Low-valent titanium-mediated cyclopropanation of vinylogous esters

Article abstract of DOI:10.1021/ol0493047

(Equation Presented) Inter- and intramolecular titanium-mediated cyclopropanation reactions of vinylogous esters are reported. Comparison between the Kulinkovich cyclopropanation of esters and vinylogous esters provides mechanistic insight regarding reaction variables such as reaction temperature, solvents, and a Lewis acid additive.

Full text of DOI:10.1021/ol0493047

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2365-2368
Low-Valent Titanium-Mediated
Cyclopropanation of Vinylogous Esters
Nikolai Masalov, Wei Feng, and Jin Kun Cha*
Department of Chemistry, Wayne State UniVersity, 5101 Cass AVe.,
Detroit, Michigan 48202
jcha@chem.wayne.edu
Received April 15, 2004
ABSTRACT
Inter- and intramolecular titanium-mediated cyclopropanation reactions of vinylogous esters are reported. Comparison between the Kulinkovich
cyclopropanation of esters and vinylogous esters provides mechanistic insight regarding reaction variables such as reaction temperature,
solvents, and a Lewis acid additive.
Cyclopropanes have long spurred a spate of synthetic and
mechanistic studies due to their unique reactivity.1 In 1989,
Kulinkovich and co-workers developed an efficient cyclo-
propanation of esters by convenient generation of low-valent
titanium species.2,3 The Kulinkovich reaction has also been
applied to other carboxylic acid derivatives to provide ready
access to heteroatom-substituted cyclopropanes.4-6 These
cyclopropanation reactions build on the presumed interme-
diacy of the key dialkoxytitanacyclopropane or titanium(II)-
alkene complex that is generated in situ from a Grignard
reagent (Scheme 1).7-9 We herein report cyclopropanation
of vinylogous esters, along with comparison with that of
carboxylic esters.
Slow addition of n-butylmagnesium bromide (excess; as
a ∼1.5 M solution in ether) to a solution of 3-methoxy-2-
cyclohexen-1-one (1) and Ti(O-i-Pr)4 (1.1 equiv) in ether at
room temperature cleanly gave cyclopropane 3a as a ∼2:1
diastereomeric mixture in 60-66% yield (entry 2 in Scheme
2). The reaction mixture was treated with water (or D2O),
followed by mild aqueous acid, to ensure complete hydrolysis
of the enol ether functionality (e.g., 2) to the corresponding
ketone (e.g., 3) so as to avoid complications due to partial
conversion during silica gel column chromatography.10 When
the reaction was carried out at 0 °C, a mixture of 3a (34%)
and 4a (25%) was obtained (entry 3). The product ratio was
also dependent on solvents: a mixture of 3a (15-20%) and
4a (35-40%) was isolated in THF (entry 4). When THF
(1) (a) de Meijere, A. Chem. ReV. 2003, 103, 931 and accompanying
reviews. (b) Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597.
(2) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pri-
tytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Kulinkovich, O. G.;
Sviridov, S. V.; Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh.
Org. Khim. 1991, 27, 294. (c) Kulinkovich, O. G.; Sorokin, V. L.; Kel’in,
A. V. Zh. Org. Khim. 1993, 29, 66. (d) Kulinkovich, O. G.; Savchenko, A.
I.; Sviridov, S. V.; Vasilevskii, D. A. MendeleeV Commun. 1993, 230.
(3) (a) Kulinkovich, O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789.
(b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835.
(4) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413.
(5) (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc.
1996, 118, 291. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198. (c) Lee, J.; Kim, Y. G.; Bae, J.; Cha, J. K. J. Org. Chem. 1996,
61, 4878. (d) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119,
8127. (e) Sung, M. J.; Lee, C.-W.; Cha, J. K. Synlett 1999, 561.
(6) (a) Bertus, P.; Gandon, V.; Szymoniak, J. J. Chem. Soc., Chem.
Commun. 2000, 171. (b) Gandon, V.; Bertus, P.; Szymoniak, J. Eur. J.
Chem. 2000, 3713. (c) Bertus, P.; Szymoniak, J. J. Chem. Soc., Chem.
Commun. 2001, 1792. (d) Gandon, V.; Szymoniak, J. J. Chem. Soc., Chem.
Commun. 2002, 1308. (e) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002,
67, 3965. (f) Laroche, C.; Bertus, P.; Szymoniak, J. Tetrahedron Lett. 2003,
44, 2485.
(7) Wu, Y.-D.; Yu, Z.-X. J. Am. Chem Soc. 2001, 123, 5777.
(8) Casey, C. P.; Strotman, N. A. J. Am. Chem. Soc. 2004, 126, 1699.
(9) Although titanium complexes are best described as six-coordinate
octahedral species, for convenience they are shown as tetrahedral intermedi-
ates devoid of coordinating solvents.
(10) (a) Actual isolated yields after column chromatography are given,
but loss occurred during purification due to the volatility of the products.
Cf. (b) 3b: Sonoda, A.; Moritani, I.; Miki, J.; Tsuji, T. Tetrahedron Lett.
1969, 3187.
10.1021/ol0493047 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/18/2004

