Sml2-promoted reformatsky-type reaction and acylation of alkyl 1-chlorocyclopropanecarboxylates

Article abstract of DOI:10.1021/ol8022038

(Chemical Equation Presented) In the presence of HMPA in THF, highly stereoselective Sml₂-promoted substitutions of alkyl 1-chlorocyclopropanecarboxylates 1 using various ketones, aldehydes (Reformatsky-type reaction), and acyl chlorides (acyla

Full text of DOI:10.1021/ol8022038

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5453-5456
SmI2-Promoted Reformatsky-Type
Reaction and Acylation of Alkyl
1-Chlorocyclopropanecarboxylates
Takao Nagano, Jiro Motoyoshiya, Akikazu Kakehi, and Yoshinori Nishii*
Department of Chemistry, Faculty of Textile Science and Technology, Shinshu
UniVersity, Ueda, Nagano 386-8567, Japan
nishii@shinshu-u.ac.jp
Received September 21, 2008
ABSTRACT
In the presence of HMPA in THF, highly stereoselective SmI2-promoted substitutions of alkyl 1-chlorocyclopropanecarboxylates 1 using various
ketones, aldehydes (Reformatsky-type reaction), and acyl chlorides (acylation) proceeded to give trans-adducts (2 or 5) in good to high yield
with excellent trans-stereoselectivity (trans-add/cis-add ) > 99/1). The Reformatsky-type reaction of 1 with aldehydes and unsymmetrical
ketones proceeded with moderate diastereoselectivity (re-face-adduct/si-face-adduct ) 60/40-75/25).
The Reformatsky reaction, which involves the zinc-promoted
addition of R-halo esters to ketones or aldehydes, has been
recognized as a fundamental and useful C-C bond-forming
reaction in organic synthesis.1 Recently, various efficient
Reformatsky-type reactions have been reported.2,3 Among
them, most of the SmI2-promoted Reformatsky-type reactions
of R-halo esters have been applied to intramolecular
cyclizations.3c-j SmI2 has found little use in intermolecular
Reformatsky-type reactions due to numerous side reactions,
such as self-coupling of aldehyde or ketone,4 self-Claisen
condensation,5a,b and self-coupling of R-halo esters.5c
On the other hand, stepwise or sequential double trans-
formation of the two carbon-halogen bonds of gem-
dihalocyclopropanes into carbon-carbon bonds is useful for
(3) SmI2-promoted Reformatsky-type reaction of Evans amide: (a)
Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J. Org. Chem. 2000, 65, 1702.
(b) Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10,
1291. For recent reviews of SmI2-promoted reactions, see: (c) Molander,
G. A.; Harris, C. H. Chem. ReV. 1996, 96, 307–338. (d) Kagan, H. B.;
Namy, J. L. Top. Organomet. Chem. 1999, 2, 155. (e) Krief, A.; Laval,
A.-M. Chem. ReV. 1999, 99, 745. (f) Kagan, H. B.; Namy, J. L. Tetrahedron
1986, 42, 6573. (g) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727–
2751. (h) Berndt, M.; Gross, S.; Hemann, A.; Reissig, H.-U. Synlett 2004,
422. (i) Concell, J. M.; Rodriguez-Solla, H. Chem. Soc. ReV. 2004, 33,
599. (j) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004,
104, 3371.
(1) (a) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210. For a
recent review of Reformatsky reactions, see: (b) Fu¨rstner, A. Synthesis 1989,
571. (c) Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325. (d)
Orsini, F.; Sello, G. Curr. Org. Synth. 2004, 1, 111. (e) Cozzi, P. G. Angew.
Chem., Int. Ed. 2007, 46, 2568.
(2) (a) Wessjohann, L.; Gabriel, T. J. Org. Chem. 1997, 62, 3772. (b)
Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549. (c) Kakiya,
H.; Nishimae, S.; Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 8807.
(d) Durandetti, M.; Meignein, C.; Pe´richon, J. Org. Lett. 2003, 5, 317. (e)
Yanagisawa, A.; Takahashi, H.; Arai, T. J. Chem. Soc., Chem. Commun.
2004, 580–581. (f) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org.
Chem. 2005, 70, 10408. (g) Durandetti, M.; Gosmini, C.; Perichon, J.
Tetrahedron 2007, 63, 1146. (h) Lombardo, M.; Gualandi, A.; Pasi, F.;
Trombini, C. AdV. Synth. Catal. 2007, 349, 465. (i) Cozzzi, P. G. Angew.
