Scope of the intramolecular titanocene-catalyzed Pauson-Khand type reaction

Article abstract of DOI:10.1021/ja990682u

A Pauson-Khand type conversion of enynes to bicyclic cyclopentenones employing the commercially available precatalyst titanocene dicarbonyl is described. This methodology shows excellent functional group tolerance for a group 4 metallocene-catalyzed process. The scope and limitations of this cyclization with respect to 1,6-, 1,7- and 1,8-enynes with a variety of terminal alkyne substituents, chiral enynes, and enynes containing substituted olefins are described in detail. A mechanism involving carbonylation of an intermediate titanacyclopentene has been proposed.

Full text of DOI:10.1021/ja990682u

J. Am. Chem. Soc. 1999, 121, 5881-5898
5881
Scope of the Intramolecular Titanocene-Catalyzed Pauson-Khand
Type Reaction1
Frederick A. Hicks,† Natasha M. Kablaoui,‡ and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed March 3, 1999
Abstract: A Pauson-Khand type conversion of enynes to bicyclic cyclopentenones employing the commercially
available precatalyst titanocene dicarbonyl is described. This methodology shows excellent functional group
tolerance for a group 4 metallocene-catalyzed process. The scope and limitations of this cyclization with respect
to 1,6-, 1,7- and 1,8-enynes with a variety of terminal alkyne substituents, chiral enynes, and enynes containing
substituted olefins are described in detail. A mechanism involving carbonylation of an intermediate
titanacyclopentene has been proposed.
Introduction
excellent reviews on the progress in this field have been
published recently.9 The proof of the utility of these methods
lies in their elegant applications to total synthesis.10
The most thoroughly investigated and utilized transition
metal-mediated cycloaddition reaction is the Pauson-Khand
reaction.11 First reported in 1973,12 the overall transformation
involves the formal [2 + 2 + 1] cycloaddition of an alkyne, an
alkene, and CO to produce a cyclopentenone (Scheme 1).13 The
first intramolecular version was reported by Schore in 1981 (eq
1).14 This work demonstrated the synthetic potential inherent
In the field of organic chemistry, the search for new and more
efficient methods of carbon-carbon bond formation for ap-
plication in the total synthesis of complex molecules continues
to be a major theme. Recently, an important area of investigation
toward this end has involved transition metal-mediated and
-catalyzed cycloaddition reactions. This work has allowed for
the combination of unsaturated functional groups in ways which
are either difficult or impossible without the action of a transition
metal complex. Examples of this approach include the intramo-
lecular Diels-Alder2 and Alder-Ene3 cyclization of unactivated
substrates, the homo-Diels-Alder reaction,4 [2 + 2 + 2] alkyne
cyclotrimerization,5 intramolecular triene-ene cyclization,6 [5
+ 2] cyclopropyl enyne and diene7 and [4 + 4] 1,3-diene
cycloadditions.8 The possibility also exists for asymmetric
induction with the use of chiral ligands, and a number of
in an intramolecular Pauson-Khand cyclization, which allows
for the formation of two rings and three new carbon-carbon
bonds. Subsequently, a large body of work has been reported
which has culminated in the utilization of the intramolecular
cyclization in a number of efforts in total synthesis.15 Initial
application to synthesis was hampered by the low to moderate
yields of cyclopentenone and harsh reaction conditions which
were required. A number of improvements on the early protocols
have been reported,16 but the one which has been most widely
adopted is the use of amine-oxide promoters, which allows for
† Current Address: Department of Chemistry, University of North
Carolina at Chapel Hill, CB 3290, Chapel Hill, NC 27599.
‡ Current address: Department of Chemistry and Chemical Biology,
Harvard University, 12 Oxford St., Cambridge, MA 02138.
(1) This paper has been adapted, in part, from the following thesis: Hicks,
F. A., Ph.D. Dissertation, Massachusetts Institute of Technology, 1999.
(2) A variety of transition metals have been shown to catalyze the
intramolecular Diels-Alder reaction. (a) Ni: 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. Rh: (c) Jolly, R. S.; Luedtke, G.; Sheehan,
D.; Livinghouse, T. J. Am. Chem. Soc. 1990, 112, 4965. (d) O’Mahony, D.
J. R.; Belanger, D. B.; Livinghouse, T. Synlett 1998, 443. (e) Gilbertson,
S. R.; Hoge, G. S. Tetrahedron Lett. 1998, 39, 2075. Pd: (f) Kumar, K.;
Jolly, R. S. Tetrahedron Lett. 1998, 39, 3047.
(9) (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (b)
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96,
635. (c) Fru¨hauf, H.-W. Chem. ReV. 1997, 97, 523.
(10) (a) dl-Estrone: Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc.
1980, 102, 5253. (b) (+)-Asteriscanolide: Wender, P. A.; Ihle, N. C.;
Correia, C. R. D. J. Am. Chem. Soc. 1988, 110, 5904. (c) (-)-Sterepolide:
Trost, B. M.; Hipskind, P. A.; Chung, J. Y. L.; Chan, C. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 1502. (d) (()-Yohimban: Wender, P. A.; Smith,
T. E. J. Org. Chem. 1996, 61, 824. (e) (+)-Isoiridomyrmecin: Takacs, J.
M.; Myoung, Y. C. Tetrahedron Lett. 1992, 33, 317.
(11) Schore, N. E. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon: Kidlington, 1995; Vol. 12, p 703.
(12) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Perkin Trans. 1 1973, 975.
(13) For related transition metal-catalyzed approaches to cyclopentenones,
see: (a) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1941. (b) Ihle, N. C.;
Heathcock, C. H. J. Org. Chem. 1993, 58, 560. (c) Ojima, I.; Fracchiolla,
D. A.; Donovan, R. J.; Banerji, P. J. Org. Chem. 1994, 59, 7594. (d) Ojima,
I.; Zhu, J.; Vidal, E. S.; Kass, D. F. J. Am. Chem. Soc. 1998, 120, 6690.
(14) Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436.
(3) Trost, B. M. Acc. Chem. Res. 1990, 23, 34.
(4) (a) Lautens, M.; Tam, W.; Lautens, J. C.; Edwards, L. G.; Crudden,
C. M.; Smith, A. C. J. Am. Chem. Soc. 1995, 117, 6863. (b) Lautens, M.;
Edwards, L. G.; Tam, W.; Lough, A. J. J. Am. Chem. Soc. 1995, 117, 10276
and references therein.
(5) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
(6) (a) Takacs, J. M.; Anderson, L. G. J. Am. Chem. Soc. 1987, 109,
2200. (b) Takacs, J. M.; Anderson, L. G.; Creswell, M. W.; Takacs, B. E.
Tetrahedron Lett. 1987, 28, 5627. (c) Takacs, B. E.; Takacs, J. M.
Tetrahedron Lett. 1990, 31, 2865.
(7) (a) Wender, P. A.; McDonald, F. E. Tetrahedron Lett. 1990, 31, 3691.
(b) Agnel, G.; Negishi, E.-i. J. Am. Chem. Soc. 1991, 113, 7424. (c) Agnel,
G.; Owczarczyk, Z.; Negishi, E.-i. Tetrahedron Lett. 1992, 33, 1543. (d)
Mori, M.; Uesaka, N.; Shibasaki, M. J. Org. Chem. 1992, 57, 3519.
(8) (a) Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678.
(b) Wender, P. A.; Snapper, M. L.Tetrahedron Lett. 1987, 28, 2221. (c)
Wender, P. A.; Ihle, N. C. Tetrahedron Lett. 1987, 28, 2451.
10.1021/ja990682u CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/15/1999

5882 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Scheme 1
upon irradiation to generate a catalytically active species under
extremely mild conditions (1 atm CO, 50 °C) (eq 3). Upon
the formation of cyclopentenones in good to excellent yield
under extremely mild conditions (0 °C to rt).17-19
One of the limitations of these Pauson-Khand type reactions
in comparison to many of the other cycloaddition reactions
mentioned above is the requirement for a stoichiometric amount
of a metal complex. Few examples of Pauson-Khand cycliza-
tions employing substoichiometric amounts of Co,20 including
a single intermolecular example employing only 0.22 mol %
Co2(CO)8,21 appeared prior to the past five years. During this
period a number of truly catalytic intramolecular Pauson-Khand
cyclizations have been developed.22
A major impediment to a Co-catalyzed process has been the
formation of inactive cluster complexes such as Co4(CO)12. In
an attempt to prevent the formation of such species, Jeong and
co-workers found that the addition of the coligand P(OPh)3
allowed for the cyclocarbonylation of a variety of enynes with
3-10 mol % Co2(CO)8 under 3 atm CO (eq 2).23 It should be
further investigation, it was found that this reaction could be
carried out thermally if the reaction temperature was maintained
in a narrow range (at 60 °C).26 Additionally, the use of air-
stable alkyne-Co complexes as precatalysts was reported.27
Chung and Jeong reported that (indenyl)Co(cod) was a
precatalyst for the cyclization of two 1,6-enynes (DME, 100
°C, 15 atm CO, 40 h).28 The presence of the indenyl ligand
appeared crucial as the corresponding complexes CpCo(CO)2
and CpCo(cod) were completely inactive under the same
reaction conditions. Chung later found that low valent cobalt
complexes generated in situ from Co(acac)2 and NaBH4 could
serve as catalysts for the conversion of several 1,6-enynes to
enones (CH2Cl2, 100 °C, 30-40 atm CO, 48 h).29 It was
proposed that the NaBH4 served not only to reduce the cobalt
but also to stabilize the reactive intermediates and prevent the
formation of unreactive clusters and complexes. However, in a
more recent report by Chung, Co4(CO)12, one of the purportedly
inactive complexes, could in fact be used as a precatalyst for
the Pauson-Khand reaction in both an inter- and intramolecular
fashion under moderately high CO pressures (CH2Cl2, 150 °C,
10 atm CO, 24 h).30 Another cobalt cluster, methylidynetricobalt
nonacarbonyl, has also proven to be an effective catalyst
(toluene, 120 °C, 7 atm CO).31 Jeong has developed a catalytic
Pauson-Khand reaction which can be carried out in supercritical
CO2.32
noted that with stoichiometric Pauson-Khand reactions, the
presence of a phosphine or phosphite ligand on the dicobalt
complex has been reported to lead to a dramatic rate decrease.1,24
Another interesting version of the intramolecular Pauson-
Khand cyclization has been developed by Livinghouse.25 He
exploited the known propensity of Co2(CO)8 to lose a CO ligand
Although the Pauson-Khand reaction refers only to Co-
mediated processes, a variety of other transition metals are also
capable of effecting stoichiometric Pauson-Khand type enyne
cyclizations. These reactions offer the possibility of developing
catalytic processes which may exhibit complementary reactivity
when compared to the cobalt-based procedures. In addition to
Co2(CO)8, other transition metal carbonyl complexes, such as
Fe(CO)4(acetone),33 W(CO)5(THF),34 Cr(CO)5F,35 Cp2Mo2-
(15) dl-Coriolin and hirsutic acid: (a) Exon, C.; Magnus, P. J. Am. Chem.
Soc. 1983, 105, 2477. (b) Magnus, P.; Exon, C. Albaugh-Robertson, P.
Tetrahedron, 1985, 41, 5861. Tetrahydroanhyroaucubigenone: (c) Billing-
ton, D. C.; Willison, D. Tetrahedron Lett. 1984, 25, 4041. Pentalene: (d)
Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3835. (e) Schore, N. E.; Rowley,
E. G. J. Am. Chem. Soc. 1988, 110, 5224. Quadrone: (f) Magnus, P.
Principe, L. M.; Slater, M. J. J. Org. Chem. 1987, 52, 1483. Methyl
deoxynorpentalenolactone H: (g) Magnus, P.; Slater, M. J.; Principe, L.
M. J. Org. Chem. 1989, 54, 5148. Pentalenic Acid: (h) Rowley, E. G.;
Schore, N. E. J. Organomet. Chem. 1991, 413, C5. (i) Rowley, E. G.;
Schore, N. E. J. Org. Chem. 1992, 57, 6853. Loganin: (j) Jeong, N.; Lee,
B. Y.; Lee, S. M.; Chung, Y. K., Lee, S.-G. Tetrahedron Lett. 1993, 34,
4023.
(CO)4,36 and Mo(CO)6 react stoichiometrically with enynes
37
(24) (a) Billington, D. C.; Helps, I. M.; Pauson, P. L.; Thomson, W.;
Willison, D. J. Organomet. Chem. 1988, 354, 233. (b) Bladon, P.; Pauson,
P. L.; Brunner, H.; Eder, R. J. Organomet. Chem. 1988, 355, 449. (c) Park,
H.-J.; Lee, B. Y.; Kang, Y. K.; Chung, Y. K. Organometallics 1995, 14,
3104.
(25) Pagenkopf, B. L.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118,
2285.
(16) Silica gel adsorption: Smit, W. A.; Simonyan, S. O.; Tarasov, V.
A.; Mikaelian, G. S.; Gybin, A. S.; Ibragimov, I. I.; Caple, R.; Froen, D.;
Kraeger, A. Synthesis 1989, 472. DMSO promotion: Chung, Y. K.; Lee,
B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L. Organometallics 1993, 12,
220.
(17) Shamabayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289.
(18) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett
1991, 204.
(26) Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T. Tetrahedron
Lett. 1998, 39, 7637.
(27) Belanger, D. B.; Livinghouse, T. Tetrahedron Lett. 1998, 39, 7641.
(28) Lee, B. Y.; Chung, Y. K.; Jeong, N.; Lee, Y.; Hwang, S. H. J. Am.
Chem. Soc. 1994, 116, 8793.
(29) Lee, N. Y.; Chung, Y. K. Tetrahedron Lett. 1996, 37, 3145.
(30) Kim, J. W.; Chung, Y. K. Synthesis 1998, 142.
(31) Sugihara, T.; Yamaguchi, M. J. Am. Chem. Soc. 1998, 120, 10782.
(32) Jeong, N.; Hwang, S. H.; Lee, Y. W.; Lim, J. S. J. Am. Chem. Soc.
1997, 119, 10549.
(33) (a) Pearson, A. J.; Dubbert, R. A. J. Chem. Soc., Chem. Commun.
1991, 202. (b) Pearson, A. J.; Dubbert, R. A. Organometallics 1994, 13,
1656.
(19) Very recently, the use of amine solvents has also been shown to
promote the Pauson-Khand cyclization under extremely mild conditions.
(a) Rajesh, T.; Periasamy, M. Tetrahedron Lett. 1998, 39, 117. (b) Sugihara,
T.; Yamada, M.; Ban, H.; Yamaguchi, M.; Kaneko, C. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2801.
(20) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman,
M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977. (b) Billington, D. C.
Tetrahedron Lett. 1983, 24, 2905. (c) Billington, D. C.; Kerr, W. J.; Pauson,
P. L.; Farnocchi, C. F. J. Organomet. Chem. 1988, 356, 213.
(21) Rautenstrauch, V.; Me´gard, P.; Conesa, J.; Ku¨ster, W. Angew.
Chem., Int. Ed. Engl. 1990, 29, 1413.
(34) Hoye, T. R.; Suriano, J. A. J. Am. Chem. Soc. 1993, 115, 1154.
(35) Jordi, L.; Segundo, A.; Camps, F.; Ricart, S.; Moreto`, J. M.
Organometallics 1993, 12, 3795.
(36) Mukai, C.; Uchiyama, M.; Hanaoka, M. J. Chem. Soc., Chem.
Commun. 1992, 1014.
(22) For a review on the development of catalytic Pauson-Khand
reactions, see: Geis, O.; Schmalz, H.-G. Angew. Chem., Int. Ed. 1998, 37,
911.
(23) Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc.
1994, 116, 3159.
(37) Jeong, N.; Lee, S. J.; Lee, B. Y.; Chung, Y. K. Tetrahedron Lett.
1993, 34, 4027.

