Titanocene-catalyzed cyclocarbonylation of o-allyl aryl ketones to γ- butyrolactones

Article abstract of DOI:10.1021/ja970115b

A method for the transformation of o-allyl aryl ketones to γ- butyrolactones using a catalytic amount of Cp₂Ti(PMe₃)₂ or Cp₂Ti(CO)₂ iS described. This catalytic 'hetero Pauson-Khand'-type process proc

Full text of DOI:10.1021/ja970115b

4424
J. Am. Chem. Soc. 1997, 119, 4424-4431
Titanocene-Catalyzed Cyclocarbonylation of o-Allyl Aryl
Ketones to γ-Butyrolactones
Natasha M. Kablaoui,† Frederick A. Hicks,‡ and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed January 15, 1997X
Abstract: A method for the transformation of o-allyl aryl ketones to γ-butyrolactones using a catalytic amount of
Cp2Ti(PMe3)2 or Cp2Ti(CO)2 is described. This catalytic “hetero Pauson-Khand”-type process proceeds Via the
carbonylation of an oxatitanacycle followed by thermally-induced reductive elimination to form a γ-butyrolactone
and to regenerate the catalyst. We have investigated the scope and limitations of this catalytic methodology. Our
results are consistent with the view that the key step in this catalytic cycle is formation of a charge transfer complex
or involves reversible electron transfer between the catalyst and the substrate.
Introduction and Background
Scheme 1
The growing interest in the development of organic reactions
mediated and catalyzed by organotransition metals stems from
the ability to assemble complex molecules from simple starting
materials1 in a convergent and atom-economical manner.2 One
reaction that exemplifies this concept is the Pauson-Khand
reaction, in which an alkyne, an alkene, and carbon monoxide
are condensed in a formal [2 + 2 + 1] cycloaddition to form
cyclopentenones using Co2(CO)8 (Scheme 1a).3 Recently we
reported a heteroatom variant of the intramolecular Pauson-
Khand reaction mediated by Cp2Ti(PMe3)2 in which either the
alkyne or the alkene can be replaced by a carbonyl.4 This new
reaction results in the diastereoselective formation of γ-buty-
rolactones or fused butenolides, respectively (Scheme 1b,c). In
that report, we showed that the “hetero Pauson-Khand” reaction
is mediated by Cp2Ti(PMe3)2 for most enones and enals studied,
but acetophenone derivatives can be transformed using a
catalytic amount of the titanium complex. We have studied
the catalytic cyclocarbonylation of enones in more detail and
have found that a variety of olefinic aryl ketones are viable
substrates for the catalytic reaction.
we6,7 and Crowe8 have developed a catalytic reductive cycliza-
tion of enones to cyclopentanols which combines oxametalla-
cycle formation with a σ-bond metathesis reaction (Scheme 2).
In this process, we postulate that the Ti-O bond of the
intermediate oxametallacycle 1 is cleaved Via a σ-bond me-
tathesis reaction9 with Ph2SiH2 to form a titanocene alkyl
hydride, 2. The hydride then undergoes ligand-induced reduc-
tive elimination10 to regenerate the titanocene catalyst and to
form the silylated cyclopentanol, 3, which can be hydrolyzed
to the desired cyclopentanol. We subsequently became inter-
ested in processes which utilize the reactivity of the Ti-C bond
in the oxatitanacycle 1. We decided to begin our investigation
by studying the formation and decomposition of 1 in the
presence of carbon monoxide. We chose CO since insertion
to form 4 (Scheme 3) followed by reductive elimination would
yield a γ-butyrolactone 5.
Our work on the reductive cyclization of enones using
titanocene reagents was inspired by the report of Hewlett and
Whitby that Cp2Ti(PMe3)2 can react with enones to form
bicyclic oxametallacycles 1 (see Scheme 2).5 Subsequently,
† Fellow of the Organic Chemistry Division of the American Chemical
Society, sponsored by Smith-Kline Beecham.
‡ National Science Foundation Predoctoral Fellow, 1994-1997.
X Abstract published in AdVance ACS Abstracts, April 15, 1997.
(1) For lead references, see: (a) Broene, R. D.; Buchwald, S. L. Science
1993, 261, 1696. (b) Broene, R. D. In ComprehensiVe Organometallic
Chemistry II; Hegedus, L. S., Ed.; Pergamon: Oxford, 1995; Vol.12, Chapter
3.7, p 323. (c) Buchwald, S. L.; Broene, R. D. In ComprehensiVe
Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon: Oxford, 1995;
Vol.12, Chapter 7.4, p 771 and references within.
In related all-carbon metallacycles, insertion of CO and
isonitriles into the Ti-C bonds is a facile process; there are
many examples of enyne cyclocarbonylation using early transi-
tion metals.11-13 Studies conducted by Caulton14 on the
carbonylation (at 1 atm) of the related Cp2Zr(Me)X system
(2) Trost, B. M. Science 1991, 254, 1471.
(3) Schore, N. E. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon: Kidlington, 1995; Vol. 12, p 703 and
references within. For catalytic examples, see: (a) Jeong, N.; Hwang, S.
H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc. 1994, 116, 3159. (b) Lee, B.
Y.; Chung, Y. K.; Jeong, N.; Lee, Y.; Hwang, S. H. J. Am. Chem. Soc.
1994, 116, 8793. (c) Pagenkopf, B. L.; Livinghouse, T. J. J. Am. Chem.
Soc. 1996, 118, 2285.
(4) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 5818.
(5) Hewlett, D. F.; Whitby, R. J. J. Chem. Soc., Chem. Comm. 1990,
1684.
(6) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117,
6785.
(7) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182.
(8) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787.
(9) Berk, S. C.; Kreutzer, K. A.; Buchwald, S. L. J. Am. Chem. Soc.
1991, 113, 5093.
(10) Gell, K. I.; Schwartz, J. J. Am. Chem. Soc. 1981, 103, 2687.
(11) Grossman, R. B.; Buchwald, S. L. J. Org. Chem. 1992, 57, 5803.
(12) Negishi, E.-i. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Ed.; Pergamon: Oxford, 1991; Vol. 5, pp 1163-1184.
S0002-7863(97)00115-7 CCC: $14.00 © 1997 American Chemical Society

Transformation of o-Allyl Aryl Ketones to γ-Butyrolactones
J. Am. Chem. Soc., Vol. 119, No. 19, 1997 4425
Scheme 2
Scheme 3
Scheme 4
Table 1. The Stoichiometric Cyclocarbonylation of Enones and an
Ynone4
showed that insertion of CO into the Zr-C bond was heavily
dependent on the nature of the ligand X. Facility of carbon-
ylation was found to decrease in the series: Me > Cl > OEt,
with no carbonylation observed for Cp2Zr(Me)OEt. These
results were deemed to reflect the ability of the lone pairs on
the alkoxide and chloride to π-donate into the vacant metal
orbital, rendering the complex coordinatively saturated (18 e-)
and thus hindering the carbonylation reaction. This study
suggested that the carbonylation of early transition metal
oxametallacycles would be difficult. Takaya,15 however, showed
that carbonylation did occur in the more electron-rich, and hence
less oxophilic, Cp*2Ti oxametallacycle systems, 6 (Scheme 4).
The CO inserted into the Ti-C bond to form carbonylated
metallacycles, 7, but these metallacycles did not undergo
thermally-induced reductive elimination to form γ-butyrolac-
tones; instead they decomposed at elevated temperatures (210
°C).
We4 and Crowe16 have found that carbonylation of the
titanacycle 1 also occurs, with CO inserting into the Ti-C bond
to form carbonylated metallacycle 4 (Scheme 3). We have
confirmed the intermediacy of this metallacycle for R ) H by
X-ray crystallography. In our system, reductive elimination is
induced thermally (70 °C) to form γ-butyrolactone 5 and Cp2-
Ti(CO)2. Table 1 shows the reaction conditions and several
examples of enones cyclocarbonylated using this methodology.
