The first cyclopropanation reaction of unmasked α,β-unsaturated carboxylic acids: Direct and complete stereospecific synthesis of cyclopropanecarboxylic acids promoted by Sm/CHl3

Article abstract of DOI:10.1021/ol0709174

Equation Presented A samarium-promoted cyclopropanation of unmasked α,β-unsaturated acids is described. This reaction can be carried out on (E)- or (Z)α,β-unsaturated carboxylic acids. In all cases the process is completely stereospecific and stereoselective. A mechanism has been proposed to explain the cyclopropanation reaction.

Full text of DOI:10.1021/ol0709174

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2685-2688
The First Cyclopropanation Reaction of
Unmasked -Unsaturated Carboxylic
Acids: Direct and Complete
r,â
Stereospecific Synthesis of
Cyclopropanecarboxylic Acids Promoted
†
by Sm/CHI3
Jose´ M. Concello´n,* Humberto Rodr´ıguez-Solla, and Carmen Simal
Departamento de Qu´ımica Orga´nica e Inorga´nica, UniVersidad de OViedo,
Julia´n ClaVer´ıa 8, 33071 OViedo, Spain
jmcg@unioVi.es
Received April 19, 2007
ABSTRACT
A samarium-promoted cyclopropanation of unmasked
-unsaturated carboxylic acids. In all cases the process is completely stereospecific and stereoselective. A mechanism has been proposed
to explain the cyclopropanation reaction.
r,â-unsaturated acids is described. This reaction can be carried out on (E)- or (Z)-
r,â
During the course of the synthesis of complex polyfunc-
tionalized molecules, it is normally necessary to carry out a
variety of protecting processes on one or multiple organic
functional groups. An incorrect choice of protecting groups
can result in failure of the synthesis since the precursor
compounds or the target molecule can suffer undesirable side
reactions during the protection/deprotection protocols. In
addition, performance of the protection and deprotection steps
increases the number of operations in the overall synthesis
and decreases its overall yield. Among the different organic
functional groups, the carboxylic acid moiety has proven to
be unsuitable under a variety of reaction conditions (e.g.,
organometallic reagents and strong bases), thus it has to be
masked (protected) through a synthetic sequence and depro-
tected in the final step to afford the corresponding carboxylic
acid derivative.
different compounds such as pyrethrins, pyrethroids, and
other industrially valuable compounds that are abundant in
nature.1
To the best of our knowledge, no methods have been
previously reported for the direct conversion of R,â-
unsaturated carboxylic acids into cyclopropanecarboxylic
acids. In the past, the reported syntheses of cyclopropane-
carboxylic acids have been carried out in two steps: (a) the
synthesis of the corresponding cyclopropanecarboxylic acid
derivatives (generally esters or amides); and (b) the hydroly-
sis of the cyclopropyl esters or amides obtained to unmask
the carboxylic acid function1 in the second step. In some
cases, this hydrolysis takes place under undesirable harsh
reaction conditions that can produce enolization reactions.
(1) (a) Wang, M.-X.; Feng, G.-Q. J. Org. Chem. 2003, 68, 621-624.
(b) Sakaguchi, K.; Mano, H.; Ohfune, Y. Tetrahedron Lett. 1998, 39, 4311-
4312. (c) Armesto, D.; Gallego, M. G.; Horspool, W. M.; Agarrabeitia, A.
R. Tetrahedron 1995, 51, 9223-9240. (d) Benedetti, F.; Berti, F.; Risaliti,
A. Tetrahedron Lett. 1993, 34, 6443-6446. (e) Krief, A.; Trabelsi, M.
Tetrahedron Lett. 1987, 28, 4225-4228. (f) Aratani, T. Pure Appl. Chem.
1985, 57, 1839-1844. (g) Singh, R. K.; Danishefsky, S. J. J. Org. Chem.
1975, 40, 2969-2970.
Cyclopropanecarboxylic acids are important building
blocks and have been used as starting materials to obtain
† This paper is dedicated with best wishes to Professor Vincente Gotor
on the occasion of his 60th birthday.
10.1021/ol0709174 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/19/2007

