Nickel-catalyzed organozinc-promoted carbocyclizations of electron-deficient alkenes with tethered unsaturation

Article abstract of DOI:10.1021/ja9702125

A nickel-catalyzed method for cyclizations of electron- deficient alkenes with tethered unsaturation in the presence of organozincs was developed. Considerable flexibility in the structure of each reactive component was observed, Enones, alkylidene malonates, unsaturated β-ketoesters, and nitroalkenes participated as the electrondeficient alkene; alkynes, enones, 1,3- dienes, and aldehydes participated as the tethered unsaturation; and a variety of sp² and sp³-hybridized organozincs, including those that possess β-hydrogens, participated as the nucleophilic component. Substrate structure, organozinc structure, and ligand structure all played a significant role in determining product selectivities. Of particular synthetic significance was the opportunity to prepare either E or Z tri- or tetrasubstituted alkenes from a common alkyne. A discussion of probable mechanisms is provided.

Full text of DOI:10.1021/ja9702125

J. Am. Chem. Soc. 1997, 119, 4911-4920
4911
Nickel-Catalyzed Organozinc-Promoted Carbocyclizations of
Electron-Deficient Alkenes with Tethered Unsaturation
John Montgomery,* Eric Oblinger, and Alexey V. Savchenko
Contribution from the Department of Chemistry, Wayne State UniVersity,
Detroit, Michigan 48202-3489
ReceiVed January 22, 1997X
Abstract: A nickel-catalyzed method for cyclizations of electron-deficient alkenes with tethered unsaturation in the
presence of organozincs was developed. Considerable flexibility in the structure of each reactive component was
observed. Enones, alkylidene malonates, unsaturated â-ketoesters, and nitroalkenes participated as the electron-
deficient alkene; alkynes, enones, 1,3-dienes, and aldehydes participated as the tethered unsaturation; and a variety
of sp2 and sp3-hybridized organozincs, including those that possess â-hydrogens, participated as the nucleophilic
component. Substrate structure, organozinc structure, and ligand structure all played a significant role in determining
product selectivities. Of particular synthetic significance was the opportunity to prepare either E or Z tri- or
tetrasubstituted alkenes from a common alkyne. A discussion of probable mechanisms is provided.
Introduction
Transition-metal catalysis provides the basis for many
important methods for complex ring system construction.1
Features of metal-mediated cyclizations that contribute to their
general utility include the impressive levels of complexity that
may be rapidly introduced from simple precursors, the facility
with which sterically-congested quaternary centers may be
introduced, and the mildness of reaction conditions accompanied
by high chemoselectivities and functional group tolerance.
Numerous strategies for initiating transition metal-catalyzed
cyclizations exist, with oxidative addition,2 metallacycle forma-
tion,3 and olefin metathesis4 representing some of the more
commonly encountered methods. The observation by Mack-
enzie that nickel(0) undergoes oxidative addition to enals in
the presence of trialkylsilyl chlorides led us to consider this
fundamental process as a method for initiating metal-catalyzed
cyclizations (eq 1).5 Whereas the mechanistic issues associated
with the transformations described herein are complex and
somewhat speculative at this stage (Vide infra), we have
considered the oxidative addition of nickel(0) to enones in the
presence of Lewis acids to produce reactive π-allyl complexes
as a working mechanistic model for the development of a new
method for initiating metal-catalyzed cyclizations.6
Three principal reaction manifolds have been discovered
during the course of our investigations: direct conjugate
addition, alkylative cyclization, and reductive cyclization.7 An
electron deficient alkene, a tethered unsaturation, and a Lewis
acidic main group organometallic are essential components of
the cyclizations. Whereas the results of Mackenzie dealt
exclusively with silyl chlorides as the Lewis acidic component
in the oxidative addition described above, we initially considered
the use of organozincs as an integral component in the coupling
reactions. The choice of this particular main group organome-
tallic derives from the studies of Negishi,8 Knochel,9 Grigg,10
and others who demonstrated many applications of organozincs
in metal-mediated cross-coupling procedures, and from the
studies of Luche who demonstrated that organozincs smoothly
underwent conjugate addition to enones in the presence of Ni-
(acac)2.11 Apparently organozincs offer appropriate Lewis
acidity to facilitate the interaction of low valent nickel catalysts
with enones while maintaining sufficient nucleophilicity to allow
unstabilized carbon substituents to readily transmetalate with
reactive intermediate nickel complexes. Our studies reported
herein provide a description of the range of electron-deficient
alkenes, tethered unsaturations, and organozincs that efficiently
undergo nickel-catalyzed cyclizations as well as preliminary
insight into the reaction mechanism.
X Abstract published in AdVance ACS Abstracts, May 1, 1997.
(1) For representative examples: (a) Trost, B. M; Shi, Y. J. Am. Chem.
Soc. 1993, 115, 9421. (b) Kucera, D. J.; O’Connor, S. J.; Overman, L. E.
J. Org. Chem. 1993, 58, 5304. (c) Cope´ret, C.; Ma, S.; Negishi, E. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2125. (d) Ojima, I.; Tzamarioudaki, M.;
Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635.
(2) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science: Mill Valley, CA, 1994; pp 103-
113. (b) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423.
(3) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science: Mill Valley, CA, 1994; pp 115-
123. (b) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182. (c) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787.
(d) Knight, K. S.; Wang, D.; Waymouth, R. M. Ziller, J. J. Am. Chem.
Soc. 1994, 116, 1845.
(4) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem Res. 1995, 28,
446.
(5) (a) Johnson, J. R.; Tully, P. S.; Mackenzie, P. B.; Sabat, M. J. Am.
Chem. Soc. 1991, 113, 6172. (b) Grisso, B. A.; Johnson, J. R.; Mackenzie,
P. B. J. Am. Chem. Soc. 1992, 114, 5160.
(6) For other examples of π-allyl complex-initiated cyclizations: (a)
Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 38. (b) Oppolzer, W.
Pure Appl. Chem. 1990, 62, 1941.
Results
Cyclizations of electron deficient alkenes tethered to terminal
alkynes upon exposure to Ni(COD)2 and an organozinc in THF
(7) Portions of this work have previously been communicated. (a)
Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099. (b)
Savchenko, A. V.; Montgomery, J. J. Org. Chem. 1996, 61, 1562.
(8) Negishi, E. Pure Appl. Chem. 1992, 64, 323.
(9) Knochel, P. Synlett 1995, 393.
(10) Grigg, R.; Dorrity, M. J.; Malone, J. F.; Sridharan, V.; Sukirthal-
ingam, S. Tetrahedron Lett. 1990, 31, 1343.
(11) Petrier, C.; de Souza Barbosa, J. C.; Dupuy, C.; Luche, J. L. J.
Org. Chem. 1985, 50, 5761.
S0002-7863(97)00212-6 CCC: $14.00 © 1997 American Chemical Society

4912 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Montgomery et al.
Table 1. Variation of the Electron-Deficient Componentd
at 0 °C were generally efficient in the production of alkylidene
cycloalkanes, with a significant ligand effect being observed.
Reactions carried out in the absence of additional ligands led
to completely stereoselective alkylative cyclizations in which
the organozinc ligand was incorporated into the cycloadduct,
whereas pretreatment of the catalyst with 4 equiv of triphen-
ylphosphine and the use of organozincs bearing sp3-hybridized
substituents with â-hydrogens led to efficient reductive cycliza-
tions with hydrogen atom incorporation rather than introduction
of the organozinc substituent (eq 2). Variation of the electron-
deficient component demonstrated that a highly electrophilic
alkene is a requirement for the organozinc/nickel (0)-promoted
cyclizations. Enones, nitroalkenes, and doubly-activated olefins
such as alkylidene malonates and unsaturated â-ketoesters were
the most efficient electron-deficient components that we have
studied (Table 1).
The exceedingly mild reaction conditions (often minutes at
0 °C in THF) afford obvious advantages in terms of chemose-
lectivities. For instance, the nickel-catalyzed direct conjugate
addition of organozincs to each of the above-mentioned
functional groups readily proceeds at room temperature; how-
ever, this undesired reaction pathway rarely competes with
alkyne insertion under the catalytic conditions. Reaction
efficiencies rapidly diminish as the electrophilicity of the enone
component decreases. Reactions with enoates tethered to
alkynes led to poor yields of the expected cyclized products. In
most instances, alkylidene malonate cyclization followed by
decarboxylation should be the most efficient strategy for
obtaining products in the carboxylic acid oxidation state. With
sterically-demanding substrates, such as those leading to spi-
rocyclizations (entry 2, Table 1), alkylative cyclizations were
generally more efficient than reductive cyclizations. Alkylative
cyclizations were also more efficient than reductive cyclizations
involving nitroalkenes, even with unhindered substrates.
a 9% direct conjugate addition was observed. b 45% direct conjugate
addition was observed. c Obtained as an inseparable mixture. d Method
A: [MeLi + ZnCl2], 5 mol % Ni(COD)2, THF, 0 °C. Method B:
Et2Zn, 5 mol % Ni(COD)2, 20 mol % PPh3, THF, 25 °C.
addition products were observed.13 Enones tethered to another
electron-deficient alkene, however, were efficiently cyclized.
In contrast to reactions with alkynyl enones, reductive cycliza-
tions were observed in the absence of triphenylphosphine with
bis-enones when sp3-hybridized organozincs were employed
(entries 6 and 7, Table 2). High cis selectivities of the
cyclopentyl substituents were typically observed, making the
nickel-catalyzed process complementary to related free-radical
reactions.14 The ketoenolates that resulted from reductive
cyclizations of bis-enones underwent aldol addition to produce
[3.3.0]bicyclooctanes in a stereoselective fashion. The stereo-
selectivity of the aldol addition was variable according to bis-
enone structure. Alkylative cyclization of bis-enones was not
observed under any conditions examined.
Enones tethered to dienes were cyclized in good yield in the
presence of diethylzinc and the catalyst generated from Ni-
(COD)2/PPh3 (entry 8, Table 2). Exclusively trans-alkenyl side
chains were introduced during the cyclizations. However, only
the conjugate addition product was obtained with Ni(COD)2/
Me2Zn-promoted reactions, both in the presence and absence
of PPh3. It is well established that migratory insertions
involving conjugated dienes produces π-allyl complexes,15 and
we speculate that the formation of such an η3-stabilized
intermediate explains why enones tethered to dienes are efficient
substrates for nickel-catalyzed cyclizations, whereas enones
Considerable flexibility was also observed in the scope of
tethered unsaturations tolerated in the nickel-catalyzed cycliza-
tions (Table 2). Both aliphatic and aromatic internal alkynes
were cyclized in modest yield by both alkylative (no PPh3) and
reductive (with PPh3) cyclization protocols (entries 1-3, Table
2). Whereas reductive cyclizations of terminal alkynes pro-
ceeded in very high yield, internal alkynes were less efficient
and typically led to alkylative cyclization byproducts. Reactions
with alkynyl silanes were efficient, leading to stereodefined
exocyclic vinylsilanes (entry 4, Table 2).12 As noted above,
both alkylative and reductive cyclizations occurred by a syn
addition mechanism, leading to the introduction of a single
isomer of the exocyclic tri- or tetrasubstituted alkenes.
Enones tethered to unactivated alkenes failed to cyclize under
all conditions examined (entry 5, Table 2). Both in the presence
and absence of triphenylphosphine, only direct conjugate
(13) These conjugate additions are considerably slower than additions
to enones lacking the pentenyl side chain. Ziegler, F. E.; Wallace, O. B. J.
Org. Chem. 1995, 60, 3626.
