A versatile synthesis, including asymmetric synthesis, of bicyclo[n.1.0]alkanes from cyclic ketones via the magnesium carbenoid 1,3-CH insertion as a key reaction

Article abstract of DOI:10.1016/j.tetlet.2006.07.140

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from various cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps, in high yields, with lithium enolate of tert-butyl acetate or its homologues gave the adducts in quantitative yields. The adducts were treated with isopropylmagnesium chloride in ether in dry toluene as the reaction solvent to afford bicyclo[n.1.0]alkanes in high to quantitative yields via magnesium carbenoid 1,3-CH insertion. When this method was carried out starting from unsymmetrical cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of bicyclo[n.1.0]alkane was realized.

Full text of DOI:10.1016/j.tetlet.2006.07.140

Tetrahedron Letters 47 (2006) 7249–7253
A versatile synthesis, including asymmetric synthesis,
of bicyclo[n.1.0]alkanes from cyclic ketones via the magnesium
carbenoid 1,3-CH insertion as a key reaction
Tsuyoshi Satoh,* Shingo Ogata and Daisuke Wakasugi
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-Funagawara-Machi 12,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 9 June 2006; revised 6 July 2006; accepted 21 July 2006
Available online 17 August 2006
Abstract—Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from various cyclic ketones and chloromethyl p-
tolyl sulfoxide in three steps, in high yields, with lithium enolate of tert-butyl acetate or its homologues gave the adducts in quan-
titative yields. The adducts were treated with isopropylmagnesium chloride in ether in dry toluene as the reaction solvent to afford
bicyclo[n.1.0]alkanes in high to quantitative yields via magnesium carbenoid 1,3-CH insertion. When this method was carried out
starting from unsymmetrical cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of bicyclo[n.1.0]alkane
was realized.
Ó 2006 Elsevier Ltd. All rights reserved.
Cyclopropanes are obviously one of the most important
compounds in organic and synthetic organic chemistry.
Because the cyclopropane ring is highly strained, ring-
opening reaction of cyclopropanes occurs under the
influence of a variety of chemical reagents under mild
conditions with carbon–carbon or carbon–hetero atom
bond-formation. These chemical properties are the rea-
son that cyclopropanes are useful as versatile com-
pounds in organic synthesis. The synthetic methods of
cyclopropanes1 and their use in organic synthesis2 have
widely been reported.
nation of cyclic olefins 2.1c,4 The second one is the intra-
molecular cyclopropanation of diazoalkenes 3.1a,c The
third is the intramolecular SN2-type reaction of 4.3b
We have also been interested in the compounds contain-
ing a cyclopropane ring.5 In continuation of our study
for the development of new synthetic methods for cyclo-
propanes, we recently established a versatile synthesis of
bicyclo[n.1.0]alkanes 1 from cyclic ketones 5 via 1-chlo-
rovinyl p-tolyl sulfoxides 6. The key reaction of this
method is the 1,3-CH insertion6 of magnesium carbe-
noid 8 derived from 7 by a sulfoxide–magnesium
exchange reaction.7
Cyclopropanes in which the cyclopropane ring is fused
with another ring, such as 1 in Scheme 1, are referred
to as bicyclo[n.1.0]alkanes and they are also quite inter-
esting compounds. For example, 2-aminobicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), an
agonist for the group II metabotropic glutamate recep-
tor, bears a bicyclo[3.1.0]hexane (1, m = 1) core struc-
ture.3 Synthesis of bicyclo[n.1.0]alkanes has been
carried out mainly by three ways as shown in Scheme
1. The first one is the Simmons–Smith type cyclopropa-
The procedure using 1-chlorovinyl p-tolyl sulfoxide 9 is
reported as a representative example as shown in Table
1. 1-Chlorovinyl p-tolyl sulfoxide 9, derived from cyclo-
pentadecanone,8 was treated with lithium enolate of
tert-butyl acetate to give the adduct 10 in quantitative
yield.9 First, a solution of the adduct 10 in THF was
added to a solution of 2.5 equiv of i-PrMgCl (in THF
solution) in THF at ꢀ78 °C with stirring and the tem-
perature of the reaction mixture was slowly allowed to
warm to 0 °C. All the starting material 10 disappeared
and two products were obtained. From a detailed
Keywords: Bicyclo[n.1.0]alkane; Cyclopropane; Sulfoxide–magnesium
exchange; Magnesium carbenoid; C–H insertion.
1
inspection of the H NMR of the products, cyclopro-
*
pane 11 and chloride 12 were recognized to be the
products. Interestingly, no cyclopropane 13 was
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.2006.07.140

