A novel one-pot synthesis of cyclopropanols based on the reaction of magnesium carbenoids with lithium enolate of ketones

Article abstract of DOI:10.1016/j.tetlet.2013.03.025

The reaction of magnesium carbenoids with lithium enolate of ketones resulted in the formation of cyclopropanols in moderate to good yields. These reactive species (i.e., magnesium carbenoids and lithium enolate of ketones) were generated from 1-chloroalkyl p-tolyl sulfoxides with i-PrMgCl and ketones with LDA in the reaction medium at -78 C in a one-pot reaction.

Full text of DOI:10.1016/j.tetlet.2013.03.025

Accepted Manuscript
A novel one-pot synthesis of cyclopropanols based on the reaction of magnesium
carbenoids with lithium enolate of ketones
Gaku Kashiwamura, Tsutomu Kimura, Tsuyoshi Satoh
PII:
S0040-4039(13)00406-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.025
TETL 42640
Reference:
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Tetrahedron Letters
Received Date:
Revised Date:
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5 March 2013
6 March 2013
Please cite this article as: Kashiwamura, G., Kimura, T., Satoh, T., A novel one-pot synthesis of cyclopropanols
based on the reaction of magnesium carbenoids with lithium enolate of ketones, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.03.025
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A novel one-pot synthesis of cyclopropanols
based on the reaction of magnesium
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carbenoids with lithium enolate of ketones
Gaku Kashiwamura, Tsutomu Kimura, Tsuyoshi Satoh*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A novel one-pot synthesis of cyclopropanols based on the reaction of magnesium
carbenoids with lithium enolate of ketones
Gaku Kashiwamura, Tsutomu Kimura, Tsuyoshi Satoh*
aGraduate School of Chemical Sciences and Technology, Tokyo University of Science; Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of magnesium carbenoids with lithium enolate of ketones resulted in the formation
of cyclopropanols in moderate to good yields. These reactive species (i.e., magnesium
carbenoids and lithium enolate of ketones) were generated from 1-chloroalkyl p-tolyl sulfoxides
with i-PrMgCl and ketones with LDA in the reaction medium at –78 °C in a one-pot reaction.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane
Cyclopropanol
Magnesium carbenoid
Lithium enolate
One-pot synthesis
Cyclopropanes and their derivatives are one of the most
important and fundamental compounds in organic and synthetic
organic chemistry. The cyclopropane skeletal structure is
frequently found in natural products and in unnatural compounds.
Cyclopropanes and their derivatives undergo a variety of ring-
opening reactions under various conditions with carbon-carbon
and carbon-heteroatom bond formation or rearrangement. Based
on these properties, cyclopropane derivatives have been
recognized to be one of the most useful compounds in organic
synthesis.1 Among the cyclopropanes, cyclopropanol and its
derivatives are versatile intermediates in organic synthesis.2, 3
in THF at –78 °C to generate magnesium carbenoid 6.8 In another
flask, lithium enolate of cyclohexanone (5 equiv) was generated
in THF at –78 °C in the usual manner. Then, the solution
containing lithium enolate was transferred into the solution
containing magnesium carbenoid 6 via a cannula, and the
reaction mixture was stirred and gradually allowed to warm to –
20 °C. From this reaction, two products were obtained that were
separable by silica gel column chromatography.
Several procedures for the synthesis of cyclopropanols are
known. For example, the Kulinkovich reaction2b,2d,4 is the method
using esters. The Simmons-Smith-type cyclopropanation of silyl
enol ethers or enol ethers is also available.2d However, in view of
the importance of cyclopropanols in organic synthesis, new
methods for their synthesis are still very much desired.
Scheme 1. Reaction of magnesium carbenoids 2 with lithium
enolate of ketones 3 to afford cyclopropanols 4.
We have been interested in the synthesis of cyclopropanes
based on our original methods, which include the 1,3-CH
insertion of magnesium carbenoids5 and the nucleophilic reaction
of cyclopropylmagnesium carbenoids with carbanions.6 As a
continuation of the development of new synthetic methods by the
reaction of magnesium carbenoids with carbanions, magnesium
carbenoid 2, which was generated from 1 with i-PrMgCl by a
sulfoxide-magnesium exchange reaction,7 was reacted with
lithium enolate of ketone 3. The reaction gave multisubstituted
cyclopropanols 4 in moderate to good yields (Scheme 1). In this
Letter, a novel method for the synthesis of the cyclopropanols
mentioned above in a one-pot procedure is reported.
