Complete stereospecific cyclopropanation of α,β-unsaturated amides promoted by Sm/CH2I2

Article abstract of DOI:10.1002/1521-3773(20020603)41:11<1917::AID-ANIE1917>3.0.CO;2-1

Samarium learns another trick: Complete stereospecific cyclopropanation of α,βunsaturated amides, in which the double bond is di-, tri-, or tetrasubstituted is promoted by Sm/CH₂I₂ [Eq. (1)]. The reaction is high yielding and unaffec

Full text of DOI:10.1002/1521-3773(20020603)41:11<1917::AID-ANIE1917>3.0.CO;2-1

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[18] D. J. Sexton, A. Muruganandam, D. J. McKenney, B. Mutus, Photo-
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other cases, synthesis of cyclopropanes from unsaturated
ˆ
compounds in which the C C bond is tri- or tetrasubstituted
cannot be carried out.[9]
In particular, and to the best of our knowledge, the
cyclopropanation of a,b-unsaturated amides in which the
À
C C double bond is tri- or tetrasubstituted has not been
published. Only the transformation of mono- or disubstituted
a,b-unsaturated amides into the corresponding cyclopropane-
carboxamides has been described.[10] Consequently new
methods for the diastereoselective construction of cyclopro-
pylamides, in which the cyclopropane ring is polysubstituted,
are of significant interest.
In their work on the synthetic applications of samarium(ii)
compounds Molander et al. reported the use of samarium
amalgam/diiodomethane to cyclopropanate allylic alcohols
with complete stereospecificity with respect to the olefin
geometry.[11] Imamoto et al. described the cyclopropanation
of lithium enolates derived from ketones by using SmI2/
CH2I2.[12] However, to the best of our knowledge, no cyclo-
propanation of a,b-unsaturated acid derivatives by using Sm/
CH2I2 has been published.[13]
Recently, we described the SmI2-promoted highly diaster-
eoselective synthesis of vinyl halides,[14] a,b-unsaturated
esters[15] and amides,[16] deuterated b,g-unsaturated esters,[17]
and vinylsilanes.[18] Here we report a new methodology for
complete stereospecific cyclopropanation of a,b-unsaturated
amides by using samarium and diiodomethane. The stereo-
specific synthesis of cyclopropylcarboxamides, in which the
cyclopropane ring is di-, tri-, or tetrasubstituted, is achieved in
high yield.
Treatment of several a,b-unsaturated amides 1 with sama-
rium metal and diiodomethane at room temperature gave,
after hydrolysis, the corresponding cyclopropylamides 2, with
complete stereospecificity and in high yield (Eq. (1), Table 1).
Complete Stereospecific Cyclopropanation of
a,b-Unsaturated Amides Promoted by
Sm/CH2I2**
¬
¬
Jose M. Concellon,* Humberto RodrÌguez-Solla, and
¬
Cecilia Gomez
The cyclopropane ring is present in a great number of
natural products.[1] In addition, the use of cyclopropanes in
mechanistic studies[2] and their utility as synthetic intermedi-
ates[3] warrants the interest in these carbocycles from various
fields in organic chemistry. The majority of the methodologies
developed for the synthesis of cyclopropanes[4] rely on
variants of the following reactions: Simmons Smith cyclo-
propanation,[5] transition-metal catalyzed cyclopropanation of
alkenes with diazomethane[6] or diazoesters,[7] and cyclopro-
panation of Michael acceptors.[8] However, these methods
leave much to be desired: total control of diastereoselectivity
in the synthesis of polysubstituted cyclopropanes is beyond
reach, some methodologies call for toxic reagents, and in
CONR24
R3
CONR24
R3
R2
R1
R2
R1
Sm / CH2I2
(1)
1
2
These results show that this cyclopropanation reaction:
a) takes place in high yield; b) is general and can be carried
out starting from aliphatic (linear, branched, or cyclic) or
aromatic a,b-unsaturated amides; c) is unaffected by the
presence of bulky groups R3 on the carbonyl amide (entries 3,
10, and 11); d) can be carried out starting from a,b-unsatu-
¬
[*] Dr. J. M. Concellon, H. RodrÌguez-Solla
¬
¬
Departamento de QuÌmica Organica e Inorganica
Facultad de QuÌmica, Universidad de Oviedo
33071 Oviedo (Spain)
Fax : (‡34)98-510-3446
E-mail: jmcg@sauron.quimica.uniovi.es
¬
Dr. C. Gomez
ˆ
rated amides 1, in which the C C bond is di-, tri-, or
¬
Departamento de QuÌmica Organica
Facultad de Ciencias, Universidad de Alicante
Apartado 99, 03080 Alicante (Spain)
tetrasubstituted; e) takes place with complete stereospecific-
ity–trans- and cis-cyclopropanamides are obtained from (E)-
and (Z)-a,b-unsaturated amides, respectively (entries 1, 2and
10, 11); f) takes place with very high chemoselectivity–
[**] We acknowledge financial support from II Plan Regional de Inves-
¬
tigacion del Principado de Asturias (PB-EXP01-11) and Ministerio de
Ciencia y TecnologÌa (BQU2001-3807). We thank Dr. Francisco J.
