Stereospecific construction of chiral tertiary and quaternary carbon by nucleophilic cyclopropanation with bis(iodozincio)methane

Article abstract of DOI:10.1002/asia.200900289

The reaction of a ketone having a leaving group at the aposition, such as a,bepoxy ketone or asulfonyloxy ketone, with bis(iodozincio) methane affords a zinc alkoxide of cyclopropanol. The reaction proceeds by nucleophilic addition of the dizinc to the carbonyl group and a sequential intramolecular nucleophilic substitution of the introduced iodozinciomethyl group to the adjacent electrophilic carbon that has a leaving group. When an optically active a,β-epoxy ketone or asulfonyloxy ketone is treated with the dizinc, a zinc alkoxide of cyclopropanol having a chiral tertiary or quaternary carbon in the cyclopropane ring is obtained, and the obtained zinc alkoxide of cyclopropanol acts as a chiral ho-moenolate. When it is treated with an electrophile in the presence of copper cyanide, it gives an optically active a-tertiary or -quaternary ketone that retains high optical purity.

Full text of DOI:10.1002/asia.200900289

DOI: 10.1002/asia.200900289
Stereospecific Construction of Chiral Tertiary and Quaternary Carbon by
Nucleophilic Cyclopropanation with Bis(iodozincio)methane
Kenichi Nomura and Seijiro Matsubara*[a]
Abstract: The reaction of a ketone
having a leaving group at the a-posi-
tion, such as a,b-epoxy ketone or a-sul-
fonyloxy ketone, with bis(iodozincio)-
methane affords a zinc alkoxide of cy-
clopropanol. The reaction proceeds by
nucleophilic addition of the dizinc to
the carbonyl group and a sequential in-
tramolecular nucleophilic substitution
of the introduced iodozinciomethyl
group to the adjacent electrophilic
carbon that has a leaving group. When
an optically active a,b-epoxy ketone or
a-sulfonyloxy ketone is treated with
the dizinc, a zinc alkoxide of cyclopro-
panol having a chiral tertiary or quater-
nary carbon in the cyclopropane ring is
obtained, and the obtained zinc alkox-
ide of cyclopropanol acts as a chiral ho-
moenolate. When it is treated with an
electrophile in the presence of copper
cyanide, it gives an optically active a-
tertiary or -quaternary ketone that re-
tains high optical purity.
Keywords: cycloaddition · ketones ·
nucleophilic addition · nucleophilic
substitution · zinc
Introduction
pare a substrate that has both a nucleophilic carbon and an
optically active secondary or tertiary electrophilic carbon in
the same molecule. As one idea for the preparation, we pro-
posed the nucleophilic addition of bis(iodozincio)methane
(1),[3] which possesses a couple of carbon–zinc bonds on a
carbon atom, to a carbonyl group of a ketone carrying an
enantiomeric enriched stereogenic center containing a leav-
ing group at the a-position, such as a,b-epoxy ketone[4] or a-
sulfonyloxy ketone.[5]
We have already reported an efficient route for cyclopro-
pane ring formation by a sequential nucleophilic reaction of
bis(iodozincio)methane (1):[4–6] As shown in Scheme 1, when
a,b-epoxy ketone or a-sulfonyloxy ketone was treated with
1, its nucleophilic addition to the carbonyl group proceeds
and introduces an iodozinciomethyl group to the adjacent
carbon of the original stereogenic center (3 in Scheme 1).
The intermediate 3 would lead to a sequential intramolecu-
lar nucleophilic attack to afford a cyclopropane derivative.
The intramolecular SN2 reaction to a target tertiary carbon
proceeds stereospecifically to afford the zinc alkoxide of cy-
clopropanol 4, which has a quaternary center. So, treatment
of an optically active substrate 2 with 1 afforded the zinc
alkoxide of cyclopropanol 4, which has the enantiomeric-en-
riched tertiary or quaternary carbon. Moreover, the ob-
tained chiral zinc alkoxide of cyclopropanol can work as a
homoenolate 5 by a ring opening.[7] Treatment of an electro-
phile with the homoenolate 5 would afford an optically
active a-tertiary or -quaternary ketone 6 that retains high
enantiomeric purity.
