pd2-
(dba)3‚CHCl3 (13 mg, 0.013 mmol) in dry degassed benzene (5
mL) was refluxed under Ar for 4 h. The solvent was then
evaporated, and the crude product was purified by silica gel
flash column chromatography (hexane/AcOEt ) 9:1) to give
Whereas no single-crystal suitable for X-ray diffraction
study was obtained, the white solid obtained from the
stoichiometric reaction was assigned to a palladium(0)
enediyne complex 25 by comparison of its spectral data
with those of the triyne complex 19 as well as the parent
triyne diester 17 and the enediyne diester 21 (Table 4).
In the IR spectra of 17 and 21, the CtC stretching
vibration appeared at around 2000 cm-1, which was
shifted to around 1970 cm-1 in 19 and 25. In the 13C NMR
spectrum of 17, three Csp signals were observed at δ
78.03, 82.02, and 82.45. Upon formation of 19, two of
them moved upfield to δ 72.90 and 75.75, and one shifted
downfield to δ 89.69. A similar correlation in the 13C
chemical shifts was observed for 21 and 25. The alkyne
and alkene carbons were observed at δ 77.74 and 83.36
(CtC) and 129.06 (CdC) in 21, while they moved to δ
77.21 and 88.22 (CtC) and 94.08 (CdC) in 25. The
downfield shifts were observed for the carbonyl carbons
from 17 and 21 (δ ∼153) to 19 and 25 (δ ∼160). The
structural assignment of 25 as the enediyne complex was
also supported by FAB mass measurement (M+ m/z 386)
and elemental analysis.
The enediyne esters involving a 1,6-diyne unit were
also explored as substrates for the intramolecular [2 + 2
+ 2] cyclocotrimerization. In the presence of 1b/2PPh3
(5 mol % Pd), 22a was heated in refluxing toluene for 1
h to afford the expected cyclohexadienecarboxylate 26a
in 71% yield as a sole product (Scheme 15). The cycliza-
tion of the corresponding methallyl derivative 22b com-
pleted within 20 min to give a similar product 26b in
81% yield. The higher efficiencies of 22a ,b than 21 are
attributed to their 1,6-diyne moieties, which undergo
facile oxidative cyclization.
1
3a a (48 mg, 64%) as colorless oil: IR (CHCl3) 1719 cm-1; H
NMR (300 MHz, CDCl3) δ 1.92-2.05 (m, 1 H), 2.91 (dd, J )
15.3, 6.6 Hz, 1 H), 2.95-3.07 (m, 1 H), 3.41 (dd, J ) 9.6, 8.7
Hz, 1 H), 3.75 (s, 3 H), 3.77 (s, 3 H), 3.79-3.83 (m, 1 H), 3.87
(dtq, J ) 12.3, 5.4, 1.5 Hz, 1 H), 4.35 (t, J ) 8.4 Hz, 1 H), 4.50
(dd, J ) 17.4, 2.4 Hz, 1 H), 4.53 (dd, J ) 13.8, 3.9 Hz, 1 H),
4.94 (dd, J ) 13.8, 1.5 Hz, 1 H), 4.93 (d, J ) 17.4 Hz, 1 H),
5.13 (dq, J ) 10.5, 1.5 Hz, 1 H), 5.21 (dq, J ) 17.1, 1.5 Hz, 1
H), 5.83 (ddt, J ) 17.4, 10.5, 5.4 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 26.7, 41.3, 51.7, 51.9, 67.8, 70.7, 71.6, 73.6, 116.9,
121.6, 124.2, 134.2, 144.4, 158.5, 165.9, 167.2; MS (FAB) m/z
309 (24) [MH+], 277 (41) [M+ - OMe], 251 (100) [M+ - OCH2-
CHdCH2]. Anal. Calcd for C16H20O6 (308.33): C, 62.33; H, 6.54.
Found: C, 62.29; H, 6.58.
Other cycloadducts were obtained similarly. The yields and
the reaction conditions are summarized in Table 1.
Typ ica l P r oced u r e for Cycloisom er iza tion s of En yn e
Ester s: Cycloisom er iza tion of 2a b Usin g P d 2(bq)2(n be)2
a n d P (OP h )3. A solution of 2a b (84 mg, 0.50 mmol), Pd2(bq)2-
(nbe)2 (8 mg, 0.013 mmol), and P(OPh)3 (8 mg, 0.026 mmol) in
dry degassed 1,2-dichloroethane (5 mL) was refluxed under
Ar for 12 h. The solvent was then evaporated, and the crude
product was purified by silica gel flash column chromatography
(hexane/AcOEt ) 10:1) to give 4a b (48 mg, 57%) as a colorless
solid (mp 56.9-57.7 °C): IR (CHCl3) 1708, 1637 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.83 (s, 3 H), 3.70 (s, 3 H), 4.13-4.16 (m,
2 H), 4.19-4.21 (m, 2 H), 5.37 (br s, 1 H), 7.35-7.37 (m, 1 H);
13C NMR (75 MHz, CDCl3) δ 15.2, 46.7, 64.3, 65.0, 104.5, 114.5,
141.2, 143.0, 162.3; MS (FAB): m/z 167 (100) [M+ - H]. Anal.
