One-carbon homologation of unsymmetrical ketones through magnesium β-oxido carbenoid rearrangement and trapping the enolate intermediates with electrophiles

Article abstract of DOI:10.1016/j.tet.2008.05.079

A procedure for one-carbon homologation of unsymmetrical ketones, including one-carbon ring-expansion of 2-substituted cyclohexanones, through magnesium β-oxido carbenoid rearrangement as the key reaction is described. Addition of the α-sulfinyl carbanion of 1-chloroethyl p-tolyl sulfoxide to an unsymmetrical ketone gave two diastereomers as adducts in good yields. The adducts were treated with a base to give alkoxides, which were treated with a Grignard reagent to give magnesium β-oxido carbenoids. The β-oxido carbenoid rearrangement then took place to afford one-carbon homologated ketones having a methyl group at the α-position. Remarkable specificity or selectivity was observed in the rearrangement. The magnesium enolate intermediates of this reaction were found to be able to get trapped with several electrophiles to give one-carbon homologated α,α-disubstituted ketones. Origin of the specificity and selectivity is also discussed.

Full text of DOI:10.1016/j.tet.2008.05.079

Tetrahedron 64 (2008) 7199–7210
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One-carbon homologation of unsymmetrical ketones through
magnesium b-oxido carbenoid rearrangement and trapping
the enolate intermediates with electrophiles
*
Shu Tanaka, Takehiro Anai, Makoto Tadokoro, Tsuyoshi Satoh
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-Funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2008
Received in revised form 16 May 2008
Accepted 16 May 2008
Available online 21 May 2008
A procedure for one-carbon homologation of unsymmetrical ketones, including one-carbon ring-ex-
pansion of 2-substituted cyclohexanones, through magnesium
key reaction is described. Addition of the -sulfinyl carbanion of 1-chloroethyl p-tolyl sulfoxide to an
unsymmetrical ketone gave two diastereomers as adducts in good yields. The adducts were treated with
a base to give alkoxides, which were treated with a Grignard reagent to give magnesium -oxido
carbenoids. The -oxido carbenoid rearrangement then took place to afford one-carbon homologated
ketones having a methyl group at the -position. Remarkable specificity or selectivity was observed in
the rearrangement. The magnesium enolate intermediates of this reaction were found to be able to get
b-oxido carbenoid rearrangement as the
a
b
b
Keywords:
Homologation of ketones
Ring-expansion
a
trapped with several electrophiles to give one-carbon homologated
the specificity and selectivity is also discussed.
a,a-disubstituted ketones. Origin of
Magnesium carbenoid
b
-Oxido carbenoid
Ó 2008 Elsevier Ltd. All rights reserved.
Rearrangement
1. Introduction
established.8 In all of our investigations mentioned above, we mainly
used symmetrical ketones and aldehydes as carbonyl compounds.
In continuation of our interest in the homologation of carbonyl
Homologation of carbonyl compounds from lower carbonyl
compounds by carbon–carbon coupling is a very useful procedure
for obtaining the desired carbonyl compounds.1 If the homologation
reactions are applied to cyclic carbonyl compounds, ring-expanded
compounds via the magnesium b-oxido carbenoid rearrangement,
we recently studied the homologation by using unsymmetrical
ketones and interesting specificity or selectivity was observed in the
rearrangement. Thus, as shown in Scheme 1, an unsymmetrical ke-
carbonyl compounds will be obtained.2 The
b-oxido carbenoid
rearrangement is reported to be one of the most reliable reactions
for one-carbon homologation of carbonyl compounds including
one-carbon ring-expansion of cyclic ketones. The methods reported
from Villieras and Normant,3 Korbrich,4 and Nozaki et al.5 are based
tone 1 was treated with the lithium a-sulfinyl carbanion of 1-chloro-
ethyl p-tolylsulfoxidetoaffordadduct2asamixtureofseparabletwo
diastereomers. The adducts 2 were separated and each isomer was
treated with t-BuMgCl (to form magnesium alkoxide) followed by
alkylmetal (Grignard reagent or in some cases t-BuLi) to give mag-
on the lithium b-oxido carbenoid rearrangement of the adduct of
carbonyl compounds with dichloromethyllithium or dibromome-
thyllithium. A similar reaction using the adduct of cyclic ketones
with bis(phenylthio)methyllithium was reported by Cohen.6
We have also been interested in the homologation of carbonyl
nesium
nesium
b
b
-oxido carbenoid 3. Stereospecific or stereoselective mag-
-oxido carbenoid rearrangement took place to give one-
carbon elongated enolate 4 and/or 5. Finally, the enolate in-
termediates were treated with electrophiles to give one-carbon ho-
compounds with the
reaction for a long time. Our previous method was based on the rear-
rangement of lithium -oxido carbenoids derived from adducts of
carbonyl compounds with the lithium -sulfinyl carbanion of aryl 1-
chloroalkyl sulfoxides.7 Recently, magnesium
-oxido carbenoid rear-
b
-oxido carbenoid rearrangement as the key
mologateda,a-disubstitutedketones6and/or7ingoodoverallyields
from the adduct 2. Details of this procedure and discussion of the
b
origin of the specificity and selectivity are described hereinafter.8d
a
b
2. Results and discussion
rangement was found to be better reaction for our homologation and
a versatile procedure for homologation of ketones and aldehydes was
2.1. One-carbon homologation of unsymmetrical acyclic
ketones and trapping the enolate intermediates
At first, lithium
a-sulfinyl carbanion of 1-chloroethyl p-tolyl
* Corresponding author. Tel.: þ81 3 5228 8272; fax: þ81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
sulfoxide was reacted with acetophenone, as an unsymmetrical
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.079

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S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
CH3
CH3
O
1) t-BuMgCl (1.2 eq)
2) R-Metal (4.0 eq)
THF, 0 °C ~ r.t.
Cl
Cl
CH3
TolS(O)CClLi
ClMgO
R1
MgCl (Li)
HO
R1
S(O)Tol
R1
R2
R2
R2
1
3
2
Separable two diastereomers
O
CH3
OMgCl
CH3
CH3
E
E
R1
CH3
O
OMgCl
R1
R1
R1
Electrophile
and/or
R2
R2
R2
R2
7
5
6
4
Scheme 1.
δ 1.73
CH3
TolS(O)CClLi
OH
OH
O
H3C
TolS(O)
H3C
TolS(O)
+
O
O
H3C
H3C
CH3
Ph
PhCCH3
CH3
Ph
Ph
CH3
TolS(O)
TolS(O)
Ph
CH3
Cl
Cl
10
11
δ 2.11
8 (44%)
9 (50%)
MgCl
CH3
1) t-BuMgCl (1.2 eq)
2) i-PrMgCl (4.0 eq)
THF, 0 °C ~ r.t.
O
O
ClMg
H3C
OMgCl
Ph
CH3OH
81%
H3C
H3C
8
Ph
CH3
Ph
CH3
Cl
14
13
12
MgCl
Ph
1) t-BuMgCl (1.2 eq)
2) MeMgCl (4.0 eq)
THF, 0 °C ~ r.t.
O
O
ClMg
OMgCl
CH3
CH3OH
70%
Ph
Ph
9
H3C
Cl
CH3
CH3
CH3
CH3
17
16
15
Scheme 2.
ketone, to give adducts as a mixture of separable two diastereomers
(less polar adduct 8 and more polar adduct 9 on a silica gel plate) in
a quantitative yield (Scheme 2). The configuration of each isomer 8
and 9 was determined as shown in Scheme 2 by using the pre-
viously reported method.9a Thus, each adduct 8 and 9 were con-
verted to sulfinyloxiranes 10 and 11,9b respectively, in high yields by
treatment with t-BuOK. The configuration of the sulfinyloxiranes
was easily determined from their 1H NMR (this case, the chemical
shift of the methyl groups mentioned in Scheme 2).9a As the ep-
oxidation is the intramolecular SN2 reaction, the configuration of 8
and 9 is easily determined from the structure of the corresponding
sulfinyloxiranes 10 and 11.
The adduct 8 was treated with t-BuMgCl followed by i-PrMgCl in
THF at 0 ꢀC and the reaction mixture was slowly allowed to warm to
room temperature. From this treatment, we obtained isopropyl
phenyl ketone 14 in 81% yield and isopropyl p-tolyl sulfoxide as the
product from the sulfoxide–magnesium exchange reaction in
a quantitative yield. Quite interestingly, the same treatment of 9
with i-PrMgCl did not give the desired ketone but a complex mix-
ture. In this case, methylmagnesium chloride was found to be the
best Grignard reagent to the reaction to afford 3-phenyl-2-butanone
17 as a sole product in 70% yield. It is worth noting that these mag-
carbenoid rearrangement would take place from back side of the
chlorine atom,5c in this case the methyl group, to give magnesium
enolate 13, from which ketone 14 is produced by the protonation
with methanol. The situation must be quite similar in the case of
the reaction with 9 (this case the phenyl group was migrated) to
give 17 via b-oxido carbenoid intermediate 15 and enolate 16.
Next, generality of this reaction was investigated with valero-
phenone, 3-methyl-1-phenyl-2-buten-1-one, trans-chalcone, 2-
decanone, and 3-undecanone as representative unsymmetrical
ketones and the results are summarized in Table 1. The addition
reaction of the lithium
sulfoxide with valerophenone resulted in the formation of adducts
18a-L and 18a-P in good yield. The magnesium -oxido carbenoid
a-sulfinyl carbanion of 1-chloroethyl p-tolyl
b
rearrangement reaction starting from 18a-L gave homologated
ketones (19a and 20a) in high yield; however, the product was
a mixture of separable two isomers and the specificity was found to
be somewhat low (entry 1).
The reaction of 18a-P with i-PrMgCl gave the desired homolo-
gated ketone 19a in low yield (28%) with isopropylated olefin 23 as
a product in 43% yield (Scheme 3; the configuration not de-
termined). The mechanism of this olefin formation is expected to be
as follows. First, reaction of 18a-P with t-BuMgCl followed by i-
nesium
b
-oxido carbenoid rearrangements are highlystereospecific.
PrMgCl gives magnesium b-oxido carbenoid 21. In this particular
These specificities are explained as follows (see Scheme 2). The
case, i-PrMgCl attacks the carbenoid carbon to give isopropylated
alkylmagnesium compound 22. Finally, elimination of the magne-
sium oxide derivative from 22 affords an olefin with an isopropyl
group 23.
sulfoxide–magnesium exchange reaction10 of the magnesium alk-
oxide of 8 gives
b
-oxido carbenoid 12, whose conformation must be
-Oxido
fixed by formation of a chelate ring as shown in Scheme 2.
b

