Insertion of cyclopropanes between a carbonyl carbon and an α-carbon of carbonyl compounds with cyclopropylmagnesium carbenoids

Article abstract of DOI:10.1016/j.tetlet.2011.06.069

The reaction of the lithium enolates of α-aryl carbonyl compounds with cyclopropylmagnesium carbenoids, derived from 1-chlorocyclopropyl p-tolyl sulfoxides with i-PrMgCl at low temperature, resulted in the formation of β-aryl carbonyl compounds bearing a

Full text of DOI:10.1016/j.tetlet.2011.06.069

Tetrahedron Letters 52 (2011) 4468–4472
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Insertion of cyclopropanes between a carbonyl carbon and an a-carbon
of carbonyl compounds with cyclopropylmagnesium carbenoids
⇑
Tsuyoshi Satoh , Gaku Kashiwamura, Shinobu Nagamoto, Yuki Sasaki, Shimpei Sugiyama
Graduate School of Chemical Sciences and Technology, 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:
The reaction of the lithium enolates of
noids, derived from 1-chlorocyclopropyl p-tolyl sulfoxides with i-PrMgCl at low temperature, resulted
in the formation of b-aryl carbonyl compounds bearing a cyclopropane ring at the -position with
one-carbon homologation in variable yields. The reaction was found to be highly stereospecific with
respect to the stereochemistry of the cyclopropylmagnesium carbenoids. Mechanism and origin of the
stereospecificity of the reaction are also discussed. This is the first example for the insertion of cyclopro-
a-aryl carbonyl compounds with cyclopropylmagnesium carbe-
Received 10 May 2011
Revised 13 June 2011
Accepted 17 June 2011
Available online 23 June 2011
a
Keywords:
Insertion
Magnesium carbenoid
Cyclopropylmagnesium carbenoid
Cyclopropane
panes in between a carbonyl carbon and an
a
-carbon of carbonyl compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
One-carbon homologation
Introduction
cyclopropyl carbonyl compounds 4 in variable yields. In this Letter,
details of this procedure and the stereochemistry of the reactions
are described.
Homologation of carbonyl compounds from lower carbonyl
compounds by carbon–carbon coupling is a very useful procedure
for obtaining the desired carbonyl compounds and innumerable
procedures have already been reported.1 If the homologation reac-
tions would be applied to cyclic carbonyl compounds, ring-ex-
panded carbonyl compounds could be obtained.2 We have also
long been interested in the homologation of carbonyl compounds
based on our original chemistry; the chemistry of magnesium
Results and discussion
In our previous studies, we reported the reactions of cyclopro-
pylmagnesium carbenoids 3 with phenolates4e and N-lithio aryl-
amines.4h Based on the experiences of these studies, we first
treated cyclopropylmagnesium carbenoid 6, generated from 1-
chloro-2,2-dimethylcyclopropyl p-tolyl sulfoxide 54h with i-PrMgCl
carbenoids or lithium carbenoids generated from
a-chloroalkyl
aryl sulfoxides with Grignard reagents or alkyllithiums,
in THF at À78 °C, with 3 equiv of the lithium enolate of
a-tetralone
-tetralone with LDA in THF at À78 °C
respectively.3
7, generated from
a
For the homologation of carbonyl compounds, as shown in
Scheme 1, one-carbon homologation of carbonyl compounds 1 to
carbonyl compounds 2 is quite general and a variety of methods
have been reported.1–3 On the other hand, homologation of 1 to
cyclopropyl carbonyl compounds 4 is very unusual and, to the best
of our knowledge, no report has appeared yet. We have recently
studied the chemistry and uses of cyclopropylmagnesium carbe-
noids 3 and a variety of unprecedented reactions have appeared.4
In continuation of our interest in the homologation of carbonyl
compounds and in the chemistry of cyclopropylmagnesium carbe-
noids in organic synthesis, we found that the reaction of the lith-
(Scheme 2). The temperature of the reaction mixture was slowly
O
R2
R1
R1
R2
O
R3
General one-carbon
homologation of
1
carbonyl compounds
2
Cl
R3
O
MgCl
R1
R2
3
ium enolates of
a
-aryl carbonyl compounds (1, R1 = Ar) with
cyclopropylmagnesium carbenoids 3 resulted in the formation of
This work (R1= Ar)
R3
4
⇑
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.069

T. Satoh et al. / Tetrahedron Letters 52 (2011) 4468–4472
4469
OLi
i-PrMgCl
(2.5 eq)
7 (3 eq)
Cl
Cl
Complex mixture
THF, -78 °C
THF, -78 to -20 °C
S(O)Tol
MgCl
5
6
OLi
8 (3 eq)
O
38%
9
Scheme 2.
allowed to warm to À20 °C. The reaction, however, gave none of
the promising products but a complex mixture.
