Highly stereoselective halocyclopropanation of α,β-unsaturated amides

Article abstract of DOI:10.1002/adsc.200900331

A convenient highly stereoselective synthesis of chloro- and bromocyclopropanamides from di- tri- or tetrasubstituted (E)- or (Z)-α,β-unsaturated amides with total or high stereoselectivity promoted by chromium dichloride or dibromide is described. The tr

Full text of DOI:10.1002/adsc.200900331

FULL PAPERS
DOI: 10.1002/adsc.200900331
Highly Stereoselective Halocyclopropanation of a,b-Unsaturated
Amides
Josꢀ M. Concellꢁn,a,* Humberto Rodrꢂguez-Solla,a Elena G. Blanco,a
Marꢂa A. Villa-Garcꢂa,a Noemꢂ Alvaredo,a Santiago Garcꢂa-Granda,a
and M. Rosario Dꢂaza
a
Departamento de Quꢂmica Orgꢃnica e Inorgꢃnica and Quꢂmica Fꢂsica y Analꢂtica, Facultad de Quꢂmica, Universidad de
Oviedo, Juliꢃn Claverꢂa 8, 33071 Oviedo, Spain
Fax : (+34)-98-510-3446; e-mail: jmcg@uniovi.es
Received: May 12, 2009; Revised: July 10, 2009; Published online: September 10, 2009
This paper is dedicated with best wishes to Professor Josꢀ Font on the occasion of his 70th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900331.
Abstract: A convenient highly stereoselective syn-
ACHTUNGTRENaNUNG mides into the corresponding ketones or amines is
thesis of chloro- and bromocyclopropanamides from also reported. A mechanism to explain these trans-
di- tri- or tetrasubstituted (E)- or (Z)-a,b-unsaturat- formations is proposed.
ed amides with total or high stereoselectivity pro-
moted by chromium dichloride or dibromide is de- Keywords: amides; chromium; cyclopropanation;
scribed. The transformation of chlorocyclopropan- stereoselectivity; synthetic methods
Introduction
The chlorocyclopropane motif can be mainly ac-
cessed through the addition of carbenoids (Simmons–
The properties and reactivity of cyclopropanes are Smith-like process)[11] or carbene[12] species to double
significantly different to those of other carbocycles.[1] bonds; from a,a-dichloroalkyl anions (conjugated nu-
The smallest cycloalkane is present in an important cleophilic addition followed by a ring closing reac-
number of naturally occurring compounds[2] and com- tion),[13] from gem-dichlorocyclopropanes,[14] and by
pounds bearing this moiety are widely used to eluci- utilizing other starting materials such as 2,2-dichloro-
date biological mechanisms.[3] In addition, an impor- butanols (Favorskii rearrangement),[15] carboalkoxy-
tant number of applications of unnatural cyclopro- chlorodiazirines,[16] or pyrazolines.[17] However, the
pane-containing compounds has been reported. Thus, majority of these methods present some drawbacks
many of these compounds have been prepared to such as: a) the use of explosive, flammable or harmful
verify theoretical calculations of the bonding features reagents[12b–c,16] or those which are not readily availa-
of these strained cycloalkanes[4] and to study enzyme ble;[13b,16,17] b) some methods proceed with low stereo-
mechanisms or inhibition.[5] From a synthetic view- selectivity,[11c–d,12c,13d,14b–c,16] or in poor yields;[11b–d,13a–b,d]
point, cyclopropanes have been used as starting mate- and finally d) other methods have shown poor gener-
rials to obtain other cycloalkanes[6] and acyclic com- ality.[11c,d,12c–d,13,14b–d,15,16,17] In the case of bromocyclo-
pounds.[7] Functionalized cyclopropanes are most in- propanation, to the best of our knowledge only one
teresting, especially when the functionality can be stereoselective synthesis of bromocyclopropanes has
readily modified with total or high selectivity such as, been reported via the bromination of cyclopropylindi-
for example, in halocyclopropanes. Thus, 1-chlorocy- um reagents prepared from the allylindation of cyclo-
clopropanecarboxylic acids are precursors to a variety propenes which are not readily available.[18] The most
of aminocyclopropanecarboxylic acids known for employed method for the synthesis of bromocyclopro-
their biological activity,[8] whereas 2-chlorocyclopro- panes is based on the debromination of dibromocyclo-
ACHTUNGTRENNUNG
panecarboxylic acids are used to obtain agrochemical propanes by using several reagents.[14a,d,19] In general
compounds,[9] and novel antitumour agents.[10]
terms, these methodologies took place with poor se-
lectivity affording a mixture of both monobrominated
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Josꢀ M. Concellꢁn et al.
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diastereoisomers and the corresponding fully debro- 2/1 mixture of the chlorocyclopropanamide I and cy-
ꢀ
minated cyclopropanes. Other methods are based on clopropanamide II (Scheme 1). To avoid this C Cl
bromocyclopropanation through the addition of car- bond reduction, we tested the reaction conditions
benoids to olefins, however these bromocyclopropane shown in Scheme 1 without improving the initial re-
derivatives are generally obtained in low yields, low sults.
stereoselectivity and poor generality.[11b,d,12a,17,20]
Therefore, we changed the chlorocyclopropanating
The development of the synthetic applications of agent, employing CCl4 instead of CHCl3. Hence treat-
these compounds has been limited by the absence of ment of cinnamamide 1 with 4 equivalents of CrCl2
a general method to obtain bromocyclopropanes in a and 2 equivalents of CCl4 in THF, at reflux afforded
selective manner. In spite of this important limitation, the corresponding chlorocyclopropanamide I in high
some synthetic applications such as the photochemical yields, with an absence of the cyclopropanamide II.
debromination,[21] dehydrobromination,[22] alkyla-
After testing several conditions (varying equiva-
tion,[23] thermolysis[24] and the stereoselective radical lents of CrCl2 or CCl4, and reaction times), we found
addition of to electron-deficient olefins[25] have been that the best reaction conditions utilized 1 equivalent
described.
of CCl4, 3 equivalent of CrCl2 in THF at reflux for
Taking into account these precedents a general, 16 h. Thus, we performed the chlorocyclopropanation
highly stereoselective chloro- and bromocyclopropa- reaction with a range of a,b-unsaturated amides as is
nation of a,b-unsaturated acid derivatives with total shown in Table 1.
stereoselectivity would be desirable.
Next efforts were directed towards the synthesis of
Related to the CrCl2-mediated cyclopropanation re- bromocyclopropanecarboxamides by using a mixture
action, Takai has reported the iodo-[26,27] and the silyl- of CrCl2/CBr4.
cyclopropanation[28] of terminal alkenes with high ste-
After trying different temperatures and conditions,
reoselectivities in the iodocyclopropanation reaction using N,N-diethylcinnamamide 1 as the model sub-
or poor selectivity for the synthesis of silylcyclopro- strate, we always observed the presence of both
panes. Both methods were carried out in the presence chloroACTHNUTRGNEcNUG yclopropane and bromocyclopropane as a con-
of N,N,N’,N’-tetraethylethylenediamine (TEEDA). sequence of a halogen cross-over in the reaction
We have also reported the use of CrCl2 to promote medium. To overcome this problem, we performed
the highly stereoselective cyclopropanation,[29] or the bromocyclopropanation reaction using CrBr2 in-
alkyl- and silylcyclopropanation[30] of a,b-unsaturated stead of CrCl2. Since CrBr2 was not commercially
amides with total or high stereoselectivity. Herein we available, our next efforts were directed towards the
report the valuable, highly stereoselective chloro- and synthesis of this salt. Several methods have previously
bromocyclopropanations of a,b-unsaturated amides been described to synthesise CrBr2. Most of them
mediated by CrCl2,or CrBr2 which take place in high employ the reaction of chromium metal. In those re-
yields and with total or high stereoselectivity.
ports, chromium metal is treated with: (a) HBr-Br2
mixture at 8558C;[31] (b) bromine vapour at 7008C;[32]
and (c) HBr at high temperatures.[33] In another
method CrBr2 was obtained by the reduction of
Results and Discussion
chromiumACTHNUGRTNEUNG(III) bromide with hydrogen at high tem-
Our first attempts to chlorocyclopropanate unsaturat- peratures (500–6008C).[34]
ed amides were performed on (E)-N,N-diethylcinna-
We initially performed the in situ synthesis of chro-
mamide as a model substrate and chloroform as cy- mium dibromide by treatment of CrBr3 with LiAlH4.
clopropanating reagent under similar conditions to Previously CrBr3 was obtained by heating
those previously reported in the cyclopropanation of CrBr3·6H2O under vacuum.[35] Thus, we attempted the
a,b-unsaturated amides.[29] Thus, treatment of (E)- synthesis of bromocyclopropanes by using this CrBr2,
N,N-diethylcinnamamide with 4 equivalents of CrCl2 again employing (E)-N,N-diethylcinnamamide as a
and 2 equivalents of CHCl3 for 6 h at reflux, gave a model substrate and CrBr2/CHBr3.
Scheme 1. Initial studies.
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Highly Stereoselective Halocyclopropanation of a,b-Unsaturated Amides
Table 1. Synthesis of chlorocyclopropanecarboxamides 2.
FULL PAPERS
Entry
2[a]
R1
R3
R4
dr[b]
dr[c]
Yield [%][d]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o[f]
Me
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
n-Bu
H
Et
Me
>98/2
78/22
95/5
95/5
93/7
>98/2
90/10
>98/2
95/5
>98/2
76/24
95/5
95/5
92/8
77
78
83
80
79
56
75
87
66
87
73
74
81
66
62
n-C5H11
n-C5H11
n-C5H11
i-Bu
Et
[e]
Et
Et
Et
Et
Et
Et
Et
i-Pr
Et
Et
Et
Cy
96/4
(E)-CH3CH=CH
n-C7H15
i-Bu
(E)-CH3CH=CH
Ph
p-ClC6H4
pMeOC6H4
p-MeOC6H4
Ph
88/18
>98/2
94/6
9
10
11
12
13
14
15
95/5
95/5
>98/2
80/20
95/5
97/3
>98/2
>98/2
80/20
95/5
96/4
>98/2
[a]
Unless otherwise noted R2 =H.
Diastereoisomeric ratio of starting materials 1.
Diastereoisomeric ratio of compounds 2, determined by GC-MS and/or H NMR (300 MHz) analysis of the crude reac-
[b]
[c]
1
tion products.
[d]
Yields of the isolated major diastereoisomer (as depicted in table heading) after column chromatography based on com-
pounds 1.
[e]
[f]
From morpholine.
R2 =Et.
When we performed this reaction, we obtained the
The white solid was thoroughly washed with dis-
corresponding bromocyclopropane in 91% yield al- tilled and deoxygenated ether, dried under vacuum
though in an almost exactly 1/1 ratio of stereoisomers. and finally kept under nitrogen.
From this result we inferred that this loss of stereose-
With the chromium(II) bromide in hand, we tested
lectivity might be a consequence of the salts present different conditions for the bromocyclopropanation
of in the reaction after the in situ generation of CrBr2. process. The best results were obtained after treat-
Next attempts were directed toward the synthesis of ment of cinnamamide 1 with 6 equivalents of CrBr2
chromium dibromide in the absence of other salts. and 2 equivalents of CBr4 in THF, at reflux. Thus,
Masaguer and Bustelo[36] reported the halogenation of bromocyclopropanamide was obtained in high yield
a number of elements in the presence of different (76%), as a single stereoisomer, and in the absence of
electron-donating solvents. However these authors chlorocyclopropanamide (see Table 4).
were not able to synthesise CrBr2 under these condi-
The reaction of a range of (E)-a,b-unsaturated
tions. We approached the synthesis of CrBr2 by under- amides 1 with CrBr2/CBr4 at reflux for 16 h afforded
taking the reaction of chromium with bromine in the the corresponding bromocyclopropanecarboxamides 3
presence of ether as electron-donor solvent. After vig- in moderate to high yields (Table 2).
orous stirring of an equimolecular mixture of chromi-
It is important to note that the relative configura-
um and deoxygenated bromine at 338C for 3 days in tion of the double bond of the starting amides was
deoxygenated and dry ether, CrBr2 was formed as a conserved in the cyclopropanation, as it was estab-
white solid (Scheme 2).[37]
lished by performing the reaction on the correspond-
ing (Z)-unsaturated amides with CrCl2/CCl4 and
CrBr2/CBr4 to afford compounds 4 and 5, respectively
(Table 3). In these cases the geometry of the alkene
was also conserved and no differences were observed
during the halocyclopropanation process of (E)- or
(Z)-a,b-unsaturated amides, except for the different
Scheme 2. Synthesis of chromium dibromide.
