One-pot carbon-carbon bond formation at the β-position of cyclic ketones: oxidative Michael addition with alkyl malonates

Article abstract of DOI:10.1016/j.tetlet.2007.03.059

A carbon-carbon bond was formed at the β-position of cyclic ketones in a one-pot manner by oxidation with N-tert-butylbenzenesulfinimidoyl chloride, followed by the reaction of malonic acid esters or potassium cyanide.

Full text of DOI:10.1016/j.tetlet.2007.03.059

Tetrahedron Letters 48 (2007) 3155–3158
One-pot carbon–carbon bond formation at the b-position of
cyclic ketones: oxidative Michael addition with alkyl malonates
Jun-ichi Matsuo,* Hiroki Kawai and Hiroyuki Ishibashi*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
Received 18 February 2007; revised 8 March 2007; accepted 9 March 2007
Available online 13 March 2007
Abstract—A carbon–carbon bond was formed at the b-position of cyclic ketones in a one-pot manner by oxidation with N-tert-
butylbenzenesulfinimidoyl chloride, followed by the reaction of malonic acid esters or potassium cyanide.
Ó 2007 Elsevier Ltd. All rights reserved.
Direct carbon–carbon bond formation at the b-position
of ketones still remains a difficult task in organic synthe-
sis. Though homoenolate chemistry1,2 offers an effective
method for carbon–carbon bond formation with electro-
philes at the b-position of carbonyl compounds, homo-
enolates are not prepared directly from the
corresponding carbonyl compounds (Scheme 1, route
a). On the other hand, carbon–carbon bond formation
at the b-position of ketones with carbon nucleophiles
is usually conducted by several steps. That is, ketones
are first converted to the corresponding a,b-unsaturated
ketones at the expense of two steps,3–7 and the synthe-
sized enones are next allowed to react with carbon
nucleophiles to form a new carbon–carbon bond at their
b-positions (route b). To the best of our knowledge,
there is no report on one-pot carbon–carbon bond for-
mation at the b-position of saturated ketones.
We have developed a new method for mild and direct
dehydrogenation of carbonyl compounds to the corre-
sponding a,b-unsaturated carbonyl compounds using
N-tert-butylbenzenesulfinimidoyl chloride (1).8,9 We
Scheme 1. Carbon–carbon bond formation at the b-position of
ketones.
considered that one-pot b-substitution of saturated ke-
tones with carbon nucleophiles would be realized by
dehydrogenation of ketone with 1 followed by 1,4-addi-
tion of carbon nucleophiles unless N-tert-butylbenzene-
sulfenamide, an oxidation co-product formed from 1,
interfered with carbon nucleophiles. In this communica-
substitution of cyclic ketones with diethyl malonates and
potassium cyanide.
tion, we present the results for the 1-mediated one-pot b-
First, one-pot carbon–carbon bond formation at the b-
position of a-benzoyl cyclic ketones with diethyl malon-
ate was tried for two reasons: (i) the intermediate, a-
acyl-a,b-unsaturated cyclic ketones,10 are difficult to be
*
Corresponding authors. Tel./fax: +81 76 234 4439 (J.M.); e-mail:
jimatsuo@p.kanazawa-u.ac.jp
prepared by the Knoevenagel condensation,11 and (ii)
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.059

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J. Matsuo et al. / Tetrahedron Letters 48 (2007) 3155–3158
Table 1. One-pot oxidative Michael addition of diethyl malonate
anion to a-benzoyl cyclic ketones 2a–e
Table 2. One-pot oxidative Michael addition of malonic acid esters to
various a-acylcyclohexanones 4a–f
Entry
R
R0
Product Isolated yield (%)
1
2
3
4
5
6
o-BrC6H4 (4a)
p-BrC6H4 (4b)
p-MeOC6H4 (4c) Et
Et (4d)
Pr (4e)
Et
Et
5a
5b
5c
5d
5e
73
69
85
64
74
74
Entry
a-Benzoyl ketone
R
Product
Yielda (%)
1
2
3
4
5
6c
n = 1 (2a)
n = 2 (2b)
n = 3 (2c)
n = 4 (2d)
n = 8 (2e)
n = 2 (2b)
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
67
84
90
50
46b
62
Et
Et
Bn 5f
OMe (4f)
a Isolated yield unless otherwise noted.
b Determined by 1H NMR analysis using an internal standard.
c A solution of sodium diethyl methylmalonate anion was added in the
presence of HMPA (4.0 equiv).
these reactive intermediates should be employed without
isolation in successive transformation. The procedure
employed in Table 1 is as follows: a-benzoyl cyclic ke-
Table 3. One-pot oxidative Michael reaction of cyclic ketones 6a-c with diethyl malonates
Entry
Cyclic ketone
R
H
Conditions
rt, 2 h
Product
Isolated yield (%)
1
6a (n = 1)
7a
7b
82
2
3
6a (n = 1)
Me
Bn
rt, 3 h
79
59
6a (n = 1)
rt, 3 h
7c
4
5
6b (n = 2)
H
H
Reflux, 6 h
7d
7e
75
55
6c (n = 3)
Reflux, 26 h

