α-alkylation of ketones by addition of zinc enamides to unactivated olefins

Article abstract of DOI:10.1021/ja0465193

A zinc enamide generated from the corresponding N-aryl imine undergoes addition to an unactivated olefin, such as ethylene, 1-octene, and isobutylene, to generate an α-alkylated γ-zincioimine intermediate in good to excellent yield. Terminal and gem-disubstituted olefins react with >99% regioselectivity, allowing the C-C bond formation to take place at the more hindered carbon of the double bond. The organozinc intermediate undergoes further C-C bond formation with a carbon electrophile to give, upon hydrolysis of the imine, an α-alkylated ketone bearing a variety of functionalized primary, secondary, and tertiary alkyl groups.

Full text of DOI:10.1021/ja0465193

Published on Web 09/04/2004
r-Alkylation of Ketones by Addition of Zinc Enamides to
Unactivated Olefins
Masaharu Nakamura,*,†,‡ Takuji Hatakeyama,‡ and Eiichi Nakamura*,‡
Contribution from the Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received June 12, 2004; E-mail: masaharu@chem.s.u-tokyo.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
Abstract: A zinc enamide generated from the corresponding N-aryl imine undergoes addition to an
unactivated olefin, such as ethylene, 1-octene, and isobutylene, to generate an R-alkylated γ-zincioimine
intermediate in good to excellent yield. Terminal and gem-disubstituted olefins react with >99%
regioselectivity, allowing the C-C bond formation to take place at the more hindered carbon of the double
bond. The organozinc intermediate undergoes further C-C bond formation with a carbon electrophile to
give, upon hydrolysis of the imine, an R-alkylated ketone bearing a variety of functionalized primary,
secondary, and tertiary alkyl groups.
Introduction
Addition of a metal enolate to a carbonyl compound is a
fundamental repertoire for carbon-carbon bond formation.
However, little attention has been paid to its isoelectronic
olefinic variant, addition of a metal enolate to a simple olefin,
because of its unfavorable thermodynamics and kinetics. One
naturally expects that the addition of a heteroatom-stabilized
anion A across an unactivated carbon-carbon double bond
would first require a high activation energy, and second suffer
from unfavorable thermodynamics.1,2 Despite this inherent
difficulty, such a transformation would provide an alternative
approach for the R-alkylation of carbonyl compounds:3 (1) a
sequential three-component coupling reaction that affords mul-
tifunctionalized compounds unavailable by the conventional
alkylation or Michael addition reactions; (2) the use of industri-
ally abundant alkenes that have been scarcely utilized for the
synthesis of fine chemicals; and (3) the synthesis of R-secondary
and R-tertiary alkylated ketones from substituted alkenes that
continues to be difficult in the conventional alkylation reaction
relying on the use of a secondary4 or tertiary alkyl halide.5
We previously reported the addition6 of a zincated hydrazone
A (X ) NN(CH3)2, M+ ) (C4H9)Zn+)7 to a variety of alkenes
such as ethylene and vinyl metals,8 and an asymmetric synthesis
of R-substituted ketones by the reaction of a chiral zinc enamide
A (X ) chiral amino ether, M+ ) CH3Zn+).9 Whereas the
carbozincation and the successive electrophilic trapping have
been achieved in high overall yield for ethylene, the first reaction
with substituted alkenes7a was found to be too slow to be
synthetically useful.10 We decided to systematically reinvestigate
the imine and hydrazone compounds to achieve high reactivity
and selectivity toward unactivated olefins so that we could
establish the carbometalation approach as a generally useful
R-alkylation reaction of carbonyl compounds.
(5) An R-tertiary alkylation of carbonyl compounds was achieved with enol
silyl ethers under Lewis acidic conditions: (a) Reetz, M. T. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 96-107. (b) Reetz, M. T.; Chatziiosifidis, I.;
Hubner, F.; Heimbach, H. Org. Synth. 1984, 62, 95-100.
(6) Reviews of carbometalation reaction: (a) Marek, I.; Normant, J. F. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998; pp 271-337. (b) Hoveyda, A. H.; Heron,
N. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, pp 431-454. (c)
Negishi, E. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; pp 165-189. (d) Asao, N.; Yamamoto, Y. Bull.
Chem. Soc. Jpn. 2000, 73, 1071-1087. (e) Fallis, A. G.; Forgione, P.
Tetrahedron 2001, 57, 5899-5913.
† PRESTO, Japan Science and Technology Corporation (JST).
‡ The University of Tokyo.
(1) (a) Lorthiois, E.; Marek, I.; Normant, F. Tetrahedron Lett. 1997, 38, 89-
92. (b) Lorthiois, E.; Marek, I.; Normant, F. J. Org. Chem. 1998, 63, 566-
574; 2442-2450.