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Table 2. Synthesis of bromocyclopropanecarboxamides 3.
Entry
3
R1
R2
R3
R4
dr[a]
dr[b]
Yield [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
Me
n-C5H11
i-Bu
Cy
(E)-CH3CH=CH
n-C7H15
i-Bu
Cy
Ph
p-ClC6H4
p-MeOC6H4
Et
n-Pr
Ph
H
H
H
H
H
H
H
H
H
H
H
Et
Me
Et
H
H
H
H
Et
Et
Et
Et
Et
Et
i-Pr
Et
Et
i-Pr
Et
Et
Et
Et
>98/2
95/5
93/7
>98/2
95/5
92/8
61
66
69
66
67
62
60
73
63
65
61
59
56
63
96/4
96/4
H
90/10
>98/2
90/10
>98/2
>98/2
>98/2
>98/2
75/25
70/30
95/5
84/16
>98/2
91/9
>98/2
>98/2
97/3
>98/2
75/25
70/30
95/5
Me
Me
Me
Me
Me
n-Bu
Me
Me
Me
9
10
11
12
13
14
[a]
dr of starting materials 1.
[b]
[c]
1
dr of compounds 3 determined by GC-MS and/or H NMR (300 MHz) analysis of the crude reaction products.
Yields of the isolated products (major diastereoisomer as depicted in table heading) after column chromatography based
on compounds 1.
Table 3. Halocylopropanation
amides.
of
(Z)-a,b-unsaturated
branched and unsaturated), and aromatic (with elec-
tron-donating or electron-withdrawing substituents)
a,b-unsaturated amides 1. (2) The cyclopropanation
took place with total chemoselectivity since the poly-
unsaturated amides (Table 1, entries 7 and 10/Table 2,
entry 5) were monocyclopropanated on the a,b-
double bond. (3) The stereoselectivity or yield of the
halocyclopropanation process was not affected by the
groups attached to the amide nitrogen in the starting
compounds (R4 =Me, Et, i-Pr and morpholine[39]). (4)
This halocyclopropanation process took place with
a,b-unsaturated amides 1 in which C=C bond is di-,
tri-, or tetrasubstituted.
Entry 4 or 5 R2
R3 R4
X
dr[a]
Yield [%][b]
1
2
3
4
5
4a
4b
4c
5a
5b
n-C5H11
Ph
H
H
Me Cl 76/24[c] 81
Et Cl >98/2 72
p-ClC6H4 Me i-Pr Cl >98/2 61
n-C5H11
p-ClC6H4 Me i-Pr Br >98/2 59
H
Me Br 78/22[c] 82
According to the silylcyclopropanation model,[30]
the relative position of the halogen atom in the cyclo-
propanes obtained from disubstituted (E)-cinnam-
[a]
1
Determined by GC-MS and/or H NMR (300 MHz) anal-
ysis of the crude reaction products.
Yields of the isolated major stereoisomer (as depicted in
table heading) after column chromatography based on
compounds (Z)-1.
AHCTUNGTREGUNaNN mides was opposite with respect to that obtained
[b]
from the other unsaturated amides, (trans with respect
to the carboxamide group). As can be observed in
Table 4, the reaction from disubstituted cinnamamides
also took place with total stereoselectivity and in high
yields. Substituents on the aromatic ring and the
[c]
dr of the starting amide 78/22.
relative position of the halogen atom in compounds 2 amine on cinnamamides (R4 =Me, Et, i-Pr or mor-
or 3 (cis), and 4 or 5 (trans) with respect to the amide pholine) did not affect the yield and the stereoselec-
group.[38] This fact will be explained in the mechanistic tivity, except for p-nitrocinnamamide (Table 4,
proposal.
entry 6), with which no reaction took place.
Several points relating to chloro- and bromocyclo-
The different relative positions of substituents on
propanation processes are worth noting: (1) this halo- halocyclopropanes 2–7 were established by analysis of
1
cyclopropanation reaction seems to be general and the H NMR coupling constants of the cyclopropane
can be carried out on aliphatic (linear, cyclic, protons and from the NOESY experiments of cyclo-
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Highly Stereoselective Halocyclopropanation of a,b-Unsaturated Amides
Table 4. Halocyclopropanation of disubstituted cinnam-
FULL PAPERS
ACHTUNGTRENNUNGamides.
Entry 6 or 7 R1
R4
X
dr[a]
Yield [%][b]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
Ph
Ph
Ph
p-FC6H4
Et Cl >98/2 91
i-Pr Cl >98/2 92
[c]
Scheme 3. Transformations of chlorocyclopropanamides 6a
and 6c.
Cl >98/2 78
Et Cl 91/9[d] 74
p-MeOC6H4 Et Cl >98/2 85
p-NO2C6H4 Et Cl No reaction
Ph
Ph
Ph
–
Et Br >98/2 76
i-Pr Br >98/2 76
In most of the reactions reported in Table 1,
Table 2, Table 3, and Table 4, only one diastereoiso-
mer of compounds 2–7 was obtained. When a mixture
of diastereoisomers was observed in the crude materi-
als, the diastereoisomeric ratio was the same as that
shown by the starting unsaturated amides. Thus, the
new stereogenic centre was generated with total or
very high stereoselectivity.
[c]
9
10
11
Br 90/10 69
p-FC6H4
p-MeOC6H4 Et Br 96/4
Et Br 92/8
70
69
[a]
1
Determined by GC-MS and/or H NMR (300 MHz) anal-
ysis of the crude reaction products.
Yields of the isolated major diastereoisomer (as depicted
in table heading) after column chromatography based on
compounds 1.
[b]
[c]
[d]
From morpholine.
dr of the starting amide 93/7.
Mechanism
This halocyclopropanation process could be explained
propylamides 2b, 2f, 2i, 2k, 2o, 3e, 4a–c, 5b, 6a, and by assuming the initial formation of a chromiumACHTUNGTRENNUNG(III)
7e. The relative configurations of 4c, 5b, 7e, and 6c carbenoid intermediate 10, after the reaction of
were unambiguously assigned based on the studies of 2 equivalents of CrX2 with 1 equivalent of CX4 (X=
single-crystal X-ray diffraction of 4c, 5b, 7e and Cl, or Br). This carbenoid could undergo a single
ketone 8a derived from 6c (see below) since in our electron transfer from another equivalent of CrX2 to
hands, no recrystallization of compounds 6 has been afford a radical intermediate 11, which subsequently
possible. The X-ray determinations confirmed the could abstract a hydrogen atom from the THF to
structural NOESY assignments of products 4c, 5b, 7e afford the cyclopropanating carbenoid 12.[42] After
and 8a and the assignments of the other compounds generating the carbenoid 12, this intermediate could
were made by analogy.[40]
react with a,b-unsaturated amides 1 to give the corre-
We also attempted the synthesis of iodocyclopro- sponding halocyclopropanes, through a similar mecha-
panes employing CrCl2/CHI3, CrBr2/CHI3, and CrCl2/ nism to that proposed by Houk for the addition of
CI4 under several conditions but no iodocyclopro- carbenoids to olefins.[43] Tentatively, we propose tran-
panes were obtained except when a CrCl2/CHI3 mix- sition state model A depicted in Scheme 4, in which
ture was used. In this latter case, a mixture of iodocy- the coordination of the Cr
ACHTUNGTNER(NUNG III) centre with the oxygen
clopropane/cyclopropane in a 1/3 ratio was obtained. atom of the amide group provides the obtained cyclo-
To illustrate some synthetic possibilities of this propylamides 2–7, while maintaining the C=C bond
method, the amide derived from morpholine[41] 6c was geometry, explaining the different relative configura-
transformed into the corresponding phenyl 8a or tions of the products obtained from Z- or E-unsatu-
butyl ketone 8b, by reaction with phenyllithium and rated amides.[44] The generation of the new stereogen-
n-butyllithium, respectively at ꢀ788C for one hour. ic centre with total or high stereoselectivity could be
As was previously indicated, the X-ray analysis of explained based on the steric hindrance between the
compound 8a was utilized to confirm the structure for halogen atom and R1 and/or R2. Thus, to minimise
6. In addition, cyclopropylamine 9 was also accessed the steric hindrances, the halogen atom could occupy
by treatment of 6a with LiAlH4 at reflux (Scheme 3). a cis relative position with respect to the H (R2 =H,
Chlorocyclopropyl ketones 8a and 8b, and chlorocy- E-amides) or (R1 =H, Z-amides). Similarly, this steric
clopropylamine 9 were isolated without any loss of hindrance could explain the absence of halocyclopro-
diastereoisomeric purity and in high yields panation in the tetrasubstituted amides due to R1 and
(Scheme 3).
R2 ¼H.
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Josꢀ M. Concellꢁn et al.
FULL PAPERS
Scheme 4. Proposed mechanism.
A variety of experimental results indirectly support rated amides, which takes place with total or high ste-
this mechanism. Thus, an alternative synthesis of com- reoselectivity and in high yields. A simple and new
pounds 2 and 4 from the corresponding gem-dichloro- synthesis of chromium(II) bromide, to promote the
cyclopropane (through a metallation process) should bromocyclopropanation reaction, is also described.
be discarded since the treatment of 2,2-dichloro-N,N- Cyclopropanamides could be transformed into other
diethyl-1-methylcyclopropanecarboxamide
with synthetically valuable compounds such as chlorocyclo-
2 equivalents of CrCl2 afforded the unchanged start- propyl ketones or amines, without any loss of diaste-
ing dichlorocyclopropane. In addition, when the reoisomeric purity. To explain the halocyclopropana-
chloro
G
reaction
of
N,N- tion reaction, a mechanism is proposed. Studies
diethylcinnamACHTUNGTRENNUNG
tion in D2O, no deuterated chlorocyclopropane was in this transformation, including explanation of the
obtained. The stoichiometry of this reaction (CCl4/ relative configuration of halocyclopropanamides from
CrCl2 1/3) is also in accordance with the proposed cinnamamides, and the synthesis of enantiopure halo-
ꢀ
CrCl2-metallation of two C Cl bonds, which would cyclopropylamides are currently under investigation
give an anionic and a radical intermediate. For this in our laboratory.
reason, generation of gem-dichromium species from
CCl4 should be also discarded.[45] In addition, when
lower amounts of CrCl2 were used the cyclopropana-
tion was incomplete. The generation of a radical inter-
Experimental Section
mediate could be also supported by the presence of
40% of the starting cinnamamide when the cyclopro-
General
All reactions involving organometallic or other moisture-
sensitive reagents were carried out under a nitrogen or
argon atmosphere using standard vacuum-line techniques
and glassware that was flame-dried and cooled under nitro-
gen before use. THF was distilled from sodium/benzophe-
none ketyl immediately prior to use. All other solvents were
used as supplied (analytical or HPLC grade) without prior
purification. All reagents were purchased in the highest
quality available and were used without further purification.
Organic layers were dried over Na2SO4. Thin layer chroma-
panation was carried out in the presence of AIBN.
The essential coordination between the Cr(III)
AHCTUNGTRENNUNG
centre and the oxygen atom of the a,b-unsaturated
amides would be consistent with the absence of cyclo-
propanation of a,b-unsaturated esters (weaker elec-
tron-donating character of the oxygen of esters than
nitrogen of amides). All experimental results were in
accordance with this proposed mechanism except the
ꢀ
relative configuration of the CH X (X=Cl, or Br)
bond obtained from E-cinnamamides. In this case, ste- tography was performed on aluminium plates coated with
60 F254 silica. Plates were visualised using UV light
(254 nm), iodine, 1% aqueous KMnO4, or 10% ethanolic
phosphomolybdic acid. Flash column chromatography was
performed on Kieselgel 60 silica. NMR spectra were record-
ed in the deuterated solvent stated and the field was locked
by external referencing to the relevant deuteron resonance.