The stereoselective construction of chiral tertiary and qua-
ternary carbon is still a challenging subject in organic syn-
theses.[1] Among several important strategies, one of the
most attractive routes would be a stereospecific substitution
reaction of a carbon nucleophile with an optically active sec-
ondary and tertiary carbon atom having a leaving group.
This method, however, contains an unavoidable problem:
An intermolecular SN2 reaction by a carbon nucleophile
would be difficult when there is steric hindrance around the
electrophilic carbon, such as with the tertiary electrophilic
carbon (R3C-X), the SN2 reaction does not proceed. Howev-
er, in cases of intramolecular reactions, an SN2 reaction,
which affords a cyclopropane compound, proceeds efficient-
ly and stereospecifically, even in the case of a substrate
having a leaving group on a tertiary carbon.[2] Although the
method seems to be attractive to construct a tertiary or qua-
ternary carbon in a cyclopropane ring, it is not easy to pre-
[a] K. Nomura, Prof. S. Matsubara
Department of Material Chemistry
Graduate School of Engineering
Kyoto University
Kyoutodaigaku-katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax : (+81)75-383-2463
E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900289.
Chem. Asian J. 2010, 5, 147 – 152
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
147

FULL PAPERS
strate was consumed complete-
ly to convert the reactants into
11a and 12a (entry 3). Instead
of a-tosyloxy ketone, the reac-
tion of a-acyloxy ketone 8 with
the dizinc 1 resulted in the
complete recovery of the start-
ing material (entry 4). Al-
though a reaction of a-bromo-
ketone 9 with the dizinc 1 af-
forded 11a and 12a, it pro-
ceeded sluggishly (entry 5). A
reaction of a-iodoketone 10
with the dizinc 1 gave a com-
plex mixture (entry 6).
Scheme 1. Strategy for the construction of a chiral tertiary or quaternary center at the a-position of a ketone
by nucleophilic cyclopropanation with bis(iodozincio)methane (1).
Thus, we attempted the preparation of an optically active
Table 1. Reactions of ketones having a leaving group at the a-position
with bis(iodozincio)methane (1).[a]
homoenolate equivalent by the reaction of a ketone that has
a stereogenic center, which contains a leaving group at the
a-position with 1. The process leads to the sequential reac-
tion of the obtained chiral homoenolate with an electrophile
to prepare a ketone, which has an optically active tertiary or
quaternary carbon at the a-position.
entry
X
y [equiv] t [h] yield of 11a [%][b] yield of 12a [%][c]
1[d]
2
OTs (7a) 1.2
OTs (7a) 2.0
OTs (7a) 3.0
OAc (8) 3.0
2
2
2
2
15
15
9
34
31
43
0
21
0
32
56
0
17
0
3
4[e]
5
Results and Discussion
Br (9)
I (10)
3.0
3.0
6[f]
To prepare a homoenolate equivalent, we treated ketones
having leaving groups at the a-position with bis(iodozincio)-
methane (1), as shown in Table 1. A solution of a-tosyloxy
ketone (1.0 mmol) in THF (4 mL) was treated with bis(iodo-
zincio)methane (1, 1.2 mmol, 0.5m in THF) at 258C. After
being stirred for 2 h, the mixture was quenched with a satu-
rated aqueous solution of NH4Cl. Purification by silica gel
column chromatography gave 1-phenyl-1-cyclopropanol
(11a) and 1-phenyl-1-propanone (12a) (Table 1, entry 1).
