One-pot β-substitution of enones with alkyl groups to β-alkyl enones

Article abstract of DOI:10.1039/b502134k

Vinylic hydrogens at the β-position of enones were effectively substituted with alkyl groups in a one-pot procedure to afford β-alkyl enones in good to high isolated yields by conjugate addition of higher-order dialkyl cyanocuprates to enones, followed by a reaction with N-tert-butylbenzenesulfinimidoyl chloride at -78 °C. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b502134k

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One-pot b-substitution of enones with alkyl groups to b-alkyl enones{
Jun-ichi Matsuo* and Yayoi Aizawa
Received (in Cambridge, UK) 11th February 2005, Accepted 9th March 2005
First published as an Advance Article on the web 21st March 2005
DOI: 10.1039/b502134k
and successive elimination of PhSeOH. Recently, Nicolaou et al.
have reported10 a new method by (i) conjugate addition of an alkyl
cuprate, followed by the trapping of the enolate with chloro-
trimethylsilane, and (ii) the reaction of the formed trimethylsilyl
enol ether with IBX (o-iodoxybenzoic acid). Snider et al. have
reported a direct method whereby the b-vinylic hydrogens of
enones were substituted with alkyl groups by using alkenes and
EtAlCl2, but applicable alkenes were limited to trisubstituted
ones.11
Vinylic hydrogens at the b-position of enones were effectively
substituted with alkyl groups in a one-pot procedure to afford
b-alkyl enones in good to high isolated yields by conjugate
addition of higher-order dialkyl cyanocuprates to enones,
followed by a reaction with N-tert-butylbenzenesulfinimidoyl
chloride at 278 uC.
Substitution of the vinylic hydrogen of a carbon–carbon double
bond with aryl, heterocyclic, benzyl, or vinyl halides in the
presence of a palladium catalyst, known as the Heck reaction, is a
useful method for the synthesis of various olefinic compounds
having a new carbon–carbon bond.1 The Heck reaction has been
effectively utilized in the total synthesis of complex natural
products because of its unique carbon–carbon bond formation
and its mild reaction conditions.2
In 2000, we introduced N-tert-butylbenzenesulfinimidoyl
chloride (1) as a new and variable oxidation (dehydrogenation)
reagent for organic synthesis,12 and various oxidation reactions
such as oxidation of alcohols,13 amines,14 and hydroxylamines15
were investigated. Among the 1-mediated oxidations, dehydro-
genation of carbonyl compounds to the corresponding
a,b-unsaturated compounds is notable because it proceeds under
rather mild conditions (278 uC) and in a one-pot manner:16 that is,
it is carried out by the reaction of 1 and lithium enolates generated
from carbonyl compounds with LDA. This unique dehydrogena-
tion has recently been utilized by other research groups for the
steps that are difficult to accomplish by conventional methods in
the total synthesis of natural products.17 Because lithium enolates
have been found to react with 1, and elimination takes place under
very mild conditions, we have hypothesized that enolate species
formed by conjugate addition of alkyl cuprates to enones would
also react with 1 to afford b-alkyl enones in a one-pot manner
(Scheme 1). We would like to describe here a new method for
direct b-substitution of enones with alkyl groups based on the
above-mentioned concept.
In the Heck reaction, however, alkyl halides are not employed
for substitution with alkyl groups, due to the very facile
b-elimination of the alkyl palladiums formed by oxidative addition
of palladium to those alkyl halides.2,3 Several other methods for
substitution of the vinylic hydrogen of olefins with alkyl groups
have been reported. For example, the vinylic hydrogen of styrene
can be replaced by alkyl groups to afford b-alkylstyrenes by using
alkyl bromide and a catalytic amount of (PPh3)2NiCl2.4 Similar
vinylic hydrogen substitution has been achieved by using cobalt
catalysts under alkyl radial–olefin coupling conditions.5 Still, the
remaining problem regarding the substitution of vinylic hydrogens
with alkyl groups, is that the above-mentioned coupling reactions
using nickel or cobalt catalysts are limited to styrene derivatives.
Considering the synthetic utility of b-alkyl a,b-unsaturated
carbonyl compounds for the Michael reaction, the Diels–Alder
reaction, etc., substitution of the b-vinylic hydrogen of an
a,b-unsaturated carbonyl compound with an alkyl group is also
an important synthetic reaction. Although b-alkyl enones are
known to be prepared by the reaction of b-bromo enones and
alkyl cuprates,6 or the reaction of b-alkoxy enones and
alkyllithium or Grignard reagents,7 the mild introduction of
leaving groups at the b-position of enones is not easy. Therefore, a
method for the efficient preparation of b-alkyl enones from simple
enones is strongly needed.
