The first example of magnesium carbenoid 1,3-CH insertion reaction: A novel method for synthesis of cyclopropanes from 1-chloroalkyl phenyl sulfoxides in high yields

Article abstract of DOI:10.1016/j.tetlet.2004.11.146

Treatment of 1-chloroalkyl phenyl sulfoxides having a geminal methyl group or a geminal benzyl group at the 2-position in THF at -78°C with isopropylmagnesium chloride gave magnesium carbenoids. Carbenoid 1,3-CH insertion reaction of the magnesium carbeno

Full text of DOI:10.1016/j.tetlet.2004.11.146

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 599–602
The first example of magnesium carbenoid 1,3-CH
insertion reaction: a novel method for synthesis of
cyclopropanes from 1-chloroalkyl phenyl sulfoxides in high yields
Tsuyoshi Satoh,* Jun Musashi and Atsushi Kondo
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 10 November 2004; revised 26November 2004; accepted 26November 2004
Available online 13 December 2004
Abstract—Treatment of 1-chloroalkyl phenyl sulfoxides having a geminal methyl group or a geminal benzyl group at the 2-position
in THF at À78 °C with isopropylmagnesium chloride gave magnesium carbenoids. Carbenoid 1,3-CH insertion reaction of the mag-
nesium carbenoids took place instantaneously to afford cyclopropanes in high to quantitative yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Carbenes and carbenoids have long been recognized to
be highly reactive carbon species and are frequently used
as useful intermediates in organic synthesis.1,2 Carbon–
hydrogen insertion (CH insertion) is a characteristic
reaction of carbenes and carbenoids. This reaction is
quite interesting, because formation of a carbon–carbon
bond between a carbene (carbenoid) carbon and inacti-
vated carbon is realized. Recently, intramolecular 1,5-
CH insertion reaction of alkylidene carbenes and the
intramolecular formation of a carbon–carbon bond with
carbenes generated from a-diazocarbonyl compounds
have been widely investigated for the construction of
cyclopentenes and cyclopentanones, respectively.2 1,3-
CH insertion reactions also have been known and used
in the synthesis of cyclopropanes.1a
1-haloalkyl sulfoxides.3 Their properties and application
to new synthetic methods were also widely studied.4 Re-
cently, simple magnesium carbenoides 2 were generated
from aryl 1-chloroalkyl sulfoxides 1 with i-PrMgCl. The
magnesium carbenoids 2 were found to be fairly stable
at below À60 °C and showed several interesting reactivi-
ties to some nucleophiles.5a For example, the carbenoids
2 reacted with N-lithio arylamines to afford nonstabilized
a-amino-substituted carbanions 3, from which a-amino
acids 4 were obtained in good yields (Scheme 1).5b
In continuation of our interest in the reactivity of mag-
nesium carbenoids, recently we investigated the reactiv-
ity of 1-chloroalkyl phenyl sulfoxides having geminal
methyl or benzyl groups at the 2-position 5 with i-
PrMgCl and found that the generated magnesium carb-
enoid 6 instantaneously underwent 1,3-CH insertion
between the methyl group to afford cyclopropanes 7 in
high to quantitative yields (Scheme 2).
In this decade, we have investigated the generation of sev-
eral magnesium carbenoids by sulfoxide–magnesium
exchange reaction of aryl 1-halovinyl sulfoxides and aryl
R1
ArNLi
O
R1
R1
i-PrMgCl
ClCOOEt
RCH2CHNAr
COOEt
RCH2CHSAr
Cl
RCH2CHMgCl
Cl
RCH2CHNAr
Li
4
2
3
1
Scheme 1.
Keywords: Cyclopropane; Sulfoxide; Sulfoxide–magnesium exchange; Magnesium carbenoid; C–H insertion.
*
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 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.146

