Sequenced elimination-reduction and elimination-cyclopropanation reactions of 2,3-epoxyamides promoted by samarium diiodide. Synthesis of 2,3-dideuterioamides and cyclopropanamides

Article abstract of DOI:10.1016/j.tet.2004.07.051

An easy and general sequenced elimination/reduction or elimination/ cyclopropanation process promoted by samarium diiodide or/and CH ₂I₂/Sm provide an efficient method for synthesising 2,3-dideuterioamides 3 or cyclopropanamides 8, respectively. The transformations take place in high yields and with total or high selectivity from the easily available 2,3-epoxyamides. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.07.051

Tetrahedron 60 (2004) 10059–10065
Sequenced elimination–reduction and
elimination–cyclopropanation reactions of 2,3-epoxyamides
promoted by samarium diiodide. Synthesis of
2,3-dideuterioamides and cyclopropanamides
*
Jose M. Concellon, Monica Huerta and Eva Bardales
´
´
´
´ ´ ´ ´ ´ ´
Departamento de Quımica Organica e Inorganica, Facultad de Quımica, Universidad de Oviedo, Julian Claverıa, 8, 33071 Oviedo, Spain
Received 30 April 2004; revised 2 July 2004; accepted 22 July 2004
Abstract—An easy and general sequenced elimination/reduction or elimination/cyclopropanation process promoted by samarium diiodide
or/and CH2I2/Sm provide an efficient method for synthesising 2,3-dideuterioamides 3 or cyclopropanamides 8, respectively. The
transformations take place in high yields and with total or high selectivity from the easily available 2,3-epoxyamides.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
products,7 the development of an effective general
method for the synthesis of 2,3-dideuterioamides would
seem to be a valuable goal.
Samarium diiodide is a polyvalent reducing agent and
constitutes an effective reagent for sequential reactions,1
which present a high potential because less time, effort,
and material are required. Epoxides are useful inter-
mediates in organic synthesis and have been widely
used because of their chemical reactivity.2 However, the
reduction of epoxides to hydrocarbons has been scarcely
reported,3 and to the best of our knowledge, transform-
ation of 2,3-epoxyamides into saturated or 2,3-
dideuterioamides has not been published. Other possible
alternative to reduce 2,3-epoxyacid derivatives can be
performed by its transformation into a,b-unsaturated
acid derivatives and subsequent reduction to correspond-
ing saturated compounds. In this sense, selective
conjugated reduction of a,b-unsaturated carboxylic acid
derivatives has been achieved by using several method-
ologies.4 However, the conjugated reduction of a,b-
unsaturated amides with deuterium instead of hydrogen
has been scarcely reported.5 To the best of our
knowledge, only two examples have hitherto been
described,6 both of wich involved catalytic addition of
D2. Taking into account the utility of isotopically
labelled compounds to establish the mechanisms of
organic reactions and the biosynthesis of many natural
Moreover, the use of cyclopropanes in mechanistic studies,8
their utility as synthetic intermediates,9 and their presence in
a great number of natural products10 warrants interest in
these carbocycles from various fields in organic chemistry.
The majority of the methodologies developed for the
synthesis of cyclopropanes11 rely on variants of the
following reactions: Simmons–Smith cyclopropanation,12
transition-metal catalyzed cyclopropanation of alkenes with
diazomethane13 or diazoesters,14 and cyclopropanation of
Michael acceptors.15 However, these methods have some
disadvantages: total control of diastereoselectivity in the
synthesis of polysubstituted cyclopropanes is beyond reach,
some methodologies call for toxic reagents, and in other
cases, synthesis of cyclopropanes from unsaturated com-
pounds in which the C]C bond is tri- or tetrasubstituted
cannot be carried out.16 Consequently, new methods for the
diastereoselective construction of cyclopropanamides, in
which the cyclopropane ring is polysubstituted, are of
significant interest.17
Previously, we reported the transformation of 2,3-epoxy-
esters into saturated esters by using SmI218 and 2-chloro-3-
hydroxyamides into cyclopropanamides promoted by
CH2I2/Sm.19 More recently, we have also reported a
b-elimination reaction of aromatic20 and aliphatic21 a,b-
epoxyamides, obtaining (Z)- or (E)-a,b-unsaturated
amides with total or very high diastereoselectivity.
Keywords: Samarium diiodide; Sequenced reactions; Deuterium; Saturated
amides; Cyclopropanamides.
* Corresponding author. Tel.: C34985103457; fax: C349853446;
e-mail: jmcg@fq.uniovi.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.051

´
J. M. Concellon et al. / Tetrahedron 60 (2004) 10059–10065
10060
Now, we describe a method to obtain saturated amides and
cyclopropanamides from 2,3-epoxyamides by an efficient
SmI2-promoted elimination–reduction or elimination–
cyclopropanation sequential reaction, respectively. We
have also performed sequenced elimination–reduction
reactions to obtain 2,3-dideuterioamides by using D2O
instead of H2O.
Scheme 1.
2. Results and discussion
This proposed methodology to obtain saturated amides 2 or
2,3-dideuterioamides 3 is general. Thus, R1 and R3 can be
aliphatic or aromatic, and can be performed from 2,3-
epoxyamides in which the oxirane ring is di-, tri- or
tetrasubstituted. No significant differences were observed in
the reaction when D2O was used instead of H2O.