(14) (a) Enholm, E. J.; Kinter, K. S. J. Org. Chem. 1995, 60, 4850. (b)
Enholm, E. J.; Kinter, K, S. J. Am. Chem. Soc. 1991, 113, 7784. (c) Hays,
D. S.; Fu, G. C. J. Org. Chem. 1996, 61, 4.
(12) Intermolecular alkyne silylcupration/conjugate addition sequences
afford the opposite alkene stereoisomer. Fleming, I.; Newton, T. W.;
Roessler, F. J. Chem. Soc., Perkin Trans. I 1981, 2527.
(15) Larock, R. C.; Berrios-Pen˜a, N.; Narayanan, K. J. Org. Chem. 1990,
55, 3447.

Ni-Catalyzed Organozinc-Promoted Carbocyclizations
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4913
Table 2. Variation of the Tethered Unsaturationd
a 8% of 16 (R ) H) was isolated. b 16% of 18c (R ) Bu) was isolated. c contaminated with 13% of 20 (R ) Et). Method A: [MeLi + ZnCl2],
5 mol % Ni(COD)2, THF, 0 °C. Method B: Et2Zn, 5 mol % Ni(COD)2, 20 mol % PPh3, THF, 25 °C.
tethered to isolated double bonds afforded only conjugate
addition products. Considering the large body of work devel-
oped by the Wender and Lautens groups on a variety of Ni-
(0)-catalyzed cycloadditions involving unactivated dienes and
dienophiles,16 it is interesting that substrate 27, which is activated
for a normal-demand Diels-Alder reaction, is converted in a
completely chemoselective fashion to the reductive cyclization
product with no cycloaddition products being observed. The
observed reductive cyclizations are reminiscent of the recent
report from Takacs involving diene/allylic ether reductive
cyclizations17 and from Mori involving diene/aldehyde reductive
cyclizations.18ab Further exploration of the chemoselectivity
with related substrates and different catalyst/ligand formulations
is currently in progress.
Aldoenones were also cyclized in moderate yield in the
presence of Ni(COD)2/PPh3 (entries 9-10, Table 2). Both five-
and six-membered rings were formed as diastereomeric mix-
tures.18 This substrate class provides another example of the
highly chemoselective nature of the nickel-mediated cycliza-
tions, as only traces of products derived from organozinc
addition to the aliphatic aldehydes were observed.
in the presence of triphenylphosphine were sluggish. However,
addition of trimethylsilyl chloride to the ZnEt2/PPh3 reactions
resulted in a 2.3:1 mixture of acyclic products 34b (R ) H)
and 35b (R ) H) derived from 1,4-reduction and 1,2-reduction.
Within the cyanoenone substrate class, no cyclization was
observed, but the PPh3 effect of favoring products derived from
â-hydride elimination is consistent with the results previously
obtained with substrate classes that underwent cyclization.
In addition to the electron-deficient component and the
tethered unsaturation, the organozinc substituent is a third
variable that influences product distributions and selectivities.
In reductive cyclizations, the influence of organozinc structure
depends heavily on substrate structure. With alkynylenone
reductive cyclizations, deuterium labeling studies demonstrated
that the major reaction pathway involves â-hydride elimination.7a
As a result, in the presence of triphenylphosphine, diethylzinc
led to reductive cyclization products, whereas dimethylzinc led
nearly exclusively to alkylative cyclization products (eq 3).
Diethylzinc (commercial) and dibutylzinc (generated in situ from
butyllithium and anhydrous zinc chloride) both led to reductive
cyclization, although commercial diethylzinc led to cleaner
reactions with smaller amounts of the product of alkylative
cyclization.
With cyanoenones, direct conjugate addition was observed,
even with sp3-hybridized organozincs that typically effected
cyclization with other substrate classes (entry 11, Table 2).
Treatment of cyanoenone 33 with ZnMe2/MeZnCl in the
presence of Ni(COD)2 resulted in formation of direct conjugate
adduct 34a (R ) Me) in 73% yield. Reactions with diethylzinc
(16) (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111,
6432. (b) Wender, P. A. Smith, T. E. J. Org. Chem. 1995, 60, 2962. (c)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (d) Gugelchuk,
M. M.; Houk, K. N. J. Am. Chem. Soc. 1994, 116, 330.
(17) Takacs, J. M.; Mehrman, S. J. Tetrahedron Lett. 1996, 37, 2749.
(18) For nickel-catalyzed cyclizations involving aldehydes: (a) Sato, Y.;
Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M. J. Am.
Chem. Soc. 1994, 116, 9771. (b) Sato, Y.; Takimoto, M.; Mori, M.
Tetrahedron Lett. 1996, 37, 887. For representative radical cyclization
methods: (c) Enholm, E. J.; Prasad, G. Tetrahedron Lett. 1989, 30, 4939.
(d) See ref 14c.
With bis-enone reductive cyclizations, all sp3-hybridized
organozincs examined, including those that lack â-hydrogens,

4914 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Montgomery et al.
Table 4. Scope of Organozincs in Alkynylenone Cyclizations
Table 3. Dependence of Bicyclooctane Stereochemistry on
Organozinc Structure and Formulationa
a Unless otherwise noted, alkylative cyclization products were
obtained. b 1.2 equiv each of MeLi and ZnCl2 was employed.
alkynyl substrates had little effect on reaction outcomes.
Alkynyl substrates were the only class of compounds examined
that underwent alkylative cyclization. A range of organozincs
generated by transmetalation of the requisite organolithium or
organomagnesium with zinc chloride, including aryl, alkenyl,
and alkyl, either lacking or possessing â-hydrogens, were
efficient components in alkynyl enone cyclizations (Table 4).
A 2- to 3-fold excess of the organozinc was typically used;
however, an experiment with 1.2 equiv each of zinc chloride
and methyl lithium proceeded in only slightly suppressed yield
(Table 4, entry 2). Initial studies employing organozinc iodides
generated by direct insertion of activated zinc into primary alkyl
iodides22 were not successful. In addition to the various
cyclization protocols reported herein, we recently reported
intermolecular three-component couplings of enones, alkynes,
and organozincs.21 Important studies in related intermolecular
three component couplings involving both organozincs and
alkynyltins were reported by Ikeda and Sato.23
a Isolated yields are given.
led to reductive cyclization. This stands in sharp contrast to
the results obtained with reductive cyclizations of alkynyl
substrates (eq 3). However, selectivities between cis-fused
bicyclooctane 24, monocyclic trans-disubstituted isomer 36, and
bis-enone dimer 37 were variable (Table 3). The most efficient
organozinc formulations leading selectively to cis-fused bicy-
clooctanes were 3:2 mixtures of butyllithium:zinc chloride or
3:1 mixtures of diethylzinc and zinc chloride. The poor
selectivities obtained with diethylzinc alone or with diethylzinc
plus lithium chloride suggest that more Lewis acidic alkylzinc
halides may be important for the substrate preorganization that
leads to high cis selectivities.
Although direct conjugate addition to substrates with tethered
unsaturation was rarely observed in these studies, reactive sp2-
hybridized organozincs such as diphenylzinc cleanly underwent
conjugate addition with bis-enones and aldoenones. In both
instances, the kinetic enolate derived from the conjugate addition
efficiently underwent subsequent Michael19 or aldol20 reactions
with the tethered electrophilic component. Bis-enones possess-
ing a three carbon tether between the enone â-carbons produced
trisubstituted cyclohexanes 38 and 39 with predominantly a
triequatorial arrangement of substituents (eq 4), whereas the
corresponding aldoenone produced trisubstituted cyclohexanol
40 possessing an axial hydroxyl as judged by 1H NMR coupling
constants (eq 5). Direct conjugate addition products also
predominated with enones possessing a tethered cyano sub-
stituent and with enones possessing a tethered alkene (entries 5
and 11, Table 2). The involvement of direct conjugate addition
is also problematic with alkynylenone and bis-enone cyclizations
if the tether length is increased.21
Discussion
Whereas the methodological investigations described in this
report involve relatively simple structures, the mild reaction
conditions and operational simplicity should make the general
synthetic procedure amenable to complex applications. One
issue that we imagine will ultimately display particular synthetic
significance is the manner in which tri- and tetrasubstituted
alkenes may be stereoselectively introduced during the cycliza-
tion of alkynyl enones. Beginning with a simple terminal alkyne
of general structure 44, alkylative cyclization in the absence of
triphenylphosphine produces exclusively the Z isomer of the
trisubstituted alkene 45 (Scheme 1). However, alkylation of
the same terminal alkyne followed by reductive cyclization of
the resulting internal alkyne 46 in the presence of triphenylphos-
phine leads exclusively to the E isomer of the trisubstituted
alkene 47. The same flexibility is available in the production
of tetrasubstituted alkenes. Alkylative cyclization of the internal
alkyne 46 produces a single isomer of the tetrasubstituted alkene
48. However, given that the substituents R2 and R3 are
(19) For related tandem Michael additions using other classes of nucleo-
philes: (a) Klimko, P. G.; Singleton, D. A. Synthesis 1994, 979. (b) Shida,
N.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1992, 57, 5049. (c) Saito,
S.; Hirohara, Y. Narahara, O. Moriwake T. J. Am. Chem. Soc. 1989, 111,
4533. (d) Yoshii, E.; Hori, K.; Nomura, K.; Yamaguchi, K. Synlett 1995,
569 and references therein.
(20) For other examples of tandem Michael/aldol reactions: (a) Na¨f, F.;
Decorzant, R.; Thommen, W. HelV. Chim. Acta 1975, 58, 1808. (b) Ho, T.
Tandem Organic Reactions; Wiley: New York, 1992; pp 4-18.
(21) Montgomery, J.; Seo, J.; Chui, H. M. P. Tetrahedron Lett. 1996,
37, 6839.
(22) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
(23) (a) Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116, 5975. (b) Ikeda,
S.; Yamamoto, H.; Kondo, K.; Sato, Y. Organometallics 1995, 14, 5015.
(c) Ikeda, S.; Kondo, K.; Sato, Y. J. Org. Chem. 1996, 61, 8248.
Organozinc structural variation in alkylatiVe cyclizations of

Ni-Catalyzed Organozinc-Promoted Carbocyclizations
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4915
Scheme 1. Stereoselectivity of Alkylidenecyclopentane Formation
Scheme 2. Proposed Mechanisms
introduced in a stepwise, controlled, stereoselective fashion, the
order of substituent introduction may be simply reversed in order
to obtain 49, the opposite isomer with respect to the tetrasub-
stituted double bond geometry. The broad range of methods
available for the alkylation of alkynes (i.e., acetylide alkylation,
Sonogashira reaction,24 etc.) coupled with the generality of the
nickel-mediated reductive and alkylative cyclizations provides
a powerful strategy for stereoselective alkene introduction.25
Whereas the seminal contributions from Mackenzie on the
preparation of enal-derived nickel π-allyl complexes led us to
initiate these studies,5 it is important to stress that the mecha-
nistic issues associated with the transformations described herein
are highly speculative. Moreover, a common mechanism for
all substrate classes may be somewhat unlikely. However, two
general mechanistic pathways leading to a key common
intermediate 55 appear to be most consistent with the data at
hand (Scheme 2). The first of these two pathways involves
oxidative addition of a low valent nickel catalyst to an
organozinc-activated electron-deficient alkene to afford nickel
π-allyl complex 50 in direct analogy to the studies of Mackenzie.
