One-carbon ring-expansion of 2-substituted cyclohexanones via lithium- and magnesium β-oxido carbenoid rearrangement: a new synthesis of 2,7-disubstituted and 2,2,7-trisubstituted cycloheptanones

Article abstract of DOI:10.1016/j.tetlet.2006.07.082

Lithium α-sulfinyl carbanion of 1-chloroethyl p-tolyl sulfoxide was reacted with 2-substituted cyclohexanones to afford adducts in good yields. The adducts were treated with LDA or t-BuMgCl to give lithium or magnesium alkoxides, which were treated with t

Full text of DOI:10.1016/j.tetlet.2006.07.082

Tetrahedron Letters 47 (2006) 6769–6773
One-carbon ring-expansion of 2-substituted cyclohexanones
via lithium- and magnesium b-oxido carbenoid
rearrangement: a new synthesis of 2,7-disubstituted
and 2,2,7-trisubstituted cycloheptanones
Tsuyoshi Satoh,* Shu Tanaka and Naoyuki Asakawa
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-Funagawara-Machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 30 June 2006; revised 14 July 2006; accepted 14 July 2006
Available online 7 August 2006
Abstract—Lithium a-sulfinyl carbanion of 1-chloroethyl p-tolyl sulfoxide was reacted with 2-substituted cyclohexanones to afford
adducts in good yields. The adducts were treated with LDA or t-BuMgCl to give lithium or magnesium alkoxides, which were trea-
ted with t-BuLi or i-PrMgCl to afford one-carbon ring-expanded 2,7-disubstituted cycloheptanones through b-oxido carbenoids.
Interestingly, 2,3-disubstituted cycloheptanones were obtained in a trace amount or were not obtained at all. The enolate inter-
mediates of this reaction were found to be able to get trapped with electrophiles to give 2,2,7-trisubstituted cycloheptanones in
moderate to good yields. This method is very useful for the synthesis of 2,7-disubstituted cycloheptanones and 2,2,7-trisubstituted
cycloheptanones from 2-substituted cyclohexanones in only two steps.
Ó 2006 Elsevier Ltd. All rights reserved.
One-carbon homologation of cyclic ketones via b-oxido
carbenoid rearrangement is one of the most useful and
reliable methods for one-carbon ring enlargement.1 A
few methods have been reported so far from Normant,2
Kobrich,3 Yamamoto,4 Hiyama,5 Cohen,6 and by us.7
In these reports, Yamamoto’s group investigated their
chemistry with 2-methylcycloalkanones. For example,
treatment of the product 2, derived from the addition
reaction of 2-methylcyclohexanone 1 with dibromo-
methyllithium, with n-BuLi in ether at ꢀ95 °C gave
3-methylcycloheptanone 3 in good yield with 97% selec-
tivity (Scheme 1).4c,d The product 3 was derived from
the one-carbon insertion between C1 and C2 carbons
by the b-oxido carbenoid rearrangement. As the b-oxido
carbenoid rearrangement is classified as nucleophilic
rearrangement similar to the Baeyer–Villiger oxidation,8
rearrangement of a more substituted carbon (C2-carbon)
was quite consistent with the tendency of the
rearrangement.
Hiyama reported selective olefinic carbon migration in
his synthesis of nootkatone using b-oxido carbenoid
O
O
LiO
CHBr2
CH3
CH3
6
C
1
LiCHBr2
6
1
n-BuLi
2
2
CH3
3
1
2
Scheme 1. Yamamoto’s one-carbon ring-expansion of 2-methylcyclohexanone by b-oxido carbenoid rearrangement with dibromomethyllithium as a
one-carbon unit.
Keywords: Sulfoxide; b-Oxido carbenoid rearrangement; One-carbon ring-expansion; 2,7-Disubstituted cycloheptanone; 2,2,7-Trisubstituted
cycloheptanone.