The major product 7a had a molecular formula of C16H22O2
and an O-H absorption in its IR spectrum. The 1H NMR
exhibited two characteristic signals at  0.43 and  0.66, which
suggested the presence of a cyclopropane skeletal structure. In
1
addition, the 13C NMR (DEPT) and H NMR spectra suggested
that the carbon bearing the hydroxyl group is quaternary. From
these data and coupling constant between two cyclopropane
protons (J = 8.2 Hz), the major product 7a was determined to be
cis-7-[2-(4-methoxyphenyl)ethyl]bicyclo[4.1.0]heptan-1-ol (cis:
relative configuration of the hydroxyl group and the 2-arylethyl
group), as shown in Scheme 2. The structure of the minor
As shown in Scheme 2, 1-chloro-3-(4-methoxyphenyl)propyl
p-tolyl sulfoxide 5 was reacted with 2.8 equivalents of i-PrMgCl

2
Tetrahedron
product was determined to be the trans-diastereomer 7b based
(entry 6). Therefore, this reaction is applicable to a variety of
on its spectral data.
ketones.
Table 1. One-pot synthesis of cyclopropanols by the reaction
of magnesium carbenoid 6 with lithium enolate of ketones 8.
Entry ketone
9
9
Yield trans:cis
(%)
1
2
74
61
53:22 a
41:20 b
Scheme 2. A two-pot synthesis of cyclopropanols 7a and 7b
from 1-chloro-3-(4-methoxyphenyl)propyl p-tolyl sulfoxide 5
and cyclohexanone.
As the transfer of the reactive species via a cannula is not an
expedient procedure, we investigated more convenient methods
for performing this reaction. Fortunately, the reaction of
sulfoxide 5 with lithium enolate of ketones was very slow at –
78 °C. Therefore, the one-pot reaction shown in Scheme 3 was
3
4
79
83
57:22
70:13
successfully designed. To
a flame-dried flask, THF and
diisopropylamine were added followed by BuLi at –78 °C to
generate LDA. Cyclohexanone was subsequently added with
stirring. After 20 min, i-PrMgCl was added followed by the
addition of a solution containing 5 in a small amount of THF.
Next, the temperature of the whole reaction mixture was slowly
warmed to room temperature. The reaction was quenched with
saturated aqueous NH4Cl to yield cyclopropanols 7a and 7b in
better yields of 57 and 27%, respectively.9
c
5
6
73
67
–
30:37
a The relative configurations were assigned on the basis of
NOESY spectra.
b The relative configurations were tentatively assigned on the
basis of spectroscopic comparison with the products in entry 1.
c A mixture of three diastereomers in a ratio of 49:13:11 was
obtained.
Next, the investigation was expanded to the synthesis of more
substituted cyclopropanols using 1-chloro-1,1-dialkyl p-tolyl
sulfoxides 10 as the magnesium carbenoid source (Scheme 4).
Sulfoxides 10a and 10b were synthesized from 5 and the
corresponding iodoalkanes with LDA as a base in high yields.
The reaction was conducted in one pot as described above and
multisubstituted cyclopropanols 11a and 11b were successfully
obtained in 55 and 56% yield, respectively.
Scheme 3. A one-pot synthesis of cyclopropanols 7a and 7b
from cyclohexanone and 1-chloro-3-(4-methoxyphenyl)propyl
p-tolyl sulfoxide 5.
The scope of this reaction was investigated with a range of
ketones 8 with sulfoxide 5 using the one-pot procedure described
above, and the results are summarized in Table 1. As shown in
entry 1, this procedure was successful with the simplest ketone
(i.e., acetone) to afford the desired cyclopropanol 9 in 74% yield.
tert-Butyl methyl ketone, which is a highly sterically hindered
ketone, afforded the desired cyclopropanol in moderate yield
(entry 2). Entries 3 to 5 show that cyclic ketones other than
cyclohexanone afforded the desired cyclopropanols with up to an
83% yield. Even 2-cyclohexenone, which is an ,-unsaturated
ketone, yielded the desired cyclopropanol with a 67% yield
Finally, a plausible reaction mechanism for this reaction is
shown in Scheme 5. The nucleophilic substitution of magnesium
carbenoid
A with lithium enolate of ketone B affords
intermediate C.6e,10 Then, the intramolecular addition reaction of
the magnesium carbanion in C proceeds to the ketone carbonyl
group to yield magnesium cyclopropanolate D, which is
hydrolyzed in the workup to afford cyclopropanol E.
