Synthesis of cyclopropane-fused α-chlorolactones utilizing the nucleophilicity of cyclopropylmagnesium carbenoids

Article abstract of DOI:10.1016/j.tetlet.2014.01.038

A novel method for the synthesis of cyclopropane-fused α-chloro- γ-lactones was developed utilizing the nucleophilicity of cyclopropylmagnesium carbenoids. Cyclopropylmagnesium carbenoids were generated from i-PrMgCl and 1-chlorocyclopropyl p-tolyl sulfoxides with a [(phenoxycarbonyl)oxy]methyl group at the 2-position of the cyclopropane ring. The resulting cyclopropylmagnesium carbenoids reacted with an intramolecular carbonate unit to give 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones in moderate to good yields. The asymmetric synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-one was achieved using optically active dichloromethyl p-tolyl sulfoxide as a starting material.

Full text of DOI:10.1016/j.tetlet.2014.01.038

Tetrahedron Letters 55 (2014) 1428–1430
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Tetrahedron Letters
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Synthesis of cyclopropane-fused
a-chlorolactones utilizing
the nucleophilicity of cyclopropylmagnesium carbenoids
Tsutomu Kimura a, Junichiro Nishida b, Gaku Kashiwamura b, Gen Kobayashi b, Tsuyoshi Satoh a,b,
⇑
a Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigayafunagawaramachi 12, Shinjuku-ku, Tokyo 162-0826, Japan
b Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigayafunagawaramachi 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:
A novel method for the synthesis of cyclopropane-fused
a
-chloro-
c
-lactones was developed utilizing the
Received 1 November 2013
Revised 7 January 2014
Accepted 10 January 2014
Available online 20 January 2014
nucleophilicity of cyclopropylmagnesium carbenoids. Cyclopropylmagnesium carbenoids were gener-
ated from i-PrMgCl and 1-chlorocyclopropyl p-tolyl sulfoxides with a [(phenoxycarbonyl)oxy]methyl
group at the 2-position of the cyclopropane ring. The resulting cyclopropylmagnesium carbenoids
reacted with an intramolecular carbonate unit to give 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones in mod-
erate to good yields. The asymmetric synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-one was achieved
using optically active dichloromethyl p-tolyl sulfoxide as a starting material.
Keywords:
Cyclopropylmagnesium carbenoid
Nucleophilic reaction
Ó 2014 Elsevier Ltd. All rights reserved.
Cyclopropane-fused
Asymmetric synthesis
1-Chlorocyclopropyl p-tolyl sulfoxide
a-chloro-c-lactone
(1-Chlorocyclopropyl)magnesium chlorides, also referred to as
cyclopropylmagnesium carbenoids, are reactive intermediates that
show reactivity similar to that of cyclopropylidenes.1 The diverse
reactivity of cyclopropylmagnesium carbenoids enables various
synthetic transformations. For instance, the Doering–Moore–Skat-
tebøl (DMS) rearrangement is a useful method for the synthesis of
allenes (Scheme 1, a).2 Intramolecular C–H insertion of cyclopro-
pylmagnesium carbenoids leads to the formation of bicyclic com-
pounds containing
a
cyclopropane ring (Scheme 1, b).3
Furthermore, cyclopropylmagnesium carbenoids react with nucle-
ophiles, such as Grignard reagents and lithium arylamides, to give
multi-substituted cyclopropane derivatives (Scheme 1, c).4 Despite
many productive synthetic applications of cyclopropylmagnesium
carbenoids, less attention has been paid to their nucleophilicity.5
During the course of our study on the synthetic applications of
cyclopropylmagnesium carbenoids, we developed a novel method
for the synthesis of cyclopropane-fused a-chloro-c-lactones utiliz-
ing the nucleophilic character of cyclopropylmagnesium
carbenoids (Scheme 1, d). Herein, we report the synthesis of
1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones by the intramolecular
nucleophilic reaction of cyclopropylmagnesium carbenoids gener-
ated from 1-chlorocyclopropyl p-tolyl sulfoxides with a phenyl
carbonate unit on the cyclopropane ring.