1H NMR spectra were recorded on spectrometers at 300 or
400 MHz. 13C NMR spectra and DEPT experiments were
determined at 75 or 100 MHz. Unless otherwise stated
NMR spectra were recorded at room temperature. Chemical
reoelectronic effects could control the cyclopropana-
tion, since the presence of an electron-withdrawing
group in the phenyl ring returned the starting materi-
al unaltered (Table 4, entry 6).
Conclusions
In conclusion, we have described a general chromi-
um(II)-promoted halocyclopropanation of a,b-unsatu- shifts are given in ppm relative to tetramethylsilane (TMS),
2190
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Adv. Synth. Catal. 2009, 351, 2185 – 2198

Highly Stereoselective Halocyclopropanation of a,b-Unsaturated Amides
FULL PAPERS
which is used as an internal standard. GC-MS and HR-MS
were measured at 70 eV. Only the most important IR ab-
sorptions (in cmꢀ1) and the molecular ions and/or base
peaks in MS are given.
[m, 10H, CHAHCTUNGTRENNNUG
Synthesis of Chlorocyclopropanes 2, 4, and 6
To a suspension of anhydrous CrCl2 (1.5 mmol, 3.0 equiv.) in
THF (5 mL) was added the corresponding a,b-unsaturated
amide 1 (0.5 mmol, 1.0 equiv.) in THF (2 mL) and CCl4
(0.5 mmol, 1 equiv.) at room temperature and under an inert
atmosphere. After stirring for 16 h at reflux the reaction
mixture was quenched by the addition of 1.0M aqueous
HCl (5 mL) and extracted with diethyl ether (3ꢅ10 mL).
The combined extracts were washed with saturated NH4Cl
solution and water, dried over Na2SO4, concentrated under
vacuum and filtered through a pad of Celiteꢆ. Purification
by column chromatography on silica gel (hexane/EtOAc,
10:1) afforded pure compounds 2, 4, and 6.
(m, 4H, NACHTUNGTRENGN(U CH2CH3)2), 1.84–1.64 (m, 2H, CHCO, CHCH2),
1.63–1.42 [m, 3H, (CH3)2CHCH2], 1.25 (t, J=7.0 Hz, 3H,
NCH2CH3), 1.21 (t, J=7.0 Hz, 3H, NCH2CH3), 0.97 [d, J=
7.6 Hz, 6H, CHACTHNUTRGNEUNG
(CH3)2]; 13C NMR (75 MHz, CDCl3): d=
169.2 (C), 42.0 (CH2), 40.7 (CH2), 40.0 (CH), 36.3 (CH2),
28.5 (CH), 27.8 (CH), 25.4 (CH), 22.3 (CH3), 22.1 (CH3),
14.8 (CH3), 13.0 (CH3); MS (70 eV, EI): m/z (%)=196
[M+ꢀCl] (100), 188 (21), 174 (20), 119 (56), 72 (53); IR
(neat): n=3055, 2985, 1628, 1265 cmꢀ1; HR-MS (70 eV):
m/z=196.1732, calcd. for [C12H22ClNOꢀCl]: 196.1701; Rf =
0.73 (hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-3-cyclohexyl-N,N-diethylcyclopro-
panecarboxamide (2f): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.57 (dd, J=7.5, 3.2 Hz, 1H, CHCl), 3.52–3.28
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-3-methylcyclopro-
panecarboxamide (2a): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.52 (dd, J=7.6, 3.2 Hz, 1H, CHCl), 3.47–3.32
(m, 4H, NACHTUNGTRENNUNG(CH2CH3)2), 1.77–1.65 (m, 1H, CHCO), 1.60 (dd,
J=5.7, 3.2 Hz, 1H, CHCH3), 1.28 (d, J=6.3 Hz, 3H,
CHCH3), 1.23 (t, J=7.0 Hz, 3H, NCH2CH3), 1.10 (t, J=
7.0 Hz, 3H, NCH2CH3); 13C NMR (75 MHz, CDCl3): d=
169.3 (C), 42.2 (CH2), 40.9 (CH2), 40.3 (CH), 29.6 (CH),
21.4 (CH), 14.9 (CH3), 13.1 (CH3), 12.3 (CH3); MS (70 eV,
EI): m/z (%)=189 [M+] (16), 154 (97), 119 (68), 72 (97), 58
(100); IR (neat): n=2976, 1632, 1485, 1150 cmꢀ1; HR-MS
(70 eV): m/z=189.0882, calcd. for C9H16ClNO: 189.0920;
Rf =0.63 (hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-N,N-dimethyl-3-pentylcyclopro-
panecarboxamide (2b): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.56 (dd, J=6.9, 3.2 Hz, 1H, CHCl), 3.16 (s,
3H, NCH3), 2.97 (s, 3H, NCH3), 1.78–1.71 (m, 1H, CHCO),
[m, 4H, N
J=6.3, 3.2 Hz, 1H, CHCy), 1.56–1.47 [m, 1H, CH
1.35–1.17 [m, 10H, CH(CH2)5], 1.27 (t, J=7.1 Hz, 3H,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
NCH2CH3), 1.12 (t, J=7.1 Hz, 3H, NCH2CH3);13C NMR
(100 MHz, CDCl3): d=169.5 (C), 42.1 (CH2), 40.8 (CH2),
39.9 (CH), 37.1 (CH), 33.2 (CH), 32.6 (CH2), 32.3 (CH2),
27.5 (CH), 26.2 (CH2), 26.1 (CH2), 25.7 (CH2), 15.0 (CH3),
13.1 (CH3); MS (70 eV, EI): m/z (%)=257 [M+] (2), 222
(100), 174 (19), 100 (41), 72 (53); IR (neat): 2926, 2851,
1633, 1483 cmꢀ1; HR-MS (70 eV): m/z=257.1560, calcd. for
C14H24ClNO: 257.1546; Rf =0.73 (hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-3-(propen-1-yl)cyclo-
propanecarboxamide (2g): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=5.75–5.61 (m, 1H, CH3CH=CH), 5.25 (dd, J=
15.2, 8.8 Hz, 1H, CH3CH=CH), 3.54 (dd, J=7.6, 3.8 Hz, 1H,
1.68–1.56 [m, 4H, CHACHTNUGTRNEGNU(CH2)2], 1.53–1.43 [m, 1H, CH-
ACHTUNGTRENNUNG(CH2)4], 1.40–1.26 [m, 4H, (CH2)2CH3], 0.91 [t, J=7.0 Hz,
3H, (CH2)4CH3]; 13C NMR (75 MHz, CDCl3): d=170.3 (C),
40.0 (CH), 37.2 (CH3), 35.7 (CH3), 31.4 (CH2), 28.5 (CH2),
28.4 (CH), 27.6 (CH2), 27.3 (CH), 22.4 (CH2), 13.9 (CH3);
MS (70 eV, EI): m/z (%)=217 [M+] (11), 182 (100), 146
(11), 102 (10), 68 (47); IR (neat): n=3054, 2987, 1634,
CHCl), 3.40–3.23 [m, 4H, NACTHNUTGRNE(UNG CH2CH3)2], 2.20 (dd, J=13.9,
7.6 Hz, 1H, CHCO), 1.83 (apparent t, J=3.8 Hz, 1H,
CH3CH=CHCH), 1.62 (dd, J=6.9, 1.3 Hz, 3H, CH3CH=
CH), 1.14 (t, J=6.9 Hz, 3H, NCH2CH3), 1.01 (t, J=6.9 Hz,
3H, NCH2CH3); 13C NMR (75 MHz, CDCl3): d=168.6 (C),
129.7 (CH), 125.4 (CH), 42.2 (CH2), 40.9 (CH2), 39.3 (CH),
29.8 (CH), 29.6 (CH), 18.1 (CH3), 14.9 (CH3), 13.1 (CH3);
MS (70 eV, EI) m/z (%)=215 [M+] (2), 180 (100), 100 (37),
1265 cmꢀ1
; HR-MS (70 eV); m/z=217.1185, calcd. for
C11H20ClNO: 217.1233; Rf =0.55 (hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-3-pentylcyclopro-
panecarboxamide (2c): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.54 (dd, J=6.4, 3.8 Hz, 1H, CHCl), 3.48–3.31
79 (22), 72 (38); IR (neat): n=3054, 2985, 1629, 1265 cmꢀ1
;
[m, 4H, N
ACHTUNGTRENNUNG
HR-MS (70 eV): m/z=215.1087, calcd. for C11H18ClNO:
215.1077; Rf =0.78 (hexane/EtOAc, 1:1).
A
ACHTUNGTRENNUNG
(CH2)2CH3], 1.24 (t, J=7.0 Hz, 3H, NCH2CH3), 1.10 (t, J=
7.0 Hz, 3H, NCH2CH3), 0.88 [t, J=7.0 Hz, 3H, (CH2)4CH3];
13C NMR (75 MHz, CDCl3): d=169.4 (C), 42.1 (CH2), 40.8
(CH2), 40.1 (CH), 31.4 (CH2), 28.6 (CH), 28.4 (CH2), 27.6
(CH2), 27.0 (CH), 22.4 (CH2), 15.0 (CH3), 13.9 (CH3), 13.1
(CH3); MS (70 eV, EI): m/z (%)=210 [M+ꢀCl] (100), 169
(8), 152 (5), 137 (6), 68 (10); IR (neat): 3054, 2934, 1627,
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-3-heptyl-1-methyl-
cyclopropanecarboxamide (2h): Orange oil. 1H NMR
(300 MHz, CDCl3): d=3.48–3.21 [m, 4H, N
ACHTNUGRTNE(NUGN CH2CH3)2],
3.36 (d, J=7.0 Hz, 1H, CHCl), 1.52–1.04 [m, 19H, CH-
ACHUTNGRENUN(G CH2)6CH3, NHCATUGNTREN(NUGN CH2CH3)2], 1.23 (s, 3H, CCH3), 0.87 [appar-
ent t, J=6.6 Hz, 3H, (CH2)6CH3]; 13C NMR (75 MHz,
CDCl3): d=172.5 (C), 41.7 (CH), 40.9 (CH2), 38.8 (CH2),
31.7 (CH2), 29.3 (CH2), 29.1 (CH2), 28.5 (CH2), 28.0 (C),
25.3 (CH), 23.2 (CH2), 22.5 (CH2), 13.9 (CH3), 13.6 (CH3),
12.3 (CH3), 11.5 (CH3); MS (70 eV, EI): m/z (%)=287 [M+]
(1), 252 (100), 188 (45), 100 (37), 72 (39); IR (neat): n=
1265 cmꢀ1
; HR-MS (70 eV): m/z=210.1860, calcd. for
[C13H24ClNOꢀCl]: 210.1857; Rf =0.50 (hexane/EtOAc, 1:1).
4-[(1S*,2S*,3R*)-2-Chloro-3-pentylcyclopropylcarbon-1-
1
yl]morpholine (2d): Yellow oil. H NMR (300 MHz, CDCl3):
d=3.74–3.56 (m, 9H, CHCl,H from morpholine), 1.71–1.26
Adv. Synth. Catal. 2009, 351, 2185 – 2198
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Josꢀ M. Concellꢁn et al.
FULL PAPERS
3054, 2929, 1630, 1265 cmꢀ1
;
HR-MS (70 eV): m/z=
3H, OCH3), 3.66 (d, J=8.2 Hz, 1H, CHCl), 3.60–3.27 [m,
287.2045, calcd. for C16H30ClNO: 287.2016; Rf =0.40
(hexane/EtOAc, 3:1).