A striking feature of the “hetero Pauson-Khand” reaction is
that γ-butyrolactones are formed with complete diastereoselec-
tivity. In contrast, both the catalytic reductive cyclization of
enones to form cyclopentanols6-8 and Crowe’s similar γ-bu-
tyrolactone synthesis,16 which proceed through the same inter-
mediate metallacycle, 1, suffer from poor diastereoselectivities
in many cases. This discrepancy can be explained by noting
that both the catalytic reductive cyclization and Crowe’s
cyclocarbonylation reaction are run at low temperature (-20
°C and room temperature, respectively); the selectivities ob-
served are therefore realized under conditions of kinetic
control.17 Since the present reaction takes place at 70 °C,
complete equilibration to the more thermodynamically stable
metallacycle leads to the formation of a single isomer of the
γ-butyrolactone.
Results and Discussion
The “hetero Pauson-Khand” reaction is the first completely
diastereoselective synthesis of γ-butyrolactones from the con-
densation of an alkene, a carbonyl moiety, and CO. In a single
process, two carbon-carbon bonds and two rings are con-
structed. A drawback to the method is the necessity of using a
stoichiometric amount of the metal to carry out the reaction. A
catalytic variant of this procedure would be a significant
improvement. This not only would decrease the amount of
waste produced by reaction but also would make the potential
use of expensive chiral catalysts more feasible.
In order to develop a catalytic reaction sequence, the metal
coproduct of the initial cyclization, Cp2Ti(CO)2, must be induced
to react again with the starting material. The metal is in the
same oxidation state as the original titanocene reagent, Cp2Ti-
(PMe3)2, and the titanocene fragment remains intact. However,
due to backbonding, CO forms much stronger bonds with the
titanium center than does PMe3, and therefore Cp2Ti(CO)2 does
not react with most enones to form oxametallacycles, 1, under
thermal conditions. Titanocene dicarbonyl18 has previously been
shown to react with ketenes,19 acetylenes,20,21 and CO2 equiva-
(13) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cedarbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336.
(14) Marsella, J. A.; Moloy, K. G.; Caulton, K. G. J. Organomet. Chem.
1980, 201, 389.
(15) Mashima, K.; Haraguchi, H.; Oyoshi, A.; Sakai, N.; Takaya, H.
Organometallics 1991, 10, 2731.
(16) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557.
(17) The metallacycles in many cases are formed initially as kinetic
mixtures of diastereomers which then equilibrate to the thermodynamically
favored product. Equilibration is slow at lower temperatures. (See ref 7)
(18) For a review on the reactivity of Cp2Ti(CO)2, see: Sikora, D. J;
Macomber, D. W.; Rausch, M. D. AdV. Organometallic Chem. 1986, 25,
317.
(19) Fachinetti, G.; Biran, C.; Floriani, C.; Chiesi-Villa, A.; Guastini,
C. J. Am. Chem. Soc. 1978, 100, 1921.

4426 J. Am. Chem. Soc., Vol. 119, No. 19, 1997
Kablaoui et al.
Scheme 5
Scheme 7
Cp2Ti(PMe3)2 as the catalyst and is run at 18 psig CO for 12-
18 h. The addition of excess PMe3 was found to decrease the
amount of catalyst necessary for complete conversion to the
product.24 The second catalyst system (B) uses the com-
25
mercially available Cp2Ti(CO)2 as the catalyst and is run at
only 5 psig CO. In this system, excess PMe3 is also required.26
We believe that the excess PMe3 may be necessary to produce
Cp2Ti(PMe3)(CO),27 which may act as a more efficient catalyst
than titanocene dicarbonyl, due to the lability of the PMe3 ligand
and/or for electronic reasons. Cp2Ti(PMe3)(CO) has been
shown to form when Cp2Ti(PMe3)2 is heated under CO pressure
or when Cp2Ti(CO)2 is heated in the presence of PMe3.
Trimethylphosphine may also play a role in facilitating the
ligand-induced reductive elimination10 of the organic fragment
from intermediate 9. We are currently investigating the
mechanism of this process to enhance our understanding of these
observations.
Scheme 6
While most of the substrates are cyclocarbonylated efficiently
using either catalyst system, substrates that contain structural
attributes that make them more difficult to cyclize are trans-
formed more efficiently using Cp2Ti(CO)2 as a catalyst. We
believe that such substrates can participate in destructive side
reactions with Cp2Ti(PMe3)2 due to the higher reactivity (lability
of the PMe3 ligands) of the complex compared to Cp2Ti(CO)2;
the titanocene is thus destroyed before it can enter into the
catalytic cycle.28 For example, in entry 9, the ketone and the
olefin are not held in proximity by a rigid backbone as in the
o-allyl arylketone cases, so formation of metallacycle 8 is
difficult. The substrate in entry 9 is successfully cyclized using
Cp2Ti(CO)2, while Cp2Ti(PMe3)2 is an ineffective catalyst.
The use of Cp2Ti(CO)2 in stoichiometric quantities has
allowed us to expand the scope of this hetero Pauson-Khand-
type methodology to another problematic enone substrate.
Acetophenone derivative 11 does not form any metallacycle
upon reaction with Cp2Ti(PMe3)2. The cyclization of other 1,7-
enones with Cp2Ti(PMe3)2 to form six-membered rings has been
attempted by us6,7 and others5,8 with no success. However, 11
reacts with 0.5 equiv of Cp2Ti(CO)2 under the conditions shown
to form the 6,6,5-tricyclic γ-butyrolactone, 12 (Scheme 8).
While this substrate is not transformed to the lactone catalyti-
cally, it is the first example of the cyclization of an enone to
form a six-membered ring using a titanocene reagent.
lents.22 More recently it was reported that Cp2Ti(CO)2 also
reacts with R,â-unsaturated aryl ketones.23 This encouraged us
to try to find a class of enone substrates that would also react
with titanocene dicarbonyl, opening the way to the development
of a catalytic process.
We have found that conjugated aromatic ketones with a
suitably positioned olefin can be converted to γ-butyrolactones
using a catalytic amount of the metal complex. In general, the
substrates feature a keto moiety and an allyl group situated in
an ortho-relationship on an aromatic ring. For example, in our
initial communication we reported that o-allylacetophenone can
be converted to the corresponding lactone in excellent yield
using 10 mol % Cp2Ti(PMe3)2.4 The proposed catalytic cycle
is shown in Scheme 5. As mentioned above, the key to
rendering the cyclocarbonylation catalytic is the ability of
o-allylacetophenone to react with the Cp2Ti(CO)2 (or possibly
the mixed ligand catalyst Cp2Ti(CO)(PMe3), Vide infra) co-
product to form oxametallacycle 8. In support of the viability
of this step in the catalytic cycle, we have found that o-
allylacetophenone reacts directly with Cp2Ti(CO)2 to form the
γ-butyrolactone upon heating under an atmosphere of argon
(Scheme 6).
Table 2 shows the results of the catalytic conversion of o-allyl
aryl ketones to γ-butyrolactones under the conditions shown in
Scheme 7. Catalyst levels range from 5% to 20% depending
on the nature of the substrate (Vide infra). This methodology
tolerates various functional groups such as aryl fluorides (entry
3), ethers (entry 5), and esters (entry 6). We have shown that
catalytic activity is not limited to o-allylacetophenone deriva-
tives, since allylacetonaphthones (entries 7 and 8) and allyl-
benzophenones (entry 4) are also viable substrates.