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 3235 2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.082

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T. Satoh et al. / Tetrahedron Letters 47 (2006) 6769–6773
rearrangement as the key reaction.5 Cohen and co-work-
ers also reported the migration of a more highly substi-
tuted alkyl group in his carbenoid-type base-induced
ring expansion.6
mixture of two diastereomers (9-Main and 9-Minor) in
a ratio of 3:1.9 The diastereomers 9 were treated with
a base to afford an alkoxide, which was then treated
with an alkyl metal. The sulfoxide–metal exchange reac-
tion took place to generate b-oxido carbenoid and one-
carbon expanded cycloheptanone 10 was obtained. The
results are summarized in Table 1.
We recently reported one-carbon ring-expansion of sym-
metrical cyclic ketones through b-oxido carbenoids
which were generated by the sulfoxide–metal exchange
reaction of b-hydroxy a-chloroalkyl aryl sulfoxides.7e
As a development of our method for the one-carbon
ring-expansion, we studied the expansion of several
unsymmetrical cycloalkanones, 2-substituted cyclohexa-
nones 4, through the adduct with 1-chloroethyl p-tolyl
sulfoxide 5 and quite interesting results were obtained
(Scheme 2).
First, 9-Main was treated with LDA, and the resultant
lithium alkoxide was treated with excess t-BuLi at
ꢀ70 °C for 30 min (entry 1). We obtained a cyclohepta-
none derivative as a main product and from detailed
inspection of its IR and 1H NMR, the product was
determined to be 2-cyclohexyl-7-methylcycloheptanone
10. Very interestingly, no 2,3-disubstituted isomer 11
was obtained at all. Entries 2 and 3 show the results
of the reaction of magnesium- and aluminum-alkoxide
with t-BuLi. Both reactions gave 10 as the sole product
in over 80% yield.
The rearrangement gave 2,7-disubstituted cyclohepta-
none 7 in high selectivity through enolate 6. It is worth
noting that the one-carbon insertion took place between
C1 and C6 carbons. The rearrangement is in reverse
direction to that of Yamamoto’s results (compare the
reaction in Scheme 1). In addition, we were able to trap
the enolate intermediate 6 with several electrophiles to
obtain 2,2,7-trisubstituted cycloheptanones 8.
The reaction of magnesium alkoxide of 9-Main with
i-PrMgCl was found not to proceed at ꢀ70 °C. When this
reaction was carried out at 0 °C to room temperature,
the alkoxide disappeared and 10 was obtained in 10%
yield. The main product was 2-cyclohexylcyclohexanone
(entry 4). Obviously, a retro aldol-type reaction took
place in this reaction. Similar treatment of 9-Minor with
t-BuMgCl followed by t-BuLi gave again only 10; how-
At first, 2-cyclohexylcyclohexanone was reacted with
lithium a-sulfinyl carbanion of 1-chloroethyl p-tolyl sulf-
oxide at ꢀ70 °C to give the adduct 9 in 80% yield as a
H3C S(O)Tol
-
O
O
O
CH3
HO
C
Cl
R
R
R
R
H3C
H3C
R
1) Base
H2O
TolS(O)CClLi
6
1
C
C
C
2
1
1
2) t-BuLi or
i-PrMgCl
6
6
4
5
7
6
R= CH3, c-Hex, Ph
O
H3C
E
Electrophile
1
6
8
Scheme 2.
Table 1. One-carbon ring-expansion of 2-cyclohexylcyclohexanone to 2-cyclohexyl-7-methylcycloheptanone 10
H3C S(O)Tol
O
O
O
HO
C
Cl
c-Hex
CH3
c-Hex
1) Base
CH3
c-Hex
H3C
TolS(O)CClLi
2) R'-Metal
THF
30 min
80%
10
9
11
Entry
9
Base
R0-metal (equiv)
Temperature (°C)
10a/Yield (%)
1
2
3
4
5
9-Main
9-Main
9-Main
9-Main
9-Minor
LDA
t-BuMgCl
Al(CH3)3
t-BuMgCl
t-BuMgCl
t-BuLi (4)
t-BuLi (4)
t-BuLi (4)
t-PrMgCl (2)
t-BuLi (4)
ꢀ70
ꢀ70
ꢀ70
0–rt
ꢀ70
62
83
87
10b
14c
a A mixture of cis/trans-isomers.
b 2-Cyclohexylcyclohexanone (36%) was obtained as a by-product.
c About 30% of the starting material 9-Minor was recovered.