600
T. Satoh et al. / Tetrahedron Letters 46(2005) 599–602
O
CH2R1
R1CH2
R1CH2
i-PrMgCl
C-H insertion
R-C-CHSPh
R-C-CHMgCl
R
R1CH2
Cl
R1CH2
Cl
R1
5
6
7
R1= H or Ph
Scheme 2.
First, 1-chloroalkyl phenyl sulfoxide 8 was synthesized
from commercially available 2,2-dimethyl-3-phenyl-1-
propanol.6 The sulfoxide 8 was treated in THF at
À78 °C with 3 equiv of i-PrMgCl. The starting material
instantaneously disappeared and after the reaction mix-
ture was allowed to warm to room temperature, we ob-
tained an inseparable mixture of two cyclopropanes, 9
and 10 (the ratio was determined to be 7:1 from 1H
NMR). Unfortunately, the products were quite volatile
and the accurate yield was obscure (Scheme 3).
A solution of 1-chloroalkyl phenyl sulfoxide 14 in THF
was added dropwise to a solution of i-PrMgCl at À78 °C
and the reaction mixture was allowed to warm to 0 °C.
This reaction gave a quite clean reaction mixture and
the desired cyclopropane 15 was obtained in 97% yield.
Somewhat surprisingly, the product was only 15 and no
isomer was observed.9
Encouraged by this result, the sulfoxides 16 and 18 were
treated with i-PrMgCl under the same conditions as de-
scribed above. The reaction mixture was again quite
clean and cyclopropanes 17 and 19 were obtained in
over 85% isolated yield as a single product.
We synthesized 1-chloroalkyl phenyl sulfoxide having a
1-naphthyl group 11 and it was treated with i-PrMgCl
under the same conditions as described above. This time
we obtained an inseparable mixture of two cyclopro-
panes, 12 and 13, and the ratio was found to be 2:1 in
97% yield. Although the 1,3-CH insertion to give the
cyclopropanes was already known by lithium carbenoid
and carbenes,7 to the best of our knowledge, the results
described above is the first example of the 1,3-CH inser-
tion reaction of magnesium carbenoid to give
cyclopropanes.
Julia and Clayden recently reported the 1,3-CH insertion
reaction of lithium carbenoid derived from primary alky
chloride by H–Li exchange reaction.10 For example, they
treated the chloride having a siloxy group at the 3-posi-
tion 20a with a mixture of n-BuLi and t-BuOK at
À70 °C and allowed it to warm to À10 °C to give three
products, 22a, 17 and 23a (Scheme 4). The intermediate
of this reaction was proposed to be the lithium carbenoid
21. It is noteworthy that the corresponding a-chlorosulf-
oxide 16 gave cyclopropane 17 in 85% yield as a single
product. The MEM-protected chloride 20b was reported
to give cyclopropane 19 in 59% yield by treatment with n-
BuLi and t-BuOK. In our case, the corresponding sulf-
oxide 18 gave the cyclopropane 19 in 89% yield.
To investigate the generality of this reaction, we synthe-
sized three 1-chloroalkyl phenyl sulfoxides 14, 16 and 18
from 2,2-dimethyl-1,3-propanediol8 and they were trea-
ted with 3 equiv of i-PrMgCl at À78 °C and the results
are summarized in Scheme 4.
3 eq. i-PrMgCl
H3C
H3C
+
THF, -78 ˚C ~ r. t.
H3C
S(O)Ph
H3C
Cl
CH3
9
8
10
9 : 10 = 7 : 1
3 eq. i-PrMgCl
H3C
H3C
+
THF, -78 ˚C ~ r. t.
H3C
S(O)Ph
H3C
97%
Cl
CH3
13
12
11
12 : 13 = 2 : 1
Scheme 3.

T. Satoh et al. / Tetrahedron Letters 46(2005) 599–602
601
O
3 eq. i-PrMgCl
H3C
O
H3C
H3C
O
O
THF, -78 ~ 0 ˚C
S(O)Ph
97%
Cl
15
14
OSiMe2Bu-t
3 eq. i-PrMgCl
H3C
OSiMe2Bu-t
H3C
THF, -78 ~ 0 ˚C
S(O)Ph
Cl
H3C
85%
17
16
OCH2OCH2CH2OCH3
3 eq. i-PrMgCl
H3C
OMEM
H3C
H3C
S(O)Ph
Cl
THF, -78 ~ 0 ˚C
89%
19
18
OR
OR
OH
n-BuLi - t-BuOK
H3C
H3C
H3C
H3C
H3C
+
Li
R
H3C
Cl
Cl
Cl
20a R=SiMe2Bu-t
20b R=CH2OCH2CH2OCH3
22a (28%)
21
H3C
OH
R
H3C
OR
+
H3C
OMEM
17 (16%)
23a (18%)
19 (from 20b, 59%)
Scheme 4.
The magnesium carbenoid 1,3-CH insertion was found
to occur not only between the carbenoid carbon and
methyl group but also between the carbenoid carbon
and methylene group. For example, we synthesized
1-chloroalkyl phenyl sulfoxide having two benzyl groups
at 2-position 24 from diethyl malonate and it was trea-
ted with i-PrMgCl. Interestingly, the C–H insertion
reaction between the carbenoid carbon and the benzyl
carbon instantaneously took place and gave cyclopro-
pane 25 in 88% yield as a 5:1 mixture of two diastereo-
mers (Scheme 5).
Finally, we synthesized 1-chloroalkyl phenyl sulfoxide
having a methyl group and hydrogen at 2-position 26
from 2-methyl-1,3-propanediol. Treatment of 26 with
i-PrMgCl under the same conditions as above gave an
olefin 27 with only trace amount of cyclopropane 28.
This result shows that when the generated magnesium
carbenoid has a hydrogen at the 2-position, rearrange-
ment of the hydrogen giving an olefin is faster reaction
compared with the 1,3-CH insertion reaction. This result
also suggests a limitation of cyclopropanation using the
magnesium carbenoids.
O
3 eq. i-PrMgCl
PhCH2
Ph
O
PhCH2
PhCH2
O
O
THF, -78 ~ 0 ˚C
S(O)Ph
88%
Cl
25
24
H
O
O
3 eq. i-PrMgCl
THF, -78 ~ 0 ˚C
CH3
+
O
CH3
O
O
O
S(O)Ph
H
Cl
28
trace
27
26
54%
Scheme 5.