4H, N
[m, 9H, NAHCUTNGTRENNUNG
ACHTUNGTRENNUNG
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-3-isobutyl-1-methyl-
d=172.0 (C), 158.4 (C), 131.6 (2ꢅCH), 125.3 (C), 113.6 (2ꢅ
CH), 55.1 (CH3), 41.9 (CH), 41.2 (CH2), 39.1 (CH2), 30.7
(C), 28.5 (CH), 13.6 (CH3), 13.5 (CH3), 12.5 (CH3); MS
(70 eV, EI): m/z (%)=260 [M+ꢀCl] (18), 259 (100), 230
(83), 202 (26), 131 (50); IR (neat): n=3055, 2984, 1630,
cyclopropanecarboxamide (2i): Orange oil. 1H NMR
(300 MHz, CDCl3): d=3.53–3.22 [m, 4H, N
3.38 (d, J=8.2 Hz, 1H, CHCl), 1.81–1.68 (m, 1H, CHCH2),
1.46–1.04 [m, 9H, N(CH2CH3)2, CH2CH(CH3)2], 1.23 (s, 3H,
CCH3), 0.98 [d, J=7.0 Hz, 6H, CH
(CH3)2]; 13C NMR
ACHTNUGRTNE(NUGN CH2CH3)2],
A
ACHTUNGTRENNUNG
A
1266 cmꢀ1
; HR-MS (70 eV): m/z=260.1623, calcd. for
(75 MHz, CDCl3): d=172.6 (C), 41.9 (CH), 41.0 (CH2), 38.8
(CH2), 31.8 (CH2), 27.9 (C), 27.8 (CH), 23.8 (CH), 22.4
(CH3), 22.3 (CH3), 13.6 (CH3), 12.4 (CH3), 11.7 (CH3); MS
(70 eV, EI): m/z (%)=245 [M+] (2), 210 (100), 154 (18), 100
[C16H22ClNO2ꢀCl]: 260.1650; Rf =0.60 (hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-1-Butyl-2-chloro-N,N-diethyl-3-(4-meth-
oxyphenyl)cyclopropanecarboxamide (2n): Yellow oil.
1H NMR (300 MHz, CDCl3): d=7.35 (d, J=8.5 Hz, 2H, p-
MeOC6H4), 6.88 (d, J=8.5 Hz, 2H, p-MeOC6H4), 3.81 (s,
3H, OCH3), 3.77 (d, J=7.9 Hz, 1H, CHCl), 3.66–3.32 [m,
(23), 72 (24); IR (neat): n=2960, 1636, 1458, 1266 cmꢀ1
;
HR-MS (70 eV): m/z=245.1567, calcd. for C13H24ClNO:
245.1546; Rf =0.30 (hexane/EtOAc, 5:1).
4H, N
[m, 4H, C
(CH2)2CH2], 0.83 [t, J=7.3 Hz, 3H, CACTHUNGTRENNNUG
ACHTUNGTRENNUNG
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-1-methyl-3-(propen-
N
ACHTUNGTRENNUNG
1-yl)cyclopropanecarboxamide (2j): White solid. 1H NMR
C
(300 MHz, CDCl3): d=5.84 (dq, J=6.4 Hz, 1H, CH3CH= (75 MHz, CDCl3): d=170.6 (C), 158.5 (C), 131.3 (2ꢅCH),
CH), 5.31–5.19 (m, 1H, CH3CH=CH), 3.55 (d, J=8.3 Hz,
1H, CHCl), 3.48–3.29 [m, 4H, N(CH2CH3)2], 2.03 (apparent
125.5 (C), 113.6 (2ꢅCH), 55.0 (CH3), 41.9 (CH), 41.1 (CH2),
39.2 (CH2), 34.8 (C), 29.3 (CH), 28.1 (CH2), 27.4 (CH2), 22.7
(CH2), 13.8 (CH3) 13.7 (CH3), 12.4 (CH3); MS (70 eV, EI):
m/z (%)=302 [M+ꢀCl] (20), 301 (100), 230 (61), 199 (24),
187 (23); IR (neat): n=3054, 2961, 1634, 1266 cmꢀ1; HR-MS
(70 eV): m/z=302.2120, calcd. for [C19H28ClNO2ꢀCl]:
302.212; Rf =0.68 (hexane/EtOAc, 1:1).
(1S*,2S*,3S*)-2-Chloro-N,N-diethyl-3-ethyl-3-phenylcyclo-
propanecarboxamide (2o): Colourless oil. 1H NMR
(300 MHz, CDCl3): d=7.35–7.09 (m, 5H, Ph), 4.28 (d, J=
3.8 Hz, 1H, CHCl), 3.81–3.27 (m, 3H, NCH2CH3,
NCHHCH3), 3.01–2.85 (m, 1H, NCHHCH3), 2.24–2.13 (m,
1H, CHHCH3), 2.12 (d, J=3.8 Hz, 1H, CHCO), 1.95–1.81
(m, 1H, CHHCH3), 1.32 (t, J=7.3 Hz, 3H, CH2CH3), 0.91
[t, J=7.3 Hz, 3H, NCH2CH3], 0.90 (t, J=7.3 Hz, 3H,
NCH2CH3); 13C NMR (100 MHz, CDCl3): d=166.0 (C),
137.8 (C), 128.8 (2ꢅCH), 127.9 (2ꢅCH), 126.8 (CH), 42.7
(CH), 41.7 (C), 41.6 (CH2), 40.0 (CH2), 35.9 (CH), 30.0
(CH2), 14.5 (CH3), 12.4 (CH3), 10.7 (CH3); MS (70 eV, EI):
m/z (%)=244 [M+ꢀCl] (40), 171 (60), 143 (45), 128 (57), 68
(100); IR (neat): n=3055, 2986, 1636, 1265 cmꢀ1; HR-MS
(70 eV): m/z=244.1668, calcd. for [C16H22ClNOꢀCl]:
244.1701; Rf =0.67 (hexane/EtOAc, 1:1).
AHCTUNGTRENNUNG
t, J=8.3 Hz, 1H, CH3CH=CHCH), 1.77 (d, J=6.4 Hz, 3H,
CH3CH=CH), 1.30 (s, 3H, CCH3), 1.27–1.06 [m, 6H, N-
ACHTUNGTRENNUNG
(CH2CH3)2]; 13C NMR (75 MHz, CDCl3): d=171.9 (C),
130.9 (CH), 122.4 (CH), 42.2 (CH), 40.9 (CH2), 38.8 (CH2),
30.2 (C), 28.6 (CH), 18.4 (CH3), 13.7 (CH3), 12.4 (CH3), 12.1
(CH3); MS (70 eV, EI): m/z (%)=229 [M+] (12), 228 (100),
181 (9), 100 (10), 72 (11); IR (neat): n=3055, 2987, 1634,
1266 cmꢀ1
; HR-MS (70 eV): m/z=229.1197, calcd. for
C12H20ClNO: 229.1233; Rf =0.65 (hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-1-methyl-3-phenyl-
cyclopropanecarboxamide (2k): Yellow oil. 1H NMR
(300 MHz, CDCl3): d=7.43–7.21 (m, 5H, Ph), 3.69 (d, J=
8.2 Hz, 1H, CHCl), 3.60–3.32 [m, 4H, N
(d, J=8.2 Hz, 1H, CHPh), 1.25 (s, 3H, CCH3), 1.31–1.10 [m,
6H, N
(CH2CH3)2]; 13C NMR (100 MHz, CDCl3): d=171.7
ACHTNUGTNERN(UGN CH2CH3)2], 2.73
ACHTUNGTRENNUNG
(C), 133.2 (C), 130.4 (2ꢅCH), 128.0 (2ꢅCH), 126.6 (CH),
41.6 (CH), 41.0 (CH2), 39.0 (CH2), 30.6 (C), 29.0 (CH), 13.6
(CH3), 13.5 (CH3), 12.3 (CH3); MS (70 eV, EI): m/z (%)=
265 [M+] (<1), 230 (100), 129 (34), 115 (16), 72 (20); IR
(neat): n=2974, 1637, 1428, 1282 cmꢀ1; HR-MS (70 eV):
m/z=265.1260, calcd. for C15H20ClNO: 265.1233; Rf =0.57
(hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-3-(4-chlorophenyl)-1-methyl-N,N-
diisopropylcyclopropanecarboxamide (2l): Colourless oil.
1H NMR (300 MHz, CDCl3): d=7.22 (d, J=8.3 Hz, 2H, p-
ClC6H4), 6.96 (d, J=8.3 Hz, 2H, p-ClC6H4), 4.36–4.21 [m,
(1R*,2S*,3R*)-2-Chloro-N,N-dimethyl-3-pentylcyclopro-
panecarboxamide (4a): Yellow oil. 1H NMR (400 MHz,
CDCl3): d=3.45 (apparent t, J=3.9 Hz, 1H, CHCl), 3.10 (s,
3H, NCH3), 2.93 (s, 3H, NCH3), 2.11 (dd, J=10.7, 3.9 Hz,
1H, CHCO), 1.68–1.56 [m, 1H, CHCATHUNGTREN(NUNG CH2)4], 1.45–1.21 [m,
1H, NCH
[m, 1H, NCH
1.11 {m, 12H, N[CHAHCTUNGTRENNUNG
G
8H, CHACTHNUGRTNEUNG(CH2)4], 0.85 [apparent t, J=6.9 Hz, 3H,
E
(CH2)4CH3]; 13C NMR (100 MHz, CDCl3): d=168.1 (C),
37.1 (CH3), 36.8 (CH), 35.3 (CH3), 31.4 (CH), 31.1 (CH2),
28.6 (CH), 28.3 (CH2), 25.7 (CH2), 22.3 (CH2), 13.8 (CH3);
MS (70 eV, EI): m/z (%)=217 [M+] (13), 182 (100), 146 (9),
(75 MHz, CDCl3): d=171.0 (C), 135.3 (C), 132.0 (C), 131.8
(2ꢅCH), 128.3 (2ꢅCH), 48.7 (CH), 45.7 (CH), 41.5 (CH),
32.1 (C), 31.4 (CH), 28.6 (CH3), 20.4 (CH3), 20.0 (CH3), 13.9
(CH3), 13.4 (CH3); MS (70 eV, EI): m/z (%)=327 [M+] (<
1), 291 (6), 192 (100), 163 (37), 128 (94); IR (neat): n=3054,
2972, 1634, 1265 cmꢀ1; HR-MS (FAB+): m/z=328.1222,
calcd. for C17H24Cl2NO+ [M+ +H]+: 328.1229; Rf =0.70
(hexane/EtOAc, 1:1).
(1S*,2S*,3R*)-2-Chloro-N,N-diethyl-3-(4-methoxyphen-
yl)-1-methylcyclopropanecarboxamide (2m): Yellow oil.
1H NMR (300 MHz, CDCl3): d=7.32 (d, J=8.8 Hz, 2H, p-
MeOC6H4), 6.89 (d, J=8.8 Hz, 2H, p-MeOC6H4), 3.81 (s,
110 (13), 68 (46); IR (neat): n=2930, 1640, 1421, 1265 cmꢀ1
;
HR-MS (70 eV): m/z=217.1185, calcd. for C11H20ClNO:
217.1233; Rf =0.70 (hexane/EtOAc, 1:1).
(1R*,2S*,3R*)-2-Chloro-N,N-diethyl-3-phenylcyclopro-
panecarboxamide (4b): Yellow solid. 1H NMR (300 MHz,
CDCl3): d=7.35–7.12 (m, 5H, Ph), 4.22 (apparent t, J=
4.4 Hz, 1H, CHCl), 3.62–3.40 (m, 2H, NCH2CH3), 3.20–3.07
(m, 1H, NCHHCH3), 3.03–2.91 (m, 1H, NCHHCH3), 2.87
(dd, J=10.7, 5.1 Hz, 1H, CHCO), 2.53 (dd, J=10.7, 4.4 Hz,
1H, CHPh), 1.14 (t, J=7.0 Hz, 3H, NCH2CH3), 0.78 (t, J=
2192
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Adv. Synth. Catal. 2009, 351, 2185 – 2198

Highly Stereoselective Halocyclopropanation of a,b-Unsaturated Amides
FULL PAPERS
7.0 Hz, 3H, NCH2CH3); 13C NMR (100 MHz, CDCl3): d=
164.9 (C), 134.2 (C), 128.0 (2ꢅCH), 127.7 (2ꢅCH), 126.8
(CH), 41.3 (CH2), 39.9 (CH2), 36.2 (CH), 34.9 (CH), 33.3
(CH), 14.1 (CH3), 12.3 (CH3); MS (70 eV, EI): m/z (%)=
216 [M+ꢀCl] (100), 144 (11), 115 (21), 100 (20), 72 (27); IR
(neat): n=2975, 1634, 1481, 1141 cmꢀ1; HR-MS (70 eV):
m/z=216.1385, calcd. for [C14H18ClNOꢀCl]: 216.1388; Rf =
0.63 (hexane/EtOAc, 1:1).
