Palladium-catalyzed cyclization of 1-iodo-substituted 1,4-, 1,5-, and 1,6-dienes as well as 5-iodo-1,5-dienes in the presence of carbon monoxide

Article abstract of DOI:10.1021/ja9533205

A series of ω-alkene-containing alkenyl iodides were prepared via (a) various allyl-, homoallyl-, and higher ω-alkenylmetalation reactions of alkynes involving Zn, Al-Zr, Zn-Zr, and Cu, (b) trans-hydroalumination and Cu-catalyzed trans-carbomagnesiation of propargyl alcohols, and (c) Zr-promoted alkyne-alkene coupling. Various factors affecting three cyclic acylpalladation (Types I-III Ac-Pd) and three cyclic carbopalladation (Types I-III C-Pd) processes of the ω-alkene-containing alkenyl iodides under the influence of CO and Pd-phosphine catalysts have been delineated. In the presence of methanol or other alcohols at relatively high pressures (30-100 atm) of CO (Conditions IV), Type II Ac-Pd products containing five-membered ketones, such as 22, 26-28, 30, and 32, can be obtained generally in high yields. The order of rates of various carbonylative cyclization reactions producing five-membered rings is as follows: lactonization > Type II Ac-Pd reaction > C-enolate trapping with malonate anion. The preparation of six-membered ketones via the Type II Ac-Pd process is less satisfactory. Attempts to prepare seven-membered ketones failed, and no attempts were made to obtain small ring ketones. In the absence of an external nucleophile (Conditions I and II), α-alkylidenecyclopentanones can be obtained in high yields via the Type I Ac-Pd process in cases where the ω-alkenyl group is 1,2-disubstituted. Terminal vinyl-containing 1,4-pentadienyl iodides can give Type I Ac-Pd products, e.g., 31, 33, 35, 56-58, and 65, in moderate to good yields only with the stoichiometric amount of a Pd-phosphine complex. In sharp contrast, 1,5-hexadienyl iodides give predominantly Type III Ac-Pd products, e.g., 5, 60, 63, and 64, in moderate yields under comparable conditions. The Type III Ac-Pd products can be cleanly converted to the corresponding Type II Ac-Pd products via alcoholysis. At 1 atm of CO in the presence of an alcohol (Conditions III), noncarbonylative cyclic carbopalladation process (Types I-III C-Pd) can be observed along with premature esterification. With terminal vinyl-containing alkenyl iodides, the cyclic Heck reaction (Type I C-Pd) is the dominant path. In cases where the ω-alkenyl group is 1,1-disubstituted, however, the Type II C-Pd process can be observed selectively using either i-PrOH as an external nucleophile or a mixture consisting of H₂O, MeOH, and DMF (1:10:20). Collectively, the three Ac-Pd processes and the Type II C-Pd process in conjunction with novel and efficient methods for the preparation of the required ω-alkene-containing alkenyl iodides provide a potentially useful methodology for the preparation of five- and six-membered-ring compounds.

Full text of DOI:10.1021/ja9533205

J. Am. Chem. Soc. 1996, 118, 5919-5931
5919
Palladium-Catalyzed Cyclization of 1-Iodo-Substituted 1,4-,
1,5-, and 1,6-Dienes as Well as of 5-Iodo-1,5-dienes in the
Presence of Carbon Monoxide
Ei-ichi Negishi,* Shengming Ma, John Amanfu, Christophe Cope´ret,
Joseph A. Miller, and James M. Tour
Contribution from the Department of Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
ReceiVed September 29, 1995X
Abstract: A series of ω-alkene-containing alkenyl iodides were prepared via (a) various allyl-, homoallyl-, and
higher ω-alkenylmetalation reactions of alkynes involving Zn, Al-Zr, Zn-Zr, and Cu, (b) trans-hydroalumination
and Cu-catalyzed trans-carbomagnesiation of propargyl alcohols, and (c) Zr-promoted alkyne-alkene coupling.
Various factors affecting three cyclic acylpalladation (Types I-III Ac-Pd) and three cyclic carbopalladation (Types
I-III C-Pd) processes of the ω-alkene-containing alkenyl iodides under the influence of CO and Pd-phosphine
catalysts have been delineated. In the presence of methanol or other alcohols at relatively high pressures (30-100
atm) of CO (Conditions IV), Type II Ac-Pd products containing five-membered ketones, such as 22, 26-28, 30, and
32, can be obtained generally in high yields. The order of rates of various carbonylative cyclization reactions producing
five-membered rings is as follows: lactonization > Type II Ac-Pd reaction > C-enolate trapping with malonate
anion. The preparation of six-membered ketones via the Type II Ac-Pd process is less satisfactory. Attempts to
prepare seven-membered ketones failed, and no attempts were made to obtain small ring ketones. In the absence of
an external nucleophile (Conditions I and II), R-alkylidenecyclopentanones can be obtained in high yields via the
Type I Ac-Pd process in cases where the ω-alkenyl group is 1,2-disubstituted. Terminal vinyl-containing 1,4-
pentadienyl iodides can give Type I Ac-Pd products, e.g., 31, 33, 35, 56-58, and 65, in moderate to good yields
only with the stoichiometric amount of a Pd-phosphine complex. In sharp contrast, 1,5-hexadienyl iodides give
predominantly Type III Ac-Pd products, e.g., 5, 60, 63, and 64, in moderate yields under comparable conditions.
The Type III Ac-Pd products can be cleanly converted to the corresponding Type II Ac-Pd products via alcoholysis.
At 1 atm of CO in the presence of an alcohol (Conditions III), noncarbonylative cyclic carbopalladation process
(Types I-III C-Pd) can be observed along with premature esterification. With terminal vinyl-containing alkenyl
iodides, the cyclic Heck reaction (Type I C-Pd) is the dominant path. In cases where the ω-alkenyl group is 1,1-
disubstituted, however, the Type II C-Pd process can be observed selectively using either i-PrOH as an external
nucleophile or a mixture consisting of H2O, MeOH, and DMF (1:10:20). Collectively, the three Ac-Pd processes
and the Type II C-Pd process in conjunction with novel and efficient methods for the preparation of the required
ω-alkene-containing alkenyl iodides provide a potentially useful methodology for the preparation of five- and six-
membered-ring compounds.
In the preceding paper1,2 we disclosed and discussed various
Pd-catalyzed reactions of ω-alkene-containing aryl halides via
cyclic acylpalladation under four different conditions shown
below: Conditions I, CO (1 atm), 5% Cl2Pd(PPh3)2, NEt3 (1.5-4
equiv); Conditions II, CO (30-100 atm), 5% Cl2Pd(PPh3)2, NEt3
(1.5-4 equiv); Conditions III, CO (1 atm), 5% Cl2Pd(PPh3)2,
NEt3 (1.5-4 equiv), ROH (R ) Me, Et, or i-Pr); and Conditions
IV, CO (30-100 atm), 5% Cl2Pd(PPh3)2, NEt3 (1.5-4 equiv),
ROH (R ) Me, Et, or i-Pr).
In short, the use of 30-100 atms of CO (Conditions II and
IV) is advantageous to induce cyclic acylpalladation (Ac-Pd).
In cases where the cyclic Ac-Pd process is favorable, the Type
I Ac-Pd reaction is dominant in the absence of an external
nucleophile, such as MeOH (Conditions II), while the use of a
suitable alcohol at 30-100 atm of CO (Conditions IV) induces
the Type II Ac-Pd reaction. In the absence of an external trap-
ping agent at 30-100 atm of CO (Conditions II), the Type III
Ac-Pd process can proceed and compete with the Type I Ac-
Pd process. The absence of an external trapping agent (Condi-
tions I and II) can also induce apparently polymeric processes3
as serious side reactions, especially with terminal alkene-
containing substrates, while premature alcoholysis of putative
acylpalladium intermediates can be competitive at 30-100 atm
of CO in the presence of an alcohol (Conditions IV). Both exo-
mode and endo-mode cyclization processes producing 5- and
6-membered Ac-Pd products have been observed. Neither
smaller nor larger rings have been obtained via cyclic Ac-Pd
reactions. In fact, attempts to obtain 7-membered Ac-Pd
products or, in some cases, even 6-membered Ac-Pd products
have led to non-carbonylative cyclic carbopalladation (C-Pd)
reactions. Both cyclic Heck reaction (Type I C-Pd process)
and Type II C-Pd reaction involving the cyclic carbopallada-
tion-carbonylative esterification tandem have been observed.
In the corresponding reaction of alkenyl halides some addi-
tional cyclization processes must be considered in addition to
the three Ac-Pd and two C-Pd reactions. Thus, one dienyl
iodide 1 gave 2 and 32b which were thought to arise via
[2 + 2] ketene cycloaddition (eq 1). In cases where cyclic C-Pd
X Abstract published in AdVance ACS Abstracts, June 1, 1996.
(1) Negishi, E.; Cope´ret, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M.
J. Am. Chem. Soc. Previous paper in this issue.
(2) For preliminary communications reporting some of the results
discussed herein, see: (a) Negishi, E.; Miller, J. A. J. Am. Chem. Soc. 1983,
105, 6761. (b) Tour, J. M.; Negishi, E. J. Am. Chem. Soc. 1985, 107, 8289.
(c) Negishi, E.; Tour, J. M. Tetrahedron Lett. 1986, 27, 4869. (d) Negishi,
E.; Sawada, H.; Tour, J. M.; Wei, Y. J. Org. Chem. 1988, 53, 913. (e)
Zhang, Y.; O’Connor, B.; Negishi, E. J. Org. Chem. 1988, 53, 5588.
reactions are observed even in the presence of CO, the Type
(3) (a) Tsuji, J.; Hosaka, S. J. Polym. Lett. 1965, 3, 705. (b) Sen, A.;
Lai, T. J. Am. Chem. Soc. 1982, 104, 3520.
S0002-7863(95)03320-8 CCC: $12.00 © 1996 American Chemical Society

5920 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Negishi et al.
Scheme 1
followed by halogenolysis provides one of the shortest and most
straightforward routes to the requisite dienyl halide precursors
(Scheme 3). Specifically, allylzincation of 1-octynyltrimethyl-
silane2a,d,7 provided 6. The preparation of 9 and 10 was
performed similarly using diallylzinc,2d while the Zr-catalyzed
allylalumination and allylzincation8 afforded 7 and 8. A recently
developed Zr-promoted alkyne-allyl coupling reaction9 also
offers an attractive route to dienyl halides although this reaction
was not used in this study. Stereo- and regiodefined 1,5-
hexadienyl halides, such as 1, are conveniently synthesized via
homoallylcupration of alkynes.10 Similarly, 11 was prepared
through the use of 4-pentenylmagnesium bromide. Trans-
hydroalumination with NaAlH2(OCH2CH2OCH3)2 (Red-Al) or
11
LiAlH4 and Cu-catalyzed trans-carbomagnesiation12 of pro-
pargyl alcohols followed by iodinolysis provide a variety of
appropriately stereodefined alkenyl iodides that either are or
are convertible into 1,4-pentaidenyl and 1,5-hexadienyl iodides
(Scheme 4). Thus, 12 was directly prepared by this process,
while 1,5-hexadienyl iodides, such as 4 and 13-15, were
prepared via allyl-allyl or allyl-propargyl coupling using either
allylmagnesium derivatives or â,γ-unsaturated enolates. Related
allylation reactions of enolates were employed to prepare 16a,
16b, and 17. Zirconium-promoted alkene-alkyne coupling13
followed by iodinolysis provides appropriately stereodefined 1,4-
diiodoalkenes convertible to various 1,5-hexadienyl iodides
(Scheme 5). For example, 18-21 were prepared via this
reaction followed by the Wittig reaction.
Pd-Catalyzed Cyclic Acylpalladation of ω-Alkene-Con-
taining Alkenyl Halides in the Presence of Methanol (Type
II Ac-Pd Process) (Table 1). A series of dienyl iodides
prepared as described above were treated with CO (30-100
atm) in the presence of 5 mol % of Cl2Pd(PPh3)2, NEt3 (1.5-4
equiv) and MeOH (4-100 equiv) at elevated temperatures
(Conditions IV) and the experimental results are summarized
in Table 1. Although varying amounts of NEt3 were used, any
excess of NEt3 beyond 1.5 equiv had relatively insignificant
effects. These results lead to the following generalizations. First,
as in the corresponding reaction of aryl halides, cyclic acylpal-
ladation may be observed only in those cases where the
formation of 5- and 6-membered rings with incorporation of
CO is possible. Whereas 8 and 1 were cleanly converted to
Type II Ac-Pd products 22 and 23, respectively, in excellent
yields (entries 1-1 and 1-2), 11 did not yield 24 to any detectable
extent (entry 1-3), the only major monomeric product being that
of premature esterification, i.e., 25. Second, in cases where
the ω-alkenyl group is the parent vinyl group, the desired Type
II Ac-Pd products containing a 5- and 6-membered ketone were
produced in good yields at 30-100 atm of CO in the presence
of MeOH (Conditions IV). Thus, cyclopentenone derivatives
22 and 26-28 were produced in 82-100% yields (entries 1-1
and 1-4 to 1-6), while the yields of cyclohexenone derivatives
23 and 29 were 73 and 50%, respectively (entries 1-2 and 1-7).
Although the number of examples of cyclohexanones is very
small, it does appear that formation of cyclopentanones is
generally more favorable than that of cyclohexanones. Third,
in cases where the ω-alkenyl group is additionally substituted
the Type I Ac-Pd process and premature esterification can be
Scheme 2
III C-Pd process involving cyclopropanation4 is also available
to alkenyl halides. Even within the category of acylpalladation
there can be significant differences between aryl and alkenyl
halides, as eloquently indicated by the results shown in Scheme
2.2e,5 It may be anticipated that alkenyl halides are generally
more prone to the Type III Ac-Pd reaction. With these
preliminary findings2 in mind we undertook to investigate the
Pd-catalyzed cyclization reactions of ω-alkene-containing alk-
enyl iodides under the influence of 1-100 atm of CO either in
the presence or absence of an external alcohol (Conditions
I-IV).
(7) Molander, G. A. J. Org. Chem. 1983, 48, 5409.
(8) Miller, J. A.; Negishi, E. Tetrahedron Lett. 1984, 25, 5863.
(9) Suzuki, N.; Kondakov, D. Y.; Kageyama, M.; Kotora, M.; Hara, R.;
Takahashi, T. Tetrahedron 1995, 51, 4519 and references therein.
(10) (a) Normant, J. F.; Bourgain, M. Tetrahedron Lett. 1971, 2583. (b)
Westmijze, H.; Kleijn, H.; Meijer, J.; Vermeer, P. Tetrahedron Lett. 1977,
869.
Results and Discussion
Preparation of ω-Alkene-Containing Alkenyl Iodides. Cis-
carbometalation of alkynes with allyl- and homoallylmetals6
(11) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem.
Soc. 1967, 89, 4245.
(4) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem.
Soc. 1992, 114, 10091.
(5) Negishi, E.; Cope´ret, C.; Sugihara, T.; Shimoyama, I.; Zhang, Y.;
Wu, G.; Tour, J. M. Tetrahedron 1994, 50, 425.
(12) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168,
1.
(13) (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A. J. Am.
Chem. Soc. 1985, 107, 2568. (b) Takahashi, T.; Kageyama, M.; Denisov,
V.; Hara, R.; Negishi, Tetrahedron Lett. 1993, 34, 687.
(6) Normant, J. F.; Alexakis, A. Synthesis 1981, 841.

