Diastereoselective synthesis of γ-butryrolactones from enones mediated or catalyzed by a titanocene complex

Full text of DOI:10.1021/ja960953q

5818
J. Am. Chem. Soc. 1996, 118, 5818-5819
Scheme 1
Diastereoselective Synthesis of γ-Butyrolactones
from Enones Mediated or Catalyzed by a
Titanocene Complex
Natasha M. Kablaoui,† Frederick A. Hicks,‡ and
Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed March 25, 1996
The Pauson-Khand reaction is a powerful transformation that
is widely used by organic chemists for the synthesis of
cyclopentenones.1 It involves the formal [2 + 2 + 1] addition
of an alkyne, an alkene, and a CO (see Scheme 1a) mediated
or catalyzed by cobalt complexes and is an excellent example
of atom economy in organic synthesis.2 Herein we report a
heteroatom variant of the intramolecular Pauson-Khand reac-
tion mediated by Cp2Ti(PMe3)2 in which either the alkyne or,
as demonstrated in one case, the alkene can be replaced with a
carbonyl for the diastereoselective synthesis of γ-butyrolactones
or a fused butenolide, respectively (Scheme 1b,c). We have
also found that in some cases, this transformation can be
accomplished using a catalytic amount of titanium complex.
We note that while this work was in progress, a similar method
for the synthesis of γ-butyrolactones using a stoichiometric
amount of Cp2Ti(PMe3)2 was reported.3
Scheme 2
°C), resulting in the formation of lactone 3 and Cp2Ti(CO)2. It
should be noted that reductive elimination also occurs when
metallacycle 2 is exposed to air, but the reaction is not as clean,
resulting in significantly lower yields.3
Table 1 shows the results of the hetero Pauson-Khand
reaction. The substrates shown are transformed in good to
excellent yields and with complete diastereoselectivity to the
corresponding γ-butyrolactones. As shown in Scheme 3, two
stoichiometric protocols have been developed. The transforma-
We4,5 and others6 have recently reported a catalytic reductive
cyclization of enones and enals to cyclopentanols using
Cp2Ti(PMe3)2 (Scheme 2, pathway ''a''). In this reaction, the
Ti-O bond of the intermediate oxatitanacycle 1 is cleaved via
σ-bond metathesis with a silane.7 The resulting titanocene alkyl
hydride 4 undergoes ligand-induced reductive elimination8 to
form silylated cyclopentanols 5 and to regenerate the catalyst.
This work represents the first catalytic reductive cyclization of
unsaturated heteroatom-containing fragments. We have been
interested in further developing this reaction sequence to yield
more highly functionalized products by taking advantage of the
potential reactivity of the Ti-C bond in metallacycle 1.
Although insertion into the Ti-C bond in titanium alkoxides is
not as facile as in all-carbon titanium species due to the
interaction of the oxygen lone pairs with the titanium,9 prior
work from our laboratory10 and others3,11 has demonstrated that
the insertion of CO into this type of bond is feasible. Indeed
we have found that, upon treatment of metallacycle 1 with CO,
carbonylated metallacycle 2 is formed (Scheme 2, pathway ''b'').
We have confirmed the structure of this intermediate by X-ray
crystallography. Reductive elimination is induced thermally (70
12
tion can be affected using either Cp2Ti(PMe3)2 or, as shown
in a few cases, a method in which the titanocene reagent is
generated in situ from the air- and moisture-stable Cp2TiCl2,
PMe3 and n-BuLi (Table 1, entries 2, 3, and 10).5,13,14
The hetero Pauson-Khand cyclization of the ynone (Table
1, entry 8) is of particular interest, since the insertion of CO
into the hindered Ti-C(sp2) bond has not been demonstrated
in previous studies. For this substrate, slightly higher pressures
(20 psig) and temperatures (85 °C) are used. Under these
conditions, reductive elimination does not occur thermally;
instead, reductive elimination is induced by exposure to air
during chromatography.