Next, the same reaction was conducted with the lithium enolate
of b-tetralone 8. We obtained a product from the reaction mixture
and, very interestingly, the product was proved to be one-carbon
homologated cycloheptanone derivative bearing dimethylcyclo-
It is very important to understand the reason why the reaction
of cyclopropylmagnesium carbenoid 6 with lithium enolate of b-
tetralone gave one-carbon homologated cyclopropyl ketone 9,
however, the lithium enolate of
rationalization for the differences of the reactivity is shown in
Scheme 3. Thus, lithium enolate of -tetralone 7 reacts with mag-
a-tetralone did not. The plausible
a
propyl group at the
yield (the yield was calculated based on the starting material 5).
We recognized that this is an unprecedented one-carbon homolo-
gation of a ketone to a ketone bearing a cyclopropane ring at the a-
a
-position of the carbonyl carbon 9 in 38%
nesium carbenoid 6 to afford cyclopropylmagnesium chloride
intermediate A. Intramolecular nucleophilic addition of the cyclo-
propylmagnesium chloride to the carbonyl carbon gave highly
strained intermediate B, from which intermediate C is generated
with C–C bond cleavage. However, the generated carbanion of
intermediate C is not stabilized at all. As a result, the reaction of
7 and 6 did not give C but a complex mixture.
On the contrary, lithium enolate of b-tetralone 8 reacts with 6
to give highly strained intermediate D, from which intermediate
E is generated with C–C bond cleavage. The generated carbanion
of intermediate E is stabilized by the benzene ring and this reaction
did indeed occur. In fact, quenching of this reaction with CH3OD,
position. Next, the investigation to find the best conditions for this
reaction was carried out and the results are summarized in Table 1.
The result shown in entry 1 has already been mentioned above.
When the amount of enolate 8 was increased to 5 equiv and the
temperature of the reaction mixture was allowed to warm to
À20 °C, the yield of 9 was improved to 68% (entry 2). Further
increasing the amount of enolate 8 did not give a better yield (en-
try 3). When the reaction was carried out with 5 equiv of 8 and the
temperature of the reaction mixture was allowed to warm to room
temperature, the yield of 9 was increased up to 78% (entries 4 and
5).5 Addition of HMPA as an additive (entry 6) or using toluene as
the solvent gave much worse results (entries 6 and 7). We decided
that the conditions described in entry 5 were the conditions of
choice for this reaction and we used them throughout in this study.
deuterated product 9 (D) was obtained with about 70% D-content.
Next, generality of this reaction was investigated with cyclopro-
pylmagnesium carbenoid 6 and a variety of carbonyl compounds,
and the results are summarized in Table 2. The reaction of 6 with
7-methoxy b-tetralone gave a high yield of the desired product
(entry 1). Seven-membered ketones gave the desired eight-mem-
bered
a-cyclopropyl ketones; however, the yields were not satis-
factory (entries 2 and 3). Dipropyl ketone gave only complex
mixture as anticipated (entry 4). On the contrary, dibenzyl ketone
gave good yield of the desired product as expected (entry 5).
Table 1
Study for the conditions of the reaction of cyclopropylmagnesium carbenoid 6 with
lithium enolate of b-tetralone 8
Although the yields were not satisfactory,
the desired homologated -cyclopropyl ketones (entries 6–8). Even
phenylacetaldehyde gave the desired one-carbon homologated
a-aryl ketones gave
a
OLi
a-cyclopropyl aldehyde in 36% yield (entry 9).
The reaction was studied by using other cyclopropylmagnesium
8
carbenoids 12 derived from 1-chlorocyclopropyl aryl sulfoxides 11
with lithium enolate of b-tetralone 8 and the results are shown in
Scheme 4. Thus, cyclopropylmagnesium carbenoid without any
substituent on the cyclopropane ring 12a reacted with 8 to give
83% yield of 13a. In a similar manner, cyclopropylmagnesium carb-
enoid bearing a methyl substituent on the cyclopropane ring 12b
reacted with 8 to give 83% yield of 13b. Even the cyclopropylmag-
nesium carbenoid bearing both a methyl and 2-trityloxymethyl
substituents on the cyclopropane ring 12c reacted with 8 to give
good yield (71%) of the desired product 13c.