Catalytic Activity. We believe that olefinic aryl ketone
derivatives can be converted to γ-butyrolactones catalytically
because of their ability to displace the CO ligands on Cp2Ti-
(24) For o-allylacetophenone, 7.5 mol % Cp2Ti(PMe3)2, at 18 psig CO,
24 h: with PMe3: 100% conversion, without PMe3: 65% conversion.
(25) Titanocene dicarbonyl is available from Strem or is easily pre-
pared: Sikora, D. J.; Moriarty, K. J.; Rausch, M. D. In Inorganic Synthesis;
Angelici, R. J., Ed.; John Wiley and Sons, Inc.: New York, 1990; Vol. 28,
p 248.
(26) For o-allylacetophenone, 5 mol % Cp2Ti(CO)2, at 5 psig CO, 24 h:
with PMe3: 85% conversion, without PMe3: 50% conversion.
(27) Edwards, B. H.; Rogers, R. D.; Sikora, D. J.; Atwood, J. L.; Rausch,
M. D. J. Am. Chem. Soc. 1983, 105, 416.
Scheme 7 shows the two catalyst systems that have been
developed for this transformation. The original system (A) uses
(20) Fachinetti, G.; Floriani, C.; Marchetti, F.; Mellini, M. J. Chem. Soc.,
Dalton Trans. 1978, 1398.
(21) He, X.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 1696.
(22) Pasquali, M.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. J. Am. Chem.
Soc. 1979, 101, 4740.
(28) For example, under some conditions, ketones have been found to
react with the cyclopentadienyl rings of Cp2Ti(PMe3)2 to form fulvenes
with concommitant destruction of the titanocene framework: Gleiter, R.;
Wittwer, W. Chem. Ber. 1994, 127, 1797.
(23) Schobert, R.; Maaref, F.; Durr, S. Synlet 1995, 83.

Transformation of o-Allyl Aryl Ketones to γ-Butyrolactones
Table 2. Results of the Catalytic “Hetero Pauson-Khand” Reaction
J. Am. Chem. Soc., Vol. 119, No. 19, 1997 4427
a System A: Cp2Ti(PMe3)2, 18 psig CO, PMe3, toluene, 12-18 h. System B: Cp2Ti(CO)2, 5 psig CO, PMe3, toluene, 36-48 h. b Yields (an
average of 2 or more runs) refer to isolated compound of >95% purity as assessed by 1H NMR, GC, and elemental analysis. c Isolated as a 14:1
mixture of isomers.
Scheme 8
tion by the enone substrate.31 In pathway “a”, a formal electron
transfer is proposed, resulting in the ketyl radical of the
acetophenone and a titanium cation as the tight ion pair, 13.
The formation of the Ti(III) alkoxide complex, 14, can either
proceed Via a pentacoordinate Ti-alkoxide complex followed
by loss of CO (pathway “c”) or by dissociation of the CO
followed by alkoxide formation (pathway “d”). Collapse of the
diradical 14 leads to the Ti(IV)-ketone complex, 15. The
alkene replaces the remaining carbonyl ligand and then cycliza-
tion leads to metallacycle 8. In pathway “b”, a charge transfer
complex is formed in which no formal change in oxidation state
(CO)2 to form a metallacycle either by transient electron transfer
(Scheme 9, pathway “a”) or by forming a charge transfer
complex (Scheme 9, pathway “b”).29 Both of these possible
pathways rely on acetophenone acting as an electron acceptor30
for the titanium center; the shift in electron density away from
the titanium reduces the backbonding interactions with the
carbonyl ligands, labilizing them towards dissociative substitu-
(30) For some examples of aromatic ketones acting as electron acceptors
in charge transfer reactions, see: (a) Ashby, E. C.; Goel, A. B.; Argy-
ropoulos, J. N. Tetrahedron Lett. 1982, 23, 2273. (b) Ashby, E. C.;
Argyropoulos, J. N. J. Org. Chem. 1986, 51, 472. (c) Fukuzumi, S.;
Okamoto, T. J. Am. Chem. Soc. 1994, 116, 1994. (d) Abe, M.; Oku, A. J.
Org. Chem. 1995, 60, 3065.
(31) For a review on electron transfer induced substitution reactions on
metal carbonyl complexes, see: Albers, M. O.; Coville, N. J. Coord. Chem.
ReV. 1984, 53, 227.
(29) (a) Eberson, L. Electron Transfer Reactions in Organic Chemistry;
Springer Verlag: New York; 1987. (b) Eberson, L. New J. Chem. 1992,
16, 151. (c) Kochi, J. K. Angew. Chem., Int. Ed. Engl. 1988, 27, 1227. (d)
Ashby, E. C. Acc. Chem. Res. 1988, 21, 414.

4428 J. Am. Chem. Soc., Vol. 119, No. 19, 1997
Kablaoui et al.
Scheme 9
occurs, but a shifting of electron density within the complex32
away from the titanium center causes the labilization of the first
carbonyl ligand and the subsequent formation of metallacycle
8.
reaction to include nonaryl ketone-containing substrates through
the use of electron transfer catalysts. In addition, more detailed
mechanistic and kinetic studies are underway.
Experimental Section
While our mechanistic hypothesis has not yet been rigorously
tested, the proposed mechanism is consistent with the results
shown in Table 2. An electron donating group para to the
carbonyl on the acetophenone moiety would be expected to
diminish the electron-accepting ability of the substrate; indeed,
p-methoxy-o-allylacetophenone (Table 2, entry 5) can only be
transformed to a low yield of the lactone using 20 mol %
catalyst. Conversely, an electron withdrawing group para to
the carbonyl on the acetophenone moiety would be expected to
facilitate electron transfer; p-tert-butylcarboxyl-o-allylacetophe-
none (Table 2, entry 6) is converted to the lactone with 7.5
mol % catalyst in excellent yield. Based on the reduction
potential of benzophenone,33 it would be expected to be a better
electron acceptor than acetophenone; indeed, it was found that
o-allylbenzophenone (entry 4) can be converted to the corre-
sponding lactone using 5 mol % catalyst in 97% isolated yield.
In the related intramolecular McMurry-type reactions34 of oxo
amides to indoles using low valent titanium catalysts,35,36
Fu¨rstner has provided evidence for an aryl titanaoxacyclopro-
pane species similar to 15 as an intermediate in the process.36
In accord with our preliminary results, they have found that
there is a correlation between the electronic properties of the
aryl ketone and the rate of the reaction; diaryl ketones react
significantly faster than arylalkyl ketones. We have noticed
similar trends in our work and are currently carrying out kinetic
studies to quantify our results.
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,
and CH2Cl2 was distilled under nitrogen from CaH2. Pyridine was
distilled under argon from CaH2. Bis(trimethylphosphine)titanocene,
Cp2Ti(PMe3)2, was prepared from titanocene dichloride (obtained from
Boulder Scientific, Boulder, CO) by the procedure of Binger et. al.37
and was stored in a glovebox under argon. Titanocene dicarbonyl is
commercially available from Strem Chemicals and is also readily
synthesized from titanocene dichloride.38 o-Allylacetophenone was
prepared by a Stille coupling of allyltributyltin and o-bromoacetophe-
none.39 o-Iodoacetophenone was synthesized by a modified Sandmeyer
procedure.40 2-Bromo-4-tert-butylcarboxylacetophenone was synthe-
sized according to the procedure described by Wakselman.41 The enone
1,3-diphenyl-5-hexen-1-one was synthesized by allylation of trans-
chalcone with allyltrimethylsilane and TiCl4.42 2-Iodobenzophenone
is commercially available from Trans World Chemicals. All other
reagents were available from commercial sources and were used without
further purification, unless otherwise noted.