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5883
Scheme 2
Scheme 3
Scheme 4
Scheme 5
reaction proved too unstable to isolate, they could be hydrolyzed
to the corresponding cyclopentenones 3; however, the trouble-
some imine hydrolysis provided disappointing yields (43-80%).
After this work, a Ni-catalyzed variant of this process was
developed by adapting Tamao’s stoichiometric reaction41 to the
use of silylcyanides.45 This methodology represented an im-
provement over the titanium-catalyzed reaction in terms of
substrate scope, with enynes containing 1,2-disubstituted olefins,
aliphatic ketones, and nitriles proving to be compatible with
the reaction conditions employed.
Attempts were also made to effect a direct titanocene-
catalyzed enyne cyclocarbonylation employing CO rather than
R′NC; however, the conditions initially investigated failed to
produce significant quantities of cyclopentenone (Scheme 5).
This finding was in accord with the earlier studies on the
stoichiometric carbonylation of titanacyclopentenes.40 Exposure
of a THF solution of titanacyclopentene 1a to an atmosphere
of CO led only to decomposition of the titanacycle without the
production of the desired cyclopentenone (Scheme 5). Only
when the reaction was carried out in CHCl3 were reasonable
yields of cyclopentenone obtained; under these conditions the
titanocene moiety is oxidized to Cp2TiCl2, which apparently
prevents a destructive interaction between a low valent titanium
intermediate and the nascent enone. The use of CHCl3, however,
removes the Ti from the oxidation state necessary for catalysis.
Following our work on stoichiometric titanium-mediated
enyne cyclocarbonylations,40 a related cyclocarbonylation of
enones was investigated.46 It was found that titanacycles derived
from Cp2Ti(PMe3)2 and a variety of enones and an ynone could
be carbonylated to yield γ-butyrolactones and a butenolide in a
in a similar fashion. In a different approach, Negishi has
shown that bicyclic zirconacyclopentenes can be formed from
“Cp2Zr” and an enyne. The resultant metallacycles can be
transformed under an atmosphere of CO into cyclopentenones
(Scheme 2).38,39
During the development of a complementary enyne cyclo-
carbonylation procedure involving “Cp2Ti” (from Cp2TiCl2 and
2 equiv EtMgBr), which displayed greater tolerance for ox-
genated functional groups in comparison to “Cp2Zr”, it was
noted that the treatment of the titanacyclopentene intermediates
with isonitriles, which are isoelectronic with CO, produced the
analogous iminocyclopentenes (2a) and isonitrile complexes of
titanocene (Scheme 3).40 A related iminocyclopentene synthesis
promoted by Ni complexes had previously been reported by
Tamao.41
The observation of the Cp2Ti(II) isonitrile complexes led to
the formulation of the catalytic cycle shown in Scheme 4. While
the use of isonitriles such as t-BuNC led to rapid catalyst
deactivation, the use of trialkylsilylcyanides (R′ ) Et3Si,(tert-
butyl)(Me)2Si),42 which exist in tautomeric equilibria with minor
amounts of the isocyanides (∼99:1 for trialkylsilyl cyanides),
allowed for the effective catalytic formation of the iminocy-
clopentenes.43,44 Although the silylimines 2 obtained from this
(38) Negishi, E.-i.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cedarbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336.
(39) Negishi, E.-i. In ComprehensiVe Organic Chemistry; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 1163.
(40) Grossman, R. B.; Buchwald, S. L. J. Org. Chem. 1992, 57, 5803.
(41) (a) Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1988, 110,
1286. (b) Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 539.
(42) Rasmussen, J. K.; Heilmann, S. M.; Krepski, L. R. In AdVances in
Silicon Chemistry; Larson, G. L., Ed.; JAI Press: Greenwich, CT, 1991;
pp 65-187.
(43) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.
1993, 115, 4912.
(44) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.
1994, 116, 8593.
(45) Zhang, M.; Buchwald, S. L. J. Org. Chem. 1996, 61, 4498.

5884 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Scheme 6
and toluene led to similar levels of conversion to the enone
product (∼40% (GC)). Hexane (∼38% conversion (GC)) and
Et2O (∼30% conversion (GC)) were found to be poor solvents
for this reaction when 5 mol % Cp2Ti(CO)2 was employed.
Procedures employing DMF and pyridine gave essentially no
enone product. The reaction temperature is important for timely
conversion of the enyne to cyclopentenone; the cyclization of
the substrate from Table 1, entry 2 is complete within 12 h at
90 °C with 5 mol % Cp2Ti(CO)2. At 75 °C, only 60%
conversion (GC) was observed in 12 h, and the use of 10 mol
% catalyst at 45 °C led to only 85% conversion (GC) to the
enone in the same amount of time. More dilute reaction
conditions (2.1 mM vs 8.3 mM in Cp2Ti(CO)2) could be
employed to effect complete conversion of the same substrate
with only 2.5 mol % catalyst in toluene. Attempts to perform
catalytic cyclizations with CO pressures higher than 18 psig
(e.g., 60 psig and 80 psig) led to no improvement in conversion
to product (substrate from Table 1, entry 2). However, there is
an interesting dichotomy between substrates which require 18
psig CO to reach complete conversion and those which can also
be cyclized at 5 psig CO (vide infra). Finally, because the
importance of an added ligand had been demonstrated in the
titanocene-catalyzed cyclocarbonylation of o-allyl aryl ketones47
and in Jeong’s23 catalytic Pauson-Khand reaction, the effects
of added PMe3 were investigated. A number of enynes were
surveyed (Table 1, entries 1, 4, 5 and 8, and Table 3, entries 1
and 3), and the difference in the conversion to product realized
for cyclizations with and without PMe3 (up to 4 equiv) was not
greater than 10%.
Two closely related general protocols have been utilized for
this reaction. In protocol A, the catalyst and toluene were added
to a Schlenk flask in a glovebox, and the enyne was subse-
quently added afterward on a Schlenk line under Ar. In protocol
B, all three components were added to the Schlenk flask in the
glovebox (See Experimental Section). The two protocols work
equally well for freshly prepared enynes. However, prolonged
storage of some enyne substrates outside the glovebox led to
partial decomposition or the acquisition of adventitious moisture,
and a concomitant decrease in conversion to cyclopentenone
was observed. Generally, if the substrates were passed through
a pipet filled with neutral alumina in the glovebox just prior to
use, conversion to the enone was restored to the maximum level.
However, to circumvent the need for this periodic repurification,
many enynes were stored in the glovebox and utilized with
protocol B.
stoichiometric fashion (eq 4). Upon further investigation, it was
shown that a certain class of enones, o-allyl aryl ketones, could
be catalytically converted to γ-butyrolactones using either
Cp2Ti(PMe3)2 or Cp2Ti(CO)2 as precatalysts (eq 5).47
These findings prompted a reinvestigation of the titanocene-
catalyzed Pauson-Khand type reaction utilizing Cp2Ti(CO)2 as
a precatalyst. It was discovered that under conditions which were
similar to those used for the o-allyl aryl ketone cyclocarbony-
lations, a diverse collection of enynes could be catalytically
converted to the corresponding enones (Scheme 6).48 In this
paper, we disclose a thorough study of this reaction which allows
the more accurate assessment of the scope of this process.
After our initial publication on this work, complexes of two
other transition metals have been shown to serve as precatalysts
for this transformation. Murai and Mitsudo, separately, reported
similar enyne cyclocarbonylations catalyzed by Ru3(CO)12.49,50
Quite recently, [RhCl(CO)2]2 and [RhCl(CO)(dppp)]2 have
also been shown to be effective catalysts for this transformation
(Scheme 7). A comparison of the synthetic scope of the different
intramolecular Pauson-Khand type cyclizations which have
been reported will also be discussed.
51
52
Results and Discussion
Optimization of Reaction Conditions. The standard reaction
conditions for the titanocene-catalyzed enyne cyclocarbonylation
are shown in Scheme 6. They involved combining the com-
mercially available titanocene dicarbonyl with toluene and an
enyne in a resealable Schlenk flask, evacuating and refilling
the Schlenk flask with CO, and heating the Schlenk flask for
the prescribed time. In addition to toluene, THF was found to
serve as an effective solvent for the cyclization process (substrate
from Table 1, entry 2). With this substrate, using 2.5 mol %
titanocene dicarbonyl, reactions conducted in DME, 1,4-dioxane,
Proposed Mechanism. The mechanism which we tentatively
propose for the titanocene-catalyzed Pauson-Khand type reac-
tion is shown in Scheme 8. Initial CO dissociation from
Cp2Ti(CO)2 yields titanocene monocarbonyl 4, which reacts with
the alkyne portion of the enyne to provide η2-alkyne carbonyl
complex 5.53 Loss of another equivalent of CO leads to 6 which
provides titanacyclopentene 1 upon insertion of the olefin into
the Ti-C bond of the titanacyclopropene. Subsequent CO
coordination gives 7 which upon migratory insertion of the
bound CO into the Ti-C sp3 bond yields acyl complex 8.54
Reductive elimination from 8 releases the cyclopentenone and
regenerates the reactive Cp2Ti(II) fragment, probably containing
(46) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 5818.
(47) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 4424.
(48) Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 9450.
(53) For the formation of an η2-alkyne carbonyl complex from Cp2Ti-
(CO)2, see: Fachinetti, G.; Floriani, C. J. Chem. Soc., Chem. Commun.
1974, 66.
(49) Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. J. Org. Chem.
1997, 62, 3762.
(50) Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T.-a. J. Am. Chem. Soc.
1997, 119, 6187.
(51) Koga, Y.; Kobayashi, T.; Narasaka, K. Chem. Lett. 1998, 249.
(52) Jeong, N.; Lee, S.; Sung, B. K. Organometallics 1998, 17, 3642.
(54) The insertion of RNC and CO has been demonstrated to occur
regiospecifically into the M-C sp3 bond of related group 4 metallacycles.
(a) Ca`mpora, J.; Buchwald, S. L.; Guite´rrez-Puebla, E.; Monge, A.
Organometallics 1995, 14, 2039. (b) Erker, G.; Kropp, K. J. Organomet.
Chem. 1980, 194, 45. (c) Grossman, R. B. Ph.D. Dissertation, Massachusetts
Institute of Technology, 1992.

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5885
Scheme 7
Scheme 8
Scheme 10
tenes.43,44 The yields for the direct cyclocarbonylation are
consistently higher than those previously obtained for the
indirect route as the yield-limiting imine hydrolysis has been
circumvented. Additionally, the quantity of catalyst required for
the cyclocarbonylation is typically less than that for the
iminocyclopentene synthesis. These differences are noted in the
tables for substrates which have been studied with both catalyst
systems.
Scheme 9
Table 1 summarizes our findings indicating the functional
group tolerance of the titanocene-catalyzed Pauson-Khand type
reaction. In general, one of the major drawbacks of early
transition metal-catalyzed and -mediated processes as compared
to those catalyzed by late transition metal complexes is the poor
levels of functional group tolerance which are seen. As with
the previously reported titanium-catalyzed iminocyclopentene
synthesis, enynes containing aliphatic ethers, amines, both tert-
butyl and ethyl esters (entries 2-5), and both TIPS- and Bn-
protected alcohols (Table 3, entries 1 and 2) are readily cyclized
to the corresponding enones. Unlike the iminocyclopentene
system, the cyclocarbonylation reaction has also been shown
to tolerate substrates containing aliphatic nitriles and ketones
(entries 6 and 7). This difference can be attributed to differences
in the precatalysts employed: Cp2Ti(PMe3)2 versus Cp2Ti(CO)2.
In stoichiometric reactions, treatment of Cp2Ti(PMe3)2 with
either of the enynes mentioned above (entries 6 and 7) leads to
rapid decomposition of the titanocene complex as indicated by
the disappearance of signals for the cyclopentadienyl peaks in
the 1H NMR. It has been demonstrated that both nitriles55
and ketones56 are capable of replacing a PMe3 ligand from
Cp2Ti(PMe3)2. It is probably this lability of the PMe3 ligand
which leads to decomposition of the titanocene moiety. How-
ever, Cp2Ti(CO)2 is fairly unreactive toward CO substitution
by nitriles and aliphatic ketones,47 relative to alkynes,53 prevent-
ing or slowing decomposition of the catalyst.
a CO or another ligand. This mechanism is analogous to the
one previously proposed for the iminocyclopentene synthesis
and the enone cyclocarbonylation.43,44,47
Although delineation of the details of this process awaits a
thorough kinetic and mechanistic study, one step deserves further
comment at this time. On the basis of our initial work on the
stoichiometric carbonylation of titanacyclopentenes (Scheme 5),
the intermediacy of titanacyclopentenes in this catalytic process
was called into question.40 Attempts to effect stoichiometric
carbonylations of titanacyclopentenes 1b failed to produce
cyclopentenone at 90 °C; however, a stoichiometric reaction
conducted at room temperature demonstrated the chemical
competence of 1b as an intermediate by providing a reasonable
yield of the corresponding cyclopentenone (Scheme 9). The use
of 1b, generated in situ from Cp2Ti(PMe3)2 and the correspond-
ing enyne, as a precatalyst also resulted in reduced levels of
conversion to cyclopentenone in comparison to the use of
Cp2Ti(CO)2 (Scheme 10). In combination with the dependence
of enyne conversion upon catalyst concentration (vide supra),
these results speak to the need to restrict the concentration of 1
under the catalytic reaction conditions (e.g., 90 °C). One
explanation for this restriction would be a bimolecular catalyst
decomposition pathway involving 1.
Another advantage of the titanocene-catalyzed enyne cyclo-
carbonylation over related group 4 cyclizations is its ability to
accommodate an enyne containing a terminal alkyne (entry 8).
The formation of group 4 metallacyclopentenes from terminal
Synthetic Scope. Inspection of entry 2 in Table 1 reveals
several advantages of this cyclocarbonylation methodology in
comparison to our previously reported titanocene-catalyzed route
to cyclopentenones via the intermediate iminocyclopen-
(55) Doxsee, K. M.; Garner, L. C.; Juliette, J. J. J.; Mouser, J. K. M.;
Weakley, T. J. R.; Hope, H. Tetrahedron 1995, 51, 4321.
(56) (a) Gleiter, R.; Wittwer, W. Chem. Ber. 1994, 127, 1797. (b)
Reference 47.

5886 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Table 1. Examples Which Demonstrate the Functional Group Tolerance of the Titanocene-Catalyzed Pauson-Khand Type Reaction
alkyne-containing enynes has been a limitation in processes
involving group 4 metallocenes.38,39 While several approaches
have been developed recently for the stoichiometric cyclization
of terminal enynes by group 4 metal complexes,57 there have
been no reports to date of catalytic reactions. The cyclocarbo-
nylation process allows us to effect the catalytic cyclization of
terminal enynes, although the amount of catalyst required for
complete conversion to the corresponding enone is quite high.
(10) group on the aromatic ring produced no cyclopentenone.
Other functional groups which have proven incompatible with
this methodology include unprotected alcohols (11) as well as
R,â-propargylic ketones (12) and esters (13).
We have also extensively explored reactions of substrates
containing functionalized aromatic groups using this methodol-
ogy. As can be seen from Table 1, ethers (entry 10), halides
(entries 11 and 12), esters (entry 13), nitriles (entry 14), and a
trifluoromethyl group (entry 15) could be accommodated.
Reactions of substrates containing a nitro (9) or methyl ketone
(57) (a) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261.
(b) Miura, K.; Funatsu, M.; Saito, H.; Ito, H.; Hosomi, A. Tetrahedron
Lett. 1996, 37, 9059. (c) Barluenga, J.; Sanz, R.; Fan˜ana´s, F. J. J. Chem.
Soc., Chem. Commun. 1995, 1009. (d) Barluenga, J.; Sanz, R.; Fan˜ana´s, F.
J. Chem.sEur. J. 1997, 3, 1324.
One limitation of the iminocyclopentene synthesis involved
the inability to convert enynes possessing sterically hindered

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5887
Table 2. Effects of the Size of the Alkyne Substituent (R) and the Length of the Carbon Tether Connecting the Alkene and Alkyne
a Reaction produces similar yields at 18 psig CO. b Reaction conducted only once.
terminal alkyne substituents to product. This was attributed to
the small size of the titanocene fragment.44 An investigation of
the reaction of substrates which contain a variety of alkyne
substituents (Table 2) revealed that the catalytic cyclocarbony-
lation reaction also suffered from the same limitations. While
enynes for which R ) Me and n-Pr (Table 2, entries 1 and 2)
were easily converted to the corresponding enones, the cycliza-
tion, while high yielding, proved more difficult with branched
groups such as R ) i-Pr and cyclopentyl (Table 2, entries 3
and 4). In instances where R ) TMS (14) or t-Bu (15), no
formation of cyclopentenone was observed.
1,7-enyne 16 nor the monosubstituted derivative 17 could be
converted to product. All attempts to cyclize 1,8-enynes, 18 and
19, also failed to produce any observable enone.
A number of reports have appeared recently describing the
cyclization of allenynes promoted by complexes of Mo, Co,
and Zr to provide either R-methylenecyclopentenones or
conjugated dieneones, depending on the metal complex and
substrate employed (Scheme 11).59 When a 1,5-allenyne was
subjected to our standard reaction conditions, clean and regio-
selective formation of the corresponding dieneone was ob-
served (eq 6). Attempts to cyclize the simple 1,6-allenyne 20
The vast majority of successful Pauson-Khand type reactions
reported to date employ 1,6-enynes as substrates.11 To explore
the ability of this catalyst system to cyclize homologous
substrates, a study involving the cyclization of 1,7- and 1,8-
enynes was undertaken. It was found that cyclization was facile
with conformationally biased 1,7-enynes (the Thorpe-Ingold
Effect)58 containing diesters (Table 2, entries 5 and 6) or in a
substrate where the two groups were positioned on contiguous
carbons of a ring system (entry 7). However, neither the simple
(58) (a) DeTar, D. F.; Luthra, N. P. J. Am. Chem. Soc. 1980, 102, 4505.
(b) Eliel, E. L. Stereochemistry of Carbon Compounds; McGraw-Hill: New
York, 1962; p 168.