Pd-Catalyzed Cyclization of 1-Iodo-Substituted Dienes
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5921
Scheme 3
serious side reactions. Furthermore, the Type II Ac-Pd/Type I
Ac-Pd ratio is very much dependent on CO pressure, solvents,
amount of an external nucleophile, e.g., MeOH, and substitution
pattern. Thus, the results obtained with 19 indicate that the
ratio of 30 to 31 is 53/45 (entry 1-8) at 40 atm of CO in DMF,
but that the yield of 30 can be improved to 93% in DMF-
MeOH (1:1) at 100 atm of CO (entry 1-10) at which pressure
the amount of 31 was 5%. Similar results were also obtained
with 20 (entries 1-11 and 1-12). In the reaction of 21 containing
a trisubstituted ω-alkenyl group, however, the yields of 34 and
35 were 30 and 66%, respectively, corresponding to the Type
II/Type I Ac-Pd ratio of 0.7 even at 100 atm of CO (entry 1-13).
Whereas cyclopentenones can be formed in moderate to high
yields even in cases where the ω-alkenyl group is di- and
trisubstituted (entries 1-8 to 1-13), related reactions leading to
the formation of cyclohexenones are more sluggish and less
clean (entries 1-14 to 1-16). In these cases, premature esteri-
fication is one of the main side reactions, and some other
unidentified byproducts were also formed. The yields of the
desired Type II Ac-Pd products, e.g., 37, 39, and 42, are low
(<30-35%). However, some such compounds may be obtained
in higher yields by an indirect route via Type III Ac-Pd products
(Vide infra).
Scheme 4
To further probe the scope of the Type II Ac-Pd reaction,
specifically its chemoselectivity aspect, the Pd-catalyzed reaction
of 12 and 16b using 40 atm of CO, 10 equiv of MeOH, and
DMF as a solvent (Conditions IV) was examined. For the sake
of comparison, the corresponding reaction of 16a was also
investigated. As the results summarized in Scheme 6 indicate,
the Type II Ac-Pd reaction of 12 to give 43 cannot compete
with premature intramolecular esterification to give a lactone
44 (87% yield). On the other hand, the corresponding reaction
of 16b gave the Type II Ac-Pd product 45 without yielding the
product of trapping by the C-enolate,14 i.e., 46. As expected
from the above, lactonization to produce 47 (E/Z ) 2)
completely overshadowed C-enolate trapping to give 48.
Although the position of the iodine-bearing double bond in each
of the three test substrates is not totally neutral with respect to
the two competing processes, it appears reasonable to tentatively
conclude that the order of relative rates of the three processes
is the following: lactonization > Type II Ac-Pd reaction >
C-enolate trapping.
Type II Cyclic Carbopalladation of 1-Iodo-1,5-hexadienes
and 1-Iodo-1,7-heptadienes (Type II C-Pd Process) (Table
2). As discussed above, our earlier attempts to observe the
formation of 7-membered enones via the cyclic Ac-Pd process
led only to the formation of premature esterification product,
such as 25 (entry 1-3), and other unidentified products. Further
investigation with 49 and 17 has indicated, whereas cyclic
acylpalladation leading to the formation of cycloheptenones may
not be observed, other interesting and potentially useful cyclic
processes can be observed at lower pressures of CO. Specif-
ically, treatment of 49 with 1 atm of CO, a 2/1 mixture of DMF,
and MeOH at 85 °C for 50 h (Conditions III) merely led to the
formation of the cyclic Heck reaction15 (Type I C-Pd) products
50a and 50b in 54% combined yield (50a/50b ) 2-3) without
incorporation of either CO or MeOH (eq 2). In fact, very similar
results were obtained in the absence of CO and MeOH.
Evidently a putative intermediate 51 undergoes â-dehydropal-
ladation with exclusion of other potentiall competitive
processes.
Scheme 5
In sharp contrast, the corresponding reaction of 17 presumably
gives initial carbopalladation products containing no â-hydrogen,
which can be further converted to 52, 53, and/or 54, as
summarized in Table 2. As expected from similar results
reported earlier,4 17 gives the Type III C-Pd product 53 in 75%
yield in the absence of CO and MeOH (entry 2-8). At 1 atm
of CO and the heating bath temperature of ca. 65 °C in MeOH,

5922 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Negishi et al.
Table 1. Pd-Catalyzed Carbonylation of ω-Alkene-Containing Alkenyl Iodides in the Presence of Methanol at 30-100 atm of CO
(Conditions IVa)
a See text. b NMR yield. The second number in parentheses is the isolated yield. c <2%, if any. d Not determined. e By GLC. f A 60/40 mixture
of two diastereomers. g K2CO3 (2 equiv) was used as a base in place of NEt3. h A 54/46 mixture of two diasteromers. i Only the E isomer was
detected. j An 90/10 mixture of the two diasteromers. k 35a: exo, 35b: endo.

Pd-Catalyzed Cyclization of 1-Iodo-Substituted Dienes
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5923
Scheme 6
Table 2. Pd-Catalyzed Reaction of 2-Methyl-4,4-bis(methoxycarbonyl)-7-iodo-1,6-undecadiene in the Presence of CO and Alcohols.
a Heating bath temperature. b By NMR. The numbers in parentheses are isolated yields. c Listed for comparison. For similar results, see ref. 4.
where no vigorous boiling of MeOH was observed, the
premature esterification product 54a was obtained in 82% yield
along with an 18% yield of 52a (entry 2-1). At somewhat higher
bath temperature, where vigorous refluxing was observed, the
desired 52a became the major product (52%), but 53 and 54a
were also formed to the extent of 23 and 22% yields,
respectively (entry 2-2). In order to suppress premature
esterification, MeOH was replaced with EtOH and i-PrOH. With
the latter as both trapping agent and solvent, the yields of 52c,
53, and 54c were 64, 10, and 6%, respectively (entry 2-5).
Similar results were obtained using a DMF-MeOH mixture
(2/1 by volume) (entry 2-6). However, by far the most
satisfactory results were obtained with a medium consisting of
DMF, MeOH, and H2O in a 20/10/1 ratio. The yield of the
Type II C-Pd product16,17 52a was 81%, and those of 53 and
54a were e2-3% (entry 2-7). In summary, it now is possible
to produce selectively and in high yield 52, 53, or 54 from 17.
of vinylcyclopropanes or ring-expanded “apparent” endo-mode
carbopalladation products.4,18 The results summarized in Table
2 now indicate that, in the presence of CO (1 atm) and a suitable
alcohol, e.g., MeOH, cyclic carbopalladation, i.e., the Type II
C-Pd process, can be achieved with nearly complete suppression
of cyclopropanation and premature esterification. Although
somewhat less clean, similar results were also observed with
14 (eq 3).
Pd-Catalyzed or Pd-Promoted Cyclic Acylpalladation of
ω-Alkene-Containing Alkenyl Halides in the Absence of
External Nucleophiles (Type I and Type III Ac-Pd Processes)
(Table 3). The first example of the Type I Ac-Pd reaction of
(14) Negishi, E.; Zhang, Y.; Shimoyama, I.; Wu, G. J. Am. Chem. Soc.
1989, 111, 8018.
(15) For a review, see: Heck, R. F Org. React. 1982, 27, 345.
(16) (a) Zhang, Y.; Negishi, E. J. Am. Chem. Soc. 1989, 111, 3454. (b)
Sugihara, T.; Cope´ret, C.; Owczarczyk, Z.; Harring, L. S.; Negishi, E. J.
Am. Chem. Soc. 1994, 116, 7923.
(17) (a) Grigg, R.; Kennewell, P.; Teasdale, A. J. Tetrahedron Lett. 1992,
33, 7789. (b) Grigg, R.; Redpath, J.; Sridharan, V.; Wilson, D. Tetrahedron
Lett. 1994, 35, 4429.
Cyclopropanation of homoallylpalladium derivatives has been
identified as one of the major side reactions in the cyclic
carbopalladation involving the interaction of alkenylpalladiums
with 1,1-disubstituted alkenes, which can lead to the formation
(18) Negishi, E. Pure Appl. Chem. 1992, 64, 323.

5924 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Negishi et al.
competitive premature esterification, the above-mentioned se-
quence consisting of the Type III Ac-Pd process and metha-
nolysis provides a potentially attractive alternative.
ω-alkene-containing alkenyl halide reported by us in 19832a in-
volved the conversion of 6 into 56 (eq 4). Under the conditions
Conclusions
1. The Pd-catalyzed reaction of ω-alkene-containing alkenyl
iodides in the presence of CO can lead to three types of cyclic
acylpalladation (Types I-III Ac-Pd) and three types of cyclic
carbopalladation (Types I-III C-Pd) processes in addition to
previously known noncyclic carbonylative esterification and
polymerization processes. Although [2 + 2] ketene cycload-
dition has been observed with one alkenyl iodide, i.e., 1, using
Pd(OAc)2 as a catalyst, this process is not competitive in cases
where Pd-phosphine complexes are used as catalysts.
used, the reaction was only stoichiometric in Pd. Several years
later, we obtained another example of the Type I Ac-Pd reaction
shown in Scheme 2, which turned out to be catalytic in Pd.2e,5
Another point of interest is to examine the extent to which the
Type III Ac-Pd process competes with the Type I Ac-Pd process.
The results shown in Scheme 2 suggest that alkenyl halides are
more prone to the Type III Ac-Pd process than the corresponding
aryl halides. The third objective of this part of the study is to
probe the scope of the [2 + 2] ketene cycloaddition, which was
observed with most of the benzylic halides examined to date,19
as well as with 1.
2. In the presence of methanol or other alcohols at relatively
higher pressures (30-100 atm) of CO (Conditions IV), Type
II Ac-Pd products containing five-membered ketones can be
obtained generally in high yields. The order of rates of various
carbonylative cyclization reactions producing various types of
five-membered rings is the following: lactonization > Type II
Ac-Pd reaction > C-enolate trapping with malonate anion.
Conversion of 1,5-hexadienyl iodides into six-membered-ring
ketones is less satisfactory, the observed yields being e50%,
except for that of 23 which was obtained in 73% yield.
Attempts to obtain seven-membered-ring ketones totally failed,
and no attempts were made to obtain small-ring ketones.
3. In the absence of an alcohol or any external nucleophile
(Conditions I and II), a considerably different reaction profile
has emerged. Thus, 1,4-pentadienyl iodides containing the
parent vinyl group can be converted to Type I Ac-Pd products
in moderate to good yields only with a stoichiometric amount
of a Pd-phosphine catalyst. On the other hand, those containing
a 1,2-disubstituted alkene can be converted to Type I Ac-Pd
products in high yields under catalytic conditions. Interestingly,
1,5-hexadienyl iodides do not give Type I Ac-Pd products in
significant yields. Under similar conditions, the predominant
course of reaction is the Type III Ac-Pd process, although the
observed yields have been generally modest (e67%).
4. At 1 atm of CO in the presence of an alcohol (Conditions
III), three noncarbonylative cyclic carbopalladation processes,
as well as the Type II Ac-Pd process and premature esterifi-
cation, compete. At relatively high temperatures the Type II
Ac-Pd process leading to the formation of six-membered-ring
ketones can be suppressed. In cases where the ω-alkenyl group
is the parent vinyl group, the Type I C-Pd process, i.e., cyclic
Heck reaction, along with premature esterification, is the
dominant path. On the other hand, in cases where the ω-alkenyl
group is a 1,1-disubstituted alkene, the Type II C-Pd process
can take place selectively by supressing premature esterification
and cyclopropanation (Type III C-Pd process). Although the
use of i-PrOH in place of MeOH in conjunction with high
reaction temperatures is effective in observing the Type II C-Pd
process, the most satisfactory conditions observed to date
involve the use of a 1:10:20 mixture of H2O, MeOH, and DMF.
A series of ω-alkene-containing alkenyl iodides were carbo-
nylated under Conditions II (40-100 atm of CO in the absence
of nucleophiles), and the results are summarized in Table 3.
Also included in Table 3 are the results of carbonylation of 6,
7, 9, and 18 with 1 atm of CO in the presence of the
stoichiometric amount of Pd(PPh3)4 (entries 3-1 to 3-4). With
5-20 mol % of a Pd-phosphine catalyst, these substrates were
converted to monomeric cyclic products only in low yields. For
example, 18 was converted to 65 in e21% yields (entries 3-5
to 3-7). On the other hand, di- or trisubstituted alkene-
containing substrates 19-21 can be converted to the corre-
sponding Type I Ac-Pd products, i.e., 31, 33, and 35, respec-
tively, in moderate to excellent yields (entries 3-10 to 3-12).
No other monomeric cyclic products, such as Type III Ac-Pd
products, are formed in significant yields. Interestingly, 1,5-
hexadienyl iodides, i.e., 4 and 13-15, afforded under similar
conditions Type III Ac-Pd products, i.e., 5, 60, 63, and 64,
respectively, in moderate to good yields (entries 3-9, 3-13, and
3-16 to 3-18). In these reactions, the yields of the Type I Ac-
Pd products were less than 5%, except that of 41 (34%) (entry
3-18). The contrasting behavior exhibited by 1,4-pentadienyl
and 1,5-hexadienyl iodides may be attributable to the greater
strain energy associated with γ-lactones containing a bicyclo-
[3.3.0]octane framework than that in γ-lactones containing a
bicyclo[4.3.0]nonane framework. In cases where Pd(PPh3)4 or
Cl2Pd(PPh3)2 was used as a catalyst, the extent of [2 + 2] ketene
cycloaddition was negligible. However, carbonylation of 1
using Pd(OAc)2 as a catalyst did produce 2 in 36% isolated
yield along with a minor amount of 3 (entry 3-14).
It is worth noting that treatment of 63 with NaOMe in MeOH
cleanly gave 37 in 85% yield (eq 5). The use of aqueous HCl
in place of NaOMe in MeOH led to several products. Since
the yield of 37 obtained from 14 at 40 atm of CO in the presence
of MeOH (4 equiv) (Conditions IV) is limited to 28%, due to
(19) Wu, G.; Shimoyama, I.; Negishi, E. J. Org. Chem. 1991, 56, 6506.

