Sequential elimination-cyclopropanation reactions promoted by Samarium: Highly diastereoselective synthesis of cyclopropylamides

Article abstract of DOI:10.1021/jo0262098

trans-Cyclopropanamides were obtained, in high yield, from 2-chloro-3-hydroxyamides by a sequenced elimination-cyclopropanation process promoted by Samarium/ diiodomethane or Samarium diiodide and Samarium/ diiodomethane.

Full text of DOI:10.1021/jo0262098

SCHEME 1. Syn th esis of Sta r tin g Com p ou n d s 2
Sequ en tia l Elim in a tion -Cyclop r op a n a tion
Rea ction s P r om oted by Sa m a r iu m : High ly
Dia ster eoselective Syn th esis of
Cyclop r op yla m id es
J ose´ M. Concello´n,* Humberto Rodr´ıguez-Solla, and
Ricardo Llavona
SCHEME 2. Syn th esis of Disu bstitu ted
Cyclop r op a n eca r boxa m id es 3
Departamento de Quı´mica Orga´nica e Inorga´nica,
Universidad de Oviedo, J ulia´n Claverı´a, 8,
33071 Oviedo, Spain
jmcg@sauron.quimica.uniovi.es
Received J uly 17, 2002
TABLE 1. Syn th esis of Disu bstitu ted
Cyclop r op yla m id es 3 (R2 ) R3 ) H)
Abstr a ct: trans-Cyclopropanamides were obtained, in high
yield, from 2-chloro-3-hydroxyamides by a sequenced elimi-
nation-cyclopropanation process promoted by Samarium/
diiodomethane or Samarium diiodide and Samarium/
diiodomethane.
entry
3a
R1
R4
yield (%)b
1
2
3
4
3a
3b
3c
3d
C7H15
i-Pr
Et
Et
96
81
94
80
MeCH(Ph)
C6H11
Ph
Et
a
All products were obtained with complete stereospecificity (see
The cyclopropyl group is unique among carbocycles in
both its properties and reactions.1 This structural unit
is found in a number of significant natural products,2 as
well as in synthetic compounds of importance in biological
studies.3 In addition, cyclopropane derivatives provide
building blocks of unprecedented synthetic potential.4
Recently, we reported a new methodology for ste-
reospecific cyclopropanation of (Z)- or (E)-R,â-unsaturated
amides, in which the cyclopropane ring is di-, tri-, or
tetrasubstituted, by using samarium and diiodomethane.5
Here we describe an easy and general methodology for
obtaining trans-cyclopropanamides in high yield starting
from 2-chloro-3-hydroxyamides through a sequenced
elimination-cyclopropanation process in which the elimi-
nation is promoted by a mixture of samarium and
diiodomethane or by SmI2 and the cyclopropanation is
carried out by using Sm/CH2I2.
1
text). Diastereoisomeric purity was determined by GC-MS and H
and 13C NMR. Isolated yield after column chromatography based
b
on compound 2.
mides. Treatment of 2-chloro-3-hydroxyamides 2a -d
with Samarium metal and diiodomethane at 0 °C gave
the corresponding trans-cyclopropylamides 3a -d , after
hydrolysis, with total diastereoselectivity and in high
yield (see Scheme 2 and Table 1).
The diastereoisomeric excess of compounds 3a -d was
determined on the crude reaction products by H NMR
spectroscopy (300 MHz) and GC-MS, showing the pres-
ence of a single diastereoisomer. The relative trans
configuration in the cyclopropane ring was established
1
1
by analysis of H NMR coupling constants between the
cyclopropane protons of compounds 3a -d 7 and by com-