If either the organozinc rapidly transmetalates to nickel (i.e.,
ZnPh2) or if the tethered unsaturation presents a sufficiently
high kinetic barrier toward migratory insertion (i.e., tethered
nitriles or unactivated alkenes), then π-allyl complex 50 may
undergo a transmetalation/reductive elimination sequence to
enolate 51, ultimately leading to conjugate addition products
52 or 53. Alternatively, insertion of the tethered unsaturation
and organozinc transmetalation would afford intermediate 55.
A second mechanistic possibility for the production of 55, in
direct analogy to the mechanism of zirconocene-catalyzed
cyclomagnesiations of dienes,3d,26 involves oxidative cyclization
to produce metallacycle 54. Transmetalation of the organozinc
to metallacycle 54 would directly afford the same key inter-
mediate 55 discussed above. Nickel metallacyclopentanes have
been rigorously studied by Grubbs,27 and several have been fully
characterized by X-ray crystallography.28 Less, however, is
known about nickel metallacyclopentenes, although their exist-
ence is commonly invoked in the mechanism of many nickel-
promoted processes.29
With the substrates that possess tethered enones and alde-
hydes, intermediate 55 would be labile toward ligand displace-
ment by further reaction with the organozinc to afford dianionic
product 56 (as the bis-zinc reagent) which would be hydrolyzed
to reductive cyclization product 57 on workup. The resulting
(26) (a) Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent, W. A.; Dixon, D.
A.; Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457. (b) Takahashi, T.;
Seki, T.; Nitto, Y.; Saburi, M.; Rousset, C. J.; Negishi, E. J. Am. Chem.
Soc. 1991, 113, 6266. (c) Didiuk, M. T.; Johannes, C. W.; Morken, J. P.;
Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 7097.
(27) (a) Grubbs, R. H.; Miyashita, A.; Liu, M. M.; Burk, P. L. J. Am.
Chem. Soc. 1977, 99, 3863. (b) Grubbs, R. H.; Miyashita, A. J. Am. Chem.
Soc. 1978, 100, 1300. (c) Grubbs, R. H.; Miyashita, A.; Burk, P. J. Am.
Chem. Soc. 1978, 100, 2418. (d) McKinney, R. J.; Thorn, D. L.; Hoffman,
R.; Stockis, A. J. Am. Chem. Soc. 1981, 103, 2595.
(24) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(25) For other methods that allow the selective preparation of either E
or Z trisubstituted alkenes from a common intermediate, see: (a) Martinez-
Grau, A.; Curran, D. P. J. Org. Chem. 1995, 60, 8332. (b) Demark, S. E.;
Amburgey, J. J. Am. Chem. Soc. 1993, 115, 10386. (c) Barrett, A. G. M.;
Hill, J. M.; Wallace, E. M. J. Org. Chem. 1992, 57, 386.
(28) (a) Binger, P.; Doyle, M. J.; Kru¨ger, C.; Tsay, Y. Naturforsch. Teil
B. 1979, 34, 1289. (b) See ref 5 of the McKinney & Hoffman theoretical
study (ref 27d above).
(29) (a) Metallacycles were proposed as intermediates in closely related
intermolecular couplings by Ikeda and Sato, see ref 23c. (b) Tamao, K.;
Kobayashi, K.; Ito, Y. Synlett, 1992, 539. (c) Sato, Y.; Nishimata, T.; Mori,
M. J. Org. Chem. 1994, 59, 6133.

4916 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Montgomery et al.
dialkylnickel complex would then regenerate the active catalyst
species. However, a different pathway for decomposition of
intermediate 55 occurs with enones tethered to alkynes. Instead,
reductive elimination and â-hydride elimination are the modes
of decomposition of 55 (in alkyne cyclizations) that are
consistent with the experimental results. In the absence of added
ligands, alkylative cyclization product 58, which likely is derived
from reductive elimination of 55, is observed. When the catalyst
is pretreated with triphenylphosphine, reductive cyclization
product 57, which is likely derived from â-hydride elimination
of 55, is observed. Deuterium labeling studies in reductive
cyclizations of alkynyl enones demonstrated that the major
reaction pathway proceeded by a mechanism in which the
hydrogen substituent on atom Y of product 57 was derived from
the organozinc; a result that is consistent with the â-hydride
elimination mechanism.7a The potential involvement of two
pathways to reductive cyclization product 57 is consistent with
the observation that bis-enone reductive cyclizations do not
require a â-hydrogen on the organozinc (Table 3), whereas
alkynylenone reductive cyclizations do require a â-hydrogen
on the organozinc (eq 3).
in each of the reactive functionalities. The most stringent
limitation lies in the requirement for a highly electrophilic
double bond, with enones, alkylidene malonates, and nitroal-
kenes being the most efficient examined to date. Although
many important mechanistic questions remain unresolved, a
detailed set of empirical rules has been established that provides
a high degree of predictability within each substrate class
examined. Our laboratory is actively pursuing more complex
methodological and mechanistic studies as well as applications
in the total synthesis of complex molecules.
Reductive elimination of dialkylpalladium and aryl(allyl)
palladium complexes is well established to be facilitated by the
coordination of electron-deficient alkenes by virtue of their
ability to serve as potent π-acceptor ligands.30 To explain the
reductive elimination/â-hydride elimination crossover in reac-
tions of alkynyl enones, we speculate that unreacted substrate
may coordinate to intermediate 55 in the absence of triphen-
ylphosphine to promote reductive elimination. The presence
of triphenylphosphine, however, could suppress enone coordina-
tion, generate a more electron-rich nickel species, and allow
â-H elimination to occur through a dissociative process. The
dramatically different reduction:alkylation ratios observed for
alkynylenones compared with alkynes tethered to nitroalkenes
clearly demonstrates that the structure of the electron-deficient
alkene plays an important role in governing selectivities between
reductive and alkylative cyclization products (compare method
B of entries 1 and 6, Table 1). Knochel recently reported a
similar phenomenon in nickel-promoted couplings of sp3-
hybridized centers.31
Finally, the possibility exists that alkynyl enone alkylative
cyclizations proceed by alkyne carbometalation followed by
conjugate addition, but a direct regiochemical comparison of
the above cyclizations with intermolecular coupling data from
Ikeda23 and from us21 suggests that such a mechanism is not
consistent with the experimental data. Cyclizations involving
terminal alkynes are highly selective for the exocyclic mode,
with the organozinc substituent adding to the terminal carbon
(Table 1). However, in intermolecular three-component cou-
plings involving terminal alkynes, the organozinc substituent
adds predominantly to the substituted position of the alkyne.21,23
Such a regiochemical reversal is not consistent with a mecha-
nism that involves irreversible alkyne carbometalation without
the direct influence of the electron-deficient alkene (eq 6).
Experimental Section
Unless otherwise noted, reagents were commercially available and
were used without purification. Tetrahydrofuran (THF) and diethyl
ether were freshly distilled from sodium/benzophenone ketyl. Dichlo-
romethane and DMSO were distilled from calcium hydride. All
organolithium reagents were freshly titrated with 2,5-dimethoxybenzyl
alcohol. Zinc chloride was dried at 150 °C at 0.1 mm overnight, then
thoroughly ground by mortar and pestle in an inert atmosphere
glovebox, and then dried again overnight at 150 °C at 0.1 mm.
Ni(COD)2 and anhydrous ZnCl2 were stored and weighed in an inert
atmosphere glovebox. All reactions were conducted in flame-dried
glassware under a nitrogen or argon atmosphere.
General Procedure A for Alkylative Cyclization. A 0.3-0.5 M
solution of ZnCl2 (2.5-3.0 equiv) in THF was stirred at 0 °C, and the
organolithium or Grignard reagent (3.7-4.5 equiv) was added by
syringe followed by stirring for 0.25-1 h at 0 °C. A 0.02-0.04 M
THF solution of Ni(COD)2 (0.04-0.06 equiv) was added, and the
resultant mixture was immediately transferred by cannula to a 0.1-
0.2 M solution of the unsaturated substrate (1.0 equiv). After
consumption of starting material by TLC analysis (typically 0.25-2.0
h at 0 °C), the reaction mixture was subjected to an extractive workup
(NaHCO3/EtOAc or NH4Cl/NH4OH pH ) 8 buffer/Et2O) followed by
flash chromatography on SiO2. Although the above procedure was
typically used, commercial diorganozincs performed comparably.
General Procedure B for Reductive Cyclization. A 0.03-0.06
M solution of triphenylphosphine (0.2-0.3 equiv) in THF was added
to Ni(COD)2 (0.04-0.06 equiv) at 25 °C and stirred for 3-5 min. The
nickel solution was transferred to a 0.5-0.6 M solution of Et2Zn in
THF at 0 °C, and the resultant mixture was immediately transferred
by cannula to a 0.10-0.50 M 0 °C THF solution of the unsaturated
substrate (1.0 equiv). After consumption of starting material by TLC
analysis (typically 0.25-2.0 h at 0 °C), the reaction mixture was
subjected to an extractive workup (NaHCO3/EtOAc or NH4Cl/NH4-
OH pH ) 8 buffer/Et2O) followed by flash chromatography on SiO2.
Slightly lower yields were obtained using organolithium-derived
diorganozinc reagents prepared by addition of n-BuLi (3.75 equiv) to
a 0.3-0.6 M solution of ZnCl2 (2.5 equiv) in THF at 0 °C. The
experiments reported with BuLi/ZnCl2 were not optimized.
Conclusions
A general and efficient nickel-catalyzed, organozinc-promoted
cyclization of electron-deficient alkenes with tethered unsat-
uration has been developed. Considerable flexibility is tolerated
(Z)-1-Ethylidene-2-(2-oxo-2-phenylethyl)cyclopentane (2a). Fol-
lowing general procedure A, (2E)-1-phenyloct-2-en-7-yn-1-one (1)7a
(60 mg, 0.30 mmol), MeLi (0.92 mL, 1.10 mmol of a 1.2 M ethyl
ether solution), zinc chloride (99 mg, 0.73 mmol), and Ni(COD)2 (7
mg, 0.025 mmol) were employed to produce, after flash chromatography
(35:1 hexanes:EtOAc), 53 mg (82%) of 2a as a colorless oil that was
contaminated with <5% of 2b. 1H NMR (300 MHz, CDCl3) δ 7.96
(m, 2H), 7.40-7.60 (m, 3H), 5.35 (m, 1H), 3.26 (s, 1H), 3.09 (dd, J )
3.9, 16.5 Hz, 1H), 2.92 (dd, J ) 10.2, 16.2 Hz, 1H), 2.15-2.45 (m,
(30) (a) Yamamoto, T.; Yamamoto, A.; Ikeda, S. J. Am. Chem. Soc. 1971,
93, 3350. (b) Kurosawa, H.; Emoto, M.; Ohnishi, H.; Miki, K.; Kasai, N.;
Tatsumi, K.; Nakamura, A. J. Am. Chem. Soc. 1987, 109, 6333. (c) Temple,
J. S.; Riediker, M.; Schwartz, J. J. Am. Chem. Soc. 1982, 104, 1310. (d)
Sustmann, R.; Lau, J.; Zipp, M. Tetrahedron Lett. 1986, 27, 5207. (e) Binger,
P.; Doyle, M. J. J. Organomet. Chem. 1978, 162, 195.
(31) Devasagayaraj, A.; Stu¨demann, T.; Knochel, P. Angew Chem. Int.
Ed. Engl. 1995, 34, 2723.