5888 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Examination of the elementary steps of the mechanism
outlined in Scheme 12 reveals a number of potential origins
for the quantitative differences between the diastereomeric ratios
seen in titanacyclopentenes, iminocyclopentenes and cyclopen-
tenones. In stoichiometric reactions, the formation of chiral
group 4 metallacyclopentenes such as 22 has been demonstrated
to be reversible; equilibration can proceed through binding of
the two diastereotopic olefin faces and subsequent reinsertion
into the titanacyclopropene moiety.62 The dr’s shown for the
titanacyclopentenes in Table 3 represent the thermodynamic ratio
obtained after heating the titanacycles for 12 h at 105 °C;
however, these values are essentially unchanged from the initial
ones observed at room temperature.63 The fact that the product
dr’s sometimes vary substantially from these metallacycle dr’s
indicates that the thermodynamic stability of the diastereomeric
titanacycles does not determine the dr of the enone products in
all cases.
One reason the final product dr’s do not reflect the thermo-
dynamic titanacycle dr’s could involve kinetic trapping of the
metallacycles via a migratory insertion process involving carbon
monoxide or isonitrile. Given that isonitriles tend to react more
rapidly (as compared to carbon monoxide) and in an irreversible
fashion with respect to migratory insertion,64 it is possible that
the ratio of products arising from the silylimine reaction more
closely reflects a kinetic ratio of intermediate metallacyclo-
pentenes than does the ratio of cyclopentenones derived from
the cyclocarbonylation process. In contrast, CO migratory
insertions have been demonstrated to be reversible in group 4
metallocene chemistry.64 The reversibility allows for an equi-
librium to be established between diastereomeric acyl intermedi-
ates 23a and b (Scheme 12) which would not be possible or
would be less likely in the iminoacyl case. Finally, a kinetic
partitioning at the point of CO or isonitrile insertion cannot be
ruled out as a possible origin for the dissimilar dr’s arising from
the two protocols.
were met with poor levels of conversion, although the product
which was obtained was exclusively the R-methylenecyclopen-
tenone.
We also studied the cyclization of chiral 1,6-enynes, which
revealed some intriguing differences between the titanocene-
catalyzed iminocyclopentene synthesis and the cyclocarbony-
lation process. For the cyclocarbonylation reactions, some
general selectivity patterns were observed with respect to the
location of the chiral center on the enyne. Substrates substituted
in the allylic position (Table 3, 1 and 2) were cyclized with
only moderate levels of stereoinduction, while those substituted
in the propargylic position (Table 3, 3 - 5) were converted to
enone with high levels of diastereoselectivity.
When the dr of the enones obtained from the cyclocarbony-
lation reaction are compared to those obtained from hydrolysis
of the corresponding iminocyclopentenes, some differences are
apparent. While general trends are observed for the cyclocar-
bonylation reaction with respect to selectivity versus the position
of enyne substitution, the cyclopentenones which are obtained
from the iminocyclopentene synthesis from propargyl- (entry 3
(1.6:1) vs entry 4 (5:1)) and allyl-substituted (entry 1(12:1) vs
entry 2 (1.2:1)) enynes are produced with variable levels of
diastereoselectivity. Analyzing the dr of the enones resulting
from hydrolysis of the intermediate silylimines, however, is not
the most accurate way to assess the diastereoselectivity of the
cyclization reaction since equilibration of different diastereomers
or selective decomposition of one isomer may occur. This is
especially relevant considering the problematic nature of the
silylimine hydrolysis. When the dr’s of the iminocyclopentenes
are analyzed and compared to those seen for cyclopentenones
formed by the cyclocarbonylation, some differences in the
selectivity of the two methodologies are still noted.
Despite these disparities, the same major isomer was observed
for both methodologies in each case. The formation of the major
isomer which is observed for enynes substituted in either the
propagylic or the allylic positions (only the propargylic case
has been pictured) has previously been rationalized as arising
from unfavorable 1,3-diaxial interactions in one of the two
lowest-energy intermediates (21a and b) whose formation
precedes cyclization (Scheme 12).44 Though caution should be
used when attributing the selectivity of metallacycle formation
to ground-state interactions, similar steric considerations are also
expected to differentiate the energies of the diastereomeric
transition states en route to metallacycles 22a and b. Since these
same interactions are expected to be present in all subsequent
intermediates and transition states in the mechanism, the same
general trends are to be predicted, regardless of which step
determines the diastereoselectivity of enone formation.61
The use of enyne substrates containing substituted olefins was
also investigated in the titanocene-catalyzed Pauson-Khand
type reaction. The cyclization of a 1,1-disubstituted olefin-
containing enyne (Table 4, entry 1) proved to be quite facile;
however, the presence of the diester substituents was important
to the success of this cyclization as a related substrate containing
an ether linkage in lieu of a diester, (24), could not be com-
pletely converted to the corresponding enone even using 20 mol
% Cp2Ti(CO)2. Analogously, enynes possessing cyclic 1,2-
disubstituted olefins (Table 4, entries 2 and 3) are cyclized
diastereoselectively to the corresponding tricyclic enones. As
in the iminocyclopentene synthesis, the ether-containing enyne
25 was not a viable substrate.
Attempts to cyclize enynes which have acyclic 1,2-disubsti-
tuted olefins revealed some interesting nuances. When an enyne
(61) For related discussions on the diastereoselective formation of group
4 metallacyclopentenes in a stoichiometric fashion, see: (a) RajanBabu, T.
V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J. Am. Chem. Soc. 1988, 110,
7128. (b) Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron 1995,
51, 4421.
(59) (a) Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995,
36, 2407. (b) Ahmar, M.; Locatelli, C.; Colombier, D.; Cazes, B.
Tetrahedron Lett. 1997, 38, 5281. (c) Brummond, K. M.; Wan, H.
Tetrahedron Lett. 1998, 39, 931. (d) Brummond, K. M.; Wan, H.; Kent, J.
L. J. Org. Chem. 1998, 63, 6535.
(62) (a) Agnel, G.; Owczarczyk, Z.; Negishi, E.-i. Tetrahedron Lett. 1992,
33, 1543. (b) Reference 39.
(63) In the case of the titanacycle for entry 4, heating caused complete
decomposition. The dr in the table therefore represents the value obtained
at room temperature.
(60) See ref. 44 for a detailed discussion.
(64) Durfee, L. D.; Rothwell, I. P. Chem. ReV. 1988, 88, 1059.

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5889
Scheme 11
Table 3. Diastereoselective Cyclization of Chiral Enynes
Scheme 12
composed of a 3:1 mixture of trans:cis isomers (Table 4, entry
4) was subjected to the standard reaction conditions, the
corresponding enone was obtained in only moderate yield with
a trans:cis ratio which was slightly higher than in the starting
enyne. Interestingly, a 12% yield of 27 was also produced by
a cycloisomerization pathway. A plausible mechanism for the
formation of 27 involving sequential â-hydride elimination and
reductive elimination from metallacycle 26 is shown in Scheme
13.65 When pure trans- and cis-enynes (Table 4, entries 5-7)
(65) It has been found that good yields of the cycloisomerization product
can be obtained in the absence of CO: Sturla, S. J.; Kablaoui, N. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1976.

5890 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Table 4. Cyclization of Enynes Containing Disubstituted Olefins
a Only attempted at 18 psig CO. b Only attempted at 5 psig CO. c Can also be performed at 18 psig CO. d Reaction conducted only once.
Scheme 13
Scheme 14
after metallacyclization and at a point where enyne cannot be
reformed. Otherwise cycloisomerization products would be ob-
served from the conversion of cis- to trans-enynes. One mech-
anism for isomerization involves a reversible â-hydride elimina-
tion from an η2-ketone complex (Scheme 14). This type of proc-
ess has been invoked for related enones produced from zir-
conacyclopentenes.38,66 Alternatively, the enone could be formed
stereoselectively and then isomerized afterward, perhaps with
the titanocene fragment serving the role of a Lewis acid catalyst.
As with enynes containing cyclic 1,2-disubstituted olefins,
attempts to cyclize substrate 28, which lacks the geminal diester
substitution, met with failure. In a similar fashion, 29, a 1,7-
enyne possessing an acyclic 1,2-disubstituted olefin was not a
suitable substrate for the catalytic cyclization. All attempts to
cyclize trisubstituted olefin-containing enynes (30-32) were also
unsuccessful.
were separately subjected to the cyclization reaction, mixtures
of trans- and cis-enones were produced in all cases. Interest-
ingly, the cycloisomerization product 27 was obtained only from
the reaction of the trans-enyne (entry 5); none was observed
for either of the cis-olefin-containing enynes.
Several plausible mechanisms for the epimerization of the
enone products can be proposed. The isomerization must occur
(66) Kemp, M. I.; Whitby, R. J.; Coote, S. J. Synthesis 1998, 552.

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5891
substituents have been efficiently transformed to product with
the Ru3(CO)12 and Rh catalysts (46-48). Additionally, the Ru
catalysts are better able to accommodate alkyne substituents such
as a TMS group (46) than is the Ti catalyst. For the Rh systems,
either significant amounts of desilylated enone were obtained
or poor levels of conversion were observed for reactions of
TMS-substituted enynes. As with the titanium system, the
ruthenium-based catalyst can cyclize 1,6-enynes containing 1,1-
and 1,2-disubstituted olefins (51 and 53) (Figure 2); the one
reported attempt to cyclize a 1,7-enyne with a Ru catalyst was
unsuccessful. While [RhCl(CO)2]2 was demonstrated to be a
successful precatalyst for the cyclization of a 1,1-disubstituted
olefin-containing enyne (52), no mention was made of attempts
to use substrates with 1,2-disubstituted olefins or 1,7-enynes
with either of the Rh precatalysts. As with the Co systems, the
levels of functional group compatibility have not been explored
in detail with the Ru and Rh catalysts, but a tolerance for
protected alcohols and aliphatic ketones coupled with the
inability to cyclize an enyne with an ester conjugated to the
alkyne seems to mirror what has been observed for the Ti
system. The Ru catalyst has also been shown to tolerate the
presence of nitrogen-containing heterocycles (49 and 50), a class
of functional groups unexplored in the Ti chemistry.
Effects of CO Pressure on Conversion. A final aspect of
the Ti-catalyzed Pauson-Khand type cyclization which warrants
discussion is the variable pressure dependence on CO noted in
the Tables. For a simple 1,6-enyne (Table 1, entry 2), 18 psig
CO is required for high levels of enyne conversion to cyclo-
pentenone. On the other hand, enynes which possess features
which make them more difficult to cyclize, such as bulky alkyne
substituents (Table 2, entries 3 and 4), a longer tethering chain
as in 1,7-enynes (Table 2, entry 6), and olefin substitution (Table
4, entry 7), can be cyclized at both 5 and 18 psig CO. One
explanation for this disparity can be found in the relative rates
of titanacyclopentene formation (1, Scheme 8) for the different
substrates. The simple enyne would be expected to form 1 most
readily; under lower CO pressures the build up of 1 could lead
to premature catalyst decomposition (see earlier discussion on
catalyst concentration effects). Thus, higher CO pressures are
required to inhibit metallacycle formation and promote catalyst
stability. In the case of enynes which are more difficult to
cyclize, there is no need for elevated CO pressure to limit the
concentration of 1 in solution.
Comparison of Catalytic Pauson-Khand Type Reactions.
It is useful at this point to compare the synthetic utility of the
published catalytic Pauson-Khand type methodologies. There
are two general classes which show similar reactivity profiless
those methods which employ complexes of Co and those
involving complexes of other transition metals: Ti, Ru,49,50 and
Rh.51,52 For the most thoroughly investigated Co-based proce-
dures, Jeong’s P(OPh)3 system,23 Livinghouse’s photochemical25
and thermal protocols,27 and Sugihara’s methylidynetricobalt
cluster catalyst,31 the cyclization of simple 1,6-enynes containing
terminal alkynes (33) appears to work well. However, it is hard
to assess the generality of these approaches with regard to the
effect of alkyne substitution since substrates with substituted
alkynes have not been thoroughly studied. With the Co cluster
catalyst, a series of analogous enynes with different substituents
(34-36) could be converted to the corresponding enones in
similar yields with the same level of catalyst loading. Though
the scope of functional group compatibility has not been
explored in depth, the ability to cyclize an enyne containing an
unprotected alcohol (37) seems to indicate the cobalt systems
are, as expected, more tolerant of polar functional groups than
is the Ti methodology. This is also consistent with what has
previously been observed in stoichiometric Pauson-Khand
reactions.11 Additionally, though 1,7-enynes (38 and 39) and
1,6-enynes containing 1,1- and 1,2-disubstituted olefins (40-
45) (see Figure 1) have been cyclized effectively with these
cobalt systems, all examples of these classes of substrates
reported to date contain terminal alkynes.
Conclusion
The development of the first early transition metal-catalyzed
Pauson-Khand type enyne cyclocarbonylation utilizing com-
mercially available titanocene dicarbonyl has been described.
The functional group tolerance for this process is excellent for
an early transition metal-mediated reaction, with the compat-
ibility of nitriles, methyl ketones, and terminal alkynes being
of particular note. There are still limitations with respect to
unprotected alcohols, aryl methyl ketones, nitro groups, and
propargylic ketones and esters. The titanocene catalyst has
proven capable of cyclizing a variety of both 1,6- and 1,7-enynes
and 1,1- and 1,2-disubstituted olefin-containing enynes. With
acyclic 1,2-disubstituted olefin containing enynes, a cyclo-
isomerization process was detected as a competing reaction and
the use of geometrically pure cis- or trans-olefins led to the
formation of mixtures of epimeric enone products. A mechanism
for the cyclocarbonylation involving reductive enyne cyclization
to provide a bicyclic titanacyclopentene which undergoes CO
insertion and subsequent reductive elimination to provide the
observed enone has been proposed. The synthetic scope of the
Ti catalyst system appears to be complementary to Co-based
protocols with respect to alkyne substitution and similar to the
Ru- and Rh-based catalysts.
Experimental Procedures
General Considerations. All manipulations involving air-sensitive
materials were conducted in a Vacuum Atmospheres glovebox under
an atmosphere of argon or using standard Schlenk techniques under
argon. THF was distilled under argon from sodium/benzophenone ketyl
before use. Toluene was distilled under argon from molten sodium.
Cp2Ti(CO)2 was purchased from Strem Chemicals, and it was further
purified by dissolution in hexane and filtration through Celite in a
glovebox under argon followed by concentration in vacuo. CO was
scientific grade (minimum purity 99.997%) from MG Industries.
Note: It is important to take appropriate safety precautions when
dealing with CO, particularly at elevated pressures; all reactions
should be conducted in an efficient fume hood behind a blast shield.
Unless otherwise stated, enynes were prepared as previously re-
ported.44,45,67 Enyne syntheses described herein are unoptimized. All
The opposite trend in efficiency vs level of alkyne substitution
is seen for the reactions employing other transition metal
catalysts. The cyclization of enynes containing terminal alkynes
is problematic for all of these systems; however, as with the
Cp2Ti(CO)2 catalyst, enynes with a wide range of alkyne
(67) Hicks, F. A.; Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1996, 61,
2713.