(4) SmI2-promoted self-coupling of R-bromo ester in THF-HMPA: (a)
Balaux, E.; Ruel, R. Tetrahedron Lett. 1996, 37, 801. SmI2-promoted self-
Claisen condensation of R-bromo ester: (b) Park, H. S.; Lee, I. S.; Kim,
Y. H. Tetrahedron Lett. 1995, 36, 1673. (c) Utimoto, K.; Matsui, T.; Takai,
T.; Matsubara, S. Chem. Lett. 1995, 197.
(5) For a discussion of SmI2-promoted self-coupling of ketones and
aldehydes, see: (a) Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett.
1983, 24, 765. (b) Fu¨rstner, A.; Csuk, R.; Rohrer, C.; Weidmann, H.
J. Chem. Soc., Perkin Trans. 1 1988, 1729. (c) Akane, N.; Kanagawa, Y.;
Nishiyama, Y.; Ishii, Y. Chem. Lett. 1992, 2431. (d) Shiue, J.-S.; Lin, C.-
C.; Fang, J.-M. Tetrahedron Lett. 1993, 34, 335. (e) Aspinall, H. C.; Greeves,
N.; Valla, C. Org. Lett. 2005, 7, 1919.
´
Chem., Int. Ed. 2006, 45, 2951. (j) Ferna´ndez-Iba´n˜ez, M. A.; Macia´, B.;
Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2008, 47, 1317,
and references cited therein
.
10.1021/ol8022038 CCC: $40.75
Published on Web 11/07/2008
2008 American Chemical Society

the synthesis of functionalized cyclopropanes because of the
preparative accessibility of gem-dihalocyclopropanes (Scheme
1).6,7 However, most of the efficient methods have been
The initial investigation was guided by the reaction of
methyl 1-chlorocyclopropanecarboxylate 1a with diethyl
ketone (Scheme 3, eq 4). The SmI2-promoted Reformatsky-
Scheme 1. Double Carbon Elongation of
Scheme 3. Initial Investigation of the SmI2-Promoted
Reformatsky-Type Reaction of Ester 1a and Contrast Reactions
gem-Dihalocyclopropanes
applied to gem-dibromo derivatives, which have a higher
reactivity than gem-dichloro derivatives during such reac-
tions.
As part of our ongoing synthetic studies on the transfor-
mation of gem-dihalocyclopropanes,8 we have recently
reported highly stereoselective radical-type carbonylations
of gem-dichlorocyclopropane derivatives with CO using
Bu3SnH or Bu3Sn(CH2CHdCH2).8c To complete the second
carbon elongation from gem-dichlorocyclopropane, we dis-
close herein a highly stereoselective SmI2-promoted Refor-
matsky-type intermolecular reaction of 1 with aldehydes,
ketones, and acyl chlorides.
Alkyl 1-chlorocyclopropanecarboxylates 1 were derived
from gem-dichlorocyclopropanes in three steps: (i) radical-
type carbonylation8c (formylation), (ii) Jones oxidation, and
(iii) alkylation (Scheme 2, eq 1). Ester 1 can be prepared by
Scheme 2. Preparative Methods of Alkyl
1-Chlorocyclopropanecarboxylates 1
type reaction of 1a with diethyl ketone at rt gave ꢀ-hydroxy
ester 2a (14% yield) along with a pinacol (75% yield), which
is afforded due to self-coupling of the ketone. The reaction
in the presence of HMPA (4.0 equiv) proceeded to give 2a
in high yield (77%). Self-coupling of the ester did not occur
under the reaction conditions. In the case of methyl R-chloro
isobutyrate, the presence of HMPA adversely affected the
Reformatsky-type reaction, causing the competitive self-
coupling of ketones and hydrodechlorination of R-chloro
esters to occur (Scheme 3, eq 5). The cyclopropyl case was
successful unlike the acyclic case, which would have been
caused by the difference between the reaction on the highly
strained sp3 carbon of cyclopropane ring and that on normal
sp3 carbon.10 Hydroxyalkylation of methyl cyclopropanecar-
(7) (a) Vu, V. A.; Marek, I.; Polborn, K.; Knochel, P. Angew. Chem.,
Int. Ed. 2002, 41, 351. (b) Inoue, R.; Shinokubo, H.; Oshima, K. Tetrahedron
Lett. 1996, 37, 5377. (c) Harada, T.; Kastuhira, T.; Hattori, K.; Oku, A. J.
Org. Chem. 1993, 58, 2958. (d) Danheiser, R. L.; Savoca, A. C. J. Org.