Scheme 1
Scheme 2
solution was added to a solution of 1 and Ti(O-i-Pr)4 in ether,
a dramatic reversal in the ratio of 3e to 4e was found (entry
6) in parallel with the above-mentioned solvent effects noted
for 3a-4a. The unexpected solvent effects could be over-
ridden by addition of a Lewis acid (2 equiv) (entry 7; also
vide infra).
Coupling of 1 and a terminal olefin under the typical olefin
exchange modification procedure (employing cyclopentyl or
cyclohexyl Grignard reagents)5 surprisingly failed to produce
appreciable amounts of the desired coupling products 3 or
4. The reductive dimerization product of the terminal olefin
employed was isolated in low yields from a complex crude
reaction mixture. This unexpected yet striking difference in
the Kulinkovich cyclopropanation reaction of esters and
vinylogous esters might be attributed in part to a subtle
difference in their relative reactivity toward the presumed
titanacyclopropane intermediate derived from the cyclopentyl
Grignard reagent vis-a`-vis the requisite olefin exchange
process.9,11 Although elucidation of mechanistic implications
must await further studies, a satisfactory solution to this
Scheme 3
was used in generating the Grignard reagent and also as the
reaction solvent, 4a was the sole product (entry 5). Exclusive
formation of 3a (77%) was observed in toluene (entry 1).
Similarly, other Grignard reagents such as ethyl, isoamyl,
2-phenethyl, and 4-triisopropylsiloxybutylmagnesium chlo-
rides or bromides afforded the corresponding cyclopropanes
3b-e in comparable yields (entries 1-7 in Scheme 3).
Again, low (∼2:1) diastereoselectivity was observed for 3c-
e. With 4-triisopropylsiloxybutylmagnesium chloride in ether,
a small amount of 4e (7%) was isolated, along with the major
product 3e (45%) (entry 4). Additionally, the product ratio
of 3e to 4e appeared to be affected by the reaction time (entry
4 vs 5), which was suggestive of a common pathway leading
to 3e and 4e. When the Grignard reagent generated in a THF
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Org. Lett., Vol. 6, No. 14, 2004