S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
7201
Table 1
One-carbon homologation of unsymmetrical ketones through magnesium
b
-oxido carbenoid
1) t-BuMgCl (1.2 eq)
CH3
TolS(O)CClLi
O
O
O
R1
OH
R1
R2
CH3
2) RMgCl (4.0 eq)
THF, 0 °C ~ r.t.
R2
R1
CClS(O)Tol
CH3
R1
R2
R2
18
CH3
1
19
20
Entry
1
18a (Yield, %)
RMgCl
Time (h)
19
20
R1
R2
Yield (%)
Yield (%)
1
2
Ph
Ph
CH2CH2CH2CH3
CH2CH2CH2CH3
18a-L (28)
18a-P (48)
i-PrMgCl
MeMgCl
0.5
1.0
29
69
60
0
3
Ph
18b-L (23)
i-PrMgCl
0.5
0
74
4
Ph
18b-P (52)
MeMgCl
1.0
75
0
5
6
CH3
CH3
18c-L (57)
18c-P (33)
i-PrMgCl
i-PrMgCl
0.5
0.5
0
93
19
Ph
19
Ph
CH2(CH2)6CH3
CH2(CH2)6CH3
CH2(CH2)6CH3
7
8
9
CH3
CH2CH3
CH2CH3
18db (85)
18e-L (38)
18e-P (43)
i-PrMgCl
i-PrMgCl
i-PrMgCl
0.5
0.5
0.5
31
33
15
35
8
49
a
The letters L and P refer to less polar and more polar products, respectively, on a silica gel plate using a mixture of hexane and ethyl acetate as a developing solvent.
A mixture of inseparable two diastereomers.
b
propionaldehyde (4 equiv) was added. The temperature of the re-
action mixture was slowly allowed to warm to room temperature
(CH3)2CHMgCl
1) t-BuMgCl (1.2 eq)
2) i-PrMgCl (4.0 eq)
THF, 0 °C ~ r.t.
for 2 h to give 3-hydroxy-2,2-dimethyl-1-phenyl-1-pentanone 24a
in 54% yield. The reaction starting from 9 (entry 4) gave 4-hydroxy-
3-methyl-3-phenyl-2-hexanone 25a, which is a structural isomer
of 24a; however, the yield was not satisfactory.
OMgCl
Ph
OH
H3C
ClMg
H3C
TolS(O)
Ph
(CH2)3CH3
(CH2)3CH3
Cl
Cl
18a-P
21
Trapping of the magnesium enolate intermediates with acid
chlorides gave the desired b-diketone derivatives in good to high
CH3
yields (entries 2, 5, 9, and 11). The allylation of the magnesium
enolate intermediates with allyl iodide proceeds in the presence of
HMPA (4 equiv) to afford the desired allylated ketones in moderate
to good yields (entries 3, 7, 10, and 12).
OMgCl
Ph
H3C
H3C
H3C
H3C
Ph
(CH2)3CH3
- (ClMg)2O
(CH2)3CH3
ClMg
CH3
22
23
2.2. One-carbon homologation of 2-substituted
Scheme 3.
cyclohexanones and trapping the enolate intermediates
Using MeMgCl instead of i-PrMgCl was again found to be
effective in this case and 19a was obtained in 69% yield as a sole
product (entry 2). The reaction starting from 3-methyl-1-phenyl-2-
buten-1-one was found to be highly stereospecific and the ho-
mologated ketones 19b and 20b were obtained in good yields
(entries 3 and 4). Highly specific rearrangement reaction of 18c-L,
derived from trans-chalcone, was observed to afford 20c in 93%
yield (entry 5). However, the reaction with isomer 18c-P gave
quite low yield of ketones 19c and 20c with almost no specificity
(entry 6). Entries 7–9 show the results with aliphatic un-
symmetrical ketones. As shown in the table, the rearrangement
shows some stereospecificities; however, the ratios of 19 and 20 are
not high.
Next, the presented homologation was applied to 2-methyl-
cyclohexanone derivative 26 as an example of unsymmetrical cyclic
ketones (Scheme 4). Thus, the reaction of the lithium
a-sulfinyl
carbanion of 1-chloroethyl p-tolyl sulfoxide with cyclohexanone
derivative 26 gave two adducts 27 (60%) and 28 (35%) as easily
separable two diastereomers. The stereochemistry of each adduct
was determined by X-ray crystallographic analysis as shown in
Figure 1 (vide infra).11 Main adduct 27 was treated with t-BuMgCl
(1.2 equiv) followed by i-PrMgCl (4 equiv) in THF at 0 ꢀC. The sulf-
oxide–magnesium exchange reaction took place smoothly to give
ring-expanded product 29 in 83% yield with trace amount of isomer
30. The cycloheptanone derivative 29 was obtained as a mixture of
separable two diastereomers (ratio about 10:1) and the main
product, 1,7-cis-dimethyl product, is shown in Scheme 4.
Significant difference in the reactivity of 27 and 28 with i-
PrMgCl was observed. Thus, when the minor adduct 28 was treated
with t-BuMgCl (1.2 equiv) followed by i-PrMgCl (4 equiv) in THF,
the reaction was rather slow and significant amount of starting
material 28 was recovered. Increasing of the amount of i-PrMgCl
(8 equiv) and prolonging the reaction time gave completed reaction
and the same cycloheptanone 29 was obtained in 64% yield.
Namely, these two reactions are highly selective.
As shown in Scheme 1, the product of the
rearrangement is known to be an enolate4–6 and in our previous
paper we established a versatile new method for a synthesis of
b-oxido carbenoid
a
,a
-
disubstituted carbonyl compounds with one-carbon homologation
in one pot by trapping of the enolate intermediates with several
electrophiles.8c As an extension of the presented reaction, we
investigated trapping the magnesium enolate intermediates with
aldehydes, acid chlorides, and allyl iodide starting from the selected
adducts (see Table 2).
Representative reaction is as follows (entry 1). Adduct 8 was
treated with t-BuMgCl followed by i-PrMgCl in THF at 0 ꢀC and the
reaction mixture was allowed to warm to room temperature. The
temperature of the reaction mixture was then cooled to ꢁ70 ꢀC, and
Obviously, the product 29 was derived from the one-carbon
insertion between C1 and C6 carbons of adduct 27 by the
b-oxido
carbenoid rearrangement (less substituted carbon was migrated).

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S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
Table 2
Generation of the magnesium
b-oxido carbenoids from adducts 8, 9, and 18 with a Grignard reagent and trapping the magnesium enolate intermediated with electrophiles to
give
a
,
a
-disubstituted ketones 24 or 25
1) t-BuMgCl (1.2 eq)
2) R MgCl (4.0 eq)
THF, 0 °C ~ r.t.
O
O
OMgCl
R2
Electrophile
(4 eq)
Conditions
OMgCl
R2
OH
R1
R2
R1
R1
R1
R2
R1
CClS(O)Tol
CH3
or
E
E
H3C
R2
H3C
CH3
CH3
8,9 R1=Ph, R2=CH3
25
24
18a-L R1=Ph, R2=CH2CH2CH2CH3
18b-P R1=Ph, R2=
18c-L R1=CH3, R2=
Ph
Entry
Adduct
R-metal
Electrophile
Conditions
E
Product 24 or 25
Yield (%)
1
2
3
4
5
6
7
8
8
i-PrMgCl
CH3CH2CHO
PhCOCl
ꢁ70 ꢀC to rt, 2 h
CH3CH2CH(OH)
PhCO
24a
24b
24c
25a
25b
25c
25d
25e
25f
54
77
64
24b
51
rt, 1 h
Ia
rt, 15 h
9
MeMgCl
MeMgCl
MeMgCl
CH3CH2CHO
ꢁ70 ꢀC, 1 h
rt, 0.5 h
CH3CH2CH(OH)
CH3CO
PhCH(OH)
CH3COCl
PhCHO
18a-P
18b-P
ꢁ70 ꢀC, 1 h
rt, 15 h
62c
72
Ia
PhCHO
ꢁ70 ꢀC, 1 h
PhCH(OH)
CH3CO
53d
75
72
99
56
9
CH3COCl
rt, 0.5 h
Ia
10
11
12
rt, 18 h
rt, 0.5 h
rt, 18 h
25g
24d
24e
18c-L
i-PrMgCl
PhCOCl
PhCO
Ia
a
HMPA (4 equiv) was added as an additive.
A mixture of two diastereomers (2.4:1).
A mixture of two diastereomers (1.7:1).
A mixture of two diastereomers (2.5:1).
b
c
d
CH3 S*
CH3 S*
Cl
Cl
O
S(O)Tol
CH3
S(O)Tol
HO
O
HO
CH3
TolS(O)CClLi
S*
S*
CH3
H3C
S*
6
1
R*
2
S*
+
R*
O
O
O
O
O
28(35%)
27(60%)
26
O
O
1) t-BuMgCl (1.2 eq)
2) i-PrMgCl (4.0 eq)
THF, 0 °C ~ r.t.
83%
H3C
CH3
CH3
CH3
27
O
O
O
O
29
30
1) t-BuMgCl (1.2 eq)
2) i-PrMgCl (8.0 eq)
THF, 0 °C ~ r.t.
28
64%
Scheme 4.
As the
b
-oxido carbenoid rearrangement is classified as nucleo-
sterically hindered, the sulfoxide–magnesium exchange reaction of
27 with i-PrMgCl is expected to proceed smoothly to give magne-
sium carbenoid A. Migration of the less substituted carbon would
occur from back side of the chlorine atom to give enolate 31. Con-
former B, from which more substituted carbon migrated, is thought
to be quite unfavorable because of the steric repulsion of two
methyl groups depicted in B.
As already mentioned, the reactivity of 28 with i-PrMgCl was
found to be far low compared with that of 27. This phenomenon
could be explained by the steric hindrance of the sulfinyl group of
28 by the methyl group on the cyclohexane ring as depicted (see
Scheme 5). In this case, rotation of the bond between the carbon
bearing the hydroxyl group and the carbon bearing the sulfinyl
philic rearrangement similar to the Baeyer–Villiger oxidation,12 it
was expected that a more substituted carbon should be migrated. In
fact, Hiyama reported selective olefinic carbon migration in his
synthesis of nootkatone using b-oxido carbenoid rearrangement as
the key reaction.13 Cohen also reported the migration of a more
highly substituted alkyl group in his carbenoid-type base-induced
ring-expansion.6 It is worth noting that the rearrangement ob-
served in our study is in reverse direction to that of Hiyama’s and
Cohen’s results.
This very interesting selectivity could be explained as follows
(Scheme 5). As mentioned above, the structure of 27 was de-
termined by X-ray analysis (see Fig. 1).11 As the sulfinyl group is not

S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
7203
by i-PrMgCl; however, the sulfoxide–magnesium exchange re-
action did not take place. In this particular case, we used t-BuLi
at ꢁ70 ꢀC and the desired 2-cyclohexyl-7-methylcyclohepanone
33a was obtained in 83% yield (entry 1). Again, one-carbon in-
sertion took place between C1 and C6 carbons and no 2,3-di-
substituted cycloheptanone was obtained.
The reaction of the isomer 32a-P with t-BuMgCl followed by t-
BuLi at ꢁ70 ꢀC was again sluggish and only 14% of the desired 33a
was obtained (entry 2). The reactions starting from 2-phenyl-
cyclohexanone showed quite similar results to afford 2-methyl-7-
phenylcycloheptanone 33b (in this cases, i-PrMgCl was effective;
entries 3 and 4).
Finally, the trapping of the enolate intermediates of the above-
mentioned reactions (34) with several electrophiles was in-
vestigated and a new method for a synthesis of 2,2,7-trisubstituted
cycloheptanones from 2-substituted cyclohexanones was realized.
The results are summarized in Table 4.
As shown in entry 1, 27 was treated with t-BuMgCl followed by
i-PrMgCl at room temperature for 5 min. The reaction was
quenched by adding excess CH3OD to give 7-deuterated ketone 35a
in 82% yield with 93% deuterium incorporation (entry 1).
Quenching of the reaction with benzaldehyde resulted in the for-
mation of alcohol 35b in 75% yield (entry 2). In a similar way, the
reaction with benzoyl chloride gave diketone 35c in 73% yield
(entry 3). When the trapping was carried out with iodomethane,
addition of HMPA as an additive was found to be effective to give
2,2,7-trimethylcycloheptanone 35d in 73% yield (entry 4). The same
reaction was carried out starting from 32a-L with t-BuLi and the
results are shown in entries 5–8. By this method, regioselectively
substituted cycloheptanone derivatives having multi substituents
can be synthesized. Structures of the trisubstituted cyclo-
heptanones 35 and 36 were easily anticipated from the structure
of the enolate intermediate. Observation of NOE between the
two hydrogen on the carbon bearing the cyclohexyl group and that
on the carbon bearing the hydroxyl group in 36b is an evidence for
the stereochemistry of the final products (see the footnote d in
Table 4).
Figure 1. Crystal structure of the adducts 27 and 28.
group would give conformer C. The sulfoxide–magnesium ex-
change reaction must occur from this conformer to give magne-
sium b-oxido carbenoid D, from which the less substituted carbon
was migrated to afford the same enolate 31.
We further investigated this chemistry by using 2-cyclo-
hexylcyclohexanone and 2-phenylcyclohexanone with 1-chloro-
ethyl p-tolyl sulfoxide and the results are summarized in Table 3.
The addition reaction of the lithium
a-sulfinyl carbanion of 1-
chloroethyl p-tolyl sulfoxide with 2-cyclohexylcyclohexanone gave
adduct 32a in good yield as two diastereomers, 32a-L (60%) and
32a-P (20%). The main adduct was treated with t-BuMgCl followed
O
S*
OH
OMgCl
OMgCl
CH3
S
Tol
MgCl
Cl
Cl
CH3
:
R*
Cl
Rotation
S*
i-PrMgCl
CH3
CH3
MgCl
CH3
S*
CH3
O
O
O
O
O
O
B
A
27
O
OMgCl
CH3
H3C
CH3
H3C
H+
O
O
O
O
29
31
O
S
S*
OMgCl
OH
OH
Cl
CH3
Cl
Tol
:
H3C
H3C
H3C
CH3
Cl
Rotation
i-PrMgCl
S*
S*
CH3
R*
MgCl
S
Tol
O
O
O
O
O
O
O
D
28
C
Scheme 5.