The starting compounds 1 were easily obtained by reaction
of aldehydes or ketones with lithium or potassium enolates
derived from chloroacetamides, by using standard
methods.20,21 Thus, epoxyamides 1 were obtained as a
mixture cis/trans and with the yields showed in Table 1.
1
The position of deuteration was established by H and 13C
NMR spectrometry of compounds 3, while complete
deuterium incorporation (O99%) was determined by mass
spectroscopy.22 The obtained 2,3-dideuterioamides 3 were
isolated as mixture of diastereoisomers (ranging between
1:1 and 2:1) due to the fact that incorporation of deuterium
generates two new stereogenic centres. It is noteworthy that
D2O is the most widely available deuteration reagent for
obtaining organic compounds isotopically labelled with
deuterium.
2.1. Synthesis of saturated 2 or 2,3-dideuterioamides 3
The reaction of different di- or tetrasubstituted 2,3-
epoxyamides 1a–c with SmI2 (5 equiv.) afforded the
corresponding a,b-unsaturated amides. After treatment
with H2O or D2O gave the corresponding saturated amides
2 or 2,3-dideuterioamides 3, respectively (Scheme 1,
Table 2).
Starting from trisubstituted 2,3-epoxyamides 1, (Table 2,
entries 2, 3 and 7,8) a complex mixture of products was
obtained. We have overcome this problem by adding
samarium diiodide in two times. Thus, the succesive
treatment of trisubstituted 2,3-epoxyamides 1 with a
solution of SmI2 in THF and HMPA (exclusively in the
case of aliphatic a,b-epoxyamides) and further treatment
with additional SmI2 and H2O or D2O, afforded the
corresponding saturated amides 2 or 2,3-dideuterioamides
3 respectively, in good yield (Scheme 1, Table 2).
A postulated mechanism is illustrated in Scheme 2. In the
first step, the metalation of 1 by SmI2 generates an enolate
intermediate 4, which suffers a b-elimination reaction
affording a,b-unsaturated amides 5.20,21 In the second
step, the 1,4-reduction of 5, is initiated by a single electron
transfer from SmI2 to generate the enolate radical 623 which,
upon reaction with a second equivalent of SmI2 produces the
dianion 7. Subsequent protonation of 7 by D2O or H2O,
affords the corresponding compound 3 or 2, respectively.
Table 1. Synthesis of epoxyamides 1
Entry
1a
R1
R2
R3
Yield (%)b
trans /cisc
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
pMeO–C6H4
Bu
Cyclohexyl
C7H15
H
H
Ph
H
H
H
H
H
Ph
H
H
62
69
74
85
92
83
79
95
2/1
1.4/1
1.6/1
1.7/1
2.7/1
1.3/1
3/1
Ph
Me
Me
Me
Me
Me
1g
1h
pMeO–C6H4
Et
1.5/1
a
General procedure to obtain compounds 1 is described in references 20 and 21.
Isolated yield after column chromatography.
b
c
Diastereoisomers ratio determined by 13C NMR analysis.
Table 2. Synthesis of saturated amides 2 and 2,3-dideuterioamides 3
Entry
Compounda
R1
R2
R3
X
Yield (%)b
1
2
3
4
5
6
7
8
2a
2c
2d
2h
3a
3b
3c
3f
Ph
Bu
Cyclohexyl
Ph
Ph
pMeO–C6H4
Bu
H
H
H
H
Et
H
H
H
Ph
H
H
H
H
H
D
D
D
D
95
69
82
66
94
71
67
61
Ph
Me
Me
H
H
Ph
Me
a
All products were fully characterized by spectroscopic methods [IR, NMR, and MS].
Isolated yield after column chromatography based on compound 1.
b

´
J. M. Concellon et al. / Tetrahedron 60 (2004) 10059–10065
10061
Scheme 2.
Scheme 4.
cyclopropanamides were obtained, while from trisubstituted
aromatic epoxyamides cis-cyclopropanamides were pre-
pared (Table 3, entries 4 and 5). Taking into account that the
cyclopropanation reaction is stereospecific, the stereochem-
istry of the cyclopropane ring is directly related with the
stereochemistry of the double bond C]C formed in the first
step.
Scheme 3.
2.2. Preparation of cyclopropanamides 8
The diastereoisomeric purity of compounds 8 was deter-
mined on the crude reaction products by 1H NMR
spectroscopy (300 MHz) and GC-MS. The relative trans
or cis configuration of substituents on the cyclopropane ring
The reaction of 2,3-epoxyamides with SmI2 at room
temperature and further treatment with a mixture of
Sm/CH2I2 afforded the corresponding cyclopropanamide 8
in high yield and with total or very high distereoselectivity
(Scheme 3 and Table 3). Starting from trisubstituted
aliphatic 2,3-epoxyamides, the elimination reaction was
carried out by using HMPA as cosolvent to enhance the
diastereoselectivity of the process (Table 3, entries 2 and 3).
In the case of trisubstituted aromatic epoxyamides, the use
of MeOH as cosolvent in the first step increases the
diastereoselectivity of the b-elimination reaction and avoids
side reactions (Table 3, entries 4 and 5). In this case, the
solvents were eliminated previously to carry out the second
step due to no cyclopropanation reaction takes place in the
presence of MeOH. Consequently, in these two cases the
process is one-pot instead of a sequential reaction. Results in
Table 3 show that this elimination–cyclopropanation
reaction is general: the starting compounds can be aliphatic
or aromatic and the oxirane ring can be di-, tri- or
tetrasubstituted.