Scheme 1. Chemical properties of cyclopropylmagnesium carbenoids.
carbenoids, bifunctional chemical species involving a nucleophilic
(1-chlorocyclopropyl)magnesium chloride moiety and an
electrophilic carbonate moiety should be generated.6 Previously,
we found that the sulfoxide/magnesium exchange reaction of
1-chlorocyclopropyl p-tolyl sulfoxides with i-PrMgCl proceeded
smoothly at low temperature to give cyclopropylmagnesium
carbenoids.2–4 Several functional groups, such as cyano and
To construct a cyclopropane-fused c-lactone framework via the
intramolecular nucleophilic reaction of cyclopropylmagnesium
⇑
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.038

T. Kimura et al. / Tetrahedron Letters 55 (2014) 1428–1430
1429
Table 1
Synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones 3
Entry
1
R
R0
R00
Ar
2
Yield of 2 (%)
3
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1d
1e
H
H
H
H
H
H
H
i-Pr
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Me
Me
Me
PMB
Ph(CH2)2
Me
H
H
H
H
H
H
H
H
Et
Ph
Ph
Ph
Ph
2a
2a
2a
2b
2b0
2b00
2c
92
—
—
99
99
85
91
86
99
3a
3a
3a
3b
3b
3b
3c
3d
3e
12a
35b
83
70
63
4-MeOC6H4
4-FC6H4
Ph
Ph
Ph
72
79
2d
2e
59c
40d
Ph(CH2)2
a
b
c
Sulfoxide 2a was treated with i-PrMgCl at ꢀ78 °C for 1 h.
Sulfoxide 2a was treated with i-PrMgCl at 0 °C for 1 h.
Chlorocyclopropane 4d was obtained in 18% yield.
Chlorocyclopropane 4e was obtained in 26% yield.
d
tert-butoxycarbonyl groups, were left intact during the exchange
reaction.2a,7 In anticipation of tolerance to the aryl carbonate unit
in the sulfoxide/magnesium exchange reaction,8 we designed
1-chlorocyclopropyl p-tolyl sulfoxides 2 having an [(aryloxycar-
bonyl)oxy]methyl group at the 2-position of the cyclopropane ring
as cyclization precursors (Table 1). 2-Hydroxymethyl-substituted
1-chlorocyclopropyl p-tolyl sulfoxides
dichloromethyl p-tolyl sulfoxide and
1
were prepared from
a
,b-unsaturated carbonyl
compounds in a short sequence according to the procedure
described in our previous reports.2c,9 The reaction of 1 with aryl
chloroformate in the presence of pyridine gave cyclization precur-
sors 2 in 85–99% yield.10
Scheme 2. Synthesis of 1-chloro-3-oxabicyclo[4.1.0]heptan-2-one 3f.
With key precursors 2 in hand, we attempted the cyclization
reaction. Sulfoxide 2a was treated with three equivalents of
i-PrMgCl in THF at ꢀ78 °C for 1 h (Table 1, entry 1). Sulfoxide 2a
was completely consumed; however, the desired bicyclic com-
pound 3a was obtained in only 12% yield. Chlorocyclopropane
4a, which was formed by the protonation of the cyclopropylmag-
nesium carbenoid, was obtained in 82% yield. The reaction of sulf-
oxide 2a with i-PrMgCl at 0 °C gave a complex mixture that
cyclization was occurring in addition to 5-exo-trig cyclization
(Scheme 2). 1-Chloro-2-(hydroxyethyl)cyclopropyl p-tolyl sulfox-
ide 1f was prepared from 1-chlorocyclopropyl p-tolyl sulfoxide
with an ethoxycarbonyl group in three steps,3b and the hydroxy
group was converted to a (phenoxycarbonyl)oxy group through
reaction with phenyl chloroformate. The reaction of sulfoxide 2f
with i-PrMgCl gave cyclopropane-fused
a-chloro-d-lactone 3f in
included bicyclic
c-lactone 3a (entry 2). These results suggested
43% yield along with 1-chlorocyclopropane 4f.
that the nucleophilic reaction of the cyclopropylmagnesium carb-
enoid was sluggish at ꢀ78 °C and that the desired product 3a re-
acted with excess i-PrMgCl at 0 °C.11 Based on these results, a
solution of sulfoxide 2a in THF was added to a solution of
i-PrMgCl in THF at ꢀ78 °C, and the mixture was gradually
warmed to ꢀ20 °C (entry 3).12 Consequently, cyclopropane-fused
The cyclization reaction utilizing the nucleophilicity of cyclo-
propylmagnesium carbenoids was applied to the synthesis of bicy-
clic lactol 3g (Scheme 3). Acetylation of alcohol 1a with acetic
anhydride in the presence of pyridine and DMAP gave the cycliza-
tion precursor 2g. The reaction of precursor 2g with i-PrMgCl gave
1-chloro-3-oxabicyclo[3.1.0]hexan-2-ol 3g as a single diastereo-
mer in 68% yield.
