Triethylgallium as a nonnucleophilic base to generate enolates from ketones

Article abstract of DOI:10.1021/ol061948m

(Chemical Equation Presented) Triethylgallium deprotonated cyclic and acyclic ketones at 125-175°C without forming carbonyl addition products, and the resulting gallium enolates underwent facile C-benzoylation and an aldol reaction. Unsymmetrical ketones were preferentially enolized at the methylene moiety, which was under kinetic control.

Full text of DOI:10.1021/ol061948m

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5077-5080
Triethylgallium as a Nonnucleophilic
Base to Generate Enolates from
Ketones
Yoshio Nishimura, Yutaka Miyake, Ryo Amemiya, and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aoba, Sendai 980-8578, Japan
yama@mail.pharm.tohoku.ac.jp
Received August 7, 2006
ABSTRACT
Triethylgallium deprotonated cyclic and acyclic ketones at 125−175 °C without forming carbonyl addition products, and the resulting gallium
enolates underwent facile C-benzoylation and an aldol reaction. Unsymmetrical ketones were preferentially enolized at the methylene moiety,
which was under kinetic control.
Reaction of metal enolates is one of the most fundamental
transformations in organic synthesis, and various methods
have been developed to generate the nucleophilic intermedi-
ate from ketones.1 Stepwise methods that involve the initial
formation of metal enolates at high concentrations and a
subsequent reaction with electrophilic reagents are often used.
Compared with the methods of equilibrating enolate forma-
tion,2 each step of a stepwise method can be more readily
controlled. Bulky alkalimetal dialkylamides, typically lithium
diisopropylamide (LDA) generated from butyllithium and
diisopropylamine, are employed as the base because butyl-
lithium adds to ketones. A combination of Lewis acid metal
halides or triflates and tertiary amines was also developed
for this purpose.3 These methods, however, require stoichio-
metric amounts of amines, which are not essential for the
transformation, and the coordination of the amines to the
metal enolates often complicates the analysis of the reaction.
The development of nonnucleophilic bases, which do not
form excessive byproducts for the stepwise method, is
desirable. Potassium hydride and sodium hydride forming
hydrogen are sometimes used,4 although it is not easy to
control their reactivities because they are insoluble in organic
solvents. Soluble alkylmetal bases are attractive because the
operation to form an enolate using them is simple, and the
byproducts generated are volatile alkanes. The alkylmetal
base method enables the control of transformation by
changing the alkyl moiety. In addition, the resulting enolates
might exhibit reactivities different from those for conven-
tional metal enolates. Few studies, however, have been
conducted on such an enolate formation because of competi-
tive carbonyl addition. The reaction of triphenylmethyl
ketones with trialkylaluminum or butyllithium for the
generation of the aluminum or lithium enolates was reported
by Seebach and others.5 Triphenylmethyllithium and potas-
sium were used in some cases.6 These methods required the
use of either hindered ketones or hindered bases to avoid
(1) Reviews, see: (a) House, H. O. In Modern Synthetic Reactions, 2nd
ed.; Benjamin: Menlo Park, 1972; Chapter 9, p 492. (b) d’Angelo, J.
Tetrahedron 1976, 32, 2979. (c) Mukaiyama, T. Org. React. 1982, 28, 203.
(d) Mekelburger, H. B.; Wilcox, C. S. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.4, p
99. (e) Caine, D. In ComprehensiVe Organic Synthesis, Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 3, Chapter 1.1, p. 1. (f) Evans, D. A.
In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
1984; Vol. 3, Chapter 1, p. 1.
(3) For example, see: (a) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead,
H. D. J. Org. Chem. 1969, 34, 2324. (b) Inoue, T.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1980, 53, 174. (c) Mukaiyama, T.; Stevens, R. W.; Iwasawa,
N. Chem. Lett. 1982, 353. (d) Cowden, C. J.; Paterson, I. Org. React. 1997,
51, 1.
(4) For example, see: (a) Groenewegen, P.; Kallenberg, H.; van der Gen,
A. Tetrahedron Lett. 1978, 19, 491. (b) Iseki, K.; Yamazaki, M.; Shibasaki,
M.; Ikegami, S. Tetrahedron 1981, 37, 4411.
(2) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.5, p. 133.
10.1021/ol061948m CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/05/2006

