Titanium-mediated [2 + 2 + 2] coupling of diynes with homoallylic alcohols

Article abstract of DOI:10.1021/ol034592c

(Matrix presented) In connection with the known diyne-ene [2 + 2 + 2] cycloaddition reactions mediated by titanium aryloxides, the ability of titanium alkoxides to promote coupling of a titanacyclopentadiene with an alkene has been assessed for the isomer

Full text of DOI:10.1021/ol034592c

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2137-2140
Titanium-Mediated [2 + 2 + 2] Coupling
of Diynes with Homoallylic Alcohols
,†
Moo Je Sung, Jin-Hyun Pang, Soon-Bong Park, and Jin Kun Cha*
Department of Chemistry, UniVersity of Alabama, Tuscaloosa, Alabama 35487
jcha@chem.wayne.edu
Received April 5, 2003
ABSTRACT
In connection with the known diyne-ene [2 + 2 + 2] cycloaddition reactions mediated by titanium aryloxides, the ability of titanium alkoxides
to promote coupling of a titanacyclopentadiene with an alkene has been assessed for the isomerization-free preparation of 1,3-cyclohexadienes.
The successful cycloaddition by titanium alkoxides is predicated on the use of homoallylic alcohols as the olefin component. With secondary
homoallylic alcohols, high 1,3-diastereoselectivity is observed, which lends itself to enantioselective preparation of functionalized
1,3-cyclohexadienes.
Transition metal-mediated [2 + 2 + 2] cycloadditions of
three unsaturated components have been extensively inves-
tigated for direct formation of benzenes, six-membered
heterocycles, and related compounds.1 Late transition metals
such as cobalt, rhodium, nickel, and ruthenium complexes
have been shown to be effective for the conceptually
appealing cyclotrimerization reactions, and a majority of
known examples have been directed at rapid assembly of
polycyclic aromatic compounds. One useful variant involves
coupling of two alkyne molecules with an alkene for the
synthesis of 1,3-cyclohexadienes, where intramolecular
processes have frequently been adopted in order to avoid
regiochemical complications in intermolecular diyne-ene [2
+ 2 + 2] cycloaddition reactions. Particular emphasis was
placed on improving the efficiency and also controlling the
regio- and stereochemistry of these cycloadditions. Titanium
aryloxides were shown to be effective under mild conditions
by Rothwell and co-workers, but the initially formed 1,3-
cyclohexadiene products were found to undergo extensive
isomerization by metal-mediated 1,5-hydrogen shifts (see 7A
f 7B in Scheme 1).2,3 We herein report isomerization-free
coupling of diynes with homoallylic alcohols in the presence
of a titanium alkoxide and a Grignard reagent.
As an extension of the Kulinkovich cyclopropanation,4 we
investigated the utility of a presumed dialkoxytitanacyclo-
propane intermediate in the [2 + 2 + 2] cycloaddition
reaction for the synthesis of functionalized bicyclic cyclo-
hexadienes. Of particular interest was the comparison of the
reactivity profiles of titanium aryloxides and alkoxides in
the context of this metal-mediated cycloaddition:5 in contrast
to Rothwell’s pioneering work on sterically demanding
titanium aryloxides,2 the use of titanium alkoxides had been
limited to either intramolecular coupling of two components
† Current address: Department of Chemistry, Wayne State University,
Detroit, MI 48202.
(2) (a) Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc. 1993, 115, 1581.
(b) Johnson, E. S.; Balaich, G. J.; Rothwell, I. P. J. Am. Chem. Soc. 1997,
119, 7685. (c) Use of allyl phenyl ether allowed formation of substituted
methylenecyclohex-3-enes as single regioisomers: Balaich, G. J.; Rothwell,
I. P. Tetrahedron 1995, 51, 4463.
(3) Cf.: Karel, K. J.; Brookhart, M.; Aumann, R. J. Am. Chem. Soc.
1981, 103, 2695.
(4) For excellent 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.
(1) For general reviews, see: (a) Vollhardt, K. P. C. Angew. Chem., Int.
Ed. Engl. 1984, 23, 539. (b) Buchwald, S. L.; Nielsen, R. B. Chem. ReV.
1988, 88, 1047. (c) Shore, N. E. Chem. ReV. 1988, 88, 1081. (d) Negishi,
E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. (e) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (f) Grotjahn, D. B. In ComprehensiVe
Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon: Oxford, 1995;
Vol. 12, p 741. (g) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96,
49. (h) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV.
1996, 96, 635. (i) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901.
10.1021/ol034592c CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/22/2003