Pd-Catalyzed Cyclization of 1-Iodo-Substituted Dienes
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5925
Table 3. Pd-Catalyzed or Pd-Promoted Cyclic Acylpalladation of ω-Alkene-Containing Alkenyl Halides in the Absence of External
Nucleophiles
a NMR yield unless otherwise mentioned. b Isolated yield. c Not determined. d E/Z ) 70/30. e Less than 2%, if any. f E/Z ) 45/55. g Not a possible
product. h E/Z ) 40/60.
5. Various factors affecting several carbonylative and non-
carbonylative cyclization reactions of ω-alkene-containing alk-
enyl iodides under the influence of CO and Pd-phosphine
catalysts have been delineated. The generalizations presented

5926 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Negishi et al.
5.5-5.9 (m, 1 H); 13C NMR δ 2.11, 14.02, 22.58, 29.31, 31.67, 35.54,
49.02, 108.88, 116.30, 134.17, 157.07.
(d) 2-Iodo-3-methyl-2(Z)-5-hexadiene (7). This compound was
prepared according to a literature procedure.8
in this work and summarized above may now be used in a
predictive manner. Although the scope of each process may
be limited, each can take place selectively to give in many cases
one predominant product, and the three Ac-Pd processes and
the Type II C-Pd process promise to provide synthetically
attractive routes to five- or six-membered-ring compounds.
(e) (Z)-1-Iodo-2-(n-hexyl)-1,4-pentadiene (8).8 Allylmagnesium
bromide in ether (5.72 mL, 0.77 M, 4.4 mmol) was treated with (i-
Bu)2AlCl (0.88 mL, 4.4 mmol) in ether (2 mL) at 0 °C. The mixture
was stirred at 25 °C for 1 h. Ether was removed under reduced pressure
(0.1 mmHg, 50 °C, 1 h) and replaced with 1,2-dichloroethane (10 mL).
To the resulting gray slurry were successively added at 25 °C Cp2-
ZrCl2 (1.16 g, 4.0 mmol) and 1-octyne (0.44 g, 4.0 mmol), and the
mixture was stirred at 25 °C for 1 h. The solvent was removed under
reduced pressure (0.1 mmHg), and the residue was dissolved in THF
(15 mL), cooled to -78 °C, treated with I2 (0.81 g, 3.2 mmol) in THF
(3 mL), stirred at -78 °C for 30 min, and warmed slowly to 25 °C.
After the usual workup, Kugelrohr distillation (70 °C at 0.1 mmHg)
afforded 0.71 g (64%) of 8: 1H NMR δ 0.85 (t, J ) 7 Hz, 3 H), 1.1-
1.6 (m, 8 H), 2.18 (m, 2 H), 2.95 (d, J ) 7 Hz, 2 H), 5.0-5.2 (m, 2
H), 5.5-6.0 (m, 1 H), 5.95 (s, 1 H); 13C NMR δ 14.04, 22.57, 27.68,
28.84, 31.63, 37.25, 41.86, 75.40, 116.54, 133.92, 149.49.
Experimental Section
General Procedures. All reactions were conducted under a dry
Ar atmosphere. Gas chromatographic measurements were performed
on SE-30 (Chromosorb W) columns with appropriate saturated
hydrocarbon standards. 1H and 13C NMR spectra were recorded in
CDCl3 on Varian Gemini-200, VXR-500, and GE QE-300 NMR
spectrometers using Me4Si as an internal standard unless otherwise
noted. All commercially available reagents were used without further
purification unless otherwise noted. THF was distilled from sodium
benzophenone ketyl. Benzene, CH3CN, DMF, and NEt3 were dried
over molecular sieves 4A. The preparation of PdCl2(PPh3)2 was
performed as reported in the literature.20 Pd-catalyzed high-pressure
carbonylation experiments were carried out in a 22-mL autoclave (Parr
Instrument Co.).
Preparation of ω-Alkene-Containing Alkenyl Iodides (Schemes
3-5). (a) (Z)-1-Iodo-2-(n-hexyl)-1,5-hexadiene (1). Following the
reported procedure,6,21 1-octyne (5.5 g, 7.4 mL, 50 mmol) was treated
with a reagent obtained by mixing CuBr (8.6 g, 60 mmol) and
3-butenylmagnesium bromide (1.1 M in ether, 52 mL, 55 mmol) in
ether (50 mL). The crude product mixture was cooled to -78 °C,
treated with iodine (15 g, 60 mmol) in THF, and warmed to 0 °C over
30 min. The reaction mixture was poured into a mixture of 3 N HCl
and pentane, filtered through Celite, extracted with pentane, washed
with NaHCO3 and brine, dried over MgSO4, and distilled at 75-80 °C
(0.5 mmHg) to afford 9.5 g (65%) of 1: 1H NMR δ 0.89 (t, J ) 7 Hz,
3 H), 1.2-1.8 (m, 8 H), 2.0-2.6 (m, 6 H), 4.9-5.2 (m, 2 H), 5.5-6.1
(m, 2 H).
(f) 1-Iodo-2-(2′-propenyl)-1-cyclopentene (9).2d 5-Iodo-1-pentyne
(5.82 g, 30 mmol) in n-hexane (100 mL) was treated successively with
n-BuLi (2.4 M, 12.5 mL, 30 mmol) in n-hexane at -90 °C for 1 h
then at -78 °C for 1 h and EtZnCl (1.0 M, 33 mL, 33 mmol), prepared
from 1 equiv each of Et2Zn and ZnCl2 in CH2Cl2 at -78 °C, for 30
min. After warming this mixture to 0 °C over 3 h, the solvents were
removed under vacuum and replaced at 0 °C with THF (100 mL). The
reaction mixture was treated with allylzinc bromide, prepared from Zn
(2.94 g, 45 mmol) in THF (45 mL) and allyl bromide (5.44 g, 3.9 mL,
45 mmol), at 25 °C for 12 h, quenched with I2 (25.4 g, 100 mmol) in
THF (50 mL) at -78 °C, and warmed to 25 °C. The reaction mixture
was diluted with pentane at 0 °C, quenched with aqueous NH4Cl,
washed with aqueous Na2S2O3, NaHCO3, and brine, and dried over
MgSO4. Distillation afforded 6.25 g (86%, 93% by GLC) of 9: bp
1
71-74 °C (5 mmHg); H NMR δ 1.8-2.1 (m, 2 H), 2.1-2.5 (m, 2
H), 2.5-2.8 (m, 2 H), 2.8-3.0 (m, 2 H), 4.9-5.2 (m, 2 H), 5.56.0 (m,
1 H); 13C NMR δ 23.36, 33.83, 37.68, 44.17, 91.54, 116.10, 134.12,
145.69.
(g) 1-Iodo-2-(2′-propenyl)-1-cyclohexene (10). This compound was
prepared according to a literature procedure.2d
(h) (Z)-1-Iodo-2-(n-hexyl)-1,6-heptadiene (11). This compound
was prepared in 56% yield (bp 80-90 °C at 0.5 mmHg, Kugelrohr
distillation) following the procedure for 1 using 4-pentenylmagnesium
bromide instead of 3-butenylmagnesium bromide: 1H NMR δ 0.89 (t,
J ) 6 Hz, 3 H), 1.1-1.7 (m, 10 H), 1.9-2.4 (m, 6 H), 4.9-5.2 (m, 2
H), 5.6-5.9 (m, 2 H).
(b) Methyl 1-(Z-3′-Iodo-2′-hepten-1′-yl)-2-cyclohexene-1-carboxy-
late (4). The procedure of Schlessinger et al.22 was used for the
following alkylation. To a solution of (i-Pr)2NH (1.1 g, 11 mmol) in
20 mL of THF were added successively n-BuLi (1.6 M in hexane, 6.25
mL, 10 mmol, 0 °C, 5 min) and HMPA (2.15 g, 12 mmol, -78 °C, 30
min), methyl 1-cyclohexenylcarboxylate (1.4 g, 10 mmol, -78 °C, 40
min), and 1-bromo-3-iodo-2(Z)-heptene (3.94 g, 13 mmol) in 2 mL of
THF. The mixture was stirred at -78 °C for 2 h, quenched with 3 N
HCl, extracted with ether, and washed with aqueous NaHCO3 and brine.
Drying over MgSO4, evaporation of the solvents, and flash column
chromatography (1:20, ether-pentane) gave 2.65 g (73%) of 4: 1H
NMR 0.89 (t, J ) 7 Hz, 3 H), 1.4-1.7 (m, 8 H), 1.9-2.5 (m, 6 H),
3.69 (s, 3 H), 5.37 (5, J ) 7 Hz, 1 H), 5.69 (bd, J ) 7 Hz, 1 H), 5.83
(dt, J ) 3 and 7 Hz, 1 H); 13C NMR δ 13.89, 19.69, 21.28, 24.90,
30.60, 31.46, 45.24, 46.34, 46.91, 52.03, 112.59, 129.09, 129.42, 129.92,
175.87.
(c) (Z)-1-Iodo-1-(trimethylsilyl)-2-(n-hexyl)-1,4-pentadiene (6).7
To a stirred mixture of granular zinc (8.64 g, 144 mmol) in THF (60
mL) was added dropwise allyl bromide (10.44 mL, 100 mmol) at a
rate which maintained the temperature below 15 °C. After 30 min at
25 °C, 1-octynyltrimethylsilane (10.9 g, 60.0 mmol) was added, and
the mixture was heated at 60 °C for 24 h, cooled to -78 °C, treated
with I2 (38.1 g, 150 mmol) in THF (60 mL), and stirred at -78 °C for
1 h. After the usual workup, Kugelrohr distillation (90-95 °C at 0.1
mmHg) gave an 84:16 mixture of the Z and E isomers of the title
compound. Z-6: 1H NMR δ 0.20 (s, 9 H), 0.80 (t, 3 H), 1.2-1.3 (m,
8 H), 2.1-2.3 (m, 2 H), 3.1 (d, J ) 7 Hz, 2 H), 4.9-5.2 (m, 2 H),
(i) (Z)-3-Iodo-2,6-heptadien-1-ol (12).11 A suspension of NaOMe
(562 mg, 10.4 mmol) in THF (10 mL) was treated with LiAlH4 in
THF (1.0 M, 5.2 mL, 5.2 mmol) at 0 °C for 30 min. To this were
added successively 6-hepten-2-yn-1-ol (550 m g, 5.0 mmol) in THF
(5 mL) at 0 °C for 6 h, ethyl acetate (0.75 mL) at 0 °C for 15 min, I2
(1.5 g, 6 mmol) in THF (10 mL) at -78 °C, concentrated NH4OH at
25 °C, aqueous Na2S2O3, and Et2O. The reaction mixture was decanted,
extracted with Et2O, washed with aqueous HCl and NaHCO3, dried
over MgSO4, and evaporated. Chromatography on silica gel (90/10
pentane-Et2O) afforded 303 mg (64%) of 12: 1H NMR δ 2.2-2.4
(m, 2 H), 2.5-2.7 (m, 2 H), 4.17 (d, J ) 5.7 Hz, 2 H), 4.95-5.2 (m,
2 H), 5.6-6.0 (m, 2 H); 13C NMR δ 33.35, 44.42, 67.12, 108.90,
115.79, 134.06, 136.29; IR (neat) 3400, 1642 cm-1; HRMS calcd for
C7H9I (M+ - H2O) 220.9927, found 220.9829.
(j) (Z)-6-Iodo-1,5-decadiene (13). Preparation of (Z)-3-Iodo-2-
hepten-1-ol.11 To a suspension of NaOMe (4.82 g, 89.2 mmol) in
THF (89 mL) at 0 °C was added a solution of LiAlH4 in THF (1.0 M,
44.6 mL, 44.6 mmol). After 30 min at 0 °C, 2-heptyn-1-ol (5.0 g,
44.6 mmol) in THF was added at 0 °C. After stirring at 0 °C for 10
h, the mixture was cooled to -5 °C and treated successively with EtOAc
(7.8 mL) to destroy unreacted LiAlH4 and I2 (13.24 g, 52.1 mmol) in
THF (50 mL) at -78 °C. The reaction mixture was quenched with
aqueous Na2S2O3 at 0 °C, extracted with ether, dried over MgSO4, and
evaporated. Chromatography on silica gel (10/1 n-hexane-EtOAc)
afforded 8.61 g (80%) of the title compound: 1H NMR δ 0.90 (t, J )
6.5 Hz, 3 H), 1.2-1.45 (m, 2 H), 1.45-1.7 (m, 2 H), 2.50 (t, J ) 6.1
Hz, 2 H), 4.20 (d, J ) 6.0 Hz, 2 H), 5.85 (t, J ) 6.0 Hz, 1 H); 13C
(20) Jenkins, J. M.; Verkad, J. G. Inorg. Synth. 1968, 11, 108.
(21) Boardman, L. D.; Bagheri, V.; Sawada, H.; Negishi, E. J. Am. Chem.
Soc. 1984, 106, 6105.
(22) Hermann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H. Tetra-
hedron Lett. 1973, 2433.
(23) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 4339.
(24) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336;
Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi, E.
Tetrahedron Lett. 1993, 34, 687.
(25) Haneishi, T.; Kitahara, N.; Takiguchi, Y.; Arai, M. J. J. Antibiot.
1974, 27, 386.