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S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
Table 3
3.2. 3-Chloro-2-phenyl-3-(toluene-4-sulfinyl)butan-2-ol (8
and 9)
One-carbon ring-expansion of 2-substituted cyclohexanones 31 to 2,7-disubstituted
cycloheptanones 33 through the magnesium
b
-oxido carbenoid rearrangement
Cl
H3C
To a solution of LDA (3.96 mmol) in 5 mL of dry THF in a flame-
dried flask at ꢁ70 ꢀC under argon atmosphere was added a solution
of 1-chloroethyl p-tolyl sulfoxide (669 mg, 3.3 mmol) in 5 mL of dry
THF dropwise with stirring and the solution was stirred at ꢁ70 ꢀC
for 10 min. To this reaction mixture was added a solution of ace-
tophenone (360 mg, 3 mmol) in 5 mL of THF dropwise with stirring.
The reaction mixture was stirred at ꢁ70 ꢀC for 30 min. The reaction
was quenched with satd aq NH4Cl. The whole was extracted with
CHCl3 and the organic layer was dried over MgSO4. The product was
purified by silica gel column chromatography to afford 8 (426 mg,
44%) and 9 (484 mg, 50%) as colorless crystals. Compound 8: col-
orless crystals; mp 166.5–167.5 ꢀC (hexane–AcOEt); IR (KBr) 3373
(OH), 3031, 2990, 1596, 1446, 1407, 1083, 1050, 1025 (SO), 1011, 699,
S(O)Tol
O
O
CH3
TolS(O)CClLi
HO
1) t-BuMgCl (1.2 eq)
R
H3C
R
R
2) R-Metal (4.0 eq)
Conditions
31a R= c-Hex
31b R= Ph
32
33
Entry
31 (R)
32a (Yield, %)
R-metal
Conditions
33
Yield (%)
1
2
3
4
c-Hex
c-Hex
Ph
32a-L (60)
32a-P (20)
32b-L (54)
32-P (30)
t-BuLi
t-BuLi
i-PrMgCl
i-PrMgCl
ꢁ70 ꢀC, 30 min
ꢁ70 ꢀC, 30 min
0 ꢀC to rt, 30 min
0 ꢀC to rt, 30 min
33a
33a
33b
33b
83b
14c
84d,e
10f
Ph
a
The letters L and P refer to less polar and more polar products, respectively, on
a silica gel plate using a mixture of hexane and ethyl acetate as a developing solvent.
506 cmꢁ1; 1H NMR
d 1.34 (3H, s), 2.18 (3H, s), 2.43 (3H, s), 4.71 (1H,
b
A 10:1 mixture of separable two diastereomers.
About 30% of the starting material was recovered.
About 5% of 2-methyl-3-phenycycloheptanone was obtained.
A 13:1 mixture of two inseparable diastereomers.
s), 7.30–7.39 (5H, m), 7.58 (2H, d, J¼8.3 Hz), 7.64–7.66 (2H, m). Anal.
Calcd for C17H19ClO2S: C, 63.24; H, 5.93; Cl, 10.98; S, 9.93. Found: C,
63.14; H, 5.94; Cl, 10.93; S, 9.84. Compound 9: colorless crystals; mp
165–166 ꢀC (hexane–AcOEt); IR (KBr) 3246 (OH), 3060, 2945, 1596,
c
d
e
f
About 20% of the starting material was recovered.
1445, 1370, 1081, 1029 (SO), 816, 765, 702, 511 cmꢁ1; 1H NMR
d 1.48
(3H, s), 1.82 (3H, s), 2.42 (3H, s), 5.70 (1H, s), 7.29 (2H, d, J¼8.0 Hz),
7.37–7.50 (5H, m), 7.71–7.73 (2H, m). Anal. Calcd for C17H19ClO2S: C,
63.24; H, 5.93; Cl, 10.98; S, 9.93. Found: C, 63.07; H, 5.94; Cl, 10.89;
S, 9.79.
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-S3 apparatus
and are uncorrected. 1H NMR spectra were measured in a CDCl3
solution with JEOL JNM-LA 300, 500, BRUKER DPX 400, and AV 600
spectrometer. Electron-impact mass spectra (MS) were obtained at
70 eV by direct insertion by HITACHI M-80B mass spectrometer. IR
spectra were recorded on a Perkin–Elmer Spectrum One FT-IR in-
strument. Silica gel 60N containing 0.5% fluorescence reagent 254
and a quartz column were used for column chromatography and
the products having UV absorption were detected by UV irradia-
tion. In experiment requiring a dry solvent and reagent, HMPA and
diisopropylamine were distilled from CaH2 and THF was distilled
from diphenylketyl. Compounds 14,14 17,15 19a,16 19b,17 19c,18 20a,19
20b,20 20c,21 20d,22 24b,23 and 24c24 are known.
3.3. Sulfinyloxiranes 10 and 11
To a solution of adduct 8 (179 mg, 0.5 mmol) in 5 mL of a 1:1
mixture of t-BuOH and THF at 0 ꢀC was added a suspension of t-
BuOK (0.6 mmol) in 2 mL of t-BuOH dropwise with stirring. The
reaction mixture was stirred at 0 ꢀC for 20 min. The reaction was
quenched with satd aq NH4Cl and the whole mixture was extracted
with CHCl3. The product was purified by silica gel column chro-
matography to give sulfinyloxirane 10 (136 mg, 95%) as colorless
crystals; mp 101–102 ꢀC (AcOEt–hexane). Spectral data see litera-
ture 9b. The similar treatment of 9 with t-BuOK gave 11 as colorless
crystals in 93% yield; mp 82–84 ꢀC (AcOEt–hexane). Spectral data
see literature 9b.
Table 4
One-carbon ring-expansion of 2-substitued cyclohexanones to 2,2,7-trisubstituted cycloheptanones 35 and 36 through the adducts 27 and 32-L
Cl
H3C
HO
S(O)Tol
R
O
OMgCl
R
H3C
E
1) t-BuMgCl (1.2 eq)
2) R-Metal (4.0 eq)
R
H3C
Electrophile
Conditions
THF, 30 min
X
X
X
X
X
X
27: X, X=OCH2CH2O, R=CH3
32a-L: X, X=H, R=c-Hex
35: X, X=OCH2CH2O, R=CH3
36: X, X=H, R=c-Hex
34
Entry
27 or 32-L
R-metal
Electrophile
Conditions
E
35 or 36
Yield (%)
1
2
3
4
5
6
7
8
27
27
27
27
32a-L
32a-L
32a-L
32a-L
i-PrMgCl
i-PrMgCl
i-PrMgCl
t-BuLi
t-BuLi
t-BuLi
CH3OD
PhCHO
PhCOCl
CH3I
CH3OD
PhCHO
PhCOCl
CH3I
rt, 5 min
rt, 30 min
rt, 30 min
rt, 15 h
ꢁ70 ꢀC, 5 min
ꢁ70 ꢀC, 30 min
ꢁ70 ꢀC, 30 min
ꢁ70 ꢀC to rt, 15 h
D
35a
35b
35c
35d
35d
36b
36c
36d
82a
75b
73b
73c
87a
82d
62b
49c
PhCH(OH)
PhCO
CH3
D
PhCH(OH)
PhCO
CH3
t-BuLi
t-BuLi
a
Deuterium content 93%.
Single product.
HMPA (4 equiv) was added as an additive.
b
c
NOE
c-Hex
H
d
H
A 7:1 mixture of two diastereomers. NOE was observed between the two hydrogens depicted.
CH3
OH
O
Ph
36b