sequent, rate-determining attack of an olefin on 2 appeared
to be unfavorable. In marked contrast, the corresponding
aryloxy derivatives 6 were shown by Rothwell to readily
undergo the metal-mediated Diels-Alder reaction with
several olefins to afford 8.2 This noticeable difference in
reactivity between ligands containing aryloxides and alkox-
ides could be attributed to electronic effects.5b
Scheme 1
To overcome the apparently unfavorable reaction of 2 with
an alkene, we decided to rely on intramolecularity by em-
ploying an alcohol-tethered olefin: the titanium metal could
serve as a suitable matrix as a result of in situ exchange
between 2 and the alcohol functionality, as we previously
demonstrated in the diastereoselective hydroxycyclopropa-
nation reactions of homoallylic alcohols.9 Indeed, the use of
3-buten-1-ol (9) afforded the desired cycloadduct 12 in 85%
yield, when ClTi(O-i-Pr)3 and cyclopentylmagnesium chlo-
ride were used and the reaction mixture was heated at 50
°C for several hours prior to aqueous workup (Scheme 2).10
Scheme 2a
involving olefins and acetylenes or the availability of
aromaticity to drive the equilibrium.6,7 When a mixture of
1,8-bis(trimethylsily)-1,7-octadiyne (1) and 1-triisopropyl-
siloxy-3-butene (3a) [or 1-hexene (3b)] was subjected to
typical modified Kulinkovich conditions involving 1.0 equiv
of ClTi(O-i-Pr)3 and 4.0 equiv of cyclopentylmagnesium
chloride,8 no [2 + 2 + 2] cycloadduct 4a,b was found in
the crude reaction mixtures (Scheme 1). Instead, the cycliza-
tion product 5 was isolated in 82% yield after aqueous
workup. Formation of diene 5 indicates facile generation of
2, which is well precedented for early transition metals
(containing cyclopentadiene or alkoxide ligands). The sub-
a Reaction conditions:10 1 equiv of 1; 3 equiv of 9; 1 equiv of
a titanium reagent; 4 equiv of a Grignard reagent.
(5) (a) For related comparison studies in the titanium-mediated cyclo-
propanation of esters, see: Lee, J. C.; Sung, M. J.; Cha, J. K. Tetrahedron
Lett. 2001, 42, 2059. (b) In a recent investigation, titanium alkoxides [e.g.,
Ti(OCH2CF3)4 and Ti(OCH(CF3)2)4] bearing electronegative substituents
seemed to be more effective than ClTi(O-i-Pr)3 for the cycloaddition
reaction: Pang, J.-H.; Cha, J. K. Unpublished results. An electron-deficient
titanium species would bind more tightly to unsaturated groups and thus
be beneficial.
(6) (a) Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119,
10014 and references therein. (b) For an excellent review, see: Sato, F.;
Urabe, H.; Okamoto, S. Synlett 2000, 753.
(7) Recently, there appeared examples on coupling of three alkynes or
nitriles: (a) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123,
7925. (b) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc.
2002, 124, 3518. (c) Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato,
F. J. Am. Chem. Soc. 2002, 124, 9682.
When no heating was applied, only trace amounts of 12 were
found in the crude reaction mixture. According to a brief
survey of several titanium alkoxide reagents and Grignard
reagents, the best yields were obtained by employing ClTi-
(O-i-Pr)3 and cyclopentylmagnesium chloride. Prefabrication
of a mixed titanate 10 from a titanium alkoxide and 9 proved
to be unnecessary. It is interesting to note that addition of
(9) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem., Int.
Ed. 2002, 41, 2160.
(8) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198.
2138
Org. Lett., Vol. 5, No. 12, 2003