Pd-Catalyzed Cyclization of 1-Iodo-Substituted Dienes
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5927
NMR δ 13.95, 21.50, 31.40, 44.50, 67.30, 110.60, 133.70. Preparation
of (Z)-1-Bromo-3-iodo-2-heptene.22 NBS (9.65 g, 54.2 mmol) in CH2-
Cl2 (180 mL) was treated successively with Me2S (4.74 mL, 54.2 mmol)
at 0 °C for 10 min and (Z)-3-iodo-2-hepten-1-ol (8.61 g, 35.9 mmol)
in CH2Cl2 (5 mL) at -20 °C. The reaction mixture was warmed to 25
°C over 12 h, quenched with cold brine, extracted with ether, dried
over MgSO4, and evaporated. Chromatography on silica gel (n-hexane)
afforded 8.51 g (78%) of the title compound: 1H NMR δ 0.90 (t, J )
6.3 Hz, 3 H), 1.2-1.45 (m, 2 H), 1.45-1.65 (m, 2 H), 2.52 (t, J ) 6.5
Hz, 2 H), 4.00 (d, J ) 8.4 Hz, 2 H), 5.82 (t, J ) 8.4 Hz, 1 H); 13C
NMR δ 13.95, 21.50, 31.50, 35.95, 45.00, 116.40, 130.20. Conversion
of (Z)-1-Bromo-3-iodo-2-heptene to (Z)-6-Iodo-1,5-decadiene (13):
Representative Procedure. (Z)-1-Bromo-3-iodo-2-heptene (2.0 g, 6.6
mmol) in THF (20 mL) was added to allylmagnesium bromide in ether
(1.0 M, 7.9 mL, 7.9 mmol). After 10 h at 25 °C, the reaction mixture
was quenched with water, extracted with ether, dried over MgSO4, and
evaporated. Chromatography on silica gel (n-hexane) afforded 1.26 g
(72%) of 13: 1H NMR δ 0.90 (t, J ) 6.6 Hz, 3 H), 1.2-1.4 (m, 2 H),
1.4-1.6 (m, 2 H), 2.05-2.3 (m, 4 H), 2.45 (t, J ) 6.7 Hz, 2 H), 4.9-
5.1 (m, 2 H), 5.47 (t, J ) 6.7 Hz, 1 H), 5.7-5.95 (m, 1 H), 13C NMR
δ 13.86, 21.26, 31.45, 32.47, 35.64, 44.82, 110.26, 115.10, 133.74,
137.69; IR (neat) 1640 cm-1; HRMS calcd for C10H17I 264.0375, found
264.0378.
Et2O): 1H NMR δ 1.4-1.9 (m, 6 H), 2.32 (bs, 1 H), 2.80 (t, J ) 6.4
Hz, 2 H), 3.4-3.65 (m, 2 H), 3.75-4.0 (m, 2 H), 4.1-4.3 (m, 2 H),
4.55-4.7 (m, 1 H), 5.95 (t, J ) 5.8 Hz, 1 H); 13C NMR δ 19.41, 25.32,
30.48, 45.23, 62.35, 65.90, 67.20, 98.83, 104.65, 135.82. A solution
of this alcohol (624 mg, 2.0 mmol) and Et3N (0.54 mL, 4.0 mmol) in
CH2Cl2 (10 mL) was treated with methanesulfonyl chloride (0.23 mL,
3 mmol) at 0 °C for 2 h. The reaction mixture was diluted with Et2O,
washed successively with 2 N HCl and aqueous NaHCO3, dried over
MgSO4, and evaporated. Chromatography on silica gel afforded 640
mg (82%) of the corresponding mesylate which was added to dimethyl
sodiomalonate in THF (1.0 M, 2 equiv, at 0 °C for 2 h) freshly prepared
by addition of dimethyl malonate to a suspension of NaH in THF at 0
°C. The reaction mixture was extracted with Et2O, washed with 1 N
HCl and aqueous NaHCO3, dried over MgSO4, and evaporated.
Chromatography on silica gel (90/10 pentane-Et2O) afforded 570 mg
(81%) of methyl (Z)-2-(methoxycarbonyl)-5-iodo-7-(2′-tetrahydro-
pyranyloxy)-4-heptenoate: 1H NMR δ 1.4-1.9 (m, 6 H), 2.6-2.85
(m, 3 H), 3.4-3.6 (m, 2 H), 3.75 (s, 3 H), 3.75-3.9 (m, 2 H), 4.55-
4.65 (m, 1 H), 5.65 (t, J ) 6.8 Hz, 1 H); 13C NMR δ 19.37, 25.40,
30.51, 35.63, 45.4, 50.41, 52.61, 62.20, 65.98, 98.73, 107.44, 132.16,
168.94. A mixture of this compound (570 mg, 1.32 mmol) and
pyridinium p-toluenesulfonate (10 mol %) in MeOH (10 mL) was stirred
for 12 h, evaporated, and filtered on silica gel to give 395 mg (88%)
of 16a: 1H NMR δ 2.1-2.2 (m, 1 H), 2.7-2.9 (m, 4 H), 3.53 (t, J )
7.2 Hz, 1 H), 3.6-3.8 (m, 7 H), 5.70 (t, J ) 6.9 Hz, 1 H); 13C NMR
δ 35.61, 48.32, 50.19, 52.77, 60.51, 107.77, 134.34, 169.01.
(n) Methyl (Z)-2-(Methoxycarbonyl)-5-iodo-4,8-nonadienoate (16b).
The corresponding mesylate of 12, prepared following the procedure
for 16a, was added to dimethyl sodiomalonate in THF (1.0 M, 2 equiv,
0 °C, 2 h) freshly prepared by addition of dimethyl malonate to a
suspension of NaH in THF. The reaction mixture was extracted with
Et2O, washed with 1 N HCl and aqueous NaHCO3, dried over MgSO4,
and evaporated. Chromatography on silica gel afforded 250 mg (74%)
of 16b: 1H NMR δ 2.2-2.35 (m, 2 H), 2.56 (t, J ) 7.2 Hz, 2 H), 2.71
(t, J ) 7.1 Hz, 2 H), 3.49 (t, J ) 7.5 Hz, 1 H), 3.75 (s, 6 H), 4.9-5.1
(m, 2 H), 5.56 (t, J ) 6.8 Hz, 1 H), 5.72 (ddt, J ) 17.0, 10.3, 6.7 Hz,
1 H); 13C NMR δ 25.11, 29.42, 50.12, 52.89, 65.49, 128.48, 134.90,
168.74, 170.69.
(k) (Z)-6-Iodo-2-methyl-1,5-decadiene (14). This compound was
prepared in 57% yield (0.53 g) according to the procedure for 13 starting
with (Z)-1-bromo-3-iodo-2-heptene (1.0 g, 3.3 mmol) in THF (5 mL)
and 2-methyl-2-propenylmagnesium chloride in THF, prepared by
adding 2-methyl-2-propenyl chloride (1.13 g, 12.5 mmol) in THF (18
mL) to a suspension of Mg (0.61 g, 25.4 mmol) in THF (5 mL), instead
of allylmagnesium bromide in ether. 14: 1H NMR δ 0.90 (t, J ) 7.7
Hz, 3 H), 1.2-1.4 (m, 2 H), 1.4-1.6 (m, 2 H), 1.72 (s, 3 H), 2.05-
2.15 (m, 2 H), 2.15-2.35 (m, 2 H), 2.45 (t, J ) 7.6 Hz, 2 H), 4.70 (s,
1 H), 4.72 (s, 1 H), 5.46 (t, J ) 7.5 Hz, 1 H); 13C NMR δ 13.84,
21.24, 22.40, 31.45, 34.52, 36.27, 44.79, 110.07, 110.45, 133.95, 144.84.
(l) (2Z,6Z)-7-Iodo-2,6-undecadiene (15). Preparation of (Z)-6-
Iododec-5-en-1-yne. Propargylmagnesium bromide prepared by adding
propargyl bromide (80% in toluene, 6.7 mL, 60 mmol) in THF to Mg
turning (2.88 g, 120 mmol) and HgCl2 (30 mg) in THF (10 mL) was
added to (Z)-1-bromo-3-iodo-2-heptene (2.75 g, 9.1 mmol) in THF (10
mL) at 25 °C. After 3 h, the reaction mixture was refluxed overnight,
quenched with aqueous NH4Cl, extracted with ether, and dried over
MgSO4. Filtration through a short column of silica gel (n-hexane)
afforded 2.04 g (86%) of (Z)-6-iododec-5-en-1-yne: 1H NMR δ 0.92
(t, J ) 7.7 Hz, 3 H), 1.2-1.4 (m, 2 H), 1.4-1.6 (m, 2 H), 1.95 (t, J )
1.3 Hz, 1 H), 2.2-2.4 (m, 4 H), 2.48 (t, J ) 7.5 Hz, 2 H), 5.60 (t, J
) 6.3 Hz, 1 H); 13C NMR δ 13.85, 17.59, 21.28, 31.43, 35.34, 44.86,
68.79, 83.49, 111.25, 132.45. Preparation of (Z)-7-Iodoundec-6-en-
2-yne. LDA prepared by treating (i-Pr)2NH (0.38 mL, 2.7 mmol) in
THF (4 mL) with n-BuLi (2.5 M in hexane, 1.12 mL, 2.8 mmol) at
-50 °C for 30 min was cooled to -90 °C and added to (Z)-6-iododec-
5-en-1-yne (0.701 g, 2.67 mmol) in THF (5 mL) at -90 °C. After 15
min at -90 °C, the mixture was kept at -70 °C for 13 min and treated
with CH3I (2 mL, 21.56 mmol) in HMPA (1.7 mL) below -65 °C.
After the usual workup, chromatography on silica gel (n-hexane)
afforded 595 mg (81%) of (Z)-7-iodoundec-6-en-2-yne: 1H NMR δ
0.90 (t, J ) 7.7 Hz, 3 H), 1.2-1.4 (m, 2 H), 1.4-1.6 (m, 2 H), 1.77
(t, J ) 1.2 Hz, 3 H), 2.1-2.4 (m, 4 H), 2.47 (t, J ) 7.5 Hz, 2 H), 5.57
(t, J ) 6.0 Hz, 1 H); 13C NMR δ 3.48, 1385, 17.89, 21.25, 31.43,
35.97, 44.85, 76.10, 78.22, 110.77, 133.07. Preparation of (2Z,6Z)-
7-Iodo-2,6-undecadiene (15). To (Z)-7-iodoundec-6-en-2-yne (0.595
g, 2.16 mmol) in n-hexane was added (i-Bu)2AlH (0.58 mL, 3.26 mmol)
at 25 °C under Ar. After 27 h at 50-55 °C, the reaction mixture was
quenched at -66 °C with aqueous NH4Cl, extracted with ether, and
dried over MgSO4. Chromatography on silica gel (n-hexane) afforded
0.416 g (69%) of 15: 1H NMR δ 0.90 (t, J ) 7.7 Hz, 3 H), 1.2-1.4
(m, 2 H), 1.4-1.6 (m, 2 H), 1.64 (d, J ) 5.8 Hz, 3 H), 2.1-2.2 (m, 4
H), 2.48 (t, J ) 7.6 Hz, 2 H), 5.35-5.55 (m, 3 H); 13C NMR δ 12.82,
13.86, 21.29, 25.74, 31.49, 36.29, 44.87, 110.10, 124.68, 129.36, 134.01.
(o) (Z)-4,4-Bis(methoxycarbonyl)-7-iodo-2-methyl-1,6-dodecadi-
ene (17). The mesylate of (Z)-3-iodo-2-hepten-1-ol, prepared similarly
as above in 70% yield, was added to dimethyl (2-methyl-2-propenyl)-
sodiomalonate in THF (1.0 M, 1 equiv, 0 °C, 2 h) freshly prepared by
addition of dimethyl (2-methyl-2-propenyl)malonate to a suspension
of NaH in THF. The reaction mixture was extracted with Et2O, washed
with 1 N HCl and aqueous NaHCO3, dried over MgSO4, and evaporated.
Chromatography on silica gel (95/5 pentane-Et2O) afforded 1.27 g
(76%) of 17: 1H NMR δ 0.90 (t, J ) 7.3 Hz, 3 H), 1.2-1.4 (m, 2 H),
1.4-1.55 (m, 2 H), 1.66 (s, 3 H), 2.46 (t, J ) 7.2 Hz, 2 H), 2.65-2.8
(m, 4 H), 3.72 (s, 6 H), 4.73 (bs, 1 H), 4.89 (t, J ) 0.5 Hz, 1 H), 5.43
(t, J ) 6.55 Hz, 3 H); 13C NMR δ 13.81, 21.23, 23.21, 31.44, 39.75,
41.00, 45.24, 52.47, 56.80, 112.90, 116.07, 128.81, 140.08, 171.33;
IR (neat) 1736 cm-1
.
(p) (Z)-4,4-Bis(methoxycarbonyl)-7-iodo-1,6-undecadiene (49).
The mesylate of 3-iodo-2-hepten-1-ol (4.0 mmol) prepared above was
treated with dimethyl sodioallylmalonate in THF (1.0 M, 2 equiv, 0
°C, 2 h) freshly prepared by addition of dimethyl allylmalonate to a
suspension of NaH in THF. The reaction mixture was extracted with
Et2O, washed with 1 N HCl and aqueous NaHCO3, dried over MgSO4,
and evaporated. Chromatography on silica gel afforded 1.29 g (82%)
of 49: 1H NMR δ 0.90 (t, J ) 7.3 Hz, 3 H), 1.2-1.4 (m, 2 H), 1.4-
1.55 (m, 2 H), 2.47 (t, J ) 7.2 Hz, 2 H), 2.74 (d, J ) 6.8 Hz, 2 H),
2.79 (d, J ) 7.6 Hz, 2 H), 3.72 (s, 6 H), 5.0-5.2 (m, 2 H), 5.38 (t, J
) 6.8 Hz, 1 H), 5.55-5.8 (m, 1 H); 13C NMR δ 13.75, 21.17, 31.34,
37.57, 39.66, 45.20, 52.45, 57.28, 113.13, 119.39, 128.51, 132.11,
170.93; IR (neat) 1736 cm-1
.
(q) (Z)-5-Iodo-4-(n-propyl)-1,4-octadiene (18). Representative
Procedure for the Preparation of 1-Iodo-1,3-pentadiene Derivatives
18-21. Preparation of (Z)-4-Iodo-3-(n-propyl)-3-heptenyltriph-
enylphosphonium Iodide. A mixture of (Z)-1,4-diiodo-3-(n-propyl)-
3-heptene (8.9 g, 22.6 mmol)24 and triphenylphosphine (17.8 g, 68.0
mmol) in CH3CN (20 mL) was refluxed for 36 h. The solvent was
removed, and the resulting light brown precipitate was recrystallized
from CH2Cl2 and Et2O to give 11.0 g (75%) of (Z)-4-iodo-3-(n-propyl)-
(m) Methyl (Z)-2-(Methoxycarbonyl)-5-iodo-7-hydroxy-4-hep-
tenoate (16a). 3-Iodo-5-(2′-tetrahydropyranyloxy)-2-penten-1-ol was
prepared in 92% yield (1.30 g) from 5-(2′-tetrahydropyranyloxy)-2-
pentyn-1-ol (920 mg, 5.0 mmol) according to the procedure described
for 12 followed by chromatography on silica gel (80/20 pentane-