(2) (a) Pei, T.; Widenhoefer, A. R. J. Am. Chem. Soc. 2001, 123, 11290-
11291. (b) Wang, X.; Pei, T.; Han, X.; Widenhoefer, A. R. Org. Lett. 2003,
5, 2699-2701.
(3) Reviews: (a) Yamamoto, Y.; Sasaki, N. In Stereochemical control, bonding,
and steric rearrangements; Bernal, I., Ed.; Stereochemistry of Organome-
tallic and Inorganic Compounds 4; Elsevier: New York, 1990; pp 3-92.
(b) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 3, pp 1-64.
(4) Certain lithioenamines undergo the R-secondary alkylation with the
corresponding alkyl iodide: (a) Meyers, A. I.; Williams, D. R.; Erickson,
G. W.; White, S.; Druelinger, M. J. Am. Chem. Soc. 1981, 103, 3081-
3086. (b) Enders, D.; Bockstiegel, B. Synthesis 1989, 493-496. (c)
Climarelli, C.; Palmieri, G. Tetrahedron 1998, 54, 15711-15720. (d)
Enders, D.; Nuhring, A.; Runsink, J. Chirality 2000, 12, 374-377.
(7) (a) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. Engl. 1997, 36, 2491-
2493. (b) Nakamura, E.; Kubota, K. J. Org. Chem. 1997, 62, 792-793.
(c) Nakamura, E.; Kubota, K.; Sakata, G. J. Am. Chem. Soc. 1997, 119,
5457-5458. (d) Nakamura, E.; Kubota, K. Tetrahedron Lett. 1997, 38,
7099-7102. (e) Nakamura, M.; Hara, K.; Sakata, G.; Nakamura, E. Org.
Lett. 1999, 1, 1505-1507.
(8) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125,
13002-13003. (b) Yamaguhi, M.; Tsukagoshi, T.; Arisawa, M. J. Am.
Chem. Soc. 1999, 121, 4074-4075. (c) Koradin, C.; Rodriguez, A.-L.;
Knochel, P. Synlett 2000, 1452-1454.
(9) Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am. Chem.
Soc. 2003, 125, 6362-6363.
(10) (a) Nakamura, M.; Inoue, T.; Sato, A.; Nakamura, E. Org. Lett. 2000, 2,
2193-2196. (b) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 4, pp 865-911.
9
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J. AM. CHEM. SOC. 2004, 126, 11820-11825
10.1021/ja0465193 CCC: $27.50 © 2004 American Chemical Society

R
-Alkylation of Ketones
A R T I C L E S
Scheme 1. R-Alkylation of Ketone by Carbometalation Approach
for a temperature of 30 °C for 11 days in Et2O to achieve 30%
yield.7a The carbometalation reaction took place with 100%
regioselectivity, favoring the C-C bond formation at the C-2
position of the 1-octene.7a,9 After protonation of the carbon-
zinc bond and hydrolysis of the imine moiety with acetic acid,
the ketone 8 was obtained as a mixture of diastereomers (syn:
anti ) 7:3 to 6:4). The poor diastereoselectivity may be
attributed to mutual face selection and/or the geometrical
flexibility of the zinc enamide intermediate.11
We found a significant increase of the reactivity of the zinc
enamide by proper choice of the nitrogen substituent, and that
the enamide thus reacts smoothly with 1-alkenes. The carbo-
metalation reaction generates a γ-zincioimine intermediate in
high yield, which can then be trapped with a variety of carbon
electrophiles either with or without a transition metal catalyst.
The overall result represents an efficient cross-coupling reaction
of an imine, an alkene, and a carbon electrophile under mild
reaction conditions. One bonus is that the reaction provides a
new entry to R-secondary and R-tertiary alkylated ketones that
have been difficult to obtain by the conventional method relying
on the reaction of a metal enamide or enolate with an alkyl
halide.
Figure 1 shows the effect of the substituent of the enamide
nitrogen atom. The zincated hydrazone 7 [R ) N(CH3)2] gave
the adduct 8 in 28% yield (entry 1). The N-cyclohexyl zinc
enamide is unstable at room temperature, producing tiny
particles of metallic zinc, and hence no adduct was obtained
under the reaction conditions (entry 2). The N-2-methoxyethyl
zinc enamide, on the other hand, is stable under the reaction
conditions, but not reactive enough (17% yield, entry 3). The
N-phenyl zinc enamide showed certain reactivity to give the
desired product in 62% yield (entry 4). The N-2-methoxy phenyl
enamide was less reactive, and the 4-methoxy one was found
to be far more reactive (entry 5 vs 6). Finally, 89% yield was
achieved by the use of N-4-diethylaminophenyl zinc enamide
(entry 7). We therefore conclude that an electron-donating
substituent enhances the reactivity of zinc enamide.
