Oxovanadium(V)-induced vicinal dialkylation of cyclic enones with organozinc compounds

Article abstract of DOI:10.1021/ol006564p

(matrix presented) Oxovanadium(V) compounds induce nucleophilic α,β-vicinal dialkylation of cyclic α,β-enones with dialkylzinc reagents. Alkylzinc enolates generated from cyclic enones and lithium trialkylzincates were also oxidized by VO(OEt)Cl₂, giving 2,3-dialkylcycloalkanones.

Full text of DOI:10.1021/ol006564p

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3659-3661
Oxovanadium(V)-Induced Vicinal
Dialkylation of Cyclic Enones with
Organozinc Compounds
Toshikazu Hirao,* Takashi Takada, and Hidehiro Sakurai
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity,
Yamada-oka, Suita, Osaka 565-0871, Japan
hirao@ap.chem.eng.osaka-u.ac.jp
Received September 8, 2000
ABSTRACT
Oxovanadium(V) compounds induce nucleophilic r,â-vicinal dialkylation of cyclic r,â-enones with dialkylzinc reagents. Alkylzinc enolates
generated from cyclic enones and lithium trialkylzincates were also oxidized by VO(OEt)Cl2, giving 2,3-dialkylcycloalkanones.
Oxidative transformation of main-group organometallics has
been expected to develop a new type of carbon-carbon
bond-forming reaction.1,2 Recently, we reported that oxo-
vanadium(V) compounds induce a selective ligand coupling
of two ligands on some organometallic compounds such as
organoaluminum,3 boron,4 zirconium,5 and zinc compounds.6
As for the organozinc compound, arylalkylzinc or aryldialkyl-
zincate is oxidized by VO(OEt)Cl2, providing a ligand
coupling product selectively (Scheme 1).6
Scheme 1
(1) For chemical redox reagents of organometallic chemistry, see:
Connelly, N. G.; Geiger, W. E. Chem. ReV. 1996, 96, 877 and references
therein.
(2) For copper-induced oxidative ligand coupling reactions of organobo-
rons and organozincs, see: (a) Yamamoto, Y.; Yatagai, H.; Maruyama,
K.; Sonoda, A.; Murahashi, S.-I. J. Am. Chem. Soc. 1977, 99, 5652. (b)
Iyoda, M.; Kabir, S. M. H.; Vorasingha, A.; Kuwatani, Y.; Yosihda, M.
Tetrahedron Lett. 1998, 39, 5393. For oxidative transformation of d0
organometallics, see: (c) Jordan, R. F.; LaPointe, R. E.; Bajgur, C. S.;
Echols, S. F.; Willet, R. J. Am. Chem. Soc. 1987, 109, 4111. (d) Borkowsky,
S. L.; Baenziger, N. C.; Jordan, R. F. Organometallics 1993, 12, 486. (e)
Burk, M. J.; Tumas, W.; Ward, M. D.; Wheeler, D. R. J. Am. Chem. Soc.
1990, 112, 6133. (f) Sato, M.; Mogi, E.; Kumakura, S. Organometallics
1995, 14, 3157. (g) Hayashi, Y.; Osawa, M.; Wakatsuki, Y. J. Organomet.
Chem. 1997, 542, 241.
On the other hand, dialkylzinc reagent (R2Zn) is recog-
nized as a mild nucleophile, and highly selective reactions
have been developed by a combination of an additional
promoter such as a Lewis acid catalyst.7 It is known that
1,4-addition of dialkylzinc to an R,â-unsaturated carbonyl
compound also requires promotion by a Lewis acid. Judging
from the characteristic features of oxovanadium(V) com-
pounds as a Lewis acid and one-electron oxidant, they are
expected to induce a novel nucleophilic vicinal dialkylation
(3) Ishikawa, T.; Ogawa, A.; Hirao, T. J. Am. Chem. Soc. 1998, 120,
5124.
(4) Ishikawa, T.; Nonaka, S.; Ogawa, A.; Hirao, T. J. Chem. Soc., Chem.
Commun. 1998, 1209.
(5) Ishikawa, T.; Ogawa, A.; Hirao, T. J. Organomet. Chem. 1999, 575,
76.
(6) Hirao, T.; Takada, T.; Ogawa, A. J. Org. Chem. 2000, 65, 1511.
(7) For organozinc mediated reactions, see: (a) Knochel, P.; Perea, J. J.
A.; Jones, P. Tetrahedron 1998, 54, 8275 and references therein. (b)
Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117 and references therein.
10.1021/ol006564p CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

