Synthesis of (E)-α,β-unsaturated amides with high selectivity by using samarium diiodide

Article abstract of DOI:10.1002/1521-3765(20010716)7:14<3062::AID-CHEM3062>3.0.CO;2-F

Stereoselective β-elimination of 2-chloro-3-hydroxyamides 1 is achieved by using samarium diiodide to yield α,β-unsaturated amides 2, in which the C=C bond is di- tri-, or tetrasubstituted. The starting compounds 1 are easily prepared by reaction of the c

Full text of DOI:10.1002/1521-3765(20010716)7:14<3062::AID-CHEM3062>3.0.CO;2-F

FULL PAPER
Synthesis of (E)-a,b-Unsaturated Amides with High Selectivity by Using
Samarium Diiodide
Jose M. ConcelloÂn,* Juan A. PeÂrez-AndreÂs, and Humberto Rodríguez-Solla[a]
Abstract: Stereoselective b-elimination of 2-chloro-3-hydroxyamides 1 is achieved
ˆ
by using samarium diiodide to yield a,b-unsaturated amides 2, in which the C C
bond is di- tri-, or tetrasubstituted. The starting compounds 1 are easily prepared by
reaction of the corresponding lithium enolates of a-chloroamides with aldehydes or
ketones at 788C. The influence of the reaction conditions and the structure of the
starting compounds on the stereoselectivity of the b-elimination reaction is also
discussed.
Keywords: alkenes ´ amides ´ dia-
stereoselection
samarium
´
elimination
´
a,b-unsaturated esters with total stereoselectivity by treat-
ment of the easily available 2-halo-3-hydroxyesters with
samarium diiodide.[10] In the latter we also described the
preparation of three disubstituted a,b-unsaturated amides
with total stereoselectivity, starting from 2-halo-3-hydroxy-
amides and samarium diiodide.
Taking into account the interest in the a,b-unsaturated
amides, our objective has been to generalize the synthesis of
di-, tri-, and tetrasubstituted a,b-unsaturated amides. This
preparation is very stereoselective. We also describe the
influence of the reaction conditions and the structure of 1 on
the stereoselectivity of the b-elimination reaction.
Introduction
a,b-Unsaturated amides belong to an important class of
natural products which show both biological[1] and insecticide
activities.[2] Moreover a,b-unsaturated amides are useful
building blocks in organic synthesis[3] and are attractive
starting materials for many natural products.[4]
However, compared with the synthesis of other a,b-
unsaturated acid derivatives such as esters, the preparation
of a,b-unsaturated amides has been scarcely reported, and the
development of effective general methods for the synthesis of
a,b-unsaturated amides is of significant value. Previously
described preparations of a,b-unsaturated amides are gener-
[5]
ˆ
ally achieved by C C bond formation by a Wittig ± Horner
or by Peterson[6] reactions, from acetylenic compounds[4, 7] or
by using 2,2-difluorovinyllithium.[8] Nevertheless, in most of
these syntheses the total control of stereoselectivity of the
carbon ± carbon double bond formation remains unsolved or
typically involves multistep transformations.[4, 5] Other meth-
odologies are limited by their poor yield,[7] and in other
Results and Discussion
Synthesis of disubstituted a,b-unsaturated amides: Our first
attempts involved the preparation of a,b-unsaturated amides
ˆ
in which the C C bond is disubstituted.
ˆ
Treatment of 2-chloro-3-hydroxyamides 1a ± c with a sol-
ution of SmI2 (2.5 equiv) in THF for 30 min at room temper-
ature afforded the corresponding disubstituted a,b-unsatu-
rated amides 2, after hydrolysis, with total stereoselectivity
and in high yield. This b-elimination reaction was general for
disubstituted a,b-unsaturated amides 2 (Scheme 1): linear or
branched aliphatic, and aromatic a,b-unsaturated amides can
be achieved (Table 1). The described conditions and stereo-
syntheses, a,b-unsaturated amides, in which the C C bond is
tri- or tetrasubstituted, cannot be prepared.[6±8]