5892 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Figure 1. Cobalt-based catalytic Pauson-Khand reactions.
Figure 2. Ruthenium- and rhodium-based catalytic Pauson-Khand reactions.
other reagents were available from commercial sources and were used
without further purification, unless otherwise noted.
mL). The combined organic layers were washed with 1 N HCl (2 ×
50 mL) and saturated brine and dried over MgSO4. Purification by
vacuum distillation provided 15.7 g (67%) of a colorless liquid: 1H
NMR (300 MHz, CDCl3) δ 7.27 (m, 2 H); 6.87 (d, J ) 8.1 Hz, 2 H);
6.79 (t, J ) 7.5 Hz, 1 H); 5.92 (m, 1 H); 5.24 (m, 1 H); 3.99 (m, 4 H);
1.82 (t, J ) 2.1 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 148.7, 134.4,
Flash chromatography was performed on E. M. Science Kieselgel
60 (230-400 mesh). Yields refer to isolated yields of compounds of
1
greater than 95% purity as estimated by capillary GC and H NMR
analysis, and in the case of unknown compounds, elemental analysis
or in one instance (eq 6) HRMS. In general, yields indicated in this
section refer to a single experiment, while those reported in the
tables are an average of two or more runs, and thus the numbers
may differ slightly. Nuclear magnetic resonance (NMR) spectra were
recorded on a Varian XL-300, a Varian XL-500, or a Varian Unity
300. Splitting patterns are designated as follows: s, singlet; bs, broad
singlet; d, doublet; dd, doublet of doublets; t, triplet; at, apparent triplet;
q, quartet; aquintet, apparent quintet; m, multiplet. All 1H NMR spectra
are reported in δ units, parts per million (ppm) downfield from
tetramethylsilane. All 13C NMR spectra are reported in ppm relative to
deuteriochloroform. Infrared (IR) spectra were recorded on a Perkin-
Elmer 1600 series Fourier transform spectrometer. Gas chromatography
(GC) analyses were performed on a Hewlet-Packard 5890 gas chro-
matograph with a 3392A integrator and FID detector using a 25-m
capillary column with cross-linked SE-30 as a stationary phase.
Elemental analyses were performed by E + R Analytical Laboratory,
Inc. and Micro-Analysis, Inc.
N-Allyl-N-(2-butynyl)-N-phenylamine (Table 1, Entry 4). 2-Bu-
tyn-1-ol (10.0 mL, 133.3 mmol), NEt3 (20.0 mL, 143.4 mmol) and
THF (150 mL) were added to a dry Schlenk flask under Ar. The flask
was cooled in an ice bath and mesyl chloride (10.6 mL, 133.3 mmol)
was added slowly inducing the formation of a thick, white precipitate.
The ice bath was removed after the addition, and the reaction was
allowed to warm to room temperature. After 1.5 h, the crude reaction
mixture was filtered through a pad of Celite with THF and concentrated.
In a separate dry Schlenk flask under Ar, N-allyl aniline (17.2 mL,
126.4 mmol) and THF (200 mL) were cooled to -78 °C. A solution
of n-BuLi in hexanes (2.5 M, 50.6 mL, 126.4 mmol) was added slowly,
and the reaction was allowed to stir for 1 h at -78 °C. Slow addition
of the crude mesylate to this solution was followed by warming to
room temperature. After 24 h at room temperature, the reaction mixture
was quenched with H2O (100 mL) and extracted with ether (2 × 100
129.3, 129.2, 117.7, 116.5, 113.9, 79.5, 75.2, 53.8, 39.1. IR (neat, cm-1
)
3061, 2918, 1599, 1504, 1346, 1229, 1174, 990, 922, 748, 691. Anal.
Calcd for C13H15N: C, 84.27; H, 8.17. Found: C, 84.31; H, 8.16.
Ethyl 4-Cyano-1-phenyl-6-hepten-1-yne-4-carboxylate (Table 1,
Entry 6). In a dry Schlenk flask under Ar, K2CO3 (3.5 g, 25 mmol),
acetone (250 mL), allyl bromide (1.7 mL, 20 mmol), and 3-phenyl-2-
propynyl ethyl malononitrile (3.8 g, 16.7 mmol), obtained from the
corresponding propargyl bromide and the sodium salt of ethyl mal-
ononitrile, were combined. The reaction mixture was stirred at room
temperature for 12 h and then at reflux for 3 h. After the reaction
mixture was cooled to room temperature, solids were removed by
vacuum filtration and washed with acetone. The acetone solution was
concentrated in vacuo and was purified via vacuum distillation to
provide 3.9 g (92%) of a light yellow oil: 1H NMR (300 MHz, CDCl3)
δ 7.38 (m, 2 H); 7.25 (m, 3 H); 5.79 (m, 1 H); 5.25 (m, 2 H); 4.26 (q,
J ) 7.2 Hz, 2 H); 3.00 (d, J ) 16.8 Hz, 1 H); 2.93 (d, J ) 16.8 Hz,
1 H); 2.72 (d, J ) 7.2 Hz, 2 H); 1.28 (t, J ) 7.2 Hz, 3 H). 13C NMR
(75 MHz, CDCl3) δ 167.4, 131.9, 130.2, 128.6, 128.4, 122.6, 121.6,
118.1, 85.2, 82.2, 63.2, 48.8, 40.1, 27.4, 14.2. IR (neat, cm-1) 2983,
2247, 1743, 1491, 1442, 1221, 1144, 1096, 931, 856, 758, 692. Anal.
Calcd for C17H17NO2: C, 76.38; H, 6.41. Found: C, 76.19; H, 6.33.
Ethyl 4-Acetyl-1-phenyl-6-hepten-1-yne-4-carboxylate (Table 1,
Entry 7). In a dry Schlenk flask under Ar, KOt-Bu (2.5 g, 22 mmol),
18-crown-6 (trace), and benzene (70 mL) were combined and stirred.
Allyl ketomalonate (3.4 g, 20 mmol), obtained from allyl bromide and
the sodium salt of ketomalonate, was added followed by 1-chloro-3-
phenyl-2-propyne. The reaction mixture was heated to reflux for 6 h.
After the reaction mixture was cooled to room temperature, it was
partitioned between H2O (50 mL) and ether (100 mL). The organic
layer was washed with 50 mL each of 1 N HCl, H2O, 1 N NaOH, and
H2O and dried over Na2SO4. The crude reaction mixture was concen-
trated in vacuo and was purified via vacuum distillation to provide 3.2

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5893
g (56%) of a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 2
H); 7.26 (m, 3 H); 5.59 (m, 1 H); 5.16 (m, 2 H); 4.22 (q, J ) 7.2 Hz,
2 H); 2.96 (s, 2 H); 2.88 (dd, J ) 7.2, 14.4 Hz, 1 H); 2.78 (dd, J )
7.2, 14.4 Hz, 1 H); 2.20 (s, 3 H); 1.26 (t, J ) 7.2 Hz, 3 H). 13C NMR
(75 MHz, CDCl3) δ 203.0, 170.7, 132.0, 131.8, 128.4, 128.2, 123.3,
857, 829. Anal. Calcd for C19H21ClO4: C, 65.42; H, 6.07. Found: C,
65.58; H, 5.90.
Diethyl 1-(p-Bromophenyl)-6-hepten-1-yne-4,4-dicarboxylate (Table
1, Entry 12). Prepared as in Table 1, entry 9, with diethyl-6-hepten-
1-yne-4,4-dicarboxylate (1.19 g, 5.0 mmol) and 4-bromo-1-iodobenzene
(1.41 g, 5.0 mmol). The crude reaction mixture was purified via flash
column chromatography (hexane:ether, 95:5) to provide 1.44 g (73%)
of a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J ) 8.4 Hz,
2 H); 7.14 (d, J ) 8.4 Hz, 2 H); 5.59 (m, 1 H); 5.09 (m, 2 H); 4.14 (q,
J ) 7.2 Hz, 4 H); 2.92 (s, 2 H); 2.77 (d, J ) 7.2 Hz, 2 H); 1.18 (t, J
) 7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 169.9, 133.2, 132.0,
131.6, 122.4, 122.3, 120.0, 85.9, 82.5, 61.8, 57.1, 36.8, 23.7, 14.3. IR
(neat, cm-1) 2981, 2936, 1734, 1486, 1289, 1215, 1190, 1071, 1012,
925, 857, 825. Anal. Calcd for C19H21BrO4: C, 58.03; H, 5.38. Found:
C, 57.90; H, 5.59.
Diethyl 1-(Ethyl-4′-benzoate)-6-hepten-1-yne-4,4-dicarboxylate
(Table 1, entry 13). Prepared as in Table 1, entry 9, with diethyl-6-
hepten-1-yne-4,4-dicarboxylate (1.19 g, 5.0 mmol) and ethyl 4-iodo-
benzoate (1.38 g, 5.0 mmol). The crude reaction mixture was purified
via flash column chromatography (hexane:ether, 85:15) to provide 1.58
g (82%) of a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J )
8.4 Hz, 2 H); 7.42 (d, J ) 8.4 Hz, 2 H); 5.67 (m, 1 H); 5.19 (m, 2 H);
4.37 (q, J ) 7.2 Hz, 2 H); 4.23 (q, J ) 7.2 Hz, 4 H); 3.04 (s, 2 H);
2.87 (d, J ) 7.5 Hz, 2 H); 1.39 (t, J ) 7.2 Hz, 3 H); 1.27 (t, J ) 7.2
Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 169.9, 166.2, 131.7, 129.8,
128.0, 120.0, 87.9, 83.1, 61.9, 61.2, 57.1, 36.8, 23.8, 14.5, 14.3. IR
(neat, cm-1) 2982, 2937, 1736, 1606, 1367, 1273, 1214, 1106, 1021,
925, 858, 770, 697. Anal. Calcd for C22H26O6: C, 68.38; H, 6.78.
Found: C, 68.66; H, 7.08.
120.0, 84.6, 83.9, 63.2, 62.0, 36.2, 26.8, 22.8, 14.3. IR (neat, cm-1
)
2980, 1717, 1442, 1357, 1280, 1206, 1070, 1018, 924, 856, 758, 692.
Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 76.15; H,
7.26.
Di-tert-butyl 6-Hepten-1-yne-4,4-dicarboxylate (Table 1, Entry
8). Diisopropylamine (1.4 mL, 10 mmol) and THF (25 mL) were added
to a dry Schlenk flask under Ar. A solution of n-BuLi (1.6 M in hexanes,
6.25 mL, 10 mmol) was added slowly, and the reaction mixture was
allowed to stir 30 min at room temperature. Allyl di-tert-butyl malonate
(2.56 g, 10 mmol) was added, and the flask was equipped with a reflux
condenser under Ar and heated to reflux. After 16 h, the reaction
mixture was cooled to -78 °C, and propargyl bromide (1.1 mL, 80 wt
% in toluene, 10 mmol) was slowly added. The reaction mixture was
allowed to warm to room temperature and quenched with saturated
aqueous NH4Cl (50 mL). Extraction with ether (3 × 50 mL), washing
with saturated brine, and drying over MgSO4 provided the crude
product. Purification via flash column chromatography (hexane:ether
95:5) provided 2.5 g (85%) of a white solid, mp 62-64 °C: 1H NMR
(300 MHz, CDCl3) δ 5.58 (m, 1 H); 5.14 (m, 2 H); 2.73 (m, 4 H);
1.97 (t, J ) 2.7 Hz, 1 H); 1.42 (s, 18 H). 13C NMR (75 MHz, CDCl3)
δ 169.2, 132.3, 119.7, 81.9, 79.5, 71.3, 57.4, 36.4, 28.0, 21.6. IR (KBr,
cm-1) 2981, 2933, 1724, 1371, 1305, 1251, 1229, 1143, 1072, 932,
844. Anal. Calcd for C17H26O4: C, 69.36; H, 8.90. Found: C, 69.47;
H, 8.81.
Diethyl 1-(p-Cyanophenyl)-6-hepten-1-yne-4,4-dicarboxylate (Table
1, Entry 14). Prepared as in Table 1, entry 9, with diethyl-6-hepten-
1-yne-4,4-dicarboxylate (1.19 g, 5.0 mmol) and 4-iodobenzonitrile (1.15
g, 5.0 mmol). The crude reaction mixture was purified via flash column
chromatography (hexane:ether, 9:1) to provide 1.04 g (61%) of a clear
liquid: 1H NMR (300 MHz, CDCl3) δ 7.58 (d, J ) 8.4 Hz, 2 H); 7.45
(d, J ) 8.4 Hz, 2 H); 5.66 (m, 1 H); 5.18 (m, 2 H); 4.23 (q, J ) 7.2
Hz, 4 H); 3.04 (s, 2 H); 2.84 (d, J ) 7.8 Hz, 2 H); 1.27 (t, J ) 7.2 Hz,
6 H). 13C NMR (75 MHz, CDCl3) δ 169.8, 132.3, 132.1, 131.8, 128.3,
Diethyl 1-(p-Methylphenyl)-6-hepten-1-yne-4,4-dicarboxylate (Table
1, Entry 9). The enyne was prepared from diethyl-6-hepten-1-yne-
4,4-dicarboxylate68 (1.05 g, 4.4 mmol) and 4-iodotoluene (959 mg, 4.4
mmol) via the procedure of Grissom.69 The crude reaction mixture was
purified via flash column chromatography (hexane:ether 9:1) to provide
1.01 g (70%) of a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.28 (d,
J ) 8.1 Hz, 2 H); 7.09 (d, J ) 8.1 Hz, 2 H); 5.72 (m, 1 H); 5.20 (m,
2 H); 4.24 (q, J ) 7.2 Hz, 4 H); 3.03 (s, 2 H); 2.89 (d, J ) 6 Hz, 2 H);
2.34 (s, 3 H); 1.28 (t, J ) 7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3)
δ 169.6, 137.6, 131.7, 131.2, 128.6, 119.9, 83.3, 61.2, 56.8, 36.3, 23.2,
21.1, 13.8. IR (neat, cm-1) 2981, 1735, 1510, 1444, 1367, 1288, 1213,
1143, 1067, 924, 857, 817. Anal. Calcd for C20H24O4: C, 73.15; H,
7.37. Found: C, 73.28; H, 7.53.
120.1, 118.6, 111.5, 89.7, 61.9, 57.0, 36.8, 23.7, 14.3. IR (neat, cm-1
)
3079, 2982, 2228, 1732, 1642, 1605, 1502, 1444, 1367, 1290, 1215,
1096, 926, 842. Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24.
Found: C, 70.96; H, 6.18.
Diethyl 1-(p-Trifluoromethylphenyl)-6-hepten-1-yne-4,4-dicar-
boxylate (Table 1, Entry 15). Prepared as in Table 1, entry 9, with
diethyl-6-hepten-1-yne-4,4-dicarboxylate (2.38 g, 10.0 mmol) and
4-trifluoromethyl-1-iodobenzene (1.47 mL, 10.0 mmol). The crude
reaction mixture was purified via flash column chromatography (hexane:
ether, 95:5) to provide 2.60 g (68%) of a clear liquid: 1H NMR (300
MHz, CDCl3) δ 7.48 (d, J ) 8.4 Hz, 2 H); 7.42 (d, J ) 8.4 Hz, 2 H);
5.63 (m, 1 H); 5.14 (m, 2 H); 4.18 (q, J ) 7.2 Hz, 4 H); 2.99 (s, 2 H);
2.82 (d, J ) 7.2 Hz, 2 H); 1.22 (t, J ) 7.2 Hz, 6 H). 13C NMR (75
MHz, CDCl3) δ 169.9, 132.1, 131.9, 130.1, 129.7, 127.2, 125.9, 125.4,
125.3, 122.3, 120.1, 87.5, 82.5, 61.9, 57.1, 36.9, 23.7, 14.3. IR (neat,
cm-1) 3080, 2983, 2224, 1736, 1616, 1324, 1216, 1127, 1018, 925,
843. Anal. Calcd for C20H21F3O4: C, 62.82; H, 5.54. Found: C, 62.96;
H, 5.47.
Di-tert-butyl 8-nonen-2-yne-6,6-dicarboxylate (Table 2, Entry 6).
Sodium hydride (480 mg, 20 mmol) was added to a dry Schlenk flask
in the glovebox. The Schlenk flask was removed from the glovebox
and attached to a Schlenk line under Ar. THF (50 mL) and di-tert-
butyl malonate (4.47 mL, 20 mmol) were added to the flask, and the
reaction mixture was allowed to stir at room temperature. In a separate
dry Schlenk flask under Ar, THF (50 mL), NEt3 (3.07 mL, 22 mmol)
and 3-pentyn-1-ol (1.84 mL, 20 mmol) were cooled in an ice bath.
Dropwise addition of mesyl chloride (1.55 mL, 20 mmol) to this
solution resulted in the formation of a thick, white precipitate. The ice
bath was removed, and the reaction mixture was allowed to warm to
room temperature. After 1 h at room temperature, the crude mesylate
solution was cannula-filtered into the malonate anion solution. After
the addition was complete, the reaction mixture was allowed to stir at
room temperature for 15 h. Then a reflux condenser was attached under
Diethyl 1-(p-Methoxyphenyl)-6-hepten-1-yne-4,4-dicarboxylate
(Table 1, Entry 10). Prepared as in Table 1, entry 9, with diethyl-6-
hepten-1-yne-4,4-dicarboxylate (1.05 g, 4.4 mmol) and 4-iodoanisole
(1.03 g, 4.4 mmol). The crude reaction mixture was purified via flash
column chromatography (hexane:ether 85:15) to provide 1.16 g (77%)
of a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.30 (d, J ) 8.7 Hz,
2 H); 6.80 (d, J ) 8.7 Hz, 2 H); 5.69 (m, 1 H); 5.17 (m, 2 H); 4.22 (q,
J ) 7.2 Hz, 4 H); 3.80 (s, 3 H); 2.99 (s, 2 H); 2.86 (d, J ) 7.2 Hz, 2
H); 1.26 (t, J ) 7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 170.1,
159.5, 133.2, 132.2, 119.8, 115.6, 114.0, 83.4, 82.9, 61.7, 57.2, 55.4,
36.8, 23.7, 14.3. IR (neat, cm-1) 2981, 2838, 1732, 1607, 1510, 1465,
1443, 1290, 1033, 833. Anal. Calcd for C20H24O5: C, 69.75; H, 7.02.
Found: C, 69.75; H, 6.90.
Diethyl 1-(p-Chlorophenyl)-6-hepten-1-yne-4,4-dicarboxylate (Table
1, Entry 11). Prepared as in Table 1, entry 9, with diethyl-6-hepten-
1-yne-4,4-dicarboxylate (1.05 g, 4.4 mmol) and 4-chloro-1-iodobenzene
(1.05 g, 4.4 mmol). The crude reaction mixture was purified via flash
column chromatography (hexane:ether, 9:1) to provide 844 mg (55%)
of a clear liquid: 1H NMR (300 MHz, CDCl3) δ 7.18 (d, J ) 8.7 Hz,
2 H); 7.12 (d, J ) 8.7 Hz, 2 H); 5.57 (m, 1 H); 5.07 (m, 2 H); 4.11 (q,
J ) 7.2 Hz, 4 H); 2.90 (s, 2 H); 2.75 (d, J ) 7.5 Hz, 2 H); 1.14 (t, J
) 7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 169.7, 133.9, 132.9,
131.9, 128.5, 121.8, 119.8, 85.6, 82.4, 61.6, 57.0, 36.7, 23.5, 14.1. IR
(neat, cm-1) 2961, 1735, 1490, 1289, 1215, 1191, 1090, 1015, 925,
(68) Chatani, N.; Takeyasu, T.; Horiuchi, N.; Hanafusa, T. J. Org. Chem.
1988, 53, 3539.
(69) Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org.
Chem. 1997, 62, 603.