In this reaction, quite interesting stereospecificity was ob-
served. Thus, as shown in Scheme 5, reaction of lithium enolate
of b-tetralone 8 with cyclopropylmagnesium carbenoid 15, derived
from 1-chlorocyclopropyl p-tolyl sulfoxide 14, gave the desired
product 16 in 81% yield as a single product. In the same manner,
( Equivalent )
Cl
O
Conditions
MgCl
6
9
Entry
Conditions
9
Solvent
Equiv of 8
Temp/°C
Yield/%
1
2
3
4
5
6
7
THF
THF
THF
THF
3
5
7
5
5
5
5
À78 to À20
À78 to À20
À78 to À20
À78 to 0
38
68
61
76
78
7
THF
À78 to rt
THF/HMPAa
Toluene
À78 to À20
À78 to À20
11
a
HMPA (5 equiv) was added as an additive.

4470
T. Satoh et al. / Tetrahedron Letters 52 (2011) 4468–4472
Cl
ClMg
Li
O
O
O
O
MgCl
6
MgCl
MgCl
MgCl
7
A
D
C
B
ClMg
(D) H
O
OLi
O
O
8
E
9
Scheme 3. A plausible rationalization for the reason why lithium enolate of b-tetralone gave one-carbon homologated
a-cyclopropyl ketone 9 but lithium enolate of a-
tetralone did not.
Table 2
One-carbon homologation of carbonyl compounds to cyclopropyl carbonyl compounds 10 with cyclopropylmagnesium carbenoid 6
O
R4
R5
O
, LDA
(5 eq)
R4
R5
MgCl
Cl
THF, -78 ºC to r.t.
6
10
Entry
Carbonyl compound
10
Yield/%
86
CH3O
O
CH3O
1
O
O
R
R
O
R = H
R
2
3
15
30
R = OCH3
O
R
4
5
Complex mixture
73
R = Et
R = Ph
O
R
R
O
O
Ph
Ph
6
41
Ph
Ph
O
R = OMe
R = F
7
8
35
20
O
R
R
O
O
9
36
Ph
H
Ph
H
the reaction of 8 with cyclopropylmagnesium carbenoid 18, de-
rived from 17, gave the desired product 19 in 82% yield, again as
a single product. The products 16 and 19 were found to be diaste-
reomers to each other. Stereochemistry of both products was
determined by NOESY spectra as shown in Scheme 5.
The rational explanation of the stereospecificity is as follows
(Scheme 6). As the sulfoxide-magnesium exchange reaction6 is
proved to proceed with retention of the configuration of the carbon
bearing the sulfoxide group,7 sulfoxide 14 gave cyclopropylmagne-
sium carbenoid 15. Nucleophilic substitution of the cyclopropyl-

T. Satoh et al. / Tetrahedron Letters 52 (2011) 4468–4472
4471
OLi
R4
R5
R5
R5
i-PrMgCl
R4
Cl
R4
Cl
8 (5 eq)
( 2.5 eq )
O
S(O)Ar
MgCl
12
-78 °C to r.t.
THF, -78 °C
13
11a R4=R5= H, Ar= Ph
13a R4=R5= H, 83%
11b R4= H or CH3, R5= CH3 or H, Ar= Ph
13b R4= H or CH3, R5= CH3 or H, 83%
13c R4= CH2OTr, R 5= CH3, 71%
11c R4= CH2OTr, R 5= CH3, Ar= Tol
Scheme 4. Reaction of cyclopropylmagnesium carbenoids 12, derived from 1-chlorocyclopropyl aryl sulfoxides 11, with lithium enolate of b-tetralone 8.
NOE
Ph
OLi
H
H
Ph
CH3
Cl
i-PrMgCl
(2.5 eq)
Ph
CH3
Cl
8 (5 eq)
CH3
O
MgCl
-78 ºC to r.t.
THF, -78 ºC
S(O)Tol
81%
16
15
14
NOE
OLi
Ph
Ph
H
H
CH2
i-PrMgCl
(2.5 eq)
8 (5 eq)
Cl
Cl
S(O)Tol
H3C
H3C
Ph
O
-78 ºC to r.t.