Chem. 1985, 50, 2401. (e) Kitatani, K.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1975, 97, 949; Bull. Chem. Soc. Jpn. 1977, 50, 1600. (f) Scott,
F.; Mafunda, B. G.; Normant, J. F.; Alexakis, A. Tetrahedron Lett. 1983,
24, 5767. (g) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911;
1968, 90, 5615.
using other methods. trans-1 (in this case, trans means trans-
Cl) can be prepared via anionic carboxylation of bromo-
chlorocyclopropanes (eq 2).8c On the other hand, cis-1 can
be prepared via rearrangement of 2,2-dichlorocyclobutanols
which are generated by reducing 2,2-dichlorocyclobutanones
with NaBH4 (eq 3).9
(8) (a) Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem.
Soc. 2004, 126, 5358. (b) Nishii, Y.; Yoshida, T.; Asano, H.; Wakasugi,
K.; Morita, J.; Aso, Y.; Yoshida, E.; Motoyoshiya, J.; Aoyama, H.; Tanabe,
Y. J. Org. Chem. 2005, 70, 2667. (c) Nishii, Y.; Nagano, T.; Gotoh, H.;
Nagase, R.; Motoyoshiya, J.; Aoyama, H.; Tanabe, Y. Org. Lett. 2007, 9,
563, and references cited therein.
(6) For a recent review, see: Fedorynski, M. Chem. ReV. 2003, 103,
(9) Verniest, G.; Bombeke, F.; Kulinkovich, O. G.; Kimpe, N. D.
Tetrahedron Lett. 2002, 43, 599.
1099, and references cited therein
.
5454
Org. Lett., Vol. 10, No. 23, 2008

boxylate using LDA gave ꢀ-hydroxy ester 2a in low yield
X-ray crystallographic analysis. The structures (trans-adduct)
of ꢀ-hydroxy esters 2a and 2c-x were determined by analogy
with 2b on the basis of their spectral data. (ii) Similar reactions
of 2,3-cis-disubstituted cyclic substrates 1c, d,h-j also gave
the corresponding trans-adducts (trans-add/cis-add ) >99/1)
(entries 8-15 and 19-21). In these cases, cis-1 was used for
the reactions because the preparative method (radical formy-
lation) afforded only the cis-isomer. Thus, trans-addition
occurred with almost complete inversion. (iii) In the case of
2,2-disubstituted substrate 1k and 2,2,3-trisubstituted substrate
1l, both reactions proceeded with excellent trans-selectivity,
avoiding the stereocongestion between the larger substituent R1
(and/or R2) on the cyclopropane ring and ketone or aldehyde
(entries 22-24). (iv) Reactions with aldehydes or unsymmetri-
cally substituted ketones also proceeded in high yield with
excellent trans-selectivity (trans-add/cis-add ) >99/1) at the
R-position and moderate to good diastereoselectvity13 [2 (re-
face-adduct)/3 (si-face-adduct) ) 60/40-75/25] at the ꢀ-position
(entries 4-6, 23, and 24). (v) The main side reaction was a
competitive self-coupling of aldehydes or ketones, which caused
a decrease in the yields. (vi) The reaction with ketone was
carried out at rt, whereas the reaction with aldehyde at -78
°C. In the case of aldehydes, at rt, a competitive self-coupling
reaction of the aldehydes mainly occurred.
(20%) because retro-aldol reaction, self-Claisen condensation,
and further side reaction occurred (Scheme 3, eq 6).11
A
similar reaction of phenyl cyclopropanecarboxylate using
TiCl4-Et3N did not proceed to give a ꢀ-hydroxy ester, but
instead, the self-aldol reaction of ketone mainly occurred
(Scheme 3, eq 7).12 This result means that the Ti-enolate is
not generated under the reaction conditions. Thus, the SmI2-
promoted Reformatsky-type reaction of 1a in the presence
of HMPA was found to be the most efficient method for the
synthesis of 2a. Next, we investigated the generality of the
reaction.