2H), 1.93 (m, 1H), 1.62 (d, J ) 6.6 Hz, 3H), 1.42-1.75 (m, 3H); 13
C

Ni-Catalyzed Organozinc-Promoted Carbocyclizations
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4917
NMR (75 MHz) δ 199.7, 146.7, 137.3, 132.9, 128.5, 128.0, 115.5, 43.1,
35.9, 33.3, 32.8, 24.1, 14.6; IR (film) 1687, 1597 cm-1; HRMS (EI)
m/e calcd for C15H18O 214.1358, found 214.1358 (M+).
2-(2-Methylidenecyclopentyl)-3-oxobutyric Acid Methyl Ester
(10b). Following general procedure B, ketoester 933 (105 mg, 0.54
mmol), Et2Zn (170 µL, 1.66 mmol), PPh3 (32 mg, 0.12 mmol), and
Ni(COD)2 (8mg, 0.03 mmol) were employed to produce, after flash
chromatography (4:1 hexanes:EtOAc), 84 mg (79%) of 10b (1:1 mixure
of diastereomers) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ
4.87 (m, 2H), 4.72 (q, J ) 2.0 Hz, 1H), 4.65 (q, J ) 2.1 Hz, 2H), 3.69
(s, 3H), 3.68 (s, 3H), 3.61 (d, J ) 9.0 Hz, 1H), 3.51 (d, J ) 9.0 Hz,
1H), 3.11 (m, 2H), 2.31 (m, 4H), 2.23 (s, 3H), 2.21 (s, 3H), 1.83-1.89
(m, 2H), 1.66-1.76 (m, 2H), 1.50-1.60 (m, 3H), 1.34-1.41 (m, 1H);
13C NMR (125 MHz) δ 202.8, 202.5, 169.5, 169.2, 152.9, 152.8, 106.6,
106.5, 63.8, 62.9, 52.2, 52.1, 43.1, 43.0, 32.9, 32.7, 30.5, 30.3, 29.9,
29.7, 23.8, 23.7; IR (film) 1744, 1717 cm-1; HRMS (EI) m/e calcd for
C9H14O2 154.0994, found 154.0997 ((M-CH2dCdO)+).
1-Methylidene-2-(2-oxo-2-phenylethyl)cyclopentane (2b). Fol-
lowing general procedure B, (2E)-1-phenyloct-2-en-7-yn-1-one (1)7a
(51 mg, 0.26 mmol), Et2Zn (74 mg, 0.061 mL, 0.60 mmol), zinc
chloride (27 mg, 0.20 mmol), PPh3 (37 mg, 0.14 mmol), and Ni(COD)2
(6 mg, 0.021 mmol) were employed to produce, after flash chroma-
tography (20:1 pentane:Et2O), 48 mg (92%) of 2b as a colorless oil
that was homogeneous by TLC analysis. 1H NMR (500 MHz, CDCl3)
δ 7.97 (m, 2H), 7.56 (m, 1H), 7.47 (m, 2H), 4.93 (d, J ) 2.0 Hz, 1H),
4.82 (d, J ) 2.0 Hz, 1H), 3.24 (dd, J ) 3.5, 15.5 Hz, 1H), 2.93-3.04
(m, 2H), 2.30-2.47 (m, 2H), 2.05 (dq, J ) 4.5, 12.0 Hz, 1H), 1.73
(m, 1H), 1.61 (m, 1H), 1.31 (m, 1H); 13C NMR (125 MHz) δ 199.8,
155.9, 137.2, 133.0, 128.6, 128.1, 104.7, 43.6, 39.8, 33.4, 33.0, 24.1;
IR (film) 1686, 1652, 1595, 1580 cm-1; HRMS (EI) m/e calcd for
C14H16O: 200.1201, found: 200.1207 (M+).
(Z)-1-Ethylidenespiro[4.5]decane-7-one (4a). Following general
procedure A, 3-(4-pentynyl)-2-cyclohexen-1-one (3)32 (70 mg, 0.43
mmol), MeLi (1.72 mL, 1.5 mmol of a 0.87 M ethyl ether solution),
zinc chloride (0.136 g, 1.0 mmol), and Ni(COD)2 (11.5 mg, 0.042
mmol) were employed to produce, after flash chromatography (4:1
hexanes:EtOAc), 55.5 mg (72%) of 4a as a pale-yellow liquid that was
homogeneous by TLC analysis. 1H NMR (500 MHz, CDCl3) δ 5.39
(tq, J ) 2.0, 7.5 Hz, 1H), 2.78 (d, J ) 14.0 Hz, 1H), 2.25-2.38 (m,
5H), 2.17 (dt, J ) 14.0, 2.0 Hz, 1H), 1.95-2.03 (m, 1H), 1.76 (dt, J
) 7.5, 2.0 Hz, 3H), 1.70-1.80 (m, 1H), 1.44-1.64 (m, 5H); 13C NMR
(125 MHz) δ 211.7, 148.0, 116.5, 50.1, 48.6, 41.3, 39.5, 36.3, 34.2,
23.3, 23.2, 13.9; IR (film) 1713, 1435 cm-1; HRMS (EI) m/e calcd for
C12H18O 178.1358, found 178.1354 (M+).
(Z)-1-Ethylidene-2-(nitromethyl)cyclopentane (12a). Following
general procedure A, nitroalkene 1134 (99 mg, 0.71 mmol), MeLi (2.3
mL, 3.2 mmol of a 1.4 M ethyl ether solution), ZnCl2 (242 mg, 1.8
mmol), and Ni(COD)2 (10 mg, 0.04 mmol) were employed to produce,
after flash chromatography (9:1 hexanes:Et2O), 44 mg (39%) of 12a
and 50 mg (45%) of the acyclic conjugate addition product 12c as
yellow oils. The purified sample of 12a was contaminated with < 5%
1
of 12c. For 12a: H NMR (CDCl3, 500 MHz) δ 5.48 (m, 1H), 4.40
(dd, J ) 11.7, 5.0 Hz, 1H), 4.14 (t, J ) 11.5 Hz, 1H), 3.42 (m, 1H),
2.20-2.34 (m, 2H), 1.85-1.93 (m, 1H), 1.61-1.73 (m, 6H); 13C NMR
(125 MHz) 141.2, 119.1, 77.7, 39.3, 32.8, 30.4, 23.7, 14.5; IR (film)
1551, 1378 cm-1; HRMS (EI) m/e calcd for C8H12 108.0939, found
1
108.0942 ((M - HNO2)+). For 12c: H NMR (CDCl3, 500 MHz) δ
4.31 (dd, J ) 11.8, 6.3 Hz, 1H), 4.19 (dd, J ) 11.8, 7.8 Hz, 1H), 2.33
(m, 1H), 2.19 (m, 2H), 1.95 (t, J ) 2.8 Hz, 1H), 1.46-1.65 (m, 3H),
1.32-1.40 (m, 1H), 1.01 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz) δ
83.7, 81.5, 68.8, 32.7, 32.3, 25.4, 18.4, 17.1; IR (film) 1551, 1383 cm-1
.
(Z)-1-Ethylidene-2-(methylmalonyl)cyclopentane (8a). Following
general procedure A, alkylidene malonate 733 (112 mg, 0.53 mmol),
MeLi (2.2 mL, 3.0 mmol of a 1.4 M ethyl ether solution), ZnCl2 (272
mg, 2.0 mmol), and Ni(COD)2 (8 mg, 0.03 mmol) were employed to
produce, after flash chromatography (85:15 hexanes:EtOAc), 89 mg
(74%) of 8a as a colorless oil that was homogeneous by TLC analysis.
1H NMR (500 MHz, CDCl3) δ 5.32-5.36 (m, 1H), 3.70 (s, 3H) 3.67
(s, 3H), 3.52 (d, J ) 9 Hz, 1H), 3.30-3.38 (m, 1H), 2.26-2.36 (m,
1H), 2.10-2.20 (m, 1H), 1.82-1.9 (m, 1H), 1.63-1.73 (m, 2H), 1.48-
1.58 (m, 4H); 13C NMR (125 MHz) δ 169.1, 169.0, 142.9, 117.8, 54.1,
Yields were variable for this particular example (40-85% combined),
but product ratios were consistent irrespective of yield.
(Z)-1-(1-Propylidene)-2-(nitromethyl)cyclopentane (12b). Fol-
lowing general procedure B, nitroalkene 1134 (104 mg, 0.75 mmol),
Et2Zn (230 µl, 2.25 mmol), PPh3 (42 mg, 0.16 mmol), and Ni(COD)2
(11 mg, 0.04 mmol) were employed to produce, after flash chroma-
tography (49:1 hexanes:EtOAc), 106 mg of an inseparable mixture of
12b (47%) and 12d (13%) as a yellow oil contaminated with 16%
triphenylphosphine. For 12b: 1H NMR (CDCl3, 500 MHz) δ 5.38 (m,
1H), 4.36 (dd, J ) 12.0, 4.5 Hz, 1H), 4.15 (t, J ) 11.3, 1H), 3.42 (m,
1H), 1.60-2.40 (m, 8H), 0.98 (t, J ) 7.5 Hz, 3H); 13C NMR (125
MHz) δ 139.5, 127.0, 78.1, 39.5, 32.8, 30.4, 23.6, 22.6, 14.4; IR (film)
1551, 1378 cm-1; MS(EI) m/e calcd for C9H14 122.1096, found
52.3, 52.2, 39.7, 32.6, 30.3, 22.8, 14.5; IR (film) 1755, 1739 cm-1
;
MS (EI) m/e calcd for C12H18O4 226.1205, found 226.1200 (M+).
1-Methylidene-2-(methylmalonyl)cyclopentane (8b). Following
general procedure B, alkylidene malonate 733 (120 mg, 0.57 mmol),
Et2Zn (1.8 mL, 1.7 mmol of a 15 wt % hexane solution), PPh3 (32 mg,
0.12 mmol), and Ni(COD)2 (8 mg, 0.03 mmol) were employed to
produce, after flash chromatography (85:15 hexanes:EtOAc), 100 mg
(83%) of 8b as a colorless oil that was homogeneous by TLC analysis.
1H NMR (500 MHz, CDCl3) δ 4.88 (q, J ) 2.0 Hz, 1H), 4.73 (q, J )
2.0 Hz, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 3.49 (d, J ) 8.5 Hz, 1H), 3.09
(q, J ) 7.7 Hz, 1H), 2.30-2.34 (m, 2H), 1.87 (m, 1H), 1.72 (m, 1H).
1.50-1.65 (m, 2H); 13C NMR (125 MHz) δ 169.1, 168.8, 152.6, 106.5,
55.1, 52.33, 52.26, 43.3, 32.9, 30.4, 23.8; IR (film) 3074, 1737, 1653.5
cm-1; HRMS (EI) m/e calcd for C11H16O4 212.1048, found 212.1049
(M+).
2-[(Z)-2-Ethylidenecyclopentyl]-3-oxobutyric Acid Methyl Ester
(10a). Following general procedure A, ketoester 933 (107 mg, 0.55
mmol), MeLi (1.9 mL, 2.5 mmol of a 1.4 M ethyl ether solution), ZnCl2
(187 mg, 1.4 mmol), and Ni(COD)2 (8 mg, 0.03 mmol) were employed
to produce, after flash chromatography (9:1 hexanes:EtOAc), 78 mg
(68%) of 10a (1:1 mixture of diastereomers) as a colorless oil. 1H
NMR (500 MHz, CDCl3) δ 5.35 (m, 2H), 3.69 (s, 3H) 3.63-3.66 (m,
4H), 3.52 (d, J ) 9 Hz, 1H), 3.30-3.40 (m, 2H), 2.30 (m, 2H), 2.23
(s, 3H), 2.19 (s, 3H), 2.17 (m, 1H), 1.77-1.86 (m, 2H), 1.60-1.67
(m, 4H), 1.50-1.58 (m, 9H); 13C NMR (125 MHz) δ 203.1, 203.0,
169.7, 169.6, 143.0, 142.9, 117.9, 117.8, 61.9, 61.2, 52.2, 52.1, 39.7,
39.5, 32.7, 32.2, 30.6, 30.3, 30.2, 29.9, 22.9, 22.4, 14.7; IR (film) 1738,
1720 cm-1; HRMS (EI) m/e calcd for C12H18O3 210.1256, found
210.1260 (M+).