1
was established by analysis of H NMR coupling constant
between the cyclopropane protons of compound 8a, by NOE
1
experiments (8h) and by comparison of their H and 13C
NMR spectra with authentic samples, as has been previously
described.19
The course of the synthesis of 8 can be thought to occur as
shown in Scheme 4, through a sequential elimination-
cyclopropanation reaction. Initially, 1 suffers an elimination
reaction promoted by SmI2, affording cis- (from trisubsti-
tuted aromatic epoxyamides) or trans-a,b-unsaturated
amides 5 (from the rest), with high diastereoselectivity. In
the second step, carbenoids of Sm (II) (e.g., ISmCH2I)24
produce a stereospecific cyclopropanation of 5.25 Tenta-
tively, we propose a transition state model I,26 in which the
coordination of the divalent samarium atom with the oxygen
atom of the amide group provides cyclopropylamide 8,
whilst maintaining the geometry about the C]C bond. The
abundance of the zwitterionic specie of the amide seems to
be the responsible of the reaction of samarium carbenes with
the olefin, in a similar way as this described for allylic
alcohols.27
The stereochemistry of the cyclopropane ring was depen-
dent on the structure starting epoxyamide. Thus, from
aliphatic (Table 3, entries 2 and 3) and di- or tetrasubstituted
aromatic epoxyamides (entries
1
and 6), trans-
Table 3. Synthesis of cyclopropanamides 8
Entry
8a
R1
R2
R3
d.e.b
Yield (%)c
1
2
3
4
5
6
8a
8d
8e
8f
8g
8h
Ph
Cyclohexyl
C7H15
H
H
Ph
H
H
H
Ph
H
O98
O98
97
O98
O98
O98
73
60
62
88
84
87
Me
Me
Me
Me
Me
PmeO–C6H4
Et
a
All products were fully characterized by spectroscopic methods [IR, NMR, and MS].
b
c
1
Diastereoisomeric excess determined by GC/MS and 300 MHz H NMR analysis of the crude products.
Isolated yield after column chromatography based on compound 1.

´
J. M. Concellon et al. / Tetrahedron 60 (2004) 10059–10065
10062
3. Conclusion
2,3-dideuterioamides 3, which were purified by column
flash chromatography over silica gel (hexane/ethyl acetate).
In conclusion, two efficient sequential methodologies have
been described. In the first, the SmI2-promoted elimination–
reduction sequence (in the presence of D2O or H2O)
provides an efficient method for synthesising 2,3-dideuterio-
amides or non-deuterated saturated amides. In the second,
elimination–cyclopropanation affords cis- or trans-cyclo-
propanamides with total or very high diastereoselectivity.
1
4.3.1. N,N-Diethyl-3-phenylpropionamide (2a). H RMN
(300 MHz, CDCl3): dZ7.32–7.15 (m, 5H), 3.38 (q, JZ
7.18 Hz, 2H), 3.21 (q, JZ7.18 Hz, 2H), 3.17–2.94 (m, 2H),
2.65–2.54 (m, 2H), 1.11 (t, JZ7.18 Hz, 3H), 1.09 (t, JZ
7.18 Hz, 3H); 13C NMR (75 MHz, CDCl3): dZ171.0 (C),
141.4 (C), 128.2 (CH), 125.8 (CH), 41.7 (CH2), 40.0 (CH2),
34.9 (CH2), 31.5 (CH2), 14.1 (CH3), 12.9 (CH3); MS
(70 eV): m/z (%): 205 (100) [M]C, 176 (12), 133 (4), 105
(28), 91 (44), 77 (16); IR 3083, 3059, 3028, 2975,
1640 cmK1; HRMS Calcd for C12H19NO 205.1466; found
205.1468; Rf 0.2 (hexane/AcOEt 5/1).
4. Experimental
4.1. General remarks
Reactions which required an inert atmosphere were
conducted under dry nitrogen, and the glassware was oven
dried (120 8C). THF was distilled from sodium/benzo-
phenone ketyl immediately prior to use. All reagents were
purchased from Aldrich or Merck and were used without
further purification. Samarium diiodide was prepared by
reaction of CH2I2 with samarium powder by ultrasonic
irradiation.28 Silica gel for flash chromatography was
purchased from Merck (230–400 mesh), and compounds
were visualized on anlytical thin layer chromatograms
(TLC) by UV light (254 nm). 1H NMR spectra were
recorded at 200 or 300 MHz. 13C NMR spectra and DEPT
experiments were determined at 50 or 75 MHz. Chemical
shifts are given in ppm relative to tetramethylsilane (TMS),
which is used as an internal standard, and coupling constants
J are reported in Hz. The diastereoisomeric excesses were
obtained from 1H NMR analysis and GC-MS of crude
products. GC-MS and HRMS were measured at 70 eV. Only
the most important IR absorptions (cmK1) and the
molecular ions and/or base peaks in MS are given.