Having achieved the high-yielding R-secondary alkylation
with 1-octene by the use of N-aryl zinc enamides, we then
examined the reaction of isobutylene so as to perform an
R-tertiary alkylation of ketone. We found, at this juncture, that
the use of LDA in THF for deprotonation of imine 6 gives a
result comparable to that obtained with the use of t-BuLi, when
resulting diisopropylamine and THF are removed in vacuo
before the reaction with ZnCl2 (eq 3).
Results and Discussion
Scheme 1 outlines the procedure for the alkylation of a ketone
based on our carbometalation approach. The imine 1 prepared
from the corresponding ketone is deprotonated with lithium
diisopropylamide (LDA). The resulting lithium enamide was
allowed to react with zinc chloride and then with butyllithium
to generate the N-aryl zinc enamide 2. The reaction of 2 with
a variety of simple olefins was examined under neat conditions
or in hexane. The γ-zincioimine product 3 was trapped with an
electrophile to obtain primary, secondary, and tertiary alkylated
ketones 5 after hydrolysis of the imine group in 4.
Reaction of 1-Octene and Isobutylene with Zinc Enamide
Possessing a Variety of Substituents on Enamide Nitrogen.
In the past several years,7,8a,9 we have examined imine, oxime,
and hydrazone derivatives of several ketones as a metal enamide
precursor, and eventually we focused our attention on the imines
bearing a variety of aryl substituents on the nitrogen atom, which
are expected to exert electronic and steric influences directly
on the transition state of the carbometalation reaction. We first
studied the addition of a variety of zinc enamides to 1-octene,
which gave poor results under our previous conditions developed
for zincated hydrazones.7a
The zinc enamide 7 was prepared from the corresponding
3-pentanone imine 6 by a sequence of deprotonation with tert-
butyllithium (or LDA, vide infra), transmetalation with zinc
chloride, and ligand exchange with butyllithium (Scheme 1).
The ligand exchange is necessary to accelerate the addition
reaction, as we previously noted.7,9 The butyl group was chosen
here because of its availability, while methyl and tert-butyl
ligands are equally useful. Solvent was removed in vacuo from
the solution of 7, and 1-octene was then added. The addition
reaction was initiated at 60 °C and continued for 24 h. Note
that our previous conditions, optimized for the addition of a
zincated hydrazone such as 7 [R ) N(CH3)2] to 1-octene, call
Figure 2 shows the results of the screening of various zinc
enamides in the reaction with isobutylene. The zincated hydra-
zone 7 [R ) N(CH3)2] gave the R-tertiary butyl ketone 9 as the
sole product but only in 6% yield (entry 1). The N-cyclohexyl
zinc enamide and N-2-methoxyethyl zinc enamide did not react
with this hindered olefin (entries 2 and 3). The parent N-phenyl
zinc enamide afforded 9 in 8% yield (entry 4). As found in the
reaction of 1-octene, an electron-donating substituent at the
4-position increases the reaction rate and the product yield (entry
(11) The reaction of a cyclohexanone imine with 1-octene showed the same
range of the low diastereoselecitivity (data not reported). We are thus
assuming that the poor diastereoselectivity in the reaction of the 3-pentanone
imine is due to low selectivity of mutual face selection, but not to the E/Z
isomerism of the zinc enamide intermediate.
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A R T I C L E S
Nakamura et al.
Figure 1. Chemical yields of the reaction of 1-octene with zinc enamides possessing a variety of substitutes on the enamide nitrogen. The yield was
determined by GC analysis with tridecane as an internal standard.
Figure 2. Chemical yields of the reaction of isobutylene with zinc enamides possessing a variety of substituents on the enamide nitrogen. The yield was
determined by GC analysis with decane as an internal standard.
5). The 2-methyl substitution enhances considerably the reactiv-
ity of the zinc enamide in comparison with the 3- or 4-methyl
substitutions (entries 6-8). Whereas a simple electronic effect
based on the Hammett rule cannot explain the observed
tendency, the 2-methyl substitution can exert a certain steric
effect on the transition structure9 and may contribute to
conformational stabilization of the transition state. 2-Methyl-
4-diethylaminophenyl substitution further improved the product
yield (entry 9). 2,4-Dimethyl substitution was found to be the
optimum in terms of both the reactivity and availability of the
starting arylamine (entry 10). 2,4,6-Trimethyl substitution may
cause a steric problem to lower the yield (entry 11).