The ketone 12a was generated by a cyclopropane-ring open-
ing by treatment with acid. When the a-tosyloxy ketone 7a
was treated with 3 equiv amounts of the dizinc 1, the sub-
[a] A ketone (7–10, 1.0 mmol), bis(iodozincio)methane (1, 0.5m in THF),
and THF (4 mL) were used. [b] Yields of 11a were determined by
1H NMR using bromoform as internal standard. [c] Yields of 12a were
determined by 1H NMR using bromoform as internal standard. [d] The
starting material was also obtained in 50% yield. [e] The starting materi-
al was recovered completely. [f] Complex mixture was obtained.
Other examples of the reaction of a-tosyloxy ketones
with the dizinc 1 are shown in Table 2. In the cases of 7a–c,
ketones 12 were also obtained as by-products (entries 1–3).
Table 2. The reaction of a-tosyloxy ketone
7
with the dizinc 1.[a]
Abstract in Japanese:
entry
R1
R2
t [h]
Yield [%][b]
dr[c]
1
2
3
4
5
6
7
8
Ph
n-Octyl
2-furyl
p-CF3C6H4
Ph
2-Naphtyl
p-MeOC6H4
p-CF3C6H4
H
H
H
H
Me
Me
Me
Me
7a
7b
7c
7d
7e
7 f
7g
7h
2
11a 56[d]
11b 31[e]
11c 38[f]
11d 95
11e 86
11 f 99
15
12
2
10
15
20
4
76/24[g]
67/33[g]
67/33[g]
72/28[g]
11g 81
11h 88
[a] An a-tosyloxy ketone (7, 1.0 mmol), bis(iodozincio)methane (1,
3.0 mmol, 0.5m in THF), and THF (4 mL) were used. [b] Yield of isolat-
ed product. [c] The diastereomeric ratios were determined by 1H NMR.
[d] 1-Phenyl-1-propanone was also obtained in 43% yield. [e] 3-Undeca-
none was also obtained in 59% yield. [f] 1-(2-Furyl)-1-propanone was
also obtained in 50% yield. [g] Stereochemistry of cyclopropane ring in
major isomer was trans.
148
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 147 – 152

Stereospecific Construction of Chiral Tertiary and Quaternary Carbon
When the reaction of 1 and 7a was quenched by chlorotri-
methylsilane instead of an aqueous solution of NH4Cl, 1-
phenyl-1-trimethylsiloxycyclopropane (13) was obtained in a
high yield (Scheme 2). In the case of a-methyl-a-tosyloxy
Instead of an isolation of cyclopropanol 11, the acylation
of the zinc homoenolate equivalent 11a’,c’ was examined
(Scheme 4).[7] After the reaction of a-tosyloxy ketone 7 with
dizinc 1, treatment of the resulting mixture with benzoyl
chloride in the presence of a palladium catalyst afforded the
corresponding 1,4-diketone 14 in good yield.
We also attempted a sequential reaction of the prepared
zinc alkoxide of cyclopropanol 11’ with allyl bromide in the
presence of copper cyanide.[8] A solution of a-tosyloxy
ketone 7 (1.0 mmol) in THF (4 mL) was treated with the
dizinc (1, 2.0 mmol, 0.5m in THF) at 258C. After being
Scheme 2. Quenching of the reaction mixture of 7a and 1 with chlorotri-
methylsilane.
ketones 7e–h, the reactions
gave the 1-alkyl-2-methylcyclo-
propanols 11e–h in high yields
(entries 5–8). The obtained 2-
alkylcyclopropanols
11e–h,
however, were diastereomeric
mixtures (entries 5-8). After
the nucleophilic addition of 1
to the carbonyl group of 7, the
Scheme 4. The reaction of acid chloride and zinc homoenolate 11’ prepared from 1 and 7.
intramolecular SN2 reaction of
the existing iodozinciomethyl
group to the adjacent stereogenic center that has a tosyloxy
group will proceed in stereospecific SN2 manner. So, the dia-
stereofacial selectivity in nucleophilic addition of 1 to the
carbonyl group of 7e–h would determine the diastereomeric
ratio of 11e–h. However, when the zinc alkoxides of cyclo-
propanols 11e–h are utilized as zinc homoenolate equiva-
lents, the stereogenic centers at the oxygen atom-substituted
carbon will be converted into carbonyl groups, retaining the
chirality of tertiary carbon at the a-position.[7e] So, the poor
diastereofacial selectivity of the nucleophilic attack to the
carbonyl group will not be significant when the zinc homoe-
nolate reaction is carried out as shown in Scheme 1.