Although the Simmons-Smith2 is considered one of the
most widely employed methods for cyclopropanation pro-
cesses, the two most commonly utilized methodologies to
access to cyclopropyl esters or amides with high stereo-
selectivity (such as precursors of cyclopropanecarboxylic
acids) are the metal-catalyzed decomposition of diazo
compounds,3 and the cyclopropanation of a variety of
Michael acceptors.4 However, these methods can present
some drawbacks: (a) the need to use explosive, flammable,
and harmful reagents in the case of the transition-metal-
catalyzed cyclopropanation of alkenes with diazo com-
pounds; (b) the fact that total control of the stereoselectivity
in the synthesis of cyclopropanes is not readily realized.3b,c
In general, it can be considered that methods for the efficient
synthesis of cyclopropanecarboxylic acids still remain un-
resolved. Consequently, the development of an efficient
method to carry out a direct cyclopropanation reaction of
unprotected R,â-unsaturated carboxylic acids that obviates
the protection-deprotection steps would be of great interest.
Recently, as part of our interest in the development of new
synthetic applications of samarium, we have reported the
syntheses of 3-hydroxycarboxylic acids5 and R,â-unsaturated
acids6 by the reaction of aldehydes with iodoacetic acid or
dibromoacetic acid, respectively. In both cases, C-C bond
formation took place using unmasked halogenated acetic
acids. These transformations were the first examples of C-C
bond formation reactions utilizing unprotected carboxylic
acids promoted by samarium diiodide.
the compatibility of samarium species with the carboxylic
acid function5-6 prompted us to study the cyclopropanation
process of unprotected R,â-unsaturated acids.
Our first attempts were directed toward the cyclopro-
panation reaction of R,â-unsaturated acids 1 using similar
conditions to those previously reported in the synthesis of
cyclopropanecarboxamides9 employing cinnamic acid 1a as
a model substrate. However, when we employed a mixture
of 3.5 equiv of Sm and 3.5 equiv of CH2I2 (for the generation
of samarium carbenoids) a 1/1 mixture of the desired
cyclopropanoic acid 2a and the product derived from the
reduction of 1a to 3-phenylpropionic acid (as a consequence
of the acidic medium and the SmI2 generated from the Sm/
CH2I2 mixture)11 was obtained. Similar results were obtained
when 6 equiv of samarium and CH2I2 mixture were utilized.
To avoid the 1,2-reduction of the conjugated carboxylic acid
1a we employed the sodium or lithium salts of the cinnamic
acid as starting compounds. However, we obtained a 1/1
mixture of product 2a and the unreacted starting material
1a.
Taking into account our previous results concerning the
generation of SmI2 from a mixture of Sm/CHI3 in the
presence of sonic waves,12 we decided to attempt the
cyclopropanation process using Sm, CHI3, and sonic waves.
Thus, after studying several reaction conditions, the best
results were obtained after treatment of R,â-unsaturated acids
with 6 equiv of samarium metal and 5 equiv of iodoform in
THF for 1 h and in the presence of sonic waves (Table 1).
When the process was performed on substrate 1a in the
absence of sonic waves, product 2a was obtained in lower
yield (15%) after a longer reaction time (8 h).
Previously, the employment of samarium(II) carbenoids
was reported7 in the stereospecific cyclopropanation of allylic
or allenic alcohols8 and R,â-unsaturated amides.9 In this
sense, (a) the structural analogy shown by R,â-unsaturated
acids when compared with allylic alcohols or R,â-enamides
(Figure 1), (b) the existence of the aforementioned methods
The results summarized in Table 1 show that this cyclo-
propanation reaction took place with complete stereoselec-
tivity (determined by GC-MS and 300 MHz 1H NMR
analysis of the crude products 2) and in moderate to high
yields.
The cyclopropanation only took place with C-C double
bonds which are activated by conjugation with an aryl group
(entries 1-12) or with another CdC bond (entry 13). When
Figure 1. Structural analogy of allylic alcohols, R,â-unsaturated
(4) (a) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.;
Tang, Y.; Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730-
9740. (b) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006,
71, 7494-7497. (c) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2003, 42, 828-831 and reference 3e.
(5) Concello´n, J. M.; Concello´n, C. J. Org. Chem. 2006, 71, 4428-
4432.
amides and acids.
for the cyclopropanation of unsaturated compounds using
samarium carbenoids,8-10 and (c) our own results regarding
(6) Concello´n, J. M.; Concello´n, C. J. Org. Chem. 2006, 71, 1728-
1731.
(2) (a) Katagiri, T.; Iguchi, N.; Kawate, T.; Takahashi, S.; Uneyama, K.
Tetrahedron: Asymmetry 2006, 17, 1157-1160. (b) Du, H.; Long, J.; Shi,
Y. Org. Lett. 2006, 8, 2827-2829. (c) Long, J.; Du, H.; Li, K.; Shi, Y.
Tetrahedron Lett. 2005, 46, 2737-2740. (d) Wipf, P.; Stephenson, C. R. J.
Org. Lett. 2005, 7, 1137-1140. (e) Kim, H. Y.; Lurain, A. E.; Garc´ıa-
Garc´ıa, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138-
13139. (f) Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632-
13633. (g) Aggarwal, V. K.; Fang, G. Y.; Meek, G. Org. Lett. 2003, 5,
4417-4420. (h) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc.
2003, 125, 2341-2350.
(3) (a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,
3437-3440. (b) Bayardon, J.; Holczknecht, O.; Pozzi, G.; Sinou, D.
Tetrahedron: Asymmetry 2006, 17, 1568-1572. (c) Branstetter, B.; Hossain,
M. M. Tetrahedron Lett. 2006, 47, 221-223. (d) Marko´, I. E.; Giard, T.;
Sumida, S.; Gies, A.-E. Tetrahedron Lett. 2002, 43, 2317-2320. (e) Faust,
R. Angew. Chem., Int. Ed. 2001, 40, 2251-2253.
(7) (a) Li, Z.-H.; Ke, Z.; Zhao, C.; Geng, Z.-Y.; Wang, Y.-C.; Philips,
D. L. Organometallics 2006, 25, 3735-3742. (b) Wang, D.; Zhao, C.;
Philips, D. L. J. Org. Chem. 2004, 69, 5512-5515. (c) Zhao, C.; Wang,
D.; Philips, D. L. J. Am. Chem. Soc. 2003, 125, 15200-15209.
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Molander, G. A.; Etter, J. B. J. Org. Chem. 1987, 52, 3942-3944. (c)
Molander, G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525-3532.
(9) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Go´mez, C. Angew. Chem.,
Int. Ed. 2002, 41, 1917-1919.
(10) (a) Concello´n, J. M.; Huerta, M.; Bardales, E. Tetrahedron 2004,
60, 10059-10065. (b) Concello´n, J. M.; Rodr´ıguez-Solla, H.; Llavona, R.
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Org. Lett., Vol. 9, No. 14, 2007