Calcd for C9H12O3 (168.19): C, 64.27; H, 7.19. Found: C, 63.98;
H, 6.91.
Other cycloisomerization reactions were carried out in a
similar manner. 5,4a 8bf,17 and 9bf17 were known compounds.
Typ ica l P r oced u r e for Rea ction of 2bb w ith DMAD.
A solution of 2bb (151 mg, 0.470 mmol), DMAD (142 mg, 1.00
mmol), Pd2(bq)2(nbe)2 (14.6 mg, 0.0237 mmol), and P(OPh)3
(14.6 mg, 0.0470 mmol) in dry degassed 1,2-dichloroethane (5
mL) was refluxed under Ar for 24 h. The solvent was then
evaporated, and the crude product was purified by silica gel
flash column chromatography (hexane/AcOEt ) 30:∼3:1) to
give 4bb (28.8 mg, 19%), 10 (23.2 mg, 15%), 11 (54.5 mg, 25%),
and 12 (79.9 mg, 40%).
Con clu sion s
We have explored the palladium(0)-catalyzed reactions
of 1,6-enyne esters. In the absence of an extra ligand,
Pd2(dba)3 or Pd2(bq)2(nbe)2 catalyzed the cyclodimeriza-
tion of enyne esters. On the other hand, the enyne esters
underwent cycloisomerizations with triphenyl phosphite
to give rise to various products depending on the substi-
tution pattern of the olefin termini. When enyne esters
bearing a methallyl moiety were used, uncommon six-
membered ring products were predominantly formed
with concomitant enyne metathesis products. In contrast,
other enyne esters having a cinnamyl, a prenyl, or a
cyclohexenylmethyl moiety selectively underwent normal
1
An a lytica l d a ta for 10: IR (CHCl3) 1721, 1163 cm-1; H
NMR (300 MHz, CDCl3) δ 1.60-1.61 (m, 3 H), 2.43 (s, 3 H),
3.74 (s, 3 H), 4.07-4.10 (m, 2 H), 4.25-4.29 (m, 2 H), 5.55 (d,
J ) 1.4 Hz, 1 H), 6.32 (d, J ) 1.4 Hz, 1 H), 7.33 (d, J ) 8.1 Hz,
2 H), 7.74 (d, J ) 8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
6704 J . Org. Chem., Vol. 69, No. 20, 2004

Pd(0)-Catalyzed Cyclization of Enyne and Enediyne Esters
12.6, 21.6, 52.2, 57.3, 59.0, 127.3, 127.4, 128.8, 129.6, 132.6,
133.8, 134.0, 143.3, 166.0; MS (EI) m/z 321 (68) [M+], 306 (11)
[M+ - Me], 246 (68) [M+ - H - Me - CO2Me], 166 (100) [M+
- SO2C6H4Me]; This compound is unstable and slowly de-
composes even at -15 °C. Thus, satisfactory elemental ana-
lytical values were not obtained. Anal. calcd for C16H19NO4S
(321.39): C, 59.79; H, 5.96; N, 4.36. Found: C, 59.42; H, 6.16;
N, 3.90.
165.5, 171.1; MS (FAB) m/z 277 (67) [M+ - 3H], 247 (100) [M+
- 2H - OMe]. Anal. Calcd for C14H16O6 (280.27): C, 59.99; H,
5.75. Found: C, 59.97; H, 5.77.
The cyclization of 22a ,b was carried out in a similar manner.
Stoich iom etr ic Rea ction of P d 2(d ba )3 w ith En ed iyn e
Diester 21. A solution of 21 (112 mg, 0.40 mmol) and Pd2-
(dba)3‚CHCl3 (145 mg, 0.14 mmol) in dry degassed acetone (4
mL) was stirred under Ar for 5 h. The solvent was then
evaporated, and the crude product was diluted with ether.
Insoluble materials were filtered off through a pad of Celite
under reduced pressure, and the residue was rinsed with ether.
During the filtration, white solids were precipitated which
were separated by filtration to give 25 (4 mg, 3.7% based on
1b). The filtrate was evaporated in vacuo, and the residue was
purified by silica gel flash column chromatography (hexane/
AcOEt ) 5:1-1:1) to give recovered 21 (11 mg, 10%) and 23
(14 mg, 12%).