In the hetero Pauson-Khand reaction reported here, the
γ-butyrolactones are formed with complete diastereoselectivity.
This is in contrast to the results obtained in our previous work
on the catalytic reductive cyclization of enones to cyclopen-
tanols4,5 and to the recent report by Crowe.3 For example,
cyclopentanols derived from substrates with substituents â to
the carbonyl (Table 1, entry 3) give at best a 6:1 ratio of product
cyclopentanols, and reactions of substrates with heteroatoms in
the backbone (Table 1, entry 6) are essentially nonselective (see
Scheme 4). This marked difference in diastereoselectivity can
be explained by comparing the conditions under which these
two reactions are run. The catalytic reductive cyclization
† Fellow of the Organic Chemistry Division of the American Chemical
Society, sponsored by Smith-Kline Beecham.
‡ National Science Foundation Predoctoral Fellow, 1994-1997.
(1) Schore, N. E. in ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon: Kidlington, 1995; Vol. 12, pp 703 and
references therein. For catalytic examples, see: Jeong, N.; Hwang, S. H.;
Lee, Y.; Chung, Y. K. J. Am. Chem. Soc. 1994, 116, 3159. Lee, B. Y.;
Chung, Y. K.; Jeong, N.; Lee, Y.; Hwang, S. H. J. Am. Chem. Soc. 1994,
116, 8793. Pagenkopf, B. L.; Livinghouse, T. J. J. Am. Chem. Soc. 1996,
118, 2285.
(2) Trost, B. M. Science 1991, 254, 1471.
(12) Representative procedure: A dry sealable Schlenk tube is charged
with 0.5 mmol of substrate, 0.55 mmol of Cp2Ti(PMe3)2, and 2 mL of
toluene in an argon-filled glovebox. The reaction flask is removed from
the glovebox, evacuated and backfilled with 15 psig CO, and heated to 70
°C for 15-18 h. After cooling to room temperature, the crude reaction
mixture is filtered through a plug of silica gel and rinsed through with diethyl
ether, and the resulting mixture is purified by flash chromatography.
(13) Hicks, F. A.; Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1996, 61,
2713.
(3) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557.
(4) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117,
6785.
(5) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182.
(6) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787.
(7) Berk, S. C.; Kreutzer, K. A.; Buchwald, S. L. J. Am. Chem. Soc.
1991, 113, 5093.
(8) Gell, K. I.; Schwartz, J. J. Am. Chem. Soc. 1981, 103, 2687.
(9) Marsella, J. A.; Moloy, K. G.; Caulton, K. G. J. Organomet. Chem.
1980, 201, 389.
(10) Lum, R. T.; Buchwald, S. L. Unpublished results.
(11) Mashima, K.; Haraguchi, H.; Ohyoshi, A.; Sakai, N.; Takaya, H.
Organometallics 1991, 10, 2731.
(14) The in situ titanocene generation is an important practical result as
Cp2Ti(PMe3)2 is pyrophoric, extremely air- and moisture-sensitive, and must
be stored and handled in a glove box under argon. The yields from the in
situ protocol are slightly lower than with the preformed Cp2Ti(PMe3)2 but
are still good to excellent (80-98%). See supporting information for
experimental details.
S0002-7863(96)00953-5 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 24, 1996 5819
Table 1. Titanocene-Mediated Hetero Pauson-Khand Reaction
Table 2. Catalytic Conversion of Acetophenone Derivatives to
γ-Butyrolactones
reaction occurs at the Ti-C bond of the intermediate metalla-
cycle, this substrate is smoothly converted to the corresponding
γ-butyrolactone.
The reductive cyclization of enones reported earlier is
catalytic due to the ability of the metal byproduct, Cp Ti(PMe3)(1
or 2), to react with the enone starting material 2 to reform
metallacycle 1. In general, the enone starting materials in Table
1 do not react with the byproduct of the hetero Pauson-Khand
reaction, Cp2Ti(CO)2, under the conditions of the reaction.