Functional group tolerability of the transformation into
cyclopropanols was demonstrated as shown in Scheme 3. It
can be performed even in the presence of another carbonyl
group in the substrate. The reaction of an a-tosyloxy ketone
having an additional carbonyl group, such as 7i and 7j, with
1 proceeded chemoselectively to give the corresponding cy-
clopropanols (11i and 11j) in good yields without affecting
the other carbonyl groups, as shown in Scheme 3.
stirred for the period (t1) shown in Table 3, the mixture was
treated with CuCN·2 LiCl (2.0 mmol) at À308C for 10 min.
Allyl bromide was added to the resulting mixture, and ev-
erything was stirred at 258C for the period (t2) shown in
Table 3. Purification by silica gel column chromatography
gave a-homoallylated ketones 15 in good yields, as shown in
Table 3. In the case of the reaction of a-methyl-a-tosyloxy
ketones 7e–h, the allylation proceeded regioselectively to
give a-methylketones 15e–h as sole products (entries 5–8).
The reaction also tolerated the existence of other carbonyl
groups (entries 9 and 10).
An optically active a-mesyloxy ketone (S)-17 can be pre-
pared easily by treatment of silyl enol ether 16 with AD-
Table 3. The reaction of allyl bromide with the homoenolates prepared
from 1 and 7.[a]
entry
R1
R2
t1 [h]
t2 [h]
yield [%][b]
1
2
3
4
5
6
7
8
Ph
n-Octyl
2-furyl
p-CF3C6H4
Ph
2-Naphtyl
p-MeOC6H4
p-CF3C6H4
p-AcC6H4
p-MeOCOC6H4
H
H
H
H
Me
Me
Me
Me
H
7a
7b
7c
7d
7e
7 f
7g
7h
7i
4
4
3
6
5
15a 85
15b 84
15c 79
15d 88
15e 76
15 f 78
15g 55
15h 87
15i 86
15j 81
24
15
3
4
4
18
24
3
2
3
20
12
5
2
4
9
10
H
7j
[a] An a-tosyloxy ketone (7, 1.0 mmol), bis(iodozincio)methane (1,
2.0 mmol, 0.5m in THF), CuCN·2 LiCl (2.0 mmol, 1m in THF), allyl bro-
mide (2.0 mmol), and THF (4 mL) were used. [b] Yield of isolated prod-
uct.
Scheme 3. The reaction of 7i or 7j with 1.
Chem. Asian J. 2010, 5, 147 – 152
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
149

S. Matsubara et al.
FULL PAPERS
purification by silica gel
column chromatography gave
a-homoallylated ketone 22aa
in 69% yield (Table 4, entry 1).
In the cases of a-methyl-a,b-
epoxy ketone 19b and 19c, b-
hydroxy ketones having a qua-
ternary carbon at the a-posi-
Scheme 5. Preparation of chiral homoenolate from (R)-17 and 1, and its reaction with allyl bromide.
mix-b to form enantiomeric enriched a-hydroxy ketone,[9]
followed by mesylation of the hydroxy group. As shown in
Scheme 5, after the preparation of the zinc alkoxide of cy-
clopropanol from the optically active a-mesyloxy ketone
(R)-17 with 1, the resulting mixture was treated with allyl
bromide in the presence of CuCN·2 LiCl. The optically
active a-tertiary ketone (R)-18 was obtained without loss of
enantiomeric purity.
tion were obtained (entries 2 and 3). Cyclic have a higher
reactivity compared with acyclic homoenolates: Treatment
of 1-acetyl-1-cyclohexene oxide (19d) under the same condi-
tions gave the corresponding a-quaternary ketone 22da in
67% yield (entry 4). Instead of allyl bromide, other electro-
philes were also examined: Treatment of methallyl bromide
with 20d also afforded the corresponding product 22db in
good yield (entry 5). The reaction of prenyl bromide with
20d proceeded regioselectively (entry 6). In the case of
propargyl bromide and 1-bromo-2-butyne, the reaction with
20d proceeded regioselectively in an SN2’ manner to give
the corresponding allenes 22dd and 22de (entries 7 and 8).