It should be noted that the zinc enamide, which shows
excellent reactivity toward the unactivated olefins, does not add
to an electron-deficient olefin used commonly as a Michael
acceptor under the reaction conditions. For instance, the zinc
enamide 10 reacts with tert-butyl acrylate to give an acrylate
polymer rather than a 1:1 adduct (70% recovery of the parent
imine 6) under the reaction conditions (65 °C, 12 h in hexane),
whereas 10 gives the adduct 8 in 92% yield (Table 1, entry 3).
As discussed previously for the reaction of an allylic metal
compound with an olefin,12 the present reaction utilizes the
favorable interaction between the zinc atom and the olefin as
well as the stability of alkyl zinc intermediate to achieve a useful
synthetic outcome.
Addition of the Aryl Zinc Amide to a Variety of Olefins.
Examination of the reactivity of the zinc enamide 10 toward
various unactivated olefins revealed the wide scope of the
reaction. The high reactivity of 10 is apparent already in the
addition to ethylene (entry 1), where the alkylated product was
obtained in 94% yield under atmospheric pressure of ethylene;
note that zincated hydrazones7a and imines possessing a chiral
etheral side chain9 require 5-30 atm of ethylene atmosphere
to achieve sufficient conversion. The addition to propylene was
also accomplished under 1 atm of propylene atmosphere to
afford the isopropylated ketone 12 in 86% yield (entry 2).
The high reactivity of the aryl zinc enamide enables us to
carry out the addition of 10 to 1-octene by the use of a nearly
stoichiometric amount (1.2 equiv) of the olefinic substrate to
achieve 92% yield (entry 3), whereas a zincated hydrazone such
as 7 [R ) N(CH3)2] needed 10 equiv of 1-octene to achieve
30% yield, even after 11 days.7a The addition introduces
exclusively a secondary alkyl group to the R-position of the
ketone. Unfortunately, the relative stereochemistry between the
newly formed chiral centers has thus far been uncontrollable,
and the ratio stays in a range of 7:3 to 6:4 (syn:anti).
Interestingly, the regioselectivity of the addition of 10 to styrene
is such that a primary and a secondary alkylated product are
produced in a 46:54 ratio (entry 4). The formation of such an
isomeric mixture stands in contrast to the general tendency of
(12) (a) Nakamura, E.; Nakamura, M.; Miyachi, Y.; Koga, N.; Morokuma, K.
J. Am. Chem. Soc. 1993, 115, 99-106. (b) Kubota, K.; Mori, S.; Nakamura,
M.; Nakamura, E. J. Am. Chem. Soc. 1998, 120, 13334-13341. (c) Hirai,
A.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2000, 122, 11791-
11798.
9
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R
-Alkylation of Ketones
A R T I C L E S
Table 2. Alkylation of a Variety of Ketones with Alkenes
Table 1. R-Alkylation of 3-Pentanone with Various Alkenes
a Zinc enamides (Ar ) 2,4-dimethylphenyl) were prepared from the
corresponding imines. b Regioselectivity of the carbozincation was >99:1
unless otherwise noted. c Isolated yield. d Determined by GC analysis with
decane as internal standard. e Linear:branched ) >98:2.
3). The addition to styrene, on the other hand, showed reversed
regioselectivity, giving only the linear adduct 21 in 87% yield
(entry 4); this selectivity is different also from the one observed
for 10 (Table 1, entry 4). The origin of this interesting difference
is unclear at this time, but the result suggests that some subtle
steric effects overwhelm the electronic effects.3 The cyclic zinc
enamide 18 gave 2-tert-butylcyclohexanone 22 in 24% yield.
An aryl alkyl ketone also took part in the alkylation reaction:
the addition of the zinc enamide 23 to propylene proceeded at
80 °C to give the R-isopropylated product 24 in 74% yield (entry
6). An unsymmetrical ketone imine such as 2-methyl-3-
pentanone can enolize in two different ways and gave a mixture
of R- and R′-alkylated product upon the addition reaction in
rather poor yield (data not shown).
Electrophilic Trapping of γ-Zincioimine: One-Pot, Three-
Component Couplings. The organozinc intermediates14 gener-
ated by the new carbometalation reaction are stable even at 80
°C and can be used for further C-C bond-forming reaction with
or without a transition metal catalyst.15 Scheme 2 shows the
results of the electrophilic trapping of γ-zincioimines 25 and
26, which are generated by the addition of the zinc enamide 10
to ethylene and isobutylene, respectively.
a Regioselectivity of the carbozincation was >99:1 unless otherwise
noted. b Determined by GC analysis with decane or tridecane as internal
standard. c Isolated yield. d Syn:anti ) 67:33. e Linear (13):branched (14)
) 46:54, syn:anti ) 66:34.
the carbometalation of styrene,13 where a benzylic anion forms
preferentially.7a,9
The reaction of methylenecyclohexane illustrates the general-
ity of the tertiary alkylation reaction (77% yield, entry 5).
