The reaction of 1-silylcyclopropyl anions with dichloromethyl methyl ether: the efficient synthesis of cyclopropyl silyl ketones via cyclopropylidene derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.12.145

The reaction of 1-silylcyclopropyl anions with dichloromethyl methyl ether is described. The reaction with an excess amount of dichloromethyl methyl ether gives the corresponding cyclopropyl silyl ketones in low yields. On the other hand, the reaction und

Full text of DOI:10.1016/j.tetlet.2009.12.145

Tetrahedron Letters 51 (2010) 1294–1297
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The reaction of 1-silylcyclopropyl anions with dichloromethyl methyl ether:
the efficient synthesis of cyclopropyl silyl ketones via cyclopropylidene
derivatives
*
*
Toshiaki Nishizawa, Kenta Nakae, Mitsunori Honda , Ko-Ki Kunimoto, Masahito Segi
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 1-silylcyclopropyl anions with dichloromethyl methyl ether is described. The reaction
with an excess amount of dichloromethyl methyl ether gives the corresponding cyclopropyl silyl ketones
in low yields. On the other hand, the reaction under basic conditions proceeded smoothly to afford the
corresponding cyclopropylidene derivatives, exclusively. The resulting cyclopropylidene compounds
are subjected to hydrolysis or trapping with electrophiles easily to give the cyclopropyl silyl ketone deriv-
atives in good yields.
Received 4 December 2009
Revised 22 December 2009
Accepted 24 December 2009
Available online 11 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dichloromethyl methyl ether (DCME) has been used extensively
as a carbon monoxide equivalent in the reactions with boranes1
and borinates,2 or formylating reagent for aromatic compounds3
and vinylsilanes4 in the presence of Lewis acids. In contrast, the
reaction of DCME with carbanions under basic conditions is not
well-known to our knowledge. Previously we have reported that
1-silylcyclopropyl anions derived from 1-silylcyclopropyl bro-
mides with n-butyllithium react with DCME to afford the corre-
sponding cyclopropyl silyl ketones.5 Cyclopropyl silyl ketones are
useful synthetic intermediates. For example, we have reported that
the efficient synthesis of silyl-substituted dihydrofurans and stere-
oselective synthesis of Z-homoallyl derivatives using cyclopropyl
silyl ketones.6 However, there have been just a few reports on
the preparation of cyclopropyl silyl ketones,7 so our synthetic
method was widely employed. But the low yield was a huge draw-
back for this procedure. The isolated yield of cyclopropyl silyl ke-
tones 1 was less than 30%8 and an equivalent amount of the
protonated compound 2 was obtained as a by-product (Scheme
1). Here, we wish to describe an improvement of the reaction con-
ditions to proceed the reaction of DCME with carbanions under ba-
sic conditions, and also the observation of cyclopropylidene
derivatives which are precursors of cyclopropyl silyl ketones 1.
This provides mechanistic evidence. As a result reasonable yields
of cyclopropyl silyl ketones 1 were achieved.
R3
R2
R3
R2
Cl
Si
Br
Si
Li+
Cl
OMe
n-BuLi
R1
R1
R3
R2
R3
R2
Si
Si
H
+
R1
1 Yield=~30%
R1
2 Yield=~30%
O
Scheme 1. Synthesis of cyclopropyl silyl ketones.
Table 1
Effect of amounts of n-BuLi and DCME
SiMe3
OMe
SiMe3
Br
Ph
SiMe3
i) n-BuLi
+
Ph
ii) DCME
O
Ph
1
3
The treatment of 2-phenyl-1-trimethylsilylcyclopropyl bromide
with n-butyllithium gave the corresponding carbanion. The follow-
ing reaction with DCME was carried out. The reaction proceeded to
Entry
n-BuLi (equiv)
DCME (equiv)
Yielda (%)
1
3
1
2
3
1.1
1.1
2.5
1.2
0.6
1.2
29
—
—
—
45
81
* Corresponding authors. Tel.: +81 76 234 4789; fax: +81 76 234 4800 (M.H.).