ˆ
selective cyclopropanation of the C C bond conjugated with
the carbonyl group is achieved in polyunsaturated amides
(entry 5).[19]
¬
Gonzalez for valuable discussions and Robin Walker for revising the
¬
¬
English manuscript. J.M.C. thanks Carmen Fernandez-Florez for her
time. H.R.S. thanks Principado de Asturias for a predoctoral fellow-
ship.
The diastereoisomeric purity of compounds 2 was deter-
mined on the crude reaction products by H NMR spectros-
copy (300 MHz) and GC-MS, which showed the presence of a
1
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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Table 1. Synthesis of cyclopropanecarboxamides by using Sm/CH2I2.
O
Entry 2[a]
R1
R2
R3
R4
Yield [%][b]
O
O
R2
R1
NR42
NR24
R2
R1
NR42
R2
R1
Sm / CH2I2
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Ph
H
Ph
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
iPr 72
Et
Et
79
71
R3
R3
R3
Me(CH)Ph
(E)-MeCH CH
Ph
C7H15
Bu
cyclohexyl
p-MeOC6H4
H
75
73
73
69
66
72
1
2
ˆ
Me Et
Me Et
Et
Me Et
Me iPr 83
Et
I
R1 R2
CH2
I
Sm
I
10
11
12
13
14
2j
2k
2l
p-MeOC6H4 Me iPr 85
Et
Me
CH2
O
Sm
I
R42N
O
Ph
Me Et
Me Et
Me Et
70
69
74
R2
R1
NR42
2m PhCH2
2n
-(CH2)5-
R3
R3
[a] All products were obtained with complete stereospecificity. Diaster-
eoisomeric purity was determined by GC-MS, and 1H and 13C NMR
(300 MHz) analysis of the crude products 2. [b] Yield after column
chromatography based on compound 1.
A
B
Scheme 1. Mechanistic proposal for the conversion of 1 into 2. A and B
depict the proposed transition state.
Experimental Section
single diastereoisomer. The relative trans or cis configuration
To a suspension of Sm (1.4 mmol) in THF (15 mL) was added the a,b-
unsaturated amide 1 (0.4 mmol) in THF (2mL) and diiodomethane
(1.4 mmol) at 08C. After stirring at room temperature for 2h the reaction
mixture was quenched by the addition of 0.1m aqueous HCl (5 mL).
Standard workup afforded the crude cyclopropanecarboxamides 2, which
were purified by flash column chromatography on silica gel (hexane/
EtOAc 5:1).
of substituents on the cyclopropane ring was established by
1
analysis of H NMR coupling constants between the cyclo-
propane protons of compounds 2a e,[20] or by NOE experi-
ments in the case of tri- and tetrasubstituted cyclopropanes
(2j, k and 2l).
Exposure of the substrate to Sm/CH2I2 for extended
periods of time appears to have no detrimental effect on
either the yield or the diastereoselectivity of the isolated
products.[21] When the same reaction conditions were used to
obtain cyclopropylesters from a,b-unsaturated esters, no
cyclopropanation was observed at room temperature or at
reflux.
The formation of products 2 may be explained by assuming
the formation of SmII carbenoids (e.g. ISmCH2I). Such species
have been proposed as intermediates in the cyclopropanation
of allylic alcohols[11] and in the generation of the SmI2 from
samarium metal and diiodomethane.[22] Our experimental
results can be explained using a model similar to the staggered
model previously proposed by Houk and co-workers for the
addition of carbenoids to olefins,[23] and which was also
utilized to explain the cyclopropanation of allylic alcohols
(Scheme 1).[11] Tentatively, we propose a transition-state
model A (similar to the Houk model), in which the
coordination of the divalent samarium atom with the oxygen
atom of the amide group provides the obtained cyclopropyl-
Received: January 21, 2002 [Z18547]
[1] a) ™Biochemistry of the Cyclopropyl Group∫: H. W. Liu, C. T. Walsh
in The Chemistry of the Cyclopropyl Group (Eds.: S. Patai, Z.
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Faust, Angew. Chem. 2001, 113, 2312 2314; Angew. Chem. Int. Ed.
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, Vol. E 1997,
p. 17a f.