Together with the results shown in Figure 1, entry 6 illustrates
the success in the tert-butylation with isobutylene (entry 6).
Heating at 80 °C accelerates the addition reaction, and a high
yield was achieved after a shorter reaction period (36 h), as
shown in entry 7.
Alkylation of a Variety of Ketones with Simple Olefins.
Having established an effective procedure for the generation of
the zinc enamide and its addition to a simple olefin, we
examined the scope of the reaction for the ketone part. The zinc
enamide of 5-nonanone 16 reacted with isobutylene more slowly
than the lower homologue (Table 2, entry 1). The cyclohexanone
zinc enamide 18 was as reactive as 10 to react with ethylene
under atmospheric pressure to give 2-ethylcyclohexanone in
90% yield (entry 2). The addition of this cyclic zinc enamide
to propylene gave exclusively a branched product, 20 (entry
The zinc intermediate 25 reacts with ethyl 2-bromomethyl-
acrylate to give the ketoester 27 in 85% yield at 25 °C without
any additives (Scheme 2a). The Pd-catalyzed cross-coupling
(14) (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1983, 105, 651-652.
(b) Kuwajima, I.; Nakamura, E. Top. Curr. Chem. 1990, 155, 1-39.
(15) Reviews: (a) Knochel, P.; Singer, D. Chem. ReV. 1993, 93, 2117-2188.
(b) Negishi, E. In Organozinc Reagents; Knochel, P., Jones, P., Eds.; Oxford
University Press: Oxford, 1999; pp 213-243.
(13) (a) Norsikian, I.; Marek, I.; Normant, J. F. Tetrahedron Lett. 1997, 38,
7523-7526. (b) Rodriguez, A. L.; Bunlalsananusorn, T.; Knochel, P. Org.
Lett. 2000, 2, 3285-3287.
9
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A R T I C L E S
Nakamura et al.
Scheme 2. Synthesis of Functionalized Ketones via Three-Component Couplinga
a Reagents and conditions: (a) ethyl 2-bromomethylacrylate (2.2 equiv), 0 °C, 4 h then H3O+; (b) 4-iodoacetylbenzene (2.2 equiv)/TMEDA (2.0 equiv)/
PdCl2(PPh3)2 (5 mol %), 25 °C, 8 h then H3O+; (c) 4-iodonitrobenzene (2.2 equiv)/TMEDA (2.0 equiv)/PdCl2(PPh3)2 (5 mol %), 25 °C, 8 h then H3O+; (d)
allyl bromide (2.4 equiv), 25 °C, 3 h then H3O+; (e) iodomethane (0.2 equiv) then in vacuo, 2-cyclohexen-1-one (2.4 equiv)/Me3SiCl (2.4 equiv)/TMEDA
(2.0 equiv)/CuCN (0.3 equiv), 0 °C, 6 h then H3O+; (f) iodomethane (0.2 equiv) then in vacuo, â-bromostyrene (>99.9% E, 2.4 equiv)/TMEDA (2.0
equiv)/CuCN (1.0 equiv), 0 °C, 8 h then H3O+.
reactions with 4-iodoacetylbenzene and 4-iodonitrobenzene
proceeded smoothly at 30 °C to yield 86% of the diketone 28
and 80% of the nitro ketone 29, respectively (Scheme 2b,c),
attesting to the high functional group compatibility of such a
reaction.9 In these latter reactions, the butyl group on the zinc
atom that is used as a dummy ligand in the first reaction reacted
faster with the electrophile in the second reaction. Therefore,
we needed to use at least 2 equiv of the electrophiles.
The addition/trapping sequence can be extended to the more
hindered adduct 26 formed by the reaction with isobutylene.
For instance, allylation of 30 was achieved in 82% yield without
any additives (Scheme 2d). In the presence of 2.4 equiv of Me3-
SiCl16 and 30 mol % of CuCN, 25 underwent 1,4-addition17 to
2-cyclohexen-1-one (Scheme 2e) to give the corresponding
cyclohexanone derivative 31 in 71% yield after hydrolysis with
acetic acid. Coupling with â-bromostyrene (Scheme 2f) pro-
ceeded in the presence of 1 equiv of CuCN to afford the cross-
coupling product 32 in 78% yield. In this reaction, we added
20 mol % of iodomethane before the 1,4-addition or the coupling
with â-bromostyrene for the purpose of trapping of unreacted
zinc enamide that interferes with the cross-coupling reaction.