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T. Satoh et al. / Tetrahedron Letters 47 (2006) 7249–7253
X
X
R
R
X
R
:
CH2
m
m
Simmons-Smith-type
cyclopropanation
Intramolecular cyclopropanation
of olefins
m
N2
1
2
3
Intramolecular
SN2 reaction
Magnesium carbenoid
1,3-CH insertion
X
R
L
X
R
MgCl
Cl
m
-
m
H
8
EWG
4
i-PrMgCl
R
Cl
X
X
X
-
O
R
S(O)Tol
R1
S(O)Tol
Cl
m
m
m
H
H
5
7
6
-
=
LiCHCOOC(CH3)3
R
Scheme 1.
Table 1. Examination of the best conditions for the cylopropanation of 10 with i-PrMgCl through the magnesium carbenoid 1,3-CH insertion
reaction to give bicyclo[13.1.0]hexadecane 11
i-PrMgCl
(2.5 eq)
CO2C(CH3)3
CO2C(CH3)3
LiCH2CO2C(CH3)3
Cl
CO2C(CH3)3
+
15
98%
Solvent
-78 ~ 0 ˚C
CHS(O)Tol
Cl
CH2Cl
12
S(O)Tol
(Lit. 9)
10
11
9
2 h
CO2C(CH3)3
13
1
obtained judging from the H NMR. Cyclopropane 11
was the desired product; however, it was contaminated
with a considerable amount of 12, which was derived
from protonation of the magnesium carbenoid interme-
diate. Unfortunately, 12 could not be separated from the
desired 11.
1. First, ether and toluene were used as the solvent
and the toluene was found to show some effect (entries
2 and 3); however, protonated product 12 was not
completely suppressed. We thought that the proton
source of the reaction would be THF as the solvent
for the Grignard reagent. We tried this reaction with
i-PrMgCl (ether solution) in THF, ether, or toluene as
the reaction solvent (entries 4–6) and, fortunately, when
this reaction was carried out in toluene, the desired 11
We studied the reaction conditions for suppressing the
by-product 12 and the results are summarized in Table

T. Satoh et al. / Tetrahedron Letters 47 (2006) 7249–7253
7251
Table 2. Synthesis of bicyclo[n.1.0]alkanes 14 from the adducts 7 derived from 1-chlorovinyl p-tolyl sulfoxides 6 with lithium enolate of tert-butyl
acetate
i-PrMgCl
CO2C(CH3)3
S(O)Tol
CO2C(CH3)3
Cl
LiCH2CO2C(CH3)3
(2.5 eq)
X
( )m
X
( )m
X
Toluene
-78 ~ 0 ºC
S(O)Tol
( )m
Cl
2 h
14
7
6
Entry
6
Yield (%)
7
14
Cl
CO2C(CH3)3
CO2C(CH3)3
1
2
3
4
98
97
99a
97
74
14a
14b
14c
S(O)Tol
Cl
68
S(O)Tol
Cl
O
O
O
O
CO2C(CH3)3
95 (93)b
S(O)Tol
Cl
S(O)Tol
CO2C(CH3)3
90
8
14d
a Two isolable diastereomers of the adducts were obtained. The ratio of the main isomer and the minor isomer was 86:14.
b The yield in parentheses was obtained from the minor isomer.
was obtained in almost quantitative yield without
chlorides to give bicyclo[n.1.0]alkanes having a tert-but-
oxycarbonylmethyl group on the bridgehead carbon 14
in up to 95% yield. From these results, this procedure
was confirmed to be effective from small (five-mem-
bered) to large-ringed (15-membered) cyclic ketones.
generation of the protonated chloride 12 (entry 6).10
This reaction is, obviously, an unprecedented and out-
standing way for the synthesis of bicyclo[n.1.0]alkanes
from cyclic ketones. We next investigated the generality
of this procedure and the results are summarized in
Table 2. The addition reaction of 1-chlorovinyl p-tolyl
sulfoxides 6, derived from cyclopentanone, cyclohexa-
none, 1,4-cyclohexanedione mono ethylene ketal, and
cyclooctanone gave the adduct 7 in almost quantitative
yields (entries 1–4). The key reaction, magnesium carb-
enoid 1,3-CH insertion, took place smoothly in toluene
with i-PrMgCl (ether solution) without the protonated
In further development of this procedure, we tried it
with tert-butyl propionate and tert-butyl hexanoate
(Table 3). 1-Chlorovinyl p-tolyl sulfoxides 6 derived
from cyclohexanone, cyclooctanone, and cyclopenta-
decanone were used and the results are summarized in
Table 3. The addition reaction of tert-butyl propionate
to 6 gave quite high yields of the adducts (entries 1–3);
however, the reaction with tert-butyl hexanoate gave
Table 3. Synthesis of bicyclo[n.1.0] alkanes 14 from the adducts 7 derived from 1-chlorovinyl p-tolyl sulfoxides 6 with lithium enolate of tert-butyl
propionate and tert-butyl hexanoate
R
R
R
i-PrMgCl
CO2C(CH3)3
S(O)Tol
CO2C(CH3)3
Cl
LiCHCO2C(CH3)3
(2.5 eq)
Toluene
-78 ~ 0 ºC
( )m
( )m
( )m
14
S(O)Tol
Cl
2 h
7
6
Entry
6
7
14a
m
R
Yield (%)
Yield (%)
1
2
3
4
5
6
1
CH3
CH3
CH3
99
88
93
99
78
89
14e
14f
14g
14h
14i
14j
76
3
10
1
3
10
96
95b
95
CH2CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2CH3
89
99c
a All the products 14, except 14g and 14j, were a single isomer.
b The product 14g was obtained as a mixture of two diastereomers (ratio about 3:1).
c 5 equiv of i-PrMgCl was used in this reaction. The product 14j was obtained as a mixture of two diastereomers (ratio about 13:10).