T. Satoh et al. / Tetrahedron Letters 47 (2006) 6769–6773
6771
ever, the yield was quite low. In this case, the sulfoxide–
lithium exchange was found to be slow and the starting
material was recovered (entry 5).
methylcycloheptanone derivative 14a in 65% yield (entry
1). Again, one-carbon insertion took place between C1
and C6 carbons and no 2,3-disubstituted cycloheptanone
15a was obtained.
The regioselectivity of this reaction is very interesting. A
rational explanation of this selectivity is as follows
(Fig. 1). By treatment of the magnesium alkoxide A with
t-BuLi, the sulfoxide–lithium exchange reaction took
place to afford lithium b-oxido carbenoid B. The confor-
mation of the carbenoid would be fixed by the formation
of the chelate ring.4d Two configurational isomers of the
carbenoids C and D must be present in equilibrium. The
isomer D has two bulky substituents (cyclohexyl and
methyl groups) close to each other and the steric repul-
sion forces the equilibrium to C. The nucleophilic rear-
rangement from the isomer C must give 10 in high
regioselectivity.
Entry 2 shows that in this case the rearrangement gave
much better yield (83%) with magnesium b-oxido carb-
enoid. In this reaction, the regioisomer 15a was obtained
in a trace amount (4%). The reaction was carried out
with the minor adduct (13a-Minor) with t-BuLi and
i-PrMgCl (entries 3 and 4). The sulfoxide–magnesium
exchange reaction of 13a-Minor was found to be
sluggish and a much lower yield was obtained; however,
the product was again 14a.
The results starting from 2-phenylcyclohexanone 12b
are summarized in entries 5 and 6. The main adduct
13b-Main was treated with t-BuMgCl followed by i-
PrMgCl to afford 14b in 84% yield with 5% of the regio-
isomer 15b (entry 5). Again, the sulfoxide–magnesium
exchange reaction took place slowly with the minor
adduct and the yield of the product was quite low
(entry 6).
We further investigated this chemistry by using 2-meth-
ylcyclohexanone derivative 12a and 2-phenylcyclohexa-
none 12b with 1-chloroethyl p-tolyl sulfoxide and the
results are summarized in Table 2. The addition reaction
of lithium a-sulfinyl carbanion with 2-methylcyclohexa-
none derivative 12a gave the adduct 13a in high yield as
two diastereomers, 13a-Main (60%) and 13a-Minor
(35%). The main adduct was treated with t-BuMgCl
followed by t-BuLi at ꢀ70 °C for 30 min to give 2,7-di-
From the viewpoint of synthetic organic chemistry,
trapping of the enolate intermediate of the b-oxido carb-
enoid rearrangement was quite useful for the synthesis
ClMgO
Li
CH3
Cl
10
R
ClMgO
R
ClMgO
Li
S(O)Tol
CH3
Cl
C
t-BuLi
CH3
Cl
R
ClMgO
Li
A
R = Cyclohexyl
B
Cl
R
CH3
D
Figure 1. A rational explanation for the selective formation of 2-cyclohexyl-7-methylcycloheptanone 10.