1
4.3.2. N,N-Diethyl-2-phenylheptanamide (2c). H NMR
(200 MHz, CDCl3): dZ7.41–7.17 (m, 5H), 3.52–3.01 (m,
4H), 2.67–2.56 (m, 1H), 2.22–1.53 (m, 2H), 1.49–1.11 (m,
6H), 1.08–0.65 (m, 9H); 13C NMR (75 MHz, CDCl3): dZ
172.0 (C), 140.8 (C), 128.3 (CH), 127.5 (CH), 126.4 (CH),
48.7 (CH), 41.4 (CH2), 40.1 (CH2), 35.2 (CH2), 31.6 (CH2),
27.4 (CH2), 22.3 (CH2), 14.2 (CH3), 13.8 (CH3), 12.6
(CH3); IR 2939, 1636, 1456, 1380 cmK1. Anal. Calcd for
C17H22NO: C, 78.11; H, 10.41; N, 5.36; found: C, 78.06; H,
10.39; N, 5.44; Rf 0.3 (hexane/AcOEt 3/1).
4.3.3. 3-Cyclohexyl-N,N-diethyl-2-methylpropanamide
1
(2d). H NMR (200 MHz, CDCl3): dZ3.63–3.29 (m, 4H),
1.88–0.72 (m, 14H), 2.19 (t, JZ7.2 Hz, 6H), 1.09 (d, JZ
7.4 Hz, 3H); 13C RMN (75 MHz, CDCl3): dZ176.2 (C),
41.9 (CH2), 41.7 (CH2), 40.2 (CH2), 35.3 (CH), 33.9 (CH2),
33.1 (CH2), 32.5 (CH), 26.5 (CH2), 26.3 (CH2), 26.2 (CH2),
18.1 (CH3), 14.8 (CH3), 13.0 (CH3); IR 2924, 1624, 1448,
1380 cmK1. Anal. Calcd for C14H27NO: C, 74.61; H, 12.08;
N, 6.21; found: C, 74.58; H, 12.07; N, 5.38; Rf 0.3 (hexane/
AcOEt 3/1).
4.2. General procedure for the synthesis of compounds 2
and 3 from di- or tetrasubstituted 2,3-epoxyamides 1
4.3.4. N,N-Diethyl-3-phenyl-2-methylpentanamide (2h).
(Diastereoisomeric mixture); H NMR (200 MHz, CDCl3):
1
A solution of SmI2 (2.3 mmol) in THF (24 mL) was added,
under nitrogen atmosphere, to a stirred solution of the
corresponding 2,3-epoxyamide 1 (0.4 mmol) in THF (4 mL)
at room temperature. After stirring for 30 min, H2O or D2O
(1 mL) was added to the reaction. The mixture was stirred
for 30 min at room temperature. Then, the reaction was
quenched with aqueous HCl (0.1 M, 10 mL). Usual workup
afforded crude saturated amides 2 or 2,3-dideuterioesters 3,
which were purified by column flash chromatography over
silica gel (hexane/ethyl acetate).
dZ7.35–7.09 (m, 10H), 3.54–2.63 (m, 16H), 1.27 (t, JZ
7.1 Hz, 6H), 1.15 (t, JZ7.1 Hz, 6H), 1.04 (t, JZ7.1 Hz,
6H), 0.83 (d, JZ5.9 Hz, 6H), 0.74–0.61 (m, 6H); 13C NMR
(50 MHz, CDCl3): dZ175.3 (C), 174.8 (C), 143.2 (C),
142.8 (C), 128.3 (CH), 128.1 (CH), 128.0 (CH), 127.7 (CH),
126.0 (CH), 125.8 (CH), 51.4 (CH), 50.4 (CH), 42.0 (CH),
41.9 (CH), 41.5 (CH2), 41.4 (CH2), 40.5 (CH2), 39.8 (CH2),
27.1 (CH2), 23.9 (CH2), 17.2 (CH3), 16.2 (CH3), 14.8 (CH3),
14.3 (CH3), 12.9 (CH3), 12.3 (CH3), 12.1 (CH3), 11.9
(CH3); IR 2968, 1635, 1456, 1380 cmK1. Anal. Calcd for
C16H25N: C, 77.68; H, 10.19; N, 5.66; found: C, 77.75; H,
10.09; N, 5.67; Rf 0.4, 0.3 (hexane/AcOEt 3/1).
4.3. General procedure for the synthesis of compounds 2
and 3 from trisubstituted 2,3-epoxyamides
A solution of SmI2 (1.6 mmol) in THF (19 mL) and HMPA
(2 mmol), in the case of aliphatic a,b-epoxyamides, was
added, under nitrogen atmosphere, to a stirred solution of
the corresponding epoxyamide 1 (0.4 mmol) in THF (4 mL)
at room temperature. After stirring for 30 min at room
temperature, a solution of SmI2 (1.1 mmol) in THF (12 mL)
and H2O or D2O (1 mL) was added to the solution and the
mixture was stirred for 3 h at room temperature. Then, the
reaction was quenched with aqueous HCl (0.1 M, 10 mL).
