Titanium-mediated alkylative cyclizations of 1,3-diene-tethered esters

Article abstract of DOI:10.1021/ol016350n

(Equation presented) An alkylative titanium-mediated cyclization reaction of 1,3-diene-tethered carboxylic esters has been developed by employing an in situ generated titanacyclopropane intermediate to afford trans-2-alkenyl cyclohexanols.

Full text of DOI:10.1021/ol016350n

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2745-2748
Titanium-Mediated Alkylative
Cyclizations of 1,3-Diene-Tethered
Esters
Long Guo Quan and Jin Kun Cha*
Department of Chemistry, UniVersity of Alabama, Tuscaloosa, Alabama 35487
jcha@bama.ua.edu
Received June 26, 2001
ABSTRACT
An alkylative titanium-mediated cyclization reaction of 1,3-diene-tethered carboxylic esters has been developed by employing an in situ generated
titanacyclopropane intermediate to afford trans-2-alkenyl cyclohexanols.
Transition-metal-promoted carbocyclizations of unsaturated
functionalities have been demonstrated to provide convenient
methods for the facile formation of rings. Procedures that
involve the formation of metallacycle intermediates by means
of low valent metals such as Zr, Ti, or Ni have been
frequently employed.1 For example, cyclizations of enynes,
diynes, and dienes have been extensively investigated, since
they proceed with good diastereoselectivity and tolerate
several functional groups. Related reactions of saturated or
R,â-unsaturated carbonyl derivatives with tethered unsatur-
ated functionalities have also been developed as useful
methods for the construction of carbocyclic rings.2 Recently,
1,3-dienes have been successfully employed for coupling to
carbonyl compounds.3 As part of our research program
expanding upon the Kulinkovich cyclopropanation reaction,4
herein we report the titanium-mediated alkylative cyclizations
of 1,3-diene-tethered carboxylic esters.
For convenience, the requisite ω-dienyl esters 1 and 25
were prepared as a 1:1 mixture of E and Z isomers (in good
yields) by standard Wittig olefination of the corresponding
aldehydes with the ylide prepared from allyltriphenylphos-
phonium bromide. Treatment of 1 with cyclopentylmagne-
sium chloride (1.8 equiv) in the presence of methyltitanium
triisopropoxide (1.1 equiv) at 0 °C afforded cyclopentanone
3a (62%) and cyclopentanol 4a (21%) (Scheme 1).6 Hy-
(3) See, inter alia: (a) Yasuda, H.; Tatsumi, K.; Nakamura, A. Acc. Chem.
Res. 1985, 18, 120. (b) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara,
T.; Takagi, K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771. (c) Sato, Y.;
Takimoto, M.; Mori, M. Tetrahedron Lett. 1996, 37, 887. (d) Gao, Y.; Urabe,
H.; Sato, F. J. Org. Chem. 1994, 59, 5521. (e) Kimura, M.; Ezoe, A.;
Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033. (f) Kimura,
M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.;
Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 397.
(4) For recent reviews, see: (a) Kulinkovich, O. G.; de Meijere, A. Chem.
ReV. 2000, 100, 2789. (b) Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV.
2000, 100, 2835. (c) Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753.
(5) Compare Hudlicky, T.; Sheth, J. P. Tetrahedron Lett. 1979, 2667.
(6) Typical Experimental Procedure. A 3.0 M solution of methylmag-
nesium chloride (0.2 mL) in THF was added at 0 °C over a period of 5
min to a solution of Ti(O-i-Pr)4 (0.16 mL, 0.55 mmol) in anhydrous THF
(5 mL). After the mixture had been stirred for an additional 5 min, 2 (84
mg, 0.5 mmol) was added, followed by slow addition (over a period of 1
h) of a 2.0 M solution of cyclopentylmagnesium chloride (0.75 mL) in
THF. The reaction mixture was then stirred for 10 min and quenched with
addition of water (0.5 mL). The resulting mixture was stirred for an
additional 1 h, dried over sodium sulfate, and filtered. The filter cake was
washed with CH2Cl2 (10 mL), and the combined filtrates were concentrated
under vacuum. Purification by column chromatography on silica gel afforded
(1) For general reviews, see: (a) Negishi, E.-i. Acc. Chem. Res. 1987,
20, 65. (b) Negishi, E.-i.; Takahashi, T. Synthesis 1988, 1. (c) Buchwald,
S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047. (d) Takahashi, T. J. Synth.
Org. Jpn. 1993, 51, 1145. (e) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan,
R. J. Chem. ReV. 1996, 96, 635.
(2) For representative examples, see: (a) Hewlett, D. F.; Whitby, R. J.
J. Chem. Soc., Chem. Commun. 1990, 1684. (b) Kablaoui, N. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1995, 117, 6785. (c) Crowe, W. E.; Rachita, M. J.
J. Am. Chem. Soc. 1995, 117, 6787. (d) Kablaoui, N. M.; Buchwald, S. L.
J. Am. Chem. Soc. 1996, 118, 3182. (e) Montgomery, J. Acc. Chem. Res.
2000, 33, 467.
10.1021/ol016350n CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/01/2001