MgCl
18
THF, -78 ºC
19
82%
17
Scheme 5. The stereospecific reaction of cyclopropylmagnesium carbenoids 15 and 18, derived from 1-chlorocyclopropyl p-tolyl sulfoxides 14 and 17, respectively, with
lithium enolate of b-tetralone 8.
Ph
CH3
Ph
CH3
Cl
compounds. Further investigation of this reaction, including asym-
metric synthesis, is underway in our laboratory.
MgCl
O
15
8
MgCl
SN2 reaction with inversion
of the carbenoid carbon
H
O
Li
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search Nos. 19590018 and 22590021 from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and TUS
Grant for Research Promotion from Tokyo University of Science,
which is gratefully acknowledged.
F
Ph
Ph
CH3
H
H
H
References and notes
O
MgCl
CH3
O
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, 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; (f) Satoh,
T. J. Syn. Org. Chem. Jpn. 2009, 67, 381.
16
G
Scheme 6. Stereochemistry of the reaction of 15 with lithium enolate of b-tetralone
8 to afford one-carbon homologated -cyclopropyl ketone 16.
a
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. Syn. 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, 49, 10749; (f) Tochtermann, W.; Kraft, P. Synlett 1996, 1029.
3. Some recent papers concerning the homologation of carbonyl compounds from
our laboratories: (a) Satoh, T.; Mizu, Y.; Hayashi, Y.; Yamakawa, K. Tetrahedron
Lett. 1994, 35, 133; (b) Satoh, T.; Hayashi, Y.; Mizu, Y.; Yamakawa, K. Bull. Chem.
Soc. Jpn. 1994, 67, 1412; (c) Satoh, T.; Itoh, N.; Gengyo, K.; Takada, S.; Asakawa,
N.; Yamani, Y.; Yamakawa, K. Tetrahedron 1994, 50, 11839; (d) Satoh, T.; Mizu,
Y.; Kawashima, T.; Yamakawa, K. Tetrahedron 1995, 51, 703; (e) Satoh, T.; Unno,
H.; Mizu, Y.; Hayashi, Y. Tetrahedron 1997, 53, 7843; (f) Satoh, T.; Kurihara, T.
Tetrahedron Lett. 1998, 39, 9215; (g) Satoh, T.; Imai, K. Chem. Pharm. Bull. 2003,
51, 602; (h) Satoh, T.; Miyashita, K. Tetrahedron Lett. 2004, 45, 4859; (i)
Miyashita, K.; Satoh, T. Tetrahedron 2005, 61, 5067; (j) Satoh, T.; Tanaka, S.;
Asakawa, N. Tetrahedron Lett. 2006, 47, 6769; (k) Tanaka, S.; Anai, T.; Tadokoro,
M.; Satoh, T. Tetrahedron 2008, 64, 7199.
magnesium carbenoids with carbanions was proved to take place
with inversion of the carbenoid carbon.4g Thus, the reaction of
carbenoid 15 with lithium enolate 8 afforded the cyclopropylmag-
nesium chloride intermediate F. Intramolecular nucleophilic addi-
tion of the carbanion to the carbonyl carbon gave intermediate G,
which afforded the product 16 with C–C bond cleavage. In the
same manner, the reaction of 18, derived from 17, with enolate 8
gave product 19 with high stereospecificity.
In conclusion, we found that the reaction of the lithium enolates
of
noids resulted in the formation of b-aryl carbonyl compounds
bearing a cyclopropane ring at the -position with one-carbon
a-aryl carbonyl compounds with cyclopropylmagnesium carbe-
a
4. The papers concerning the chemistry and synthetic uses of
cyclopropylmagnesium carbenoids: (a) Satoh, T.; Kurihara, T.; Fujita, K.
Tetrahedron 2001, 57, 5369; (b) Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45,
347; (c) Satoh, T.; Miura, M.; Sakai, K.; Yokoyama, Y. Tetrahedron 2006, 62, 4253;
(d) Yamada, Y.; Miura, M.; Satoh, T. Tetrahedron Lett. 2008, 49, 169; (e) Satoh, T.;
homologation. The reaction was found to be highly stereospecific
with respect to the stereochemistry of the cyclopropylmagnesium
carbenoids. This is the first example for the insertion of cyclopro-
panes in between a carbonyl carbon and an
a-carbon of carbonyl

4472
T. Satoh et al. / Tetrahedron Letters 52 (2011) 4468–4472
Nagamoto, S.; Yajima, M.; Yamada, Y.; Ohata, Y.; Tadokoro, M. Tetrahedron Lett.