5894 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Ar, and the reaction was heated to reflux for another 22 h. After cooling
to room temperature, the reaction mixture was quenched with saturated
NH4Cl (50 mL) and extracted with ether (3 × 50 mL). The combined
organic layers were washed with saturated brine and dried over MgSO4.
Purification via vacuum distillation provided 3.16 g (56%) of the desired
monoalkylated malonate product. The malonate deprotonation procedure
was repeated with NaH (144 mg, 6 mmol) in THF (10 mL) and the
new malonate derivative (1.58 g, 5.6 mmol) in THF (10 mL). Allyl
bromide was added to this mixture, and the reaction was allowed to
stir 14 h at room temperature. The workup procedure described above
was also employed for this reaction. Purification via flash column
chromatography (hexane:ether, 95:5) provided 1.55 g (86%) of a white
solid, mp 36-38 °C: 1H NMR (300 MHz, CDCl3) δ 5.66 (m, 1 H);
5.09 (m, 2 H); 2.54 (d, J ) 7.5 Hz, 2 H); 2.01 (m, 4 H); 1.73 (s, 3 H)
1.42 (s, 18 H). 13C NMR (75 MHz, CDCl3) δ 170.2, 132.7, 119.0,
81.6, 78.5, 76.0, 57.8, 36.9, 31.8, 28.1, 14.1, 3.7. IR (KBR, cm-1) 2976,
2919, 1724, 1458, 1368, 1305, 1248, 1221, 1139, 1084, 987, 931, 844.
Anal. Calcd for C19H30O4: C, 70.76; H, 9.38. Found: C, 70.59; H,
9.30.
3-(Benzyloxy)-4,4-dimethyl-1-phenyl-6-hepten-1-yne (Table 3,
Entry 5). In a dry Schlenk flask under Ar, phenylacetylene (10 mL,
91.2 mmol) and THF (200 mL) were combined, and the flask was
cooled with an ice bath. A solution of n-BuLi (2.5 M in hexanes, 44
mL, 109.4 mmol) was added, and after 10 min the ice bath was
removed. After the addition of 2,2-dimethyl-4-penten-1-al70 (10.2 g,
91.2 mmol), the reaction mixture was allowed to stir at room
temperature for 21 h and at 60 °C for 8 h. After cooling to room
temperature, the reaction mixture was quenched with saturated aqueous
NH4Cl (150 mL) and partitioned between ether (300 mL) and H2O (2
× 100 mL). The combined aqueous phase was extracted with ether (2
× 100 mL), and the combined organic layers were dried over MgSO4.
The crude product was concentrated in vacuo and purified twice by
vacuum distillation to provide 12.4 g (63%) of 4,4-dimethyl-1-phenyl-
6-hepten-1-yn-3-ol. NaH (900 mg, 36 mmol) was added to a dry
Schlenk flask in the glovebox. The Schlenk flask was removed from
the glovebox and attached to a Schlenk line under Ar. THF (100 mL)
was added, and the Schlenk flask was cooled with an ice bath. 4,4-
Dimethyl-1-phenyl-6-hepten-1-yn-3-ol (6.42 g, 30 mmol) and benzyl
bromide (4.3 mL, 36 mmol) were added to the Schlenk flask, and the
reaction mixture was stirred at room temperature for 19 h. The Schlenk
flask was recooled with an ice bath, and the reaction mixture was
quenched with saturated aqueous NH4Cl (100 mL). After addition of
ether (200 mL), the organic phase was washed with 50 mL each of 1
N NaOH, H2O, 1 N HCl, and H2O. The organic phase was dried over
MgSO4, and the crude product was concentrated in vacuo and was
purified via vacuum distillation to provide 6.6 g (72%) of a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 7.48-7.25 (m, 10 H); 5.81 (m, 1
H); 5.04 (m, 2 H); 4.90 (d, J ) 12 Hz, 1 H); 4.53 (d, J ) 12 Hz, 1 H);
3.99 (s, 1 H); 2.23 (m, 2 H); 1.06 (s, 3 H); 1.03 (s, 3 H). 13C NMR (75
MHz, CDCl3) δ 138.6, 135.2, 131.9, 128.4, 128.3, 128.0, 127.6, 123.2,
117.6, 87.2, 77.0, 61.2, 43.3, 38.9, 23.5, 23.2. IR (neat, cm-1) 2965,
2870, 1704, 1639, 1598, 1489, 1453, 1384, 1324, 1270, 1069, 915,
756, 692. Anal. Calcd for C22H24O: C, 87.08; H, 7.65. Found: C, 86.72;
H, 7.52.
NMR (75 MHz, CDCl3) δ 208.7, 89.1, 81.1, 79.5, 75.4, 31.4, 28.4,
22.1, 19.0, 18.6, 13.9. IR (neat, cm-1) 2957, 2930, 2861, 1957, 1435,
844. Anal. Calcd for C11H16: C, 89.11; H, 10.89. Found: C, 88.80; H,
10.86.
Di-tert-butyl 7-methyl-7-octen-2-yne-5,5-dicarboxylate (Table 4,
Entry 1). Diisopropylamine (2.1 mL, 15 mmol) and THF (15 mL)
were added to a dry two-neck flask under Ar. The flask was cooled in
an ice bath, and a solution of n-BuLi (2.5 M in hexanes, 6 mL, 15
mmol) was added. This solution was transferred via cannula under Ar
into another flask containing (2-butynyl) di-tert-butyl malonate (3 g,
11.2 mmol) in THF (25 mL) at -78 °C. After addition was complete,
the reaction mixture was allowed to stir for 15 min at -78 °C, followed
by addition of 1-bromo-2-methylpropene (1.57 mL, 15.6 mmol). The
reaction mixture was allowed to warm to room temperature and was
maintained at room temperature for 19 h. The reaction mixture was
quenched with saturated aqueous NH4Cl and partitioned between ether
(50 mL) and H2O (50 mL). The organic layer was washed with saturated
aqueous CuSO4 (2 × 50 mL) and saturated brine (2 × 50 mL).
Subsequent drying over MgSO4 and concentration in vacuo provided
the crude product. Purification via vacuum distillation followed by flash
column chromatography (hexane:ether, 97:3) provided 2.17 g (60%)
of the pure product as a clear liquid: 1H NMR (300 MHz, CDCl3) δ
4.82 (s, 1 H); 4.79 (s, 1 H); 2.63 (m, 4 H); 1.69 (t, J ) 2.6 Hz, 3 H);
1.66 (s, 3 H); 1.40 (s, 18 H). 13C NMR (75 MHz, CDCl3) δ 169.9,
141.0, 115.7, 81.6, 78.7, 57.6, 39.4, 28.0, 23.8, 23.1. IR (neat, cm-1
)
2977, 2932, 1729, 1644, 1458, 1368, 1246, 1219, 1167, 1141, 1071,
898, 849. Anal. Calcd for C19H30O4: C, 70.77; H, 9.38. Found: C,
70.65; H, 9.15.
Diethyl 4-(3-Cyclohexenyl)-1-phenylbut-1-yne-4,4-dicarboxylate
(Table 4, Entry 2). The malonate deprotonation procedure described
for Table 2, entry 6, was employed with NaH (185 mg, 7.7 mmol) and
(3-cyclohexenyl) diethyl malonate (1.68 g, 7 mmol) in THF (30 mL).
Crude 3-phenyl-2-propyn-1-mesylate, prepared as described for Table
1, entry 4 with 3-phenyl-2-propyn-1-ol (1.06 g, 8 mmol), NEt3 (1.25
mL, 9 mmol) and mesyl chloride (619 µL, 8 mmol) in THF (30 mL),
was cannula-filtered into the solution, and the reaction mixture was
allowed to stir for 15 h at room temperature. The workup procedure
described above for Table 2, entry 6, was also employed for this
reaction. Purification via flash column chromatography (hexane:ether,
95:5) provided 1.78 g (72%) of a clear liquid: 1H NMR (300 MHz,
CDCl3) δ 7.32 (m, 2 H); 7.26 (m, 3 H); 5.75 (m, 2 H); 4.20 (m, 4 H);
3.19 (m, 1 H); 3.08 (d, J ) 17.1 Hz, 1 H); 2.99 (d, J ) 17.1 Hz, 1 H);
1.88 (m, 4 H), 1.55 (m, 1 H); 1.40 (m, 1 H); 1.24 (m, 6 H). 13C NMR
(75 MHz, CDCl3) δ 170.2, 170.1, 131.8, 129.1, 128.4, 128.1, 128.0,
123.7, 85.5, 83.4, 61.5, 60.7, 39.1, 25.1, 24.5, 23.4, 22.6, 14.3. IR (neat,
cm-1) 2980, 2935, 1731, 1491, 1443, 1269, 1221, 1190, 1095, 1073,
1050, 757, 692. Anal. Calcd for C22H26O4: C, 74.55; H, 7.39. Found:
C, 74.68; H, 7.58.
Diethyl 5-(3-Cyclohexenyl)-pent-2-yne-5,5-dicarboxylate (Table
4, Entry 3). The malonate deprotonation procedure described for Table
2, entry 6, was employed using NaH (528 mg, 22 mmol) and diethyl
malonate (3.04 mL, 20 mmol) in THF (50 mL). 3-Bromocyclohexene
was added to the solution, and the reaction mixture was allowed to stir
18 h at room temperature. The reaction mixture was quenched with
saturated NH4Cl (50 mL) and extracted with ether (3 × 50 mL). The
combined organic layers were washed with saturated brine and dried
over MgSO4. Purification via vacuum distillation provided 3.5 g (73%)
of the desired monoalkylated malonate. The deprotonation procedure
was repeated on the new malonate derivative (1.68 g, 7 mmol) with
NaH (185 mg, 7.7 mmol) in THF (40 mL). 1-Bromo-2-butyne (700
µL, 8 mmol) was added to the solution, and the reaction mixture was
allowed to stir 15 h at room temperature. The workup procedure
described above for Table 2, entry 6, was also employed for this
reaction. Purification via vacuum distillation provided 1.43 g (70%)
of the desired enyne as a clear liquid: 1H NMR (300 MHz, CDCl3) δ
5.72 (m, 2 H); 4.17 (m, 4 H); 3.08 (m, 1 H); 2.76 (m, 2 H); 1.85 (m,
4 H); 1.72 (t, J ) 2.7 Hz, 3 H); 1.55 (m, 1 H); 1.32 (m, 1 H); 1.21 (m,
6 H). 13C NMR (75 MHz, CDCl3) δ 170.4, 170.2, 128.7, 128.3, 78.7,
74.2, 61.4, 61.3, 60.5, 38.7, 25.1, 24.4, 23.1, 22.6, 14.3, 14.2. IR (neat
cm-1) 2980, 2935, 1730, 1445, 1367, 1220, 1190, 1096, 1051, 861,
9,10-Undecadien-5-yne (eq 6). This compound was obtained by a
modification of the procedure of Crabbe´.71 To a dry Schlenk flask under
Ar were added sequentially THF (50 mL), 1,5-decadiyne (2.01 mL,
15 mmol), CuI (2.90 g, 7.5 mmol), diisopropylamine (4.22 mL, 30
mmol), and paraformaldehyde (680 mg, 37.5 mmol). A reflux condenser
was attached under Ar, and the reaction mixture was heated to reflux
for 14 h. After cooling to room temperature, the reaction mixture was
quenched with 1 N HCl (2 × 100 mL) and 1 N NaOH (2 × 100 mL),
washed with saturated brine, and dried over MgSO4. Excess solvent
was removed by distillation at atmospheric pressure, with subsequent
vacuum distillation of the product and in vacuo removal of trace solvent
1
to provide 534 mg (24%) of the desired allenyne as a clear oil. H
NMR (300 MHz, CDCl3) δ 5.12 (aquintet, J ) 6.6 Hz, 1 H); 4.58 (m,
2 H); 2.17-2.04 (m, 6 H); 1.38-1.32 (m, 4 H); 0.79 (m, 3 H). 13C
(70) Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273.
(71) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbe´,
P. J. Chem. Soc., Perkin Trans. 1 1984, 747.