S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
7205
3.4. Isopropyl phenyl ketone (14)
3.8. 4-Chloro-3-methyl-1-phenyl-4-(toluene-4-sulfinyl)pent-
1-en-3-ol (18c-L and 18c-P)
To a solution of t-BuMgCl (0.24 mmol) in 2 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added
a solution of adduct 8 (64.6 mg, 0.2 mmol) in 2 mL of dry THF
dropwise with stirring. The reaction mixture was stirred at 0 ꢀC for
10 min. To the solution of the magnesium alkoxide was added i-
PrMgCl (0.8 mmol) dropwise with stirring. The reaction mixture
was slowly allowed to warm to room temperature for 30 min. The
reaction was quenched with MeOH. The whole was extracted with
CHCl3. The organic layer was dried over MgSO4 and the product was
purified by silica gel column chromatography to afford 14 (24 mg,
81%) as colorless oil. The spectral data of this product is identical to
that reported in literature 14.
Compound 18c-L: colorless crystals; mp 94–95 ꢀC (hexane–
AcOEt); IR (KBr) 3324 (OH), 2989, 1596, 1419, 1054, 1022 (SO),
752 cmꢁ1; 1H NMR
d
1.55 (3H, d, J¼1.2 Hz), 1.56 (3H, s), 2.44 (3H, s),
5.16 (1H, s), 6.62 (1H, d, J¼15.7 Hz), 7.10 (1H, d, J¼15.7 Hz), 7.29 (1H,
tt, J¼7.4, 1.5 Hz), 7.34–7.39 (4H, m), 7.50–7.51 (2H, m), 7.58 (2H, d,
J¼8.3 Hz). Anal. Calcd for C19H21ClO2S: C, 65.41; H, 6.07; Cl, 10.16; S,
8.60. Found: C, 65.25; H, 5.89; Cl, 9.98; S, 9.03. Compound 18c-P:
colorless crystals; mp 82–83 ꢀC (hexane–AcOEt); IR (KBr) 3282
(OH), 3026, 1597, 1494, 1445, 1369, 1034 (SO) cmꢁ1; 1H NMR
d 1.56
(3H, s), 1.86 (3H, s), 2.42 (3H, s), 4.28 (1H, s), 6.40 (1H, d, J¼15.0 Hz),
6.79 (1H, d, J¼16.0 Hz), 7.24–7.28 (1H, m), 7.30–7.34 (4H, m), 7.39–
7.41 (2H, m), 7.61 (2H, d, J¼7.9 Hz). Anal. Calcd for C19H21ClO2S: C,
65.41; H, 6.07; Cl, 10.16; S, 8.60. Found: C, 65.32; H, 5.97; Cl, 10.06; S,
9.04.
3.5. 3-Phenyl-2-butanone (17)
To a solution of t-BuMgCl (0.24 mmol) in 2 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added
a solution of adduct 9 (64.6 mg, 0.2 mmol) in 2 mL of dry THF
dropwise with stirring. The reaction mixture was stirred at 0 ꢀC for
10 min. To the solution of the magnesium alkoxide was added
MeMgCl (0.8 mmol) dropwise with stirring. The reaction mixture
was slowly allowed to warm to room temperature for 60 min. The
reaction was quenched with MeOH. The whole was extracted with
CHCl3 and the organic layer was dried over MgSO4. The product was
purified by silica gel column chromatography to afford 17 (20.7 mg,
70%) as colorless oil. The spectral data of this product is identical to
that reported in the literature 15.
3.9. 2-Chloro-3-methyl-2-(toluene-4-sulfinyl)undecan-3-ol
(18d)
A mixture of 1:1 inseparable two diastereomers; colorless
crystals; mp 84–86 ꢀC (hexane–AcOEt); IR (KBr) 3349 (OH), 2925,
1598, 1466, 1377, 1036 (SO), 812 cmꢁ1; 1H NMR
d 0.86–0.91 (3H, m),
1.25–1.53 (16H, m), 1.67 (2H, s), 1.71–1.78 (0.5H, m), 1.84–1.91 (1H,
m), 2.12–2.19 (0.5H, m), 2.44 (3H, s), 3.98 (0.5H, s), 4.00 (0.5H, s),
7.34 (2H, d, J¼10.1 Hz), 7.61 (2H, dd, J¼10.3, 1.8 Hz). Anal. Calcd for
C19H31ClO2S: C, 63.57; H, 8.70; Cl, 9.88; S, 8.93. Found: C, 63.54; H,
8.65; Cl, 9.73; S, 8.93.
3.6. 2-Chloro-3-phenyl-2-(toluene-4-sulfinyl)heptan-3-ol
(18a-L and 18a-P)
3.10. 2-Chloro-3-ethyl-2-(toluene-4-sulfinyl)undecan-3-ol
(18e-L and 18e-P)
Compound 18a-L: colorless crystals; mp 132–133 ꢀC (hexane–
Compound 18e-L: colorless crystals; mp 56–57 ꢀC (hexane); IR
AcOEt); IR (KBr) 3364 (OH), 2953, 2869, 1449, 1367, 1082, 1049 (SO),
(KBr) 3316 (OH), 2923, 1598, 1401, 1039 (SO), 809 cmꢁ1 1H NMR
;
d
817, 703, 510 cmꢁ1; 1H NMR
m), 1.31–1.43 (2H, m), 1.35 (3H, s), 1.45–1.55 (1H, m), 2.45 (1H, ddd,
J¼13.8, 11.5, 4.3 Hz), 2.42 (3H, s), 2.63 (1H, ddd, J¼13.7, 11.4, 4.3 Hz),
4.53 (1H, br s), 7.29–7.39 (5H, m), 7.57–7.60 (4H, m). Anal. Calcd for
d
0.87 (3H, t, J¼7.3 Hz), 0.97–1.08 (1H,
0.88 (3H, t, J¼6.8 Hz), 1.12 (3H, t, J¼7.5 Hz), 1.21–1.34 (10H, m),
1.41–1.56 (2H, m), 1.46 (3H, s), 1.70–1.87 (2H, m), 2.04 (1H, dq,
J¼14.6, 7.4 Hz), 2.19 (1H, dq, J¼14.8, 7.4 Hz), 2.43 (3H, s), 3.96 (1H,
s), 7.33 (2H, d, J¼8.2 Hz), 7.60 (2H, d, J¼8.2 Hz). Anal. Calcd for
C
20H25ClO2S: C, 65.83; H, 6.91; Cl, 9.71; S, 8.79. Found: C, 65.80; H,
C20H33ClO2S: C, 64.40; H, 8.92; Cl, 9.50; S, 8.60. Found: C, 64.46; H,
6.88; Cl, 9.62; S, 8.68. Compound 18a-P: colorless crystals; mp 122–
8.85; Cl, 9.41; S, 8.67. Compound 18e-P: colorless crystals; mp 63–
123 ꢀC (hexane–AcOEt); IR (KBr) 3319 (OH), 2962, 2872, 1447, 1424,
64 ꢀC (hexane); IR (KBr) 3344 (OH), 2923, 1598, 1466, 1400, 1379,
1149, 1061, 1030 (SO), 1010, 815, 711 cmꢁ1; 1H NMR
d
0.74–0.83 (1H,
1031 (SO), 811 cmꢁ1
;
1H NMR
d
0.89 (3H, t, J¼6.9 Hz), 1.02 (3H, t,
m), 0.82 (3H, t, J¼7.3 Hz), 1.18–1.35 (2H, m), 1.37–1.48 (1H, m), 1.50
(3H, s), 2.16 (1H, dddd, J¼13.4, 12.0, 4.3, 2.0 Hz), 2.28 (1H, ddd,
J¼13.2, 12.2, 4.5 Hz), 2.41 (3H, s), 5.68 (1H, d, J¼1.9 Hz), 7.28 (2H, d,
J¼7.9 Hz), 7.39 (1H, tt, J¼7.2, 1.1 Hz), 7.44–7.48 (4H, m), 7.61–7.74
(2H, m). Anal. Calcd for C20H25ClO2S: C, 65.83; H, 6.91; Cl, 9.71; S,
8.79. Found: C, 65.80; H, 6.92; Cl, 9.61; S, 8.65.
J¼7.5 Hz), 1.24–1.40 (10H, m), 1.46 (3H, s), 1.48–1.53 (1H, m), 1.58–
1.65 (1H, m), 1.81 (1H, dq, J¼14.5, 7.2 Hz), 1.92 (1H, dq, J¼14.6,
7.4 Hz), 1.99 (1H, ddd, J¼14.1, 12.0, 5.0 Hz), 2.10 (1H, ddd, J¼14.2,
12.3, 4.3 Hz), 2.44 (3H, s), 4.01 (1H, s), 7.34 (2H, d, J¼8.3 Hz), 7.60
(2H, d, J¼8.3 Hz). Anal. Calcd for C20H33ClO2S: C, 64.40; H, 8.92; Cl,
9.50; S, 8.60. Found: C, 64.48; H, 8.85; Cl, 9.40; S, 8.67.
3.7. 2-Chloro-5-methyl-3-phenyl-2-(toluene-4-sulfinyl)hex-4-
en-3-ol (18b-L and 18b-P)
3.11. 2-Methylundecan-3-one (19d)
Colorless oil; IR (neat) 2925, 1715 (CO), 1465 cmꢁ1 1H NMR
;
Compound 18b-L: colorless crystals; mp 151–152 ꢀC (hexane–
d
0.88 (3H, t, J¼6.9 Hz), 1.09 (6H, d, J¼6.8 Hz), 1.21–1.32 (10H, m),
AcOEt); IR (KBr) 3343 (OH), 2983, 2919, 1660, 1449, 1050, 1025 (SO),
1.52–1.59 (2H, m), 2.43 (2H, t, J¼7.4 Hz), 2.59 (1H, septet, J¼6.9 Hz).
MS m/z (%) 184 (Mþ, 23), 141 (100), 99 (5), 86 (33), 71 (56), 43 (47).
Calcd for C12H24O: M, 184.1827. Found: m/z 184.1828.
808, 701, 507 cmꢁ1; 1H NMR
d 1.32 (3H, s), 1.52 (3H, s), 1.90 (3H, d,
J¼0.9 Hz), 2.42 (3H, s), 4.91 (1H, br s), 6.50 (1H, s), 7.28–7.34 (5H, m),
7.59 (2H, d, J¼8.0 Hz), 7.64 (2H, d, J¼6.9 Hz). Anal. Calcd for
C
20H23ClO2S: C, 66.19; H, 6.39; Cl, 9.77; S, 8.83. Found: C, 66.09; H,
3.12. 3-Methyldodecan-4-one (19e)
6.40; Cl, 9.67; S, 8.74. Compound 18b-P: colorless crystals; mp 164–
165 ꢀC (hexane–AcOEt); IR (KBr) 3231 (OH), 3061, 2911, 1662, 1595,
Colorless oil; IR (neat) 2928, 1713 (CO), 1461, 1379, 1072 cmꢁ1
1H NMR
m), 1.37 (1H, double quintet, J¼14.1, 7.1 Hz), 1.52–1.58 (2H, m), 1.67
(1H, double quintet, J¼14.2, 7.1 Hz), 2.37–2.49 (3H, m). MS m/z (%)
198 (Mþ, 15), 141 (68), 85 (23), 72 (42), 57 (100). Calcd for C13H26O:
M, 198.1982. Found: m/z 198.1988.
;
1447,1385,1078,1045,1034 (SO), 816, 701 cmꢁ1; 1H NMR
d
1.32 (3H,
d
0.85–0.89 (6H, m), 1.05 (3H, d, J¼6.9 Hz), 1.20–1.32 (10H,
d, J¼1.2 Hz),1.43 (3H, s), 1.76 (3H, d, J¼1.3 Hz), 2.42 (3H, s), 5.22 (1H,
s), 6.13 (1H, s), 7.29 (2H, d, J¼8.0 Hz), 7.33–7.39 (3H, m), 7.53 (2H, d,
J¼8.3 Hz), 7.67–7.69 (2H, m,). Anal. Calcd for C20H23ClO2S: C, 66.19;
H, 6.39; Cl, 9.77; S, 8.83. Found: C, 66.16; H, 6.38; Cl, 9.68; S, 8.77.