5928 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Negishi et al.
3-heptenyltriphenylphosphonium iodide: 1H NMR δ 0.8-1.0 (m, 6
H), 1.2-1.65 (m, 4 H), 2.4-2.6 (m, 6 H), 3.5-3.7 (m, 2 H), 7.7-7.8
(m, 15 H); 13C NMR δ 12.82, 13.55, 20.74, 21.69, 21.76, 22.74, 33.36,
34.60, 34.65, 42.73, 108.50, 116.37, 118.08, 130.30, 130.55, 133.48,
133.68, 135.08, 135.14, 140.66, 140.98. Conversion of (Z)-4-Iodo-
51.63, 128.34, 172.51, 181.48, 209.10; IR (neat) 1740, 1705 1616 cm-1
HRMS calcd from C14H22O3 (M+) 238.1569, found 238.1570.
;
(c) Carbonylation of 11. Under Conditions IV (40 atm of CO,
MeCN-C6H6 (1/1), 100 °C, 24 h), 11 (0.47 g, 1.5 mmol) afforded
methyl (Z)-3-(n-hexyl)-2,7-octadienoate (25) in 50% GLC yield: 1H
NMR δ 0.89 (t, J ) 7 Hz, 3 H), 1.1-1.8 (m, 8 H), 2.0-2.3 (m, 4 H),
2.66 (bt, J ) 10 Hz, 2 H), 3.69 (s, 3 H), 4.9-5.1 (m, 2 H), 5.6-6.1
3-(n-propyl)-3-heptenyltriphenylphosphonium Iodide to 18.
A
suspension of 4-iodo-3-(n-propyl)-3-heptenyltriphenylphosphonium
iodide (3.3 g, 5.0 mmol) in THF (15 mL) was treated successively at
25 °C with NaN(SiMe3)2 (1.0 in THF, 5 mL, 5 mmol) for 10 min,
HMPA (1.5 mL) at -60 °C, and paraformaldehyde (320 mg, 10 mmol)
at -78 °C. After 3 h at 25 °C, the reaction mixture was diluted with
hexane, filtered, washing with aqueous NaCl and water, dried over
MgSO4, and evaporated. Chromatography on silica gel (n-hexane)
afforded 1.25 g (90% yield) of 18: 1H NMR δ 0.85-0.95 (m, 6 H),
1.35-1.65 (m, 4 H), 2.1-2.2 (m, 2 H), 2.5-2.55 (m, 2 H), 3.02 (d, J
) 6.2 Hz, 2 H), 5.05-5.15 (m, 2 H), 5.65-5.8 (m, 1 H); 13C NMR δ
12.91, 14.00, 21.80, 23.06, 33.62, 42.99, 46.96, 106.31, 115.86, 134.66,
141.57; IR (neat) 1638, 1624 cm-1; HRMS calcd for C11H19I (M+)
278.0532, found 278.0532.
(m, 2 H); 13
C NMR δ 14.06, 22.64, 27.77, 28.01, 29.10, 31.77, 34.06,
38.51, 50.71, 114.71, 115.12, 138.59, 138.59, 164.74, 166.74, 166.92;
IR (neat) 1720, 1640 cm-1; MS (M+ + 1) 239.
(d) Carbonylation of 6. Under Conditions IV (40 atm of CO,
MeCN-C6H6 (1/1), 100 °C, 24 h), 6 (0.71 g, 2.0 mmol) afforded 0.47
g (75%) of 3-(n-hexyl)-2-(trimethylsilyl)-5-(methoxycarbonyl)cyclo-
pent-2-enone (26): 1H NMR δ 0.22 (s, 9 H), 0.89 (t, J ) 5 Hz, 3 H),
1.0-1.7 (m, 8 H), 2.1-3.1 (m, 7 H), 3.68 (s, 3 H); 13C NMR δ 0.76,
13.59, 22.13, 28.16, 29.07, 31.26, 33.68, 34.84, 39.27, 42.53, 51.14,
137.91, 172.34, 187.53, 212.84; IR (neat) 1742, 1691, 1586 cm-1
HRMS calcd for C17H30O3Si (M+) 310.1964, found 310.1967.
;
(e) Carbonylation of 9. Under Conditions IV (40 atm of CO,
MeCN-C6H6 (1/1), 100 °C, 24 h), 9 (0.71 g, 3.0 mmol) afforded 0.48
g (82%) of 3-((methoxycarbonyl)methyl)bicyclo[3.3.0]oct-1(5)-en-2-
one (27) via Kugelrohr distillation (100-105 °C at 0.15 mmHg): 1H
NMR δ 2.2-3.1 (m, 11 H), 3.70 (s, 3 H); 13C NMR δ 24.70, 27.61,
32.00, 32.66, 35.30, 48.50, 51.53, 147.65, 172.39, 185.14, 202.72; IR
(neat) 1735, 1695, 1633 cm-1; HRMS C11H14O3 (M+) 194.0943, found
194.0937.
(f) Carbonylation of 10. Under Conditions IV (40 atm of CO,
MeCN-C6H6 (1/1), 100 °C, 24 h), 10 (0.83 g, 3.0 mmol) afforded
0.59 g (85%) of 8-((methoxycarbonyl)methyl)bicyclo[4.3.0]non-1(6)-
en-7-one (28) via Kugelrohr distillation (100-105 °C at 0.15 mmHg)
(100 GLC % yield): 1H NMR δ 1.6-1.9 (m, 4 H), 2.0-3.0 (m, 9 H),
3.68 (s, 3 H); 13C NMR δ 20.22, 21.85, 22.33, 28.42, 35.26, 37.22,
41.74, 51.48, 137.60, 171.67, 172.42, 207.60; IR (neat) 1740, 1698,
1645 cm-1; HRMS calcd for C12H16O3 (M+) 208.1100, found 208.1106.
(g) Carbonylation of 13. Under Conditions IV (40 atm of CO,
MeCN-C6H6 (1/1), 100 °C, 24 h), 13 (0.14 g, 0.53 mmol) gave
6-((methoxycarbonyl)methyl)-2-(n-butyl)cyclohex-2-enone (29) in 50%
NMR yield. Chromatography on silica gel (10/1 hexane-ethyl acetate)
afforded 52 mg (44%) of 29: 1H NMR δ 0.89 (t, J ) 7.3 Hz, 3 H),
1.2-1.45 (m, 4 H), 1.65-1.9 (m, 1 H), 2.0-2.5 (m, 6 H), 2.75-2.95
(m, 2 H), 3.70 (s, 3 H), 6.6-6.7 (m, 1 H); 13C NMR δ 3.84, 22.42,
25.74, 29.03, 29.30, 30.72, 34.64, 43.88, 51.59, 139.28, 144.07, 173.09,
199.51; IR (neat) 1736, 1674 cm-1; HRMS calcd for C13H20O3 (M+)
224.1412, found 224.1417.
(r) (4Z,7Z)-4-Iodo-5-(n-propyl)-4,7-tridecadiene (19). Use of
n-hexanal (0.58 g, 0.70 mL, 5.5 mmol) in place of paraformaldehyde
(10 mmol) in the representative procedure for the preparation of 18
provided, after chromatography on silica gel (n-hexane), 1.50 g (86%)
of 19: 1H NMR δ 0.85-1.0 (m, 9 H), 1.2-1.65 (m, 10 H), 2.0-2.2
(m, 4 H), 2.4-2.55 (t, J ) 7.3 Hz, 2 H), 2.95-3.05 (d, J ) 7.0 Hz, 2
H), 5.15-5.35 (m, 1 H), 5.35-5.55 (m, 1 H); 13C NMR δ 12.91, 14.07,
21.84, 22.60, 23.05, 27.64, 29.37, 31.60, 33.65, 41.01, 43.03, 105.35,
126.12, 131.43, 142.84; IR (neat) 1670, 1624 cm-1; HRMS calcd for
C16H29I (M+) 348.1314, found 348.1317.
(s) (1Z,4Z)-5-Iodo-1-phenyl-4-(n-propyl)-1,4-octadiene (20). This
compound was prepared in 79% yield (1.40 g) following the procedure
for 18 and using benzaldehyde (0.63 g, 5.8 mmol) instead of
paraformaldehyde: 1H NMR δ 0.81 (t, J ) 7.3 Hz, 3 H), 0.91 (t, J )
7.3 Hz, 3 H), 1.2-1.4 (m, 2 H), 1.4-1.7 (m, 2 H), 2.05-2.2 (m, 2 H),
2.52 (t, J ) 7.0 Hz, 2 H), 3.32 (d, J ) 7.0 Hz, 2 H), 5.55 (dt, J ) 7.0
and 11.6 Hz, 1 H), 6.55 (d, J ) 11.6 Hz, 1 H), 7.15-7.4 (m, 5 H); 13
C
NMR δ 12.90, 13.90, 21.63, 23.04, 33.95, 42.09, 42.96, 106.05, 126.61,
128.12, 128.72, 129.57, 130.33, 137.38, 142.76; IR (neat) 1622, 1600
cm-1; HRMS calcd for C17H23I (M+) 354.0845, found 354.0849.
(t) (Z)-5-Iodo-1,1-pentamethylene-4-(n-propyl)-1,4-octadiene (21).
This compound was prepared in 84% yield (1.46 g) following the
procedure for 18 and using cyclohexanone (0.54 g, 5.5 mmol) instead
of paraformaldehyde: 1H NMR δ 0.85-1.0 (m, 6 H), 1.3-1.65 (m,
10 H), 2.1-2.25 (m, 6 H), 2.50 (t, J ) 7.4 Hz, 2 H), 3.00 (d, J ) 7.3
Hz, 2 H), 5.01 (t, J ) 7.3 Hz, 1 H); 13C NMR δ 12.95, 14.11, 21.87,
23.07, 26.93, 27.83, 28.57, 29.11, 33.51, 37.25, 40.90, 43.03, 105.00,
117.73, 140.74, 143.23; IR (neat) 1664, 1624 cm-1; HRMS calcd for
C16H27I (M+) 346.1158, found 346.1162.
(h) Carbonylation of 19. At 100 atm of CO in a 1:1 mixture of
DMF-MeOH at 100 °C for 69 h, 19 (0.35 g, 1.0 mmol) was converted
to 2,3-dipropyl-5-(1′-(methoxycarbonyl)hexyl)cyclopent-2-enone (30)
in 93% NMR yield (diastereomeric ratio ) 54:46) along with a 5%
yield of the E isomer of 31. Chromatography on silica gel afforded
0.27 g (88%) of 30: 1H NMR δ 0.85-1.0 (m, 18 H), 1.25-1.55 (m,
16 H), 1.55-1.85 (m, 4 H), 2.15 (t, J ) 7.5 Hz, 4 H), 2.35-2.95 (m,
12 H), [3.57 (s), 3.72 (s), 3 H)]; 13C NMR δ 13.83, 13.92, 20.64, 20.68,
21.59, 21.64, 22.27, 22.32, 25.00, 27.03, 27.16, 27.86, 30.09, 30.09,
31.49, 32.55, 32.69, 32.81, 45.03, 45.51, 46.01, 46.56, 51.15, 51.45,
139.72, 140.08, 171.97, 172.61, 174.15, 175.49, 208.78, 209.24; IR
(neat) 1736, 1700, 1642 cm-1; HRMS calcd for C19H33O3 (M+ + 1)
309.2430, found 309.2417. The results of carbonylation of 19 under
other condictions were summarized in Table 1, entries 1-8 and 1-9.
(i) Carbonylation of 20. Under the conditions for carbonylation
of 19 described above, 20 (0.354 g, 1.0 mmol) was converted in 24 h
to 2,3-dipropyl-5-(1′-(methoxycarbonyl)-1′-phenylmethyl)cyclopent-2-
enone (32) in 94% NMR yield (diastereomeric ratio ) 60:40) along
with a trace, if any, of 33. Preparative TLC (90/10 hexanes-EtOAc)
afforded 0.295 g (94% yield) of 32: 1H NMR δ 0.8-9.9 (m, 6 H),
1.25-1.65 (m, 4 H), 2.0-3.3 (m, 7 H), [3.64 (s), 3.75 (s), 3 H], 3.85
(d, J ) 8.4 Hz, 1 H), 4.31 (d, J ) 5.0 Hz, 1 H), 7.25-7.4 (m, 5 H);
13C NMR δ 13.86, 1395, 20.57, 20.71, 21.52, 21.68, 24.99, 25.10, 32.75,
32.86, 33.25, 47.25, 48.68, 50.54, 51.80, 52.09, 127.17, 127.47, 128.28,
128.44, 128.51, 128.57, 136.09, 137.62, 139.64, 172.21, 172.21, 172.39,
Pd-Catalyzed Carbonylation of ω-Alkene-Containing Alkenyl
Iodides in the Presence of an Alcohol (Table 1). (a) Carbonylation
of 1. Representative Procedure (Conditions IV). A mixture of (Z)-
1-iodo-2-(n-hexyl)-1,5-hexadiene (1) (0.44 g, 1.5 mmol), MeOH (0.19
g, 0.24 mL, 6.0 mmol), NEt3 (0.23 g, 0.31 mL, 2.3 mmol), and Cl2-
Pd(PPh3)2 (0.053 g, 0.075 mmol) in benzene (2 mL) and CH3CN (2
mL) was charged with 40 atm of CO in an autoclave and heated to
100 °C for 24 h with stirring. The autoclave was cooled to 25 °C, and
CO was vented. The reaction mixture was poured into a mixture of
10 mL each of ether and water, extracted with ether, dried over MgSO4,
and evaporated. Kugelrohr distillation (115-120 °C at 0.4 mmHg)
afforded 0.25 g (66%) of 3-(n-hexyl)-6-((methoxcarbonyl)methyl)-2-
cyclohexenone (23): 1H NMR δ 0.89 (t, J ) 6 Hz, 3 H), 1.1-3.1 (m,
17 H), 3.70 (s, 3 H), 5.89 (bs, 1 H); 13C NMR δ 14.05, 22.59, 27.08,
28.81, 29.00, 29.83, 31.67, 34.42, 37.88, 43.08, 51.48, 125.01, 165.82,
172.91, 198.94; IR (neat) 1740, 1670, 1630 cm-1; HRMS calcd for
C15H24O3 (M+) 252.1725, found 252.1722.
(b) Carbonylation of 8. Under Conditions IV (40 atm of CO,
MeCN-C6H6 (1/1), 100 °C, 24 h), 8 (0.42 g, 1.5 mmol) gave a
quantitative yield of 22. Kugelrohr distillation (105-110 °C at 0.1
mmHg) afforded 0.32 g (90%) of 3-(n-hexyl)-5-((methoxycarbonyl)-
methyl)-2-cyclopentenone (22): 1H NMR δ 0.89 (t, J ) 6 Hz, 3 H),
172.88, 173.65, 208.36, 208.92; IR (neat) 1638, 1696, 1736 cm-1
;
HRMS calcd for C20H27O3 (M+ + 1) 315.1960, found, 315.1941.
1.1-1.8 (m, 8 H), 2.2-3.5 (m, 7 H), 3.69 (s, 3 H), 5.94 (bs, 1 H); 13
C
(j) Carbonylation of 21. Under the conditions for carbonylation
of 19 described above, 21 (170 mg, 0.5 mmol) was converted in 37 h
NMR δ 14.02, 22.56, 27.07, 29.06, 31.61, 33.54, 35.07, 38.41, 42.54,