1
122.1095 ((M - HNO2)+). Distinct H NMR signals for 12d: 5.03
(m, 1H), 4.86 (m, 1H), 4.48 (dd, J ) 12.0, 5.5 Hz, 1H), 4.27 (dd, J )
12.0, 9.5 Hz, 1H) 3.20 (m, 1H). HRMS(EI) m/e calcd for C7H10
94.0783, found 94.0785 ((M - HNO2)+).
(E)-1-Ethylidene-2-(methylmalonyl)cyclopentane (14b). Follow-
ing general procedure B, alkylidene malonate 1333 (94 mg, 0.42 mmol),
Et2Zn (130 µl, 1.27 mmol), PPh3 (29 mg, 0.11 mmol), and Ni(COD)2
(6 mg, 0.02 mmol) were employed to produce, after flash chromatog-
raphy (4:1 hexanes:Et2O), 84 mg (83%) of 14b as a colorless oil that
was homogeneous by TLC analysis. 1H NMR (500 MHz, CDCl3) δ
5.19 (m, 1H), 3.69 (s, 3H), 3.42 (d, J ) 9.3 Hz, 1H), 3.07 (m,1H),
2.22 (m, 2H), 1.63-1.82 (m, 2H), 1.51-1.61 (m, 5H); 13C NMR (125
MHz) δ 169.2, 168.9, 143.4, 116.3, 55.3, 52.2, 43.9, 30.4, 28.3, 23.3,
14.7; IR (film) 1759, 1738 cm-1; HRMS (EI) m/e calcd for C12H18O4
226.1205, found 226.1208 (M+). Anal. Calcd for C12H18O4: C, 63.70;
H, 8.02. Found: C, 63.94; H, 8.19.
2-(2-Oxo-2-phenylethyl)-(E)-1-(1-phenylpentylidene)cyclopen-
tane (16a). Following general procedure A, (2E)-1,8-diphenyloct-2-
en-7-yne-1-one (15)7a (53 mg, 0.19 mmol), n-BuLi (0.41 mL, 0.83 mmol
of a 2.03 M hexane solution), zinc chloride (68 mg, 0.50 mmol), and
Ni(COD)2 (6.9 mg, 0.025 mmol) were employed to produce, after flash
chromatography (49:1 hexanes:EtOAc), in order of elution, 43 mg
(68%) of 16a as a colorless oil and 4.0 mg (8%) of 16b as a white
solid that were both homogeneous by TLC analysis. For 16a: 1H NMR
(300 MHz, CDCl3) δ 8.00-8.20 (m, 2H), 7.57-7.60 (m, 1H), 7.48-
7.51 (m, 2H), 7.30-7.33 (m, 2H), 7.19-7.23 (m, 1H), 7.13-7.14 (m,
(32) Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org. Chem. 1993, 58,
2694.
(33) Alkylidene malonate 7 and â-ketoester 9 were prepared from hex-
5-ynal and dimethyl malonate by the Lehnert modification of the Knoev-
enagel condensation. Lehnert, W. Tetrahedron Lett. 1970, 4723
(34) Nitroalkene 11 was prepared from nitromethane and 5-hexyn-1-al
by a nitroaldol condensation, acylation, and elimination sequence. Denmark,
S. E.; Senanayake, C. B. W. Tetrahedron 1996, 52, 11579.

4918 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Montgomery et al.
2H), 3.46 (m, 1H), 3.13 (dd, J ) 4.0, 16.5 Hz, 1H), 3.07 (dd, J )
10.0, 16.5 Hz, 1H), 2.38 (t, J ) 7.0 Hz, 2H), 2.16-2.24 (m, 1H), 2.08-
2.14 (m, 1H), 1.87-1.94 (m, 1H), 1.52-1.71 (m, 3H), 1.16-1.28 (m,
4H), 0.80 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz) δ 199.7, 143.6,
142.3, 137.4, 133.7, 133.0, 128.6, 128.3, 128.1, 127.9, 125.9, 43.7,
37.7, 34.6, 32.4, 31.4, 30.8, 24.0, 22.8, 14.0; IR (film) 1686, 1598,
1580 cm-1; HRMS (EI) m/e calcd for C24H28O 332.2140, found
332.2135 (M+). Anal. Calcd for C24H28O: C, 86.70; H, 8.49.
Found: C, 86.69; H, 8.51. The alkene stereochemistry was assigned
by observation of 7.6% NOE of the cyclopentyl ring methine proton
(δ 3.46) and 2.9% and 0.8% NOEs of the two diastereotopic protons
R to the carbonyl (δ 3.13 and 3.07, respectively) upon irradiation of
the allylic protons in the butyl group (δ 2.38). Assignments were
confirmed by homonuclear decoupling experiments.
(E)-1-Benzylidene-2-(2-oxo-2-phenylethyl)cyclopentane (16b). Fol-
lowing general procedure B, (2E)-1,8-diphenyloct-2-en-7-yne-1-one
(15)7a (157 mg, 0.57 mmol), Et2Zn (0.17 mL, 1.65 mmol), Ni(COD)2
(30 mg, 0.11 mmol), and triphenylphosphine (115 mg, 0.44 mmol) were
employed to produce, after flash chromatography (24:1 hexanes:EtOAc),
in order of elution, 108 mg (69%) of 16b as a white solid that was
homogeneous by TLC analysis. For 16b: 1H NMR (300 MHz, CDCl3)
δ 8.01 (m, 2H), 7.59 (m, 1H), 7.48 (m, 2H), 7.32 (m, 4H), 7.19 (m,
1H), 6.31 (q, J ) 2.5 Hz, 1H), 3.34 (dd, J ) 4.8, 16.3 Hz, 1H), 3.24
(m, 1H), 3.08 (dd, J ) 8.75, 16.3 Hz, 1H), 2.58-2.74 (m, 2H), 2.05
(m, 1H), 1.88 (m, 1H), 1.71 (m, 1H), 1.37 (m, 1H); 13C NMR (75
MHz) δ 199.7, 149.4, 138.5, 137.3, 133.0, 128.6, 128.20, 128.17,
128.14, 126.0, 121.1, 44.1, 42.0, 32.5, 31.5, 24.9; IR (KBr) 1681, 1644,
1594, 1578 cm-1; HRMS (EI) m/e calcd for C20H20O 276.1514, found
276.1517 (M+). Anal. Calcd for C20H20O: C, 86.92; H, 7.29.
Found: C, 86.60; H, 7.48.
2-(2-Oxo-2-phenylethyl)-(Z)-1-(1-phenylpentylidene)cyclopen-
tane (18a). Following general procedure A, (2E)-1-phenyldodec-2-
en-7-yn-1-one (17)7a (69 mg, 0.27 mmol), PhMgBr (1.05 mL, 1.05
mmol of a 1.0 M THF solution), zinc chloride (95 mg, 0.70 mmol),
and Ni(COD)2 (6 mg, 0.021 mmol) were employed to produce, after
flash chromatography (50:1 pentane:Et2O) 34 mg (38%) of 18a as
colorless glass that was homogeneous by TLC analysis. 1H NMR (500
MHz, CDCl3) δ 7.18-7.46 (m, 10H), 3.09 (m, 1H), 2.83 (dd, J ) 4.0,
14.5 Hz, 1H), 2.45-2.54 (m, 1H), 2.35-2.45 (m, 2H), 2.33 (dd, J )
12.0, 14.0 Hz, 1H), 2.26 (m, 1H), 1.76-1.87 (m, 1H), 1.62-1.76 (m,
2H), 1.49-1.57 (m, 1H), 1.22-1.35 (m, 4H), 0.86 (m, 3H); 13C NMR
(125 MHz) δ 200.1, 143.6, 142.2, 136.4, 134.3, 132.5, 128.8, 128.6,
128.4, 128.2, 126.2, 42.8, 39.0, 36.1, 31.1, 30.2, 29.8, 23.6, 22.6, 14.1;
IR (film) 1678, 1597, 1580 cm-1; HRMS (EI) m/e calcd for C24H28O
332.2140, found 332.2139 (M+).
2-(2-Oxo-2-phenylethyl)-(E)-1-(1-pentylidene)cyclopentane (18b).
Following general procedure B, (2E)-1-phenyldodec-2-en-7-yn-1-one
(17)7a (70 mg, 0.28 mmol), n-BuLi (0.42 mL, 1.05 mmol of a 2.5 M
hexanes solution), zinc chloride (95 mg, 0.70 mmol), PPh3 (34 mg,
0.13 mmol), and Ni(COD)2 (6 mg, 0.021 mmol) were employed to
produce, after flash chromatography (42:1 pentane:Et2O), in order of
elution, 14 mg (16%) of 18c (R ) Bu) and 41 mg (58%) of 18b (R )
H), both as colorless oils that were homogeneous by TLC analysis.
For 18b: 1H NMR (500 MHz, CDCl3) δ 7.97 (m, 2H), 7.55 (tt, J )
1.5, 7.5 Hz, 1H), 7.46 (m, 2H), 5.18 (m, 1H), 3.19 (dd, J ) 4.5, 16.0
Hz, 1H), 2.94 (m, 1H), 2.88 (dd, J ) 9.0, 15.5 Hz, 1H), 2.16-2.36 (m,
2H), 1.92-2.02 (m, 3H), 1.75 (m, 1H), 1.53-1.63 (m, 1H), 1.20-
1.35 (m, 5H), 0.89 (m, 3H); 13C NMR (125 MHz) δ 200.2, 145.3, 137.4,
132.9, 128.5, 128.1, 120.6, 43.9, 40.2, 33.3, 31.8, 29.2, 28.9, 24.0, 22.4,
14.0; IR (film) 1688, 1597, 1581 cm-1; HRMS (EI) m/e calcd for
C18H24O 256.1827, found 256.1823 (M+).
(s, 3H) 3.67 (s, 3H), 3.62 (d, J ) 9 Hz, 1H), 3.50 (m, 1H), 2.20-2.36
(m, 2H), 1.85 (m, 1H), 1.75 (m, 2H), 1.68 (s, 3H), 1.54 (m, 1H), 0.08
(s, 9H); 13C NMR (125 MHz) δ 169.3, 169.2, 152.7, 127.9, 53.6, 52.2,
52.1, 41.8, 32.5, 29.2, 23.6, 18.9, -0.4; IR (film) 1757, 1739 cm-1
;
HRMS (EI) m/e calcd for C15H26O4Si 298.1600, found 298.1597 (M+).
Anal. Calcd for C15H26O4Si: C, 60.37; H, 8.78. Found: C, 60.49; H,
8.82.