7206
S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
3.13. 4-Methyldodecan-3-one (20e)
stirred for 10 min. Allyl iodide (0.8 mmol) was added dropwise to
the reaction mixture and the solution was stirred at room tem-
perature for 15 h. The reaction was quenched with MeOH and the
whole was extracted with CHCl3. The organic layer was dried over
MgSO4. The product was purified by silica gel column chromatog-
raphy to afford 24c (24.1 mg, 64%) as colorless oil. The spectral data
of this compound are identical to that reported in the literature 24.
Colorless oil; IR (neat) 2927, 1717 (CO), 1460, 1377, 1106,
1026 cmꢁ1
;
1H NMR
d
0.88 (3H, t, J¼6.9 Hz), 1.04 (3H, t, J¼7.3 Hz),
1.06 (3H, d, J¼6.9 Hz), 1.17–1.36 (13H, m), 1.58–1.67 (1H, m), 2.44
(2H, dq, J¼7.3, 2.4 Hz), 2.52 (1H, sextet, J¼6.9 Hz). MS m/z (%) 198
(Mþ, 3), 169 (2), 141 (2), 99 (10), 86 (100), 71 (20), 57 (76). Calcd for
C
13H26O: M, 198.1982. Found: m/z 198.1975.
3.18. 4-Hydroxy-3-methyl-3-phenylhexan-2-one (25a)
3.14. 2,3-Dimethyl-4-phenyl-3-octene (23)
About 2.4:1 mixture of separable two diastereomers. Main
product: colorless oil; IR (neat) 3547 (OH), 2964, 1699 (CO), 1600,
To a solution of t-BuMgCl (0.24 mmol) in 2 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added
a solution of adduct 18a-P (730 mg, 0.2 mmol) in 2 mL of dry THF
dropwise with stirring. The reaction mixture was stirred at 0 ꢀC for
10 min. i-PrMgCl (0.8 mmol) was added to the solution of the
magnesium alkoxide dropwise with stirring. The reaction mixture
was slowly allowed to warm to room temperature for 30 min. The
reaction was quenched with MeOH and the whole was extracted
with CHCl3. The organic layer was dried over MgSO4 and the
product was purified by silica gel column chromatography to afford
19a (10.7 mg, 28%) and olefin 23 (18.7 mg, 43%). Olefin 23: colorless
1446, 1354, 1228, 978 cmꢁ1; 1H NMR
d 0.83–0.98 (4H, m), 1.37–1.43
(1H, m), 1.54 (3H, s), 1.95 (3H, s), 2.71 (1H, dd, J¼1.8, 3.8 Hz), 3.98–
4.02 (1H, m), 7.28–7.32 (3H, m), 7.35–7.39 (2H, m). MS m/z (%) 205
([MꢁH]þ, 5), 163 (6), 148 (100), 131 (16), 105 (46), 91 (12). Minor
product: colorless oil; IR (neat) 3567 (OH), 2930, 1699 (CO), 1353,
1223, 976 cmꢁ1 1H NMR
; d 0.76–0.89 (4H, m), 1.16–1.23 (1H, m),
1.56 (3H, s), 1.90 (3H, s), 3.30 (1H, s), 4.17 (1H, d, J¼11.6 Hz), 7.21
(2H, d, J¼7.8 Hz), 7.28–7.38 (3H, m). MS m/z (%) 205 ([MꢁH]þ, 3),
163 (3), 148 (100), 131 (30), 105 (36), 91 (12).
oil; IR (neat) 2961, 1600, 1467, 704 cmꢁ1
;
1H NMR
d
0.83 (3H, t,
3.19. 3-Methyl-3-phenylpentane-2,4-dione (25b)
J¼6.9 Hz), 1.04 (6H, d, J¼6.8 Hz), 1.19–1.28 (4H, m), 1.37 (3H, s),
2.31–2.36 (2H, m), 2.99 (1H, septet, J¼6.9 Hz), 7.06 (2H, d, J¼7.6 Hz),
7.14–7.21 (1H, m), 7.29 (2H, t, J¼7.6 Hz). MS m/z (%) 216 (Mþ, 66),
201 (26), 173 (8), 159 (100), 145 (41), 131 (45), 117 (49). Calcd for
Colorless oil; IR (neat) 2923, 1756, 1747 (CO), 1602, 1368, 1226,
1173 cmꢁ1; 1H NMR
d 1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 7.17–7.22
(3H, m), 7.29 (2H, t, J¼7.5 Hz). MS m/z (%) 190 (Mþ, 6), 148 (100), 133
(12), 115 (8), 105 (46), 91 (20). Calcd for C12H14O2: M, 190.0992.
Found: m/z 190.0983.
C
16H24: M, 216.1876. Found: m/z 216.1876.
3.15. 3-Hydroxy-2,2-dimethyl-1-phenyl-1-pentanone (24a)
3.20. 1-Hydroxy-2-methyl-1,2-diphenylheptan-3-one (25c)
To a solution of t-BuMgCl (0.24 mmol) in 2 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added
a solution of adduct 8 (64.6 mg, 0.2 mmol) in 2 mL of dry THF
dropwise with stirring. The reaction mixture was stirred at 0 ꢀC for
10 min. To the solution of the magnesium alkoxide was added i-
PrMgCl (0.8 mmol) dropwisewithstirring. Thereactionmixturewas
slowly allowed to warm to room temperature for 30 min. The re-
action mixture was cooled to ꢁ70 ꢀC and propionaldehyde
(0.8 mmol) was added with stirring. The temperature of the reaction
mixture was slowly allowed to warm to room temperature for 2 h.
The reactionwas quenched with MeOH and the whole was extracted
with CHCl3. The organic layer was dried over MgSO4. The product
was purified by silica gel column chromatography to afford 24a
(22.3 mg, 54%) as colorless oil; IR (neat) 3484 (OH), 2971, 1671 (CO),
About 1.7:1 mixture of separable two diastereomers. Main
product: colorless crystals; mp 40–41 ꢀC (pentane); IR (KBr) 3513
(OH), 2929, 1695 (CO), 1453, 1373, 1042 cmꢁ1; 1H NMR
d 0.80 (3H, t,
J¼7.3 Hz), 1.12–1.26 (2H, m), 1.42–1.59 (2H, m), 1.51 (3H, s), 2.17–
2.36 (2H, m), 3.97 (1H, d, J¼2.4 Hz), 5.44 (1H, d, J¼1.9 Hz), 6.67 (2H,
d, J¼7.5 Hz), 6.98–7.04 (4H, m), 7.09 (1H, t, J¼7.1 Hz), 7.26–7.28 (3H,
m). Anal. Calcd for C20H24O2: C, 81.04; H, 8.16. Found: C, 81.05; H,
8.04.
Minor product: colorless oil; IR (neat) 3546 (OH), 2917, 1694
(CO), 1454, 1028 cmꢁ1
;
1H NMR
d
0.82 (3H, t, J¼7.3 Hz), 1.14–1.25
(2H, m), 1.41 (3H, s), 1.45–1.59 (2H, m), 2.22–2.34 (2H, m), 3.76 (1H,
d, J¼2.7 Hz), 5.26 (1H, d, J¼2.7 Hz), 6.73 (2H, d, J¼7.6 Hz), 7.01–7.11
(4H, m), 7.16 (1H, t, J¼7.6 Hz), 7.25–7.33 (3H, m). MS m/z (%) 296
(Mþ, trace), 295 ([MꢁH]þ, 3), 278 (8), 190 (87), 148 (12), 105 (100),
85 (72).
1598,1466,1263, 979 cmꢁ1; 1H NMR
d
1.03 (3H, t, J¼7.4 Hz),1.31 (3H,
s),1.33 (3H, s),1.38 (1H, double quintet, J¼10.5, 7.1 Hz),1.56 (1H, ddq,
J¼13.8, 7.5, 2.0 Hz), 2.48 (1H, d, J¼6.2 Hz), 3.78 (1H, ddd, J¼14.6, 6.0,
1.8 Hz), 7.38–7.42 (2H, m), 7.44–7.49 (1H, m), 7.61–7.64 (2H, m). MS
m/z (%) 206 (Mþ, 2), 188 (6), 148 (49), 105 (100), 84 (48), 77 (40).
3.21. 4-Methyl-4-phenylnon-1-en-5-one (25d)
Colorless oil; IR (neat) 2959, 1709 (CO), 1600, 1446, 916,
3.16. 2,2-Dimethyl-1,3-diphenylpropane-1,3-dione (24b)
703 cmꢁ1; 1H NMR
d
0.77 (3H, t, J¼7.3 Hz), 1.08–1.17 (2H, m), 1.37–
1.49 (2H, m),1.47 (3H, s), 2.15 (1H, ddd, J¼17.0, 8.2, 6.6 Hz), 2.22 (1H,
ddd, J¼17.0, 8.2, 6.5 Hz), 2.67 (2H, d, J¼7.2 Hz), 4.97–5.04 (2H, m),
5.47 (1H, ddt, J¼17.2, 10.0, 7.2 Hz), 7.19–7.24 (2H, m), 7.25–7.27 (1H,
m), 7.32–7.36 (2H, m). MS m/z (%) 230 (Mþ, 4), 145 (100), 129 (10),
117 (16), 85 (22). Calcd for C16H22O: M, 230.1668. Found: m/z
230.1664.
After generation of the enolate in a similar way as described
above, benzoyl chloride (0.8 mmol) was added dropwise to the
reaction mixture and the solution was stirred at room temperature
for 1 h. The reaction was quenched with MeOH. The whole was
extracted with CHCl3. The organic layer was dried over MgSO4. The
product was purified by silica gel column chromatography to afford
24b (38.8 mg, 77%) as colorless oil. The spectral data of this com-
pound are identical to that reported in the literature 23.
3.22. 1-Hydroxy-2,5-dimethyl-1,2-diphenylhex-4-en-3-one
(25e)
3.17. 2,2-Dimethyl-1-phenylpent-4-en-1-one (24c)
About 2.5:1 mixture of separable two diastereomers. Main
product: colorless crystals; mp 106–107 ꢀC (pentane); IR (KBr) 3539
After generation of the enolate in a similar way as described
above, HMPA (0.14 ml) was added to the solution of the enolate and
(OH), 2981, 1667 (CO), 1604, 1446, 1043, 1027, 700 cmꢁ1 1H NMR
;
d
1.49 (3H, s), 1.76 (3H, d, J¼1.1 Hz), 2.22 (3H, d, J¼1.1 Hz), 4.51 (1H,