carbonyl addition. During our investigations on the use of
gallium enolates in organic synthesis,7-9 R-ethynylation
reaction of ketones, which involved in situ generation of
enolates from ketones and trialkylgalliums, was developed.10
Described here is a study of the stepwise method using
triethylgallium as a nonnucleophilic base for ketone eno-
lization (Scheme 1). The regioselectivity in this enolization
(entries 2 and 3). Carbonyl addition products, namely,
cyclopentanol 4 and ethylcarbinol 5, were not detected. The
reaction of trimethylgallium and triisopropylgallium gave 2
and 3 in modest yields (entries 4 and 5). For comparison, 1
was reacted with triethylaluminum, which after acetylation
gave only a 16% yield of 3 accompanied by considerable
amounts of 4 and 5 (Scheme 2). Although triethylgallium is
Scheme 2
Scheme 1
was compared with that in conventional methods.
2,5-Dibenzylcyclopentanone 1 and triethylgallium (1.5
equiv) were treated in chlorobenzene at 125 °C for 1 h. After
being cooled to room temperature, acetic anhydride (2 equiv)
was added, and the reaction for 3 h gave C-acetylated 2 (cis/
trans ) 2:1) and O-acetylated 3 in 37 and 59% yields,
respectively (Table 1, entry 1). The yield of this enolate
a nonnucleophilic base for ketone enolization, the corre-
sponding aluminum compound exhibits nucleophilic and
reducing characteristics.
Several symmetrical ketones possessing R-methylene
groups were converted to enolates employing the above
conditions, and the intermediates were trapped with benzoyl
chloride giving C-benzoyl derivatives in high yields (Scheme
3). The reaction of 4-(tert-butyl)cyclohexanone with trieth-
Table 1. Deprotonation and Acetylation of 1
Scheme 3
entry
GaX3
temp/°C yield/% 2 + 3 (2:3) recovery of 1/%
1
2
3
4
5
GaEt3
125
100
75
125
125
96 (37:59)
52 (12:40)
4 (3 only)
67 (23:44)
28 (23:5)
0
41
95
33
27a
GaMe3
GaiPr3
ylgallium followed by reaction of benzaldehyde gave aldol
products with equatorial isomers (82%) predominating
(Scheme 4). The stereochemistry is highly contrasted with
a Reduced ketone 4 was obtained in 28% yield.
formation then was calculated to be 96%. The enolization
required a high temperature, and the combined yields
decreased to 52 and 4% at 100 and 75 °C, respectively
Scheme 4
(5) (a) Jeffery, E. A.; Meisters, A. J. Organomet. Chem. 1972, 82, 307.
(b) Seebach, D.; Ertas, M.; Locher, R.; Schweizer, W. B. HelV. Chim. Acta
1985, 68, 264. (c) Ertas, M.; Seebach, D. HelV. Chim. Acta 1985, 68, 961.
(6) For example, see: (a) House, H. O.; Kramar, V. J. Org. Chem. 1963,
28, 3362. (b) House, H. O.; Trost, B. M. J. Org. Chem. 1965, 30, 1341.
(7) (a) Yamaguchi, M. In Main Group Metals In Organic Synthesis;
Yamamoto, H.; Oshima, K., Eds.; Wiley-VCH Verlag: Weinheim, 2004;
Chapter 7, p. 307. (b) Amemiya, R.; Yamaguchi, M. Eur. J. Org. Chem.
2005, 5145.
(8) For gallium enolates by transmetalation, see: (a) Yamaguchi, M.;
Tsukagoshi, T.; Arisawa, M. J. Am. Chem. Soc. 1999, 121, 4074. (b)
Arisawa, M.; Amemiya, R.; Yamaguchi, M. Org. Lett. 2002, 4, 2209. (c)
Amemiya, R.; Fujii, A.; Arisawa, M.; Yamaguchi, M. Chem. Lett. 2003,
298. (d) Amemiya, R.; Fujii, A.; Arisawa, M.; Yamaguchi, M. J. Organomet.
Chem. 2003, 686, 94. Also see references cited.
those of the lithium enolates exhibiting axial preferences.11
5078
Org. Lett., Vol. 8, No. 22, 2006