Usual workup afforded crude saturated amides 2 or
4.3.5. 2,3-Dideuterio-N,N-diethyl-3-phenylpropanamide
(3a). H NMR (300 MHz, CDCl3): dZ7.34–7.19 (m, 5H),
1
3.38 (q, JZ7.18 Hz, 2H), 3.23 (q, JZ7.18 Hz, 2H), 3.00–
2.94 (m, 1H), 2.61–2.55 (m, 1H), 1.12 (t, JZ7.18 Hz, 3H),
1.11 (t, JZ7.18 Hz, 3H); 13C NMR (75 MHz, CDCl3): dZ
171.0 (C), 141.2 (CH), 128.2 (CH), 125.8 (CH), 41.6 (CH2),
39.9 (CH2), 34.4 (t, JZ19.7 Hz, CHD), 31.0 (t, JZ19.7 Hz,
CHD), 14.0 (CH3), 12.8 (CH3); MS (70 eV): m/z (%): 207
(42) [M]C, 178 (7), 149 (10), 135 (4), 107 (18), 92 (53), 77
(50); IR 3083, 3060, 3025, 2973, 2932, 1638 cmK1; HRMS

´
J. M. Concellon et al. / Tetrahedron 60 (2004) 10059–10065
10063
Calcd for C13H17D2NO 207.1466; found 207.1589; Rf 0.2
(hexane/AcOEt 5/1).
MeOH (0.4 mL) were used, respectively, as cosolvent to
carry out the first step.9,10 In the last case, previously to the
addition of CH2I2 and Sm, solvents were eliminated to
dryness.
4.3.6. 2,3-Dideuterio-N,N-diethyl-3-[4-(methoxy)phe-
1
nyl]propanamide (3b). H NMR (300 MHz, CDCl3): dZ
In the obtention of 8a, cyclopropanation took place at 0 8C,
during 2 h and just with 1.4 mmol of samarium powder and
1.4 mmol of CH2I2.
7.14 (d, JZ8.7 Hz, 2H), 6.83 (d, JZ8.7 Hz, 2H), 3.78 (s,
3H), 3.37 (q, JZ7.2 Hz, 2H), 3.21 (q, JZ7.2 Hz, 2H), 2.98–
2.78 (m, 1H), 2.62–2.44 (m, 1H), 1.11 (t, JZ7.2 Hz, 3H),
1.10 (t, JZ7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): dZ
171.2 (C), 157.8 (C), 133.4 (C), 129.2 (CH), 113.7 (CH),
55.1 (CH3), 41.7 (CH2), 40.0 (CH2), 34.8 (CHD, t, JZ
19.2 Hz), 30.2 (CHD, t, JZ19.2 Hz), 14.1 (CH3), 12.9
(CH3); MS (70 eV): m/z (%): 227 (2) [M]C, 222 (2), 147
(35), 72 (100); IR 3060, 1636, 1514, 1458 cmK1; Rf 0.3
(hexane/AcOEt 3/1).
4.4.1. (1S*,2S*)-N,N-Diethyl-2-phenylcyclopropanocar-
boxamide (8a). 1H NMR (300 MHz, CDCl3): dZ7.31–
7.10 (m, 5H), 3.44 (q, JZ7.18 Hz, 2H), 3.43 (q, JZ7.18 Hz,
2H), 2.49 (ddd, JZ9.11, 5.98, 4.27 Hz, 1H), 1.93 (ddd, JZ
8.25, 5.41, 4.27 Hz, 1H), 1.65 (ddd, JZ9.11, 5.41, 3.99 Hz,
1H), 1.25 (ddd, JZ8.25, 5.98, 3.99 Hz, 1H), 1.19 (t, JZ
7.18 Hz, 3H), 1.14 (t, JZ7.18 Hz, 3H); 13C NMR (75 MHz,
CDCl3): dZ170.9 (C), 141.0 (C), 128.3 (CH), 126.0 (CH),
42.0 (CH2), 40.8 (CH2), 25.3 (CH), 23.1 (CH), 16.1 (CH2),
14.8 (CH3), 13.2 (CH3); MS (70 eV): m/z (%): 217 (37)
[M]C, 145 (25), 117 (39), 72 (91), 42 (100); IR 3019, 2971,
1627, 1452, 1377 cmK1; HRMS Calcd for C14H19NO
217.1467; found 217.1495; Rf 0.3 (hexane/AcOEt 3/1).
4.3.7. 2,3-Dideuterio-N,N-diethyl-2-phenylheptanamide
1
(3c). H NMR (200 MHz, CDCl3): dZ7.39–7.19 (m, 5H),
3.56–3.06 (m, 4H), 2.18–1.53 (m, 2H), 1.49–1.10 (m, 5H),
1.17–0.78 (m, 9H); 13C NMR (50 MHz, CDCl3): dZ172.1
(C), 140.8 (C), 128.5 (CH), 127.7 (CH), 126.5 (CH), 48.3
(CD, t, JZ19.4 Hz), 41.5 (CH2), 40.3 (CH2), 34.9 (CHD, t,
JZ19.4 Hz), 31.7 (CH2), 27.4 (CH2), 22.4 (CH2), 14.4
(CH3), 13.9 (CH3), 12.8 (CH3); IR 2939, 1636, 1456,
1380 cmK1. Anal. Calcd for C17H25D2NO: C, 74.61; H,
11.10; N, 5.32; found: C, 74.60; H, 10.09; N, 5.39; Rf 0.3
(hexane/AcOEt 3/1).