S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
7207
d, J¼2.5 Hz), 5.41(1H, d, J¼2.3 Hz), 5.71 (1H, t, J¼1.3 Hz), 6.67 (2H, d,
J¼7.1 Hz), 6.95–7.04 (4H, m), 7.06–7.10 (1H, m), 7.22–7.27 (3H, m).
Anal. Calcd for C20H22O2: C, 81.60; H, 7.53. Found: C, 81.60; H, 7.45.
Minor product: colorless oil; IR (neat) 3534 (OH), 2933, 1670 (CO),
m), 3.92 (1H, s), 3.94–4.01 (4H, m), 7.35 (2H, d, J¼8.1 Hz), 7.56 (2H, d,
J¼8.1 Hz). Anal. Calcd for C18H25ClO4S: C, 57.98; H, 6.76; Cl, 9.51; S,
8.60. Found: C, 58.11; H, 6.71; Cl, 9.56; S, 8.73. Compound 28: col-
orless crystals; mp 126–127 ꢀC (hexane–AcOEt); IR (KBr) 3371 (OH),
1613, 1445, 1381, 1022, 701 cmꢁ1; 1H NMR
d
1.40 (3H, s), 1.77 (3H, d,
2960, 1596, 1440, 1361, 1097, 1048 (SO), 976 cmꢁ1 1H NMR
; d 1.34
J¼1.0 Hz), 2.23 (3H, d, J¼1.0 Hz), 4.07 (1H, d, J¼3.3 Hz), 5.26 (1H, d,
J¼3.0 Hz), 5.76 (1H, t, J¼3.0 Hz), 6.68 (2H, d, J¼7.2 Hz), 6.99–7.02
(2H, m), 7.07 (2H, t, J¼7.4 Hz), 7.13–7.17 (1H, m), 7.23–7.32 (3H, m).
MS m/z (%) 293 ([MꢁH]þ, 5), 188 (100), 173 (57), 105 (36), 83 (89),
77 (32). Calcd for C20H21O2: [MꢁH]þ, 293.1542. Found: m/z
293.1542.
(3H, d, J¼6.7 Hz), 1.43 (3H, s), 1.49 (1H, dt, J¼13.1, 3.4 Hz), 1.61 (1H,
dq, J¼12.9, 3.4 Hz), 1.83 (1H, ddt, J¼13.6, 4.0, 1.2 Hz), 1.95–2.02 (2H,
m), 2.23 (1H, ddd, J¼13.3, 3.9, 3.3 Hz), 2.27–2.34 (1H, m), 2.44 (3H, s),
3.80 (1H, s), 3.92–3.99 (4H, m), 7.33 (2H, d, J¼7.8 Hz), 7.61 (2H, d,
J¼8.3 Hz). Anal. Calcd for C18H25ClO4S: C, 57.98; H, 6.76; Cl, 9.51; S,
8.60. Found: C, 57.85; H, 6.72; Cl, 9.38; S, 8.47.
3.23. 3,6-Dimethyl-3-phenylhept-5-ene-2,4-dione (25f)
3.28. 7,9-Dimethyl-1,4-dioxaspiro[4.6]undecan-8-one (29)
Colorless oil; IR (neat) 2915, 1755 (CO), 1660 (CO), 1600, 1493,
To a solution of t-BuMgCl (0.36 mmol) in 3 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added
a solution of 27 (112 mg, 0.3 mmol) in 2 mL of dry THF dropwise
with stirring. The reaction mixture was stirred at 0 ꢀC for 10 min. To
the solution of the magnesium alkoxide was added i-PrMgCl
(1.2 mmol) dropwise. The reaction mixture was slowly allowed to
warm to room temperature for 30 min. The reaction mixture was
quenched with satd aq NH4Cl and the whole was extracted with
CHCl3. The organic layer was dried over MgSO4 and the product was
purified by silica gel column chromatography to afford 29 (49 mg,
83%) as a mixture of separable cis/trans isomers. cis-Isomer: col-
orless oil; IR (neat) 2934, 1705 (CO), 1463, 1377, 1114, 1059 cmꢁ1; 1H
1443,1368,1225,1200 cmꢁ1; 1H NMR
d 1.81 (3H, s),1.85 (3H, s),1.86
(3H, d, J¼0.9 Hz), 2.01 (3H, s), 5.89 (1H, s), 7.20–7.25 (3H, m), 7.29–
7.32 (2H, m). MS m/z (%) 230 (Mþ, 28), 188 (100), 173 (85), 159 (21),
145 (18), 129 (18), 83 (85). Calcd for C15H18O2: M, 230.1305. Found:
m/z 230.1304.
3.24. 2,5-Dimethyl-5-phenylocta-2,7-dien-4-one (25g)
Colorless oil; IR (neat) 2978, 1682 (CO), 1621, 1496, 1446, 1378,
1020, 701 cmꢁ1
;
1H NMR
d
1.43 (3H, s), 1.73 (3H, d, J¼1.1 Hz), 2.13
(3H, d, J¼1.1 Hz), 2.62–2.72 (2H, m), 4.96–5.02 (2H, m), 5.49 (1H, ddt,
J¼17.4, 10.4, 7.1 Hz), 5.76 (1H, quintet, J¼1.3 Hz), 7.20–7.26 (3H, m),
7.31–7.35 (2H, m). MS m/z (%) 228 (Mþ, 3),145 (15),129 (8),117 (8), 91
(10), 83 (100). Calcd for C16H20O: M, 228.1513. Found: m/z 228.1504.
NMR
d
1.06 (3H, d, J¼6.7 Hz), 1.11 (3H, d, J¼7.0 Hz), 1.55 (1H, dddd,
J¼15.0, 8.7, 4.5, 1.8 Hz), 1.61 (1H, dd, J¼14.1, 10.9 Hz), 1.62 (1H, dd,
J¼14.3, 11.1 Hz), 1.75–1.81 (2H, m), 2.30 (1H, dddd, J¼15.5, 10.3, 5.3,
1.7 Hz), 2.61 (1H, sextet, J¼6.2 Hz), 2.96 (1H, ddq, J¼11.2, 6.7,
2.9 Hz), 3.88–3.99 (4H, m). MS m/z (%) 198 (Mþ, 10), 170 (21), 155
(5), 127 (14), 113 (59), 99 (76), 86 (100). Calcd for C11H18O3: M,
198.1254. Found: m/z 198.1248. trans-Isomer: colorless oil; IR (neat)
3.25. 2-Methyl-1-phenyl-2-styrylbutane-1,3-dione (24d)
Colorless oil; IR (neat) 3027, 1716 (CO), 1683 (CO), 1597, 1448,
1243, 970, 749 cmꢁ1; 1H NMR
d
1.69 (3H, s), 2.08 (3H, s), 6.34 (1H, d,
2932, 1705 (CO), 1456, 1376, 1112, 1082 cmꢁ1; 1H NMR
d 1.06 (3H, d,
J¼16.7 Hz), 7.22–7.31 (4H, m), 7.36–7.41 (4H, m), 7.50 (1H, tt, J¼7.4,
1.5 Hz), 7.85–7.87 (2H, m). MS m/z (%) 278 (Mþ, 7), 236 (35), 221 (7),
129 (7), 115 (7), 105 (100), 77 (33). Calcd for C19H18O2: M, 278.1305.
Found: m/z 278.1312.
J¼6.9 Hz), 1.08 (3H, d, J¼7.0 Hz), 1.58–1.65 (1H, m), 1.66–1.81 (4H,
m), 1.88 (1H, ddt, J¼13.3, 6.2, 2.0 Hz), 2.56 (1H, m), 2.90 (1H, ddq,
J¼10.8, 6.8, 4.3 Hz), 3.92–3.97 (4H, m). MS m/z (%) 198 (Mþ, 14), 170
(35), 155 (12), 127 (18), 113 (72), 99 (80), 86 (100). Calcd for
C11H18O3: M, 198.1255. Found: m/z 198.1259.
3.26. 3-Methyl-3-styrylhex-5-en-2-one (24e)
3.29. 9,10-Dimethyl-1,4-dioxaspiro[4.6]undecan-8-one (30)
Colorless oil; IR (neat) 2978, 1707 (CO), 1639, 1448, 1353,
972 cmꢁ1
;
1H NMR
d
1.33 (3H, s), 2.15 (3H, s), 2.44–2.55 (2H, m),
Colorless oil; IR (neat) 2927, 1731 (CO), 1456, 1363, 1086,
5.06–5.12 (2H, m), 5.70 (1H, ddt, J¼17.3, 10.0, 7.2 Hz), 6.26 (1H, d,
J¼16.3 Hz), 6.46 (1H, d, J¼16.0 Hz), 7.22–7.26 (1H, m), 7.30–7.38 (4H,
m). MS m/z (%) 214 (Mþ, 5), 171 (81), 143 (19), 129 (53), 115 (26), 91
(100), 77 (15). Calcd for C15H18O: M, 214.1356. Found: m/z 214.1351.
965 cmꢁ1
;
1H NMR
d
0.96 (3H, d, J¼7.3 Hz), 1.08 (3H, d, J¼7.0 Hz),
1.68–1.75 (1H, m), 1.80–1.87 (2H, m), 2.00 (1H, dddd, J¼14.5, 9.2,
3.2, 1.7 Hz), 2.29–2.37 (1H, m), 2.42 (1H, ddd, J¼16.0, 9.2, 3.0 Hz),
2.64–2.74 (2H, m), 3.91–3.98 (4H, m). MS m/z (%) 198 (Mþ, 3), 156
(45), 113 (40), 99 (78), 86 (100), 55 (23). Calcd for C11H18O3: M,
198.1255. Found: m/z 198.1255.
3.27. 8-[1-Chloro-1-(toluene-4-sulfinyl)ethyl]-7-methyl-1,4-
dioxaspiro[4.5]decan-8-ol (27 and 28)
3.30. 1-[1-Chloro-1-(toluene-4-sulfinyl)ethyl]-2-
cyclohexylcyclohexanol (32a-L and 32a-P)
To a solution of LDA (3.96 mmol) in 5 mL of dry THF in a flame-
dried flask at ꢁ70 ꢀC under argon atmosphere was added a solution
of 1-chloroethyl p-tolyl sulfoxide (669 mg, 3.3 mmol) in 5 mL of dry
THF dropwise with stirring and the solutionwas stirred at ꢁ70 ꢀC for
10 min. To the reaction mixture was added 26 (510 mg, 3 mmol)
dissolved in 5 mL THF dropwise with stirring. The reaction mixture
was stirred at ꢁ70 ꢀC for 30 min. The reaction was quenched with
satd aq NH4Cl. The whole was extracted with CHCl3 and the organic
layer was dried over MgSO4. The product was purified by silica gel
column chromatography to afford 27 (671 mg, 60%) and 28 (391 mg,
35%) both as colorless crystals. Compound 27: colorless crystals; mp
139–140 ꢀC (hexane–AcOEt); IR (KBr) 3373 (OH), 2933, 1598, 1459,
Compound 32a-L: colorless crystals; mp 147–148 ꢀC (hexane–
AcOEt); IR (KBr) 3428 (OH), 2923, 1448, 1399, 1037 (SO), 807 cmꢁ1
;
1H NMR
d
0.93 (1H, dq, J¼12.5, 3.0 Hz), 1.00–1.12 (2H, m), 1.14–1.33
(4H, m), 1.37 (1H, d, J¼11.9 Hz), 1.51–1.59 (2H, m), 1.54 (3H, s), 1.63–
1.74 (4H, m), 1.78–1.83 (2H, m), 1.92 (1H, tq, J¼12.9, 3.8 Hz), 2.17–
2.24 (2H, m), 2.44 (3H, s), 2.54 (1H, d, J¼12.5 Hz), 3.72 (1H, s), 7.34
(2H, d, J¼8.0 Hz), 7.57 (2H, d, J¼8.2 Hz). Anal. Calcd for C21H31ClO2S:
C, 65.86; H, 8.16; Cl, 9.26; S, 8.37. Found: C, 66.03; H, 8.29; Cl, 9.30;
S, 8.50. Compound 32a-P: colorless crystals; mp 125–126 ꢀC (hex-
ane–AcOEt); IR (KBr) 3368 (OH), 2927, 1450, 1384, 1055 (SO),
1404, 1242, 1140, 1055 (SO), 973, 815 cmꢁ1
;
1H NMR
d
1.09 (3H, d,
812 cmꢁ1; 1H NMR
d 1.10–1.20 (3H, m), 1.25–1.45 (6H, m), 1.35 (3H,
J¼6.6 Hz),1.41 (1H, dt, J¼13.0, 3.1 Hz),1.55 (3H, s),1.74–1.81 (1H, m),
s),1.58–1.86 (8H, m), 2.16 (1H, d, J¼13.4 Hz), 2.22–2.28 (2H, m), 2.43
2.01 (1H, t, J¼12.8 Hz), 2.11–2.21 (3H, m), 2.45 (3H, s), 2.58–2.63 (1H,
(3H, s), 2.67 (1H, s), 7.33 (2H, d, J¼8.3 Hz), 7.64 (2H, d, J¼8.3 Hz).