The reactions of electrophiles with a homoenolate prepared
from 1-acetyl-1-cyclopentene oxide (19e) with 1 also afford-
ed the corresponding a-quaternary ketones in good yields
(entries 9 and 10).
An optically active a,b-epoxy ketone can be prepared
easily by Katsuki–Sharpless asymmetric epoxidation of a
corresponding allyl alcohol 23, followed by Swern oxidation.
As shown in Scheme 7a, treatment of allyl bromide with a
homoenolate prepared from (S)-19a and 1 under the same
conditions, afforded (R)-2-(hydroxymethyl)-1-phenyl-5-
hexen-1-one ((R)-22aa), which possesses an optically active
tertiary carbon at the a-position, in good yield. High enan-
tiomeric excess was retained. In the case of (1S,2R)-1-acetyl-
1-cyclohexene oxide ((1S,2R)-19d), the reaction gave opti-
cally active a-quaternary ketone (1R,2R)-22da without loss
of enantiomeric excess (Scheme 7b). The ORTEP figure of
a compound derived from (1R,2R)-22da and 3,5-dinitroben-
zoyl chloride is shown in Figure 1.
Though this method worked well to construct a chiral ter-
tiary carbon at the a-position of a ketone, it was difficult to
apply for the construction of a chiral quaternary carbon at
the a-position from a a-sulfonyloxy ketone: Treatment of 2-
mesyloxy-2-methyl-1-phenyl-1-propanone with the dizinc 1
resulted in complete recovery of the starting material. That
is, the preparation of zinc homoenolate equivalent contain-
ing a quaternary carbon in a cyclopropane ring is difficult
from a reaction of a,a-dialkyl-a-sulfonyloxy ketone with 1.
Meanwhile, as we reported previously, the reaction of an a-
alkyl-a,b-epoxy ketone 19 with 1 proceeds smoothly to
afford a 2-(1-hydroxyalkyl)-1,2-dialkylcyclopropanol having
a quaternary center in the cyclopropane ring in a high
yield.[4] An epoxide is superior as a leaving group. The zinc
alkoxide of 2-(1-hydroxyalkyl)-1,2-dialkylcyclopropanol 20
would act as a homoenolate equivalent. We speculated that
the treatment of electrophiles with the obtained zinc alkox-
ide of cyclopropanol 20 in the presence of CuCN·2 LiCl
would afford a-quaternary ketone 22 as shown in Scheme 6.
So, the reactions of a zinc homoenolate, which was prepared
from a,b-epoxy ketone 19 and the dizinc 1, with electro-
philes were examined.
A solution of a,b-epoxy ketone 19a (1.0 mmol) in THF
(4 mL) was treated with the dizinc(1, 1.2 mmol, 0.5m in
THF) at 258C for 1 h. Then, the mixture was treated with
CuCN·2 LiCl (2.4 mmol) at À308C for 10 min. Allyl bro-
mide was added to the resulting mixture, and everything
was stirred at 258C for 12 h. After an aqueous work-up, a
Conclusions
We demonstrate the preparation of a zinc homoenolate
equivalent from a-sulfonyloxy ketone and bis(iodozincio)-
methane. The prepared zinc
homoenolate reacts with allyl
bromide mediated by CuCN·2
LiCl to give an a-tertiary
ketone. The reaction proceeds
regioselectively and chemose-
lectively. The zinc homoeno-
late, prepared by the reaction
of an a,b-epoxy ketone with
the dizinc, also reacts with var-
ious electrophiles under the
same condition to give an a-
tertiary or -quaternary ketone.