It is noteworthy that this process took place with complete
stereospecificity since trans- and cis-cyclopropanecarboxylic
acids were obtained from (E)- and (Z)-R,â-unsaturated
carboxylic acids, respectively (Table 1, entries 1 and 2). It
is also important to point out that this process takes place
with total chemoselectivity. Hence, when the reaction was
carried out using a dienic carboxylic acid (sorbic acid, Table
1, entry 13), only selective cyclopropanation of the 2,3-
double bond was observed.
Table 1. Synthesis of Cyclopropanecarboxylic Acids 2
In the crude reaction products both the R,â-unsaturated
carboxylic acids 1 and the cyclopropyl acids 2 were always
observed. Therefore, to simplify the chromatographic separa-
tion of the obtained mixture of 1 and 2, the addition of
bromine in CCl4 to the crude reaction mixture was performed
to transform the unsaturated acid 1 into the corresponding
2,3-dibromo derivative.14 In the case of compounds 2d the
bromination of the corresponding crude reaction mixture
afforded the product derived from the regioselective bromi-
nation of the aryl group. Hence, 2e (2d-brominated deriva-
tive) was isolated in 86% yield rather than product 2d (Table
1, entry 5).
The synthesis of products 2 could be explained by
assuming the generation of samarium(II) carbenoids,7 which
have been also proposed as intermediates in the cyclopro-
panation reaction of allylic alcohols,8b,c R,â-unsaturated
amides,9 or during the generation of SmI2 solutions from
samarium metal and a variety of iodo compounds such as
diiodomethane, 1,2-diiodomethane, or iodoform.12,15 Hence,
during the sonication of the Sm/CHI3 mixture in THF, an
iodocarbenoid 3 could be generated. The reaction of this
carbenoid 3 with the R,â-unsaturated acid could take place
through a transition state (depicted as A in Scheme 1) similar
Scheme 1. Proposed Mechanism
a Diastereoisomeric ratio (dr) was determined by GC-MS and 300 MHz
1H NMR analysis of the crude products 2. b Isolated yield after column
chromatography purification based on compound 1. c In compound 1e R1
is the same as that for compound 1d; therefore, 2e proceeds from the
bromination of 2d.
aliphatic R,â-unsaturated carboxylic acids, were utilized as
starting materials, no reaction was observed, affording the
unaltered unsaturated acids. In the case of maleic or fumaric
acids no cyclopropanation took place either, probably because
of the low solubility of the starting materials in THF.
Thus, the cyclopropanation of aromatic R,â-unsaturated
carboxylic acids seems to be general and can be carried out
using a range of cinnamic acid derivatives (with electron-
donating or -withdrawing substituents) and with a variety
of substitution patterns (Table 1, entries 3-4, 6-7, and 10-
11).
to the model proposed by Houk for the addition of carbenoids
to olefins,16 and which was also utilized to explain other
samarium promoted cyclopropanation processes.8,9 This
The relative trans- or cis- configuration of the cyclopro-
pane ring was established by analysis of 1H NMR coupling
constants between the cyclopropane protons and by com-
parison with the coupling constants shown by other related
cyclopropanecarboxamides previously reported.9,13
(13) Morris, D. G. Nuclear Magnetic Resonance and Infrared Spectra
of Cyclopropanes and Cyclopropenes. In The Chemistry of the Cyclopropyl
Group; Patai, S., Rappoport Z., Eds.; John Wiley and Sons: New York,
1987; Chapter 3, pp 101-172.
Org. Lett., Vol. 9, No. 14, 2007
2687