E-mail addresses: honda@se.kanazawa-u.ac.jp (M. Honda), segi@se.kanazawa-
u.ac.jp (M. Segi).
a
Isolated yield.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.145

T. Nishizawa et al. / Tetrahedron Letters 51 (2010) 1294–1297
1295
Table 2
Effect of substituents on cyclopropane ring and silicon atom
SiMe3
OMe
H2SO4
Ph
SiMe3
MeOH
Ph
R3
R2
Si
Br
R3
R2
O
Si
30 ºC, 0.5 h
i) n-BuLi
3
1 Yield=83%
OMe
ii) DCME
R1
R1
Scheme 2. Conversion of cyclopropylidene derivative into acylsilane with protic
3
acid.
Entry
1
Product
Yielda (%)
cyclopropane 2 was also obtained as a by-product. To improve the
yield of the cyclopropylidene derivative 3, the reaction using
2.5 equiv of n-butyllithium and 1.2 equiv of DCME was examined,
and then the best yield was observed (entry 3).
SiMe2Ph
74 (>99/1)b
64 (>99/1)b
Ph
Ph
OMe
SiEt3
The reaction of other 1-silylcyclopropyl bromides having differ-
ent groups on the cyclopropane ring or silicon atom was carried
out.9 These results are shown in Table 2. These reactions also pro-
ceeded smoothly to furnish the corresponding cyclopropylidene
derivatives 3 in good yields, regardless of the kind of the substitu-
ents. As previously indicated, of the two possible diastereomeric
products, E-isomers were selectively obtained (entries 1–3).
These cyclopropylidene derivatives were not very stable and
hydrolyzed slowly during attempted chromatography on silica
gel to give the cyclopropyl silyl ketones in the purification of crude
products. So the hydrolysis of the cyclopropylidene derivative 3
with sulfuric acid in methanol was carried out (Scheme 2). The
reaction was complete in 0.5 h at 30 °C and gave the corresponding
cyclopropyl silyl ketone 1 in good yield.
2
3
OMe
SiMe3
74 (>99/1)b
Me
Me
OMe
Me
Me
Me
SiMe3
OMe
4
5
70
69
SiMe2Ph
OMe
Me
SiMe3
OMe
The results mentioned above suggest that more than two equiv-
alents of n-butyllithium are required to complete the reaction. Thus,
the following mechanism for the reaction was proposed (Scheme 3).
n-Butyllithium acts as a base and formally eliminates HCl from
DCME to give the chloromethoxycarbene.10 Also, n-butyllithium
debrominates cyclopropyl bromides and the resulting bromine–
lithium exchange affords the corresponding cyclopropyllithium.
The reaction of chloromethoxycarbene with the cyclopropyllithium
provides lithium carbenoid intermediate A.11 The loss of molecular
lithium chloride from A gives cyclopropylmethoxycarbene B. The
1,2-migration of the silyl group on the adjacent carbon to this car-
bene center affords the cyclopropylidene derivative 3.12 In this
migration process, the thermodynamically favored E-isomer is pro-
duced, exclusively. This cyclopropylidene 3 is easily hydrolyzed to
the corresponding silyl ketone derivative 1 under acidic conditions.
On the other hand, in the reaction with a smaller amount of n-butyl-
lithium (Table 1, entry 1), a part of cyclopropyllithium acts as a base
and reacts with DCME. In other words, cyclopropyl anion abstracts a
proton from DCME to afford the silyl cyclopropane 2.
Me
Me
6
7
72
76
SiMe3
OMe
Molar ratio, cyclopropyl bromide/n-BuLi/DCME = 1:2.5:1.2.
a
Isolated yield.
b
The E/Z ratios of the compounds are given in parentheses.
afford the corresponding cyclopropyl silyl ketone 1 or cyclopropy-
lidene derivative 3 according to the reaction conditions. The results
are summarized in Table 1. In accordance with the previous study,5
1.1 equiv of n-butyllithium was used to lithiate the cyclopropyl
bromide and then 1.2 equiv of DCME was added to the reaction
mixture (entry 1). In this case, the ketone product 1 was isolated
in low yield accompanied by the formation of compound 2 as men-
tioned above previously. Interestingly, when 0.6 equiv of DCME
was used, the cyclopropylidene product 3 was formed exclusively
in moderate yield with complete E-selectivity and the ketone 1
was not obtained at all (entry 2). However, a small amount of silyl-
In order to further evaluate the potential of the resulting cyclo-
propylidene derivatives as synthetic intermediates, the generation
of cyclopropylidene derivatives and the following trapping by some
Cl
n-BuLi
Cl
OMe
Cl
OMe
R3
R2
R3
R2
R3
R2
Si
Si
Li
Si
Li
Cl
Cl
OMe
n-BuLi
Br
MeO
R1
R1
R1
A
R3
R2
R3
R2
Si
R3
R2
Si
H3O+
Si
LiCl
1,2-Shift
OMe
R1
R1
O
R1
OMe
3
B
1
Scheme 3. Plausible reaction mechanism.