Table 1 lists the results of the Reformatsky-type reaction
of 1 with various ketones and aldehydes. The salient features
Table 1. Stereoselective SmI2-Promoted Reformatsky-Type
Reaction of Alkyl 1-Chlorocyclopropanecarboxylates 1a
An increase in the stereocongestion around the newly
formed C-C bond caused lactonization to give ꢀ-lactones
4, instead of the retro-aldol reaction14 (Table 2). The reaction
ratioe
yieldd of
entry substratec R1 R2 R3 R4 R5 R6 product (%) 2/3
1
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
1d
1d
1e
1f
Ph
H
H
Me Et Et
2a
77
95
82
2
i-Pr i-Pr 2b
-(CH2)4- 2c
Me Ph
Me t-Bu 2e, 3e 93 75/25
H t-Bu 2f, 3f 82 75/25
3
Table 2. Stereoselective SmI2-Promoted Reformatsky-Type
Reaction of Methyl 1-Chlorocyclopropanecarboxylates 1 To
Afford ꢀ-Lactones 4a
4
2d, 3d 82 67/34
5
6
7
Hex H
-(CH2)4- H Me Et Et
H
Me Et Et
2g
2h
90
83
68
71
78
81
82
86
87
91
83
80
86
77
79
79
8
9
i-Pr i-Pr 2i
-(CH2)4- 2j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
H
H
Hept 2k
Ph 2l
t-Bu 2m
2n
-(CH2)4- 2o
yieldb (%)
-(CH2)6- H Me Et Et
entry substrate R1 R2
R3 T (°C) product
2
4
Ph
H
H
Et Et Et
i-Pr
Bn
2p
2q
2r
2s
2t
2u
2v
1g
1h
1i
1
2
3
4
1c
1l
1l
1l
H
Me t-Bu rt
4y
2z,4z
4z
0
25
0
80
63
84
73
-(CH2)4- H Et
Me Et Et
rt
i-Pr
Bn
-78
-78
1j
iPr iPr
4r
0
1k
1k
1l
Ph
H
Me Me Et Et
a Reactions were carried out under an Ar atmosphere. b Isolated.
H
Hept 2w,3w 88 75/25
-(CH2)4- Me Me H Hept 2x, 3x 72 60/40
a Reactions were carried out under an Ar atmosphere at rt (using ketones:
entries 1-5, 7-10, and 14-22) or -78 °C (using aldehydes: entries 6,
11-13, 23, and 24). b Determined by using 1H NMR spectroscopy. In this
case, trans-add means trans-adduct. c A 3/1 mixture of cis-1 and trans-1
(in this case, cis means cis-Cl) was used for the reaction of 1a, 1b, whereas
cis-1 was used for the reaction of 1c, 1d, and 1e-l. d Isolated. e Determined
of R-chloro ester 1c with diisopropyl ketone and pivalalde-
hyde occurred to give ꢀ-hydroxy esters 2i and 2m in good
to high yield, respectively (Table 1, entry 9, and 13). Notably,
1
by using H NMR spectroscopy.
(10) The reactivity of C-Cl on the cyclopropane ring is higher than
that on the normal sp3-carbon of methyl R-chloro isobutyrate. The
stereocongestion around the newly formed C-C bond of 2 is less than that
of acyclic R,R-dimethyl ꢀ-hydroxy ester because of the strained angle of
the cyclopropane ring.
(11) For discussion of side reactions, see: (a) Pinnick, H. W.; Chang,
Y.-H.; Foster, S. C.; Govindan, M. J. Org. Chem. 1980, 45, 4505. (b) Kai,
Y.; Knochel, P.; Kwiatkowski, S.; Dunitz, J. D.; Oth, J. F. M.; Seebach,
D.; Kalinowski, H. O. HelV. Chim. Acta 1982, 65, 137. For a similar reaction
of siloxy-substituted derivatives, see: (f) Bru¨ckner, C.; Reissig, H.-U. J.
Org. Chem. 1988, 53, 2440.
were as follows: (i) R1-monosubstituted-1-chlorocyclopropan-
ecarboxylates 1a,b,e-g underwent the desired Reformatsky-
type addition with ketones and aldehydes to give trans-adducts
2a,b,e-g, respectively, with excellent stereoselectivity (trans-
add/cis-add ) >99/1) (entries 1-7 and 16-18). The relative
configuration of 2b was unambiguously determined by using
Org. Lett., Vol. 10, No. 23, 2008
5455

a similar reaction of 1c with t-butyl methyl ketone gave only
ꢀ-lactone 4y (Table 2, entry 1). The reaction of 1l with
diethylketone at rt proceeded to give a mixture of ꢀ-hydroxy
ester 2z and ꢀ-lactone 4z (Table 2, entry 2). Treatment of
2z with NaH gave 3z in quantitative yield.15 The yield of
4z increased at -78 °C (Table 2, entry 3). A similar reaction
of 1l with diisopropyl ketone also proceeded smoothly to
give ꢀ-lactone 4r (Table 2, entry 4).
These successful results led us to investigate the SmI2-
promoted acylation of methyl 1-chlorocyclopropanecarboxy-
lates with acyl chlorides. As expected, acylation of 1a and
1c proceeded smoothly (Table 3). It should be noted that
intermediate,11a,16 which reacts with carbonyl compounds
on only the trans-face because of the stereocongestion
between R1 (and/or R2) and the carbonyl compounds
(ketones, aldehydes, or acyl chlorides) (Scheme 4). Detailed
studies on the reaction mechanism are now being performed.