[4] For some reviews, see: a) ™Preparation of Cyclopropyl Derivatives∫:
T. Tsuji, S. Nishida in The Chemistry of the Cyclopropyl Group (Eds.:
S. Patai, Z. Rappoport), Wiley, New York, 1987, pp. 308 373; b) J.
Sala¸n, Chem. Rev. 1989, 89, 1247 1270.
[5] a) T. Morikawa, H. Sasaki, R. Hanai, A. Shibuya, T. Taguchi, J. Org.
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[6] a) R. Paulissen, A. J. Hubert, P. Teyssie, Tetrahedron Lett. 1972, 13,
1465 1468; b) M. Suda, Synthesis 1981, 714 714; c) J. E. A. Luithle,
J. Pietruszka, J. Org. Chem. 1999, 64, 8287 8297.
[7] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds, Wiley, New York, 1998,
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[8] A. H. Li, L. X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97, 2341 2372.
[9] E. V. Dehmlow, K. Eulenberg, Liebigs Ann. Chem. 1978, 1112 1115.
[10] For recent reports on the cyclopropanation of a,b-unsaturated amides
see: a) S. Goumri-Magnet, T. Kato, H. Gornitzka, A. Baceiredo, G.
Bertrand, J. Am. Chem. Soc. 2000, 122, 4464 4470; b) S. Ye, L. Yuan,
Z. Z. Huang, Y. Tang, L. X. Dai, J. Org. Chem. 2000, 65, 6257 6260;
c) A. Mamai, J. S. Madalengoitia, Tetrahedron Lett. 2000, 41, 9009
9014.
ˆ
amide 2, whilst maintaining the geometry about the C C
bond. Another view of the same transition state is shown in B.
Indirect support for this mechanism is the non-cyclopropana-
tion of a,b-unsaturated esters, because of the decreased ability
of the oxygen atom of the carbonyl group in esters relative to
that in amides to coordinate with the SmII center.
In conclusion, an easy, rapid, and general cyclopropanation
of a,b-unsaturated amides with complete stereospecificity by
using samarium/diiodomethane has been developed. This
cyclopropanation reaction is achieved from a,b-unsaturated
ˆ
amides in which the C C bond is di-, tri-, or tetrasubstituted.
Studies designed to prepare enantiopure cyclopropylcarbox-
amides are currently in progress.
1918
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1433-7851/02/4111-1918 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 11

COMMUNICATIONS
solvent.[1] Recently, Balaban et al.[2] demonstrated that image
contrast can be altered by applying a frequency-selective RF
pulse at the resonance frequency of an NH or OH group of an
intrinsic amino acid, sugar, nucleotide, or other metabolite
prior to collection of the imaging data. An advantage of a
chemical exchange saturation transfer (CEST) agent over a
paramagnetic relaxation agent is that image contrast can be
switched on and off at will. A disadvantage is that the amount
of CEST agent required to produce significant water contrast
is unrealistically high,[3] although a later report demonstrated
that the CEST effect can be amplified considerably by using
polymers that contain a large number of amide NH groups.[4]
As the chemical shifts of diamagnetic NH or OH protons are
typically within 5 ppm of that of bulk water, it may ultimately
prove difficult to avoid off-resonance direct saturation of the
bulk-water signal or indirect saturation via water tightly
bound to tissue macromolecules. The latter effect provides the
basis of magnetization-transfer (MT) imaging.[5]
[11] a) G. A. Molander, J. B. Etter, J. Org. Chem. 1987, 52, 3942 3944;
b) G. A. Molander, L. S. Harring, J. Org. Chem. 1989, 54, 3525 3532.
[12] T. Imamoto, N. Takiyama, Tetrahedron Lett. 1987, 28, 1307 1308.
[13] Previously, it was indicated that the cyclopropanation promoted by
samarium carbenoids takes place exclusively with allylic alcohols, and
other functionalized olefinic substrates are inert (see ref. [11b]).
¬
¬
¬
[14] J. M. Concellon, P. L. Bernad, J. A. Perez-Andres, Angew. Chem.
1999, 111, 2528 2530; Angew. Chem. Int. Ed. 1999, 38, 2384 2386.
¬
¬
¬
[15] J. M. Concellon, J. A. Perez-Andres, H. RodrÌguez-Solla, Angew.
Chem. 2000, 112, 2866 2868; Angew. Chem. Int. Ed. 2000, 39, 2773
2775.
¬
¬
¬
[16] J. M. Concellon, J. A. Perez-Andres, H. RodrÌguez-Solla, Chem. Eur.
J. 2001, 7, 3062 3068.
¬
[17] J. M. Concellon, P. L. Bernad, H. RodrÌguez-Solla, Angew. Chem.
2001, 113, 4015 4017; Angew. Chem. Int. Ed. 2001, 40, 3897 3899.