2-(Methylmalonyl)-(E)-1-[(1-trimethylsilyl)-1-propylidene]cyclo-
pentane (20b). Following general procedure B, alkylidene malonate
1935 (564 mg, 2.0 mmol), Et2Zn (7.0 mL, 7.7 mmol, PPh3 (105 mg,
0.4 mmol), and Ni(COD)2 (28 mg, 0.1 mmol) were employed to
produce, after flash chromatography (9:1 hexanes:EtOAc), 100 mg
(75%) of a 5:1 mixture of 20b (R ) H) and 20c (R ) Et) as a colorless
oil that was homogeneous by TLC analysis. For 20b: 1H NMR (CDCl3,
500 MHz) δ 5.12 (m, 1H), 3.69 (s, 3H), 3.67 (s, 3H), 3.55 (d, J ) 8.0
Hz, 1H), 3.05 (q, J)7.5 Hz, 1H), 2.23 (m, 3H), 1.55-1.87 (m, 4H),
0.04 (m, 9H); 13C NMR (125 MHz) δ 169.3, 168.8, 161.4, 119.7, 54.8,
52.2, 52.1, 46.6, 32.3, 29.4, 24.1, -0.5; IR 1759, 1740 cm-1; HRMS
(EI) m/e calcd for 20b C14H24O4Si 284.1444, found 284.1442 (M+).
Diagnostic 1H NMR signals for 20c: δ 0.87 (t, J ) 7.3 Hz, 3H), 0.09
(s, 9H).
3-Butyl-1-phenyl-7-hepten-1-one (22a). Following general pro-
cedure A, enone 2136 (90 mg, 0.45 mmol), n-BuLi (0.62 mL of a 2.43
M hexane solution, 1.5 mmol), ZnCl2 (1.0 mL of a 1.0 M ether solution,
1.0 mmol), and Ni(COD)2 (3 mg, 0.01 mmol) were employed to
produce, after flash chromatography (6:1 hexanes:EtOAc), 87 mg (75%)
of 22a as a colorless oil that was homogeneous by TLC analysis. The
product was identical to authentic material prepared by addition of
Bu2CuLi to enone 21. 1H NMR (300 MHz, CDCl3) δ 7.90-8.00 (m,
2H), 7.40-7.60 (m, 3H), 5.70-5.85 (m, 1H), 4.90-5.05 (m, 2H), 2.88
(d, J ) 6.6 Hz, 2H), 2.00-2.15 (m, 3H), 1.20-1.50 (m, 10H), 0.88 (t,
J ) 6.6 Hz, 3H); 13C NMR (75 MHz) δ 200.5, 138.8, 137.5, 132.7,
128.5, 128.0, 114.3, 43.4, 34.1, 34.0, 33.8, 33.6, 28.8, 26.0, 22.9, 14.0;
IR (film) 1685 cm-1; HRMS (EI) m/e calcd for C18H26O: 258.1984,
found: 258.1982 (M+).
1S*,2R*,3S*,5S*2-Benzoyl-3-hydroxy-3-phenylbicyclo[3.3.0] oc-
tane (24). Following general procedure A, bis-enone 2336 (91 mg,
0.30 mmol), n-BuLi (0.43 mL of a 2.44 M hexane solution, 1.05 mmol),
ZnCl2 (0.70 mL of a 1.0 M ether solution, 0.70 mmol), and Ni(COD)2
(3 mg, 0.01 mmol) were employed to produce, after flash chromatog-
raphy, in order of elution, 56 mg (60%) of 24 as a white crystalline
solid and 12 mg (13%) of 36. Spectral data of 36 were identical to
that previously reported.14a For 24: 1H NMR (500 MHz, CDCl3) δ
7.10-7.80 (m, 10H), 5.53 (d, J ) 2.0 Hz, 1H), 3.87 (d, J ) 9.5 Hz,
1H), 3.08 (quintet of doublets, J ) 9.0, 2.5 Hz, 1H), 2.95-3.05 (m,
1H), 2.38 (dd, J ) 8.0, 13.5 Hz, 1H), 1.65-1.85 (m, 4H), 1.50-1.60
(m, 3H); 13C NMR (75 MHz) δ 207.2, 144.5, 137.7, 133.6, 128.6, 128.3,
128.1, 126.8, 124.7, 87.1, 59.6, 50.2, 49.6, 42.6, 32.7, 31.9, 25.6; IR
(KBr) 3412, 1646 cm-1; HRMS (EI) m/e calcd for C21H22O2: 306.1619,
found: 306.1614 (M+). Anal. Calcd for C21H22O2: C, 82.32; H, 7.24.
Found: C, 82.63; H, 7.37. The structure was proven by single crystal
X-ray analysis.37
Compound 37. Following general procedure A, bis-enone 2336 (190
mg, 0.62 mmol), MeLi (1.85 mL of a 1.20 M ether solution, 2.20
mmol), ZnCl2 (1.50 mL of a 1.0 M ether solution, 1.50 mmol), and
Ni(COD)2 (10 mg, 0.04 mmol) were employed to produce, after flash
chromatography (5:1 hexanes:EtOAc), in order of elution, 110 mg of
the mixture of 24 and 36 (2:1 ratio based on 1H NMR) as a white solid
and 62 mg (32%) of 37 as a white solid that was homogeneous by
TLC analysis. For 37: 1H NMR (500 MHz, C6D6) d 7.60 (d, J ) 7.5
Hz, 2H), 7.50-7.55 (m, 2H), 7.45-7.50 (m, 2H), 7.38 (d, J ) 6.5 Hz,
2H), 7.03 (tt, J ) 1.5, 7.0 Hz, 1H), 6.84-6.98 (m, 9H), 6.75 (t, J )
8.0 Hz, 2H), 5.79 (d, J ) 1.0 Hz, 1H), 3.67 (d, J ) 10.0 Hz, 1H),
2.95-3.02 (m, 1H), 2.97 (t, J ) 10.5 Hz, 1H), 2.83 (dq, J ) 2.5, 9.5
Hz, 1H), 2.63 (d, J ) 14.0 Hz, 1H), 2.55 (dd, J)3.2, 15.2 Hz, 1H),
2.50-2.58 (m, 1H), 2.34-2.43 (m, 1H), 2.21 (dd, J ) 9.5, 15.0 Hz,
1H), 2.02-2.10 (m, 1H), 1.82-1.95 (m, 1H), 1.85 (d, J ) 10.5 Hz,
2-(Methylmalonyl)-(E)-1-[(1-trimethylsilyl)ethylidene]cyclo-
pentane (20a). Following general procedure A, alkylidene malonate
1935 (100 mg, 0.35 mmol), MeLi (1.6 mL, 2.1 mmol of a 1.3 M ethyl
ether solution), ZnCl2 (190 mg, 1.4 mmol), and Ni(COD)2 (5 mg, 0.02
mmol) were employed to produce, after flash chromatography (93:7
hexanes:EtOAc), 73 mg (70%) of 20a as a colorless oil that was
homogeneous by TLC analysis. 1H NMR (500 MHz, CDCl3) δ 3.69
(36) Montgomery, J.; Savchenko, A. V.; Zhao, Y. J. Org. Chem. 1995,
60, 5699.
(37) The author has deposited atomic coordinates for 24 with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK.
(35) 6-Trimethylsilylhex-5-ynal was employed as the aldehyde compo-
nent in the Knoevenagel condensation (see ref 32) to prepare alkynyl silane
19. 6-Trimethylsilanylhex-5-yn-1-al was prepared from hex-5-yn-1-ol by
bis-silylation, monodesilylation, and PCC oxidation. Harris, G. D.; Herr,
R. J.; Weinreb, S. M. J. Org. Chem. 1993, 52, 5452.

Ni-Catalyzed Organozinc-Promoted Carbocyclizations
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4919
1H), 1.71-1.73 (m, 2H), 1.48-1.68 (m, 3H), 0.97-1.27 (m, 4H); 13
C
Cl/NH4OH pH ) 8 buffer, Et2O), followed by flash chromatography
(7:3 hexanes: EtOAc) on silica gel to afford 52 mg (47%) of 30 (1.5:1
mixture of diastereomers) as a colorless oil. For the major diastere-
omer: 1H NMR (300 MHz, CDCl3) δ 7.99 (m, 2H), 7.57 (m, 1H),
7.45 (m, 2H), 3.86 (q, J ) 6.2 Hz, 1H), 3.48 (s, 1H), 3.21 (dd, J )
17.7, 5.4 Hz, 1H), 3.04 (dd, J ) 17.7, 8.4 Hz, 1H), 2.20-2.34 (m,
NMR (125 MHz, CDCl3) d 206.9, 205.9, 199.2, 144.1, 138.8, 137.8,
136.5, 133.5, 133.0, 132.8, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0,
126.5, 125.3, 87.3, 60.8, 59.3, 53.4, 48.1, 46.6, 44.9, 42.5, 40.8, 31.9,
31.7, 30.4, 28.5, 26.3, 25.1; IR (KBr) 3360, 1680, 1670, 1648 cm-1
;
MS (FAB, thioglycerol matrix) m/e (% rel intensity) 611 (1%, (M +
1)+), 593 (7%), 305 (3%), 217 (19%), 181 (11%), 91 (100%).
Stereochemical assignments were made on the basis of coupling
constants and on homonuclear decoupling and NOE experiments.7b
1H), 1.90-2.06 (m, 2H), 1.56-1.80 (m, 3H), 1.20-1.34 (m, 1H); 13
C
NMR (75 MHz) δ 201.4, 136.8, 133.2, 128.6, 128.1, 79.0, 44.2, 43.3,
34.5, 31.2, 22.4; IR (film) 3417, 1680 cm-1; HRMS (EI) m/e calcd for
C13H16O2 204.1150 found 218.1147 M+).
1S*,2R*,3R*,5S*-2-Acetyl-3-hydroxy-3-methylbicyclo[3.3.0]-
octane (26a). Following general procedure A, bis-enone 2536 (200
mg, 1.11 mmol), n-BuLi (1.40 mL of a 2.43 M hexane solution, 3.40
mmol), ZnCl2 (2.25 mL of a 1.0 M ether solution, 2.25 mmol), and
Ni(COD)2 (12 mg, 0.04 mmol) were employed to produce, after flash
chromatography (5:1 hexanes:EtOAc), in order of elution, 35 mg (17%)
of 26b as a white crystalline solid, 11 mg (5%) of trans isomer 36b14a
as a colorless oil, and 109 mg (54%) of 26a as a pale yellow solid that
all were homogeneous by TLC analysis. Spectral data of 26b and 36b
were identical to that previously reported.14a For 26a: 1H NMR (300
MHz, CDCl3) d 2.70-2.85 (m, 1H), 2.54 (s, 1H), 2.50 (d, J ) 9.8 Hz,
1H), 2.25-2.45 (m, 1H), 2.21 (s, 3H), 1.96 (dd, J ) 8.3, 12.0 Hz,
1H), 1.50-1.65 (m, 4H), 1.45 (t, J ) 11.0 Hz, 1H), 1.30-1.40 (m,
2H), 1.10 (s, 3H); 13C NMR (75 MHz) d 210.7, 80.7, 68.1, 49.6, 41.7,
37.9, 33.0, 32.9, 31.3, 24.8, 23.2; IR (KBr) 3372, 1682 cm-1; HRMS
(EI) m/e calcd for C10H15O2: 167.1072, found: 167.1068 ((M - CH3)+).
Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.66; H,
10.13. Stereochemical assignments were made on the basis of NOE
data.