In our previous study, we found that the sulfoxide/magnesium
exchange reaction proceeded with the retention of configuration
at the carbon atom bearing a p-tolylsulfinyl group.1 In addition,
the resulting cyclopropylmagnesium carbenoids proved to be
a-chloro-c-lactone 3a was obtained in 83% yield. Electron-donat-
ing or withdrawing groups at the p-position of the phenyl group
hardly affected the efficiency of the reaction (entries 4–6). When
sulfoxides 2b and 2c, which have an alkyl substituent on the
cyclopropane ring, were subjected to reaction with i-PrMgCl un-
der the reaction conditions described above, monoalkyl-substi-
tuted 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones 3b and 3c were
formed in 70% and 79% yield, respectively (entries 4 and 7). The
reaction of sulfoxide 2d with i-PrMgCl gave bicyclic
3d, bearing substituents at the 5- and 6-positions, in 59% yield
(entry 8). Bicyclic -lactone 3e, bearing substituents at the 4-,
c-lactone
c
5-, and 6-positions, were obtained from sulfoxide 2e with some-
what lower efficiency (entry 9). Using sulfoxides 2d and 2e with
i-PrMgCl, considerable amounts of chlorocyclopropanes 4d and 4e
were formed as byproducts (entries 8 and 9).
The cyclization of a substrate elongated by an additional
methylene tether was attempted to investigate whether 6-exo-trig
Scheme 3. Synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ol 3g.

1430
T. Kimura et al. / Tetrahedron Letters 55 (2014) 1428–1430
Organomagnesium Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley:
Chichester, UK, 2008; 717; (e) Kimura, T. In Density Functional Theory:
p
Principles, Applications and Analysis; Morin, J., Pelletier, J. M., Eds.; Nova Science
Publishers: Hauppauge, NY, 2013; p 59.
2. (a) Satoh, T.; Kurihara, T.; Fujita, K. Tetrahedron 2001, 57, 5369; (b) Satoh, T.;
Gouda, Y. Tetrahedron Lett. 2006, 47, 2835; (c) Satoh, T.; Noguchi, T.; Miyagawa,
T. Tetrahedron Lett. 2008, 49, 5689; (d) Momochi, H.; Noguchi, T.; Miyagawa, T.;
Ogawa, N.; Tadokoro, M.; Satoh, T. Tetrahedron Lett. 2011, 52, 3016.
3. (a) Satoh, T.; Ikeda, S.; Miyagawa, T.; Noguchi, T. Tetrahedron Lett. 2010, 51,
1955; (b) Satoh, T.; Tsuru, T.; Ikeda, S.; Miyagawa, T.; Momochi, H.; Kimura, T.
Tetrahedron 2012, 68, 1071.
4. (a) Satoh, T.; Saito, S. Tetrahedron Lett. 2004, 45, 347; (b) Satoh, T.; Miura, M.;
Sakai, K.; Yokoyama, Y. Tetrahedron 2006, 62, 4253; (c) Yamada, Y.; Miura, M.;
Satoh, T. Tetrahedron Lett. 2008, 49, 169; (d) Satoh, T.; Nagamoto, S.; Yajima, M.;
Yamada, Y.; Ohata, Y.; Tadokoro, M. Tetrahedron Lett. 2008, 49, 5431; (e)
Yamada, Y.; Mizuno, M.; Nagamoto, S.; Satoh, T. Tetrahedron 2009, 65, 10025;
(f) Yajima, M.; Nonaka, R.; Yamashita, H.; Satoh, T. Tetrahedron Lett. 2009, 50,
4754; (g) Satoh, T.; Kashiwamura, G.; Nagamoto, S.; Sasaki, Y.; Sugiyama, S.
Tetrahedron Lett. 2011, 52, 4468; (h) Satoh, T.; Kimura, T.; Sasaki, Y.; Nagamoto,
S. Synthesis 2012, 44, 2091; (i) Kimura, T.; Inumaru, M.; Migimatsu, T.; Ishigaki,
M.; Satoh, T. Tetrahedron 2013, 69, 3961; (j) Kimura, T.; Satoh, T. Tetrahedron
Lett. 2013, 54, 5072.