Scheme 1
Scheme 2
drolysis of the reaction mixture with D2O provided mono-
deuterated 3b (58%) and dideuterated 4b (18%). When a
larger excess (4 equiv) of the Grignard reagent was added,
a mixture of 3a (10%) and 4a (31%) was obtained with
considerably lower material balance. The structures (includ-
ing the stereochemistry) of 4a and 4b were determined by
1H NMR, 13C NMR, and mass spectral analysis, along with
1
comparison of the H NMR chemical shifts of the methine
proton R to the hydroxyl group with those of closely related
known cyclopentanol isomers.7
containing only trace amounts of the respective cycloheptanol
products. Thus, the titanium-mediated cyclizations were
limited to the formation of five- and six-membered rings.
Although the Kulinkovich cyclopropanation reactions of
carboxylic esters were in general marginally affected by the
nature of a titanium alkoxide,4,8 the choice of methyltitanium
triisopropoxide9 proved to be critical for the successful
cyclization. Titanium tetraisopropoxide or chlorotitanium
triisopropoxide was ineffective. An unexpected advantage
of MeTi(O-i-Pr)3, compared to Ti(O-i-Pr)4 and ClTi(O-i-Pr)3,
can be attributed to its efficacy in inducing the requisite
â-elimination (vide infra). A stoichiometric amount of MeTi-
(O-i-Pr)3 was also necessary to obtain good yields of 5 and/
or 6. No attempt was made to develop a variant that was
catalytic in titanium.
A plausible mechanism for the formation of the cyclization
products is outlined in Scheme 3. â-Elimination of the
dialkyltitanium intermediate 7 would be expected to generate
a titanacyclopropane intermediate or a Ti(II)-alkene complex.
Subsequent ligand exchange with diene 1 or 2 would then
afford 8a,b,4,10 which could exist in equilibrium with
titanacyclopentene 9a,b.11,12 Subsequent addition of 8a,b or
9a,b to the tethered ester function would then lead to the
Similarly, cyclization of the homologue 2 under identical
conditions using 1.8 equiv of cyclopentylmagnesium chloride
produced a mixture of 5 (54%) and 6a (30%) (Scheme 2).
By utilizing an additional amount of the Grignard reagent,
the isolated yield of 6a was increased at the expense of 5.
When 3 equiv of the Grignard reagent was added slowly
over a period of 1 h, the trans-substituted cyclohexanol 6a,
the stereochemistry of which was unequivocally established
by the observation of a diaxial coupling (J ) 9.9 Hz) for
the methine proton (3.17 ppm, dt, J ) 4.0, 9.9 Hz, 1 H) R
to the hydroxyl group, was obtained in 81% yield, along
with a trace amount of 5.6 This observation clearly indicated
that both 5 and 6a were derived from a common reaction
intermediate. Additionally, the titanium-mediated cyclization
reaction of 2 appears to be general with a range of Grignard
reagents. For example, use of ethyl, n-butyl, and isopropyl
Grignard reagents afforded the corresponding adducts 6b-d
in comparable yields, whereas tert-butyl Grignard reagent
afforded a mixture of 5 (58%) and 6e (18%). Only the
E-olefin isomers, free from Z-isomers, were found for 6a-
e. It is interesting that 6c was obtained as a 1:1 mixture of
the two regioisomers. Not surprisingly, extension of this
procedure to methyl 7,9-decadienoate gave complex mixtures
(8) Compare Lee, J. C.; Sung, M. J.; Cha, J. K. Tetrahedron Lett. 2001,
42, 2059.
(9) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A. Synlett 1997,
111.
(10) Compare (a) Kulinkovich, O. G.; Savchenko, A. I.; Sviridov, S.
V.; Vasilevski, D. A. MendeleeV Commun. 1993, 230. (b) Kasatkin, A.;
Sato, F. Tetrahedron Lett. 1995, 36, 6079. (c) Lee, J.; Kang, C. H.; Kim,
H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291. (d) Lee, J.; Kim, H.; Cha,
J. K. J. Am. Chem. Soc. 1996, 118, 4198.
84.3 mg (81%) of 6. When 1.8 equiv of cyclopentylmagnesium chloride
(e.g., 0.45 mL of a 2.0 M solution in THF) was employed under otherwise
identical conditions, 1 (77 mg, 0.5 mmol) gave 38.5 mg (62%) of 3a and
20.4 mg (21%) of 4a.
(7) The stereochemistry of 2-alkenylcyclopentanols and -cyclohexanols
can be easily determined by the diagnostic chemical shift of the methine
proton, which is more shielded in trans isomers than in cis isomers: Snider,
B. B.; Karras, M.; Price, R. T.; Rodini, D. J. J. Org. Chem. 1982, 47, 4538.
2746
Org. Lett., Vol. 3, No. 17, 2001