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T. Satoh et al. / Tetrahedron Letters 47 (2006) 7249–7253
O
S
H
H
Cl
H
Tol
LiCH2COOC(CH3)3
S(O)Tol
i-PrMgCl
:
(S)
90%
96%
Cl
CH2COOC(CH3)3
CH2COOC(CH3)3
(R)
H
15
16
17
(1S,6R)-bicyclo[4.1.0]hept-2-ene
Scheme 2.
somewhat lower yields of the adducts 7 (entries 4–6).
The magnesium carbenoid 1,3-CH insertion took place
smoothly to give up to 99% yield of the bicyclo-
[n.1.0]alkanes having a carboxylic ester at the bridge-
head position 14e–14j.
References and notes
1. Some selected recent reviews concerning chemistry and
synthesis of cyclopropanes: (a) Doyle, M. P.; Protopop-
ova, M. N. Tetrahedron 1998, 54, 7919; (b) Donaldson, W.
A. Tetrahedron 2001, 57, 8589; (c) Label, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003,
103, 977.
2. Some selected recent reviews concerning reactions and
synthetic use of cyclopropanes: (a) Murakami, M.;
Nishida, S. J. Syn. Org. Chem. Jpn. 1983, 41, 22; (b)
Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165; (c)
Sonawane, H.; Gellur, N. S.; Kulkarni, D. G.; Ahuja, J.
R. Synlett 1993, 875; (d) Kulinkovich, O. G. Chem. Rev.
2003, 103, 2597.
3. (a) Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R.
A.; Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J.
P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528; (b) Yasuda, N.; Tan, L.; Yoshikawa,
N.; Hartner, F. W. J. Syn. Org. Chem. Jpn. 2005, 63, 1147.
4. (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307; (b) Li, J. J. Name Reactions; Springer:
Berlin, 2002; (c) Hassner, A.; Stumer, C. Organic Synthe-
ses Based on Name Reactions; Pergamon, 2002; (d) Long,
J. L.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46,
2737.
Finally, this procedure was applied to an asymmetric syn-
thesis of bicyclo[n.1.0]alkanes. A synthesis of optically
active bicyclo[4.1.0]hept-2-ene derivative 17 was investi-
gated as a representative example (Scheme 2). First,
1-chlorovinyl p-tolyl sulfoxide 15 was synthesized from
2-cyclohexenone and optically pure (R)-chloromethyl
p-tolyl sulfoxide,11 and it was treated with lithium enolate
of tert-butyl acetate to afford the adduct 16 in 96% yield.
The enantiomeric excess (over 99%) and the absolute
configuration of 16 were reported previously.12
The optically pure adduct 16 was treated with i-PrMgCl
under the conditions described above to afford a quite
clean reaction and only one product, (1S,6R)-bicy-
28
clo[4.1.0]hept-2-ene 17 (½aꢁD +137.2 (c 0.1, EtOH)), was
obtained in 90% yield. Interestingly, as expected, the mag-
nesium carbenoid 1,3-CH insertion reaction occurred
only at the methylene carbon on the cyclohexene ring.
In conclusion, we have developed a new method for a
synthesis of bicyclo[n.1.0]alkanes in good overall yields
from cyclic ketones with magnesium carbenoid 1,3-CH