Scheme 6. Strategy for the construction of a chiral tertiary or quaternary carbon at the a-position of a ketone
by nucleophilic cyclopropanation of a,b-epoxy ketone 19 with 1.
150
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 147 – 152

Stereospecific Construction of Chiral Tertiary and Quaternary Carbon
Table 4. Preparation of homoenolate from an a,b-epoxy ketone 19 and
the dizinc 1, and its reaction with electrophiles.[a]
entry
1
substrate
El+
product
yield [%][b]
19a
19b
19c
22aa 69
2[c]
22ba 52
Scheme 7. Preparation of optically active homoenolates, and their reac-
tions with allyl bromide.
3[c]
22ca 27[d]
4
5
19d
19d
22da 67
22 db 70
6
19d
22dc 54
Figure 1. The ORTEP of the compound derived from (1R,2R)-22da and
3,5-dinitrobenzoyl chloride.
7
8
19d
19d
22dd 27[e]
22de 73
Experimental Section
Bis(iodozincio)methane (1): A mixture of Zn (25 mmol), diiodomethane
(1.0 mmol), and PbCl2 (0.01 mmol) in THF (2.0 mL) was sonicated for
1 h in an ultrasonic cleaner bath under Ar. To the mixture, diiodome-
thane (10 mmol) in THF (20 mL) was added dropwise over 15 min at
08C with vigorous stirring. The mixture was stirred for 2 h at 08C. After
the stirring was stopped, the reaction vessel was left undisturbed for sev-
eral hours. Excess zinc was separated by sedimentation. 1H NMR spectra
of the obtained supernatant showed a broad singlet at À1.2 ppm at 08C,
which corresponded to the methylene proton of 1. The supernatant was
used for further reaction as a solution of 1 in THF (0.5–0.6m). Bis(Iodo-
zincio)methane in THF can be kept unchanged at least for a month in
the sealed reaction vessel.
9
19e
19e
22ea 57
22eb 55
10
[a] An a,b-epoxy ketone (19, 1.0 mmol), bis(iodozincio)methane (1,
1.2 mmol, 0.5m in THF), CuCN·2 LiCl (2.4 mmol, 1m in THF), electro-
phile (2.4 mmol), and THF (4 mL) were used. [b] Yield of isolated prod-
uct. [c] The reactions of allyl bromide with the prepared homoenolate 20
were carried out at 408C. [d] (1R*,2R*)-1-butyl-2-hydroxymethyl-2-meth-
ylcyclopropanol was also obtained in 32% yield. [e] Unidentified prod-
ucts were also observed.
General procedure for the nucleophilic cyclopropanation of a-sulfonylox-
yketone:
A mixture of a-sulfonyloxy ketone (7, 1.0 mmol) in THF
(4 mL) was treated with bis(iodozincio)methane (1, 0.5m solution in
THF, 3.0 mmol) at 258C. Then, aqueous solution of NH4Cl was added to
quench the reaction, and ethyl acetate was used for the extraction. The
combined organic layers were washed with brine, and dried over Na2SO4.
The solvent was removed under reduced pressure, and the residue was
purified by silica gel column chromatography to give the corresponding
cyclopropanol 11.
The transformation proceeds in a stereospecific manner, so,
treatment of electrophile with the homoenolate prepared by
the reaction of optically active a-sulfonyloxyketone or a,b-
epoxy ketone with the dizinc gives the corresponding opti-
cally active a-tertiary or -quaternary ketone; high enantio-
meric purity is retained. The high optical purity of the sub-
strate can be introduced easily by the reliable asymmetric
reactions, so, this stereospecific method can be applied for
pharmaceuticals or natural product syntheses containing ter-
tiary or quaternary carbons.