Scheme 4
.
Proposed Mechanism of the SmI2-Promoted
Reformatsky-Type Reaction
Table 3. Stereoselective SmI2-Promoted Acylation of Methyl
1-Chlorocyclopropanecarboxylates 1a b
,
entry substrated
R1
R2
H
R3
product yielde (%)
In conclusion, we developed a stereoselective synthesis
of cyclopropane derivatives utilizing a highly stereoselective
SmI2-promoted Reformatsky-type reaction and acylation of
1-chlorocyclopropanecarboxylic esters. The present method
is a new avenue for the stereoselective synthesis of highly
substituted cyclopropylcarbonyl compounds. Utilizing radical
formylation and the present protocols, we achieved a highly
stereoselective double-carbon elongation on the dichloro-
carbon of gem-dichlorocyclopropanes.
1
2
3
5
6
7
1a
1a
1a
1c
1c
1c
Ph
Hept
t-Bu
Ph
Hept
t-Bu
Ph
5a
5b
5c
5d
5e
5f
88
89
92
89
78
82
-(CH2)4-
a Reactions were carried out at -78 °C under an Ar atmosphere.
b Acylchloride was added after generation of Sm-enolate. c In this case,
1
trans means trans-adduct. Ratios were determined from H NMR spectra.
d A mixture of cis-1a and trans-1a (cis/trans ) 3/1) was used for the reaction
of 1a, whereas cis-1c was used for the reaction of 1c. e Isolated.
Acknowledgment. We thank Dr. M. Shiro (Rigaku
Corporation) for X-ray crystallographic analysis. We also
thank Dr. T. Tsuchida (Shinshu University) and Dr. M.
Hirota (Shinshu University) for the HRMS. This research
was partially supported by Grants-in-Aid for Scientific
Research on Basic Areas (B) “18350056” and Basic Areas
(C) “20550036” and by the Global COE Program of MEXT.
the reactions proceeded with nearly complete trans-selectivity
(trans-add/cis-add ) >99/1) for every case examined. Under
the reaction conditions, self-coupling or self-Claisen con-
densation of esters 1 did not occur.4
Due to the high trans-selectivity of the present reactions,
we believe that the reaction proceeds via a samarium enolate
Note Added after ASAP Publication. The version
published ASAP on November 7, 2008 contained errors in
Table 1; the corrected version was published ASAP on
November 11, 2008.
(12) The use of phenyl esters has an advantage over that of methyl esters
under the reaction condition, see: Nagase, R.; Matsumoto, N.; Hosomi, K.;
Higashi, T.; Funakoshi, S.; Misaki, T.; Tanabe, Y. Org. Biomol. Chem.
2007, 5, 151.
(13) The relative structure of 2/3 (re-face-add/si-face-add) was assigned
on the basis of the typical selectivity of SmI2-promoted Reformatsky reaction
(see ref 3) and Shuto’s report of highly stereoselective reduction of trans-
substituted cyclopropanes; see: Kazuta, Y.; Abe, H.; Yamamoto, T.;
Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 3511.
Supporting Information Available: Experimental details,
analytical and crystallographic data, and characterization for
reactions in Tables 1-3. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) For discussion of the retro-aldol reaction, see: (a) March’s AdVanced
Organic Chemistry, 5th ed.; Smith, M. B., March, J., Eds.; Wiley-
Interscience: New York, 2001; p 1220. (b) Murakami, K.; Ohmiya, H.;
Yorimitsu, H.; Oshima, K. Tetrahedron Lett. 2000, 49, 2388. (c) Houminer,
Y.; Kao, J.; Seeman, J. I. J. Chem. Soc., Chem. Commun. 1984, 1608. (d)
Hatano, M.; Takagi, E.; Ishihara, K. Org. Lett. 2007, 9, 4527.
(15) In contrast, in the similar treatment of 2h with NaH, a retro-aldol
reaction occurred to give methyl bicyclo[4.1.0]heptane-7-carboxylate in 87%
yield.
OL8022038
(16) (a) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am.
Chem. Soc. 1991, 113, 8036. (b) Utimoto, K.; Matsui, T.; Takai, T.;
Matsubara, S. Chem. Lett. 1995, 197. For a discussion of the pyramidal
enolate of cyclopropanecarboxylate, see: (c) Reissig, H.-U.; Bo¨hm, I. J. Am.
Chem. Soc. 1982, 104, 1735
.
5456
Org. Lett., Vol. 10, No. 23, 2008