J. Matsuo et al. / Tetrahedron Letters 48 (2007) 3155–3158
3157
tones were dehydrogenated to the corresponding enones
by treatment with sodium hydride followed by the reac-
tion with 1 at ꢀ78 °C. The in situ formed enones were
then treated at ꢀ78 °C with sodium diethyl malonate
anion which was prepared in advance. It was found that
the 1-mediated dehydrogenation of a-benzoyl cyclic ke-
tones 2a–e proceeded smoothly at ꢀ78 °C in each case,
and sodium diethyl malonate anion reacted with the
formed enones at ꢀ78 °C. a-Benzoylcyclohexanone
(2b) and a-benzoylcycloheptanone (2c) gave b-bis(eth-
oxycarbonyl)methyl ketones in high yields (entries 2
and 3), whereas five-membered ketone 2a and med-
ium-sized cyclic ketones such as 2d and 2e gave the cor-
responding b-substituted products in moderate yields
(entries 1, 4, and 5).12 Raising the reaction temperature
from ꢀ78 °C to room temperature did not improve the
yields of adducts. It was observed that adduct 3e was
unstable at room temperature and retro-Michael reac-
tion proceeded. b-Substitution of 2b with diethyl meth-
ylmalonate anion also proceeded in the presence of
HMPA (entry 6).13
Scheme 2. One-pot b-substitution of 2b with cyanide ion.
In summary, we have developed an efficient and conve-
nient one-pot carbon–carbon bond formation at the b-
position of cyclic ketones with malonic acid esters and
cyanide ion. The present procedure will be applicable
to other carbon nucleophiles to form various types of
carbon–carbon bonds at the b-position of carbonyl
compounds.
Acknowledgments
The authors are grateful for the financial support from
Takeda Science Foundation, and this work was partially
supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan.
Various a-acylcyclohexanones were employed in order
to investigate the scope and limitations of the present
one-pot carbon–carbon bond formation (Table 2).
The kind of substituent on the aromatic a-acyl group
gave a little effect on the present reaction. Thus, 4c
bearing p-methoxy group was converted to 5c in a
slightly better yield than 4a or 4b bearing o- or p-bro-
mo group (entries 1–3). Cyclohexanones having an ali-
phatic a-acyl group 4d–e also gave the adducts 5d–e in
good yields (entries 4 and 5). In addition to b-dike-
tones, b-ketoester 4f reacted effectively with sodium
dibenzyl malonate anion to give 5f in 74% yield (entry
6).
Supplementary data
Supplementary data including spectral data of the prod-
ucts (3a–f, 5a–f, 7a–e, and 8) and experimental proce-
dures can be found. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.03.059.
References and notes
Next, one-pot carbon–carbon bond formation of simple
cyclic ketones such as cyclopentanone (6a), cyclohexa-
none (6b) and cycloheptanone (6c) were examined (Ta-
ble 3). In situ formation of enone was performed by
deprotonation with LDA followed by reaction with 1
at ꢀ78 °C in THF.9 The addition of malonic acid esters
was carried out by using a catalytic amount14 of sodium
hydride at room temperature. It was found that dehy-
drogenation of 6a–c with 1 proceeded rapidly at
ꢀ78 °C, and cyclopentenone generated directly from
cyclopentanone (6a) reacted with diethyl malonate more
smoothly than did cyclohexenone and cycloheptenone
generated from 6b and 6c, respectively, (entries 1–3 vs
entries 4–5). Various diethyl 2-alkylmalonates such as
diethyl methylmalonate and diethyl benzylmalonate
reacted with in situ formed cyclopentenone to give
adducts 7b–c in good yields (entries 2 and 3).
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b-Cyano ketones are valuable synthetic intermediates in
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tution at the b-position of ketone with cyanide ion was
performed by using a-benzoylcyclohexanone (2b) as a
model substrate (Scheme 2). Addition of an aqueous
solution of potassium cyanide to enone directly formed
by using 2b and 1 resulted in the formation of a desir-
able carbon–carbon bond to afford 8.

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J. Matsuo et al. / Tetrahedron Letters 48 (2007) 3155–3158
6. Elimination of a-haloketones: (a) Warnhoff, E. W.;
12. Typical procedure (Table 1, entry 3): To a stirred mixture
of sodium hydride (60%, 21.7 mg, 0.54 mmol) in THF
(2 mL) was added a solution of 2c (99.5 mg, 0.46 mmol) in
THF (1.5 mL) at room temperature, and the mixture was
stirred for 30 min. A solution of 1 (122 mg, 0.57 mmol) in
THF (1.5 mL) was added at ꢀ78 °C, and the mixture was
stirred for 30 min. Then a solution of diethyl malonate
anion (prepared by diethyl malonate and NaH,
0.60 mmol) in THF (1.9 mL) was added at ꢀ78 °C, and
the mixture was stirred for 30 min. After adding saturated
aqueous sodium bicarbonate solution, the mixture was
extracted with ethyl acetate (three times), and the extracts
were washed with brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The crude
product was purified by thin-layer chromatography on
silica gel (hexane–ethyl acetate = 2:1) to afford 3c
(154.3 mg, 0.412 mmol, 90%).
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10. a-Acyl-a,b-unsaturated carbonyl compounds are usually
prepared by elimination of the corresponding a-seleninyl
compounds. See Ref. 3.
13. In the absence of HMPA, the 1,4-addition did not proceed.
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sodium diethylmalonate anion gave 7d in 55–57% yields.
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