(50.2 mg, 78%) as light yellow oil. IR (neat); 2941, 1693 (CO), 1454, 1378, 1366,
and 759 cmÀ1 1H NMR (400 MHz, CDCl3) d 0.53 (1H, d, J = 4.4 Hz), 0.94 (3H, s),
2008, 49, 5431; (f) Satoh, T.; Noguchi, T.; Miyagawa, T. Tetrahedron Lett. 2008, 49,
5689; (g) Yajima, M.; Nonaka, R.; Yamashita, H.; Satoh, T. Tetrahedron Lett. 2009,
50, 4754; (h) Yamada, Y.; Mizuno, M.; Nagamoto, S.; Satoh, T. Tetrahedron 2009,
65, 10025; (i) Satoh, T.; Ikeda, S.; Miyagawa, T.; Noguchi, T. Tetrahedron Lett.
2010, 51, 1955; (j) Momochi, H.; Noguchi, T.; Miyagawa, T.; Ogawa, N.;
Tadokoro, M.; Satoh, T. Tetrahedron Lett. 2011, 52, 3016.
;
1.12 (3H, s), 1.52 (1H, d, J = 4.4 Hz), 2.51–2.57 (1H, m), 2.76 (1H, d, J = 16.2 Hz),
2.98–3.08 (3H, m), 3.40 (1H, d, J = 16.2 Hz), 7.09–7.17 (4H, m); 13C NMR
(125.65 MHz, CDCl3) d 20.7 (CH3), 22.2 (CH3), 26.2 (CH2), 27.4 (C), 29.9 (CH2),
37.7 (CH2), 40.8 (C), 43.4 (CH2), 126.3 (CH), 126.5 (CH), 129.3 (CH), 130.3 (CH),
138.6 (C), 139.3 (C), 210.1 (CO). MS m/z (%): 214 (M+, 100), 158 (36), 146 (40),
130 (58), 115 (30). Calcd for C15H18O: M, 214.1358. Found: m/z 214.1359.
6. (a) Satoh, T. Chem. Rec. 2004, 3, 329; (b) Satoh, T. Chem. Soc. Rev. 2007, 36, 1561;
(c) Satoh, T. In The Chemistry of Organomagnesium Compounds; Rappoport, Z.,
Marek, I., Eds.; John Wiley and Sons: Chichester, 2008; pp 717–769; (d) Satoh, T.
Yakugaku Zasshi 2009, 129, 1013.
7. (a) Satoh, T.; Kobayashi, S.; Nakanishi, S.; Horiguchi, K.; Irisa, S. Tetrahedron
1999, 55, 2515; (b) Hoffmann, R. W.; Holzer, B.; Knopff, O.; Harms, K. Angew.
Chem., Int. Ed. 2000, 39, 3072; (c) Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S.
Tetrahedron 2001, 57, 3891; (d) Hoffmann, R. W. Chem. Soc. Rev. 2003, 32, 225;
(e) Mitusnaga, S.; Ohbayashi, T.; Sugiyama, S.; Saitou, T.; Tadokoro, M.; Satoh, T.
Tetrahedron: Asymmetry 2009, 20, 1697; (f) Satoh, T.; Kuramoto, T.; Ogata, S.;
Watanabe, H.; Saitou, T.; Tadokoro, M. Tetrahedron: Asymmetry 2010, 21, 1.
5. To a solution of 1-chloro-2,2-dimethylcyclopropyl p-tolyl sulfoxide 5 (73 mg;
0.3 mmol) in 0.7 mL of dry THF in a flame-dried flask at À78 °C under argon
atmosphere was added a solution of i-PrMgCl (2.0 mol/L in THF; 0.38 mL;
0.75 mmol) dropwise with stirring and the reaction mixture was stirred for
10 min to give cyclopropylmagnesium carbenoid 6. In another flame-dried flask,
b-tetralone (0.20 mL; 1.5 mmol) was added to a solution of LDA (1.5 mmol) in
0.8 mL of dry THF at À78 °C under argon atmosphere. This solution was added to
the solution of 6 through a cannula. The temperature of the reaction mixture
was allowed to warm slowly to room temperature. The reaction was quenched
by satd aq NH4Cl and the whole mixture was extracted with CHCl3. The organic
layer was washed once with water and dried over MgSO4. After removal of the
solvent, the product was purified by silica gel column chromatography to give 9