Such stereoselectivity was observed in reactions of gallium
enolate generated from gallium trichloride9 and appears to
be a general feature of gallium enolate.
Symmetrical cyclic ketones possessing R-methine groups,
namely, 2,5-dibenzylcyclopentanone and 2,6-dibenzylcyclo-
hexanone, were C-benzoylated in high yields (Scheme 5).
ylcyclooctanone. Acyclic ketones, namely, 2-methyl-3-
heptanone and 1-cyclohexyl-1-pentanone, exclusively provided
enolate at the less-hindered site. The regioselectivities were
consistent with kinetic enolate formation.
Unsymmetrical ketones possessing R-methyl and R-me-
thylene groups were also enolized by triethylgallium. The
reaction of 2-octanone 6 with triethylgallium at 150 °C for
2 h followed by benzoylation gave the C-benzoylated product
8 reacted at the methylene moiety in 53% yield (Scheme 7).
Scheme 5
Scheme 7
A 4:1 mixture of diastereomers was formed in the former
reaction, whereas a 2,6-cis-dibenzyl isomer was obtained
selectively in the latter. Acyclic ketones, diisopropyl ketone,
and 5,7-dibutyl-6-undecanone did not give these products.
The reason enolate formation took place with cyclic ketones
but not with acyclic ketones can be ascribed to steric factors.
Regioselectivity in the enolization of unsymmetrical
ketones has been the focus of considerable interest1 and was
examined here for gallium enolates. The reaction of 2-me-
thylcyclopentanone with triethylgallium at 125 °C for 2 h
followed by reaction with benzoyl chloride gave 5-benzoyl
and 2-benzoyl derivatives in 88 and 7% yields, respectively,
indicating that deprotonation took place at a less-hindered
site (Scheme 6). A similar result was obtained for 2-meth-
Small amounts of the self-aldol product 10 were formed,
which were generated by deprotonation at the methyl moiety.
The enolization of 6 predominantly took place at the hindered
methylene moiety. The result, however, suggests kinetic
enolate formation because the initial deprotonation at the
methyl group predominantly provides the self-aldols. Similar
results were obtained with 2-undecanone 7. A benzyl methyl
ketone was deprotonated selectively at the methylene moiety,
and a C-benzoylated product was obtained in 87% yield.
Scheme 6
Regiochemistry in the enolate formation using triethyl-
gallium showed a notable methylene preference. Both
methylene-methine and methyl-methylene ketones were
deprotonated at the methylene moiety. To determine the
mechanism, 1,1,1-trideutero-2-octanone 6-d3 was reacted
with triethylgallium at 150 °C for 2 h and quenched with
water. Recovered 6-d3 (81%) contained 90%-d at the methyl
group and 3%-d at the methylene group (Scheme 8). When
the reaction was quenched with benzoyl chloride, 8-d3 was
obtained in 54% yield with 87%-d at the methyl group and
(9) For gallium enolates from ketones and GaCl3, see: (a) Amemiya,
R.; Nishimura, Y.; Yamaguchi, M. Synthesis 2004, 1307. (b) Amemiya,
R.; Miyake, Y.; Yamaguchi, M. Tetrahedron Lett. 2006, 47, 1797.
Deprotonation reactions of 1,4-enynes were also reported. (c) Amemiya,
R.; Suwa, K.; Toriyama, J.; Nishimura, Y.; Yamaguchi, M. J. Am. Chem.
Soc. 2005, 127, 8252.
(10) Nishimura, Y.; Amemiya, R.; Yamaguchi, M. Tetrahedron Lett.
2006, 47, 1839.
(11) Majewski, M.; Gleave, D. M. Tetrahedron Lett. 1989, 30, 5681.
ylcyclohexanone, and the selectivity decreased for 2-meth-
Org. Lett., Vol. 8, No. 22, 2006
5079

Compared with the LDA method, the triethylgallium
method has several notable properties in the enolate forma-
tion from ketones: (1) simple operation of heating with a
reagent; (2) formation of volatile ethane as the byproduct;
(3) preferential enolization of symmetrical cyclic ketones
possessing an R-methine group over that of acyclic ketones;
(4) methylene preference in the enolization of unsymmetrical
ketones; (5) kinetic enolate formation.
Scheme 8
Acknowledgment. R.A. acknowledges JSPS for financial
support (No. 18790004). The fellowship for young scientists
to Y.N. from JSPS is also gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
14%-d at the methine group. The lack of serious deuterium
scrambling indicated the formation of a kinetic enolate.
Methylene deprotonation at a high temperature under kinetic
control is another interesting aspect of this method.
OL061948M
5080
Org. Lett., Vol. 8, No. 22, 2006