Table 2. One-carbon ring-expansion of 2-substituted cyclohexanones 12 to 2-methyl-7-substituted cycloheptanones 14
H3C S(O)Tol
O
O
O
HO
C
Cl
R
CH3
1) t-BuMgCl
R
CH3
R
H3C
R
TolS(O)CClLi
2) R'-Metal
THF
30 min
X
X
X
X
X
X
X
X
12a X, X= OCH2CH2O, R=CH3
12b X, X= H, R=Ph
14
15
13
Entry
12
13
R0-metal (equiv)
Temperature (°C)
14/Yield (%)
15/Yield (%)
1
2
3
4
12a
13a-Main (60%)
13a-Main
13a-Minor (35%)
13a-Minor
t-BuLi (4)
i-PrMgCl (4)
t-BuLi (4)
ꢀ70
0–rt
ꢀ70
0–rt
65
Trace
4
0
83a
25
i-PrMgCl (8)
64a
Trace
5
6
12b
13b-Main (54%)
13b-Minor (30%)
i-PrMgCl (4)
i-PrMgCl (4)
0–rt
0–rt
84b
10c
5
0
a A mixture of two diastereomers (10:1).
b A mixture of two diastereomers (13:1).
c About 20% of 13b-Minor was recovered.

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T. Satoh et al. / Tetrahedron Letters 47 (2006) 6769–6773
Table 3. One-carbon ring-expansion of 2-cyclohexylcyclohexanone and 12a to 2,2,7-trisubstituted cycloheptanones 17a and 17b through the adducts
9 and 13a
H3C S(O)Tol
O
OMgCl
HO
C
Cl
R
R
H3C
E
1) t-BuMgCl (1.2 eq)
R
H3C
Electrophile
Conditions
2) R'-Metal (4 eq)
THF
30 min
X
X
X
X
X
X
16
9 X, X=H, R=c-Hex
17a X, X=H, R=c-Hex
13a X, X=OCH2CH2O, R=CH3
17b X, X=OCH2CH2O, R=CH3
Entry
9 or 13a
R0-metal
Electrophile
Conditions
E
17/Yield (%)
1
2
3
4
9a
t-BuLi
t-BuLi
t-BuLi
t-BuLi
CH3OD
PhCHO
PhCOCl
CH3If
ꢀ70 °C, 5 min
ꢀ70 °C, 30 min
ꢀ70 °C, 30 min
ꢀ70 °C–rt, 15 h
rt, 5 min
rt, 30 min
rt, 30 min
rt, 15 h
D
87c
82d
62e
49
PhCH(OH)
PhCO
CH3
5
6
7
8
13ab
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
CH3OD
PhCHO
PhCOCl
CH3If
D
82c
75e
73e
73
PhCH(OH)
PhCO
CH3
a 9-Main was used.
b 13a-Main was used.
c D content 93%.
d A mixture of two diastereomers (7:1).
e Single product was obtained.
f HMPA (4 equiv) was added as an additive.
of multi-substituted carbonyl compounds.7d,e We tried
to trap the enolate intermediates of the above-men-
tioned reactions with several electrophiles and a new
method for synthesis of 2,2,7-trisubstituted cyclohepta-
nones from 2-substituted cyclohexanones was realized.
The results are summarized in Table 3.
References and notes
1. (a) Hiyama, T.; Nozaki, H. J. Syn. Org. Chem. Jpn. 1977,
35, 979; (b) Krow, G. R. Tetrahedron 1987, 43, 3; (c)
Hesse, M. In Ring Enlargement in Organic Chemistry;
VHC: Weinheim, 1991; (d) Dowd, P.; Zhang, W. Chem.
Rev. 1993, 93, 2091.
2. (a) Villieras, J.; Bacquet, C.; Normant, J. F. J. Organo-
metal. Chem. 1972, 40, C1; (b) Villieras, J.; Bacquet, C.;
Masure, D.; Normant, J. F. J. Organometal. Chem. 1973,
50, C7.
3. (a) Kobrich, G.; Grosser, J. Tetrahedron Lett. 1972, 4117;
(b) Kobrich, G.; Grosser, J. Chem. Ber. 1973, 106,
2626.