General procedure for the tandem reaction of bis(iodozincio)methane
(1), a-sulfonyloxyketone 7, and allyl bromide: A mixture of a-sulfony-
loxy ketone (7, 1.0 mmol) in THF (4 mL) was treated with bis(iodozin-
cio)methane (1, 0.5m solution in THF, 2.0 mmol) at 258C. The mixture
was treated with CuCN·2 LiCl (2.0 mmol) at À308C for 10 min. Allyl
bromide (2 mmol) was added to the resulting mixture, and everything
was stirred at 258C. Then, aqueous solution of NH4Cl was added, and ex-
traction was done using ethyl acetate. The combined organic layers were
washed with brine, and dried over Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by silica gel column
chromatography to give the corresponding a-homoallylated ketone 15.
Chem. Asian J. 2010, 5, 147 – 152
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
151

S. Matsubara et al.
FULL PAPERS
General procedure for the tandem reaction of bis(iodozincio)methane
(1), a,b-epoxyketone 19, and an electrophile: A mixture of a,b-epoxy
ketone (19, 1.0 mmol) in THF (4 mL) was treated with bis(iodozincio)-
methane (1, 0.5m solution in THF, 1.2 mmol) at 258C. The mixture was
treated with CuCN·2 LiCl (2.4 mmol) at À308C for 10 min. An electro-
phile (2.4 mmol) was added to the resulting mixture, and this was stirred
at 258C. Then, aqueous solution of NH4Cl was added to quench the reac-
tion, and extraction was done using ethyl acetate. The combined organic
layers were washed with brine, and dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified by silica
gel column chromatography to give the corresponding a-tertiary or -qua-
ternary ketone 22.
[5] K. Nomura, S. Matsubara, Chem. Lett. 2007, 36, 164.
[6] a) K. Ukai, K. Oshima, S. Matsubara, J. Am. Chem. Soc. 2000, 122,
12047; b) S. Matsubara, K. Ukai, H. Fushimi, Y. Yokota, H. Yoshino,
K. Oshima, K. Omoto, A. Ogawa, Y. Hioki, H. Fujimoto, Tetrahe-
dron 2002, 58, 8255; c) K. Nomura, K. Oshima, S. Matsubara, Tetra-
hedron Lett. 2004, 45, 5957; d) T. Hirayama, K. Oshima, S. Matsu-
bara, Angew. Chem. 2005, 117, 3357; Angew. Chem. Int. Ed. 2005,
44, 3293; e) K. Nomura, K. Asano, T. Kurahashi, S. Matsubara, Het-
erocycles 2008, 76, 1381; f) K. Nimura, T. Hirayama, S. Matsubara,
Chem. Asian J. 2009, 6, 1298.
[7] a) E. Nakamura, I. Kuwajima, J. Am. Chem. Soc. 1977, 99, 7360;
b) E. Nakamura, I. Kuwajima, J. Am. Chem. Soc. 1983, 105, 651;
c) E. Nakamura, H. Oshino, I. Kuwajima, J. Am. Chem. Soc. 1986,
108, 3745; d) E. Nakamura, J. Shimada, I. Kuwajima, Organometal-
lics 1985, 4, 641; e) E. Nakamura, K. Sekiya, I. Kuwajima, Tetrahe-
dron Lett. 1987, 28, 337; f) I. Kuwajima, E. Nakamura, Top. Curr.
Chem. 1990, 155, 1; g) E. Nakamura, I. Kuwajima, J. Am. Chem.
Soc. 1984, 106, 3368; h) E. Nakamura, I. Kuwajima, Tetrahedron
Lett. 1986, 27, 83; i) E. Nakamura, S. Aoki, K. Sekiya, H. Oshino, I.
Kuwajima, J. Am. Chem. Soc. 1987, 109, 8056; j) S. Aoki, T. Fuji-
mura, E. Nakamura, I. Kuwajima, J. Am. Chem. Soc. 1988, 110,
3296; k) S. Aoki, E. Nakamura, I. Kuwajima, Tetrahedron Lett. 1988,
29, 1541; l) S. Aoki, T. Fujimura, E. Nakamura, I. Kuwajima, Tetra-
hedron Lett. 1989, 30, 6541; m) E. Nakamura, I Kuwajima, Org.