4.4.2. (1S*,2R*)-2-Cyclohexyl-N,N-diethyl-1-methyl-
cyclopropanocarboxamide (8d). 1H NMR (400 MHz,
[D6]DMSO): dZ3.48 (q, JZ7.05 Hz, 4H), 1.95–1.69 (m,
5H), 1.45–0.98 (m, 6H), 1.33 (s, 3H), 1.17 (t, JZ7.05 Hz,
6H), 1.06 (dd, JZ8.97, 4.20 Hz, 1H), 0.90 (dd, JZ8.97,
4.77 Hz, 1H), 0.27 (dd, JZ4.77, 4.20 Hz, 1H); 13C NMR
(100 MHz, [D6]DMSO): dZ172.7 (C), 39.1 (CH2), 36.9
(CH), 32.2 (CH2), 27.8 (CH), 25.5 (CH2), 25.3 (CH2), 25.1
(CH2), 24.5 (C), 16.9 (CH2), 15.7 (CH3), 12.6 (CH3); MS
(70 eV): m/z (%): 237 (10) [M]C, 222 (5), 100 (25), 55 (52),
41 (100); IR 2981, 2924, 1627, 1429, 1379 cmK1; HRMS
Cald. for C15H27NO 237.2093 found 237.2101; Rf 0.4
(hexane/AcOEt 3/1).
4.3.8. 2,3-Dideuterio-N,N-diethyl-3-phenyl-2-methyl-
propanamide (3f). (Diastereoisomeric mixture); H NMR
1
(300 MHz, CDCl3): dZ7.30–7.15 (m, 10H), 3.48–3.36 (m,
2H), 3.25–3.13 (m, 2H), 3.05 (q, JZ7.18 Hz, 4H), 2.62 (s,
2H), 1.26 (s, 3H), 1.16 (s, 3H), 1.02 (t, JZ7.18 Hz, 6H),
0.93 (t, JZ7.18 Hz, 6H); 13C NMR (75 MHz, CDCl3): dZ
175.0 (C), 140.6 (C), 140.1 (C), 129.0 (CH), 128.9 (CH),
128.1 (CH), 126.0 (CH), 125.7 (CH), 41.6 (CH2), 40.3
(CH2), 40.3 (t, JZ19.8 Hz, CHD), 37.6 (t, JZ19.8 Hz, CD),
18.0 (CH3), 14.5 (CH3), 12.9 (CH3); MS (70 eV): m/z (%):
221 (36) [M]C, 206 (22), 121 (19), 92 (100); IR 3062, 3026,
2971, 1636, 1379 cmK1; HRMS Calcd for C14H19D2NO
221.1735; found 221.1749; Rf 0.3 (hexane/AcOEt 3/1).
4.4.3. (1S*,2S*)-N,N-Diethyl-2-heptyl-1-methylcyclo-
propanocarboxamide (8e). H NMR (200 MHz, CDCl3):
1
dZ3.59–3.19 (m, 4H), 1.60–0.95 (m, 17H), 1.20 (s, 3H),
1.09 (t, JZ7.12 Hz, 3H), 0.83 (t, JZ6.55 Hz, 3H), 0.13 (dd,
JZ5.41, 4. 84 Hz, 1H); 13C RMN (50 MHz, CDCl3): dZ
174.5 (C), 40.8 (CH2), 40.1 (CH2), 31.7 (CH2), 29.4 (CH2),
29.3 (CH2), 29.2 (CH2), 24.4 (C), 22.6 (CH2), 22.3 (CH),
18.5 (CH2), 16.4 (CH3), 14.3 (CH3), 14.0 (CH3), 13.6
(CH3); MS (70 eV): m/z (%): 253 (18) [M]C, 238 (10), 154
4.4. General procedure for the synthesis of compounds 8
Over a solution of SmI2 (1.1 mmol for di- or tetrasubstituted
aromatic 2,3-epoxyamides 1 and 1.7 mmol for the rest) in
THF (12 and 20 mL, respectively), a solution of the
corresponding 2,3-epoxyamide 1 (0.4 mmol) in THF
(4 mL) was added, under nitrogen atmosphere, at room
temperature. After stirring for 30 min, the complete
formation of 5 was checked by TLC. Then, when samarium
diiodide remained, iodine pearls were added till colour
changed from blue to yellow. The reaction mixture was
cooled to K30 8C and 16 mL of dry THF, 2.4 mmol of
samarium powder and 2.4 mmol of CH2I2 were added. After
stirring at K30 8C during 10 h, the excess samarium
diiodide was destroyed by oxidation with air, and the
reaction was quenched with aqueous HCl (0.1 M, 10 mL).
Usual workup afforded crude cyclopropanamides 8, which
were purified by short column flash chromatography over
silica gel (hexane/ethyl acetate 3:1).
(18), 100 (81), 41 (100); IR 2929, 1626, 1425, 1377 cmK1
;
HRMS Calcd for C16H31NO 253.2406; found 253.2406; Rf
0.4 (hexane/AcOEt 3/1).