5. (a) Seyferth, D.; Lambert, R. L., Jr. J. Organomet. Chem. 1975, 88, 287; (b) Baird,
M. S.; Nizovtsev, A. V.; Bolesov, I. G. Tetrahedron 2002, 58, 1581; (c) Vu, V. A.;
Marek, I.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 351; (d) Kopp,
F.; Sklute, G.; Polborn, K.; Marek, I.; Knochel, P. Org. Lett. 2005, 7, 3789; (e)
Kimura, T.; Satoh, T. J. Organomet. Chem. 2012, 715, 1.
Scheme 4. Asymmetric synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-one
(1R,5S,6R)-3d.
6. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;
Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
7. (a) Saitoh, H.; Sampei, T.; Kimura, T.; Kato, Y.; Ishida, N.; Satoh, T. Tetrahedron
Lett. 2012, 53, 3004; (b) Kimura, T.; Hattori, Y.; Momochi, H.; Nakaya, N.; Satoh,
T. Synlett 2013, 483.
configurationally stable at low temperature.2a,13 Considering
the above aspects, the asymmetric synthesis of 1-chloro-3-
oxabicyclo[3.1.0]hexan-2-one was examined using
a chiral
8. Avolio, S.; Malan, C.; Marek, I.; Knochel, P. Synlett 1999, 1820.
cyclopropylmagnesium carbenoid (Scheme 4).14 2-Hydroxymethyl-
substituted 1-chlorocyclopropyl p-tolyl sulfoxide (1S,2R,3R,RS)-1d
was prepared from (R)-dichloromethyl p-tolyl sulfoxide [(R)-5]
and (Z)-ethyl 4-methyl-2-phenethylpent-2-enoate in a highly dia-
stereoselective manner with a high enantiomeric excess (ee).15
Then, the phenoxycarbonyl group was introduced to sulfoxide
(1S,2R,3R,RS)-1d without significant loss of the ee. The reaction of
optically active sulfoxide (1S,2R,3R,RS)-2d with i-PrMgCl afforded
9. Miyagawa, T.; Tatenuma, T.; Tadokoro, M.; Satoh, T. Tetrahedron 2008, 64, 5279.
10. Typical procedure: Phenyl chloroformate (5.48 g, 35.0 mmol) was added to a
solution of 1a (2.43 g, 6.98 mmol) and pyridine (2.77 g, 35.0 mmol) in CHCl3
(70 mL) at 0 °C, and the mixture was stirred at that temperature for 30 min.
The reaction was quenched with satd aq NH4Cl (15 mL), and the mixture was
extracted with CHCl3 (3 ꢁ 30 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel [Rf = 0.30 (hexane–EtOAc, 3:1) to give 2a (3.04 g,
6.48 mmol, 92%) as a colorless solid. Mp 94.0–94.5 °C (EtOAc/hexane); IR (KBr):
3062, 3029, 2989, 2924, 1761 (C@O), 1598, 1495, 1457, 1394, 1249, 1228,
1214, 1086, 1067, 1051, 1042, 1027, 960, 812, 765, 743, 697 cmꢀ1 1H NMR
;
bicyclic c-lactone (1R,5S,6R)-3d with 99% ee.
(500 MHz, CDCl3): d = 1.36 (d, J = 7.4 Hz, 1H), 1.97–2.04 (m, 1H), 2.15 (d,
J = 7.4 Hz, 1H), 2.17–2.23 (m, 1H), 2.44 (s, 3H), 2.75 (t, J = 8.3 Hz, 2H), 4.64 (d,
J = 11.7 Hz, 1H), 4.85 (d, J = 11.7 Hz, 1H), 7.16–7.43 (m, 8H), 7.35 (d, J = 8.2 Hz,
2H), 7.41 (br t, J = 7.7 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H); 13C NMR (126 MHz,
CDCl3): d = 21.5 (CH3), 23.5 (CH2), 32.3 (CH2), 34.2 (C), 34.8 (CH2), 66.3 (C), 68.1
(CH2), 120.9 (CH), 125.9 (CH ꢁ 2), 126.2 (CH), 128.3 (CH), 128.5 (CH), 129.5
(CH), 129.6 (CH), 138.4 (C), 140.9 (C), 142.6 (C), 151.0 (C), 153.3 (C); MS (FAB):
m/z (%) = 469 [(M+H)+, 67], 331 (32), 191 (38), 155 (29), 139 (100), 91 (64);
HRMS (FAB): m/z [(M+H)+] calcd for C26H26ClO4S: 469.1240; found: 469.1240.