Pd-Catalyzed Cyclization of 1-Iodo-Substituted Dienes
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5929
to a 90/10 diastereomeric mixture of 5-(1′-(methoxycarbonyl)cyclo-
hexyl)-2,3-dipropylcyclopent-2-en-1-one (34) in 30% NMR yield along
with a 50% NMR yield of 5-cyclohexylidene-2,3-dipropylcyclopent-
2-en-1-one (35a) and a 16% NMR yield of 5-(1′-cyclohexenyl)-2,3-
dipropylcyclopent-2-en-1-one (35b). Chromatography on silica gel
(19/1 hexane-EtOAc) afforded 35 mg (23%) of 34, 57 mg (46%) of
35a, and 15 mg (12%) of 35b. 34: 1H NMR δ 0.82 (t, J ) 8.0 Hz, 3
H), 0.91 (t, J ) 8.0 Hz, 3 H), 1.1-1.7 (m, 12 H), 1.95-2.2 (m, 4 H),
2.2-2.5 (m, 4 H), 2.55 (dt, J ) 7.5 and 2.4 Hz, 1 H), 3.65 (s, 3 H);
13C NMR δ 14.12, 20.83, 21.77, 22.84, 23.08, 25.09, 25.63, 30.68,
31.04, 32.39, 32.87, 49.33, 50.81, 51.60, 140.73, 171.42, 175.92, 208.63;
IR (neat) 1646, 1696, 1730 cm-1; HRMS calcd for C19H3O3 (M+)
306.2195, found 306.2198. 35a: 1H NMR δ 0.87-1.0 (m, 6 H), 1.38-
1.63 (m, 10 H), 2.16-2.24 (m, 4 H), 2.36-2.40 (t, J ) 7.7 Hz, 2 H),
2.99 (s, 2 H), 3.06-3.08 (m, 2 H); 13C NMR δ 14.13, 20.97, 21.81,
25.37, 26.40, 28.00, 32.32, 35.76, 34.34, 125.78, 143.88, 151.66, 163.32,
197.58; IR (neat) 1628, 1654, 1680 cm-1; HRMS calcd for C17H26O
(M+ + 1) 247.2062, found 247.2062. 35b: 1H NMR δ 0.86 (t, J )
7.5 Hz, 3 H), 0.96 (t, J ) 7.5 Hz, 3 H), 1.3-1.5 (m, 2 H), 1.5-1.7 (m,
6 H), 1.7-1.85 (m, 2 H), 1.95-2.1 (m, 2 H), 2.15 (t, J ) 8.3 Hz, 2
H), 2.3-2.5 (m, 3 H), 2.6-2.8 (m, 1 H), 2.9-3.0 (m, 1 H), 5.5 (bs, 1
H); 13C NMR δ 14.08, 14.17, 20.83, 21.82, 22.22, 22.70, 25.02, 25.17,
25.26, 32.98, 35.65, 53.10, 124.62, 135.67, 140.41, 172.70, 209.99;
IR (neat) 1638, 1648, 1700 cm-1; HRMS calcd for C17H26O (M+)
246.1984, found 246.1982.
31.26, 70.17, 115.78, 133.52, 136.91, 144.74, 174.31; IR (neat) 1752
cm-1; HRMS calcd for C8H11O2 (M+ + 1) 139.0759, found 139.0758.
(b) Acylpalladation vs C-Enolate Trapping. Carbonylation of 16b
(176 mg, 0.5 mmol) under Conditions IV (DMF, MeOH (10 equiv),
100 °C, 12 h) gave (Z)-2-(3′,3′-bis(methoxycarbonyl)propylidene)-5-
((methoxycarbonyl)methyl)cyclopentanone (45) in 48% NMR yield with
no trace (<2%) of 46. 45: 1H NMR δ 1.4-1.6 (m, 1 H), 2.2-2.55
(m, 3 H), 2.6-2.95 (m, 4 H), 3.53 (t, J ) 7.5 Hz, 1 H), 3.69 (s, 3 H),
3.75 (s, 6 H), 6.4-6.55 (m, 1 H); 13C NMR (CDCl3, Me4Si) δ 24.88,
26.53, 28.83, 34.15, 45.66, 50.40, 51.78, 52.78, 131.05, 139.10, 168.89,
172.62, 205.44; IR (neat) 1734 cm-1; HRMS calcd for C15H21O7 (M+
+ 1) 313.1287, found 313.1280.
(c) C-Enolate Trapping vs Lactonization. Carbonylation of 16a
(170 mg, 0.5 mmol) under Conditions IV (DMF, MeOH (10 equiv),
100 °C, 12 h) gave 2-(3′,3′-bis(methoxycarbonyl)propylidene)butan-
4-olide 47 in 80% NMR yield as a 1:2 mixture of the E and Z isomers
with no sign of 48. Z-47 (major):
1H NMR δ 2.85-3.0 (m, 2 H),
3.29 (tt, J ) 7.3 and 1.9 Hz, 2 H), 3.56 (t, J ) 7.1 Hz, 1 H), 3.75 (s,
6 H), 4.33 (t, J ) 7.4 Hz, 2 H), 6.26 (tt, J ) 7.5 and 2.4 Hz, 1 H); 13
C
NMR δ 26.32, 29.01, 50.81, 52.67, 65.43, 126.37, 137.96, 169.05,
169.62; IR (neat) 1752 cm-1; HRMS calcd for C11H15O6 (M+ + 1)
1
243.0869, found 243.0867. E-47 (minor): H NMR δ 2.79 (tt, J )
7.5 and 1.6 Hz, 2 H), 2.9-3.05 (m, 2 H), 3.56 (t, J ) 7.5 Hz, 1 H),
3.76 (s, 6 H), 4.39 (t, J ) 7.4 Hz, 2 H), 6.61 (tt, J ) 7.5, 3.0 Hz, 1 H);
13C NMR δ 25.11, 29.42, 50.12, 52.89, 65.49, 128.48, 134.90, 168.74,
170.69.
(k) Carbonylation of 14. Under Conditions IV (40 atm of CO,
DMF, 100 °C, 17 h), 14 (0.14 g, 0.5 mmol) gave methyl 2-(n-butyl)-
6-(methoxycarbonyl)-6-methylcyclohex-2-enone (37) in 28% NMR
yield and (Z)-2-(n-butyl)-6-methyl-2,6-heptadienoate (38) in 39% NMR
yield. Chromatography on silica gel (10/1 n-hexane-ethyl acetate)
afforded 30 mg (25%) of 37 and 40 mg (38%) of 38. 37: 1H NMR δ
0.90 (t, J ) 7.0 Hz, 3 H), 1.28 (s, 3 H), 1.2-1.45 (m, 4 H), 1.7-2.45
(m, 6 H), 2.38 (d, J ) 15.5 Hz, 1 H), 2.75 (d, J ) 15.5 Hz, 1 H), 3.64
(s, 3 H), 6.60 (t, J ) 4.0 Hz, 1 H); 13C NMR δ 13.92, 21.96, 22.48,
22.68, 29.67, 30.82, 33.04, 41.86, 43.43, 51.38, 138.15, 142.77, 172.03,
201.87; IR (neat) 1736, 1670 cm-1; HRMS calcd for C14H22O3 (M+)
238.1569, found 238.1568. 38: 1H NMR 0.89 (t, J ) 7.3 Hz, 3 H),
1.2-1.45 (m, 4 H), 1.72 (s, 3 H), 2.12 (t, J ) 7.3 Hz, 2 H), 2.25 (t, J
) 7.0 Hz, 2 H), 2.55 (q, J ) 7.0 Hz, 2 H), 3.73 (s, 3 H), 4.68 (bs, 1
H), 4.72 (bs, 1 H), 5.84 (t, J ) 7.0 Hz, 1 H); 13C NMR 13.91, 22.21,
22.34, 27.61, 31.31, 34.24, 37.38, 51.16, 110.45, 132.19, 141.06, 144.93,
168.62.
Pd-Catalyzed Carbonylation of ω-Alkene-Containing Alkenyl
Iodides in the Presence of an Alcohol (Table 2, Eqs 2 and 3). (a)
Carbonylation of 17. Representative Procedure (Conditions III).
(i) A mixture of 17 (204 mg, 0.5 mmol), Et3N (0.28 mL, 0.20 g, 2.0
mmol), Cl2Pd(PPh3)2 (17 mg, 0.025 mmol), and MeOH (2.0 mL, 1.58
g, 49 mmol) was stirred at 65 °C (temperature of the oil bath) at 1 atm
of CO for 40 h, treated with H2O, extracted with Et2O, dried over
MgSO4, filtered, and evaporated. Analysis of the crude reaction mixture
1
by H NMR spectroscopy showed the formation of 5,5-bis(methoxy-
carbonyl)-2-(n-butyl)-3-methyl-3-((methoxycarbonyl)methyl)cyclohex-
ene (52a) in 18% NMR yield along with less than a 1% NMR yield of
1-(n-butyl)-4,4-bis(methoxycarbonyl)-6-methylbicyclo[4.1.0]hept-2-
ene (53) and an 82% NMR yield of (Z)-2-methyl-4,4,7-tris(methoxy-
carbonyl)-1,6-undecadiene (54a). Chromatography on silica gel (93/7
pentane-Et2O) afforded 124 mg (73%) of 54a: 1H NMR δ 0.89 (t, J
) 7.1 Hz, 3 H), 1.2-1.45 (m, 4 H), 1.64 (s, 3 H), 2.2-2.3 (m, 2 H),
2.71 (s, 2 H), 3.03 (d, J ) 7.2 Hz, 2 H), 3.71 (s, 6 H), 3.73 (s, 3 H),
(l) Carbonylation of 15. Under Conditions IV (70 atm of CO,
MeCN, 100 °C, 24 h), 15 (33.5 mg, 0.12 mmol) gave 2.6 mg (10%) of
methyl (Z)-2-(n-butyl)-2,6-octadienoate (40) and 9.7 mg (34%) of a
mixture of 6-(1′-(methoxycarbonyl)ethyl)-2-(n-butyl)cyclohex-2-enone
(39) (diastereomeric ratio ) 89:11) and 6-(2′-(methoxycarbonyl)ethyl)-
2-(n-butyl)cyclohex-2-enone (42) (39:42 ) 61:39). 40: 1H NMR δ
0.90 (m, 3 H), 1.2-1.5 (m, 4 H), 1.6 (s, 3 H), 2.1-2.5 (m, 6 H), 3.75
(s, 3 H), 5.3-5.6 (m, 3 H); IR (neat) 1718, 1620 cm-1; HRMS calcd
for C13H22O2 (M+) 210.1620, found 210.1627. 39: 1H NMR δ 0.89
(t, J ) 6.9 Hz, 3 H), [1.12 (d, J ) 7.6 Hz), 1.28 (d, J ) 7.6 Hz), 3 H],
1.2-1.4 (m, 4 H), 1.9-2.05 (m, 2 H), 2.1-2.25 (m, 2 H), 2.35-2.5
(m, 2 H), 2.6-2.75 (dt, J ) 5.0 and 11.5 Hz, 1 H), 2.9-3.05 (m, 1 H),
3.68 (s, 3 H), 6.67 (t, J ) 3.8 Hz, 1 H); 13C NMR δ 13.99, 14.41,
22.98, 25.96, 26.29, 29.84, 31.30, 13.99, 14.41, 22.98, 25.96, 26.29,
29.84, 31.30, 39.36, 50.30, 52.15, 140.30, 144.24, 175.84, 199.55; IR
(neat) 1736, 1670 cm-1; HRMS calcd for C14H22O3 (M+) 238.1569,
found 238.1569. 42: 1H NMR δ 0.90 (t, J ) 7.0 Hz, 3 H), 1.25-1.45
(m, 4 H), 1.85 (m, 2 H), 2.0-2.5 (m, 7 H), 2.42 (t, J ) 7.7 Hz, 2 H),
3.78 (s, 3 H), 6.62 (t, J ) 3.8 Hz, 1 H); 13C NMR δ 13.93, 22.50,
25.02, 25.13, 28.50, 29.37, 30.83, 31.71, 45.96, 51.56, 139.43, 143.59,
175.00, 200.50; IR (neat) 1736, 1670 cm-1; HRMS calcd for C14H22O3
(M+) 238.1569, found 238.1569.
4.70 (s, 1 H), 4.86 (t, J ) 1.5 Hz, 1 H), 5.75 (t, J ) 7.2 Hz, 1 H); 13
C
NMR δ 13.85, 22.18, 23.17, 31.19, 32.72, 34.46, 41.11, 51.31, 52.43,
57.13, 115.86, 133.93, 135.26, 140.25, 168.28, 171.50; IR (neat) 1736
cm-1; HRMS calcd for C18H29O6 (M+ + 1) 341.1964, found 341.1955.
(ii) Carbonylation of 17 (0.5 mmol) under Conditions III (refluxing
MeOH, 30 h) gave 52a in 52% NMR yield along with a 23% NMR
yield of 53 and a 22% NMR yield of 54a. Chromatography on silica
gel (93/7 pentane-Et2O) afforded 77 mg (45%) of 52a: 1H NMR δ
0.89 (t, J ) 7.1 Hz, 3 H), 1.08 (s, 3 H), 1.2-1.5 (m, 4 H), 1.8-2.0 (m,
2 H), 2.1-2.7 (m, 6 H), 3.65 (s, 3 H), 3.69 (s, 3 H), 3.70 (s, 3 H),
5.4-5.5 (m, 1 H); 13C NMR δ 14.09, 22.81, 26.32, 29.70, 30.61, 30.92,
36.70, 39.03, 44.16, 51.25, 51.62, 52.33, 52.58, 118.20, 141.53, 171.80,
172.17, 172.46; IR (neat) 1736 cm-1; HRMS calcd for C18H29O4 (M+
+ 1) 341.1964, found 341.1947.
(iii) Carbonylation of 17 (0.5 mmol) under Conditions III (refluxing
EtOH (70 equiv), 24 h) gave 5,5-bis(methoxycarbonyl)-2-(n-butyl)-3-
methyl-3-((ethoxycarbonyl)methyl)cyclohexene (52b) in 30% NMR
yield along with a 2% NMR yield of 53 and a 59% NMR yield of
(Z)-4,4-bis(methoxycarbonyl)-2-methyl-7-(ethoxycarbonyl)-1,6-undeca-
diene (54b). Chromatography on silica gel (90/10 pentane/Et2O)
afforded 46 mg (26%) of 52b and 80 mg (45%) of 54b. 52b: 1H
NMR δ 0.90 (t, J ) 7.1 Hz, 3 H), 1.07 (s, 3 H), 1.2-1.5 (m, 7 H),
1.85-2.0 (m, 2 H), 2.1-2.7 (m, 6 H), 3.69 (s, 3 H), 3.70 (s, 3 H), 4.11
(q, J ) 7.1 Hz, 2 H), 5.4-5.5 (m, 1 H); 13C NMR δ 14.09, 14.26,
22.83, 26.40, 29.72, 30.64, 30.91, 36.80, 39.08, 44.54, 51.57, 52.30,
52.59, 60.08, 118.15, 141.59, 171.35, 172.18, 172.50; IR (neat) 1736
cm-1; HRMS calcd for C19H30O6 (M+) 354.2042, found 354.2035.
54b: 1H NMR δ 0.89 (t, J ) 7.1 Hz, 3 H), 1.2-1.45 (m, 7 H), 1.64
(s, 3 H), 2.2-2.3 (m, 2 H), 2.71 (s, 2 H), 3.03 (d, J ) 7.2 Hz, 2 H),
3.71 (s, 6 H), 4.20 (q, J ) 7.1, 2 H), 4.71 (s, 1 H), 4.8-4.9 (m, 1 H),
Study of the Chemoselectivity in the Pd-Catalyzed Acylpalla-
dation Reaction (Scheme 6). (a) Lactonization vs Acylpalladation.
Carbonylation of 12 (119 mg, 0.5 mmol) under Conditions IV (DMF,
MeOH (10 equiv), 100 °C, 12 h) gave 2-(3′-butenyl)-2-buten-4-olide
(44) in 87% NMR yield with no sign (<1%) of the formation of 43.
Chromatography on silica gel (95/5 pentane-Et2O) afforded 60 mg
(87%) of 44: 1H NMR δ 2.3-2.5 (m, 4 H), 4.75-4.85 (m, 2 H), 5.0-
5.15 (m, 2 H), 5.7-5.9 (m, 1 H), 7.1-7.2 (m, 1 H); 13C NMR δ 24.55,