parison with authentic samples.5
The starting 2-chloro-3-hydroxyamides 2 were easily
prepared in high yield by reaction of the corresponding
lithium enolates of R-chloroamides6 (generated by reac-
tion of R-chloroamides 1 with LDA at -85 °C) with
aldehydes or ketones at -78 °C (Scheme 1).
Results in Table 1 show that this cyclopropanation
reaction (a) is general and can be carried out starting
from aliphatic (lineal, branched or cyclic) or aromatic
compounds and (b) is unaffected by the presence of bulky
groups R4 on the carbonyl amide (Table 1, entry 1).
To explain this transformation, a sequential process
is proposed. In the first step a â-elimination reaction
With the starting compounds 2 in hand, studies were
first performed to obtain disubstituted cyclopropana-
8
promoted by in situ-generated SmI2 takes place, afford-
(1) The Chemistry of the Cyclopropyl Group, Patai, S.; Rappoport,
Z., Eds.; Wiley and Sons: New York, 1987.
ing (E)-R,â-unsaturated amide 4 with total diastereo-
selectivity.9 In the second step of this process, a cyclo-
propanation reaction of the obtained 4 is produced by a
samarium carbenoid. This cyclopropanation reaction
takes place with complete stereospecificity5 (Scheme 3).
(2) (a) Liu, H. W.; Walsh, C. T. Biochemistry of the Cyclopropyl
Group. In The Chemistry of the Cyclopropyl Group; Patai, S., Rap-
poport, Z., Eds.; Wiley and Sons: New York, 1987; Chapter 16. (b)
Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2252-2253. (c) Donaldson,
W. A. Tetrahedron 2001, 57, 8589-8627. (d) Solau¨n, J . Top. Curr.
Chem. 2000, 207, 1-67. (e) Beumer, R.; Reiser, O. Tetrahedron 2001,
57, 6497-6503. (f) Alami, A.; Calnes, M.; Daunis, J .; J acquier, R. Bull.
Soc. Chim. Fr. 1993, 130, 5-24.
(3) (a) Breckenridge, R. J .; Suckling, C. J . Tetrahedron 1986, 42,
5665-5677. (b) Arai, Y.; Konno, M.; Shimoji, K.; Konishi, Y.; Niwa,
H.; Toda, M.; Hayashi, M. Chem. Pharm. Bull. 1982, 30, 379-382.
(4) Carbocyclic Three- and Four-Membered Ring Systems. In Houben-
Weyl Methods of Organic Chemistry; De Meijere, A., Ed.; 1997; Vol.
E17a-f.
(7) Morris, D. G. Nuclear Magnetic Resonance and Infrared Spectra
of Cyclopropanes and Cyclopropenes. In The Chemistry of the Cyclo-
propyl Group; Patai, S., Rappoport, Z., Eds.; Wiley and Sons: New
York, 1987; Chapter 3.
(8) When the metalation reaction of 2 was carried out, at room
temperature or at reflux, by using samarium metal without of
diiodomethane, no reaction was observed.
(5) Concello´n, J . M.; Rodr´ıguez-Solla, H.; Go´mez, C. Angew. Chem.
2002, 114, 1997-1999; Angew. Chem., Int. Ed. 2002, 41, 1917-1919.
(6) Chloroamides 1 were prepared by treatment of 2-chloroacid
chlorides with amines.
(9) (a) Concello´n, J . M.; Pe´rez-Andre´s, J . A.; Rodr´ıguez-Solla, H.
Angew. Chem. 2000, 112, 2866-2868; Angew. Chem., Int. Ed. 2000,
39, 2773-2775. (b) Concello´n, J . M.; Pe´rez-Andre´s, J . A.; Rodr´ıguez-
Solla, H. Chem. Eur. J . 2001, 7, 3062-3068
10.1021/jo0262098 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/10/2003
1132
J . Org. Chem. 2003, 68, 1132-1133