11. Treatment of lactone 3a with three equivalents of i-PrMgCl in THF at 0 °C for
1 h resulted in a complex mixture, and lactone 3a was recovered in 28% yield.
12. Typical procedure: A solution of 2a (46.8 mg, 0.100 mmol) in THF (2.0 mL) was
added to a solution of i-PrMgCl (0.30 mmol) in THF (3.15 mL) at ꢀ78 °C, and
the mixture was allowed to warm to ꢀ20 °C over a period of 2 h. The reaction
was quenched with satd aq NH4Cl (2 mL), and the mixture was extracted with
CHCl3 (3 ꢁ 10 mL). The organic layer was dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by column chromatography
on silica gel [Rf = 0.35 (hexane–EtOAc, 3:1) to give 3a (19.6 mg, 0.0828 mmol,
83%) as a colorless oil. IR (neat): 3029, 2956, 2930, 1772 (C@O), 1603, 1497,
1458, 1385, 1362, 1346, 1311, 1212, 1149, 1085, 1032, 997, 965, 921, 793, 766,
In summary, we have developed a novel method for the synthe-
sis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones utilizing the
nucleophilicity of cyclopropylmagnesium carbenoids. The chemo-
selective reaction of i-PrMgCl with the p-tolylsulfinyl group al-
lowed the generation of bifunctional reactive species, that is,
cyclopropylmagnesium carbenoids featuring a phenyl carbonate
unit, and the subsequent intramolecular nucleophilic reaction of
the carbenoids with the carbonate unit gave 1-chloro-3-oxabicy-
clo[3.1.0]hexan-2-ones. Further synthetic applications utilizing
the nucleophilicity of magnesium carbenoids are currently under-
way and will be reported in due course.
Acknowledgments
This work was supported by MEXT KAKENHI Grant Number
22590021 (T.S.), JSPS KAKENHI Grant Number 25810030 (T.K.),
and a TUS Grant for Research Promotion from the Tokyo University
of Science, which are gratefully acknowledged.
749, 723, 704, 684, 650 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 1.41 (d, J = 5.9 Hz,
;
1H), 1.45 (dd, J = 1.1, 5.9 Hz, 1H), 1.96 (ddd, J = 6.5, 8.7, 15.0 Hz, 1H), 2.15–2.25
(m, 1H), 2.72–2.91 (m, 2H), 3.96 (d, J = 9.4 Hz, 1H), 4.07 (d, J = 9.4 Hz, 1H), 7.19–
7.34 (m, 5H); 13C NMR (126 MHz, CDCl3): d = 26.1 (CH2), 32.1 (CH2), 33.1 (CH2),
33.7 (C), 45.0 (C), 72.1 (CH2), 126.7 (CH), 128.2 (CH), 128.7 (CH), 140.3 (C),
172.2 (C); MS (EI): m/z (%) = 236 (M+, 10), 201 (18), 130 (45), 105 (25), 91 (100),
65 (15); HRMS (EI): m/z [M+] calcd for C13H13ClO2: 236.0604; found: 236.0606.
13. (a) Warner, P. M.; Chang, S.-C.; Koszewski, N. J. Tetrahedron Lett. 1985, 26,
5371; (b) Schmidt, A.; Köbrich, G.; Hoffmann, R. W. Chem. Ber. 1991, 124, 1253;
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01
.038.
´
(c) Topolski, M.; Duraisamy, M.; Rachon, J.; Gawronski, J.; Gawronska, K.;
Goedken, V.; Walborsky, H. M. J. Org. Chem. 1993, 58, 546.
14. Hoffmann, R. W. Chem. Soc. Rev. 2003, 32, 225.
15. (a) Noguchi, T.; Miyagawa, T.; Satoh, T. Tetrahedron: Asymmetry 2009, 20, 2073;
(b) Satoh, T.; Momochi, H.; Noguchi, T. Tetrahedron: Asymmetry 2010, 21, 382;
(c) Kimura, T.; Tsuru, T.; Momochi, H.; Satoh, T. Heteroat. Chem. 2013, 24, 131.
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