at both the â- and R-positions of an R,â-unsaturated carbonyl
compound with a dialkylzinc reagent (Scheme 2). That is,
Table 1. Vicinal Dimethytlation of 1 with Dimethylzinca
Scheme 2
the oxovanadium (V) compound might promote 1,4-addition
of R2Zn to enone 1, and the resulting zinc enolate is
immediately oxidized by the adjacent oxovanadium(V)
species, giving the corresponding vicinally dialkylated
compound 2.
To accomplish this kind of vicinal alkylation, first, the
reaction of 2-cyclohexenone (1) with dimethylzinc in THF
was investigated (Table 1). Dimethylzinc was inert to 1
without an oxovanadium(V) complex (entry 1), whereas VO-
(OPri)3 activated only the 1,4-addition process to give
3-methylcyclohexanone (3a) in 34% yield (entry 2). Use of
VO(OEt)Cl2, a more efficient Lewis acid and oxidant than
VO(OPri)3,8 led to the formation of 2,3-dimethylcyclohex-
anone (2a) in 26% yield as a diastereomeric mixture.9 This
result encouraged us to examine the precise reaction condi-
tions. When the reaction was carried out at -78 °C for 4 h
and then at -30 °C for 6 h, the yield of 2a was increased to
60% (entry 4). Next, the substituent of oraganovanadium-
(V) compounds was screened to find that the stronger Lewis
acid and oxidant gave the better results. Accordingly, the
yield of 2a decreased in the order VO(OEt)Cl2 > VO(OPri)-
Cl2 > VO(OPri)2Cl to 60%, 56%, and 20%, respectively
(entries 4-6).8 Finally, the yield of 2a was improved to 78%
when 2 molar equiv of dimethylzinc and 2 molar equiv of
VO(OEt)Cl2 were employed at -78 °C for 20 h (entry 7).10
When the solvent was replaced with ether or dichlo-
romethane, the yield of 2a decreased (entries 8 and 9).
The same dialkylation takes place with diethylzinc as
shown in Table 2. Furthermore, this method could be applied
to trialkylaluminum (R3Al)3 and trialkylborane (R3B)4 com-
pounds. Diethylation of 1 with diethylzinc, triethylalminum,
Table 2. Dialkylation of 1 with Organometallic Reagenta
(8) The order of the reactivity of oxovanadium(V) reagents is as
follows: VO(OR)Cl2-AgOTf or Me3SiOTf > VO(OR)Cl2 > VO(OR)2Cl
> VO(OR)3. Hirao, T.; Mori, M.; Ohshiro, Y. Bull. Chem. Soc. Jpn. 1989,
62, 2399. Hirao, T.; Mori, M.; Ohshiro, Y. J. Org. Chem. 1990, 55, 358.
Hirao, T.; Mori, M.; Ohshiro, Y. Chem. Lett. 1991, 783.
(9) The regiochemistry of dialkylated compounds 2a-c was determined
by 13C-13C cosy using the 2D-INADEQUATE technique (CDCl3, 25 °C)
and that of 7 was determined by 1D,2D-HOHAHA. The trans/cis stereo-
chemistry of 2a and 7 was determined by NOE. The trans/cis stereochem-
istry of 2b and 2c was determined by JCH-CH coupling constant (for example,
major trans-2c, 7.8 Hz, minor cis-2c, 4.9 Hz).12
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Org. Lett., Vol. 2, No. 23, 2000

and triethylborane proceeded smoothly to afford the 2,3-
diethylcyclohexanone 2b in 74%, 84%, and 50% yields,
respectively (Table 2, entries 1-3). In contrast, an organo-
cuprate reagent exhibited no reactivity toward the oxidative
coupling at the R-position and gave only conjugate addition
product 3a quantitatively (entry 4).
Table 3. Oxidative Coupling Reaction with Zincatea
Contrary to dialkylzinc, lithium trialkylzincate (R3ZnLi)
has enough nucleophilicity for conjugate addition to an R,â-
unsaturated carbonyl compound without the aid of a Lewis
acid.7 Moreover, the oxovanadium(V)-induced ligand cou-
pling of aryldialkylzincates proceeds more effectively than
that of alkylarylzinc compounds as reported.6 In fact, Me3-
ZnLi (1.2 equiv) added to 2-cyclohexenone to afford the zinc
enolate, which underwent oxovanadium(V)-induced oxida-
tion, giving 2a in 78% yield (Table 3, entry 1). This two-
step procedure can be applied to various lithium trialkyl-
zincates, affording the corresponding vicinally dialkylated
cycloalkanones in good yields (Table 3). Butylzinc enolate
5c generated from 1 and Bu3ZnLi was oxidized by VO(OEt)-
Cl2, giving dibutylcyclohexanone 2c in 75% yield (entry 2).
When Bu3ZnLi-TMEDA,11 prepared from a ZnCl2-
TMEDA complex and BuLi, was used as a reagent for vicinal
alkylation of 1, 2c was obtained in 98% yield (entry 3).
2-Cyclopentenone similarly underwent oxidative vicinal
alkylation with Bu3ZnLi-TMEDA to give 2,3-dibutyl-
cyclopentanone (7) in 56% yield (entry 4). It is noteworthy
that two different alkyl groups can be introduced regio-
selectively, giving 2-methyl-3-butylcyclohexanone 2d, when
Me2BuZnLi11 was employed (entry 5).
organozinc compound is induced by an oxovanadium(V)
compound. This method permits selective 1,4-addition and
oxidative ligand coupling in a one- or two-step procedure.
Acknowledgment. The use of the facilities of the
Analytical Center, Faculty of Engineering, Osaka University,
is acknowledged. This work was partly supported by a Grant-
in-Aid for Scientific Research (No. 11450341) from the
Ministry of Education, Science, and Culture, Japan.
In summary, a novel nucleophilic vicinal dialkylation at
both the R- and â-positions of cyclic R,â-enones with an
(10) Typical procedure for vicinal dialkylation: To a solution of 1
(1.0 mmol) in THF (2.0 mL) under argon at -78 °C was added Me2Zn
(2.0 mmol, 2.0 mL, 1.0 M in Hexane) followed by VO(OEt)Cl2 (2.0 mmol),
and the mixture was stirred for 20 h at -78 °C. Workup gave the desired
dialkylated product 2.
(11) Tu¨ckmantel, W.; Oshima, K.; Nozaki, H. Chem. Ber. 1986, 119,
1581.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett.
1996, 37, 5141.
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