Flash chromatography was performed on E. M. Science Kieselgel
60 (230-400 mesh) unless otherwise noted. Yields refer to isolated
yields of compounds of greater than 95% purity as estimated by
capillary GC and 1H NMR analysis, and, in the cases of unknown
compounds, elemental analysis. Yields indicated in this section refer
to a single experiment, while those reported in the tables are an average
of two or more runs, so the numbers may differ slightly. All compounds
were characterized by 1H NMR, 13C NMR, and IR spectroscopies.
Previously unreported compounds were also characterized by elemental
analysis (E & R Analytical Laboratory, Inc.). Nuclear magnetic
Conclusion
In summary, we have developed the first catalytic method
for the formation of γ-butyrolactones from enones containing
an arylketone moiety using Cp2Ti(PMe3)2 or Cp2Ti(CO)2. We
are currently working to extend the scope of this catalytic
(37) Binger, P.; Mu¨ller, P.; Benn, R.; Rufinska, A.; Gabor, B.; Kru¨ger,
C.; Betz, P. Chem. Ber. 1989, 122, 1035-1042.
(38) Sikora, D. J.; Moriarty, K. J.; Rausch, M. C. In Inorganic Synthesis;
Angelici, R. J., Ed.; John Wiley and Sons, Inc.: New York, 1990; Vol. 28,
p 248.
(39) Yasuo, F.; Suzuki, Y.; Tanaka, Y.; Tominaga, T.; Takeda, H.;
Sekine, H.; Morito, N.; Miyaoca, Y. Heterocycles 1977, 6, 1604.
(40) Heaney, H.; Millar, I. T. Organic Synthesis; Wiley & Sons: New
York, 1990; Vol. V, p 1120.
(41) Joyeau, R.; Yadav, L. D. S.; Wakselman, M. J. Chem. Soc., Perkin
Trans. I 1987, 1899.
(32) (a) Kaim, W. Acc. Chem. Res. 1985, 18, 160. (b) Kochi, J. K.
Organometallic Mechanisms and Catalysis; Academic Press: New York,
1978.
(33) Asano, T.; Ohkata, K.; Hanafusa, T. Chem. Lett. 1974, 10, 1149.
(34) Fu¨rstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996,
35, 2442.
(35) Fu¨rstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991.
(36) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem.
1994, 59, 5215.
(42) Sakurai, H.; Hosomi, A.; Hayashi, J. Organic Synthesis; Wiley &
Sons: New York, 1990; Vol. VII, pp 443.

Transformation of o-Allyl Aryl Ketones to γ-Butyrolactones
J. Am. Chem. Soc., Vol. 119, No. 19, 1997 4429
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; d, doublet; dd, doublet of doublets; t, triplet; q,
quartet; qd, quartet of doublets; m, multiplet. All 1H NMR spectra are
reported in δ units, parts per million (ppm) downfield from tetra-
methylsilane. All 13C NMR spectra are reported in ppm relative to
deuterochloroform. Infrared (IR) spectra were recorded on a Perkin-
Elmer 1600 Series Fourier transform spectrometer. Gas chromatog-
raphy (GC) analysis were performed on a Hewlett-Packard 5890 gas
chromatograph with a 3392A integrator and FID detector using a 25
m capillary column with cross-linked SE-30 as a stationary phase.
temperature. The solvent was removed in Vacuo, and the residue was
dissolved in diethyl ether (10 mL), washed with 10% aqueous KF
solution (10 mL), and then dried over MgSO4. The solvent was
removed in Vacuo, and the crude product was purified by flash
chromatography (hexane:diethyl ether ) 46:1) to afford 0.9 g (75%
yield) of a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.80 (d, J ) 7.3
Hz, 2 H); 7.59 (t, J ) 7.2 Hz, 1 H); 7.45 (m, 3 H); 7.30 (m, 3 H); 5.88
(m, 1 H); 4.96 (m, 2 H); 3.45 (d, J ) 6.5 Hz, 2 H). 13C NMR (75
MHz, CDCl3): δ 198.1, 139.2, 139.1, 138.8, 138.0, 137.1, 133.4, 130.6,
130.4, 128.9, 128.6, 125.9, 116.4, 37.7. IR (neat): 3062, 1666, 1597,
1448, 1315, 1269, 925, 703, 638 cm-1
.
2′-Allyl-4′-methoxyacetophenone (Table 2, Entry 5). Using the
general procedure, 2′-hydroxy-4′-methoxyacetophenone (2.5 g, 15
mmol) and triflic anhydride (2.8 mL, 17 mmol) were converted to the
desired product. Flash chromatography (hexane:diethyl ether ) 3:2)
afforded 2.1 g (47% yield) of a colorless oil. The triflate (1.5 g, 5.0
mmol) was reacted with allyltributyltin (1.87 mL, 6.0 mmol), Pd2dba3
(0.092 g, 0.1 mmol), P(2-furyl)3 (0.19 g, 0.8 mmol), LiCl (0.64 g, 15
mmol), and THF (10 mL). The crude product was purified by flash
chromatography (hexane:diethyl ether ) 4:1) to afford 0.6 g (63% yield)
of a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.73 (d, J ) 8.2 Hz, 1
H); 6.77 (m, 2 H); 5.98 (m, 1 H); 5.02 (m, 2 H); 3.85 (s, 3 H); 3.72 (d,
J ) 6.5 Hz, 2 H); 2.54 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ
199.7, 162.2, 143.7, 137.5, 132.6, 130.0, 116.9, 115.8, 110.9, 55.4,
38.8, 29.3. IR (neat): 2974, 1675, 1602, 1567, 1354, 1250, 1134, 1031
cm-1. Anal. Calcd for C12H14O2: C, 75.76; H, 7.42 Found: C, 75.67;
H, 7.32.
2′-Allyl-4′-tert-butylcarboxylacetophenone (Table 2, Entry 6).
Using Stille coupling conditions,39 2′-bromo-4′-tert-butylcarboxylac-
etophenone41 (1.6 g, 5.4 mmol), allyltributyltin (1.83 mL, 6 mmol),
and tetrakis(triphenylphosphine)palladium (0.31 g, 0.3 mmol) were
combined in a dry sealable Schlenk flask with benzene (3 mL). The
reaction was heated to 100 °C for 12 h, and then the solvent was
removed in Vacuo. The crude reaction mixture was diluted with diethyl
ether (25 mL), washed with H2O (25 mL) and 10% aqueous KF
solution, and dried over MgSO4. The crude product was purified by
flash chromatography (hexane:diethyl ether ) 9:1) to afford 0.91 g
(65% yield) of a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.88 (m,
2 H); 7.62 (d, J ) 8.4 Hz, 1 H); 5.97 (m, 1 H); 5.04 (m, 2 H); 3.65 (d,
J ) 6.4 Hz, 2 H); 2.57 (s, 3 H); 1.60 (s, 9 H). 13C NMR (125 MHz,
CDCl3): δ 202.2, 165.0, 141.9, 139.4, 137.0, 134.3, 132.1, 128.4, 127.3,
116.4, 81.7, 37.8, 30.2, 28.3. IR (neat): 2978, 1717, 1702, 1394, 1368,
1356, 1301, 1254, 1166, 1117, 771 cm-1. Anal. Calcd for C16H20O3:
C, 73.82; H, 7.74. Found: C, 73.86; H, 7.57.
Preparation of the Enone Starting Materials: General Procedure
for the Conversion of 2′-Hydroxyacetophenones into 2′-Allylac-
etophenones. In a dry Schlenk flask, the 2′-hydroxyacetophenone and
pyridine (20-30 mL) were combined under argon and cooled to 0 °C.
Triflic anhydride was added slowly, and the reaction mixture was
allowed to slowly warm to room temperature overnight. The mixture
was diluted with diethyl ether (50 mL) and washed with 1 N aqueous
HCl solution (2 × 50 mL) followed by brine (50 mL). The organic
layer was dried over MgSO4, and the solvent was removed in Vacuo.