(1R*,2S*,3R*)-2-Chloro-3-(4-chlorophenyl)-1-methyl-
N,N-diisopropylcyclopropanecarboxamide (4c): Yellow oil.
1H NMR (400 MHz, CDCl3): d=7.21 (d, J=8.3 Hz, 2H, p-
ClC6H4), 6.95 (d, J=8.3 Hz, 2H, p-ClC6H4), 4.07 (d, J=
(CH); MS (70 eV, EI): m/z (%)=265 [M+] (3), 230 (100),
144 (12), 124 (8), 115 (73); IR (neat): n=3055, 1636, 1443,
1265 cmꢀ1
; HR-MS (70 eV): m/z=265.0864, calcd. for
C14H16ClNO2: 265.0870; Rf =0.45 (hexane/EtOAc, 1:1).
(1S*,2R*,3S*)-2-Chloro-N,N-diethyl-3-(4-fluorophenyl)-
cyclopropanecarboxamide (6d): Yellow oil. 1H NMR
(300 MHz, CDCl3): d=7.29–7.22 (m, 2H, p-FC6H4), 7.07–
7.01 (m, 2H, p-FC6H4), 3.75 (dd, J=7.8, 3.9 Hz, 1H, CHCl),
3.53 (q, J=7.0 Hz, 2H, NCH2CH3), 3.44 (q, J-=7.0 Hz, 2H,
NCH2CH3), 2.98 (apparent t, J=7.5 Hz, 1 H CHCO), 2.38
(dd, J=6.9, 3.9 Hz, 1H, CHPh), 1.30 (t, J=7.0 Hz, 3H,
NCH2CH3), 1.16 (t, J=7.0 Hz, 3H, NCH2CH3); 13C NMR
1
(100 MHz, CDCl3): d=168.2 (C), 161.7 (d, JCF =245.1 Hz,
5.0 Hz, 1H, CHCl), 3.93–3.84 [m, 1H, NCH
3.08 [m, 1H, NCH(CH3)2], 2.21 (d, J=5.0 Hz, 1H, CHPh),
1.59 (s, 3H, CCH3), 1.34 [d, J=6.6 Hz, 3H, NCH(CH3)2],
1.22 [d, J=6.6 Hz, 3H, NCH(CH3)2], 1.13 [d, J=6.6 Hz, 3H,
NCH (CH3)2];
ACHTUGNTRNEN(UNG CH3)2], 3.17–
C), 130.4 (d, 3JCF =7.1 Hz, 2ꢅCH), 129.9 (C), 114.9 (d,
2JCF =21.4 Hz, 2ꢅCH), 42.2 (CH2), 41.0 (CH2), 39.6 (CH),
30.4 (CH), 28.2 (CH), 14.9 (CH3), 12.9 (CH3); MS (70 eV,
EI): m/z (%)=234 [M+ꢀCl] (100), 162 (14), 133 (36), 100
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(CH3)2], 0.17 [d, J=6.6 Hz, 3H, NCHCAHTUNGTRENNUNG
(12), 72 (28); IR (neat): n=2983, 1636, 1464, 1266 cmꢀ1
;
13C NMR (100 MHz, CDCl3): d=167.7 (C), 135.3 (C), 132.6
(C), 128.4 (2ꢅCH), 127.9 (2ꢅCH), 48.4 (CH), 45.9 (CH),
44.6 (CH), 40.3 (CH), 38.8 (C), 20.8 (CH3), 19.9 (CH3), 19.8
(2ꢅCH3), 18.1 (CH3); MS (70 eV, EI): m/z (%)=327 [M+]
(20), 312 (100), 192 (42), 157 (44), 118 (72); IR (neat): n=
HR-MS
(70 eV):
m/z=234.1301,
calcd.
for
[C14H17ClFNOꢀCl]: 234.1294; Rf =0.70 (hexane/EtOAc,
1:1).
(1S*,2R*,3S*)-2-Chloro-N,N-diethyl-3-(4-methoxyphenyl)-
cyclopropanecarboxamide (6e): Yellow oil. 1H NMR
(300 MHz, CDCl3): d=7.19 (d, J=8.5 Hz, 2H, p-
MeOC6H4), 6.89 (d, J=8.5 Hz, 2H, p-MeOC6H4), 3.81 (s,
3H, OCH3), 3.75 (dd, J=7.6, 3.5 Hz, 1H, CHCl), 3.51 (q,
J=7.1 Hz, 2H, NCH2CH3), 3.42 (q, J=7.1 Hz, 2H,
NCH2CH3), 2.93 (apparent t, J=7.0 Hz, 1H, CHCO), 2.35
(dd, J=6.4, 3.5 Hz, 1H, CHPh), 1.29 (t, J=7.1 Hz, 3H,
NCH2CH3), 1.14 (t, J=7.1 Hz, 3H, NCH2CH3); 13C NMR
(100 MHz, CDCl3): d=168.5 (C), 158.4 (C), 129.7 (2ꢅCH),
126.0 (C), 113.3 (2ꢅCH), 54.9 (CH3), 42.1 (CH2), 40.8
(CH2), 39.8 (CH), 30.5 (CH), 28.0 (CH), 14.8 (CH3), 12.9
(CH3); MS (70 eV, EI): m/z (%)=246 [M+ꢀCl] (100), 230
(28), 216 (17), 188 (17), 100 (9); IR (neat): n=2983, 1631,
1463, 1265 cmꢀ1; HR-MS (70 eV): m/z=246.1535, calcd. for
[C15H20ClNO2ꢀCl]: 246.1494; Rf =0.60 (hexane/EtOAc, 1:1).
2975, 1625, 1496, 1265 cmꢀ1
; HR-MS (70 eV): m/z=
327.1217, calcd. for C17H23Cl2NO: 327.1157; Rf =0.83
(hexane/EtOAc, 1:1).
(1S*,2R*,3S*)-2-Chloro-N,N-diethyl-3-phenylcyclopro-
panecarboxamide (6a): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=7.41–7.27 (m, 5H, Ph), 3.80 (dd, J=7.2, 3.8 Hz,
1H, CHCl), 3.54 (q, J=7.1 Hz, 2H, NCH2CH3), 3.45 (q, J=
7.1 Hz, 2H, NCH2CH3), 3.01 (apparent t, J=7.2 Hz, 1H,
CHCO), 2.45 (dd, J=6.3, 3.8 Hz, 1H, CHPh), 1.31 (t, J=
7.1 Hz, 3H, NCH2CH3), 1.16 (t, J=7.1 Hz, 3H, NCH2CH3);
13C NMR (100 MHz, CDCl3): d=168.5 (C), 134.2 (C), 128.8
(2ꢅCH), 128.0 (2ꢅCH), 127.0 (CH), 42.3 (CH2), 41.0
(CH2), 39.8 (CH), 31.3 (CH), 28.0 (CH), 15.0 (CH3), 13.0
(CH3); MS (70 eV, EI): m/z (%)=251 [M+] (3), 216 (100),
144 (14), 115 (73), 100 (45), 72 (56); IR (neat): n=2975,
1633, 1462, 1270 cmꢀ1; HR-MS (70 eV): m/z=251.1100,
calcd. for C14H18ClNO: 251.1077; Rf =0.63 (hexane/EtOAc,
1:1).
Synthesis of Anhydrous CrBr2
To a suspension of anhydrous chromium powder (3.0 mmol)
in diethyl ether (30 mL) was added dropwise bromine
(3.0 mmol) at room temperature and under an inert atmos-
phere. After stirring for 72 h at 308C a white solid was
formed. The solvent was removed by decantation, the solid
was washed with anhydrous diethyl ether (3ꢅ15 mL) and
used without further purification.
(1S*,2R*,3S*)-2-Chloro-3-phenyl-N,N-diisopropylcyclo-
propanecarboxamide (6b): Yellow oil. H NMR (300 MHz,
CDCl3): d=7.40–7.27 (m, 5H, Ph), 4.30–4.10 [m, 1H, NCH-
ACHTUNGTRENNUNG(CH3)2], 4.06–3.87 [m, 1H, NCHAHCTUNGTRENN(UGN CH3)2], 3.79 (dd, J=7.6,
1
3.5 Hz, 1H, CHCl), 3.01 (apparent t, J=7.3 Hz, 1H,
CHCO), 2.49 (dd, J=6.9, 3.5 Hz, 1 H ,CHPh), 1.40–1.30 {m,
12H, N[CHACHTUNGTRENNUNG
(CH3)2]2]; 13C NMR (75 MHz, CDCl3): d=168.1
(C), 134.4 (C), 128.8 (2ꢅCH), 128.0 (2ꢅCH), 127.0 (CH),
47.3 (CH), 45.8 (CH), 39.5 (CH), 30.8 (CH), 30.1 (CH), 21.7
(CH3), 21.6 (CH3), 20.4 (CH3), 20.3 (CH3); MS (70 eV, EI):
m/z (%)=279 [M+] (3), 244 (100), 130 (28), 115 (89), 86
(76); IR (neat): n=2974, 1631, 1449, 1265 cmꢀ1; HR-MS
(70 eV): m/z=279.1408, calcd. for C16H22ClNO: 279.1390;
Rf =0.77 (hexane/EtOAc, 1:1).
Synthesis of Bromocyclopropanes 3, 5, and 7
To a suspension of anhydrous CrBr2 (1.5 mmol, 3.0 equiv.)
in THF (5 mL) was added the corresponding a,b-unsaturat-
ed amide 1 (0.5 mmol, 1.0 equiv.) in THF (2 mL) and CBr4
(0.5 mmol, 1 equiv.) at room temperature and under an inert
atmosphere. After stirring for 16 h at reflux the reaction
mixture was quenched by the addition of 1.0M aqueous
HCl (5 mL) and extracted with diethyl ether (3ꢅ10 mL).
The combined extracts were washed with saturated NH4Cl
solution and water, dried over Na2SO4, concentrated under
vacuum and filtered through a pad of Celiteꢆ. Purification
by column chromatography on silica gel (hexane/EtOAc,
10:1) afforded pure compounds 3, 5, and 7.
4-[(1S*,2R*,3S*)-(2-Chloro-3-phenylcyclopropyl)carbon-
1
yl]morpholine (6c): Yellow oil. H NMR (300 MHz, CDCl3):
d=7.41–7.24 (m, 5H, Ph), 3.83 (dd, J=7.9, 3.4 Hz, 1H,
CHCl), 3.79–3.64 (m, 8H, H from morpholine), 3.01 (appar-
ent t, J=7.2 Hz, 1H, CHCO), 2.47 (dd, J=6.6, 3.4 Hz, 1H,
CHPh); 13C NMR (75 MHz, CDCl3): d=168.2 (C), 133.9
(C), 128.8 (2ꢅCH), 128.1 (2ꢅCH), 127.2 (CH), 66.5 (2ꢅ
CH2), 45.9 (CH2), 42.5 (CH2), 39.6 (CH), 31.5 (CH), 27.6
Adv. Synth. Catal. 2009, 351, 2185 – 2198
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2193

Josꢀ M. Concellꢁn et al.