However, we have found that acetophenone derivatives with
the phenyl fused to the backbone of the enone (Table 2) can be
converted to their corresponding γ-butyrolactones in excellent
yield using 10 mol % of Cp2Ti(PMe3)2. Table 2 shows the
preliminary results from this discovery, which suggest that the
acetophenone derivatives are able to induce displacement of the
CO ligands from the relatively unreactive Cp2Ti(CO)2 complex
to form metallacycle 1. This complex has previously been
shown to react with phenylacetylenes,16 ketenes,17 and CO2
equivalents;18 the ready reaction with enones was somewhat
unexpected. We believe that acetophenone-containing substrates
can activate the Cp2Ti(CO)2 by transient electron transfer or
by forming a charge transfer complex. We are currently
investigating the use of additives and electron transfer catalysts19
to activate Cp2Ti(CO)2 to extend the substrate scope of this new
catalytic process. We note that the phenyl ketone substrate
(Table 1, entry 9) does not transform catalytically, but the
stoichiometric reaction of this substrate with Cp2Ti(CO)2 results
in a 25% higher yield than that obtained using Cp2Ti(PMe3)2.
In conclusion, we have developed a diastereoselective and
high-yielding synthesis of γ-butyrolactones from enones either
mediated by Cp2Ti(PMe3)2 or using Cp2Ti(PMe3)2 as a pre-
catalyst. We have also described the first example of the
formation of a fused butenolide from an ynone using the same
metal reagent. We are currently investigating the development
of a general catalytic protocol and a catalytic, asymmetric
version of this transformation.
Scheme 3
Scheme 4
Acknowledgment. We thank the National Institutes of Health (GM
34917) for their generous support of this work. N.M.K. is a National
Cancer Institute Predoctoral Trainee supported by NIH Cancer Training
Grant CI T32CAO9112. Additional support from Pfizer and from the
Dow Chemical Company is also gratefully acknowledged. N.M.K.
thanks the American Chemical Society Organic Division, Smith-Kline
Beecham, and Boehringer Ingelheim Inc. for additional support in the
form of predoctoral fellowships. F.A.H. thanks the National Science
Foundation for a predoctoral fellowship.
(pathway ''a'') is run at low temperature (-20 °C), so the
selectivities are under kinetic control. These conditions prevent
the metallacycle from equilibrating to the thermodynamically
favored isomer. However, the hetero Pauson-Khand reaction
(pathway ''b'') is run at 70 °C, allowing complete conversion to
a single isomer of metallacycle 1.15
We note that the phenyl ketone (Table 1, entry 9) is not a
viable substrate for our previously reported catalytic reductive
cyclization reaction, presumably due to the large phenyl group
blocking the silane from reaction with the Ti-O bond of
metallacycle 1. Since insertion in the hetero Pauson-Khand
Supporting Information Available: Complete experimental pro-
cedures as well as analytical and spectroscopic data for all new
compounds and spectroscopic data for known organic products (8
pages). Ordering information is given on any current masthead page.
JA960953Q
(16) Fachinetti, G.; Floriani, C.; Marchetti, F.; Mellini, M. J. Chem. Soc.,
Dalton Trans. 1978, 1398.
(17) Fachinetti, G.; Biran, C.; Floriani, C.; Chiesi-Villa, A.; Guastini,
C. J. Am. Chem. Soc. 1978, 100, 1921.
(18) Pasquali, M.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem.
Soc. 1979, 101, 4740.
(15) We note that if the reaction is run at room temperature, the
diasteroselectivities suffer.3
(19) Albers, M. O.; Coville, N. J. Coord. Chem. ReV. 1984, 53, 227.
Connelly, N. G.; Geiger, W. E. Chem. ReV. 1996, 96, 877.