5930 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Negishi et al.
5.73 (t, J ) 7.2 Hz, 1 H); 13C NMR δ 13.77, 14.18, 22.09, 23.07,
31.10, 32.64, 34.38, 41.09, 52.33, 57.07, 60.16, 115.81, 133.35, 135.48,
140.17, 167.79, 171.43; IR (neat) 1736 cm-1; HRMS calcd for C19H30O6
(M+) 354.2042, found 354.2035.
119.76, 126.66, 127.82, 130.73, 171.28; IR (neat) 1736 cm-1; HRMS
calcd for C15H22O4 266.1518, found 266.1515.
Pd-Catalyzed Carbonylation of ω-Alkene-Containing Alkenyl
Iodides in the Absence of an Alcohol (Table 3). (a) Carbonylation
of 6. Representative Procedure (Conditions I). A mixture of Pd-
(PPh3)4 (1.16 g, 1.0 mmol), NEt3 (0.16 mL, 1.1 mmol), and (Z)-1-
(trimethylsilyl)-1-iodo-2-(n-hexyl)-1,4-pentadiene (6) (0.35 g, 1.0 mmol)
in THF (5 mL) was heated at 60 °C for 24 h at 1 atm of CO. The
reaction mixture was quenched with aqueous NH4Cl, extracted with
ether, washed with aqueous NaCl, dried over MgSO4, and evaporated.
Column chromatography (Florisil, CH2Cl2) afforded 0.135 g (54%) of
2-(trimethylsilyl)-3-(n-hexyl)-5-methylenecyclopent-2-en-1-one (56):
2a 1H NMR 0.15 (s, 9 H), 0.80 (t, 3 H), 1.2-1.4 (m, 8 H), 2.4 (t, 2 H),
3.05 (s, 2 H), 5.15 (d, J ) 1 Hz, 1 H), 5.85 (d, J ) 1 Hz, 1 H); IR
(iv) Carbonylation of 17 (0.5 mmol) under Conditions III (i-PrOH
(50 equiv), 85 °C, 24 h) gave 52c (R ) i-Pr) in 53% NMR yield along
with a 3% NMR yield of 53 and a 27% NMR yield of 54c (R ) i-Pr).
(v) Carbonylation of 17 (0.5 mmol) under Conditions III (refluxing
i-PrOH (50 equiv), 24 h) gave a 64% NMR yield of 5,5-bis-
(methoxycarbonyl)-2-(n-butyl)-3-methyl-3-((isopropoxycarbonyl)meth-
yl)cyclohexene (52c) along with a 10% yield of 53 and a 6% yield of
(Z)-4,4-bis(methoxycarbonyl)-2-methyl-7-(isopropoxycarbonyl)-1,6-un-
decadiene (54c). Chromatography on silica gel afforded 111 mg (55%)
of 52c and 5 mg (3%) of 54c. 52c: 1H NMR δ 0.90 (t, J ) 7.1 Hz,
3 H), 1.05 (s, 3 H), 1.2-1.5 (m, 10 H), 1.85-2.0 (m, 2 H), 2.1-2.4
(m, 4 H), 2.55-2.8 (m, 2 H), 3.68 (s, 3 H), 3.70 (s, 3 H), 5.00 (sept,
J ) 6.2 Hz, 1 H), 5.4-5.5 (m, 1 H); 13C NMR δ 14.10, 21.86, 22.85,
326.47, 29.72, 30.66, 30.85, 36.90, 39.08, 44.99, 51.56, 52.26, 52.61,
(neat) 1750, 1690, 1650 cm-1
.
(b) Carbonylation of 7. Under the same conditions as above (1
atm of CO, THF, 1 equiv of Pd(PPh3)4, NEt3 (1.1 equiv) 60 °C, 24 h),
7 (1.11 g, 5.0 mmol) gave 0.31 g (51%) of methylenomycin B (57)24
after Kugelrohr distillation (60 °C at 0.1 mmHg): 1H NMR 1.75 (s, 3
H), 2.05 (s, 3 H), 3.05 (br s, 2 H), 5.3 (d, J ) 1 Hz, 1 H), 6.0 (d, J )
1 Hz, 1 H); 13C NMR 8.23, 16.64, 36.97, 114.85, 138.23, 141.78,
67.44, 118.06, 141.58, 170.85, 172.16, 172.51; IR (neat) 1736 cm-1
;
HRMS calcd for C20H32O6 (M+) 368.2199, found 368.2191. The
following signals are discernible for 54c: 1H NMR δ 0.88 (t, J ) 7.0
Hz, 3 H), 1.1-1.4 (m, 10 H), 1.64 (s, 3 H), 2.1-2.3 (m, 2 H), 2.71 (s,
2 H), 3.02 (d, J ) 7.1 Hz, 2 H), 3.71 (s, 6 H), 4.6-4.9 (m, 2 H),
5.0-5.2 (m, 1 H), 5.69 (t, J ) 7.1 Hz, 1 H).
164.02, 196.04; IR (neat) 1690, 1665, 1630 cm-1
.
(c) Carbonylation of 18. Under similar conditions as above (1 atm
of CO, THF, 1 equiv of Pd(PPh3)4, 4 equiv of Et3N, 60 °C, 24 h), 18
(140 mg, 0.5 mmol) gave, after purification by preparative TLC (SiO2,
19/1 hexanes-EtOAc), 62 mg (70% yield, 76% by NMR) of 65: 1H
NMR δ 0.9-1.0 (m, 6 H), 1.4-1.65 (m, 4 H), 2.28 (t, J ) 7.6 Hz, 2
H), 2.48 (t, J ) 7.7 Hz, 2 H), 3.12 (s, 2 H), 3.12 (s, 2 H), 5.37 (s, 1 H),
6.07 (s, 1 H); 13C NMR δ 14.16 (2 C), 20.82,21.75, 25.43, 32.56, 34.40,
115.08, 141.75, 142.39, 168.06, 196.31; HRMS calcd for C12H18O (M+)
178.1358, found 178.1360.
The results of the carbonylation reaction of 18 run under other
conditions were summarized in Table 3 (entries 3-5 to 3-8).
(d) Carbonylation of 4 To Give 5. The details of this experiment
have been previously described.5
(e) Carbonylation of 19. Under Conditions II (40 atm of CO, DMF,
Cl2Pd(PPh3)2 (5 mol %), 100 °C, 12 h), 19 (0.35 g, 1.0 mmol) gave
2,3-dipropyl-5-hexylidenecyclopent-2-enone (31) in 82% NMR yield
(E/Z ) 70/30). Chromatography on silica gel afforded 0.04 g (16%)
of the Z isomer and 0.14 g (56%) of the E isomer. (Z)-31: 1H NMR
δ 0.8-1.0 (m, 9 H), 1.2-1.65 (m, 10 H), 2.18 (t, J ) 7.7 Hz, 2 H),
2.38 (t, J ) 7.7 Hz, 2 H), 2.7-2.9 (m, 2 H), 3.00 (s, 2 H), 5.96 (t, J
) 7.6 Hz, 1 H); 13C NMR δ 14.04, 14.20, 20.99, 21.85, 22.53, 25.33,
27.36, 29.14, 31.59, 32.41, 35.72, 132.80, 139.84, 143.86, 165.83,
197.65. E-31: 1H NMR δ 0.8-1.05 (m, 9 H), 1.25-1.75 (m, 10 H),
2.1-2.5 (m, 6 H), 3.03 (s, 2 H), 6.57 (t, J ) 7.2 Hz, 1 H); IR (neat)
1628, 1654, 1688 cm-1; HRMS calcd for C17H29O (M+) 249.2218,
found 249.2200.
(f) Carbonylation of 20. Under Conditions II (40 atm of CO, DMF,
Cl2Pd(PPh3)2 (5 mol %), 100 °C, 24 h), 20 (0.354 g, 1.0 mmol) gave
2,3-dipropyl-5-benzylidenecyclopent-2-enone (33) in 100% NMR yield
(E/Z ) 45:55). Chromatography on silica gel (95/5 hexane-Et2O)
afforded 0.13 g (52%) of the Z isomer and 0.12 g (48%) of the E isomer.
(Z)-33: isomer: 1H NMR δ 0.92 (t, J ) 7.3 Hz, 3 H), 1.0 (t, J ) 7.3
Hz, 3 H), 1.35-1.7 (m, 4 H), 2.25 (t, J ) 7.7 Hz, 2 H), 2.45 (t, J )
7.7 Hz, 2 H), 3.25 (s, 2 H), 6.74 (s, 1 H), 7.3-7.45 (m, 3 H), 8.0-8.1
(m, 2 H); 13C NMR δ 14.15, 14.19, 20.92, 21.78, 25.57, 32.36, 37.72,
127.85, 129.07, 130.69, 133.66, 34.67, 135.02, 144.33, 165.56, 194.8;
IR (neat) 1612, 1644, 1678 cm-1. (E)-33: 1H NMR δ 0.83 (t, J ) 7.0
Hz, 3 H), 1.0 (t, J ) 7.0 Hz, 3 H), 1.4-1.75 (m, 4 H), 2.28 (t, J ) 7.6
Hz, 2 H), 2.5 (t, J ) 7.7 Hz, 2 H), 3.41 (s, 2 H), 7.35-7.5 (m, 4 H),
7.55-7.6 (m, 2 H); 13C NMR δ 14.14, 14.19, 20.99, 21.83, 25.45, 32.56,
34.93, 128.73, 128.96, 129.78, 130.21, 133.34, 135.70, 141.80, 166.82,
197.39; IR (neat) 1690, 1652, 1622 cm-1; HRMS calcd for C18H23O
(M+ + 1) 255.1749, found 255.1711.
(vi) Carbonylation of 17 (0.5 mmol) under Conditions III (2/1
mixture of DMF and MeOH (50 equiv), 85 °C, 1 h) gave 52a in 63%
NMR yield along with an 8% NMR yield of 53, and a less than 3%
NMR yield of 54a.
(vii) Carbonylation of 17 (0.5 mmol) under Conditions III (2/1/0.1
mixture of DMF, MeOH (50 equiv), and H2O (10 equiv), 85 °C, 1 h)
afforded 52a in 81% NMR yield along with a 3% NMR yield of 53
and a less than 3% NMR yield of 54a. Chromatography on silica gel
afforded 126 mg (74%) of 52a.
(viii) Pd-Catalyzed cyclization of 17 (0.5 mmol) in the absence of
CO using 5 mol % of Cl2Pd(PPh3)2 and NEt3 (4 equiv) in refluxing
MeCN for 48 h gave 53 in 75% NMR yield along with the starting
material (5% of the initial amount). Chromatography on silica gel (97/3
pentane-Et2O) afforded 99 mg (71%) of 53: 1H NMR δ 0.4-0.5 (m,
2 H), 0.8-0.95 (m, 3 H), 1.2-1.4 (m, 9 H), 1.98 (d, J ) 4.0 Hz, 1 H),
2.60 (d, J ) 4.0 Hz, 1 H), 3.71 (s, 3 H), 3.72 (s, 3 H), 5.66 (d, J )
10.0 Hz, 1 H), 6.14 (d, J ) 10.0 Hz, 1 H); 13C NMR δ 14.10, 21.47,
21.97, 23.01, 24.48, 29.66, 30.32, 33.23, 34.62, 52.85, 54.27, 119.55,
137.36, 171.58, 172.26; IR (neat) 1738 cm-1; HRMS calcd for C16H24O4
(M+ 280.1675, found 280.1674.
(b) Carbonylation of 14. Under Conditions III (2/1 mixture of DMF
and MeOH, 85 °C, 1 h), 14 (0.5 mmol) afforded 2-(n-butyl)-3-methyl-
3-((methoxycarbonyl)methyl)-1-cyclopentene (55) in 63% NMR yield
along with a 16% yield of 38 and a trace (<2%), if any, of 37.
Chromatography on silica gel (97/3 pentane-Et2O) afforded 58 mg
(56% yield) of 55: 1H NMR δ 0.84 (t, J ) 7.3 Hz, 3 H), 1.09 (s, 3 H),
1.15-2.3 (m, 12 H), 3.56 (s, 3 H), 5.24 (s, 1 H); 13C NMR δ 14.02,
22.81, 24.99, 26.11, 29.24, 30.10, 37.27, 43.34, 48.71, 51.12, 110.35,
122.45, 172.76; IR (neat) 1734 cm-1; HRMS calcd for C13H22O2 (M+)
210.1620, found 210.1622. In the NMR spectra of the crude product,
the following signals for 38 were discernible: 1H NMR δ 2.48 (q, J )
7.4 Hz, 2 H), 3.66 (s, 3 H), 4.62 (bs, 1 H), 4.65 (bs, 1 H), 5.78 (t, J )
7.2 Hz, 1 H); 13C NMR δ 13.84, 22.14, 22.26, 27.57, 31.26, 34.17,
37.33, 132.15, 141.00, 144.90, 149.90, 168.95.
(c) Carbonylation of 49. Under Conditions III (2/1 mixture of DMF
and MeOH (50 equiv), 85 °C, 50 h), 49 (197 mg, 0.5 mmol) gave a
37% NMR yield of 5,5-bis(methoxycarbonyl)-2-(n-butyl)-3-methyl-
enecyclohexene (50a) along with a 17% yield of 5,5-bis(methoxycar-
bonyl)-2-(n-butyl)-1-methyl-1,3-cyclohexadiene (50b). Chromatogra-
phy on silica gel afforded 50 mg (45%) of a 2:1 mixture of 50a and
50b. 50a: 1H NMR δ 0.89 (t, J ) 7.1 Hz, 3 H), 1.2-1.45 (m, 4 H),
2.16 (t, J ) 7.2 Hz, 2 H), 2.65-2.75 (m, 2 H), 2.87 (s, 2 H), 3.70 (s,
6 H), 4.9 (bs, 1 H), 5.03 (bs, 1 H), 5.55-6.05 (m, 1 H); 13C NMR δ
13.92, 22.51, 30.61, 31.73, 32.07, 37.59, 52.60, 54.20, 110.67, 123.07,
136.74, 138.99, 171.39. The following signals were discernible for
50b: 1H NMR δ 1.77 (s, 3 H), 2.0-2.1 (m, 2 H), 2.72 (s, 2 H), 3.71
(s, 3 H), 5.80 (d, J ) 9.5 Hz, 1 H), 5.97 (d, J ) 9.5 Hz, 1 H); 13C
NMR (CDCl3) δ 13.92, 18.76, 22.10, 30.52, 30.93, 35.94, 52.74, 54.64,
(g) Carbonylation 21. Under Conditions II (100 atm of CO, DMF,
Cl2Pd(PPh3)2 (5 mol %), Et3N (2 equiv), 100 °C, 24 h), 21 (170 mg,
0.5 mmol) gave 2,3-dipropyl-5-cyclohexylidenecyclopent-2-enone (35)
in 77% NMR yield. Chromatography on silica gel (95/5 hexane-Et2O)
afforded 0.057 g (48%) of 35: 1H NMR δ 0.90 (t, J ) 7.7 Hz, 3 H),
0.95 (t, J ) 7.7 Hz, 3 H), 1.3-1.7 (m, 10 H), 2.1-2.3 (m, 4 H), 2.4
0 (t, J ) 7.7 Hz, 2 H), 2.99 (s, 2 H), 3.0-3.15 (m, 2 H); 13C NMR δ
14.13, 20.97, 21.81, 25.37, 26.40, 28.00, 32.32, 33.76, 34.34, 125.78,