We first tried to substitute the b-vinylic hydrogen of
2-cyclohexen-1-one (2) with
a methyl group as a model
reaction (Table 1). When 1.1 equivalents of Me2CuCNLi2 were
added to 2 at 278 uC in diethyl ether, and then 1.1 equivalents of 1
were added at the same temperature, the desired product,
Several methods for substitution of the b-vinylic hydrogen of
enones with an alkyl group, by longer than single-step procedures
have been reported:8 for example, Reich et al. have reported9
substitution by (i) conjugate addition of alkyl cuprates to enones,
followed by reaction of the formed enolates with phenylselenyl
bromide, and (ii) oxidation of the isolated a-phenylselenyl ketones
{ Electronic supplementary information (ESI) available: experimental
procedures and characterization data for all new compounds. See http://
www.rsc.org/suppdata/cc/b5/b502134k/
Scheme 1 A concept for one-pot substitution of the b-vinylic hydrogen
of enones with an alkyl group by using alkyl cuprate and 1.
*matuo@lisci.kitasato-u.ac.jp
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Table 1 One-pot b-substitution of 2-cyclohexen-1-one (2) with a
methyl group to give 3-methyl-2-cyclohexen-1-one (3a)
Table 2 One-pot b-substitution of enones with alkyl and phenyl
groups
EntrySubstrate
Product
Yield (%)a
Entry
‘‘Me–Cu’’
1 (equiv.)
Yield (%)a
1
2
R 5 n-Bu (3b)
sec-Bu (3c)
tert-Bu (3d)
80b
81b
84b
1
2
3
4
5
6
7
8
a
Me2CuCNLi2
Me2CuCNLi2
Me2CuCNLi2
Me2CuLi
Me(2-Th)CuCNLi2
Me(2-Th)CuCNLi2
Me(Imid)CuCNLi2
Me(Imid)CuCNLi2
1.1
2.2
3.0
3.0
1.5
3.0
1.5
3.0
32
62
88
27
31
55
7
3
4c
CH2SiMe3 (3e) 46
CH2CH2Ph (3f)34
5d,e
6d,f
7d
8d
9d
10d
11d
Ph (3g)
R 5 n-Bu (5a)
sec-Bu (5b)
tert-Bu (5c)
Me (5d)
80
81
80g
89
94
1
Determined by GC-analysis using an internal standard.
CH2SiMe3 (5e) 41
(5f)
12d
84
83b
3-methyl-2-cyclohexen-1-one (3a), was obtained in 32% yield
(Entry 1). After screening various reaction conditions, it was found
that the yield of 3a was greatly improved by increasing the amount
of 1 employed: the use of 2.2 and 3.0 equivalents of 1 gave the
desired product 3a in 62 and 88% yields, respectively (Entries 2 and
3). In contrast, the use of a Gilman reagent (Me2CuLi), which was
prepared from 2 equivalents of MeLi and CuI, gave 3a in a low
yield, even when 3 equivalents of 1 were used (Entry 4). It was
thought that the lithium iodide generated in the preparation of the
Gilman reagent would influence the reaction of 1 (vide infra). Also,
higher-order cyanocuprates having dummy ligands such as
2-lithiothiophene18 or N-lithioimidazole19 gave insufficient yields
of 3a (Entries 5–8).
13
14
R 5 Me (7a)
n-Bu (7b)
64b
15
88
16
17
R 5 n-Bu (11a)
sec-Bu (11b)
53
39
18d
67h
Next, the scope and limitations of 1-mediated b-substitution of
enones with alkyl groups were investigated by using 1.1 equivalents
of higher-order dialkyl cyanocuprates and 3 equivalents of 1 in
diethyl ether (Table 2). In addition to a methyl group, n-butyl,
sec-butyl, and even tert-butyl groups were smoothly introduced
to the b-position of 2 or 4-phenyl-2-cyclohexen-1-one (4),
and the corresponding enones were obtained in high yields
(Entries 1–3, 7–10). When 4 was used as a substrate, the cuprate
addition was carried out at 223 uC, but an elimination step after
the addition of 1 proceeded at 278 uC within a few minutes to
afford b-alkyl enones in high yields after isolation by silica gel
a
b
Isolated yield unless noted otherwise. Determined by GC-analysis
c
using an internal standard. The cuprate addition was carried out at
d
278 y 250 uC. The cuprate addition was carried out at 223 uC.
2.2 equiv. of cuprate were employed. THF was used as solvent.
e
f
g
h
Two diastereomers were formed (dr 5 41:59). E/Z 5 1:1.
from cyclopropyl bromide20 was employed for the preparation of a
cyanocuprate, and it was found that the desired reaction proceeded
smoothly to give b-cyclopropyl enone in 84% isolated yield (Entry
12). These results suggested that cyanocuprates for the present
b-substitution of enones should be prepared from alkyl chlorides
or bromides.
column chromatography (Entries 7–10).