In conclusion, we found that the reaction of magnesium
carbenoids with lithium enolate of ketones yielded
multisubstituted cyclopropanols with the consecutive formation

3
4. Mundy, B. P.; Ellerd, M. G.; Favaloro, Jr., F. G. Name
Reactions and Reagents in Organic Synthesis, Second Ed., John
Wiley and Sons, 2005, 796.
5. Selected papers on the synthesis of cyclopropanes based on the
1,3-CH insertion of magnesium carbenoids: (a) Satoh, T.;
of two carbon-carbon bonds. Although the current yields are not
always high, the one-pot synthesis described is an unprecedented
method and we believe it will substantially contribute to the
synthesis of cyclopropanols.
Musashi, J.; Kondo, A. Tetrahedron Lett. 2005, 46, 599; (b) Satoh,
T.; Ogata, S.; Wakasugi, D. Tetrahedron Lett. 2006, 47, 7253; (c)
Ogata, S.; Masaoka, S.; Sakai, K.; Satoh, T. Tetrahedron Lett.
2007, 48, 5017; (d) Ogata, S.; Saitoh, H.; Wakasugi, D.; Satoh, T.
Tetrahedron 2008, 64, 5711; (e) Satoh, T.; Kuramoto, T.; Ogata,
S.; Watanabe, H.; Saitou, T.; Tadokoro, M. Tetrahedron:
Asymmetry 2010, 21, 1; (f) Watanabe, H.; Ogata, S.; Satoh, T.
Tetrahedron 2010, 66, 5675.
6. Selected papers on the synthesis of cyclopropanes based on the
reaction of cyclopropylmagnesium carbenoids with carbon
nucleophiles: (a) Yamada, Y.; Miura, M.; Satoh, T. Tetrahedron
Lett. 2008, 49, 169; (b) Satoh, T.; Nagamoto, S.; Yajima, M.;
Yamada, Y.; Ohata, Y.; Tadokoro, M. Tetrahedron Lett. 2008, 49,
5431; (c) Yajima, M.; Nonaka, R.; Yamashita, H.; Satoh, T.
Tetrahedron Lett. 2009, 50, 4754; (d) Yamada, Y.; Mizuno, M.;
Nagamoto, S.; Satoh, T. Tetrahedron 2009, 65, 10025; (e) Satoh,
T.; Kashiwamura, G.; Nagamoto, S.; Sasaki, Y.; Sugiyama, S.
Tetrahedron Lett. 2011, 52, 4468; (f) Satoh, T.; Kimura, T.;
Sasaki, Y.; Nagamoto, S. Synthesis, 2012, 44, 2091.
Scheme 4. Synthesis of highly substituted cyclopropanols 11
from 1-chloro-1,1-dialkylmethyl p-tolyl sulfoxides 10 and
lithium enolate of cyclohexanone.
7. (a) Satoh, T. Chem. Soc. Rev. 2007, 36, 1561; (b) Satoh, T. In The
Chemistry of Organomagnesium Compounds; Rappoport, Z.;
Marek, I. Eds.; John Wiley and Sons: Chichester, 2008, 717-769;
(c) Satoh, T. Heterocycles 2012, 85, 1.
8. Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron 2004, 60, 5453.
9. A 1.64 M solution of n-BuLi in hexane (0.61 mL, 1.0 mmol) was
added dropwise to a solution of diisopropylamine (0.15 mL, 1.1
mmol) in THF (1.6 mL) at 0 °C. The mixture was stirred for 10
min at 0 °C and cooled to –78 °C. Cyclohexanone (0.10 mL, 0.97
mmol) was added dropwise to the resulting solution at -78°C.
After further stirring for 20 min, a 2.0 M solution of i-PrMgCl in
THF (0.28 mL; 0.56 mmol) and a solution of sulfoxide (65 mg;
0.2 mmol) in THF (0.4 mL) were added in turn to the resulting
solution at –78 °C. The reaction mixture was warmed to room
temperature over a period of 2 h. The reaction was quenched with
sat. aq. NH4Cl (1.5 mL), and the mixture was extracted with
CHCl3 (3 × 7 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to yield cis-7-[2-(4-
Scheme 5. A plausible mechanism for the reaction of
magnesium carbenoids with lithium enolate of ketones.