7208
S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
Anal. Calcd for C21H31ClO2S: C, 65.86; H, 8.16; Cl, 9.26; S, 8.37.
Found: C, 65.68; H, 8.11; Cl, 9.43; S, 8.30.
a solution of 27 (112 mg, 0.3 mmol) in 2 mL of dry THF dropwise
with stirring. The reaction mixture was stirred at 0 ꢀC for 10 min. To
the solution of the magnesium alkoxide was added i-PrMgCl
(1.2 mmol) dropwise with stirring. The reaction mixture was slowly
allowed to warm to room temperature for 5 min. The reaction was
quenched with CH3OD and the whole was extracted with CHCl3.
The organic layer was dried over MgSO4 and the product was pu-
rified by silica gel column chromatography to afford 35a (49 mg,
82%) as colorless oil; IR (neat) 2934, 2879, 1707 (CO), 1460, 1376,
3.31. 1-[1-Chloro-1-(toluene-4-sulfinyl)ethyl]-2-
phenylcyclohexanol (32b-L and 32b-P)
Compound 32b-L: colorless crystals; mp 151–152 ꢀC (hexane–
AcOEt); IR (KBr) 3418 (OH), 2940, 1596, 1453, 1398, 1084, 1036 (SO),
822, 707 cmꢁ1
;
1H NMR
d
1.19 (3H, s), 1.43 (1H, tq, J¼13.3, 4.0 Hz),
1.63 (1H, d, J¼13.3 Hz), 1.78–1.83 (2H, m), 2.0 (1H, q, J¼12.8 Hz),
2.11–2.24 (2H, m), 2.37 (3H, s), 2.54 (1H, d, J¼13.1 Hz), 3.00 (1H, d,
J¼11.2 Hz), 3.39 (1H, br s), 7.15–7.25 (5H, m), 7.28–7.66 (4H, m).
Anal. Calcd for C21H25ClO2S: C, 66.91; H, 6.69; Cl, 9.41; S, 8.51.
Found: C, 67.02; H, 6.60; Cl, 9.42; S, 8.62. Compound 32b-P: col-
orless crystals; mp 124–125 ꢀC (hexane–AcOEt); IR (KBr) 3403
1261, 1117, 861 cmꢁ1
;
1H NMR
d
1.06 (3H, d, J¼6.8 Hz), 1.10 (3H, s),
1.54 (1H, dd, J¼15.1, 8.9 Hz), 1.60 (1H, d, J¼11.5 Hz), 1.63 (1H, d,
J¼11.3 Hz), 1.76–1.81 (2H, m), 2.28 (1H, dd, J¼14.3, 11.1 Hz), 2.95
(1H, ddq, J¼10.9, 6.7, 3.0 Hz), 3.88–3.98 (4H, m). MS m/z (%) 199
(Mþ, 6), 171 (21), 156 (6), 128 (6), 113 (58), 99 (75), 86 (100). Calcd
for C11H17DO3: M, 199.1318. Found: m/z 199.1319.
(OH), 2937, 1492, 1448, 1406, 1080, 1031 (SO), 807, 702 cmꢁ1
;
1H
NMR 1.24–1.38 (1H, m), 1.41 (3H, s), 1.55–1.72 (3H, m), 1.75–1.95
d
3.35. 9-[Hydroxy(phenyl)methyl]-7,9-dimethyl-1,4-
dioxaspiro[4.6]undecan-8-one (35b)
(2H, m), 2.23 (1H, dq, J¼13.0, 3.7 Hz), 2.36 (3H, s), 2.38–2.43 (1H,
m), 2.85 (1H, dd, J¼12.4, 3.4 Hz), 4.54 (1H, s), 7.19 (2H, d, J¼7.8 Hz),
7.23–7.62 (7H, m). Anal. Calcd for C21H25ClO2S: C, 66.91; H, 6.69; Cl,
9.41; S, 8.51. Found: C, 66.90; H, 6.62; Cl, 9.32; S, 8.46.
After the enolate intermediate was generated in a similar way as
described above, benzaldehyde (1.2 mmol) was added dropwise to
the reaction mixture and the solution was stirred at room tem-
perature for 30 min. The reaction was quenched with satd aq NH4Cl
and the whole was extracted with CHCl3. The organic layer was
dried over MgSO4 and the product was purified by silica gel column
chromatography to afford 35b (68.5 mg, 75%) as colorless crystals;
mp 120–121 ꢀC (hexane–AcOEt); IR (KBr) 3348 (OH), 2974, 1698
3.32. 2-Cyclohexyl-7-methylcycloheptanone (33a)
To a solution of t-BuMgCl (0.36 mmol) in 3 mL of dry THF in
a flame-dried flask at ꢁ70 ꢀC under argon atmosphere was added
a solution of 32a-L (115 mg, 0.3 mmol) in 2 mL of dry THF dropwise
with stirring. The reaction mixture was stirred at ꢁ70 ꢀC for 10 min.
To the solution of the magnesium alkoxide was added t-BuLi
(1.2 mmol) dropwise with stirring and the mixture was stirred at
ꢁ70 ꢀC for 30 min. The reaction was quenched with satd aq NH4Cl
and the whole was extracted with CHCl3. The organic layer was dried
over MgSO4. The product was purified by silica gel column chro-
matography to afford 33a (52 mg, 83%) as a mixture of separable cis/
trans isomers. cis-Isomer: colorless oil; IR (neat) 2924, 1707 (CO),
(CO), 1454, 1375, 1093, 1044 cmꢁ1; 1H NMR
d
1.02 (3H, d, J¼6.6 Hz),
1.05 (3H, s), 1.20 (1H, ddd, J¼14.9, 7.9, 0.9 Hz), 1.53 (1H, dd, J¼14.2,
12.1 Hz), 1.59–1.64 (2H, m), 1.73–1.78 (1H, m), 2.52 (1H, t,
J¼13.7 Hz), 2.61 (1H, dd, J¼4.2, 2.1 Hz), 3.12 (1H, ddq, J¼12.0, 6.6,
1.9 Hz), 3.89–3.96 (4H, m), 4.63 (1H, d, J¼4.3 Hz), 7.26–7.32 (5H, m).
MS m/z (%) 304 (Mþ, trace), 198 (93), 170 (95), 155 (74), 127 (90), 113
(100), 99 (96), 86 (96). Calcd for C18H24O4: M, 304.1675. Found: m/z
304.1678. Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found: C,
71.07; H, 7.93.
1449,1376,1150 cmꢁ1; 1H NMR
d
0.85 (1H, ddd, J¼16.3,12.5, 3.6 Hz),
0.89 (1H, ddd, J¼16.0, 12.5, 3.4 Hz), 1.03 (3H, d, J¼6.7 Hz), 1.09–1.28
(4H, m), 1.32–1.39 (2H, m), 1.50–1.57 (3H, m), 1.60–1.66 (3H, m),
1.67–1.73 (2H, m), 1.77–1.82 (2H, m), 1.89–1.94 (1H, m), 2.47 (1H,
ddd, J¼10.4, 9.2, 4.6 Hz), 2.58 (1H, sextet, J¼6.6 Hz). MS m/z (%) 208
(Mþ, 9), 126 (100), 109 (17), 97 (12), 84 (44), 67 (38). Calcd for
3.36. 9-Benzoyl-7,9-dimethyl-1,4-dioxaspiro[4.6]undecan-8-
one (35c)
Colorless crystals; mp 69–70 ꢀC (hexane); IR (KBr) 2932, 1719
C
14H24O: M, 208.1826. Found: m/z 208.1827. trans-Isomer: colorless
(CO), 1672 (CO), 1459, 1448, 1231, 1119, 756 cmꢁ1 1H NMR
; d 0.84
oil; IR (neat) 2925, 1702 (CO), 1449, 1374, 1164, 938 cmꢁ1; 1H NMR
(3H, d, J¼6.6 Hz), 1.50–1.55 (1H, m), 1.55 (3H, s), 1.69 (2H, d,
J¼8.5 Hz), 1.79–1.85 (2H, m), 2.78–2.91 (2H, m), 3.86–3.97 (4H, m),
7.41 (2H, t, J¼7.9 Hz), 7.51 (1H, tt, J¼7.5, 1.1 Hz), 7.77–7.79 (2H, m).
MS m/z (%) 302 (Mþ, 11), 180 (8), 149 (11), 113 (39), 105 (100), 86
(42). Calcd for C18H22O4: M, 302.1519. Found: m/z 302.1515. Anal.
Calcd for C18H22O4: C, 71.50; H, 7.33. Found: C, 71.36; H, 7.30.
d
0.90–1.00 (2H, m), 1.03 (3H, d, J¼6.7 Hz), 1.08–1.15 (2H, m), 1.17–
1.36 (5H, m),1.50–1.55 (2H, m),1.61–1.64 (1H, m),1.66–1.76 (4H, m),
1.81–1.85 (1H, s),1.87–1.91 (1H, m),1.97–2.01 (1H, m), 2.22 (1H, ddd,
J¼11.4, 7.8, 5.1 Hz), 2.66 (1H, ddd, J¼10.0, 6.7, 3.4 Hz). MS m/z (%) 208
(Mþ, 9), 165 (7), 126 (100), 109 (13), 95 (12), 84 (43). Calcd for
C
14H24O: M, 208.1826. Found: m/z 208.1833.
3.37. 7,9,9-Trimethyl-1,4-dioxaspiro[4.6]undecan-8-one (35d)
3.33. 2-Methyl-7-phenylcycloheptanone (33b)
To a solution of t-BuMgCl (0.36 mmol) in 3 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added
a solution of 27 (112 mg, 0.3 mmol) in 2 ml of dry THF dropwise
with stirring. The reaction mixture was stirred at 0 ꢀC for 10 min. To
the solution of the magnesium alkoxide was added i-PrMgCl
(1.2 mmol) dropwise with stirring. The reaction mixture was slowly
allowed to warm to room temperature for 30 min. HMPA (0.21 mL)
was added to a solution of the ring-expanded enolate intermediate
and the reaction mixture was stirred for 10 min. Iodomethane
(1.2 mmol) was added dropwise to the reaction mixture and the
solution was stirred at room temperature for 15 h. The reaction was
quenched with satd aq NH4Cl and the whole was extracted with
CHCl3. The organic layer was dried over MgSO4 and the product was
purified by silica gel column chromatography to afford 35d (47 mg,
73%) as colorless crystals; mp 36–37 ꢀC (hexane–AcOEt); IR (KBr)
About 13:1 mixture of inseparable two diastereomers. Colorless
oil; IR (neat) 2930, 1712 (CO), 1602, 1497, 1455, 1375, 1124,
698 cmꢁ1; 1H NMR
d
1.08 (3H, d, J¼6.8 Hz), 1.39–1.50 (1H, m), 1.54–
1.64 (1H, m), 1.66–1.79 (3H, m), 1.84–1.93 (1H, m), 1.98–2.06 (2H,
m), 2.84 (1H, sextet, J¼6.4 Hz), 3.74 (0.07H, dd, J¼12.0, 4.4 Hz), 3.98
(0.93H, dd, J¼10.0, 4.2 Hz), 7.20–7.32 (5H, m). MS m/z (%) 202 (Mþ,
39),130 (7),117 (54),104 (100), 91 (48), 78 (8). Calcd for C14H18O: M,
202.1356. Found: m/z 202.1359.
3.34. 9-Deuterio-7,9-dimethyl-1,4-dioxaspiro[4.6]undecan-8-
one (35a)
To a solution of t-BuMgCl (0.36 mmol) in 3 mL of dry THF in
a flame-dried flask at 0 ꢀC under argon atmosphere was added