FULL PAPERS
(1S*,2S*,3R*)-2-Bromo-N,N-diethyl-3-methylcyclopro-
42.2 (CH2), 40.9 (CH2), 29.8 (CH), 28.9 (CH), 27.6 (CH),
17.9 (CH3), 14.9 (CH3), 13.1 (CH3); MS (70 eV, EI): m/z
(%)=180 [M+ꢀBr] (100), 169 (45), 131 (13), 100 (27), 69
(39); IR (neat): n=2981, 1629, 1265, 739 cmꢀ1; HR-MS
(70 eV): m/z=180.1375, calcd. for [C11H18BrNOꢀBr]:
180.1389; Rf =0.50 (hexane/EtOAc, 3:1).
panecarboxamide (3a): Orange oil. 1H NMR (300 MHz,
CDCl3): d=3.47–3.30 [m, 5H, NACHTNUTRGEN(UNG CH2CH3)2, CHBr], 1.72–
1.56 (m, 2H, CHCO, CHCH3), 1.29 (d, J=6.0 Hz, 3H,
CHCH3), 1.24 (t, J=7.1 Hz, 3H, NCH2CH3), 1.17–1.03 (m,
3H, NCH2CH3); 13C NMR (75 MHz, CDCl3): d=169.5 (C),
42.2 (CH2), 40.9 (CH2), 29.9 (CH), 29.8 (CH), 20.8 (CH),
14.9 (CH3), 14.6 (CH3), 13.1 (CH3); MS (70 eV, EI): m/z
(%)=233 [M+] (2), 154 (100), 133 (11), 126 (9), 83 (30); IR
(neat): n=2984, 1629, 739 cmꢀ1; HR-MS (ESI+): m/z=
234.0488, calcd. for [C9H17BrNO]+ [M+ +H]+: 234.0494; Rf =
0.43 (hexane/EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-N,N-diethyl-3-heptyl-1-methyl-
cyclopropanecarboxamide (3f): Orange oil. 1H NMR
(300 MHz, CDCl3): d=3.49–3.22 [m, 4H, N
3.35 (d, J=7.6 Hz, 1H, CHBr), 1.52–1.04 [m, 19H, N-
(CH2CH3)2,CH(CH2)6CH3], 1.26 (s, 3H, CCH3), 0.89 [appar-
ACHTNUGRTNE(NUGN CH2CH3)2],
A
ACHTUNGTRENNUNG
ent t, J=5.3 Hz, 3H, (CH2)6CH3]; 13C NMR (75 MHz,
CDCl3): d=172.5 (C), 40.9 (CH2), 38.8 (CH2), 34.4 (CH),
31.7 (CH2), 29.3 (CH2), 29.1 (CH2), 28.3 (CH2), 27.6 (C),
25.4 (CH2), 24.8 (CH), 22.5 (CH2), 14.0 (CH3), 13.7 (CH3),
13.6 (CH3), 12.4 (CH3); MS (70 eV, EI): m/z (%)=252
[M+ꢀBr] (100), 232 (2), 180 (2), 166 (2), 109 (2); IR (neat):
n=2928, 1630, 1428, 741 cmꢀ1; HR-MS (70 eV): m/z=
252.2312, calcd. for [C16H30BrNOꢀBr]: 252.2328; Rf =0.61
(hexane/EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-N,N-dimethyl-3-pentylcyclopro-
panecarboxamide (3b): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.48–3.31 [m, 5H, N
(apparent dd, J=5.1, 3.8 Hz, 1H, CHCO), 1.62–1.28 [m,
9H, CH(CH2)4CH3], 1.24 (t, J=7.0 Hz, 3H, NCH2CH3),
ACHTNUGTRNEN(NUG CH2CH3)2, CHBr], 1.71
ACHTUNGTRENNUNG
1.10 (t, J=7.0 Hz, 3H, NCH2CH3), 0.88 [t, J=7.0 Hz, 3H,
(CH2)4CH3]; 13C NMR (75 MHz, CDCl3): d=169.5 (C), 42.1
(CH2), 40.9 (CH2), 31.4 (CH2), 29.9 (CH2), 29.3 (CH), 28.8
(CH), 28.3 (CH2), 26.3 (CH), 22.4 (CH2), 15.0 (CH3), 13.9
(CH3), 13.1 (CH3); MS (70 eV, EI): m/z (%)=210 [M+ꢀBr]
(100), 181 (38), 131 (51), 100 (27), 69 (26); IR (neat): n=
2933, 1629, 1461, 740 cmꢀ1; HR-MS (70 eV): m/z=210.1853,
calcd. for [C13H24BrNOꢀBr]: 210.1858; Rf =0.53 (hexane/
EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-3-isobutyl-1-methyl-N,N-diisopro-
pylcyclopropanecarboxamide (3g): Orange oil. 1H NMR
(300 MHz, CDCl3): d=4.25–4.08 [m, 1H, NCH
3.39–3.20 [m, 1H, NCH(CH3)2], 3.33 (d, J=8.2 Hz, 1H,
CHBr), 1.82–1.66 [m, 2H, CH2CH(CH3)2], 1.45–1.09 {m,
14H, N[CH(CH3)2]2, CHCH2CH(CH3)2}, 1.21 (s, 3H,
CCH3), 0.97 [dd, J=6.3, 2.5 Hz, 6H, CH
(CH3)2]; 13C NMR
ACHTUNGTRENNUNG(CH3)2],
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(1S*,2S*,3R*)-2-Bromo-N,N-diethyl-3-isobutylcyclopro-
ACHTUNGTRENNUNG
panecarboxamide (3c): Orange oil. 1H NMR (300 MHz,
(75 MHz, CDCl3): d=172.0 (C), 48.4 (CH), 45.5 (CH), 34.8
(CH), 34.0 (CH2), 28.6 (C), 27.7 (CH), 23.3 (CH), 22.4 (2ꢅ
CH3), 22.3 (2ꢅCH3), 20.3 (2ꢅCH3), 13.7 (CH3); MS (70 eV,
EI): m/z (%)=240 [M+ꢀBr] (100), 198 (9), 101 (14), 96
(11), 68 (11); IR (neat): n=2967, 1629, 1439, 740 cmꢀ1; HR-
MS (ESI+): m/z=318.1427, calcd. for [C15H29BrNO]+ [M+ +
H]+: 318.1432; Rf =0.83 (hexane/EtOAc, 3:1).
CDCl3): d=3.51–3.32 [m, 5H, NACHTNUTRGEN(UNG CH2CH3)2, CHBr], 1.84–
1.68 (m, 2H, CHCO, CHCH2), 1.64–1.50 [m, 2H,
(CH3)2CHCH2], 1.49–1.38 [m, 1H, (CH3)2CHCH2], 1.24 (t,
J=7.0 Hz, 3H, NCH2CH3), 1.11 (t, J=7.0 Hz, 3H,
NCH2CH3), 0.96 [d, J=6.9 Hz, 6H, CHACHTUNGTRNEUNG
(CH3)2]; 13C NMR
(75 MHz, CDCl3): d=169.5 (C), 42.1 (CH2), 40.9 (CH2),
38.6 (CH2), 29.4 (CH), 28.9 (CH), 27.8 (CH), 24.8 (CH),
22.6 (CH3), 22.1 (CH3), 15.80 (CH3), 13.1 (CH3); MS (70 eV,
EI): m/z (%)=196 [M+ꢀBr] (100), 181 (22), 169 (36), 131
(1S*,2S*,3R*)-2-Bromo-3-cyclohexyl-N,N-diethyl-1-meth-
ylcyclopropanecarboxamide (3h): Yellow oil. 1H NMR
(300 MHz, CDCl3): d=3.48–3.16 [m, 4H, N
3.25 (d, J=7.4 Hz, 1H, CHBr), 1.88–1.56 [m, 2H, CHCH-
(CH2)5], 1.27 (s, 3H, CCH3), 1.25–0.98 [m, 16H, CH(CH2)5,
(CH2CH3)2]; 13C NMR (75 MHz, CDCl3): d=172.3 (C),
ACHTNUGRTNE(NUGN CH2CH3)2],
(31), 119 (51); IR (neat): n=2961, 1628, 1463, 739 cmꢀ1
;
HR-MS
(70 eV):
m/z=196.1658,
calcd.
for
A
ACHTUNGTRENNUNG
[C12H22BrNOꢀBr]: 196.1702; Rf =0.55 (hexane/EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-3-cyclohexyl-N,N-diethylcyclopro-
panecarboxamide (3d): Orange solid. 1H NMR (300 MHz,
NACHTUNGTRENNUNG
40.9 (CH2), 39.0 (CH2), 35.1 (CH), 33.3 (CH), 31.5 (CH2),
31.3 (CH2), 30.2 (CH), 27.8 (C), 26.1 (CH2), 25.8 (CH2), 25.7
(CH2), 14.0 (CH3), 13.8 (CH3), 12.4 (CH3); MS (70 eV, EI):
m/z (%)=236 [M+ꢀBr] (100), 163 (7), 153 (5), 121 (5), 72
(6); IR (neat): n=2930, 1629, 1429, 739 cmꢀ1; HR-MS
(70 eV): m/z=236.2017, calcd. for [C15H26BrNOꢀBr]:
236.2015; Rf =0.53 (hexane/EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-N,N-diethyl-1-methyl-3-phenyl-
cyclopropanecarboxamide (3i): Orange solid. 1H NMR
(300 MHz, CDCl3): d=7.45–7.22 (m, 5H, Ph), 3.62 (d, J=
CDCl3): d=3.49–3.25 [m, 5H, N
1.89 (m, 1H, CHCO), 1.80–1.59 [m, 2H, CHCH
1.39–1.04 [m, 10H, CH(CH2)5], 1.24 (t, J=7.1 Hz, 3H,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
NCH2CH3), 1.09 (t, J=7.1 Hz, 3H, NCH2CH3);13C NMR
(75 MHz, CDCl3): d=169.6 (C), 42.1 (CH2), 40.8 (CH2),
39.1 (CH), 32.5 (CH2), 32.3 (CH), 32.0 (CH2), 28.8 (CH),
27.7 (CH), 26.1 (CH2), 26.0 (CH2), 25.6 (CH2), 15.0 (CH3),
13.1 (CH3); MS (70 eV, EI): m/z (%)=301 [M+] (2), 222
(100), 208 (4), 100 (9), 72 (7); IR (neat): n=2928, 1626,
1462, 739 cmꢀ1; HR-MS (70 eV): m/z=301.1043, calcd. for
C14H24BrNO: 301.1041; Rf =0.50 (hexane/EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-N,N-diethyl-3-(propen-1-yl)cyclo-
8.0 Hz, 1H, CHBr), 3.58–3.23 [m, 4H, N
(d, J=8.0 Hz, 1H, CHPh), 1.23 (s, 3H, CCH3), 1.31–1.05 [m,
6H, N
(CH2CH3)2]; 13C NMR (75 MHz, CDCl3): d=171.8
ACHTNUGTNERN(UGN CH2CH3)2], 2.72
AHCTUNGTRENNUNG
(C), 134.0 (C), 130.5 (2ꢅCH), 128.0 (2ꢅCH), 126.7 (CH),
41.1 (CH2), 39.2 (CH2), 33.1 (CH), 30.2 (C), 28.6 (CH), 16.0
(CH3), 13.8 (CH3), 12.4 (CH3); MS (70 eV, EI): m/z (%)=
230 [M+ꢀBr] (12), 229 (100), 214 (14), 200 (31), 172 (26);
IR (neat): n=2979, 1630, 1430, 739 cmꢀ1; HR-MS (70 eV):
m/z=230.1483, calcd. for [C15H20BrNOꢀBr]: 230.1545; Rf =
0.70 (hexane/EtOAc, 1:1).
1
propanecarboxamide (3e): Orange oil. H NMR (300 MHz,
CDCl3): d=5.80–5.67 (m, 1H, CH3CH=CH), 5.35–5.22 (m,
1H, CH3CH=CH), 3.51 (dd, J=7.6, 3.8 Hz, 1H, CHBr),
3.44–3.30 [m, 4H, NACTHNUTRGNEUNG(CH2CH3)2], 2.21–2.11 (m, 1H, CHCO),
1.94 (dd, J=5.7, 3.8 Hz, 1H, CH3CH=CHCH), 1.70 (dd, J=
6.3, 1.9 Hz, 3H, CH3CH=CH), 1.20 (t, J=7.0 Hz, 3H,
NCH2CH3), 1.08 (t, J=7.0 Hz, 3H, NCH2CH3); 13C NMR
(75 MHz, CDCl3): d=168.6 (C), 129.5 (CH), 127.2 (CH),
(1S*,2S*,3R*)-2-Bromo-3-(4-chlorophenyl)-1-methyl-N,N-
diisopropylcyclopropanecarboxamide (3j): Orange solid.