The crude product was purified by flash chromatography and im-
mediately used in the next step. Using an adaptation of Farina’s
procedure,43 the triflate, 1.1 equiv allytributyltin, 0.02 equiv Pd2dba3,
0.16 equiv P(2-furyl)3, 3 equiv LiCl (anhydrous), and THF were
combined in a dry Schlenk flask fitted with a reflux condenser and
heated to 85 °C for 18 h. The crude reaction mixture was diluted with
diethyl ether (50 mL), shaken vigorously with saturated aqueous KF
solution (25 mL) for 5 min, then washed with brine, and dried over
MgSO4. Purification by flash chromatography yielded the desired
allylacetophenone.
2′-Allyl-5′-methylacetophenone (Table 2, Entry 2). Using the
general procedure, 2′-hydroxy-5′-methylacetophenone (2.3 g, 15 mmol)
and triflic anhydride (2.8 mL, 17 mmol) were converted to the desired
product. Purification by flash chromatography (hexane:diethyl ether
) 3: 2) afforded 2.5 g (57% yield) of a clear oil. The triflate (2.45 g,
8.7 mmol) was reacted with allyltributyltin (3.23 mL, 10.4 mmol),
Pd2dba3 (0.16 g, 0.2 mmol), P(2-furyl)3 (0.32 g, 1.4 mmol), LiCl (1.1
g, 26 mmol), and THF (20 mL). The crude product was purified by
flash chromatography (hexane:diethyl ether ) 9:1) to afford 1.2 g (79%
yield) of a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.44 (s, 1 H);
7.23 (m, 1 H); 7.16 (d, J ) 7.9 Hz, 1 H); 5.96 (m, 1 H); 4.99 (m, 2 H);
3.60 (d, J ) 6.4 Hz, 2 H); 2.56 (s, 3 H); 2.37 (s, 3 H). 13C NMR (125
MHz, CDCl3): δ 202.3, 138.2, 137.8, 136.7, 135.8, 132.3, 131.3, 129.7,
115.5, 37.7, 29.9, 21.1. IR (neat): 2977, 2921, 1686, 1355, 1267, 1205,
1182, 914, 829 cm-1. Anal. Calcd for C12H14O: C, 82.72; H, 8.10.
Found: C, 82.62; H, 8.01.
1′-Allyl-2′-acetylnaphthalene (Table 2, Entry 7). Using the general
procedure, 1′-hydroxy-2′-acetylnaphthalene (2.8 g, 15 mmol) and triflic
anhydride (2.8 mL, 16.5 mmol) were converted to the desired product.
Flash chromatography (hexane:diethyl ether ) 3:1) followed by
Kugelrohr distillation afforded 1.3 g (27% yield) of a colorless oil.
The triflate (1.27 g, 4 mmol) was reacted with allyltributyltin (1.49
mL, 4.8 mmol), Pd2dba3 (45 m g, 0.05 mmol), P(2-furyl)3 (0.096 g,
0.4 mmol), LiCl (0.51 g, 12 mmol), and THF (5 mL). The crude
product was purified by flash chromatography (hexane:diethyl ether
) 19:1) to afford 0.48 g (57% yield) of a clear oil. 1H NMR (300
MHz, CDCl3): δ 8.16 (m, 1 H); 7.85 (m, 1 H); 7.80 (d, J ) 8.5 Hz,
1 H); 7.53 (m, 3 H); 6.09 (m, 1 H); 5.04 (dd, J ) 1.8 Hz, J ) 24.8 Hz,
1 H); 5.00 (dd, J ) 1.6 Hz, J ) 31.6 Hz, 1 H); 4.02 (dt, J ) 5.9 Hz,
J ) 1.6 Hz, 2 H); 2.65 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 204.1,
137.3, 137.2, 135.0, 134.6, 132.5, 128.7, 127.2, 127.1, 126.9, 125.8,
124.2, 116.1, 33.0, 31.1. IR (neat): 3005, 1692, 1468, 1352, 1269,
2′-Allyl-5′-fluoroacetophenone (Table 2, Entry 3). Using the
general procedure, 2′-hydroxy-5′-fluoroacetophenone (3.1 g, 20 mmol)
and triflic anhydride (4.1 mL, 24 mmol) were converted to the desired
product. Kugelrohr distillation followed by recrystallization from
CH2Cl2 and hexane afforded 3.9 g (68% yield) of white crystalline
material. The triflate (2.8 g, 9.8 mmol) was reacted with allyltributyltin
(3.42 mL, 11 mmol), Pd2dba3 (0.179 g, 0.2 mmol), P(2-furyl)3 (0.36 g,
1.5 mmol), LiCl (1.2 g, 28 mmol), and THF (10 mL). The crude
product was purified by flash chromatography (hexane:diethyl ether
) 19: 1) to afford 0.87 g (50% yield) of a clear oil. 1H NMR (300
MHz, CDCl3): δ 7.31 (dd, J ) 9.1 Hz, J ) 2.7 Hz, 1 H); 7.27 (m, 1
H); 7.12 (td, J ) 8.2 Hz, J ) 2.7 Hz, 1 H); 5.95 (m, 1 H); 4.99 (m, 2
H); 3.60 (d, J ) 6.4 Hz, 2 H); 2.55 (s, 3 H). 13C NMR (125 MHz,
CDCl3): δ 201.0, 161.0 (JF ) 245 Hz), 139.6 (JF ) 5.5 Hz), 137.4,
135.4 (JF ) 3.1 Hz), 133.0 (JF ) 7.3 Hz), 118.5 (JF ) 21 Hz), 116.1,
115.8 (JF ) 22 Hz), 37.3, 30.0. IR (neat): 3079, 1694, 1488, 1357,
1262, 1191, 911, 871 cm-1. Anal. Calcd for C11H11FO: C, 74.14; H,
6.22. Found: C, 74.18; H, 6.25.
1235, 814 cm-1
. Anal. Calcd for C15H14O: C, 85.68; H, 6.71.
Found: C, 85.80; H, 6.54.
2′-Allyl-1′-acetylnaphthalene (Table 2, Entry 8). Using the general
procedure, 2′-hydroxy-1′-acetylnaphthalene (2.8 g, 15 mmol) and triflic
anhydride (2.8 mL, 16.5 mmol) were converted to the desired product.
Flash chromatography (hexane:diethyl ether ) 3:1) followed by
Kugelrohr distillation afforded 3.8 g (80% yield) of a yellow solid.
The triflate (1.27 g, 4 mmol) was reacted with allyltributyltin (1.49
mL, 4.8 mmol), Pd2dba3 (45 m g, 0.05 mmol), P(2-furyl)3 (0.096 g,
0.4 mmol), LiCl (0.51 g, 12 mmol), and THF (5 mL). The crude
product was purified by flash chromatography (hexane:diethyl ether
) 19:1) to afford 0.5 g (59% yield) of a clear oil. 1H NMR (300 MHz,
2-Allylbenzophenone (Table 2, Entry 4).39,44 In a dry resealable
Schlenk flask, 2-iodobenzophenone (1.0 mL, 5.4 mmol), allyltributyltin
(1.85 mL, 5.9 mmol), palladium tetrakis(triphenylphosphine) (63 mg,
0.054 mmol), and benzene (1 mL) were combined. The reaction
mixture was heated to 100 °C for 24 h and then cooled to room
(43) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(44) Rosenfeldt, F.; Erker, G. Tetrahedron Lett. 1980, 21, 1637.

4430 J. Am. Chem. Soc., Vol. 119, No. 19, 1997
Kablaoui et al.