the Grignard reagent at 0 °C or room temperature resulted
in lower yields (50 and 55%, respectively) than at -78 °C.
This unexpected temperature dependence is in conspicuous
contrast to that of the olefin exchange-mediated cyclopro-
panation reactions of carboxylic esters and derivatives.8,11
Under optimized reaction conditions, several alcohols
containing longer tethers and also different diynes were next
examined (Scheme 3); the homoallylic alcohol group proved
to yield the corresponding allylic titanium reagents.4 Longer
tethers resulted in not only lower yields but also competing
isomerization. It is clear that the homoallylic tether is useful
in promoting the desired Diels-Alder reaction,12 as well as
preventing subsequent metal-mediated 1,5-hydrogen shift
(e.g., 17a and 17b) due to geometrical constraints imposed
by the six-membered titanate in 11. As was the case in the
titanium-mediated cyclopropanations, disubstituted olefins
(e.g., 18) did not undergo the [2 + 2 + 2] cycloaddition. To
facilitate the removal of the vinylsilyl groups, use of 19 was
next examined to afford the cycloadduct 20 in 66% yield.
Treatment of 20 with TBAF in 2:1 THF-DMSO at 80 °C
cleanly gave 21 in 80% yield.13,14 In the above-mentioned
preliminary study, no attempt was made to develop a catalytic
procedure with respect to a titanium reagent since it is
inexpensive and readily available. However, successful
development of such a catalytic process would seem feasible,
as 7 was shown to enter a catalytic cycle presumably because
of instability of a Ti(II) species.2b
Scheme 3
Finally, the 1,3-diastereoselectivity, which was previously
utilized for the stereoselective synthesis of trans-1,2-dialkyl-
cyclopropanols,9 was examined by employing secondary
homoallylic alcohols 22a,b. In both cases, the cycloadducts
24a,b were obtained as single diastereomers in 47 and 48%
(unoptimized) yields, respectively.15 The stereochemistry of
24a,b was tentatively assigned as shown in Scheme 4 on
Scheme 4
the basis of the expected bias for the transition state having
an alkyl substituent in the equatorial position leading to
to be optimal. Allylic alcohols were not examined because
they were already known to react under identical conditions
(11) Origin of the observed temperature dependence is unclear. In the
present case, the requisite low valent titanium was readily generated at low
temperatures, as the presence of coordinating alkynes would facilitate
reductive elimination.
(12) Rothwell and co-workers presented strong evidence in favor of the
Diels-Alder-like cyclization of a titanacyclopentadiene rather than an
alternate, stepwise insertion of an olefin into the Ti-C bonds.2b
(13) (a) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.
Tetrahedron 1985, 41, 3257. (b) Other procedures for desilylation by
employing HI or I2 were unsuccessful.
(14) Diels-Alder reaction of the acetate of diene 21 and maleic anhydride
gave the corresponding adduct as a single diastereomer in excellent yield.
(15) Compounds 24a and 24b were found to undergo a 1,5-hydrogen
shift in a CDCl3 solution.
(10) Typical Experimental Procedure. To a mixture of 1 (72.8 mg,
0.29 mmol) and ClTi(O-i-Pr)3 (0.29 mL of a 1 M solution in THF) was
added 9 (75 µL, 0.87 mmol). After the mixture had been stirred at room
temperature for 1 h and then cooled to -78 °C, cyclopentylmagnesium
chloride (1.45 mL of a 1 M solution in THF) was added over a period of
10 min. The reaction mixture was stirred at -20 °C for 1 h and then allowed
to warm to room temperature. Benzene (0.3 mL) was added, and the
resulting mixture was heated at 50 °C for 8-10 h (monitored by TLC).
The reaction was quenched by addition of water, and the mixture was
extracted with EtOAc. The extract was washed with brine and dried over
MgSO4. Purification by column chromatography (1:5 EtOAc-hexane)
afforded 12 (80 mg, 85%) as a colorless oil.
Org. Lett., Vol. 5, No. 12, 2003
2139

23a,b. The exceptional level of the diastereoselectivity lends
itself to a convenient, enantioselective synthesis of 1,3-
cyclohexadienes by starting with enantiomerically pure
homoallylic alcohols.
In summary, the ability of titanium alkoxides to promote
the diyne-ene [2 + 2 + 2] cycloaddition reaction has been
evaluated in comparison to the known examples involving
titanium aryloxides: unlike the latter, the titanium alkoxide-
mediated cycloaddition requires the use of homoallylic alco-
hols as the olefin component. Of particular importance is
high 1,3-diastereoselectivity offered by secondary homoal-
lylic alcohols, which should be of general utility in titanium-
mediated C-C bond-forming reactions. Further refinement
of this strategy, along with mechanistic studies and synthetic
applications, will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health (GM35956) for generous financial support.
OL034592C
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Org. Lett., Vol. 5, No. 12, 2003