2194
asc.wiley-vch.de
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2185 – 2198

Highly Stereoselective Halocyclopropanation of a,b-Unsaturated Amides
FULL PAPERS
1H NMR (300 MHz, CDCl3): d=7.38–7.27 (m, 4H, p-
ClC6H4), 4.36–4.20 [m, 1H, NCH(CH3)2], 3.61 (d, J=8.2 Hz,
1H, CHBr), 3.44–3.28 [m, 1H, NCH(CH3)2], 2.67 (d, J=
8.2 Hz, 1H, CHPh), 1.48–1.16 {m, 12H, N[CH(CH3)2]2}, 1.19
J=7.2 Hz, 3H, CCH2CH3); 13C NMR (75 MHz, CDCl3): d=
169.8 (C), 137.4 (C), 128.1 (2ꢅCH), 127.9 (2ꢅCH), 126.6
(CH), 41.2 (CH2), 38.4 (CH2), 38.3 (C), 38.2 (CH), 36.0 (C),
24.1 (CH2), 15.4 (CH3), 13.5 (CH3), 11.06 (CH3), 10.0 (CH3);
MS (ESI+-TOF): m/z (%)=338 [M+ +H]+ (88), 280 (58),
277 (10), 258 (100), 245 (9); IR (neat): n=2984, 1625, 1430,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(s, 3H, CCH3); 13C NMR (75 MHz, CDCl3): d=171.0 (C),
132.6 (2ꢅC), 131.7 (2ꢅCH), 128.2 (2ꢅCH), 48.6 (CH), 45.8
(CH), 32.7 (CH), 31.5 (C), 28.2 (CH), 20.3 (2ꢅCH3), 20.0
(CH3), 15.7 (2ꢅCH3); MS (ESI+-TOF): m/z (%)=372
[M+ +H]+ (75), 332 (2), 314 (10), 292 (40); IR (neat): n=
2972, 1630, 1439, 739 cmꢀ1; HR-MS (ESI+): m/z=372.0724,
calcd. for [C17H24ClBrNO]+ [M+ +H]+: 372.0730; Rf =0.65
(hexane/EtOAc, 3:1).
740 cmꢀ1
;
HR-MS (ESI+): m/z=338.1114, calcd. for
[C17H25BrNO]+ [M+ +H]+: 338.1119; Rf =0.58 (hexane/
EtOAc, 3:1).
(1R*,2S*,3R*)-2-Bromo-N,N-dimethyl-3-pentylcyclopro-
panecarboxamide (5a): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.31 (apparent t, J=4.0 Hz, 1H, CHBr), 3.09 (s,
3H, NCH3), 2.92 (s, 3H, NCH3), 2.15 (dd, J=10.3, 4.0 Hz,
(1S*,2S*,3R*)-2-Bromo-1-butyl-N,N-diethyl-3-(4-meth-
oxyphenyl)cyclopropanecarboxamide (3k): Orange oil.
1H NMR (300 MHz, CDCl3): d=7.35 (d, J=8.4 Hz, 2H, p-
MeOC6H4), 6.87 (d, J=8.4 Hz, 2H, p-MeOC6H4), 3.80 (s,
3H, OCH3), 3.66 (d, J=8.2 Hz, 1H, CHBr), 3.62–3.36 [m,
1H, CHCO), 1.71–1.62 [m, 1H, CHCATHUNGTREN(NUNG CH2)4], 1.44–1.19 [m,
8H, CHACHTNGUTRNE(NUG CH2)4], 0.84 [apparent t, J=6.3 Hz, 3H,
(CH2)4CH3]; 13C NMR (75 MHz, CDCl3): d=168.2 (C), 37.1
(CH3), 35.4 (CH3), 31.6 (CH), 31.1 (CH2), 28.7 (CH), 28.3
(CH2), 26.1 (CH2), 23.4 (CH), 22.3 (CH2), 13.8 (CH3); MS
(70 eV, EI): m/z (%)=182 [M+ꢀBr] (70), 148 (5), 124 (2),
4H, N
[m, 4H, C
(CH2)2CH2], 0.82 [t, J=7.2 Hz, 3H, C
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
E
U
72 (100), 41 (11); IR (neat): n=2929, 1638, 1420, 739 cmꢀ1
;
(75 MHz, CDCl3): d=170.6 (C), 158.3 (C), 131.1 (2ꢅCH),
126.1 (C), 113.5 (2ꢅCH), 55.0 (CH3), 41.1 (CH2), 39.3
(CH2), 34.1 (C), 33.2 (CH), 29.6 (CH2), 28.9 (CH), 28.1
(CH2), 22.7 (CH2), 13.7 (2ꢅCH3), 12.4 (CH3); MS (70 eV,
EI): m/z (%)=302 [M+ꢀBr] (100), 201 (16), 187 (12), 159
HR-MS (ESI+): m/z=262.0801, calcd. for [C11H21BrNO]+
[M+ +H]+: 262.0806; Rf =0.50 (hexane/EtOAc, 3:1).
(1R*,2S*,3R*)-2-Bromo-3-(4-chlorophenyl)-1-methyl-
N,N-diisopropylcyclopropanecarboxamide (5b): White solid.
1H NMR (300 MHz, CDCl3): d=7.21 (d, J=8.5 Hz, 2H, p-
ClC6H4), 6.95 (d, J=8.5 Hz, 2H, p-ClC6H4), 4.04 (d, J=
(12), 121 (10); IR (neat): n=2961, 1629, 1515, 739 cmꢀ1
;
HR-MS (ESI+): m/z=382.1376, calcd. for [C19H29BrNO2]+
5.4 Hz, 1H, CHBr), 3.90–3.811 [m, 1H, NCH
3.04 [m, 1H, NCH(CH3)2], 2.29 (d, J=5.4 Hz, 1H, CHPh),
1.61 (s, 3H, CCH3), 1.33 [d, J=6.8 Hz, 3H, NCH(CH3)2],
1.21 [d, J=6.8 Hz, 3H, NCH(CH3)2], 1.12 [d, J=6.8 Hz, 3H,
NCH (CH3)2];
ACHTUGNTRNEN(UNG CH3)2], 3.17–
[M+ +H]+: 382.1382; Rf =0.40 (hexane/EtOAc, 3:1).
AHCTUNGTRENNUNG
(1S*,2S*)-2-Bromo-3,3-diethyl-N,N-diethyl-1-methylcyclo-
ACHTUNGTRENNUNG
propanecarboxamide (3l): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=3.54–3.38 (m, 3H, NCH2CH3, CHBr), 3.29–3.08
ACHTUNGTRENNUNG
ACHUTNGRENN(UG CH3)2], 0.18 [d, J=6.8 Hz, 3H, NCHACHTUNGTRENNUNG
(m, 2H, NCH2CH3), 1.62–1.18 [m, 4H, C
N
13C NMR (75 MHz, CDCl3): d=167.5 (C), 135.5 (C), 132.7
(C), 128.4 (2ꢅCH), 127.9 (2ꢅCH), 48.5 (CH), 46.0 (CH),
40.8 (CH), 38.1 (C), 34.1 (CH), 20.8 (CH3), 20.7 (CH3), 20.0
(CH3), 19.9 (CH3), 19.8 (CH3); MS (ESI+-TOF): m/z (%)=
372 [M+ +H]+ (74), 314 (18), 292 (60), 258 (3); IR (neat):
(s, 3H, CCH3), 1.21 (t, J=7.1 Hz, 3H, NCH2CH3), 1.12–1.01
(m, 6H, NCH2CH3, CCH2CH3), 0.85 (t, J=7.1 Hz, 3 H
CCH2CH3); 13C NMR (75 MHz, CDCl3): d=171.5 (C), 41.1
(CH2), 40.3 (CH), 38.6 (CH2), 33.0 (C), 29.1 (C), 19.4 (2ꢅ
CH2), 15.5 (CH3), 14.6 (CH3), 13.9 (2ꢅCH3), 12.2 (CH3);
MS (70 eV, EI): m/z (%)=210 [M+ꢀBr] (100), 110 (15), 101
n=2971, 1625, 1265, 739 cmꢀ1
;
HR-MS (ESI+): m/z=
372.0724, calcd. for [C17H24BrClNO]+ [M+ +H]+: 372.0730;
Rf =0.68 (hexane/EtOAc, 3:1).
(7), 73 (7), 67 (8); IR (neat): n=2964, 1627, 1459, 740 cmꢀ1
;
HR-MS (ESI+): m/z=290.1114, calcd. for [C13H25BrNO]+
[M+ +H]+: 290.1119; Rf =0.50 (hexane/EtOAc, 3:1).
(1S*,2S*,3R*)-2-Bromo-3-ethyl-N,N-diethyl-1-methyl-3-
(1S*,2R*,3S*)-2-Bromo-N,N-diethyl-3-phenylcyclopro-
panecarboxamide (7a): Yellow oil. 1H NMR (300 MHz,
CDCl3): d=7.43–7.26 (m, 5H, Ph), 3.72 (dd, J=8.2, 3.8 Hz,
1H, CHBr), 3.54 (q, J=7.3 Hz, 2H, NCH2CH3), 3.45 (q, J=
7.3 Hz, 2H, NCH2CH3), 2.96 (apparent t, J=7.0 Hz, 1H,
CHCO), 2.51 (dd, J=6.4, 3.8 Hz, 1H, CHPh), 1.32 (t, J=
7.3 Hz, 3H, NCH2CH3), 1.17 (t, J=7.3 Hz, 3H, NCH2CH3);
13C NMR (100 MHz, CDCl3): d=168.6 (C), 135.2 (C), 128.8
(2ꢅCH), 127.9 (2ꢅCH), 127.0 (CH), 42.2 (CH2), 41.0
(CH2), 30.5 (CH), 28.7 (CH), 27.9 (CH), 14.9 (CH3), 13.0
(CH3); MS (70 eV, EI): m/z (%)=295 [M+] (2), 216 (100),
200 (18), 158 (11), 115 (25); IR (neat): n=2986, 1632, 1447,
1
propylcyclopropanecarboxamide (3m): Yellow oil. H NMR
(300 MHz, CDCl3): d=3.58–3.39 (m, 3H, NCH2CH3,
CHBr), 3.30–3.11 (m, 2H, NCH2CH3), 1.67–0.72 [m, 4H, C-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(75 MHz, CDCl3): d=171.5 (C), 41.1 (CH2), 40.3 (CH), 38.6
(CH2), 33.8 (C), 33.0 (C), 19.4 (CH2), 18.7 (CH2), 15.5
(CH3), 14.6 (CH3), 13.9 (2ꢅCH3), 12.2 (CH3); MS (70 eV,
EI): m/z (%)=210 [M+ꢀBr] (100), 110 (14), 96 (6), 73 (7),
70 (8); IR (neat): n=2965, 1626, 1459, 745 cmꢀ1; HR-MS
(ESI+): m/z=290.1114, calcd. for [C13H25BrNO]+ [M+ +H]+:
290.1119; Rf =0.55 (hexane/EtOAc, 3:1).
739 cmꢀ1
;
HR-MS (70 eV): m/z=295.0564, calcd. for
C14H18BrNO: 295.0572; Rf =0.65 (hexane/EtOAc, 1:1).
(1S*,2R*,3S*)-2-Bromo-3-phenyl-N,N-diisopropylcyclo-
1
propanecarboxamide (7b): Orange oil. H NMR (300 MHz,
(1S*,2S*,3R*)-2-Bromo-3-ethyl-N,N-diethyl-1-methyl-3-
phenylcyclopropanecarboxamide (3n): White solid. H NMR
CDCl3): d=7.39–7.23 (m, 5H, Ph), 4.26–4.15 [m, 1H, NCH-
ACHTUTGNRENNGU(CH3)2], 4.00–3.83 [m, 1H, NCHACHTUGNTRENN(UGN CH3)2], 3.67 (dd, J=8.0,
1
(300 MHz, CDCl3): d=7.30–7.14 (m, 5H, Ph), 3.60–3.47 (m,
1H, CHBr), 3.38–3.26 (m, 1H, NCHHCH3), 2.88–2.62 (m,
2H, NCH2CH3), 2.25–2.12 (m, 1H, NCHHCH3), 1.80–1.67
(m, 2H, CCH2CH3),1.52 (s, 3H, CCH3), 1.13 (t, J=7.2 Hz,
3H, NCH2CH3), 0.80 (t, J=7.2 Hz, 3H, NCH2CH3), 0.43 (t,
4.0 Hz, 1H, CHBr), 2.93 (apparent t, J=7.3 Hz, 1H,
CHCO), 2.50 (dd, J=6.5, 4.0 Hz, 1H, CHPh), 1.43–1.26 {m,
12H, N[CHACTHNUTRGNEUNG
(CH3)2]2}; 13C NMR (75 MHz, CDCl3): d=168.3
(C), 135.4 (C), 128.8 (2ꢅCH), 128.0 (2ꢅCH), 127.0 (CH),
47.4 (CH), 45.8 (CH), 30.1 (CH), 30.0 (CH), 28.7 (CH), 21.8
Adv. Synth. Catal. 2009, 351, 2185 – 2198
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2195

Josꢀ M. Concellꢁn et al.