N,N,N′,N′-Tetramethylethylenediamine (TMEDA) was necessary
to bring the reaction to completion since the reaction otherwise
stopped halfway.18 The examples of the three-component
coupling reactions shown in Scheme 2 demonstrate the new
opportunities provided by the present carbometalation reaction
in the synthesis of densely functionalized organic molecules.
because of its apparently unfavorable thermodynamics.19 The
addition of a zinc enamide to an alkene reported here has opened
a new possibility for the chemical transformation in the synthesis
of R-alkylated ketones. A particularly useful nature of the
present reaction is its potential to introduce a wide variety of
secondary and tertiary alkyl groups next to the carbonyl groups
a synthetic sequence rather difficult to achieve so far. We have
shown that installation of an electron-donating aryl group on
the enamide nitrogen dramatically enhances the reactivity of
the zinc enamide to effect high-yielding and regioselective
carbozincation of unactivated olefins. For instance, the zinc
enamide 10 undergoes smooth addition to a variety of alkenes
to produce the corresponding γ-zincioimines. Furthermore, the
organozinc addition product serves as a carbon nucleophile for
the succeeding C-C bond formations, which allows further
introduction of a wide range of functional groups onto the
alkylated carbonyl compounds. We have demonstrated a pos-
sibility for the utilization of unactivated olefins, provided directly
as a primary product of the chemical industry, for controlled
C-C bond formation. The use of industrially abundant carbon
resources, such as ethylene and 1-alkenes, is highly attractive
and desirable and will become an important subject in organic
synthesis.20
Experimental Section
General. Flash column chromatography was performed on Kanto
Silica gel 60 (spherical, neutral, 140-325 mesh) as described by Still
et al.21 High-pressure reactions were conducted in a glass autoclave
purchased from Taiatsu Techno Co. (Hyper Glass Cylinder). Proton
nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic
resonance (13C NMR) spectra were recorded with JEOL AL-400 (400
MHz), JEOL ECX-400 (400 MHz), or JEOL ECA-500 (500 MHz)
NMR spectrometers. Gas chromatographic (GC) analyses were per-
formed on Shimadzu GC-14B instruments equipped with an FID
detector and a capillary column, HR-1 (Shinwa, 25 m × 0.25 mm i.d.,
Conclusion
The addition of a metal enolate or its equivalent to an alkene
has thus far been regarded as a difficult reaction to perform
(16) (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368-3370.
(b) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron
1989, 45, 349-362.
(17) Reviews: (a) Knochel, P.; Jones, P.; Langer, F. In Organozinc Reagents;
Knochel, P., Jones, P., Eds.; Oxford University Press: Oxford, 1999; pp
179-212. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061.
(c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002;
pp 224-258.
(18) Effect of TMEDA on the reaction of organozinc reagents: (a) Tuckmantel,
W.; Oshima, K.; Nozaki, H. Chem. Ber. 1986, 119, 1581-1593. (b) Arai,
M.; Kawasuji, T.; Nakamura, E. Chem. Lett. 1993, 2, 357-360. (c)
Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2000, 122, 978-
979.
(19) (a) Hegedus, L. S.; Williams, R. E.; McGuire, M. A.; Hayashi, T. J. Am.
Chem. Soc. 1980, 102, 4973-4979. (b) Ito, Y.; Nakatsuka, M.; Saegusa,
T. Tetrahedron Lett. 1980, 21, 2873-2876.
(20) During the preparation of this article, two catalytic alkylation reactions of
1,3-dicarbonyl compounds with unactivated olefins were reported: (a) Yao,
X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884-6885. (b) Wang, X.;
Widenhoefer, R. A. Chem. Commun. 2004, 660-661.
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11824 J. AM. CHEM. SOC. VOL. 126, NO. 38, 2004

R
-Alkylation of Ketones
A R T I C L E S
0.25 µm film), or a CP-Chirasil-DEX CB (Chrompack, 25 × 0.25 mm
i.d., 0.25 µm film). IR spectra recorded on a FT/IR-420 (JASCO) or a
React IR 1000 reaction analysis system equipped with DuraSample IR
(ASI Applied System) are reported in cm-1. High-resolution mass
spectra are taken with the EI (electron impact) method on a JEOL GC-
mate II. ZnCl2 (anhydrous, beads) was purchased from Aldrich Inc.