A phenyl and a
trimethylsilylmethyl group were also introduced in 80 and 46–
41% isolated yields, respectively (Entries 6, 4, and 11), by preparing
a cyanocuprate using commercially available phenyllithium or
trimethylsilylmethyllithium.
In addition to six-membered enones (2 and 4), cyclopentenone
(6), cycloheptenone (8), and non-cyclic enones were effectively
employed in the 1-mediated b-substitution with alkyl groups
(Entries 13–17). In the case of vinyl ketone 10 (Entries 16 and 17),
many by-products were detected that were primarily formed in the
conjugate addition step. b-Substitution of N-crotonoyl-2-oxazoli-
dinone (12) with the butyl group also gave the desired product 13
[as separable (E),(Z)-isomers, E/Z 5 1:1] in 67% combined yield
(Entry 18). It was noted that the regioselectivity of the reaction of 1
was controlled, and the elimination step proceeded at 278 uC in
all cases.
In order to introduce various alkyl groups, we tried to use alkyl
halides as
a source of alkyl groups. When higher-order
cyanocuprate was prepared from CuCN and 2-phenylethyllithium,
which was formed from 2-phenylethyl iodide and 2 equivalents of
tert-butyllithium, the desired enone having a phenylethyl group at
the b-position was isolated in only 34% yield (Entry 5). It was
assumed that lithium iodide, formed in the lithiation of the alkyl
iodide with tert-butyllithium, produced an unfavorable effect in the
reaction of the enolate with 1. Then, cyclopropyllithium generated
2400 | Chem. Commun., 2005, 2399–2401
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2 A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945–2963;
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A. Pfaltz and H. Yamamoto, 2004, Supplement 1, pp. 73–81.
3 Only those alkyl halides with a halide atom at a bridgehead position,
such as 1-bromoadamantane, have been successfully employed in Heck
reactions, see: S. Bra¨se, B. Waegell and A. de Meijere, Synthesis, 1998,
148–152.
Thus, a new method for the one-pot substitution of vinylic
hydrogen of enones was established{ by using higher-order dialkyl
cyanocuprates and 1. The present method can be regarded as
an alternative to Heck-type alkylation,4,5 and can be employed
for synthesizing
conditions.§
a variety of b-alkyl enones under mild
Jun-ichi Matsuo* and Yayoi Aizawa
Center for Basic Research, The Kitasato Institute, 1-15-1-S105,
Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
E-mail: matuo@lisci.kitasato-u.ac.jp; Fax: +81-42-778-9931;
Tel: +81-42-778-9931
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Notes and references
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{ Typical experimental procedure (Table 2, Entry 10) is as follows: to a
stirred solution of CuCN (29.9 mg, 0.33 mmol) in dry ether (2 mL) was
added a solution of methyllithium in diethyl ether (0.98 N, 0.63 mL,
0.62 mmol) at 278 uC, and the mixture was stirred for 10 min at 0 uC.
Then, a solution of 4 (49.6 mg, 0.28 mmol) in ether (1.5 mL) was added at
278 uC, and the reaction mixture was stirred for 20 min at 223 uC. During
this period, the bright yellow color of the mixture faded out. Next, a
solution of 1 (183 mg, 0.85 mmol) in ether (1 mL) was added at 278 uC,
and the mixture was stirred for 30 min. The reaction was quenched by
adding 10% NH4OH in saturated NH4Cl (5 mL) at 278 uC, and the
resulting mixture was extracted with ether three times. The combined
extracts were washed with water and brine, dried over anhydrous Na2SO4,
filtered and concentrated. The crude product was purified by silica gel
column chromatography (hexanes–ether) to afford 3-methyl-4-phenyl-2-
cyclohexen-1-one (5d) (48.8 mg, 0.26 mmol, 94%) as a colorless oil. 1H
NMR (500 MHz, CDCl3): d 7.35–7.15 (m, 5H), 6.09 (s, 1H), 3.57 (t, J 5
4.6 Hz, 1H), 2.40–2.25 (m 3H), 2.10–2.00 (m, 1H), 1.81 (s, 3H). 13C NMR
(125 MHz, CDCl3): d 199.4, 162.5, 140.5, 128.7, 128.4, 128.0, 127.0, 46.4,
33.9, 31.4, 23.4.
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Jpn., 2002, 75, 223–234; J. Matsuo, H. Kitagawa, D. Iida and
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2001, 712–713; T. Mukaiyama, A. Kawana, Y. Fukuda and J. Matsuo,
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§ The authors thank Professor Teruaki Mukaiyama (The Kitasato
¯
Institute) and Professor Satoshi Omura (The Kitasato Institute) for their
kind and generous support. The present work was partially supported by
Grant-in-Aids for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan. We thank the Fujisawa
Foundation for funding of this research.
17 K. C. Nicolaou, T. V. Koftis, S. Vyskocil, G. Petrovic, T. Ling, Y. M.
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