1296
T. Nishizawa et al. / Tetrahedron Letters 51 (2010) 1294–1297
Table 3
The one-pot synthesis of cyclopropyl silyl ketones via cyclopropilidene derivatives
R3
R2
R3
R2
SiMe3
Br
E
R3
R2
SiMe3
OMe
SiMe3
i) n-BuLi
Electrophile
ii) DCME
R1
R1
O
R1
3
1
Entry
1
Electrophile
H3O+
Product
Yielda,b (%)
73 (64/36)
H
Ph
SiMe3
O
Cl
Ph
SiMe3
SiMe3
2
3
4
5
6
NCS
64 (76/24)
56 (75/25)
48 (86/14)
59 (71/29)
17
O
Br
Ph
NBS
O
SPh
SiMe3
Ph
Ph
PhSCl
PhSeCl
PhSeCl
O
SePh
SiMe3
O
SePh
Me
Me
SiMe3
O
Me
SePh
SiMe3
7
8
9
PhSeCl
PhSeCl
PhSeCl
63
O
Me
Me
Me
SePh
SiMe3
28 (>99/1)
50 (>99/1)
O
SePh
SiMe3
O
Molar ratio, cyclopropyl bromide/n-BuLi/DCME = 1:2.5:1.2.
a
Isolated yield.
b
The diastereomeric ratios of the compounds are given in parentheses.
electrophileswerecarriedoutin aone-potprocedure. Theresultsare
summarized in Table 3. The reaction with protic acid as an electro-
phile gave the corresponding acylsilane in 73% yield (entry 1). There-
fore cyclopropyl silyl ketones 1 are conveniently prepared in a one-
pot reaction of 1-silylcyclopropyl anions with DCME followed by
hydrolysis in good yields. On the other hand, the reaction with
NCS, NBS, PhSCl, and PhSeCl proceeded to afford the corresponding
cyclopropyl silyl ketones having different substituents on the 1-po-
sition of cyclopropane ring in moderate yields.13 In these reactions,
one isomer of the two possible diastereomeric isomers was prefer-
entially formed. At the present time, however, the configurations
of these major isomers have not yet been determined.
conditions the reaction proceeded smoothly to afford the corre-
spondingcyclopropylidene derivatives. Theresulting cyclopropylid-
ene compounds were subjected to hydrolysis, which gave the
cyclopropyl silyl ketones in good yields. As a result, DCME acts as
an insertion reagent of carbon monoxide to C–Si bond of 1-silylcy-
clopropyl anions under basic conditions. Further studies in our lab-
oratory are aimed at expanding the scope of these reactions. The
results will be reported in due course.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology (MEXT), Japan.
In conclusion, the reaction of DCME with n-butyllithium in the
presence of 1-silylcyclopropyl anions was investigated. Under basic

T. Nishizawa et al. / Tetrahedron Letters 51 (2010) 1294–1297
1297
then a solution of dichloromethyl methyl ether (DCME) (0.69 g, 6 mmol) in THF
(2.5 ml) was added. After stirring for 30 min, 1 ml of methanol was added and the
reaction mixture was allowed to warm to ambient temperature and then poured
into brine. The aqueous layer was extracted with diethyl ether for three times.
The combined organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by
column chromatographyon silicagel withhexane/ethyl acetate/triethylamineto
give the cyclopropylidene derivative. Selected spectral properties of methoxy-2-
phenylcyclopropylidenemethylsilane are as follows. IR (neat) 2958, 1720, 1604,
References and notes
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Katz, J.-J.; Carlson, B. A. J. Org. Chem. 1973, 38, 3968.