FULL PAPERS
(2ꢅCH3), 20.3 (2ꢅCH3); MS (70 eV, EI): m/z (%)=323
[M+] (7), 244 (97), 160 (53), 144 (45), 115 (100); IR (neat):
n=2972, 1630, 1448, 738 cmꢀ1; HR-MS (70 eV): m/z=
323.0885, calcd. for C16H22BrNO: 323.0885; Rf =0.65
(hexane/EtOAc, 3:1).
4-[(1S*,2R*,3S*)-(2-Bromo-3-phenylcyclopropyl)carbon-
yl]morpholine (7c): Yellow solid. 1H NMR (300 MHz,
CDCl3): d=7.40–7.21 (m, 5H, Ph), 3.81–3.63 (m, 9H, H
from morpholine, CHBr), 2.95 (apparent t, J=7.3 Hz, 1H,
CHCO), 2.51 (dd, J=6.4, 3.8 Hz, 1H, CHPh); 13C NMR
(75 MHz, CDCl3): d=168.4 (C), 135.0 (C), 128.8 (2ꢅCH),
128.1 (2ꢅCH), 127.3 (CH), 66.6 (2ꢅCH2), 46.0 (CH2), 42.6
(CH2), 30.7 (CH), 28.4 (CH), 27.7 (CH); MS (70 eV, EI):
m/z (%)=309 [M+] (3), 230 (100), 202 (7), 115 (53), 70 (18);
IR (neat): n=2987, 1638, 1442, 739 cmꢀ1; HR-MS (70 eV):
m/z=309.0361, calcd. for C14H16BrNO2: 309.0364; Rf =0.20
(hexane/EtOAc, 3:1).
(1S*,2R*,3S*)-2-Bromo-N,N-diethyl-3-(4-fluorophenyl)-
cyclopropanecarboxamide (7d): Orange oil. 1H NMR
(300 MHz, CDCl3): d=7.27–7.17 (m, 2H, p-FC6H4), 7.07–
6.97 (m, 2H, p-FC6H4), 3.64 (dd, J=7.7, 4.0 Hz, 1H, CHBr),
3.64 (q, J=7.1 Hz, 2H, NCH2CH3), 3.51 (q, J=7.1 Hz, 2H,
NCH2CH3), 2.90 (apparent t, J=7.1 Hz, 1H, CHCO), 2.41
(dd, J=6.2, 4.0 Hz, 1H, CHPh), 1.28 (t, J=7.1 Hz, 3H,
NCH2CH3), 1.14 (t, J=7.0 Hz, 3H, NCH2CH3); 13C NMR
(75 MHz, CDCl3): d=168.5 (C), 161.9 (d, 1JC,F =244.2 Hz,
C), 131.1 (C), 130.4 (d, 3JC,F =8.1 Hz, 2ꢅCH), 115.0 (d,
2JC,F =21.4 Hz, 2ꢅCH), 42.3 (CH2), 41.1 (CH2), 29.7 (CH),
28.6 (CH), 28.3 (CH), 15.1 (CH3), 13.1 (CH3); MS (70 eV,
EI): m/z (%)=313 [M+] (3), 234 (100), 218 (18), 133 (20),
69 (17); IR (neat): n=2982, 1633, 1514, 739 cmꢀ1; HR-MS
(70 eV): m/z=313.0509, calcd. for C14H17BrFNO: 213.0478;
Rf =0.70 (hexane/EtOAc, 1:1).
(1S*,2R*,3S*)-2-Bromo-N,N-diethyl-3-(4-methoxyphenyl)-
cyclopropanecarboxamide (7e): Brown solid. 1H NMR
(300 MHz, CDCl3): d=7.17 (d, J=8.5 Hz, 2H, p-
MeOC6H4), 6.87 (d, J=8.5 Hz, 2H, p-MeOC6H4), 3.79 (s,
3H, OCH3), 3.66 (dd, J=7.0, 4.0 Hz, 1H, CHBr), 3.51 (q,
J=7.2 Hz, 2H, NCH2CH3), 3.42 (q, J=7.2 Hz, 2H,
NCH2CH3), 2.85 (apparent t, J=7.0 Hz, 1H, CHCO), 2.41
(dd, J=6.2, 4.0 Hz, 1H, CHPh), 1.28 (t, J=7.2 Hz, 3H,
NCH2CH3), 1.14 (t, J=7.2 Hz, 3H, NCH2CH3); 13C NMR
(75 MHz, CDCl3): d=168.8 (C), 158.6 (C), 129.8 (2ꢅCH),
127.3 (C), 113.5 (2ꢅCH), 55.1 (CH3), 42.3 (CH2), 41.0
(CH2), 29.9 (CH), 29.1 (CH), 28.2 (CH), 15.0 (CH3), 13.1
(CH3); MS (70 eV, EI): m/z (%)=246 [M+ꢀBr] (17), 245
(100), 230 (32), 202 (3), 188 (20); IR (neat): n=2976, 1631,
1517, 1251 cmꢀ1; HR-MS (70 eV): m/z=246.1462, calcd. for
[C15H20BrNO2ꢀBr]: 246.1494; Rf =0.75 (hexane/EtOAc,
1:1).
raphy on silica gel (hexane/EtOAc, 5:1) yielded the ketones
8.
(1S*,2R*,3S*)-[2-Chloro-3-phenylcycloprop-1-yl] phenyl
1
ketone (8a): Colourless oil. H NMR (300 MHz, CDCl3): d=
8.10–7.35 (m, 10H, Ph), 3.90 (dd, J=7.7, 3.5 Hz, 1H,
CHCl), 3.30 (dd, J=6.2, 3.5 Hz, 1H, CHCO), 3.10 (apparent
t, J=7.7 Hz, 1H, CHPh); 13C NMR (75 MHz, CDCl3): d=
196.4 (C), 136.9 (C), 133.9 (C), 133.5 (CH), 129.1 (2ꢅCH),
128.8 (2ꢅCH), 128.3 (2ꢅCH), 128.2 (2ꢅCH), 127.5 (CH),
42.0 (CH), 34.8 (CH), 33.4 (CH); MS (70 eV, EI): m/z
(%)=256 [M+] (<1), 221 (100), 181 (11), 169 (12), 115 (12);
IR (neat): n=3063, 1667, 1216, 793 cmꢀ1; HR-MS (70 eV):
m/z=256.0627, calcd. for C16H13ClO: 256.0655; Rf =0.80
(hexane/EtOAc, 1:1).
(1S*,2R*,3S*)-Butyl
[2-chloro-3-phenylcycloprop-1-yl]
ketone (8b): Colourless oil. 1H NMR (300 MHz, CDCl3):
d=7.40–7.10 (m, 5H, Ph), 3.65 (dd, J=7.8, 3.5 Hz, 1H,
CHCl), 2.87 (apparent t, J=7.8 Hz, 1H, CHCO), 2.62–2.54
[m, 3H, CHPh, CH2ACTHNUTRGNEUNG(CH2)2CH3], 1.58 (m, J=7.2 Hz, 2H,
CH2CH2CH3), 1.30 (m, J=7.2 Hz, 2H, CH2CH2CH3), 0.86
[t, J=7.2, 3H, (CH2)3CH3]; 13C NMR (75 MHz, CDCl3): d=
207.1 (C), 133.7 (C), 128.9 (2ꢅCH), 128.2 (2ꢅCH), 127.4
(CH), 44.1 (CH2), 41.3 (CH), 36.0 (CH), 34.3 (CH), 25.8
(CH2), 22.2 (CH2), 13.7 (CH3); MS (70 eV, EI): m/z (%)=
201 [M+ꢀCl] (18), 131 (13), 115 (45), 85 (100), 57 (41); IR
(neat): n=3062, 1701, 1402, 765 cmꢀ1; HR-MS (70 eV):
m/z=201.1296, calcd. for [C14H17ClOꢀCl]: 201.1279; Rf =
0.83 (hexane/EtOAc, 1:1).
Synthesis of (1S*,2R*,3S*)-2-Chloro-1-(N,N-
diethylaminomethyl)-3-phenylcyclopropane (9)
To a suspension of LiAlH4 (2 mmol, 5 equiv.) in THF
(2 mL) was added dropwise a solution of 6a (0.4 mmol,
1 equiv.) in anhydrous THF (4 mL) at 08C. The mixture was
stirred for 15 h at reflux, then cooled at 08C and the reac-
tion quenched by the addition of a mixture of ice/water. The
mixture was then filtered through a pad of Celite and ex-
tracted with diethyl ether (3ꢅ10 mL). The organic layers
were washed with water, dried over Na2SO4, and concentrat-
ed under vacuum. Purification by chromatography on silica
gel (hexane/EtOAc, 5:1) afforded the pure compound 9 as a
1
colourless oil. H NMR (300 MHz, CDCl3): d=7.30–7.00 (m,
5H, Ph), 3.10 (dd, J=7.5, 3.9 Hz, 1H, CHCl), 2.80–2.40 [m,
6H, CH2N
CHPh), 1.67–1.59 (m, 1H, CHCH2N), 1.07 [t, J=7.3 Hz,
6H, N
(CH2CH3)2]; 13C NMR (75 MHz, CDCl3): d=135.7
ACHTNUGRTNE(NUGN CH2CH3)2], 2.09 (apparent t, J=7.5 Hz, 1H,
AHCTUNGTRENNUNG
(C), 129.0 (2ꢅCH), 127.9 (2ꢅCH), 126.6 (CH), 54.8 (CH2),
46.7 (2 x CH2), 39.4 (CH), 28.6 (CH), 25.6 (CH), 11.6 (2ꢅ
CH3); MS (70 eV, EI): m/z (%)=237 [M+] (4), 222 (40), 202
(82), 129 (45), 86 (100); IR (neat): n=3031, 1455, 1373,
780 cmꢀ1
;
HR-MS (70 eV): m/z=237.1255, calcd. for
C14H20ClN: 237.1284; Rf =0.35 (hexane/EtOAc, 3:1).
Synthesis of Cyclopropyl Ketones 8
The corresponding organolithium compound (1.2 mmol,
3.0 equiv.) was added dropwise to a solution of the amide 6c
(0.4 mmol, 1.0 equiv.) in anhydrous THF (2 mL) at ꢀ788C
under a nitrogen atmosphere. The mixture was stirred at
ꢀ788C for 1 h. The reaction was then quenched with an sa-
turated aqueous solution of ammonium chloride (5 mL) and
extracted with dichloromethane (3ꢅ10 mL). The organic
layers were washed with water, dried over Na2SO4, and con-
centrated under vacuum. Purification by column chromatog-
Acknowledgements
We acknowledge MICINN (CTQ2007-61132 and MAT2006-
01997), Principado de Asturias (FICYT IB08-028) and Euro-
pean Union (Fondo Europeo de Desarrollo Regional) for fi-
nancial support. J.M.C. thanks his wife Carmen Fernꢀndez-
2196
asc.wiley-vch.de
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2185 – 2198

Highly Stereoselective Halocyclopropanation of a,b-Unsaturated Amides
FULL PAPERS
Flꢁrez for her time. H.R.S. and E.G.B thank MICINN for a
Ramꢁn y Cajal Contract and Principado the Asturias for a
predoctoral fellowship, respectively. Our thanks to Dr Euan
C. Goddard (CRL, University of Oxford) for his revision of
the English.
202; d) J. Nishimura, J. Furukawa, J. Chem. Soc. Chem.
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Tetrahedron Lett. 1984, 25, 901–904.
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lissier, Tetrahedron 2008, 64, 7041–7095; b) A. de Mei-
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