CDCl3): δ 7.82 (m, 2 H); 7.60 (m, 1 H); 7.49 (m, 2 H); 7.35 (d, J )
8.5 Hz, 1 H); 5.98 (m, 1 H); 5.08 (m, 2 H); 3.47 (dt, J ) 6.4 Hz, J )
1.6 Hz, 2 H); 2.64 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 208.0,
139.0, 136.6, 132.1, 131.9, 129.1, 129.0, 128.4, 127.8, 127.0, 125.9,
124.2, 116.7, 37.6, 33.5. IR (neat): 3056, 1698, 1508, 1417, 1351,
1244, 1203, 918, 819, 756 cm-1. Anal. Calcd for C15H14O: C, 85.68;
H, 6.71. Found: C, 85.58; H, 6.53.
The reaction was heated to 100 °C for 36-48 h. After cooling the
reaction mixture to room temperature, the CO was cautiously released
in the hood. The crude reaction mixture was filtered through a plug
of silica gel with the aid of diethyl ether and purified by flash
chromatography.
cis-2,3,4,6a-Tetrahydro-6a-methyl-2H-indanyl[b]furan-2-one (Table
2, Entry 1). Using catalyst system A, Cp2Ti(PMe3)2 (12 mg, 7.5 mol
%) and PMe3 (16 µL, 30 mol %) were used to convert o-allylacetophe-
none (80 mg, 0.50 mmol) to the desired product. Purification by flash
chromatography (hexane:diethyl ether ) 1:1) yielded 86 mg (91% yield)
of a clear colorless oil. Using catalyst system B, Cp2Ti(CO)2 (9 mg,
7.5 mol %) and PMe3 (16 µL, 30 mol %) were used to convert
o-allylacetophenone (80 mg, 0.50 mmol) to 90 mg (96% yield) of the
desired product. 1H NMR (300 MHz, CDCl3): δ 7.42 (m, 1 H); 7.28
(m, 3 H); 3.31 (dd, J ) 7.1 Hz, J ) 16.5 Hz, 1 H); 2.95 (m, 2 H); 2.83
2′-(3-cyclopentene)acetophenone (Table 2, Entry 10). Using the
procedure of Larock,45 2-iodoacetophenone (3.05 g, 12.3 mmol),
cyclopentene (5.4 mL, 61 mmol), palladium acetate (0.139 g, 0.62
mmol), triphenylphosphine (0.162 g, 0.62 mmol), (nBu)4NCl (anhy-
drous, 3.32 g, 12.3 mmol), KOAc (3.63 g, 37 mmol), and DMF (30
mL) were combined in a dry Schlenk flask fitted with a reflux condenser
and heated to 100 °C for 17 h. The reaction mixture was diluted with
water and extracted with diethyl ether (3 × 20 mL). The combined
organic layers were washed with brine (30 mL) and dried over MgSO4.
The solvent was removed in Vacuo, and the crude material was purified
by flash chromatography (hexane:diethyl ether ) 19:1) to afford 0.58
g (25% yield) of a colorless oil, which was a 9:1 mixture of the desired
product to the isomeric 2′-(4-cyclopentene)acetophenone. 1H NMR
(300 MHz, CDCl3): δ 7.56 (d, J ) 7.7 Hz, 1 H); 7.39 (m, 1 H); 7.31
(d, J ) 6.8 Hz, 1 H); 7.26 (m, 1 H); 5.97 (m, 1 H); 5.81 (m, 1 H); 4.39
(m, 1 H); 2.60 (s, 3 H); 2.56 (m, 2 H); 2.45 (m, 2 H). 13C NMR (75
MHz, CDCl3): δ 203.2, 146.0, 134.3, 132.7, 131.6, 130.0, 128.4, 128.3,
125.9, 47.7, 34.4, 32.6, 30.6. IR (neat): 2849, 1686, 1443, 1356, 1264,
1241, 760, 741, 600 cm-1. Anal. Calcd for C13H14O: C, 83.83; H,
7.58. Found: C, 84.01; H, 7.72.
(dd, J ) 2.0 Hz, J ) 16.45 Hz, 1 H); 2.40 (m, 1 H); 1.74 (s, 3 H). 13
C
NMR (75 MHz, CDCl3): δ 176.1, 142.5, 141.1, 129.6, 127.6, 125.3,
124.2, 95.4, 44.2, 36.9, 36.6, 25.0. IR (neat): 2929, 1766, 1442, 1379,
1206, 1066, 954, 768 cm-1. Anal. Calcd for C12H12O2: C, 76.57; H,
6.43. Found: C, 76.36; H, 6.54.
cis-2,3,4,6a-Tetrahydro-6a-methyl-4′-methyl-2H-indanyl[b]furan-
2-one (Table 2, Entry 2). Using catalyst system A, Cp2Ti(PMe3)2
(16 mg, 10 mol %) was used to convert 2′-allyl-5′-methylacetophenone
(87 mg, 0.50 mmol) to the desired product. Purification by flash
chromatography (hexane: ethyl ether ) 1:1) yielded 90 mg (89% yield)
of a white solid. Using catalyst system B, Cp2Ti(CO)2 (9 mg, 7.5 mol
%) and PMe3 (16 µL, 30 mol %) were used to convert 2′-allyl-5′-
methylacetophenone (87 mg, 0.50 mmol) to 87 mg (87% yield) of the
desired product. 1H NMR (300 MHz, CDCl3): δ 7.23 (s, 1 H); 7.13
(m, 2 H); 3.25 (dd, J ) 7 Hz, J ) 16.5 Hz; 1 H); 2.95 (m, 2 H); 2.77
(dd, J ) 2.4 Hz, J ) 16.5 Hz, 1 H); 2.38 (m, 1 H); 2.36 (s, 3 H), 1.72
(s, 3 H). 13C NMR (75 MHz, CDCl3): δ 167.3, 133.7, 129.1, 128.6,
121.7, 116.2, 115.8, 86.5, 35.6, 27.8, 27.6, 16.1, 12.4. IR (KBr): 2918,
2847, 1751, 1493, 1310, 1242, 1208, 1147, 1069, 936, 858, 810. Mp
) 82-84 °C. Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found:
C, 77.20; H, 7.18.
cis-2,3,4,6a-Tetrahydro-6a-methyl-4′-Fluoro-2H-indanyl[b]furan-
2-one (Table 2, Entry 3). Cp2Ti(PMe3)2 (16 mg, 10 mol %) and PMe3
(20 µL, 40 mol %) were used to convert 5-fluoro-o-allylacetophenone
(89 mg, 0.5 mmol) to the desired product. Purification by flash
chromatography (hexane:diethyl ether ) 1:1) afforded 82 mg (80%
yield) of a clear oil. 1H NMR (300 MHz, CDCl3): δ 7.19 (m, 1 H);
7.08 (m, 3 H); 3.27 (dd, J ) 6.8 Hz, J ) 15.6 Hz, 1 H); 2.95 (m, 2 H);
2.79 (d, J ) 16.5 Hz, 1 H); 2.41 (m, 1 H); 1.72 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ 176.0, 162.8 (JF ) 244 Hz), 144.7 (JF ) 8 Hz),
136.5, 126.8 (JF ) 8 Hz), 117.2 (JF ) 23 Hz), 111.2 (JF ) 22 Hz),
95.0, 45.0, 36.7, 36.4, 25.1. IR (neat): 2972, 1769, 1599, 1487, 1307,
1257, 1202, 1187, 925, 817 cm-1. Anal. Calcd for C12H11FO2: C,
69.89; H, 5.38. Found: C, 69.73; H, 5.25.