4.4.4. (1R*,2S*)-N,N-Diethyl-1-methyl-2-phenylcyclo-
propanocarboxamide (8f). H NMR (300 MHz, CDCl3):
1
dZ7.28–7.03 (m, 5H), 3.48–3.33 (m, 2H), 2.96–2.87 (m,
1H), 2.74–2.87 (m, 1H), 2.16 (dd, JZ5.6, 8.8 Hz, 1H), 2.10
(dd, JZ6.5, 8.8 Hz, 1H), 1.73 (aparent t, JZ6.0 Hz, 1H),
1.45 (s, 3H), 0.76 (t, JZ7.1 Hz, 6H); 13C RMN (75 MHz,
CDCl3): dZ170.5 (C), 138.6 (C), 127.9 (CH), 126.3 (CH),
125.8 (CH), 40.4 (CH2), 38.2 (CH2), 31.7 (CH), 31.5 (C),
23.3 (CH3), 19.5 (CH2), 13.2 (CH3), 11.8 (CH3); MS
(70 eV): m/z (%): 231 (64) [M]C, 216 (12), 202 (5), 158
(32), 144 (11), 140 (26), 131 (46), 115 (38), 100 (72), 91
(100), 72 (82); IR 3062, 2975, 2931, 2878, 1632, 1461,
In the case of synthesis of 8b,c or 8d,e, HMPA (0.5 mL) or

´
J. M. Concellon et al. / Tetrahedron 60 (2004) 10059–10065
10064
1427, 1382, 1253, 1129, 1066 cmK1; Rf (0.2 hexane/AcOEt
3/1).
4. Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989; pp 12–17.
5. Sequential b-elimination-reduction (by using D2O) of 2-
4.4.5. (1R*,2S*)-N,N-Diethyl-1-methyl-2-(4-methoxy-
phenyl)cyclopropanocarboxamide (8g). 1H NMR
(300 MHz, CDCl3): dZ6.97–6.72 (m, 4H), 3.50 (s, 3H),
3.48–3.29 (m, 2H), 3.07–2.89 (m, 1H), 2.79–2.67 (m, 1H),
2.06–2.01 (m, 1H), 1.65 (aparent t, JZ6.0 Hz, 1H), 1.42 (s,
3H), 1.01 (dd, JZ5.5, 8.8 Hz, 1H), 0.86–0.76 (m, 6H); 13C
RMN (100 MHz, CDCl3): dZ170.6 (C), 157.7 (C), 130.6
(C), 127.2 (CH), 113.2 (CH), 55.0 (CH3), 40.4 (CH2), 38.1
(CH2), 31.0 (C), 30.9 (CH), 23.2 (CH3), 19.1 (CH2), 13.2
(CH3), 11.8 (CH3); MS (70 eV): m/z (%): 261 (32) [M]C,
192 (28), 188 (100), 174 (19), 161 (49), 145 (31), 134 (20),
121 (43), 115 (29), 100 (26), 91 (47), 72 (56); IR 3035,
2947, 2878, 2837, 1628, 1516, 1442, 1381, 1300, 1249,
1129, 1034 cmK1; Rf (0. 28 hexane/AcOEt 1/1).
´
chloro-3-hydroxiamides has been reported: Concellon, J. M.;
´
Rodrıguez-Solla, H. Chem. Eur. J. 2001, 7, 4266–4271.
6. (a) Oba, M.; Miyakawa, A.; Nishiyama, K. J. Org. Chem.
1999, 64, 9275–9278. (b) Lutz, G. P.; Walling, A. P.; Kerrick,
S. T.; Beak, P. J. Org. Chem. 1991, 56, 4938–4943.
7. Mann, J. Secondary Metabolism; Oxford University Press:
Oxford, 1986; p 23.
8. (a) Maier, G.; Senger, S. Angew Chem., Int. Ed. Engl. 1994,
33, 558–559. (b) Dechoux, L.; Doris, E. Tetrahedron Lett.
1994, 35, 2017–2020.
9. De Meijere, A., Ed.; Carbocyclic three- and four-membered
ring systems Methods of Organic Chemistry, 1997; Vol. E
17a–f, Houben-Weyl.
10. (a) Liu, H. W.; Walsh, C. T. Biochemistry of the Cyclopropyl
Group. Patai, S., Rappoport, Z., Eds.; The Chemistry of the
Cyclopropyl Group; Wiley: 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.
11. For some reviews, see: (a) Tsuji, T.; Nishida, S. Preparation of
Cyclopropyl Derivatives. Patai, S., Rappoport, Z., Eds.; The
Chemistry of the Cyclopropyl Group; Wiley: New York; 1987;
pp 308–373. (b) Salau¨n, J. Chem. Rev. 1989, 89, 1247–1270.
12. (a) Morikawa, T.; Sasaki, H.; Hanai, R.; Shibuya, A.; Taguchi,
T. J. Org. Chem. 1994, 59, 97–103. (b) Charette, A. B.;
Marcoux, J. F. Synlett 1995, 1197–1207. (c) Charette,
A. B.; Marcoux, J. F. J. Am Chem. Soc. 1996, 118,
4539–4549.