Recently, we described the first general methodology to
promote stereoselective b-elimination reactions using SmI2.
We reported a synthesis of (Z)-vinyl halides with high
stereoselectivity by reaction of O-acetylated 1,1-dihaloal-
kan-2-ols with samarium diiodide[9] and the preparation of
Â
Â
Â
Â
OH O
[a] Dr. J. M. Concellon, Dr. J. A. Perez-Andres, H. Rodríguez-Solla
R2
R1
4
R2
R1
CONR2
SmI2
Â
Departamento de Química Organica e Inorganica
Facultad de Química, Universidad de Oviedo
33071 Oviedo (Spain)
4
NR2
R3
Cl R3
1
2
Fax : (‡34)98-510-34-46
E-mail: jmcg@sauron.quimica.uniovi.es
Scheme 1. Synthesis of (E)-a,b-unsaturated amides.
3062
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3062±3068
Table 1. Synthesis of disubstituted a,b-unsaturated amides 2 (R2 ˆ R3 ˆ
consequently, different amounts of starting compound 1 were
recovered (Table 2, entries 2 and 7). Increasing the reaction
temperature (Table 2, entry 1) or the amount of SmI2 (4 equiv,
Table 2, entries 3 and 11), led to complete reaction, but with
the same stereoselectivity. The decrease of reactivity of 1d ± k
with respect to 1a ± c could be owing to the increase of the
steric hindrance when R3=H.
H).
Entry
2[a]
R1
R4
T [8C]
de[b]
Yield [%][c]
1
2
3
2a
2b
2c
Ph
C7H15
MeCH(Ph)
Et
Et
Et
25
25
25
> 98
> 98
> 98
90
89
82
[a] All reactions were carried out by using 2.5 equivalents of SmI2 with a
reaction time of 30 min. [b] Diastereoisomeric excess (de) determined by
1
GC-MS and 300 MHz H and 13C NMR analysis of the crude products 2.
[c] Yield of isolated product after column chromatography (based on
compound 1).
Table 2. Synthesis of trisubstituted a,b-unsaturated amides 2 (R2 ˆ H).
Entry
2
R1
R3 R4 T [8C][a] de[b] Yield
[%][c]
selectivity of the reaction were the same as in the synthesis of
a,b-unsaturated esters.[10]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2d Ph
2d Ph
2d Ph
2d Ph
Me Et
Me Et
Me Et
Me Et
Me iPr
Me Et
Me iPr
Me iPr
Me iPr
Me Et
66[d]
25[d]
25[f]
25
87 98[e]
89 51[e]
93 97[e]
> 98 88
91 63
> 98 81
83 86[e]
93 75
The diastereoisomeric excess of the crude reaction products
was determined by GC-MS and 1H NMR spectroscopy.
The E stereochemistry of the C C double bond of a,b-
unsaturated amides 2 was assigned on the basis of the value of
the 1H NMR coupling constant of the olefinic protons of
compounds 2a ± 2c.[11] In the case of compound 2a compar-
ison with the 1H values described in the bibliography has also
been carried out.[12] This stereochemistry is in agreement with
the previously reported synthesis of a,b-unsaturated esters
with SmI2.[10]
2e Ph
25
2 f C7H15
2g pMeO-C6H4
2g pMeO-C6H4
2 h pCl-C6H4
2i Cyclohexyl
2j Me2C CH(CH2)2CH(Me)CH2 Me Et
2j Me2C CH(CH2)2CH(Me)CH2 Me Et
2j Me2C CH(CH2)2CH(Me)CH2 Me Et
2k Bu Et Et
25[g]
25[d]
25
25
25
90 65
> 98 95
65 78[e]
80 70[e]
> 95 76
> 98 79
25[f]
0[g]
ˆ
ˆ
25[g]
25[g]
ˆ
The starting 2-chloro-3-hydroxyamides 1 used to prepare
di-, tri-, and tetra-substituted a,b-unsaturated amides were
easily prepared by reaction of the corresponding lithium
enolates of a-chloroamides 4[13] (generated by treatment of a-
chloroamides 3 with lithium diisopropylamide (LDA) at
858C) with aldehydes or ketones at 788C (Scheme 2).
[a] Unless otherwise noted, reactions were carried out with four equivalents of
SmI2 with a reaction time of 12 h. [b] Diastereoisomeric excess (de) determined
by GC-MS and 300 MHz 1H and 13C NMR analysis of the crude products 2.
[c] Yield of isolated product after column chromatography (based on compound
1). [d] 2.5 equivalents of SmI2 were used with a reaction time of 30 min. [e] Yield
of the crude products isolated (based on compound 1). [f] Four equivalents of
SmI2 were used with a reaction time of 1 h. [g] Four equivalents of SmI2 were
used with a reaction time of 90 min.