resonance structures for the resulting metal-E-alkene com-
plex, can be viewed as an intramolecular diene cyclization.1
While tentative, it is tempting to speculate that the relative
configuration of 13A/13B, based on steric considerations,
is as shown in Scheme 3. Subsequent reduction of the
hemiacetal functionality would occur next, via a ketone
intermediate (formed by the initial migration of the methoxy
group to the titanium), from the bottom face directed by the
E-olefin functionality to give the trans-substituted cyclo-
hexanol isomer 6a. A priori, there was another reaction
manifold possibly available for 10a,b or 11a,b, but no
corresponding bicyclic cyclopropanol was found in the crude
reaction mixture.
Scheme 3
The stereoselective formation of 6b-e by use of other
Grignard reagents in place of cyclopentylmagnesium chloride
can be rationalized by an identical pathway. As evidenced
in the formation of both regioisomers of 6c, little regio-
selectivity was observed for 12 f 13 with a primary
Grignard reagent. On the other hand, use of a secondary or
a tertiary Grignard reagent afforded excellent regiocontrol,
where the subsequent carbocyclization took place at the more
substituted olefinic carbon. Attempts to intercept the pre-
sumed intermediate 12 by exchange with an excess (5 equiv)
of an external alkene were unsuccessful. Apparently, 12 f
13 must take place more rapidly than an intermolecular olefin
exchange of 12. These results, taken together, suggest that
the formation of 12 by â-elimination is the slowest step for
11b f 12 f 13. The different regiochemical outcome
between the reaction of primary and secondary/tertiary
Grignard reagents with 11b can be attributed to preferential
â-elimination by one of the two diastereotopic alkyl groups
bound to the titanium metal with the latter reagents.
Sato and co-workers reported a related intramolecular
coupling of alka-3,5-dienyl carbonates by employing (η2-
propene)Ti(O-i-Pr)2.13 The present work differs from Sato’s
previous cyclization in the subsequent incorporation of
various alkyl groups arising from the Grignard reagents. Also,
a similar mechanism has previously been advanced by de
Meijere for the preparation of alkenyl cyclopropylamines
from the titanium-mediated intermolecular cyclopropanation
of N,N-dibenzylformamide with a diene or a triene.11
Surprisingly, an intramolecular variant of 1,3-diene-tethered
tertiary amides, which is analogous to the present study, gave
only an intractable reaction mixture.14b To make an additional
comparison, the titanium-mediated intermolecular cyclopro-
panation of esters with dienes afforded little of the corre-
sponding cyclopropanols.14 The divergence in the reactivity
of esters and amides in their intramolecular and intermo-
lecular titanium-induced coupling reactions with dienes was
atypical, especially in view of comparable reactivities with
terminal olefins, yet their origin is unclear.
formation of 10a,b, which could undergo an allylic rear-
rangement to give 11a,b. When n ) 1, 10a would be
preferred to 11a in the latter interconversion, as might be
expected on the basis of strain associated with a titanaoxabi-
cyclo[3.3.0]octane ring system. Hydrolysis of 10a,b would
afford 3a,b or 5 with the Z configuration of the double bond
(J ) 10.8 Hz). On the other hand, it is evident that 11b (n
) 2) should be favored over 10b, and it could react with an
additional 2 equiv of the Grignard reagent to provide 12.
The ensuing cyclization of 12 to 13A/13B, the two limiting
In summary, an alkylative titanium-mediated cyclization
reaction of 1,3-diene-tethered carboxylic esters has been
(13) (a) Zubaidha, P. K.; Kasatkin, A.; Sato, F. J. Chem. Soc., Chem.
Commun. 1996, 197. Compare (b) Yoshida, Y.; Okamoto, S.; Sato, F. J.
Org. Chem. 1996, 61, 7826.
(14) (a) See footnote 11 of ref 11. (b) Lee, J.; Quan, L. G.; Cha, J. K.,
unpublished observations. (c) For an alternative approach, see: Lee, J.; Kim,
H.; Cha, J. K. J. Am. Chem. Soc. 1995, 117, 9919.
(11) Williams, C. M.; Chaplinski, V.; Schreiner, P. R.; de Meijere, A.
Tetrahedron Lett. 1998, 39, 7695.
(12) Similar rearrangements have been reported for zirconocene-diene
complexes: (a) Erker, G.; Dorf, U. Angew. Chem., Int. Ed. Engl. 1983, 22,
777. (b) Erker, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 397.
Org. Lett., Vol. 3, No. 17, 2001
2747

developed by employing an in situ generated titanacyclo-
propane intermediate to afford trans-2-alkenyl cyclohex-
anols.15 Mechanistic and synthetic studies will be reported
in due course.
Acknowledgment. We thank the National Science Foun-
dation (CHE98-13975) for financial support.
Supporting Information Available: Characterization
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) The internal double bond of the 1,3-diene functionality can
accommodate alkyl substituents (e.g., methyl 6-methyl-octa-5,7-dienoate,
methyl 7-methyl-nona-6,8-dienoate): Quan, L. G.; Cha, J. K., unpublished
results.
OL016350N
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Org. Lett., Vol. 3, No. 17, 2001