3-Methyl-1-phenyl-(E)-7,9-decadien-1-one (28a). Following gen-
eral procedure A, enone 2738 (114 mg, 0.5 mmol), MeLi (1.5 mL, 2.1
mmol of a 1.4 M ethyl ether solution), ZnCl2 (136 mg, 1.2 mmol), and
Ni(COD)2 (7 mg, 0.03 mmol), were employed to produce, after flash
chromatography (95:5 hexanes:EtOAc), 80 mg (66%) of 28a as a
colorless oil that was >97% pure by capillary GC analysis. 1H NMR
(CDCl3, 500 MHz) δ 7.94 (m, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 6.30
(dt, J ) 17.0, 10.3 Hz, 1H), 6.04 (dd, J ) 15.3, 10.3, 1H), 5.69 (dt, J
) 15.0, 7.3 Hz, 1H), 5.08 (dd, J ) 17.0, 1.0 Hz, 1H), 4.96 (d, J )
10.0 Hz, 1H), 2.94 (dd, J ) 16.0, 5.5 Hz, 1 H), 2.76 (dd, J ) 16.0, 8.0
Hz, 1H), 2.05-2.21 (m, 3H), 1.36-1.52 (m, 3H), 1.22-1.30 (m, 1H),
0.96 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz) δ 200.3, 137.4, 137.3,
135.2, 132.9, 131.1, 128.5, 128.1, 114.8, 45.9, 36.7, 32.7, 29.6, 26.6,
20.0; IR 3085, 3061, 1686 cm-1; HRMS (EI) m/e calcd for C17H22O
242.1671, found 242.1667 (M+).
1-(2-Oxo-2-phenylethyl)-(E)-2-(1-propenyl)cyclopentane (28b).
Following general procedure B, enone 2738 (115 mg, 0.51 mmol), Et2Zn
(150 µL, 1.46 mmol), PPh3 (20 mg, 0.08 mmol), and Ni(COD)2 (7
mg, 0.03 mmol) were employed to produce, after flash chromatography
(9:1 hexanes:EtOAc), 81 mg (70%) of 28b as a colorless oil
contaminated with 5-10% of a diastereomer. 1H NMR (500 MHz,
CDCl3) δ 7.93 (m, 2H), 7.53 (m, 1H), 7.44 (m, 2H), 5.44 dq, J ) 15
Hz, 6.5 Hz, 1H), 5.29 (m, 1H), 3.17 (dd, J ) 16.0, 3.0 Hz, 1H), 2.71
(dd, J ) 16.0, 9.0 Hz, 1H), 1.96-2.06 (m, 3H), 1.79-1.87 (m, 1H),
1.64 (dd, J ) 6.5, 1.5 Hz, 3H), 1.56-1.66 (m, 2H), 1.33-1.42 (m,
1H), 1.14-1.24 (m, 1H); 13C NMR (125 MHz) δ 200.6, 137.3 134.7,
132.8, 128.5, 128.1, 125.3, 50.4, 43.1, 42.3, 32.7, 32.1, 23.4, 17.9 ; IR
(film) 3060, 3026, 2954, 2869, 1687 cm-1; HRMS (EI) m/e calcd for
C16H20O 228.1514, found 228.1510 (M+).
2-(2-Oxo-2-phenylethyl)-cyclopentan-1-ol (30). A mixture of
n-BuLi (1.5 mL of a 2.4 M hexane solution, 3.6 mmol) and ZnCl2 (2.0
mL of a 1 M ethyl ether solution, 2.0 mmol) in 40 mL of THF was
stirred for 20 min at 0 °C. A 4 mL THF solution of triphenylphosphine
(68 mg, 0.26 mmol) was added to Ni(COD)2 (7 mg, 0.03 mmol) and
stirred 5 min at 25 °C. The nickel solution was transferred by cannula
to the organozinc reagent and stirred at 0 °C. A 10 mL THF solution
of 29 (107 mg, 0.50 mmol) was added to the nickel/organozinc mixture,
and the reaction mixture was stirred at 0 °C. After stirring 30 min at
0 °C, the reaction mixture was subjected to an extractive workup (NH4-
2-(2-Oxo-2-phenylethyl)cyclohexan-1-ol (32). A mixture of n-BuLi
(1.2ml of a 2.5 M hexane solution, 3.0 mmol) and ZnCl2 (2.0 mL of a
1 M ethyl ether solution, 2.0 mmol) in 40 mL THF was stirred for 20
minutes at 0 °C. A 5 mL THF solution of triphenylphosphine (21 mg,
0.08 mmol) was added to Ni(COD)2 (12 mg, 0.04 mmol) and stirred 5
min at 25 °C. The nickel solution was transferred by cannula to the
organozinc reagent and stirred at 0 °C. A 10 mL THF solution of 31
(107 mg, 0.50 mmol) was added to the nickel/organozinc mixture at 0
°C by syringe drive addition over a 1.5 h period. After stirring 30
min at 0 °C, the reaction mixture was subjected to an extractive workup
(NH4Cl/NH4OH pH ) 8 buffer, Et2O), followed by flash chromatog-
raphy (7:3 hexanes:EtOAc) on silica gel to afford 62 mg (57%) of 32
(2:1 mixture of diastereomers) as a colorless oil. For the major dia-
stereomer: 1H NMR (300 MHz, CDCl3) δ 7.97 (m, 2H), 7.54 (m, 1H).
7.44 (m, 2H), 3.45 (dd, J ) 16.4, 5.6 Hz, 1H) 3.26 (dt, J ) 10.0, 4.3
Hz, 1H), 2.78 (dd, J ) 16.5, 6.8 Hz, 1H), 2.18-2.30 (br s, 1H), 1.90-
2.06 (m, 2H), 1.72-1.85 (m, 2H), 1.59-1.66 (m, 1H), 0.90-1.36 (m,
4H); 13C NMR (75 MHz) δ 201.3, 137.2, 133.0, 128.5, 128.2, 75.1,
43.0, 41.9, 36.1, 31.8, 25.5, 24.9; IR (film) 3426, 3061, 1679 cm-1
;
HRMS (EI) m/e calcd for C14H18O2 218.1307, found 218.1300 (M+).
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 76.29; H,
8.28.
6-Cyano-3-methyl-1-phenylhexan-1-one (34a): Following general
procedure A, enone 3339 (110 mg, 0.55 mmol), MeLi (2.0 mL, 2.3
mmol of a 1.1 M ethyl ether solution), ZnCl2 (170 mg, 1.3 mmol), and
Ni(COD)2 (7 mg, 0.03 mmol) were employed to produce, after flash
chromatography (4:1 hexanes:EtOAc), 86 mg (73%) of 34a as a yellow
oil that was homogeneous by TLC analysis. 1H NMR (500 MHz,
CDCl3) δ 7.93 (m, 2H), 7.55 (m, 1H) 7.46 (m, 2H), 2.92 (dd, J )
16.2, 6.2 Hz, 1H), 2.83 (dd, J ) 16.2, 6.2 Hz, 1H), 2.34 (m, 2H), 2.22
(octet, J ) 6.5 Hz, 1H), 1.61-1.78 (m, 2H), 1.50-1.58 (m, 1H), 1.34-
1.43 (m, 1H) , 0.99 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz) δ 199.6,
137.2, 133.1, 128.6, 128.0, 119.7, 45.6, 35.9, 28.8, 23.1, 19.8, 17.3;
IR (film) 3060, 2244, 1684 cm-1; HRMS (EI) m/e calcd for C14H17NO
215.1310, found 215.1306 (M+).
6-Cyano-1-phenylhexan-1-one (34b) and 6-Cyano-1-phenyl-2-
hexen-1-ol (35b). General procedure B was followed except that
trimethylsilyl chloride (115 µL, 0.9 mmol) was added as the last reagent
dropwise by syringe. Enone 3339 (120 mg, 0.6 mmol), Et2Zn (185
µL, 1.8 mmol), PPh3 (16 mg, 0.06 mmol), and Ni(COD)2 (9 mg, 0.03
mmol) were employed to produce, after flash chromatography (3:2
hexanes:EtOAc), 70 mg (58%) of 34b and 30 mg (25%) of 35b as
colorless oils that were both homogeneous by TLC analysis. For 34b:
1H NMR (500 MHz, CDCl3) δ 7.95 (m, 2H), 7.56 (m, 1H), 7.46 (m,
2H), 3.00 (t, J ) 7.3 Hz, 2H), 2.37 (t, J ) 7.3 Hz, 2H), 1.79 (quintet,
7.5 Hz, 2H), 1.73 (quintet, J ) 7.5 Hz, 2H), 1.55 (m, 2H); 13C NMR
(125 MHz) δ 199.7, 136.8, 133.1 128.6, 128.0, 119.6, 38.0, 28.3, 25.3,
23.2, 17.0; IR (film) 2244, 1683 cm-1; MS (EI) m/e calcd for C13H15-
NO 201.1154, found 201.1151 (M+). For 35b: 1H NMR (500 MHz,
CDCl3) δ 7.35 (m, 4H), 7.28 (m, 1H), 5.66-5.79 (m, 2H), 5.17 (d, J
) 6.0 Hz, 1H), 2.32 (t, J ) 7.2 Hz, 2H), 2.22 (q, 7.3 Hz, 2H), 2.13 (br
s, 1H), 1.76 (quintet, J ) 7.2 Hz, 2H); 13C NMR (125 MHz) δ 143.0,
134.5, 129.1, 128.6, 127.7, 126.1, 119.6, 74.8, 30.9, 24.7, 16.5; IR (film)
3424.6, 3025.0, 2931.0, 2249.4, 1666.3 cm-1; HRMS (EI) m/e calcd
for C13H15NO 201.1154, found 201.1149 (M+).
1R*,2R*,6R*-1-Benzoyl-6-(2-oxo-2-phenylethyl)-2-phenylcyclo-
hexane (38a). General procedure A was followed except that PhLi
(38) Diene 27 was prepared by Wittig olefination of (E)-5,7-octadienal.
(E)-5,7-Octadienal was prepared from 2,3-dihydropyran by R-alkylation (a),
ring-opening (b), and Taber modified swern oxidation (c). (a) Margot, C.;
Rizzolio, M.; Schlosser, M. Tetrahedron 1990, 46, 2411. (b) Viola, A.;
Collins, J. J.; Fillip, N.; Locke, J. S. J. Org. Chem. 1993, 58, 5067. (c)
Taber, D. F., Amedio Jr., J. C.; Jung, K-Y. J. Org. Chem. 1987, 52, 5621.
(39) Nitrile 33 was prepared by Wittig olefination of 4-cyano-butanal.
4-Cyanobutanal was prepared from THF by ZnCl2-mediated ring opening
and acylation, ester hydrolysis, and Taber-modified Swern oxidation (see
ref 38c). (a) Synerholm, M. E. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol III, p 187. (b) Earl, H. A., Sterling, J. M. J. Chem. Soc., Perkin
Trans. II 1987, 1273.

4920 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Montgomery et al.
was freshly prepared as follows: t-BuLi (1.55 mL of a 1.44 M pentane
solution, 2.23 mmol) was added dropwise to a 5 mL -78 °C solution
of phenyl iodide (0.225 g, 0.125 mL, 1.10 mmol). After stirring for
30 min at -78 °C, the mixture was allowed to warm to 0 °C, and
ZnCl2 (0.70 mL of a 1.0 M ether solution, 0.70 mmol) was added
dropwise by syringe. Bis-enone 2336 (91 mg, 0.30 mmol) and Ni-
(COD)2 (3 mg, 0.01 mmol) were employed to produce, after flash
chromatography (7:1 hexanes:EtOAc), 74 mg (65%) of 38a as a pale-
yellow solid which was homogeneous by TLC analysis: mp 118-
118.5 °C (recrystallized from Et2O/hexane); 1H NMR (300 MHz,
CDCl3) δ 6.90-7.90 (m, 15H), 3.65 (t, J ) 10.5 Hz, 1H), 2.90-3.10
(m, 2H), 2.50-2.70 (m, 2H), 1.85-2.00 (m, 3H), 1.65-1.85 (m, 1H),
1.45-1.65 (m, 1H), 1.25-1.45 (m, 1H); 13C NMR (75 MHz) δ 205.5,
199.1, 143.4, 138.9, 136.7, 133.0, 132.5, 128.5, 128.2, 128.0, 127.8,
127.6, 126.3, 56.2, 48.7, 43.9, 38.6, 33.5, 31.3, 25.6; IR (KBr) 1681,
1667 cm-1; HRMS (EI) m/e calcd for C27H26O2: 382.1933, found:
382.1926 (M+). Anal. Calcd for C27H26O2: C, 84.78; H, 6.85.