2,4-Dimethylaniline was purchased from Wako Co. Isobutylene was
purchased from Tokyo Kasei Kogyo Co. and dried over molecular
sieves in an autoclave before use. Ethylene and propylene were
purchased from Nippon Sanso Co.
Preparation of Zinc Enamide (Procedure A). To a solution of
diisopropylamine (0.16 mL, 1.1 mmol) in THF (1.2 mL) was added
dropwise BuLi (1.55 M in hexane, 0.65 mL, 1.02 mmol) at 0 °C. After
30 min, imine 33 (0.209 mL, 1.0 mmol) was slowly added at 0 °C.
After 6 h, the solvents were removed in vacuo (30 min, 0 °C, 0.1
mmHg). Residual sludgy lithium enamide was dissolved in Et2O (0.5
mL), and ZnCl2 (0.5 M in Et2O, 2.0 mL, 1.0 mmol) was added at 0
°C. After 30 min, BuLi (1.55 M in hexane, 0.65 mL, 1.0 mmol) was
added at -78 °C (or added dropwise at 0 °C), and the reaction mixture
was warmed to ambient temperature.
Addition to Ethylene; 4-Methylhexan-3-one (11) (Procedure B).
After the reaction performed according to procedure A, Et2O was
removed at 50 °C with N2 flow. The reaction mixture was heated to
50 °C for 12 h under an ethylene atmosphere (1 atm) and then cooled
to 0 °C. Acetic acid (1.0 mL) and water (0.5 mL) were added at 0 °C.
Hydrolysis was carried out at room temperature for 1 h, and then water
(4.5 mL) was added at that temperature. The aqueous layer was
extracted five times with pentane. The combined organic extracts were
washed sequentially with saturated aqueous sodium bicarbonate, 0.5
N HCl, and saturated aqueous sodium bicarbonate. Gas chromatography
analysis was carried out (94% yield) by using decane (39.0 µL, 0.2
mmol) as an internal standard. The organic layer was chromatographed
on silica gel (3 g, pentane and then 3% Et2O in pentane) to obtain the
corresponding ketone (0.068 g, 60% yield).
1.01 (d, J ) 7.2 Hz, 3H, COCHCH3), 1.04 (t, J ) 7.2 Hz, 3H,
COCH2CH3), 1.10-1.35 (m, 10H, CH(CH2)5CH3), 1.73-1.83 (m, 1H,
COCHCH), 2.37-2.51 (m, 3H, COCHCH, COCH2CH3); 13C NMR
(100 MHz, CDCl3) δ 7.7, 13.1, 14.0, 17.8, 22.6, 26.7, 29.5, 32.7, 35.1,
35.1, 51.6, 215.5.
Addition to Isobutylene; 4,5,5-Trimethylhexan-3-one (9). After
the reaction performed according to procedure A, the solvents were
removed in vacuo (10 min, room temperature, 0.1 mmHg). Isobutylene
(ca. 0.5 mL) was added at -78 °C, and the reaction mixture was charged
in an autoclave. The autoclave was maintained at 65 °C for 60 h with
stirring (4 atm) and cooled to ambient temperature. After the removal
of unreacted isobutylene, the reaction mixture was moved to an ice
bath, and acetic acid (1.0 mL) and water (0.5 mL) were added.
Hydrolysis was carried out at 90 °C for 6 h, and then water (4.5 mL)
was added at ambient temperature. The aqueous layer was extracted
five times with pentane. The combined organic extracts were washed
sequentially with saturated aqueous sodium bicarbonate, 0.5 N HCl,
and saturated aqueous sodium bicarbonate. Gas chromatography
analysis was carried out (85% yield) using decane (39.0 µL, 0.2 mmol)
as an internal standard. The organic layer was chromatographed on
silica gel (3 g, pentane and then 3% Et2O in pentane) to obtain the
corresponding ketone (0.108 g, 76% yield).