4. (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.
5. Hiyama, T.; Shinoda, M.; Nozaki, H. Tetrahedron Lett.
1979, 3529.
6. Abraham, W. D.; Bhupathy, M.; Cohen, T. Tetrahedron
Lett. 1987, 28, 2203.
7. (a) Satoh, T.; Itoh, N.; Gengyo, K.; Yamakawa, K.
Tetrahedron Lett. 1992, 33, 7543; (b) Satoh, T.; Itoh, N.;
Gengyo, K.; Takada, S.; Asakawa, N.; Yamani, Y.;
Yamakawa, K. Tetrahedron 1994, 50, 11839; (c) Satoh, T.;
Mizu, Y.; Kawashima, T.; Yamakawa, K. Tetrahedron
1995, 51, 703; (d) Satoh, T.; Miyashita, K. Tetrahedron
Lett. 2004, 45, 4859; (e) Miyashita, K.; Satoh, T. Tetra-
hedron 2005, 61, 5067.
As shown in entry 1, 9-Main was treated with t-BuMgCl
followed by t-BuLi at ꢀ70 °C for 30 min. The reaction
was quenched by adding excess CH3OD to give 7-deu-
terated ketone in 87% yield with 93% deuterium incor-
poration (entry 1). Quenching of the reaction with
benzaldehyde produced the adduct alcohol in 82% yield
(entry 2). In a similar way, the reaction with benzoyl
chloride gave diketone in 62% 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-cyclohexyl-7,7-dimethylcycloheptanone in 49%
yield (entry 4). The same reaction was carried out start-
ing from 13a-Main and the results are shown in entries
5–8. By this method, regioselectively substituted cyclo-
heptanone derivatives having multisubstituents can be
synthesized.10
We are continuing to study the scope and limitations of
this procedure and the applications to new synthetic
methods, which will be reported in due course.
8. Smith, M. B.; March, J. In March’s Advanced Organic
Chemistry, 5th ed.; John Wiley and Sons: New York,
2001; pp 1377–1505.
9. 1,2-Asymmetric induction occurs from the sulfur chiral
center to the carbon bearing the chlorine atom in the
addition reaction of lithium a-sulfinyl carbanion of 1-
Acknowledgements
This work was supported by Tokyo University of
Science, Joint Study Program in Graduate Course,
which is gratefully acknowledged.

T. Satoh et al. / Tetrahedron Letters 47 (2006) 6769–6773
6773
chloroalkyl p-tolyl sulfoxides to carbonyl carbon. Only
two diastereomers were obtained although the adducts
have four chiral centers. Satoh, T.; Oohara, T.; Ueda, Y.;
Yamakawa, K. J. Org. Chem. 1989, 54, 3130.
solution of the ring-expanded enolate and 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 and
the product was purified by silica-gel column chromato-
graphy to afford 4,4-ethylenedioxy-2,7,7-trimethylcyclohep-
tanone (47 mg; 73%) as colorless crystals; mp 36–37 °C
(hexane). IR (KBr) 2965, 2875, 1705 (CO), 1458, 1120,
1096, 947, 860 cmꢀ1. 1H NMR: d 1.04 (3H, d, J = 6.6 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, J = 13.5, 12 Hz), 3.11–3.20 (1H,
m), 3.89–3.99 (4H, m). MS m/z (%) 212 (M+, 6), 184 (36),
156 (12), 141 (11), 113 (87), 99 (75), 86 (100). Calcd for
C12H20O3: M, 212.1412. Found: m/z 212.1405.
10. A synthesis of 4,4-ethylenedioxy-2,7,7-trimethylcyclohep-
tanone (Table 3, entry 8) is reported as a representative
example of this method. To a solution of t-BuMgCl
(0.36 mmol) in 3 mL of dry THF in a flame-dried flask at
0 °C under Ar atmosphere was added a solution of the
adduct 13a-Main (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 a 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