insertion as the key reaction. The interesting character-
istics of this procedure are as follows. (1) Almost
unprecedented and high yielding magnesium carbenoid
1,3-CH insertion was successfully used. As a result, a
carbon–carbon bond can be formed at a nonactivated
carbon on the ring to give cyclopropanes. (2) Although
five steps are requited from cyclic ketones to bicy-
clo[n.1.0]alkanes 1, the yields of all steps are quite high.
(3) Three carbon–carbon bonds are formed in this pro-
cedure. (4) All the reactions in this procedure are mild
enough and some functional groups such as ester, acetal,
olefine, are compatible. (5) Asymmetric synthesis with
high optical purity can be realized starting from unsym-
metrical ketones and (R)-chloromethyl p-tolyl sulfoxide.
5. (a) Satoh, T.; Kawase, Y.; Yamakawa, K. Tetrahedron
Lett. 1990, 31, 3609; (b) Satoh, T.; Kawase, Y.; Yama-
kawa, K. Bull. Chem. Soc. Jpn. 1991, 64, 1129; (c) Satoh,
T.; Saito, S. Tetrahedron Lett. 2004, 45, 347; (d) Satoh, T.;
Miura, M.; Sakai, K.; Yokoyama, Y. Tetrahedron 2006,
62, 4253.
6. (a) Clayden, J.; Julia, M. Synlett 1995, 103; (b) Satoh, T.;
Musashi, J.; Kondo, A. Tetrahedron Lett. 2005, 46, 599.
7. (a) Satoh, T. J. Syn. Org. Chem. Jpn. 1996, 54, 481; (b)
Satoh, T. J. Syn. Org. Chem. Jpn. 2003, 61, 97; (c) Satoh,
T. The Chemical Record 2004, 3, 329.
8. Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.;
Koyama, M. Tetrahedron 1998, 54, 5557.
9. Satoh, T.; Sugiyama, S.; Kamide, Y.; Ota, H. Tetrahedron
2003, 59, 4327.
10. To a flame-dried flask was added dry toluene (4 mL)
followed by i-PrMgCl (0.5 mmol; 2.5 equiv) in ether at
ꢀ78 °C. A solution of the adduct 10 (102 mg; 0.2 mmol) in
toluene (2.5 mL) was added to the solution of Grignard
reagent dropwise with stirring and the reaction mixture
was slowly allowed to warm to 0 °C for 2 h. The reaction
was quenched with satd aq NH4Cl and the whole was
extracted with CHCl3. The product was purified over silica
gel column to afford 64.5 mg (96%) of cyclopropane 11 as
a colorless oil. IR (neat) 2929, 2857, 1735 (CO), 1459,
Acknowledgement
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan to promote
multi-disciplinary research project, which is gratefully
acknowledged.
1366, 1309, 1250, 1147, 959, 758 cmꢀ1 1H NMR d 0.25
;
(1H, dd, J = 5.8, 4.8 Hz), 0.47–0.53 (2H, m), 0.59–0.68
(1H, m), 1.08–1.17 (1H, m), 1.21–1.49 (22H, m), 1.46 (9H,

T. Satoh et al. / Tetrahedron Letters 47 (2006) 7249–7253
7253
s), 1.54–1.59 (1H, m), 1.76 (1H, d, J = 15.6 Hz), 1.99–2.15
(1H, m), 2.57 (1H, d, J = 15.6 Hz). MS m/z (%) 336 (M+,
2), 321 (3), 280 (29), 262 (10), 220 (100), 135 (3), 109 (5).
Calcd for C22H40O2: M, 336.3028. Found: m/z 336.3023.
11. Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. J. Org.
Chem. 1989, 54, 3130.
12. Sugiyama, S.; Satoh, T. Tetrahedron: Asymmetry 2005, 16,
665.