Acknowledgments
methoxyphenyl)ethyl]bicyclo[4.1.0]heptan-1-ol 7a (28.0 mg,
57%) and 7b (13.5 mg, 27%) as light yellow oils. 7a: IR (neat)
3407 (OH), 2931, 2854, 1612, 1512, 1464, 1448, 1246, 1177,
1037, 828 cm-1; 1H NMR (300 MHz, CDCl3)  0.43 (td, J = 5.8,
8.2 Hz, 1H), 0.66 (ddd, J = 1.6, 6.1, 8.2 Hz, 1H), 1.03-1.07 (m,
1H), 1.15-1.24 (m, 2H), 1.31-1.47 (m, 2H), 1.60-1.79 (m, 3H),
1.83-1.97 (m, 3H), 2.55 (ddd, J = 6.8, 8.7, 13.5 Hz, 1H), 2.72 (td,
J = 6.3, 13.5 Hz, 1H), 3.79 (s, 3H), 6.82-6.86 (m, 2H), 7.09-7.13
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 21.4 (CH2), 21.7 (CH2),
24.3 (CH2), 24.7 (CH), 28.9 (CH), 30.1 (CH2), 32.8 (CH2), 35.3
(CH2), 55.2 (CH3), 57.7 (C), 113.7 (CH), 129.5 (CH), 134.7 (C),
157.7 (C); MS (EI) m/z (%) = 246 (M+, 28), 148 (27), 134 (49),
121 (100); HRMS (EI) calcd for C16H22O2: 246.1620, found:
246.1621. 7b: IR (neat) 3346 (OH), 2931, 2855, 1612, 1512, 1465,
1447, 1246, 1177, 1038, 821 cm-1; 1H NMR (300 MHz, CDCl3) 
0.95 (td, J = 7.0, 10.5 Hz, 1H), 1.14 (ddd, J = 2.2, 9.0, 10.5 Hz,
1H), 1.17-1.31 (m, 4H), 1.45-1.68 (m, 3H), 1.78 (br s, 1H), 1.83-
1.94 (m, 3H), 2.61 (ddd, J = 7.1, 8.9, 13.6 Hz, 1H), 2.68 (ddd, J =
6.6, 8.5, 13.6 Hz, 1H), 3.79 (s, 3H), 6.82-6.85 (m, 2H), 7.11-7.14
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 18.8 (CH2), 21.4 (CH),
22.0 (CH2), 22.3 (CH2), 26.2 (CH2), 28.3 (CH), 28.8 (CH2), 35.2
(CH2), 55.2 (CH3), 55.7 (C), 113.7 (CH), 129.3 (CH), 134.5 (C),
157.7 (C); MS (EI) m/z (%) = 246 (M+, 33), 148 (30), 134 (50),
121 (100); HRMS (EI) calcd for C16H22O2: 246.1620, found:
246.1617.
We gratefully acknowledge support from a Grant-in-Aid for
Scientific Research No. 22590021 from the Ministry of
Education, Culture, Sports, Science and Technology, Japan and a
TUS Grant for Research Promotion from Tokyo University of
Science.
References and notes
1. Recent reviews on the chemistry, synthesis, and synthetic uses of
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Chem. Jpn. 1983, 41, 22; (b) Wong, H. N. C.; Hon, M.-Y.; Tse,
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R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875;
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(f) Donaldson, W. A. Tetrahedron 2001, 57, 8589; (g) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003,
103, 977; (h) Pietruszka, J. Chem. Rev. 2003, 103, 1051; (i)
Fedorynsky, M. Chem. Rev. 2003, 103, 1099; (j) Halton, B.;
Harvey, J. Synlett 2006, 1975; (k) Rubin, M.; Rubina, M.;
Gevorgyan, V. Chem. Rev. 2007, 107, 3117: (l) Pellissier, H.
Tetrahedron 2008, 64, 7041.
2. Recent reviews on the chemistry, synthesis, and synthetic uses of
cyclopropanols: (a) Gibson, D. H.; DePuy, C. H. Chem. Rev.
1974, 74, 605; (b) Kulinkovich, O. G.; de Meijere, A. Chem. Rev.
2000, 100, 2789; (c) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003,
103, 1151; (d) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
3. Selected papers on the synthetic uses of cyclopropanols: (a)
Tsuchida, H.; Tamura, M.; Hasegawa, E. J. Org. Chem. 2009, 74,
2467; (b) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
9178; (c) Wang, Y.-F.; Toh, K. K.; Ng, E. P. J.; Chiba, S. J. Am.
Chem. Soc. 2011, 133, 6411.
10. (a) Satoh, T.; Kaneta, H.; Matsushima, A.; Yajima, M.
Tetrahedron Lett. 2009, 50, 6280; (b) Kimura,T.; Kobayashi, G.;
Ishigaki, M.; Inumaru, M.; Sakurada, J.; Satoh, T. Synthesis 2012,
44, 3623.