unexpected difficulty was found in the use of a homoallylic
alcohol: on the basis of our previous hydroxycyclopropa-
nation of 5a,b,12 the intermediate F is presumably involved,
where an internal hydroxy group helps to increase the rate
of olefin exchange to afford the desired cyclopropane 6a,b
in 45 and 52% yields (Scheme 4).
with a substituted tricyclic cyclopropane, a Lewis acid was
required to induce ring closure of G even when ether was
employed as the reaction solvent.
A plausible mechanism involves addition to the vinylogous
ester of the postulated titanacyclopropane intermediate,
generated from the Grignard reagent and Ti(O-i-Pr)4, to
afford D, as indicated in Scheme 1. Subsequent rearrange-
ment of D to 2 likely entails a delocalized oxonium ion E,
formation of which would in turn be facilitated by an
electrophilic titanate, followed by facile ring closure. Thus,
noncoordinating solvents such as toluene are best for the
cyclopropanation. On the other hand, formation of E would
be hindered by use of Lewis basic solvents (e.g., THF) or
low reaction temperatures (e.g., entries 2 vs 3 and 4 vs 5 in
Scheme 2). Analogous observations for the competing
production of 3e and 4e in Scheme 3 can be attributed to
internal chelation by a siloxy or benzyloxymethoxy14 group
to the titanium, whereas subsequent addition of a Lewis acid
promotes cyclopropanation (entries 6 and 7).
Scheme 4
It is informative to compare D f E f 2 with the
respective processes in the original Kulinkovich reaction of
esters, i.e., B f C f the cyclopropanol product (Scheme
1): in contrast to the former rearrangement, the latter would
be promoted by a nucleophilic titanate involving either the
migration of an alkoxy group or the formation of an ate
complex (by addition of an external alkoxy group or excess
Grignard reagent). Therefore, no significant solvent effects
were observed for the Kulinkovich cyclopropanation of
esters.
Cyclization of 7 also took place smoothly to provide 8a
in 68% yield (Scheme 5).13 The intermediacy of the titana-
Scheme 5
On a final note, the isolation and characterization of 4a-e
provides additional evidence that it is the less substituted
Ti-C bond of the presumed titanacyclopropane or π-com-
plex intermediate that first adds to the carbonyl group (i.e.,
1 f D), as well as in related coupling reactions of imides5d
and ketones.15,16
In summary, we have developed inter- and intramolecular
titanium-mediated cyclopropanation reactions of vinylogous
esters.17 Synthetically useful cyclopropanes can be readily
introduced at otherwise inaccessible sites. More importantly,
the comparison study between the Kulinkovich cyclopropa-
nation of esters and vinylogous esters provides mechanistic
insight regarding these reactions: the unusual effects exerted
(13) Both diastereomers of 8a were previously prepared by a different
method: Kakiuchi, K.; Ue, M.; Tsukahara, H.; Shimizu, T.; Miyao, T.;
Tobe, Y.; Odaira, Y.; Yasuda, M.; Shima, K. J. Am. Chem. Soc. 1989,
111, 3707. Unfortunately, the close similarity in 1H and 13C NMR chemical
shifts reported for these diastereomers precluded unequivocal differentiation
of the two possible diastereomers. The stereochemistry of 8a is tentatively
assigned on the basis of the requisite geometry for cyclization.
(14) Coupling reaction of 1 and benzyloxymethoxybutylmagnesium
chloride was comparable to that with the corresponding triisopropylsiloxy-
butyl Grignard reagent leading to 3e and/or 4e.
oxacyclopentane G was gleaned from the deuterium labeling
experiment (i.e., formation of 8b). Addition of BF3‚Et2O
(2-5 equiv) prior to aqueous workup resulted in clean
cyclopropanation to deliver 10 in 75-80% yield (upon
exposure to p-TsOH‚H2O to ensure complete hydrolysis of
the enol ether 9). Because of the additional strain associated
(15) Morlender-Vais, N.; Solodovnikova, N.; Marek, I. J. Chem. Soc.,
Chem. Commun. 2000, 1849.
(11) In most cases, the original Kulinkovich cyclopropanation procedure
and the olefin exchange modification can be utilized interchangeably with
only small differences in yields. Rare exceptions include cyclopropanation
of benzoates and nitriles: (a) Lee, J.; Cha, Unpublished results. See also:
(b) Gensini, M.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A. K.; Es-
Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 2002, 2499. (c) Footnote 16
in ref 6f.
(12) (a) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem.,
Int. Ed. 2002, 41, 2160. See also: (b) Savchenko, A. I.; Kulinkovich, O.
G. Zh. Org. Khim. 1997, 33, 913. (c) Isakov, V. E.; Kulinkovich, O. G.
Synlett 2003, 967.
(16) Coupling of zirconocene-alkene complexes with aldehydes is also
known to occur at the less substituted metal-C bond, and this regiochemistry
is opposite to that with alkenes: Takahashi, T.; Suzuki, N.; Hasegawa, M.;
Nitto, Y.; Aoyagi, K.; Saburi, M. Chem. Lett. 1992, 331. This interesting
dichotomy might be attributed to kinetic control of the coupling with a
carbonyl functionality due to the well-known oxophilicity of titanium or
zirconium, whereas the corresponding coupling with an alkene would be
subject to thermodynamic control.
(17) Cyclopropanation of vinylogous amides also proceeds cleanly under
similar conditions: Feng, W.; Cha, J. K. Unpublished results.
Org. Lett., Vol. 6, No. 14, 2004
2367

by reaction temperature, solvents, and a Lewis acid additive
have been rationalized. Further mechanistic and synthetic
studies are currently in progress.
tutes of Health (GM35956) for generous financial support.
Supporting Information Available: Representative ex-
perimental procedures and characterization data. This mate-
rialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
Acknowledgment. We are grateful to the National
Science Foundation (CHE-0209321) and the National Insti-
OL0493047
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Org. Lett., Vol. 6, No. 14, 2004