4.4.6. (1S*,2R*)-N,N-Diethyl-2-ethyl-2-phenyl-1-methyl-
cyclopropanocarboxamide (8h). 1H NMR (300 MHz,
CDCl3): dZ7.45–7.01 (m, 5H), 3.54–3.27 (m, 4H), 2.75–
2.49 (m, 2H), 2.21 (d, JZ5.41 Hz, 1H), 1.46 (s, 3H), 1.03 (t,
JZ7.12 Hz, 3H), 0.82 (t, JZ7.12 Hz, 3H), 0.53 (d, JZ
5.41 Hz, 1H), 0.32 (t, JZ7.12 Hz, 3H); 13C NMR (50 MHz,
CDCl3): dZ171.4 (C), 138.8 (C), 127.6 (CH), 127.5 (CH),
125.7 (CH), 40.8 (CH2), 37.9 (CH2), 35.6 (C), 34.3 (C), 25.7
(CH2), 22.9 (CH2), 18.8 (CH3), 13.5 (CH3), 11.0 (CH3), 10.8
(CH3); MS (70 eV): m/z (%): 259 (25) [M]C, 244 (12), 91
(91), 42 (100); IR 3058, 2968, 1628, 1450, 1381 cmK1
;
HRMS Calcd for C17H25NO 259.1936; found 259.1933; Rf
0.3 (hexane/AcOEt 3/1).
13. (a) Paulissen, R.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett.
1972, 13, 1465–1468. (b) Suda, M. Synthesis 1981, 714.
(c) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 1999, 64,
8287–8297.
Acknowledgements
14. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley: New York, 1998; pp 163–288.
´
We thank Ministerio de Ciencia y Tecnologıa (BQU2001-
3807) for financial support. J. M. C. thanks Carmen
´
´
Fernandez–Florez for her time, E. B. to Principado de
Asturias for a predoctoral fellowship, and M. H. thanks to
15. Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97,
2341–2372.
´
Ministerio de Educacion, Cultura y Deporte for a pre-
16. Dehmlow, E. V.; Eulenberg, K. Liebigs Ann. Chem. 1978,
1112–1115.
doctoral fellowship. Our Thanks to Scott J. S. Hartman for
his revision of the English.
17. For recent reports on the cyclopropanation of a,b-unsaturated
amides, see: (a) Goumri-Magnet, S.; Kato, T.; Gornitzka, H.;
Baceiredo, A.; Bertrand, G. J. Am. Chem. Soc. 2000, 122,
4464–4470. (b) Ye, S.; Yuan, L.; Huang, Z. Z.; Tang, Y.; Dai,
L. X. J. Org. Chem. 2000, 65, 6257–6260. (c) Mamai, A.;
Madalengoitia, J. S. Tetrahedron Lett. 2000, 41, 9009–9014.
References and notes
´
18. Concellon, J. M.; Bardales, E.; Llavona, R. J. Org. Chem.
2003, 68, 1585–1588.
´ ´
19. Concellon, J. M.; Rodrıguez-Solla, H.; Llavona, R. J. Org.
Chem. 2003, 68, 1132–1133.
1. For reviews on sequenced reactions promoted by samarium
diiodide: (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996,
96, 307–338. (b) Molander, G. A.; Harris, C. R. Tetrahedron
1998, 54, 3321–3354.
´
20. Concellon, J. M.; Bardales, E. J. Org. Chem. 2003, 68,
9492–9495.
2. For a review on epoxide chemistry and reactivity see: (a) Rao,
A. S.; Panikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39,
2323–2365. (b) Gorzynski-Smith, J. Synthesis 1984, 629–656.
(c) For some recent synthetic application of epoxides see
Marshall, J. A.; Chobanian, H. R. Org. Lett. 2003, 4,
3777–3779. (d) Molinaro, C.; Jamison, T. F. J. Am. Chem.
Soc. 2003, 125, 8076–8077.
´
21. Concellon, J. M.; Bardales, E. Eur. J. Org. Chem. 2004,
1523–1526.
22. MS and HRMS spectra of compounds 3 show lack or very
weak peak of the [M]C of the corresponding non-deuterated
compound, indicating a presence of the non-deuterated
compound !1%.
23. Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997, 38,
2121–2124.
3. (a) Fry, J. L.; Mraz, T. J. Tetrahedron Lett. 1979, 20, 849–852.
(b) Van Temelen, E. E.; Gladysz, J. A. J. Am Chem. Soc. 1974,
96, 5290–5291.

´
J. M. Concellon et al. / Tetrahedron 60 (2004) 10059–10065
10065
24. (a) Carbenoids of samarium have been proposed as intermedi-
ates in the cyclopropanation of allylic alcohols. Molander,
G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525–3532; and
in the generation of the SmI2 from samarium metal and
diiodomethane: (b) Namy, J. L.; Caro, P. E.; Girard, P.; Kagan,
H. B. Nouv. J. Chim. 1981, 5, 479–484. (c) Imamoto, T.; Koto,
H.; Takeyama, T. Tetrahedron Lett. 1986, 27, 3243–3246.
(d) Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett.
1986, 27, 3891–3894.
26. A similar model was previously proposed by HoukMareda, J.;
Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1983, 105,
6997–6999 for the addition of carbenoids to olefins, and to
explain the cyclopropanation of allylic alcohols promoted by
SmI2.
27. The absence of cyclopropanation in alkenes or in a,b-
unsaturated esters can be explained by the non-existence of
an electronically rich oxygen wich can coordinate the
samarium carbenes.
25. Cyclopropanation of a,b-unsaturated amides takes place
´ ´
stereospecificaly: Concellon, J. M.; Rodrıguez-Solla, H.;
´ ´
28. Concellon, J. M.; Rodrıguez-Solla, H.; Bardales, E.; Huerta,
M.; Eur J. Org. Chem. 2003, 1775–1778.
´
Gomez, C. Angew. Chem., Int. Ed. 2002, 42, 1917–1919.