cis-2,3,4,6a-Tetrahydro-6a-phenyl-2H-indanyl[b]furan-2-one (Table
2, Entry 4). Cp2Ti(PMe3)2 (9 mg, 5 mol %) and PMe3 (11 µL, 20
mol %) were used to convert o-allylbenzophenone (116 mg, 0.52 mmol)
to the desired product. Purification by flash chromatography (hexane:
diethyl ether ) 1:1) afforded 110 mg (97% yield) of a clear oil. 1H
NMR (300 MHz, CDCl3): δ 7.30 (m, 8 H); 7.17 (d, J ) 7.7 Hz, 1 H);
3.47 (dd, J ) 8.1 Hz, J ) 16.5 Hz, 1 H); 3.25 (m, 1 H); 2.95 (m, 2 H);
2.51 (dd, J ) 5.2 Hz, J ) 18.1 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): δ 176.3, 142.8, 142.7, 143.3, 130.0, 128.7 (2), 128.1, 126.3,
125.3, 125.2, 98.5, 47.5, 37.7, 36.6. IR (neat): 3028, 1769, 1448, 1231,
1189, 1146, 1001, 976, 754, 700 cm-1. Anal. Calcd for C17H14O2:
C, 81.58; H, 5.64. Found: C, 81.73; H, 5.80.
cis-2,3,4,6a-Tetrahydro-6a-methyl-3′-methoxy-2H-indanyl[b]fu-
ran-2-one (Table 2, Entry 5). Using catalyst system A, Cp2Ti(PMe3)2
(33 mg, 20 mol %) and PMe3 (33 µL, 60 mol %) were used to convert
4′-methoxy-6′-allylacetophenone (95 mg, 0.50 mmol) to the desired
product. Purification by flash chromatography (hexane: ethyl ether
) 1:1) yielded 80 mg (74% yield) of a white solid. 1H NMR (300
MHz, CDCl3): δ 7.31 (d, J ) 8.4 Hz, 1 H); 6.83 (dd, J ) 8.5 Hz, J
) 2.4 Hz, 1 H); 6.74 (d, J ) 2.3 Hz, 1 H); 3.80 (s, 3 H); 3.27 (dd, J
) 7.5 Hz, J ) 16.6 Hz, 1 H); 2.95 (m, 2 H); 2.78 (dd, J ) 3.3 Hz, J
) 16.5 Hz, 1 H); 2.43 (m, 1 H); 1.71 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 176.0, 161.6, 143.4, 135.2, 125.3, 114.4, 110.2, 95.2, 55.7,
O-Allyl-2′-hydroxyacetophenone.46 In a dry Schlenk flask under
argon, sodium carbonate (2.12 g, 20 mmol), THF (20 mL), DMF (20
mL), and then 2′-hydroxyacetophenone (2.41 mL, 20 mmol) were
combined. Allyl bromide (2.60 mL, 30 mmol) was added, and the
reaction mixture was heated to reflux for 20 h. After cooling to room
temperature, the reaction mixture was diluted with diethyl ether (50
mL) and water (50 mL) and then extracted with diethyl ether (2 × 30
mL). The combined organic layers were then washed with saturated
CuSO4 solution (3 × 20 mL), 1 N aqueous NaOH solution (2 × 30
mL), and brine and dried over MgSO4, and the solvent was then
removed in Vacuo. The crude material was purified by flash chroma-
tography (hexane:diethyl ether ) 6:1) to afford 1.4 g (40% yield) of a
colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.74 (dd, J ) 1.2 Hz,
J ) 7.6 Hz, 1 H); 7.44 (t, J ) 6.6 Hz, 1 H); 6.97 (m, 2 H); 6.10 (m,
1 H); 5.39 (m, 2 H); 4.65 (d, J ) 5.3 Hz, 2 H); 2.65 (s, 3 H). 13C
NMR (75 MHz, CDCl3): δ 200.1, 158.1, 133.7, 132.8, 130.6, 128.8,
120.9, 118.4, 112.9, 69.6, 32.2. IR (neat): 1674, 1597, 1483, 1450,
1424, 1358, 1294, 1238, 758 cm-1
.
General Procedure for the Conversion of Enones to γ-Butyro-
lactones. Catalyst System A. In an argon-filled glovebox, a dry
sealable Schlenk flask was charged with the enone, Cp2Ti(PMe3)2,
PMe3, and toluene (2 mL). [Note: the enone was run through a plug
of activated alumina in the glovebox and stored under argon. On
particularly humid days, the alumina had to be dried under vacuum at
180 °C overnight prior to use to effectively dry the substrate.] The
flask was removed from the glovebox, attached to a Schlenk line under
Ar, evacuated, and backfilled with 18 psig CO. Caution: Appropriate
precautions should be taken when performing reactions under elevated
CO pressure. The reaction was heated to 100 °C for 12-18 h. After
cooling the reaction mixture to room temperature, the CO was
cautiously released in the hood. The crude reaction mixture was filtered
through a plug of silica gel with the aid of diethyl ether and purified
by flash chromatography.
Catalyst System B. In an argon-filled glovebox, a dry sealable
Schlenk flask was charged with the enone, Cp2Ti(CO)2, PMe3, and
toluene (2 mL). [Note: the enone was run through a plug of activated
alumina in the glovebox and stored under argon. On particularly humid
days, the alumina had to be dried under vacuum at 180 °C overnight
prior to use to effectively dry the substrate.] The flask was removed
from the glovebox, attached to a Schlenk line under Ar, evacuated,
and backfilled with 5 psig CO. Caution: Appropriate precautions
should be taken when performing reactions under elevated CO pressure.
(45) Larock, R. C.; Gong, W. H.; Baker, B. E. Tetrahedron Lett. 1989,
30, 2603.
(46) Woulfe, S. R.; Miller, M. J. J. Org. Chem. 1986, 51, 3133.

Transformation of o-Allyl Aryl Ketones to γ-Butyrolactones
J. Am. Chem. Soc., Vol. 119, No. 19, 1997 4431
44.9, 37.4, 36.9, 25.3. IR (KBr): 1750, 1503, 1305, 1243, 1138, 1064,
913, 837 Mp ) 73-75 °C. Anal. Calcd for C13H14O3: C, 71.54; H,
6.47. Found: C, 71.63; H, 6.63.
white solid. 1H NMR (300 MHz, CDCl3): δ 7.35 (m, 10 H); 3.53 (m,
1 H); 2.97 (m, 1 H); 2.4-2.8 (m, 5 H); 1.83 (q, J ) 12.4 Hz, 1 H). 13
C
NMR (75 MHz, CDCl3): δ 176.4, 143.9, 142.2, 128.7, 128.7, 127.7,
126.9, 126.8, 123.9, 96.2, 49.6, 48.5, 46.0, 41.3, 34.1. IR (KBr): 3026,
2966, 1775, 1600, 1452, 1179, 970, 699 cm-1. Mp ) 89-91 °C. Anal.