Pd-Catalyzed Cyclization of 1-Iodo-Substituted Dienes
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5931
143.88, 151.66, 163.32, 197.58; IR (neat) 1628, 1654, 1680 cm-1
;
206.1307, found 206.1307. Another experiment run in DMF in place
of benzene led to a 47% NMR yield of 63 (entry 3-17).
HRMS calcd for C17H27O (M+ + 1) 247.2062, found 247.2062.
(h) Carbonylation of 13. Under Conditions II (40 atm of CO,
benzene, Cl2Pd(PPh3)2 (5 mol %), 100 °C, 47 h), 13 (50 mg, 0.189
mmol) gave 60 in 53% NMR yield. Chromatography on silica gel
(10/1 hexane-EtOAc) afforded 15.4 mg (42%) of 2-(n-butyl)-9-
oxabicyclo[4.3.0]nona-1,6-dien-8-one (60): 1H NMR δ 0.92 (t, J )
7.2 Hz, 3 H), 1.2-1.6 (m, 4 H), 1.75-1.95 (m, 2 H), 2.25-2.4 (m, 4
H), 2.66 (t, J ) 7.0 Hz, 2 H), 5.70 (s, 1 H); 13C NMR δ 13.79, 22.53,
22.75, 24.16, 27.86, 29.36, 30.46, 109.28, 127.44, 145.95, 155.59,
170.50; IR (neat) 1716 cm-1; HRMS calcd for C12H16O2 (M+) 192.1150,
found 192.1153.
(i) Carbonylation of 1. At 40 atm of CO in the presence of Pd-
(OAc)2 (10 mol %) and Et3N (3 equiv) in MeCN at 100 °C for 24 h,
1 (54.6 mg, 0.187 mmol) gave 13 mg (36%) of 2-(n-hexyl)bicyclo-
[3.2.0]hept-2-en-7-one (2) by chromatography on silica gel (20/1
hexane-EtOAc): 1H NMR δ 0.89 (t, J ) 7.0 Hz, 3 H), 1.1-1.7 (m,
8 H), 2.0-3.5 (m, 7 H), 4.15 (bs, 1 H), 5.55 (bs, 1 H); 13C NMR δ
14.08, 22.68, 26.52, 27.51, 29.61, 29.96, 31.74, 40.21, 53.46, 75.29,
125.29, 139.94, 206.71; IR (neat) 1775, 1637 cm-1; HRMS calcd for
C13H21O (M+ + 1) 193.1592, found 193.1592. The results of another
experiment run under Conditions II are summarized in Table 3 (entry
3-15).
(k) Carbonylation of 15. Under Conditions II (40 atm of CO,
benzene, Cl2Pd(PPh3)2 (5 mol %), 100 °C, 22 h), 15 (34.5 mg, 0.124
mmol) gave 2-(n-butyl)-6-ethylidenecyclohex-2-enone (41) (E/Z ) 40/
60) in 34% NMR yield and 2-(n-butyl)-7-methyl-9-oxabicyclo[4.3.0]-
nona-1,6-dien-8-one (64a) and 2-(n-butyl)-10-oxabicyclo[4.4.0]deca-
1(6),2-dien-9-one (64b) in 33% NMR yield. Chromatography on silica
gel (20/1 hexane-EtOAc) afforded 5.9 mg (27%) of 41 and 8.2 mg
(32%) of 64a (contaminated with 64b to the extent of 8%). 41: 1H
NMR δ 0.91 (t, J ) 7.0 Hz, 3 H), 1.25-1.3 (m, 4 H), 1.70 (d, J ) 6.8
Hz, 3 H, E isomer), 2.00 (d, J ) 6.8 Hz, Z isomer), 2.1-2.45 (m, 4
H), 2.5-2.7 (m, 2 H), 5.90 (q, J ) 6.8 Hz, 1 H, Z isomer), 6.85 (q, J
) 6.8 Hz, 1 H, E isomer); IR (neat) 1638 cm-1; HRMS calcd for
C12H18O (M+) 178.1358, found 178.1362, 64a: 1H NMR δ 0.90 (m, 3
H), 1.25-1.5 (m, 4 H), 1.5-1.8 (m, 2 H), 2.1-2.25 (m, 2 H), 2.2 (s,
3 H), 2.26 (t, J ) 6.50 Hz, 2 H), 2.65 (t, J ) 6.50 Hz, 2 H); IR (neat)
1718, 1630 cm-1; HRMS calcd for C13H18O2 (M+) 206.1307, found
206.1303.
Methanolysis of 63. A mixture of 63 (10.5 mg, 0.051 mmol) and
NaOMe (14 mg, 0.26 mmol) in MeOH (1 mL) was heated at 70 °C for
5 h. Filtration through a short column of silica gel (10/1 hexane-
ethyl acetate) afforded 9.2 mg (85%) of 37.
(j) Carbonylation of 14. Under Conditions II (40 atm of CO,
benzene, Cl2Pd(PPh3)2 (5 mol %), 100 C, 23 h), 14 (35 mg, 0.126 mmol)
gave 2-(n-butyl)-6-methyl-9-oxabicyclo[4.3.0]nona-1,6-dien-8-one (63)
in 46% NMR yield. Chromatography on silica gel (10/1 hexane-
EtOAc) afforded 12 mg (46%) of 63: 1H NMR δ 0.88 (t, J ) 7.7 Hz,
3 H), 1.08 (s, 3 H), 1.2-1.5 (m, 4 H), 2.3-2.35 (m, 2 H), 2.32 (d, J
) 4.1 Hz, 2 H), 2.52 (d, J ) 4.3 Hz, 1 H), 5.63 (dt, J ) 4.3 and 9.4
Hz, 1 H), 5.90 (dt, J ) 1.2 and 9.4 Hz, 1 H); 13C NMR δ 13.89, 21.63,
22.17, 27.26, 30.36, 36.78, 36.89, 44.10, 109.76, 120.51, 126.90, 150.84,
174.20; IR (neat) 1736, 1678 cm-1; HRMS calcd for C13H18O2 (M+)
Acknowledgment. We thank the National Institutes of
Health (GM 36792) for support of this research. Johnson
Matthey kindly provided PdCl2. C.C. was a Purdue Research
Foundation Graduate Research Fellow (1993-94). Y. Zhang,
G. Wu, I. Shimoyama, T. Sugihara, and T. Mita have made
some direct and indirect contributions to this work. This paper
is dedicated to the memory of Professor Wolfgang Oppolzer.
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