¬
[18] J. M. Concellon, P. L. Bernad, E. Bardales, Org. Lett. 2001, 3, 937
939.
[19] The product of double cyclopropanation was obtained in 2% yield
(GC-MS).
[20] ™Nuclear Magnetic Resonance and Infrared Spectra of Cyclopropanes
and Cyclopropenes∫: D. G. Morris in The Chemistry of the Cyclo-
propyl Group (Eds.: S. Patai, Z. Rappoport), Wiley, New York, 1987,
chap. 3, pp. 101 172.
[21] When the reaction time is increased, the yield of some Simmon
Smith cyclopropanations decrease: C. D. Poulter, E. C. Fiedrich, S.
Winstein, J. Am. Chem. Soc. 1969, 91, 6892 6894.
We recently reported that the weakly paramagnetic com-
plex [Eu(2)]3‡, which has a bound-water signal near d ˆ
50 ppm with an exchange lifetime of t2M98 ꢀ 350 ms, acts as an
[22] a) J. L. Namy, P. E. Caro, P. Girard, H. B. Kagan, Nouv. J. Chim. 1981,
5, 479 484; b) T. Imamoto, H. Koto, T. Takeyama, Tetrahedron Lett.
1986, 27, 3243 3246; c) T. Tabuchi, J. Inanaga, M. Yamaguchi,
Tetrahedron Lett. 1986, 27, 3891 3894.
[23] a) M. N. Paddon-Row, N. G. Rondan, K. N. Houk, J. Am. Chem. Soc.
1982, 104, 7162 7166; b) J. Mareda, N. G. Rondan, K. N. Houk, J.
Am. Chem. Soc. 1983, 105, 6997 6999.
MT contrast agent.[6] Aime et al.[7] also demonstrated that the
MT effect can be used to measure pH by using two different
exchange sites (OH in [Eu(3)]À and NH in [Yb(3)]À) to
eliminate the concentration dependence. Although paramag-
netic systems offer the advantage over diamagnetic systems of
having exchangeable protons that are shifted well away from
the bulk-water signal,[2, 3] they suffer from a similar lack of
sensitivity. One way to increase the sensitivity of a para-
magnetic MTagent and thereby make it more practical would
be to increase the number of exchangeable protons[4] at a
hyperfine-shifted site. Here the Yb3‡ complex of 1,4,7,10-
tetraazacyclododecane-1,4,7,10-tetraacetamide (1), which has
eight exchangeable, hyperfine-shifted amide protons, is re-
ported as a prototype high-sensitivity MT agent. The eight
amide protons of this complex should in principle allow a
fourfold reduction in concentration compared to an agent
with a single exchangeable bound water molecule.[8]
The Amide Protons of an Ytterbium(iii) dota
Tetraamide Complex Act as Efficient Antennae
for Transfer of Magnetization to Bulk Water**
Shanrong Zhang, Lydie Michaudet, Shawn Burgess,
and A. Dean Sherry*
Current diagnostic contrast agents (CAs) for magnetic
resonance imaging (MRI) are largely based on paramagnetic
gadolinium complexes that shorten the relaxation time of
bulk-water protons in tissue by rapid exchange of at least one
gadolinium-bound inner sphere water molecule with bulk
[*] Prof. A. D. Sherry, Dr. S. Zhang, Dr. L. Michaudet
Department of Chemistry, University of Texas at Dallas
PO Box 830688, Richardson, TX 75083 (USA)
Fax : (‡1)972-883-2925
E-mail: sherry@utdallas.edu
À
A crystal of [Yb(1)(H2O)](CF3SO3 )3 ¥ 4H2O was grown
Prof. A. D. Sherry, Dr. S. Burgess
from water at room temperature and studied by X-ray
diffraction at 153 K (Figure 1).[9] The geometry around the
Yb3‡ ion is a typical square antiprism with average N-C-C-N
and N-C-C-O torsion angles of 58.3 and À22.58, respectively.
The Yb3‡ ion is nine-coordinate with average macrocyclic
Department of Radiology, Rogers Magnetic Resonance Center
5801 Forest Park Road, Dallas, TX 75235 (USA)
[**] This work was supported in part by grants from the Robert A. Welch
Foundation (AT-584), the National Institutes of Health (CA-84697),
and the Division of Research Resources, National Institutes of Health
(RR-02584). We thank Professor Silvio Aime for providing a copy of
his manuscript prior to publication.
À
À
Yb N and Yb O bond lengths of 2.608 and 2.301 ä,
respectively, and a Yb3‡ Owater distance of 2.335 ä. The
À
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Yb3‡ macrocyclic ligand distances are similar to those
Angew. Chem. Int. Ed. 2002, 41, No. 11
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4111-1919 $ 20.00+.50/0
1919