Calcd for C19H18O2: C, 81.99; H, 6.52. Found: C, 81.80; H, 6.39.
cis-2,3,4,6a-Tetrahydro-6a-methyl-3′-tert-butylcarboxylate-2H-in-
danyl[b]furan-2-one (Table 2, Entry 6). Using catalyst system A,
Cp2Ti(PMe3)2 (10 mg, 7.5 mol %) and PMe3 (12 µL, 30 mol %) were
used to convert 4′-tert-butylcarboxylate-6′-allylacetophenone (130 mg,
0.50 mmol) to the desired product. Purification by flash chromatog-
raphy (hexane: ethyl ether ) 1:1) yielded 136 mg (93% yield) of a
white solid. 1H NMR (300 MHz, CDCl3): δ 7.93 (d, J ) 8.0 Hz, 1
H); 7.87 (s, 1 H); 7.45 (d, J ) 8.0 Hz, 1 H); 3.33 (dd, J ) 7.5 Hz, J
) 16.5 Hz, 1 H); 2.97 (m, 2 H); 2.87 (d, J ) 16.8 Hz, 1 H); 2.39 (m,
1 H); 1.73 (s, 3 H); 1.59 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ
175.5, 165.5, 147.0, 141.3, 134.1, 129.4, 126.8, 124.3, 94.7, 81.5, 44.8,
36.9, 36.7, 28.4, 25.2. IR (KBr): 2971, 1758, 1708, 1458, 1417, 1335,
1298, 1169, 1095, 955, 772 cm-1. Mp ) 95-97 °C. Anal. Calcd
for C17H20O4: C, 70.81; H, 6.99. Found: C, 71.02; H, 7.21.
cis-2,3,4,6a-Tetrahydro-6a-methyl-1′,2′-benzo-2H-indanyl[b]fu-
ran-2-one (Table 2, Entry 7). Using catalyst system A, Cp2Ti(PMe3)2
(16 mg, 10 mol %) and PMe3 (20 µL, 40 mol %) were used to convert
1′-allyl-2′-acetyl-napthalene (100 mg, 0.48 mmol) to the desired product.
Purification by flash chromatography (hexane:ethyl ether ) 1:1) yielded
97 mg (87% yield) of a pale yellow solid. 1H NMR (300 MHz,
CDCl3): δ 7.91 (m, 1 H); 7.82 (m, 2 H); 7.54 (m, 3 H); 3.62 (dd, J )
7.5 Hz, J ) 17.0 Hz, 1 H); 3.19 (m, 2 H); 3.10 (m, 1 H); 2.50 (dd, J
) 4.9 Hz, J ) 17.1 Hz, 1 H); 1.82 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 176.3, 139.6, 137.6, 134.,3, 130.3, 128.9, 128.8, 126.8,
126.7, 124.6, 121.5, 96.5, 44.1, 37.3, 35.8, 25.4. IR (KBr): 2968, 1760,
1296, 1229, 1141, 1065, 916, 811, 756 cm-1 Mp ) 131 - 134 °C.
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C, 80.89; H,
6.13.
cis-2,3,4,6a-Tetrahydro-6a-methyl-3′,4′-benzo-2H-indanyl[b]fu-
ran-2-one (Table 2, Entry 8). Using catalyst system A, Cp2Ti(PMe3)2
(12 mg, 7.5 mol %) and PMe3 (15 µL, 30 mol %) were used to convert
1′-acetyl-2′-allyl-napthalene (100 mg, 0.48 mmol) to the desired product.
Purification by flash chromatography (hexane:ethyl ether ) 1:1) yielded
103 mg (92% yield) of a white solid. Using catalyst system B,
Cp2Ti(CO)2 (6 mg, 7.5 mol %) and PMe3 (11 µL, 30 mol %) were
used to convert 1′-acetyl-2′-allylnaphthalene (75 mg, 0.36 mmol) to
78 mg (93% yield) of the desired product. 1H NMR (300 MHz,
CDCl3): δ 8.26 (d, J ) 8.4 Hz, 1 H); 7.85 (dd, J ) 8.0 Hz, J ) 17.0
Hz, 2 H); 7.52 (m, 2 H); 7.34 (d, J ) 8.4 Hz, 1 H); 3.39 (dd, J ) 6.7
Hz, J ) 16.5 Hz, 1 H); 3.01 (m, 3 H); 2.37 (dd, J ) 7.5 Hz, J ) 16.3
Hz, 1 H); 1.94 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 176.4, 137.8,
137.2, 133.8, 130.8, 129.6, 128.9, 127.1, 125.9, 124.3, 123.5, 97.1,
45.7, 37.1, 36.5, 25.6. IR (KBr): 1766, 1412, 1250, 1211, 1093, 955,
938, 812, 752 cm-1. Mp ) 103-106 °C. Anal. Calcd for C16H14O2:
C, 80.65; H, 5.92. Found: C, 80.78; H, 6.04.
Table 2, Entry 10. Using catalyst system A, Cp2Ti(PMe3)2 (8 mg,
10 mol %) and PMe3 (10 µL, 40 mol %) were used to convert 2′-(3-
cyclopentene) acetophenone (47 mg, 0.25 mmol) to the desired product.
The starting enone was contaminated with approximately 9% of the
isomeric 2′-(4-cyclopentene) acetophenone, which was carried through
the reaction and recovered unchanged. Purification by flash chroma-
tography (hexane:diethyl ether ) 3:2) yielded 44 mg (82% yield) of a
colorless oil. Using catalyst system B, Cp2Ti(CO)2 (6 mg, 5 mol %)
and PMe3 (10 µL, 20 mol %) were used to convert 2′-(3-cyclopentene)-
acetophenone (93 mg, 0.5 mmol) to 88 mg (82% yield) of the desired
product. 1H NMR (300 MHz, CDCl3): δ 7.35 (m, 3 H); 7.22 (d, J )
6.5 Hz, 1 H); 3.81 (dd, J ) 7.4 Hz, J ) 13.1 Hz, 1 H); 3.37 (t, J ) 9.7
Hz, 1 H); 3.25 (m, 1 H); 2.13 (m, 2 H); 1.89 (m, 1 H); 1.78 (s, 3 H);
1.74 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ 179.5, 145.9, 143.5,
130.2, 128.0, 124.8, 124.3, 93.5, 56.1, 50.0, 47.1, 35.0, 32.1, 26.4. IR
(neat): 2965, 1758, 1223, 1145, 1129, 1064, 761 cm-1. Anal. Calcd
for C14H14O2: C, 78.48; H, 6.59. Found: C, 78.51; H, 6.62.
Compound 12. Using general procedure B, Cp2Ti(CO)2 (59 mg,
0.25 mmol) and PMe3 (52 µL, 1 equiv) were used to convert o-allyl-
2′-hydroxyacetophenone (88 mg, 0.5 mmol) to the desired product.
Purification by flash chromatography (hexane:diethyl ether ) 3:2)
yielded 44 mg (43% yield) of the a pale yellow oil. 1H NMR (300
MHz, CDCl3): δ 7.45 (dd, J ) 1.6 Hz, J ) 7.8 Hz, 1 H); 7.22 (td, J
) 1.6 Hz, J ) 6.7 Hz, 1 H); 7.02 (dd, J ) 1.1 Hz, J ) 8.0 Hz, 1 H);
6.87 (dd, J ) 1.1 Hz, J ) 8.3 Hz, 1 H); 4.19 (m, 1 H); 4.10 (dd, J )
10.4 Hz, J ) 2.6 Hz, 1 H); 2.71 (m, 3 H); 1.82 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ 175.1, 153.4, 130.2, 129.0, 124.0, 122.5, 117.4, 81.2,
64.3, 41.3, 31.1, 28.5. IR (neat): 2977, 1770, 1488, 1306, 1230, 1129,
944, 762 cm-1
. Anal. Calcd for C12H12O3: C, 70.58; H, 5.92.
Found: C, 70.49; H, 5.99.
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. We thank Boulder
Scientific for a gift of Cp2TiCl2. 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. We acknowledge the
helpful comments of a referee who suggested an alternate
explanation for the role of trimethylphosphine in this reaction.
cis-Hexahydro-6a-phenyl-5-endo-phenyl-2H-cyclopenta[b]furan-
2-one (Table 2, Entry 9). Using catalyst system B, Cp2Ti(CO)2 (23
mg, 20 mol %) and PMe3 (51 µL, 1 equiv) were used to convert 1,3-
diphenyl-5-hexen-2-one (0.125 g, 0.5 mmol) to the desired product.
Purification by flash chromatography (hexane:diethyl ether ) 9:1)
yielded 120 mg (86% yield) of a 14:1 mixture of diastereomers of a
JA970115B