An a lytica l d a ta for 11: mp 160.0-161.1 °C; IR (CHCl3)
1
1724, 1163 cm-1; H NMR (300 MHz, CDCl3) δ 1.18 (s, 3 H),
2.36 (d, J ) 16.8 Hz, 1 H), 2.44 (s, 3 H), 2.59 (d, J ) 16.8 Hz,
1 H), 2.79 (d, J ) 9.2 Hz, 1 H), 3.62 (d, J ) 9.2 Hz, 1 H), 3.74
(s, 3 H), 3.75 (s, 3 H), 3.79 (s, 3 H), 4.08 (d, J ) 19.8 Hz, 1 H),
4.64 (d, J ) 19.8 Hz, 1 H), 7.36 (d, J ) 8.1 Hz, 2 H), 7.73 (d,
J ) 8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 20.7, 21.7, 34.0,
44.0, 52.2, 52.4, 52.5, 60.2, 65.1, 119.0, 127.3, 127.6, 129.8,
132.4, 134.2, 144.0, 161.4, 163.6, 166.4, 167.3; MS (EI) m/z 463
(23) [M+], 431 (58) [M+ - H - OMe], 404 (46) [M+ - CO2Me],
276 (100) [M+ - H-OMe - SO2C6H4Me]. Anal. Calcd for
An a lytica l d a ta for 25: mp 145.0-146.0 °C; IR (CHCl3)
1970, 1710, cm-1; 1H NMR (300 MHz, CDCl3) δ 3.03-3.13 (m,
2 H), 3.86 (s, 6 H), 3.99 (d, J ) 15.5 Hz, 2 H), 4.19-4.22 (m,
C
22H25NO8S (463.50): C, 57.01; H, 5.44; N, 3.02. Found: C,
56.81; H, 5.49; N, 2.95.
2 H), 4.85 (d, J ) 14.4 Hz, 2 H), 5.12 (d, J ) 15.5 Hz, 2 H); 13
C
Typ ica l P r oced u r e for Cycliza tion s of En ed iyn e Es-
ter s: Cycliza tion of 21 Usin g P d 2(d ba )3 a n d P P h 3. A
solution of 21 (200 mg, 0.71 mmol), Pd2(dba)3‚CHCl3 (18.5 mg,
0.018 mmol), and PPh3 (9.4 mg, 0.036 mmol) in dry degassed
toluene (7 mL) was refluxed under Ar for 2.5 h. The solvent
was then evaporated, and the crude product was purified by
silica gel flash column chromatography (hexane/AcOEt ) 3:1)
to give a mixture of 23 and 24 (73 mg, 36%) as a pale yellow
NMR (75 MHz, CDCl3) δ 52.7, 54.5, 68.0, 77.2, 88.2, 94.1,
160.7; MS (FAB) m/z 386 (100) [M+], 355 (50) [M+ - OMe].
Anal. Calcd for
C14H16O6Pd (386.69): C, 43.48; H, 4.17.
Found: C, 43.22; H, 4.08.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the Ministry of Education, Cul-
ture, Sports, Science and Technology, J apan. Y.Y.
thanks Dr. Manabu Hatano for helpful discussions.
1
oil: IR (CHCl3) 1719 cm-1; H NMR (300 MHz, CDCl3) [23] δ
2.91-2.98 (m, 2 H), 3.42-3.49 (m, 2 H), 3.76 (s, 6 H), 4.28-
4.33 (m, 2 H), 4.52 (d, J ) 17.4 Hz, 2 H), 4.98 (d, J ) 17.4 Hz,
2 H), [24] δ 3.39-3.40 (m, 2 H), 3.72 (s, 3 H), 3.76 (s, 3 H),
4.10-4.15 (m, 1 H), 4.23 (br s, 1 H), 4.46-4.51 (m, 1 H), 4.57-
4.61 (m, 1 H), 4.67-4.73 (m, 1 H), 4.80 (dd, J ) 10.5, 1.8 Hz,
1 H), 4.90 (dt, J ) 10.5, 1.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
[23] δ 45.3, 51.8, 70.2, 72.7, 120.3, 155.6, 165.2, [24] δ 41.7,
43.8, 52.0, 52.5, 69.3, 70.4, 75.6, 75.7, 117.1, 129.5, 129.5, 156.1,
Su p p or tin g In for m a tion Ava ila ble: Analytical data for
starting materials and products. X-ray crystallographic analy-
sis data for 3ba , 4bb, 6bb, 4be, 6be, 7bc, and 10bh and CIF
files. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O049072P
J . Org. Chem, Vol. 69, No. 20, 2004 6705