602
T. Satoh et al. / Tetrahedron Letters 46(2005) 599–602
3. (a) Satoh, T. J. Synth. Org. Chem. Jpn. 1996, 54, 481; (b)
Satoh, T. J. Synth. Org. Chem. Jpn. 2003, 61, 98; (c) Satoh,
T. The Chemical Record 2004, 3, 329.
In conclusion, we have discovered that the magnesium
carbenoids generated from 1-chloroalkyl phenyl sulfox-
ide having a geminal methyl group and a geminal benzyl
group with i-PrMgCl gave cyclopropanes by 1,3-CH
insertion in high to quantitative yields. This is the first
example for 1,3-CH insertion of the magnesium carbe-
noid.11 Because the a-chlorosulfoxides were easily syn-
thesized from haloalkanes or alcohols and the yields
giving cyclopropanes were quite good, the procedure de-
scribed above will become a good way for synthesis of
cyclopropanes. We are continuing to study the scope
and limitations of this chemistry.
4. (a) Satoh, T.; Takano, K.; Someya, H.; Matsuda, K.
Tetrahedron Lett. 1995, 36, 7097; (b) Satoh, T.; Takano,
K.; Ota, H.; Someya, H.; Matsuda, K.; Koyama, M.
Tetrahedron 1998, 54, 5557; (c) Satoh, T.; Kurihara, T.;
Fujita, K. Tetrahedron 2001, 57, 5369; (d) Satoh, T.;
Sakamoto, T.; Watanabe, M. Tetrahedron Lett. 2002, 43,
2043; (e) Satoh, T.; Sakamoto, T.; Watanabe, M.; Takano,
K. Chem. Pharm. Bull. 2003, 51, 966; (f) Satoh, T.; Saito,
S. Tetrahedron Lett. 2004, 45, 347.
5. (a) Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron 2004,
60, 5453; (b) Satoh, T.; Osawa, A.; Kondo, A. Tetrahedron
Lett. 2004, 45, 6703.
6. 2,2-Dimethyl-3-phenyl-1-propanol was treated with
PhSSPh and Bu3P in THF to give a sulfide, which was
oxidized with m-chloroperbenzoic acid to afford a sulfox-
ide. The sulfoxide was chlorinated with NCS in CCl4 to
give the desired 8 in high overall yield.
Acknowledgements
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.
7. Lit.,1a pp 209–266.
8. 2,2-Dimethyl-1,3-propanediol was treated with PhSSPh
and Bu3P to give mono sulfide, which was oxidized with
m-chloroperbenzoic acid to give a sulfoxide having a
hydroxyl group. The hydroxyl group was protected with
dihydropyrane and finally the THP-protected sulfoxide
was chlorinated with NCS in THF to give 14 in good yield.
The 1-chloroalkyl phenyl sulfoxides 16 and 18 were
synthesized from 14.
9. A solution of i-PrMgCl (0.72 mmol) was added to 1.2 mL
of THF in a flame-dried flask at À78 °C under Ar
atmosphere. After being stirred for 10 min, a solution of
14 (80 mg; 0.24 mmol) in 1.2 mL of dry THF was added to
the reaction mixture. The reaction mixture was stirred and
slowly allowed to warm to 0 °C and stirred for 1 h at 0 °C.
The reaction was quenched by adding satd aq NH4Cl and
the whole was extracted with ether and dried over MgSO4.
The product was purified by silica gel column chromato-
graphy to give 39.5 mg (97%) of 15 as a colorless oil; IR
(neat) 2944, 2871, 1455, 1353, 1202 cmÀ1. 1H NMR d 0.31
(2H, m), 0.42 (2H, m), 1.14 (3H, s), 1.51–1.90 (6H, m),
3.17 (1H, d, J = 10.4 Hz), 3.46–3.51 (1H, m), 3.54 (1H, d,
J = 10.4 Hz), 3.86(1H, m), 4.62 (1H, t, J = 3.4 Hz). MS
m/z (%) 170 (M+, 0.4), 155 (0.5), 101 (7), 85 (100), 69
(42). Calcd for C10H18O2: M, 170.1307. Found: m/z
170.1308.
References and notes
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Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361; (d)
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10. Clayden, J.; Julia, M. Synlett 1995, 103.
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give a cyclopentane was reported: Knopff, O.; Stiasny, H.;
Hoffmann,
705.
R.
W.
Organometallics
2004,
23,