S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
7209
2965, 2875, 1705 (CO), 1458, 1120, 1096, 947, 860 cmꢁ1
;
1H NMR
s), 1.52–1.82 (7H, m), 1.84–1.96 (2H, m), 2.57 (1H, ddd, J¼11.3, 9.2,
2.5 Hz). MS m/z (%) 222 (Mþ, 18), 140 (100), 125 (15), 109 (30), 96
(31), 81 (46), 55 (67). Calcd for C15H26O: M, 222.1983. Found: m/z
222.1983.
d
1.04 (3H, d, J¼6.6 Hz), 1.07 (3H, s), 1.11 (3H, s), 1.47–1.59 (3H, m),
1.65–1.78 (2H, m), 2.16 (1H, dd, J¼13.5, 12.0 Hz), 3.16 (1H, ddq,
J¼12.2, 6.6, 2.3 Hz), 3.89–3.99 (4H, m). MS m/z (%) 212 (Mþ, 6), 184
(36), 156 (12), 141 (11), 113 (87), 99 (75), 86 (100). Calcd for
C
C
12H20O3: M, 212.1412. Found: m/z 212.1405. Anal. Calcd for
12H20O3: C, 67.89; H, 9.50. Found: C, 68.06; H, 9.71.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, which is gratefully
acknowledged.
3.38. 7-Cyclohexyl-2-deuterio-2-methylcycloheptanone (36a)
To a solution of t-BuMgCl (0.36 mmol) in 3 mL of dry THF in
a flame-dried flask at ꢁ70 ꢀC under argon atmosphere was added
a solution of 32a-L (115 mg, 0.3 mmol) in 2 mL of dry THF dropwise
with stirring. The reaction mixture was stirred at ꢁ70 ꢀC for 10 min.
To the solution of the magnesium alkoxide was added t-BuLi
(1.2 mmol) dropwise with stirring. The mixture was stirred at
ꢁ70 ꢀC for 5 min. The reaction was quenched with CH3OD and the
whole was extracted with CHCl3. The organic layer was dried over
MgSO4 and the product was purified by silica gel column chroma-
tography to afford 36a (54.6 mg, 87%) as colorless oil; IR (neat)
References and notes
1.
A monograph and some reviews concerning homologation of carbonyl
compounds: (a) Hase, T. A. Umpoled Synthons: A Survey of Sources and Uses in
Synthesis; John Wiley and Sons: New York, NY, 1987; (b) Martin, S. F. Synthesis
1979, 633; (c) Hase, T. A.; Koskimies, J. K. Aldrichimica Acta 1981, 14, 73; (d)
Stowell, J. C. Chem. Rev. 1984, 84, 409; (e) Badham, N. F. Tetrahedron 2004,
60, 11.
2. A monograph and some reviews concerning ring-expansion reactions: (a)
Hesse, M. Ring Enlargement in Organic Synthesis; VCH: Weinheim, 1991; (b)
Hiyama, T.; Nozaki, H. J. Synth. Org. Chem. Jpn. 1977, 35, 979; (c) Krow, G. R.
Tetrahedron 1987, 43, 3; (d) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091; (e)
Roxburgh, C. J. Tetrahedron 1993, 47, 10749; (f) Tochtermann, W.; Kraft, P. Synlett
1996, 1029.
3. (a) Villieras, J.; Bacquet, C.; Normant, J. F. J. Organomet. Chem. 1972, 40, C1; (b)
Villieras, J.; Bacquet, C.; Masure, D.; Normant, J. F. J. Organomet. Chem. 1973, 50,
C7; (c) Villieras, J.; Perriot, P.; Normant, J. F. Synthesis 1979, 968.
4. (a) Kobrich, G.; Grosser, J. Tetrahedron Lett. 1972, 4117; (b) Kobrich, G.; Grosser, J.
Chem. Ber. 1973, 106, 2626.
2925, 1707 (CO), 1449, 1375, 996 cmꢁ1 1H NMR
; d 0.81–0.92 (2H,
m), 1.02 (3H, s), 1.08–1.29 (4H, m), 1.32–1.40 (2H, m), 1.47–1.59 (3H,
m),1.59–1.66 (3H, m),1.67–1.75 (2H, m),1.76–1.83 (2H, m),1.91 (1H,
ddd, J¼14.1, 8.9, 2.8 Hz), 2.46 (1H, ddd, J¼10.7, 9.0, 4.9 Hz). MS m/z
(%) 209 (Mþ, 12), 127 (100), 109 (12), 95 (11), 84 (32), 67 (26). Calcd
for C14H23DO: M, 209.1889. Found: m/z 209.1890.
5. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett. 1972, 4661; (b)
Taguchi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1974, 96, 6510; (c)
Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett. 1976, 2617; (d) Taguchi,
H.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. Jpn. 1977, 50, 1592.
6. Abraham, W. D.; Bhupathy, M.; Cohen, T. Tetrahedron Lett. 1987, 28, 2203.
7. (a) Satoh, T.; Hayashi, Y.; Mizu, Y.; Yamakawa, K. Tetrahedron Lett. 1992, 33,
7181; (b) Satoh, T.; Itoh, N.; Gengyo, K.; Yamakawa, K. Tetrahedron Lett. 1992, 33,
7543; (c) Satoh, T.; Hayashi, Y.; Mizu, Y.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1994,
67, 1412; (d) Satoh, T.; Itoh, N.; Gengyo, K.; Takada, S.; Asakawa, N.; Yamani, Y.;
Yamakawa, K. Tetrahedron 1994, 50, 11839.
8. (a) Satoh, T.; Mizu, Y.; Kawashima, T.; Yamakawa, K. Tetrahedron 1995, 51, 703;
(b) Satoh, T.; Miyashita, K. Tetrahedron Lett. 2004, 45, 4859; (c) Miyashita, K.;
Satoh, T. Tetrahedron 2005, 61, 5067; (d) Preliminary results of this study were
reported as a communication: Satoh, T.; Tanaka, S.; Asakawa, N. Tetrahedron
Lett. 2006, 47, 6769; (e) Recent paper for a synthesis of bicyclo[n.1.0]alkanes by
using chemistry of magnesium carbenoid: Ogata, S.; Saitoh, H.; Wakasugi, D.;
Satoh, T. Tetrahedron 2008, 62, 5711.
3.39. 7-Cyclohexyl-2-[hydroxyl(phenyl)methyl]-2-
methylcycloheptanone (36b)
About 7:1 mixture of separable two diastereomers. Main prod-
uct: colorless crystals; mp 70–71 ꢀC (hexane–AcOEt); IR (KBr) 3480
(OH), 2924, 1695 (CO), 1451, 1378, 998, 703 cmꢁ1 1H NMR
; d 0.89–
0.99 (2H, m), 1.03 (3H, s), 1.04–1.17 (4H, m), 1.20–1.37 (3H, m), 1.64–
1.71 (5H, m), 1.72–1.81 (3H, m), 1.93–2.00 (2H, m), 2.17 (1H, d,
J¼2.8 Hz), 2.72 (1H, ddd, J¼11.0, 8.3, 2.5 Hz), 4.78 (1H, d, J¼2.5 Hz),
7.27–7.36 (5H, m). MS m/z (%) 314 (Mþ, trace), 208 (68), 126 (100),
109 (16), 105 (46), 84 (35), 77 (50). Calcd for C21H30O2: M, 314.2244.
Found: m/z 314.2245. Anal. Calcd for C21H30O2: C, 80.21; H, 9.62.
Found: C, 80.32; H, 9.51. Minor product: colorless crystals; mp 93–
94 ꢀC (hexane–AcOEt); IR (KBr) 3502 (OH), 2923, 1685 (CO), 1468,
9. (a) Satoh, T.; Hirano, M.; Kuroiwa, A.; Kaneko, Y. Tetrahedron 2006, 62, 9268; (b)
Satoh, T.; Kobayashi, S.; Nakanishi, S.; Horiguchi, K.; Irisa, S. Tetrahedron 1999,
55, 2515.
1450, 1043, 704 cmꢁ1 1H NMR
; d 0.87–1.16 (4H, m), 1.00 (3H, s),
1.22–1.41 (5H, m), 1.51 (1H, d, J¼12.8 Hz), 1.64–1.94 (8H, m), 2.17
(1H, t, J¼13.1 Hz), 2.38 (1H, d, J¼4.0 Hz), 2.60 (1H, ddd, J¼10.7, 6.1,
1.5 Hz), 4.60 (1H, d, J¼4.0 Hz), 7.27–7.33 (5H, m). MS m/z (%) 314
(Mþ, 2), 208 (86), 179 (11), 165 (47), 151 (33), 126 (100), 105 (85), 84
(85), 77 (81). Calcd for C21H30O2: M, 314.2246. Found: m/z 314.2237.
10. (a) Satoh, T. J. Synth. Org. Chem. Jpn. 1996, 54, 481; (b) Hoffmann, R. W.; Nell,
P. G. Angew. Chem., Int. Ed. 1999, 38, 338; (c) Satoh, T. Chem. Soc. Rev. 2007, 36,
1561.
11. Crystal data for alcohol 27: C18H25ClO4S, M¼372.89, monoclinic, space group P21/
c (#14), a¼14.7778(10) Å, b¼12.2868(8) Å, c¼20.2419(13) Å,
b
¼100.0160(10)ꢀ,
V¼3619.3(4) Å3, Z¼8, F(000)¼1584, Dcalcd¼1.369 g cmꢁ3
,
m
(Mo K
a
)¼3.45 cmꢁ1
,
T¼173 K, radiation¼0.71073 Å, R1¼0.0406 for I>2.0 (I), wR2¼0.1070 for all data
s
(8321 reflections), GOF¼0.954 (441 parameters), crystal dimensions 0.55ꢂ0.
51ꢂ0.46 mm3. Crystal data for alcohol 28: C18H25ClO4S, M¼372.89, monoclinic,
space group P21/n (#14), a¼13.6179(11) Å, b¼9.1203(8) Å, c¼15.9592(14) Å,
3.40. 2-Benzoyl-7-cyclohexyl-2-methylcycloheptanone (36c)
b
K
¼113.8050(10)ꢀ, V¼1813.5(3) Å3, Z¼4, F(000)¼792, Dcalcd¼1.366 g cmꢁ3
,
m(Mo
Colorless crystals; mp 65–66 ꢀC (hexane–AcOEt); IR (KBr) 2925,
a
)¼3.45 cmꢁ1, T¼173 K, radiation¼0.71073 Å, R1¼0.0381 for I>2.0
s
(I), wR2¼0.
1706 (CO), 1670 (CO), 1447, 1233, 952, 700 cmꢁ1 1H NMR
; d 0.54
1088 for all data (4157 reflections), GOF¼1.014 (221 parameters), crystal di-
mensions 0.45ꢂ0.41ꢂ0.06 mm3. The single crystals of 27 and 28 were mounted
on glass fibers. Diffraction datawere measured on a Bruker APEXCCD-Detector X-
(1H, dq, J¼12.1, 3.6 Hz), 0.79 (1H, dq, J¼12.4, 3.6 Hz), 0.91–1.03 (2H,
m), 1.06–1.16 (2H, m), 1.18–1.25 (2H, m), 1.36–1.54 (4H, m), 1.51 (3H,
s), 1.61–1.65 (1H, m),1.73 (1H, dd, J¼14.6, 8.2 Hz), 1.79–1.87 (3H, m),
1.89–1.94 (1H, m), 2.57 (1H, ddd, J¼11.6, 7.6, 2.6 Hz), 2.65 (1H, dd,
J¼14.5, 11.3 Hz), 7.37–7.40 (2H, m), 7.49 (1H, tt, J¼7.4, 1.4 Hz), 7.79–
7.81 (2H, m). MS m/z (%) 312 (Mþ, 19), 207 (36), 178 (16), 159 (11),
147 (24), 134 (26), 105 (100). Calcd for C21H28O2: M, 312.2087.
Found: m/z 312.2091. Anal. Calcd for C21H28O2: C, 80.73; H, 9.03.
Found: C, 80.72; H, 9.00.
ray diffractometer with monochromated Mo Ka radiation from a rotating anode
source apparatus. The data reduction, structure solution and refinement, and all
the necessary computational data processes were performed using APEX, SAINT,
SHELXTL programs. Crystallographic data excluding structures have been de-
posited with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 678426 for 27 and CCDC 678427 for 28, respectively. A
copy of the data can be obtained free of charge from CCDC, 12 Union road, Cam-
bridge CB2 1EZ, UK [direct line: þ44 1223 762910, fax: þ44 (0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk.
12. Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; John Wiley
and Sons: New York, NY, 2001; pp 1377-1505.
13. Hiyama, T.; Shinoda, M.; Nozaki, H. Tetrahedron Lett. 1979, 3529.
14. Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005, 127, 6172.
15. Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem. Soc. Jpn. 1984, 57,
242.
3.41. 7-Cyclohexyl-2,2-dimethylcycloheptanone (36d)
Colorless oil; IR (neat) 2926, 1704 (CO), 1471, 1449, 1384,
958 cmꢁ1; 1H NMR
d
0.76–0.92 (2H, m), 0.98–1.37 (8H, m), 1.05 (6H,
16. Baigrie, M. L.; Seiklay, R. H.; Tidwell, T. T. J. Am. Chem. Soc. 1985, 107, 5391.

7210
S. Tanaka et al. / Tetrahedron 64 (2008) 7199–7210
17. Hong, Y.-T.; Barchuk, A.; Krische, J. M. Angew. Chem., Int. Ed 2006, 45, 6885.
18. Peach, P.; Cross, J. D.; Kenny, A. J.; Mann, I.; Houson, I.; Campvell, L.; Walsgrove,
T.; Wills, M. Tetrahedron 2006, 62, 1864.
19. Cho, C. S.; Kim, B. T.; Lee, M. J.; Kim, T.-J.; Shim, S. C. Angew. Chem., Int. Ed. 2001,
40, 958.
21. Ohe, T.; Ohse, T.; Mori, K.; Ohtaka, S.; Uemura, S. Bull. Chem. Soc. Jpn. 2003, 76,
1823.
22. Sakai, T.; Matsumoto, S.; Hidaka, S.; Imajo, N.; Tsuboi, S.; Utaka, M. Bull. Chem.
Soc. Jpn. 1991, 64, 3473.
23. Choundhary, A.; Baumstark, L. A. Synthesis 1989, 9, 688.
24. Barentsen, M. H.; Sieval, B. A.; Cornelisse, J. Tetrahedron 1995, 51, 7495.
20. Jun, C.-H.; Koo, B.-T.; Kang, J.-B.; Kim, K.-J. Bull. Korean Chem. Soc. 1994, 15, 1064.