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5895
724. Anal. Calcd for C17H24O4: C, 69.84; H, 8.27. Found: C, 69.51;
H, 8.28.
of a clear liquid: 1H NMR (300 MHz, CDCl3) δ 5.62 (m, 1 H); 5.21
(m, 1 H); 4.20 (m, 4 H); 2.81 (d, J ) 7.8 Hz, 2 H); 2.73 (d, J ) 2.4
Hz, 2 H); 1.75 (t, J ) 2.4 Hz, 3 H); 1.66, (dd, J ) 6.4, 1.0 Hz, 3 H);
1.25 (t, J ) 7.3 Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 170.3, 128.6,
123.4, 78.6, 73.8, 61.5, 57.1, 29.4, 22.8, 14.1, 13.0, 3.5. IR (neat) 2982,
2922, 1736, 1445, 1336, 1289, 1207, 1096, 1068, 1045, 860, 701. Anal.
Calcd for C15H22O4: C, 67.65; H, 8.33. Found: C, 67.90; H, 8.37.
Diethyl 1-Phenyl-6-octen-1-yne-4,4-dicarboxylate (Table 4, Entry
4). Sodium hydride (540 mg, 22.5 mmol) was added to a dry Schlenk
flask in the glovebox. The Schlenk flask was removed from the
glovebox and attached to a Schlenk line under Ar. THF (150 mL) was
added, and the reaction mixture was cooled in an ice bath. 3-Phenyl-
2-propynyl diethyl malonate (5.5 g, 20 mmol), obtained from diethyl
malonate anion and 1-bromo-3-phenyl-2-propyne, was added to the
flask, and the reaction mixture was allowed to stir at 0 °C for 10 min.
1-Bromo-2-butene was added, and the temperature was maintained
between 0 °C and room temperature for 12 h. The reaction mixture
was cooled to 0 °C, quenched with saturated aqueous NH4Cl (40 mL),
and partitioned between H2O (20 mL) and ether (100 mL). The organic
layer was separated and washed with 30 mL each of 0.5 N aqueous
HCl, saturated aqueous NaHCO3, H2O, and saturated brine and dried
over MgSO4. The crude product was concentrated in vacuo and was
purified via vacuum distillation to provide 5.5 g (84%) of a clear oil:
1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 5 H); 5.62 (m, 1 H);
5.29 (m, 2 H); 4.20 (m, 4 H); 3.00 (s, 2 H); 2.90 (d, J ) 6.0 Hz, 1 H
General Procedure A for the Conversion of Enynes to Cyclo-
pentenones. In an argon-filled glovebox, a dry resealable Schlenk flask
was charged with Cp2Ti(CO)2 (0.025 mmol) and toluene (2-3 mL).
The flask was removed from the glovebox and attached to a Schlenk
line under Ar. The enyne (0.50 mmol) was added, and the Schlenk
flask was evacuated and backfilled with 18 psig CO. Caution:
Appropriate precautions should be taken when performing reactions
using carbon monoxide, particularly under elevated pressure. The
reaction mixture was heated to 90 °C for 12-48 h. After the reaction
mixture was cooled to room temperature, the CO was cautiously
released in the hood. The crude reaction mixture was filtered through
a pad of silica gel with additional ether (100 mL) and concentrated in
vacuo.
min); 2.79 (d, J ) 7.4 Hz, 2 H maj); 1.67 (m, 3 H); 1.26 (m, 6 H). 13
C
General Procedure B for the Conversion of Enynes to Cyclo-
pentenones. In an argon-filled glovebox, a dry resealable Schlenk flask
was charged with Cp2Ti(CO)2 (0.025 mmol), toluene (2-3 mL), and
enyne (0.50 mmol). The flask was removed from the glovebox, attached
to a Schlenk line, evacuated, and backfilled with 18 psig CO. Caution:
Appropriate precautions should be taken when performing reactions
under elevated pressure. The reaction protocol was conducted in an
analogous fashion to procedure A after this point.
NMR (75 MHz, CDCl3) δ 170.2, 131.8, 130.6, 129.0, 128.3, 124.3,
123.5, 123.4, 84.8, 83.5, 61.7, 57.4, 57.3, 35.6, 29.7, 23.6, 18.2, 14.3,
13.2. IR (neat, cm-1) 2982, 2936, 1732, 1598, 1491, 1443, 1366, 1279,
1205, 1050, 969, 858, 758, 692. Anal. Calcd for C20H24O4: C, 73.13;
H, 7.37. Found: C, 73.30; H, 7.30.
Diethyl trans-1-Phenyl-6-octen-1-yne-4,4-dicarboxylate (Table 4,
Entry 5). In a flame-dried Schlenk flask, trans-2-butene-1-ol (1.28 mL,
15 mmol), NEt3 (2.30 mL, 16.5 mmol), and THF (30 mL) were
combined and cooled to 0 °C. Slow addition of mesyl chloride (1.16
mL, 15 mmol) resulted in the formation of a thick, white precipitate.
To a separate flame-dried Schlenk flask in the glovebox, NaH (0.26 g,
10.8 mmol) was added. The Schlenk flask was removed from the
glovebox and placed on a vacuum line under Ar. THF (50 mL) was
added, and the solution was cooled to 0 °C. (3-Phenyl-2-propynyl)
diethyl malonate (2.74 g, 10 mmol), obtained from diethyl malonate
anion and 3-phenyl-2-propyn-1-mesylate, was added slowly to the NaH
suspension, and the reaction mixture was allowed to warm to room
temperature after the addition was complete. After 1 h at room
temperature, the reaction mixture was cooled again to 0 °C, and the
crude mesylate solution prepared earlier was cannula-filtered into the
malonate anion solution. After the additon was complete, the reaction
was allowed to warm to room temperature and to stir 12 h at room
temperature. Workup was performed as stated above for Table 2, entry
6. Purification via flash column chromatography (hexane:ether, 9:1)
provided 2.45 g (75%) of a clear liquid: 1H NMR matched that of the
major isomer for Table 4, entry 4, with ∼4% of the cis isomer also
present in the sample. Anal. Calcd for C20H24O4: C, 73.13; H, 7.37.
Found: C, 73.30; H, 7.30.
Diethyl cis-1-Phenyl-6-octen-1-yne-4,4-dicarboxylate (Table 4,
Entry 6). The procedure employed was analogous to that for Table 4,
entry 5, with the use of cis-2-butene-1-ol (1.23 mL, 14.4 mmol), NEt3
(2.20 mL, 15.8 mmol), THF (30 mL), and mesyl chloride (1.10 mL,
14.2 mmol) for the first part and (3-phenyl-2-propynyl) diethyl malonate
(2.61 g, 9.5 mmol) and NaH (0.25 g, 10.4 mmol) for the second part.
Purification via flash column chromatography (hexane:ether, 9:1)
provided the desired enyne as a clear liquid: 1H NMR (300 MHz,
CDCl3) δ 7.2-7.4 (m, 5 H); 5.67 (m, 1 H); 5.24 (m, 1 H); 4.20 (m, 4
H); 3.00 (s, 2 H); 2.90 (d, J ) 8.0 Hz, 2 H); 1.69 (d, J ) 6.7 Hz, 3 H);
1.27 (t, J ) 7.12 Hz, 6 H). 13C NMR (75 MHz, CDCl3) δ 170.3, 131.8,
129.1, 128.4, 128.1, 123.5, 85.0, 83.5, 61.8, 57.4, 29.7, 14.3, 13.3. IR
(neat, cm-1) 2981, 2936, 1735, 1598, 1490, 1442, 1366, 1289, 1206,
1095, 1068, 858, 757, 692. Anal. Calcd for C20H24O4: C, 73.13; H,
7.37. Found: C, 72.74; H, 7.12.
2-Phenylbicyclo[3.3.0]oct-1-en-3-one (Table 1, Entry 1). General
procedure A was used to convert 1-phenyl-6-hepten-1-yne44 (86 mg,
0.50 mmol) to the desired product in 15 h. Purification by flash
chromatography (hexane:ether, 7:3) afforded 88 mg (89% yield) of a
1
clear oil. The H NMR spectrum matched the published spectrum.44
2-Phenyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 1, Entry 2).
General procedure A was used to convert 3-(allyloxy)-1-phenyl-1-
propyne44 (85 µL, 0.50 mmol) to the desired product in 12 h.
Purification by flash chromatography (hexane:ether, 3:7) afforded 89
1
mg (89% yield) of a clear oil. The H NMR spectrum matched the
published spectrum.44
Di-tert-butyl 2-Methyl-3-oxobicycl[3.3.0]oct-1-ene-7,7-dicarboxy-
late (Table 1, Entry 3). General procedure A was used to convert
di-tert-butyl 7-octen-2-yne-4,4-dicarboxylate44 (154 mg, 0.50 mmol)
to the desired product in 14 h. Purification by flash chromatography
(hexane:ether, 4:1) afforded 147 mg (88% yield) of a clear oil. The 1H
NMR spectrum matched the published spectrum.44
2-Methyl-7-phenyl-7-azabicyclo[3.3.1]oct-1-en-3-one (Table 1,
Entry 4). General procedure A was used to convert N-(3-phenyl-2-
butynyl)-N-allylaniline (93 mg, 0.50 mmol) to the desired product in
12 h. Purification by flash chromatography (hexane:ether, 3:7) afforded
98 mg (92% yield) of a light orange solid, mp 112-114 °C: 1H NMR
(300 MHz, CDCl3) δ 7.27 (m, 2 H); 6.75 (t, J ) 7.2 Hz, 1 H); 6.63 (d,
J ) 7.2 Hz, 2 H); 4.32 (d, J ) 15.6 Hz, 1 H); 3.95 (m, 2 H); 3.31 (bs,
1 H); 2.74 (m, 2 H); 2.25 (d, J ) 18 Hz, 1 H); 1.79 (s, 3 H). 13C NMR
(75 MHz, CDCl3) δ 200.0, 165.3, 138.5, 124.0, 120.5, 108.2, 103.1,
43.4, 39.0, 33.0, 31.0. IR (KBR, cm-1) 2827, 1716, 1684, 1601, 1507,
1368, 1304, 1149, 1052, 753, 692. Anal. Calcd for C14H15NO: C, 78.84;
H, 7.09. Found: C, 78.69; H, 7.17.
Diethyl 2-Phenyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate
(Table 1, Entry 5). General procedure A was used to convert diethyl
1-phenyl-6-hepten-1-yne-4,4-dicarboxylate45 (157 mg, 0.50 mmol) to
the desired product in 12 h. Purification by flash chromatography
(hexane:ether, 2:1) afforded 162 mg (95% yield) of a white solid, mp
78-80 °C. The 1H NMR spectrum matched the published spectrum.45
Diethyl cis-7-Nonen-2-yne-5,5-dicarboxylate (Table 4, Entry 7).
The procedure employed was analogous to that described above with
the use of cis-2-butene-1-ol (1.15 mL, 13.4 mmol), NEt3 (2.07 mL,
14.8 mmol), THF (30 mL), and mesyl chloride (1.04 mL, 13.4 mmol)
for the first part and (2-butynyl) diethyl malonate (1.8 g, 9 mmol) and
NaH (0.24 g, 10 mmol) for the second part. Purification via flash
column chromatography (hexane:ether, 95:5) provided 1.56 g (64%)
Ethyl 7-Cyano-2-phenyl-3-oxobicyclo[3.3.0]oct-1-ene-7-carboxy-
late (Table 1, Entry 6). General procedure A with 0.0375 mmol Cp2-
Ti(CO)2 was used to convert ethyl 4-cyano-1-phenyl-6-hepten-1-yn-
4-carboxylate (118 mg, 0.50 mmol) to the desired product in 12 h.
Purification by flash chromatography (hexane:ether, 3:2) afforded 100
mg (76% yield) of a 1:1 mixture of diastereomers as a white solid.
1
The H NMR spectrum matched the published spectrum.45