SCHEME 3. P r op osed Sequ en tia l Rea ction s for
th e Con ver sion of 2 in to 3
SCHEME 4. Syn th esis of Tr i- a n d
Tetr a su bstitu ted Cyclop r op a n eca r boxa m id es 3
spectroscopy (300 MHz) and GC-MS. The relative trans
configuration in the cyclopropane ring of compounds 3e-j
was established by NOE experiments (3g and 3j) and by
comparison with authentic samples.5
In conclusion, an easy, simple, and general transfor-
mation of 2-chloro-3-hydroxyamides into cyclopropyla-
mides with very high or total diastereoselectivity has
been developed. This sequenced elimination-cyclopro-
panation process was carried out by using Samarium/
diiodomethane, in the case of disubstituted cyclopropan-
amides, and by successive addition of SmI2 and a mixture
of Sm/CH2I2, in the case of tri- or tetrasubstituted
cyclopropanamides.
TABLE 2. Syn th esis of Tr i- a n d Tetr a su bstitu ted
Cyclop r op a n oca r boxa m id es 3
entry
3a
R1
R2
R3
deb
yield (%)c
1
2
3
4
5
6
7
3e
3f
Bu
C6H11
pMeO-C6H4
pMeO-C6H4
-(CH2)5-
PhCH2
H
H
H
H
Et
93
85
95
63
59
90
91
78
Me
Me
Me
Me
Me
Me
>98
76e
91
3gd
3gd
3h
3i
Exp er im en ta l Section
Gen er a l. Reactions requiring an inert atmosphere were
conducted under dry nitrogen, and the glassware was oven dried
(120 °C). THF was distilled from sodium/benzophenone ketyl
immediately prior to use. All reagents were purchased in the
higher quality available and used without further purification.
1H NMR spectra were recorded at 200, 300, or 400 MHz. 13C
NMR spectra and DEPT experiments were determined at 50,
75, or 100 MHz. GC-MS and HRMS were measured at 70 eV. A
general procedure for the synthesis of R-chloro-â-hydroxyamides
1 and spectroscopic data have previously been described.9b
Gen er a l P r oced u r e for th e Syn th esis of Disu bstitu ted
Cyclop r op a n oca r boxa m id es 3a -d a n d 3h . A solution of the
corresponding 2-chloro-3-hydroxyamide (0.4 mmol) in THF (2
mL) was added to a suspension of samarium powder (2.4 mmol)
in THF (24 mL). The mixture was cooled to 0 °C, and di-
iodomethane (2.4 mmol) was added dropwise. After the mixture
was stirred at room temperature for 4 h, the reaction was
quenched by the addition of 0.1 M aqueous HCl. Standard
workup afforded the crude cyclopropanecarboxamides 3a -d or
the tetrasubstituted cyclopropylamide 3h , which were purified
by flash column chromatography on silica gel (5/1 hexane/ethyl
acetate).
Gen er a l P r oced u r e for th e Syn th esis of Tr i- or Tetr a -
su bstitu ted Cyclop r op a n oca r boxa m id es 3e-j. A solution of
SmI2 (1.6 mmol) in THF (12 mL) was added very slowly
dropwise, under a nitrogen atmosphere, to a stirred solution of
the corresponding 2-cloro-3-hydroxyamides 2e-j (0.4 mmol) in
THF (2 mL) at -25 °C. After 12 h, the mixture was cooled to
-30 °C and metallic samarium (2.4 mmol), diiodomethane (2.4
mmol), and THF (16 mL) were added. The reaction mixture was
stirred for 10 h, and then the reaction was quenched by the
addition of 0.1 M aqueous HCl. Standard workup afforded the
crude cyclopropanecarboxamides 3e-j, which were purified by
flash column chromatography on silica gel (5/1 hexane/ethyl
acetate).
Me
Et
>98
91
3j
Ph
a
b
Unless otherwise noted, R4 ) Et. Diastereoisomeric excess
was determined by GC-MS and 1H and 13C NMR. c Isolated yield
after column chromatography based on compound 2. R4 ) i-Pr.
d
e Elimination-cyclopropanation reaction was carried out using Sm/
CH2I2 at 0 °C.
When the same reaction conditions (Sm/CH2I2, 0 °C)
were used to prepare tri- or tetrasubstituted cyclopro-
panamides, a mixture of cis- and trans-cyclopropana-
mides was obtained (Table 2, entry 3). Taking into
account that the cyclopropanation reaction is diaste-
reospecific,5 the loss of diastereoselectivity in the total
sequenced process could be due to the low diastereo-
selectivity in the generation of tri- or tetrasubstituted R,â-
unsaturated amides from 2.10 To increase the diastereo-
selectivity of the first step (â-elimination reaction), the
reaction was performed at a lower temperature (-25 °C).
However, satisfactory results were not obtained because
the â-elimination reaction was incomplete, and a mixture
of the corresponding cyclopropanamide 3 (with total or
high diastereoselectivity) and starting compound 2 was
isolated. To complete the first step, SmI2 was used to
promote the elimination instead of a mixture of metallic
Sm and CH2I2. Thus, the successive treatment of 2-chloro-
3-hydroxyamides 2e-j with Samarium diiodide at -25
°C for 12 h and then with Sm metal and diiodomethane
for 10 h gave the corresponding trans-cyclopropylamides
3d -j, after hydrolysis, with total or high diastereoselec-
tivity and in high yield (see Scheme 4 and Table 2).
Under these reaction conditions, the synthesis of tri-
or tetrasubstituted cyclopropylamides is general and no
important differences were observed upon changing R1,
R2, R3, or R.4
Ack n ow led gm en t. We thank III Plan Regional de
Investigacio´n del Principado de Asturias (PB-EXP01-
11) and Ministerio de Educacio´n y Cultura (BQU2001-
3807) for financial support. J .M.C. thanks Carmen
Ferna´ndez-Flo´rez for her time. H.R.S. thanks Princi-
pado de Asturias for a predoctoral fellowship. Robin
Walker revised the English of the manuscript.
The diastereoisomeric excess of compounds 3e-j was
1
determined on the crude reaction products by H NMR
Su p p or tin g In for m a tion Ava ila ble: Spectral data and
copies of 13C NMR spectra of 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
(10) Comparatively, the elimination reaction from compounds 2,
promoted by SmI2, afforded tri- or tetrasubstituted R,â-unsaturated
amides, with lower diastereoselectivity than that of disubstituted R,
â-unsaturated amides; see ref 9b.
J O0262098
J . Org. Chem, Vol. 68, No. 3, 2003 1133