Synth. 1983, 61.
Acknowledgements
This work was supported financially by the Japanese Ministry of Educa-
tion, Culture, Sports, Science, and Technology, and by Kyoto University,
International Innovation Center. The authors acknowledge the support
by the Global COE Program “Integrated Materials Science” (#B-09).
K.N. acknowledges the Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists for financial support.
[1] Selected reviews, see: a) S. F. Martin, Tetrahedron 1980, 36, 419;
b) I. Denissova, L. Barriault, Tetrahedron 2003, 59, 10105; c) P. G.
Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2007, 5969;
d) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347, 1473; e) J.
Christoffers, A. Mann, Angew. Chem. 2001, 113, 4725; Angew.
Chem. Int. Ed. 2001, 40, 4591; f) B. M. Trost, C. Jiang, Synthesis
2006, 369; g) K. Fuji, Chem. Rev. 1993, 93, 2037.
[2] a) D. Yang, Y.-L. Yan, K.-L. Law, N.-Y. Zhu, Tetrahedron 2003, 59,
10465; b) V. Singh, G. P. Yadav, P. R. Maulik, S. Batra, Tetrahedron
2006, 62, 8731; c) M. Helliwell, D. Fengas, C. K. Knight, J. Parker, P.
Quayle, J. Raftery, S. N. Richards, Tetrahedron Lett. 2005, 46, 7129.
[3] a) K. Takai, T. Kakiuchi, Y. Kataoka, K. Utimoto, J. Org. Chem.
1994, 59, 2668; b) S. Matsubara, J. Synth. Org. Soc. Jpn. 2000, 58,
108; c) S. Matsubara, K. Oshima, K. Utimoto, J. Organomet. Chem.
2001, 617–618, 39; d) S. Matsubara in The Chemistry of Organozinc
Compounds, Part 2 (Eds.: Z. Rappoport, I. Marek), Wiley, New
York, 2006, Chap. 14, p. 641.
[8] a) N. Harrington-Frost, H. Leuser, M. I. Calaza, F. F. Kneisel, P.
Knochel, Org. Lett. 2003, 5, 2111; b) M. I. Calaza, E. Hupe, P. Kno-
chel, Org. Lett. 2003, 5, 1059; c) H. Leuser, S. Perrone, F. Liron, F. F.
Kneisel, P. Knochel, Angew. Chem. 2005, 117, 4703; Angew. Chem.
Int. Ed. 2005, 44, 4627; d) D. Soorukram, P. Knochel, Synthesis 2007,
638; e) D. Soorukram, P. Knochel, Angew. Chem. 2006, 118, 3768;
Angew. Chem. Int. Ed. 2006, 45, 3686; f) A. Yanagisawa, N.
Nomura, H. Yamamoto, Synlett 1993, 689; g) A. Yanagisawa, Y.
Noritake, N. Nomura, H. Yamamoto, Synlett 1991, 251.
[9] T. Hashiyama, K. Morikawa, K. B. Sharpless, J. Org. Chem. 1992,
57, 5067.
[10] M=390.39, Monoclinic, a=9.758(8), b=5.772(5), c=16.977(13) ꢁ,
b=96.7028, V=949.7(13) ꢁ3, Z=2, 1calc =1.365 gcmÀ3
, lACHTUNGTRENNUNG(Moka)=
0.71073 ꢁ, T=293 K, 2qmax =54.08, R=0.050 for 3638 reflections
(I>2s(I)).
Received: July 20, 2009
Published online: November 17, 2009
[4] K. Nomura, K. Oshima, S. Matsubara, Angew. Chem. 2005, 117,
6010; Angew. Chem. Int. Ed. 2005, 44, 5860.
152
www.chemasianj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 147 – 152