Palladium-Catalyzed Coupling Reaction of Organozinc Inter-
mediate with 4-Iodoacetylbenzene; 6-(4-Acetylphenyl)-4-methyl-
hexan-3-one (28). The addition reaction was carried out according to
procedure B on a 10 mmol scale at 50 °C for 24 h. The solvents were
removed in vacuo. To the reaction mixture were added TMEDA (3.0
mL, 20 mmol), 4-iodoacetylbenzene (5.4 g, 22 mmol), PdCl2(PPh3)2
(0.35 g, 0.5 mmol), and THF (20 mL) in turn at 0 °C. The reaction
mixture was stirred at room temperature (ca. 25 °C) for 8 h, and then
acetic acid (5 mL) and water (5 mL) were added at 0 °C. Hydrolysis
was carried out at room temperature for 1 h, and then water (40 mL)
was added at ambient temperature. The aqueous layer was extracted
five times with Et2O. The combined organic extracts were washed
sequentially with saturated aqueous sodium bicarbonate, 0.5 N HCl,
and saturated aqueous sodium bicarbonate, and then in vacuo. The crude
product was chromatographed on silica gel (100 g, pentane and then
10, 20% Et2O in pentane) to obtain the corresponding diketone (1.928
g, 83% yield): Rf ) 0.18, 20% Et2O in pentane; IR (neat) 1710 and
1679 (CdO), 1606 (aromatic CdC), 1358, 1267, 1182, 956.0, 819.9;
1H NMR (400 MHz, CDCl3) δ 0.96 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.04
(d, J ) 7.2 Hz, 3H, CHCH3), 1.55 (dq, J ) 7.2, 13.5 Hz, 1H, CHCHH),
1.93 (dq, J ) 7.2, 13.5 Hz, 1H, CHCHH), 2.30-2.50 (m, 3H, CHC-
(dO)CH2), 2.49 (s, 3H, CCH3), 2.54 (t, J ) 7.2 Hz, 2H, CH2Ar), 7.17
(d, J ) 8.5 Hz, 2H, aromatic CH), 7.79 (d, J ) 8.5 Hz, 2H, aromatic
CH); 13C NMR (100 MHz, CDCl3) δ 7.6, 16.6, 26.4, 33.3, 33.9, 34.2,
45.2, 128.4 (2C), 128.4 (2C), 135.0, 147.5, 197.6, 214.6; EI-HRMS
calcd for C15H20O2 [M]+ 232.1463, found 232.1424. Anal. Calcd for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.33; H, 8.81.
Addition to 1-Octene; 4,5-Dimethylundecan-3-one (8). After the
reaction performed according to procedure A, the solvents was removed
removed in vacuo (10 min, room temperature, 0.1 mmHg). 1-Octene
(0.19 mL, 1.2 mmol) and hexane (0.1 mL) were added, and then the
reaction mixture was heated to 65 °C for 12 h. Acetic acid (1.0 mL)
and water (0.5 mL) were added at 0 °C. Hydrolysis was carried out at
65 °C for 1 h, and then water (4.5 mL) was added at ambient
temperature. The aqueous layer was extracted five times with pentane.
The combined organic extracts were washed sequentially with saturated
aqueous sodium bicarbonate, 0.5 N HCl, and saturated aqueous sodium
bicarbonate. Gas chromatography analysis was carried out (92% yield,
syn:anti ) 7:3) by using tridecane (48.8 µL, 0.2 mmol) as an internal
standard. The organic layer was chromatographed on silica gel (5 g,
pentane and then 3% Et2O in pentane) to obtain the corresponding
ketone (0.178 g, 90% yield): Rf ) 0.66, 10% Et2O in pentane; IR-
(neat) 1712 (vs, CdO), 1459, 1378, 1261, 1108, 1023, 975.3, 804.5;
EI-HRMS calcd for C13H26O [M]+ 198.1984, found 198.1988.
Major diastereomer (syn; determined by comparison of the NMR
shifts with those of 4,5-dimethyldecan-3-one22): 1H NMR (400 MHz,
CDCl3) δ 0.78 (d, J ) 7.2 Hz, 3H, COCHCHCH3), 0.88 (t, J ) 7.2
Hz, 3H, CH2CH2CH3), 0.96 (d, J ) 7.2 Hz, 3H, COCHCH3), 1.05 (t,
J ) 7.2 Hz, 3H, COCH2CH3), 1.10-1.35 (m, 10H, CH(CH2)5CH3),
1.80-1.90 (m, 1H, COCHCH), 2.37-2.51 (m, 3H, COCHCH, COCH2-
CH3); 13C NMR (100 MHz, CDCl3) δ 7.8, 11.3, 14.0, 15.3, 22.6, 27.3,
29.4 31.8, 34.5, 34.5, 35.3, 50.6, 215.3.
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science, and Technology of Japan for financial
supports, a Grant-in-Aid for Specially Promoted Research, a
Grant-in-Aid for Young Scientists (A) (KAKENHI 14703011),
and the 21st Century COE Program for Frontiers in Fundamental
Chemistry.
Supporting Information Available: Experimental procedure
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Minor diastereomer (anti): 1H NMR (400 MHz, CDCl3) δ 0.87 (d,
J ) 7.2 Hz, 3H, COCHCHCH3), 0.88 (t, J ) 7.2 Hz, 3H, CH2CH2CH3),
(22) Yamaguchi, M.; Nitta, A.; Reddy, R. S.; Hirama, M. Synlett 1997, 117-
118.
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