5896 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
Ethyl 7-Acetyl-2-phenyl-3-oxobicyclo[3.3.0]oct-1-ene-7-carboxy-
late (Table 1, Entry 7). General procedure A with 0.0375 mmol
Cp2Ti(CO)2 was used to convert ethyl-4-acetyl-1-phenyl-6-hepten-1-
yne-4-carboxylate (126 mg, 0.50 mmol) to the desired product in 12
h. Purification by flash chromatography (hexane:ether, 1:1) afforded
131 mg (93% yield) of a 1:1 mixture of diastereomers as a yellow oil.
white solid, mp 94-95 °C: 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J
) 8.6 Hz, 2 H); 7.45 (d, J ) 8.5 Hz, 2 H); 4.28 (q, J ) 7.2 Hz, 2 H);
4.18 (m, 2 H); 3.62 (d, J ) 18.9 Hz, 1 H); 3.25 (d, J ) 19.4 Hz, 1 H);
3.13 (m, 1 H); 2.84 (m, 2 H); 2.30 (dd, J ) 3.3, 18.0 Hz, 1 H); 1.76
(at, J ) 12.7 Hz, 1 H); 1.31 (t, J ) 7.2 Hz, 3 H); 1.24 (t, J ) 7.2 Hz,
3 H). 13C NMR (75 MHz, CDCl3) δ 206.7, 179.6, 171.5, 134.4, 131.7,
130.1, 130.0, 122.4, 62.3, 62.1, 61.4, 43.1, 42.6, 38.7, 36.0, 14.2, 14.1.
IR (KBr, cm-1) 2984, 1722, 1707, 1487, 1276, 1155, 1061, 1008, 821,
604. Anal. Calcd for C20H21BrO5: C, 57.02; H, 5.02. Found: C, 57.00;
H, 5.53.
Diethyl 2-(Ethyl-4′-benzoate)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Table 1, Entry 13). General procedure B was used to
convert diethyl 1-(ethyl-4′-benzoate)-6-hepten-1-yne-4,4-dicarboxylate
(193 mg, 0.50 mmol) to the desired product in 15 h. Purification by
flash chromatography (hexane:ether, 7:3) afforded 183 mg (88% yield)
of a white solid, mp 87-88 °C: 1H NMR (300 MHz, CDCl3) δ 8.03
(d, J ) 8.4 Hz, 2 H); 7.62 (d, J ) 8.4 Hz, 2 H); 4.34 (q, J ) 7.2 Hz,
2 H); 4.25 (q, J ) 7.2 Hz, 2 H); 4.14 (m, 2 H); 3.63 (d, J ) 19.5 Hz,
1 H); 3.26 (d, J ) 19.5 Hz, 1 H); 3.14 (m, 1 H); 2.80 (m, 2 H); 2.29
(dd, J ) 33, 18 Hz, 1 H); 1.74 (at, J ) 12.6 Hz, 1 H); 1.36 (t, J ) 7.2
Hz, 3 H); 1.28 (t, J ) 7.2 Hz, 3 H); 1.19 (t, J ) 7.2 Hz, 3 H). 13C
NMR (75 MHz, CDCl3) δ 206.6, 181.0, 171.5, 170.6, 166.3, 135.3,
134.6, 129.9, 129.6, 128.3, 62.3, 62.1, 61.3, 61.0, 43.2, 42.7, 38.6, 36.1,
14.4, 14.1, 14.0. IR (neat, cm-1) 2982, 2937, 1714, 1650, 1608, 1448,
1367, 1272, 1181, 1103, 928, 858, 774, 705. Anal. Calcd for
C23H26O6: C, 66.65; H, 6.32. Found: C, 66.44; H, 6.49.
Diethyl 2-(p-Cyanophenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Table 1, Entry 14). General procedure B was used to
convert diethyl 1-(p-cyanophenyl)-6-hepten-1-yne-4,4-dicarboxylate
(113 mg, 0.33 mmol) to the desired product in 16 h. Purification by
flash chromatography (hexane:ether, 1:1) afforded 86 mg (70% yield)
of a yellow liquid: 1H NMR (300 MHz, CDCl3) δ 7.70 (m, 4 H); 4.30
(q, J ) 7.2 Hz, 2 H); 4.19 (q, J ) 7.2 Hz, 2 H); 3.67 (d, J ) 19.5 Hz,
1 H); 3.30 (d, J ) 19.5 Hz, 1 H); 3.20 (m, 1 H); 2.87 (m, 2 H); 2.34
(dd, J ) 3.3, 18 Hz, 1 H); 1.78 (at, J ) 12.6 Hz, 1 H); 1.32 (t, J ) 7.2
Hz, 3 H); 1.24 (t, J ) 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ
206.2, 182.0, 171.3, 170.6, 135.6, 133.9, 132.2, 128.9, 118.8, 111.7,
62.4, 62.2, 61.3, 43.4, 42.6, 38.6, 36.1, 14.1, 14.0. IR (neat, cm-1) 2984,
2937, 2227, 1722, 1702, 1656, 1274, 1254, 1181, 1158, 1061, 926,
857. Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76. Found: C, 68.41;
H, 5.79.
Diethyl 2-(p-Trifluoromethylphenyl)-3-oxobicyclo[3.3.0]oct-1-ene-
7,7-dicarboxylate (Table 1, Entry 15). General procedure B was used
to convert diethyl 1-(p-trifluoromethylphenyl)-6-hepten-1-yne-4,4-
dicarboxylate (191 mg, 0.50 mmol) to the desired product in 14 h.
Purification by flash chromatography (hexane:ether, 4:1) afforded 191
mg (93% yield) of a clear liquid. 1H NMR (300 MHz, CDCl3) δ 7.70
(d, J ) 8.4 Hz, 2 H); 7.65 (d, J ) 8.4 Hz, 2 H); 4.29 (q, J ) 7.2 Hz,
2 H); 4.18 (m, 2 H); 3.68 (d, J ) 19.5 Hz, 1 H); 3.30 (d, J ) 19.5 Hz,
1 H); 3.19 (m, 1 H); 2.86 (m, 2 H); 2.33 (dd, J ) 3.3, 18 Hz, 1 H);
1.79 (at, J ) 12.7, 1 H); 1.32 (t, J ) 7.2 Hz, 3 H); 1.23 (t, J ) 7.2 Hz,
3 H). 13C NMR (75 MHz, CDCl3) δ 206.5, 181.1, 171.5, 170.7, 134.6,
134.4, 130.2, 129.8, 128.8, 126.0, 125.4, 125.3. IR (neat, cm-1) 2983,
2939, 1732, 1651, 1616, 1411, 1324, 1273, 1120, 1066, 1017, 928,
839, 686. Anal. Calcd for C21H21F3O5: C, 61.46; H, 5.16. Found: C,
61.77; H, 5.16.
1
The H NMR spectrum matched the published spectrum.45
Di-tert-butyl 3-Oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate (Table
1, Entry 8). General procedure A was used to convert di-tert-butyl
6-hepten-1-yne-4,4-dicarboxylate (73 mg, 0.25 mmol) to the desired
product in 12 h. Purification by flash chromatography (hexane:ether,
1:1) afforded 73 mg (90% yield) of a white solid, mp 115-117 °C:
1H NMR (500 MHz, CDCl3) δ 5.91 (s, 1 H); 3.25 (d, J ) 18.8 Hz, 1
H); 3.15 (d, J ) 18.8 Hz, 1 H); 3.17 (m, 1 H); 2.69 (dd, J ) 12.7 Hz,
J ) 7.6 Hz, 1 H); 2.62 (dd, J ) 17.8 Hz, J ) 6.4 Hz, 1 H); 2.12 (dd,
J ) 17.8 Hz, J ) 3.4 Hz, 1 H); 1.65 (t, J ) 12.7 Hz, 1 H); 1.49 (s, 9
H); 1.46 (s, 9 H). 13C NMR (75 MHz, CDCl3) δ 210.0, 186.5, 170.9,
170.1, 125.6, 82.2, 82.1, 62.3, 45.2, 42.4, 38.9, 35.1, 28.0 (2). IR (KBr,
cm-1) 2980, 1719, 1701, 1676, 1289, 1167, 1140. Anal. Calcd for
C18H26O5: C, 67.06; H, 8.13. Found: C, 66.85; H, 8.13.
Diethyl 2-(p-Methylphenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Table 1, Entry 9). General procedure B was used to
convert diethyl 1-(p-methylphenyl)-6-hepten-1-yne-4,4-dicarboxylate
(172 mg, 0.50 mmol) to the desired product in 18 h. Purification by
flash chromatography (hexane:ether, 3:2) afforded 169 mg (91% yield)
of a white solid, mp 99-101 °C: 1H NMR (300 MHz, CDCl3) δ 7.54
(d, J ) 8.8 Hz, 2 H); 6.94 (d, J ) 8.8 Hz, 2 H); 4.28 (q, J ) 7.2 Hz,
2 H); 4.17 (qd, J ) 3, 7.2 Hz, 2 H); 3.83 (s, 3 H); 3.63 (d, J ) 19.2
Hz, 1 H); 3.26 (d, J ) 19.5 Hz, 1 H); 3.11 (m, 1 H); 2.81 (m, 2 H);
2.29 (dd, J ) 3.3, 17.7 Hz, 1 H); 1.75 (at, J ) 12.6 Hz, 3 H); 1.31 (t,
J ) 7.2 Hz, 3 H); 1.23 (t, J ) 7.2 Hz, 3 H). 13C NMR (75 MHz,
CDCl3) δ 207.5, 177.2, 171.7, 170.8, 159.5, 134.9, 129.8, 123.6, 113.9,
62.2, 62.0, 61.4, 55.3, 42.8, 42.7, 38.8, 36.0, 14.1, 14.0. IR (KBr, cm-1
)
2982, 1728, 1704, 1606, 1571, 1271, 1182, 1120, 1061, 1030, 835.
Anal. Calcd for C21H24O6: C, 67.73; H, 6.50. Found: C, 67.59; H,
6.31.
Diethyl 2-(p-Methoxyphenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Table 1, Entry 10). General procedure B was used to
convert diethyl 1-(p-methoxyphenyl)-6-hepten-1-yne-4,4-dicarboxylate
(164 mg, 0.50 mmol) to the desired product in 14 h. Purification by
flash chromatography (hexane:ether, 3:2) afforded 161 mg (90% yield)
of a white solid, mp 96-98 °C: 1H NMR (300 MHz, CDCl3) δ 7.47
(d, J ) 7.8 Hz, 2 H); 7.21 (d, J ) 7.8 Hz, 2 H); 4.27 (q, J ) 7.2 Hz,
2 H); 4.16 (m, 2 H); 3.64 (d, J ) 19.2 Hz, 1 H); 3.27 (d, J ) 19.2 Hz,
1 H); 3.11 (m, 1 H); 2.80 (m, 2 H); 2.36 (s, 3 H); 2.29 (dd, J ) 3, 18
Hz, 1 H); 1.76 (at, J ) 12.6 Hz, 1 H); 1.31 (t, J ) 7.2 Hz, 3 H); 1.22
(t, J ) 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 207.3, 178.2, 171.7,
170.8, 138.1, 135.4, 129.2, 128.4, 128.2, 62.2, 62.0, 61.4, 42.9, 42.7,
38.8, 36.0, 21.4, 14.2, 14.1. IR (KBr cm-1) 2982, 1730, 1698, 1514,
1270, 1187, 1066, 927, 891, 857, 821. Anal. Calcd for C21H24O5: C,
70.77; H, 7.03. Found: C, 70.74; H, 6.79.
Diethyl 2-(p-Chlorophenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Table 1, Entry 11). General procedure B was used to
convert diethyl 1-(p-chlorophenyl)-6-hepten-1-yne-4,4-dicarboxylate
(174 mg, 0.50 mmol) to the desired product in 14 h. Purification by
flash chromatography (hexane:ether, 2:1) afforded 174 mg (92% yield)
of a white solid, mp 83-85 °C: 1H NMR (300 MHz, CDCl3) δ 7.53
(d, J ) 8.4 Hz, 2 H); 7.37 (d, J ) 8.4 Hz, 2 H); 4.28 (q, J ) 7.2 Hz,
2 H); 4.18 (m, 2 H); 3.63 (d, J ) 19.2 Hz, 1 H); 3.27 (d, J ) 19.2 Hz,
1 H); 3.13 (m, 1 H); 2.74 (m, 2 H); 2.30 (dd, J ) 3.3, 18 Hz, 1 H);
1.76 (at, J ) 12.6 Hz, 1 H); 1.31 (t, J ) 7.2 Hz, 3 H); 1.23 (t, J ) 7.2
Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 206.9, 179.5, 171.6, 170.7,
134.4, 134.1, 129.8, 129.5, 128.7, 62.4, 62.1, 61.4, 43.1, 42.6, 38.7,
36.0, 14.2, 14.1. IR (KBr, cm-1) 2982, 1729, 1696, 1492, 1271, 1179,
1092, 1066, 927, 890, 824. Anal. Calcd for C20H21ClO5: C, 63.75; H,
6.21. Found: C, 63.47; H, 5.91.
Diethyl 2-Methyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate
(Table 2, Entry 1). General procedure A was used to convert diethyl
7-octen-2-yne-4,4-dicarboxylate44 (126 mg, 0.50 mmol) to the desired
product in 15 h. Purification by flash chromatography (hexane:ether,
3:2) afforded 129 mg (92% yield) of a clear liquid. The 1H NMR
spectrum matched the published spectrum.44
Diethyl 2-Propyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxylate
(Table 2, Entry 2). General procedure A was used to convert diethyl
9-decen-4-yne-7,7-dicarboxylate45 (140 mg, 0.50 mmol) to the desired
product in 13 h. Purification by flash chromatography (hexane:ether,
2:1) afforded 138 mg (90% yield) of a clear liquid. The 1H NMR
spectrum matched the published spectrum.45
Diethyl 2-(p-Bromophenyl)-3-oxobicyclo[3.3.0]oct-1-ene-7,7-di-
carboxylate (Table 1, Entry 12). General procedure B was used to
convert diethyl 1-(p-bromophenyl)-6-hepten-1-yne-4,4-dicarboxylate
(197 mg, 0.50 mmol) to the desired product in 18 h. Purification byflash
chromatography (hexane:ether, 7:3) afforded 190 mg (90% yield) of a
Diethyl 2-Isopropyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxy-
late (Table 2, Entry 3). General procedure B was used except at 5
psig CO to convert diethyl 2-methyl-8-nonen-3-yn-6,6-dicarboxylate45