Found: C, 84.78; H, 6.96.
that were homogeneous by TLC analysis. For 41a: 1H NMR (300
MHz, CDCl3) δ 7.97 (m, 2H), 7.40-7.60 (m, 3H), 5.27 (tq, J ) 7.3,
1.9 Hz, 1H), 3.24 (m, 1H), 3.06 (dd, J ) 3.8, 16.6 Hz, 1H), 2.94 (dd,
J ) 10.5, 16.6 Hz, 1H), 2.34 (m, 1H), 2.25 (m, 1H), 1.86-2.06 (m,
3H), 1.41-1.76 (m, 3H), 1.32 (m, 4H), 0.88 (m, 3H); 13C NMR (75
MHz) δ 199.7, 145.5, 137.3, 132.9, 128.5, 128.0, 121.8, 43.6, 36.1,
33.2, 32.8, 32.2, 29.0, 24.0, 22.4, 14.0; IR (film) 1684, 1596, 1579;
cm-1; HRMS (EI) m/e calcd for C18H24O 256.1827, found 256.1822
(M+). Anal. Calcd for C18H24O: C, 84.32; H, 9.44. Found: C, 84.16;
H, 9.57. The alkene stereochemistry was assigned by observation of
1.3% and 1.0% NOE of the allylic ring methylene protons (δ 2.25 and
2.34) that are syn to the alkene proton upon irradiation of that alkene
proton at δ 5.27. Assignments were confirmed by homonuclear
decoupling experiments.
(Z)-1-Benzylidene-2-(2-oxo-2-phenylethyl)cyclopentane (42). Fol-
lowing general procedure A, (2E)-1-phenyloct-2-en-7-yn-1-one (1)7a
(43.5 mg, 0.22 mmol), PhMgBr (1.10 mL, 1.10 mmol of a 1.0 M THF
solution), zinc chloride (98 mg, 0.72 mmol), and Ni(COD)2 (5.5 mg,
0.020 mmol) were employed to produce, after flash chromatography
(21:1 hexanes:EtOAc), 37 mg (61%) of 42 as a white crystalline solid
1R*,2R*,6R*-1-Acetyl-6-(2-oxopropyl)-2-phenylcyclohexane (39a)
and 1R*,2R*,6S*-1-Acetyl-6-(2-oxopropyl)-2-phenylcyclohexane (39b).
The procedure for compound 38a was followed, employing bis-enone
2536 (72 mg, 0.40 mmol), t-BuLi (1.7 mL of a 1.59 mmol pentane
solution, 2.7 mmol), phenyl iodide (0.273 g, 0.150 mL, 1.34 mmol),
ZnCl2 (0.90 mL of a 1.0 M ether solution, 0.90 mmol), and Ni(COD)2
(5 mg, 0.018 mmol) to afford, after flash chromatography (5:1 hexanes:
EtOAc), 12 mg (12%) of 39b as a pale yellow oil and 60 mg (58%) of
39a as a white solid that were both homogeneous by TLC analysis.
1
that was recrystallized from hexanes/ether: mp 96-97 °C, H NMR
(500 MHz, CDCl3) δ 7.80 (m, 2H), 7.55 (m, 1H), 7.38 (m, 2H), 7.28
(m, 4H), 7.15 (m, 1H), 6.44 (m, 1H), 3.76 (m, 1H), 3.07 (dd, J ) 3.0,
17.0 Hz, 1H), 2.86 (dd, J ) 11.5, 17.0 Hz, 1H), 2.59 (m, 1H), 2.53
(m, 1H), 2.05 (dq, J ) 12.8, 7.8 Hz, 1H), 1.71 (m, 2H), 1.58 (m, 1H);
13C NMR (125 MHz) δ 199.7, 149.8, 138.0, 137.1, 132.9, 128.5, 128.03,
128.01, 126.1, 121.6, 41.7, 36.5, 36.0, 33.5, 23.4; IR (KBr) 1673, 1593
cm-1; HRMS (EI) m/e calcd for C20H20O: 276.1514, found: 276.1510
(M+). Anal. Calcd for C20H20O: C, 86.92; H, 7.29. Found: C, 87.12;
H, 7.48. The alkene stereochemistry was assigned by observation of
1.4% and 1.3% NOE of the allylic ring methylene protons (δ 2.53 and
2.59) that are syn to the alkene proton upon irradiation of that alkene
proton at δ 6.44. Assignments were confirmed by homonuclear
decoupling experiments.
1
For 39a: mp 92-93 °C (recrystallized Et2O/hexane); H NMR (300
MHz, CDCl3) d 7.10-7.35 (m, 5H), 2.72 (dt, J ) 3.3, 11.4 Hz, 1H),
2.55 (t, J ) 10.8 Hz, 1H), 2.15-2.40 (m, 3H), 2.10 (s, 3H), 1.80-
1.95 (m, 3H), 1.68 (s, 3H), 1.40-1.65 (m, 2H), 1.05-1.25 (m, 1H);
13C NMR (75 MHz) d 212.7, 207.5, 143.6, 128.6, 127.3, 126.7, 62.7,
48.6, 47.8, 35.8, 34.2, 31.7, 30.9, 30.3, 25.6; IR (KBr) 1707, 1690
cm-1; HRMS (EI) m/e calcd for C17H22O2: 258.1620, found: 258.1614
(M+). Anal. Calcd for C17H22O2: C, 79.03; H, 8.58. Found: C, 79.22;
H, 8.64. For (39b): 1H NMR (300 MHz, CDCl3) δ 7.10-7.30 (m,
5H), 3.11 (dd, J ) 4.2, 11.7 Hz, 1H), 2.86-3.00 (m, 2H), 2.80 (dd, J
) 6.3, 18.0 Hz, 1H), 2.40 (dd, J ) 6.3, 18.0 Hz, 1H), 2.12 (s, 3H),
1.92 (s, 3H), 1.80-1.90 (m, 1H), 1.55-1.80 (m, 3H), 1.35-1.55 (m,
2H); 13C NMR (75 MHz) δ 210.9, 207.3, 145.1, 128.3, 127.2, 126.1,
58.0, 42.2, 40.3, 34.6, 31.4, 31.2, 30.4, 29.7, 21.1; IR (film) 1705, 1700
cm-1; HRMS (EI) m/e calcd for C17H22O2: 258.1620, found: 258.1615
(M+).
(Z)-1-(3-Butenylidene)-2-(2-oxo-2-phenylethyl)cyclopentane (43a).
Following general procedure A, (2E)-1-phenyloct-2-en-7-yn-1-one (1)7a
(60 mg, 0.30 mmol), vinylmagnesium bromide (1.05 mL, 1.05 mmol
of a 1.0 M THF solution), zinc chloride (95 mg, 0.70 mmol), and Ni-
(COD)2 (6 mg, 0.021 mmol) were employed to produce, after flash
chromatography (25:1 pentane:Et2O), in order of elution, 10.5 mg of
43a as a yellow oil and 35 mg of mixture of 43a and 2b (6:1 molar
ratio based on 1H NMR integration.) Total combined yield of 43a: 41
mg, 59%. For 43a: 1H NMR (500 MHz, CDCl3) δ 7.96 (m, 2H),
7.56 (tt, J ) 1.5, 7.5 Hz, 1H), 7.46 (m, 2H), 6.46 (dt, J ) 10.5, 17.0
Hz, 1H), 5.99 (dd, J ) 2.0, 11.0 Hz, 1H), 5.07 (dd, J ) 1.0, 17.0 Hz,
1H), 4.97 (d, J ) 10.0 Hz, 1H), 3.45 (m, 1H), 3.00-3.10 (m, 2H),
2.42-2.52 (m, 1H), 2.28-2.38 (m, 1H), 1.95 (m, 1H), 1.67 (m, 2H),
1.49-1.55 (m, 1H); 13C NMR (125 MHz) δ 199.3, 150.7, 137.1, 133.9,
133.0, 128.6, 128.1, 122.0, 114.9, 43.9, 36.5, 33.6, 32.8, 23.8; IR (film)
1685, 1652, 1597, 1581 cm-1; HRMS (EI) m/e calcd for C16H18O
226.1358, found 226.1354 (M+).
1S*,2R*,3S*-2-Benzoyl-3-phenylcyclohexanol (40). PhMgBr (3.0
mL of a 1.0 M THF solution, 3.0 mmol) was added to ZnCl2 (278 mg,
2.0 mmol) in 40 mL of THF at 0 °C. After stirring 30 min the solution
was added by syringe drive addition over a 2 h period to a mixture of
enone 2936 (102 mg, 0.50 mmol) and Ni(COD)2 (9 mg, 0.03 mmol) in
15 mL of THF at 0 °C. After stirring 15 min at 0 °C, the reaction
mixture was subjected to aqueous workup (NH4Cl/NH4OH pH ) 8
buffer, Et2O) followed by flash chromatography on silica gel to afford
58 mg (41%) of 40 as a white crystalline solid (mp 119-120 °C) that
was >97% pure by capillary GC analysis. 1H NMR (CDCl3, 500 MHz)
δ 7.00-7.70 (m, 10H), 4.24 (br s, 1H) 3.82 (dd, 2.0, 11.7 Hz, 1H),
3.53 (br s, 1H), 3.47 (dt, 3.7, 11.8 Hz, 1H), 1.96-2.10 (m, 3H), 1.58-
1.76 (m, 3H); 13C NMR (125 MHz) δ 205.3, 143.8, 137.0, 133.2, 128.4,
128.3, 128.1, 127.5, 126.4, 66.7, 54.0, 40.8, 33.7, 31.8, 19.7; IR (film)
3468, 1645 cm-1; HRMS (EI) m/e calcd for C19H20O2 280.1463, found
280.1464 (M+).
2-(2-Oxo-2-phenylethyl)-(Z)-1-(1-pentylidene)cyclopentane (41a).
Following general procedure A, (2E)-1-phenyloct-2-en-7-yn-1-one (1)7a
(0.10 g, 0.50 mmol), n-BuLi (0.58 mL, 1.4 mmol of a 2.43 M hexane
solution), zinc chloride (0.75 mL, 0.75 mmol of a 1.0 M ether solution),
and Ni(COD)2 (6.9 mg, 0.025 mmol) were employed to produce, after
flash chromatography (24:1 to 9:1 hexanes:EtOAc), in order of elution,
65 mg (51%) of 41a and 11 mg (11%) of 2b, both as colorless oils
Acknowledgment. J.M. acknowledges receipt of a National
Science Foundation CAREER Award (1996-2000) and a New
Faculty Award from 3M Pharmaceuticals. Acknowledgment is
made to the Donors of The Petroleum Research Fund, admin-
istered by the American Chemical Society for partial support
of this research. Dr. Mary Jane Heeg of Wayne State University
is kindly acknowledged for the X-ray crystallographic analysis
of 24.
1
Supporting Information Available: Copies of H NMR
spectra of representative compounds (25 pages). See any current
masthead page for ordering and Internet access instructions.
JA9702125