transition-state model shows the coordination between the
samarium and the oxygen atom from the carboxylic acid
(owing to the oxophilic nature of samarium)17 which could
explain the conservation of the geometry of the CdC bond
of the starting unsaturated acid 1 in the cyclopropanation
reaction and, consequently, the stereospecificity. Therefore,
cyclopropanation through the transition state A could provide
the iodocyclopropyl carboxylic acid 4. Indirect support for
this mechanism could be the detection of small amounts
(<5%) of the corresponding compounds 4 (determined by
1H NMR) in the crude reaction mixture of 2j and 2m.
The iodocyclopropane 4 generated could be metalated in
situ by SmI2 to afford 5, which could undergo an intra-
molecular hydrolysis to give the final cyclopropyl acid 2.
In conclusion, the first method to cyclopropanate unpro-
tected R,â-unsaturated carboxylic acids with complete stereo-
specificity has been described. Studies to fully delineate the
factors involved in this transformation are currently under
investigation within our laboratory.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2004-1191/BQU) for financial support.
J.M.C. thanks Carmen Ferna´ndez-Flo´rez for her time. H.R.S.
and C.S. thank the Ministerio de Educacio´n y Ciencia for a
Ramo´n y Cajal Contract (Fondo Social Europeo) and a
predoctoral FPI fellowship, respectively. Our thanks to Euan
C. Goddard for his revision of the English.
(14) During the isolation of cyclopropyl acids bearing activated aromatic
rings (compounds 2c, 2d, 2f, 2g, and 2l), no bromination was carried out
due to the generation of unidentified brominated materials other than those
desired, as a consequence of an indiscriminate bromination of the aromatic
ring. The only exception was product 2d which afforded regioselectively
2e.
(15) (a) Namy, J. L.; Caro, P. E.; Girard, P.; Kagan, H. B. NouV. J.
Chim. 1981, 5, 479-484. (b) Imamoto, T.; Koto, H.; Takeyama, T.
Tetrahedron Lett. 1986, 27, 3243-3246; (c) Tabuchi, T.; Inanaga, J.;
Yamaguchi, M. Tetrahedron Lett. 1986, 27, 3891-3894.
Supporting Information Available: General procedure,
1
spectroscopic data, and copies of H and 13C NMR spectra
for compounds 2. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) (a) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J. Am. Chem.
Soc. 1982, 104, 7162-7166. (b) Mareda, J.; Rondan, N. G.; Houk, K. N.
J. Am. Chem. Soc. 1983, 105, 6997-6999.
(17) (a) Molander, G. A. Org. React. 1995, 46, 211-368. (b) Keck, G.
E.; Truong, A. P. Org. Lett. 2002, 4, 3131-3134.
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