2. (a) Brown, H. C.; Katz, J.-J.; Carlson, B. A. J. Org. Chem. 1974, 39, 2817; (b) Brown,
H. C.; Katz, J.-J.; Carlson, B. A. J. Org. Chem. 1975, 40, 813.
3. McBride, B. J.; Garst, M. E. Tetrahedron 1993, 49, 2839.
4. (a) Yamamoto, K.; Ninokawa, O.; Tsuji, J. Synthesis 1977, 721; (b) Yamamoto, K.;
Yoshitake, J.; Qui, N.; Tsuji, J. Chem. Lett. 1978, 859.
5. Nakajima, T.; Tanabe, M.; Ohno, K.; Segi, M.; Suga, S. Chem. Lett. 1986, 177.
6. (a) Honda, M.; Yamamoto, Y.; Tsuchida, H.; Segi, M.; Nakajima, T. Tetrahedron
Lett. 2005, 46, 6465; (b) Honda, M.; Naitou, T.; Hoshino, H.; Takagi, S.; Segi, M.;
Nakajima, T. Tetrahedron Lett. 2005, 46, 7345.
7. For reports about synthesis and reaction of cyclopropyl silyl ketones, see: (a)
Danheiser, R. L.; Fink, D. M. Tetrahedron Lett. 1985, 26, 2513; (b) Scheller, M. E.;
Frei, B. Helv. Chim. Acta 1986, 69, 44; (c) Kang, J.; Lee, J. H.; Kim, K. S.; Jeong, J. U.;
Ryun, C. Tetrahedron Lett. 1987, 28, 3261; (d) Nowick, J. S.; Danheiser, R. L.
Tetrahedron 1988, 44, 4113; (e) Clayden, J.; Watson, D. W.; Chambers, M.
Tetrahedron 2005, 61, 3195.
1496, 1452, 1248, 1203, 1147, 839 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.08–7.25
.
(m, 5H), 3.82 (s, 3H), 2.52 (dd, J = 4.2 Hz, 7.8 Hz, 1H), 2.01 (t, J = 7.6 Hz, 1H), 1.43
(dd, J = 4.2 Hz, 7.6 Hz, 1H), À0.01 (s, 9H). 13C NMR (100 MHz, CDCl3): d 153.5,
143.9, 128.2, 125.8, 125.5, 107.8, 56.0, 18.4, 18.3, À2.1. HRMS calcd for C14H20OSi
(M+) 232.1284, found 232.1280.
10. Hine, J.; Porter, J.-J. J. Am. Chem. Soc. 1960, 82, 6120.
11. Cross, G. L. J. Am. Chem. Soc. 1962, 84, 809.
12. (a) Creary, X.; Wang, Y.-X. Tetrahedron Lett. 1989, 30, 2493; (b) Creary, X.;
Butchko, M. A. J. Org. Chem. 2001, 66, 1115; (c) Creary, X.; Butchko, M. A. J. Org.
Chem. 2002, 67, 112.
13. Selected spectroscopic data for 2,3-dimethyl-1-phenylselenocyclopropyl
trimethylsilyl ketone (Table 3, entry 7). IR (neat) 3059, 2957, 1617, 1479,
8. The yields denoted in Ref. 5 are determined by G.C.
9. Typical procedure for the generation of 1-silylcyclopropyl anions and the
following reaction with DCME: A 100-ml four-necked, round-bottomed flask
equipped with argon inlet adapter, rubber septum, thermometer, drop funnel,
and magnetic stirrer bar was charged with 20 ml of dry THF and 5 mmol of
1-bromo-1-trimethylsilylcyclopropane. This solution was cooled to À90 °C and
n-butyllithium(1.66 M solutionin hexane) 7.5 ml (12.5 mmol)was added slowly
over several minutes. The resulting reaction mixture was stirred for 0.5 h, and
1247, 1077, 844 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.32–7.17 (m, 5H), 1.98
.
(dq, J = 6.3 Hz, 5.9 Hz, 1H), 1.46 (dq, J = 6.3 Hz, 5.9 Hz, 1H), 1.25 (d, J = 6.3 Hz,
3H), 1.08 (d, J = 6.3 Hz, 3H), 0.23 (s, 9H). 13C NMR (100 MHz, CDCl3): d 240.9,
132.0, 129.0, 128.3, 125.7, 49.0, 31.5, 22.5, 15.8, 13.3, À1.8. HRMS calcd for
C15H22OSeSi (M+) 326.0605, found 326.0604.