Titanocene-Catalyzed Pauson-Khand Type Reaction
J. Am. Chem. Soc., Vol. 121, No. 25, 1999 5897
(140 mg, 0.25 mmol) to the desired product in 48 h. Purification by
flash chromatography (hexane:ether, 2:1) afforded 65 mg (85% yield)
of a clear liquid. The 1H NMR spectrum matched the published
spectrum.45
of an 8:1 mixture of diastereomers as a pale yellow oil. The 1H
NMR spectrum matched the published spectrum. Identification of
the major isomer was based upon comparison to the published
spectrum.44
Diethyl 2-Cyclopentyl-3-oxobicyclo[3.3.0]oct-1-ene-7,7-dicarboxy-
late (Table 2, Entry 4). General procedure B was used except at 5
psig CO to convert diethyl 1-cyclopentyl-6-hepten-1-yne-4,4-dicar-
boxylate45 (77 mg, 0.25 mmol) to the desired product in 48 h.
Purification by flash chromatography (hexane:ether, 2:1) afforded 66
mg (81% yield) of a clear liquid. The 1H NMR spectrum matched the
published spectrum.45
Di-tert-butyl 2-Methyl-3-oxobicyclo[3.4.0]non-1-en-8,8-dicarboxy-
late (Table 2, Entry 5). General procedure A was used to convert
di-tert-butyl 8-nonen-2-yne-4,4-dicarboxylate44 (81 mg, 0.25 mmol) to
the desired product in 14 h. Purification by flash chromatography
(hexane:ether, 7:3) afforded 77 mg (88% yield) of a clear liquid. The
1H NMR spectrum matched the published spectrum.44
Di-tert-butyl 2-Methyl-3-oxobicyclo[3.4.0]non-1-en-7,7-dicarboxy-
late (Table 2, Entry 6). General procedure B was used except at 5
psig CO to convert di-tert-butyl 8-nonen-2-yne-3,3-dicarboxylate (80
mg, 0.25 mmol) to the desired product in 16 h. Purification by flash
chromatography (hexane:ether, 7:3) afforded 75 mg (86% yield) of a
white solid, mp 60-62 °C: 1H NMR (300 MHz, CDCl3) δ 2.76 (m, 2
H); 2.55 (m, 3 H); 2.37 (m, 1 H); 1.92 (d, J ) 18.9 Hz, 1 H); 1.65 (m,
4 H); 1.47 (s, 9 H); 1.41 (s, 9 H); 1.33 (d, J ) 12.9 Hz, 1 H). 13C
NMR (75 MHz, CDCl3) δ 208.5, 173.1, 170.6, 169.9, 133.8, 81.9, 81.7,
56.0, 41.2, 38.8, 36.3, 31.1, 28.0, 27.9, 24.9, 7.8. IR (neat, cm-1) 2980,
2934, 1725, 1706, 1660, 1455, 1370, 1297, 1254, 1166, 1073, 1027,
845. Anal. Calcd for C20H30O5: C, 68.55; H, 8.63. Found: C, 68.60;
H, 9.00.
2-Phenyl-8-methyl-7-oxabicyclo[3.3.0]oct-1-en-3-one (Table 3,
Entry 4). General procedure B was used to convert 3-(allyloxy)-1-
phenyl-1-butyne44 (93 mg, 0.50 mmol) to the desired product in 24 h.
Purification by flash chromatography (hexane:ether, 7:3) afforded 102
mg (95% yield) of a 10:1 mixture of diastereomers as a clear liquid.
The 1H NMR spectrum matched the published spectrum. Identification
of the major isomer was based upon comparison to the published
spectrum.44
8-(Benzyloxy)-7,7-dimethyl-2-phenylbicyclo[3.3.0]oct-1-en-3-
one (Table 3, Entry 5). General procedure B was used to convert
3-(benzyloxy)-4,4-dimethyl-1-phenyl-hepten-1-yne (152 mg, 0.50 mmol)
to the desired product in 15 h. Purification by flash chromatography
(hexane:ether, 85:15) afforded 156 mg (94% yield) of a single
diastereomer as a pale yellow solid. Attempts to establish the relative
configuration by nOe studies were unsuccessful. The assignment is
based upon a comparison of the shift of the allylic proton in the NMR
spectrum with a series of related enones obtained from other Pauson-
Khand type cyclizations.15b,33b Mp 107-109 °C: 1H NMR (300 MHz,
CDCl3) δ 7.47-7.22 (m, 10 H); 4.55 (d, J ) 11.4 Hz, 1 H); 4.47 (d,
J ) 11.4 Hz, 1 H); 4.12 (s, 1 H); 3.35 (m, 1 H); 2.86 (dd, J ) 6.6, 18
Hz, 1 H); 2.19 (dd, J ) 6.6, 18 Hz, 1 H); 2.11 (dd, J ) 9.9, 12.6 Hz,
1 H); 1.25 (s, 3 H); 1.14 (dd, J ) 8.1, 12.6 Hz, 1 H); 0.97 (s, 3 H). 13
C
NMR (75 MHz, CDCl3) δ 209.0, 180.5, 138.7, 138.1, 131.4, 128.8,
128.4, 127.9, 127.8, 83.4, 72.3, 45.0, 44.7, 44.1, 39.9, 30.1, 23.8. IR
(KBr, cm-1) 2953, 2860, 1706, 1498, 1444, 1381, 1302, 1105, 1031,
927, 736, 694. Anal. Calcd for C23H23O2: C, 83.10; H, 7.28. Found:
C, 83.01; H, 7.18.
(Table 2, Entry 7). General procedure A was used to convert trans-
1-(allyloxy)-2-(phenylethynl)cyclohexane (120 mg, 0.50 mmol)67 to the
desired product in 24 h. Purification by flash chromatography (hexane:
ether, 1:4) afforded 125 mg (93% yield) of an off-white solid, mp 116-
2-Butylbicyclo[3.3.0]oct-1,5-dien-3-one (eq 6). General procedure
A was used with 0.05 mmol Cp2Ti(CO)2 to convert 9,10-undecadien-
5-yne (74 mg, 0.50 mmol) to the desired product in 12 h. Purification
by flash chromatography (hexane:ether, 7:3) afforded 102 mg (83%
yield) of a clear oil. The product decomposes upon prolonged storage
1
118 °C. Lit. mp 118-120 °C. The H NMR spectrum matched the
published spectrum.67
1
at room temperature. H NMR (300 MHz, CDCl3) δ 5.95 (s, 1 H);
2-Butyl-6-(benzyloxy)bicyclo[3.3.0]oct-1-en-3-one (Table 3, Entry
1). General procedure A with 0.0375 mmol Cp2Ti(CO)2 was used to
convert 3-(benzyloxy)-1-undecen-6-yne44 (128 mg, 0.50 mmol) to the
desired product in 12 h. Purification by flash chromatography (hexane:
ether, 4:1) afforded 130 mg (92% yield) of a 3.5:1 mixture of
2.80 (m, 6 H); 2.24 (t, J ) 7.5 Hz, 2 H); 1.45 (m, 2 H); 1.29 (m, 2 H);
0.88 (t, J ) 7.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 199.0, 172.5,
135.2, 125.1, 119.6, 26.9, 26.7, 20.9, 16.1, 14.8, 13.8, 5.0. IR (neat)
2926, 2857, 1696, 1447, 1307, 1209, 1052, 899. Exact mass calcd for
C12H16O [M]+: 176.1201. Found: 176.1201.
1
diastereomers as a pale yellow oil. The H NMR spectrum matched
Di-tert-butyl 2,5-Dimethylbicyclo[3.3.0]oct-1-ene-7,7-dicarboxy-
late (Table 4, Entry 1). General procedure A with 0.0125 mmol Cp2-
Ti(CO)2 was used to convert di-tert-butyl 6-methyl-7-octen-2-yn-5,5-
dicarboxylate (81 mg, 0.25 mmol) to the desired product in 12 h.
Purification by flash chromatography (hexane:ether, 4:1) afforded 83
mg (95% yield) of a white solid, mp 79-81 °C: 1H NMR (300 MHz,
CDCl3) δ 3.26 (d, J ) 17.7 Hz, 1 H); 3.02 (d, J ) 17.7 Hz, 1 H); 2.45
(d, J ) 13.8 Hz, 1 H); 2.37 (d, J ) 17.4 Hz, 1 H); 2.29 (d, J ) 17.4
the published spectrum. Identification of the major isomer was based
upon comparison to the published spectrum.44
2-Butyl-6-(triisopropylsilyloxy)bicyclo[3.3.0]oct-1-en-3-one (Table
3, Entry 2). General procedure B was used to convert 3-((triisopro-
pylsilyl)oxy)-1-undecen-6-yne67 (163 mg, 0.50 mmol) to the desired
product in 14 h. Purification by flash chromatography (hexane:ether,
95:5) afforded a combined 154 mg (88% yield) of a 2.3:1 mixture of
diastereomers as a clear oil. The isomers were separated and character-
ized. Major isomer: 1H NMR (300 MHz, CDCl3) δ 3.82 (m, 1 H);
2.88 (m, 1 H); 2.74-2.62 (m, 2 H); 2.48 (m, 1 H); 2.31-2.15 (m, 3
H); 2.10-1.99 (m, 2 H); 1.43-1.37 (m, 2 H); 1.28 (m, 2 H); 1.06 (s,
21 H); 0.89 (t, J ) 7.3 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 210.2,
179.3, 138.2, 77.8, 52.1, 41.0, 35.8, 30.3, 24.4, 23.5, 22.9, 18.2, 14.1,
12.4. IR (neat, cm-1) 2942, 2866, 1710, 1665, 1464, 1376, 1263, 1132,
1068, 996, 882, 833, 682. Anal. Calcd for C21H38O2Si: C, 71.94; H,
10.92. Found: C, 72.23; H, 10.77. Minor isomer: 1H NMR (300 MHz,
CDCl3) δ 4.40 (at, J ) 3.5 Hz, 1 H); 2.82 (m, 1 H); 2.60-2.38 (m, 4
H); 2.21-2.09 (m, 4 H); 1.41 (m, 2 H); 1.27 (m, 2 H); 1.01 (m, 2 H);
0.87 (m, 21 H); 0.87 (t, J ) 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3)
δ 211.8, 181.7, 137.2, 71.4, 51.0, 36.8, 36.7, 30.2, 23.8, 23.6, 22.8,
18.2 (2), 14.1, 12.5. IR (neat, cm-1) 2942, 2866, 1707, 1667, 1464,
1366, 1247, 1170, 1134, 1086, 1053, 882, 678. Assignment of the major
isomer was based upon analogy to a related allylic amide derived from
the same enyne.67
Hz, 1 H); 1.67 (s, 3 H); 1.47 (s, 9 H); 1.41 (s, 9 H); 1.09 (s, 3 H). 13
C
NMR (75 MHz, CDCl3) δ 200.5, 172.7, 161.9, 161.7, 122.3, 73.0, 72.8,
52.7, 42.2, 38.5, 35.6, 23.9, 18.8, 17.7. IR (neat, cm-1) 2976, 2931,
1725, 1677, 1456, 1369, 1280, 1143, 1063, 918, 845, 734. Anal. Calcd
for C20H30O5: C, 68.55; H, 8.63. Found: C, 68.54; H, 8.55.
(Table 4, Entry 2). General procedure A with 5 psig CO was used
to convert diethyl 1-phenyl-4-(2-cyclohexenyl)-but-1-yn-4,4-dicarboxy-
late (88 mg, 0.25 mmol) to the desired product in 12 h. Purification by
flash chromatography (hexane:ether, 7:3) afforded 96 mg (91% yield)
of a white solid, mp 141-143 °C: 1H NMR (300 MHz, CDCl3) δ
7.60 (d, J ) 7.2 Hz, 2 H); 7.36 (t, J ) 7.2 Hz, 2 H); 7.29 (t, J ) 7.2
Hz, 1 H); 4.22 (m, 4 H); 3.75 (dd, J ) 1.8 Hz, 21.3 Hz, 1 H); 3.75 (m,
2 H); 2.95 (m, 1 H); 2.85 (m, 1 H); 2.08 (m, 1 H); 1.64 (m, 1 H); 1.45
(m, 1 H); 1.25 (m, 7 H); 1.05 (m, 1 H); 0.66 (m, 1 H). 13C NMR (75
MHz, CDCl3) δ 201.7, 166.8, 162.6, 160.1, 123.6, 122.7, 119.6, 119.1,
119.0, 57.0, 53.1, 52.9, 38.6, 37.8, 32.4, 26.3, 16.2, 14.3, 13.9, 5.3,
5.2. IR (KBr, cm-1) 2948, 1734, 1697, 1446, 1239, 1184, 1145, 1062,
1036, 749, 693. Anal. Calcd for C23H26O5: C, 72.23; H, 6.85. Found:
C, 72.37; H, 7.10.
2-Butyl-8-((triisopropylsilyl)oxy)bicyclo[3.3.0]oct-1-en-3-one (Table
3, Entry 3). General procedure A with 0.05 mmol Cp2Ti(CO)2 was
used to convert 5-((triisopropylsilyl)oxy)-1-undecen-6-yne44 (162 mg,0.50
mmol) to the desired product in 16.5 h. Purification by flash chroma-
tography (hexane:ether, 95:5) afforded 167 mg (95% yield)
(Table 4, Entry 3). General procedure A with 5 psig CO was used
to convert diethyl 4-(2-cyclohexenyl)-pent-2-yn-4,4-dicarboxlate (73

5898 J. Am. Chem. Soc., Vol. 121, No. 25, 1999
Hicks et al.
mg, 0.25 mmol) to the desired product in 36 h. Purification by flash
chromatography (hexane:ether, 3:2) afforded 71 mg (88% yield) of a
white solid, mp 52-54 °C: 1H NMR (300 MHz, CDCl3) δ 4.17 (m, 4
H); 3.49 (d, J ) 20 Hz, 1 H); 3.20 (bs, 1 H); 2.97 (d, J ) 20 Hz,
1 H); 2.88 (m, 1 H); 2.67 (m, 1 H); 1.96 (m, 1 H); 1.66 (s, 3 H); 1.57
(m, 1 H); 1.38 (m, 1 H); 1.18 (m, 7 H); 0.89 (m, 1 H); 0.60 (m,1 H).
13C NMR (75 MHz, CDCl3) δ 204.3, 166.3, 162.7, 160.3, 121.4, 56.8,
52.9, 52.8, 38.2, 36.5, 32.9, 24.1, 16.4, 14.1, 14.0, 5.2, 5.1. IR (neat)
2938, 2858, 1732, 1668, 1447, 1366, 1254, 1151, 1039, 963, 857, 701.
Anal. Calcd for C18H24O5: C, 67.47; H, 7.55. Found: C, 67.29; H,
7.67.
mg, 0.25 mmol) to the desired product as a 4.2:1 mixture of isomers
in 48 h. Purification by flash chromatography (hexane:ethyl ether, 3:1)
afforded 50 mg (57% yield) of a colorless oil. The 1H NMR spectrum
confirmed the same major isomer as for entry 4.
(Table 4, Entry 4). General procedure A with 5 psig CO and 0.10
mmol Cp2Ti(CO)2 was used to convert diethyl 1-phenyl-6-octen-1-yn-
4,4-dicarboxylate (164 mg, 0.50 mmol) to the desired product as a 4:1
mixture of isomers in 12 h. Purification by flash chromatography
(hexane:ethyl ether, 3:1) afforded 120 mg (67% yield) of a colorless
oil. In one case, the two isomers were separated for characterization.
(Table 4, Entry 6). General procedure B with 5 psig CO was used
to convert diethyl cis-1-phenyl-6-octen-1-yn-4,4-dicarboxylate (82 mg,
0.25 mmol) to the desired product as a 1:1.6 mixture of isomers in 48
h. Purification by flash chromatography (hexane:ethyl ether, 3:1)
afforded 73 mg (82% yield) of a colorless oil. The 1H NMR spectrum
revealed the major isomer to be the opposite of that for entry 4.
1
Major isomer (trans) H NMR (300 MHz, CDCl3) δ 7.57 (d, J ) 7.0
Hz, 2 H); 7.41 (t, J ) 7.2 Hz, 2 H); 7.32 (t, J ) 7.3 Hz, 1 H); 4.29 (q,
J ) 6.5 Hz, 2 H); 4.18 (m, 2 H); 3.64 (d, J ) 19.6 Hz, 1 H); 3.29 (d,
J ) 20.0 Hz, 1 H); 2.87 (dd, J ) 7.5 Hz, J ) 12.1 Hz, 1 H); 2.76 (m,
1 H); 2.30 (qd, J ) 7.2 Hz, J ) 3.6 Hz, 1 H); 1.81 (t, J ) 12.1 Hz, 1
H); 1.32 (t, J ) 7.5 Hz, 3 H); 1.30 (d, J ) 7.5 Hz, 3 H); 1.23 (t, J )
7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3) δ 209.0, 176.2, 171.8, 170.9,
134.8, 131.4, 128.5 (2), 128.3, 62.3, 62.1, 61.7, 51.9, 50.0, 38.4, 36.1,
(Table 4, Entry 7). General procedure A with 5 psig CO was used
to convert cis-diethyl 7-nonen-2-yn-4,4-dicarboxylate (67 mg, 0.25
mmol) to the desired product as a 2:1 mixture of isomers in 48 h.
Purification by flash chromatography (hexane:ethyl ether, 9:1) afforded
44 mg (60% yield) of a colorless oil: 1H NMR (300 MHz, CDCl3)
mixture δ 4.23 (m, 2 H’s each); 3.20 (m, 3 H major, 2 H minor); 2.81
(dd, J ) 7.4 Hz, J ) 12.9 Hz, 1 H minor); 2.60 (m, 2 H major, 1 H
minor); 2.08 (m, 1 H minor); 1.80 (t, J ) 13.6 Hz, 1 H major); 1.70
(m, 1 H minor); 1.71 (s, 3 H each); 1.27 (m, 6 H major, 9 H minor);
1.04 (d, J ) 6.9 Hz, 3 H major). 13C NMR (75 MHz, CDCl3) mixture
δ 213.0, 176.8, 175.5, 171.8, 171.3, 132.2, 131.0, 62.2, 62.1, 61.2, 60.6,
51.8, 48.6, 47.1, 42.9, 38.8, 34.3, 34.1, 14.2, 14.1, 13.5, 8.7. IR (neat,
cm-1) 3027, 1777, 1685, 1494, 1448, 1275, 1232, 1193, 977, 915, 755,
700. Anal. Calcd for C16H22O5: C, 65.29; H, 7.53. Found: C, 65.03;
H, 7.56. The major isomer was assigned by comparison of spectroscopic
data to the products from Table 2, entry 4.
1
14.2, 14.1, 14.0. Minor isomer (cis) H NMR (300 MHz, CDCl3) δ
7.57 (d, J ) 7.0, 2 H); 7.41 (t, J ) 7.5 Hz, 2 H); 7.32 (d, J ) 7.5 Hz,
1 H); 4.28 (q, J ) 7.2 Hz, 2 H); 4.18 (q, J ) 7.2 Hz, 2 H); 3.68 (d, J
) 19.6 Hz, 1 H); 3.27 (d, J ) 19.7 Hz, 1 H); 3.22 (m, 1 H); 2.68 (m,
1 H); 2.58 (dd, J ) 7.7 Hz, J ) 12.4 Hz, 1 H); 1.31 (t, J ) 7.0 Hz, 3
H); 1.24 (t, J ) 7.2 Hz, 3 H); 1.16 (d, J ) 7.7 Hz, 3 H). 13C NMR (75
MHz, CDCl3) δ 210.8, 178.1, 171.8, 171.0, 133.5, 131.3, 128.6, 128.4,
128.3, 62.4, 62.3, 60.9, 47.3, 44.0, 36.2, 33.7, 14.3, 14.2, 13.7. IR (neat,
cm-1) 2981, 1732, 1650, 1446, 1367, 1269, 1230, 1179, 1065, 697.
Anal. Calcd for C21H24O5 (mixture of isomers): C, 70.77; H, 6.79.
Found: C, 70.77; H, 6.70. A nOe study was undertaken in C6D6 to
determine the relative configurations of the isomers observed. For the
isomer with the C-4 methyl cis to the ring junction hydrogen (major
isomer), irradiation of the C-5 H at δ 2.51 gave a 4% enhancement at
the C-4 methyl and a 3% enhancement at the C-4 H. For the isomer
with the C-4 methyl trans to the ring junction hydrogen (minor isomer),
irradiation of the C-5 H at δ 2.51 gave no enhancement at the C-4
methyl and a 16% enhancement at the C-4 H. Based on these
observations, the configurations of the two isomers were assigned as
shown.
Acknowledgment. We thank the National Institutes of
Health (GM 34917), Pfizer, Novartis, and Merck for their
support of this work. F.A.H. thanks the National Science
Foundation for a predoctoral fellowship. N.M.K. thanks Boe-
hringer Ingelheim Inc., the Division of Organic Chemistry of
the ACS, and Smith-Kline Beecham for fellowships. We also
acknowledge Dr. Minghui Zhang and Andrew Tseng for the
synthesis of several substrates.
(Table 4, Entry 5). General procedure B with 5 psig CO was used
to convert diethyl trans-1-phenyl-6-octen-1-yn-4,4-dicarboxylate (82
JA990682U