OH
O
O
R2
R1
1) LDA
R3
4
4
2) R1R2CO
3) H3O+
To enhance the stereoselectivity, the b-elimination reaction
was carried out at lower temperature. Therefore, total or very
high stereoselectivity (de > 90%) was obtained at 258C, a
longer time reaction (12 h) and larger amount of SmI2
(4 equiv) being necessary at this temperature.
NR2
NR2
Cl R3
Cl
3
1
Scheme 2. Preparation of starting compounds 1.
The presence of SmI2 during the hydrolysis of the reaction
afforded the partial reduction of the C C double bond. To
avoid this problem the excess SmI2 was transformed into SmIII
by bubbling a stream of air through the reaction mixture
before the hydrolysis.
Preparation of trisubstituted a,b-unsaturated amides: Signifi-
cant differences were detected when the same reaction
conditions (2.5 equiv of SmI2 at room temperature) were
used to obtain trisubstituted a,b-unsaturated amides 2d ± k; a
decrease in the reactivity of the starting compounds 1d ± k and
lower stereoselectivity of the b-elimination reaction were
observed (determined on the crude reaction products by GC-
MS). Therefore, the elimination was uncompleted and,
This methodology for obtaining trisubstituted a,b-unsatu-
rated amides, with high diastereoselection, is general: R1, R3,
and R4 can be varied widely. Thus, aliphatic (linear, branched
or cyclic), unsaturated or aromatic aldehydes could be used to
introduce different R1 groups; R3 and R4 could also be
changed using different aliphatic a-chloroamides to prepare
the starting compounds 1 (Scheme 2) and subsequently to
obtain 2. The stereoselectivity was only slightly affected to
changes of R1, R3 or R4. It is noteworthy that only a slight
decrease of the stereoselectivity was observed with amides
with bulky substituents on nitrogen (Table 2, entries 5, 8, and
9). The reaction also showed tolerance to other functional
groups (Table 2, entries 8, 9, and 13).
Â
Â
Abstract in Spanish: La reaccion de b-eliminacion de 2-cloro-
3-hidroxiamidas 1, promovida por diyoduro de samario,
Â
produce amidas a,b-insaturadas con elevada estereoseleccion.
Â
Los compuestos de partida 1 empleados se preparan facilmente
Â
por reaccion, a 788C, de enolatos de litio derivados de a-
Â
cloroamidas con aldehídos o cetonas. Tambien se estudia la
Â
influencia de las condiciones de reaccion y de la estructura de
The E stereochemistry in the C C double bond of
trisubstituted a,b-unsaturated amides 2 was assigned by
NOESY experiments (compounds 2d and 2 f).
Â
los compuestos de partida en la estereoseleccion con que
Â
Â
transcurre la reaccion de b-eliminacion.
Chem. Eur. J. 2001, 7, No. 14
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3063

Â
J. M. Concellon et al.
FULL PAPER
Synthesis of tetrasubstituted a,b-unsaturated amides: In
contrast with the previously described[10] synthesis of esters,[14]
tetrasubstituted a,b-unsaturated amides 2l ± s were obtained.
The reaction conditions were the same as those described for
the preparation of trisubstituted a,b-unsaturated amides 2d ±
2k. Our first trials were carried out to test the possibility of
carrying out the synthesis of a,b-unsaturated amides when the
reactions described, the corresponding di-, tri- or tetrasub-
stituted a,b-unsaturated amides 2 were obtained with high
stereoselectivity.
Mechanism: The observed stereochemistry of products 2 may
be explained by assuming the formation of the enolate
intermediate (Scheme 3), in which the oxophilic SmIII center
ˆ
C C bond is tetrasubstituted.
Treatment of amides 1, obtained by reaction of symmetrical
ketones (pentan-3-one and cyclohexanone) and 2-chloro-
N,N-diethylpropanamide, with samarium diiodide (4 equiv) at
258C afforded the corresponding a,b-unsaturated amides in
high yield (Table 3, entries 1 and 2).
SmI2
H
R2
R1
OH
O
R2
R1
O
O
SmI2
4
1
2
NR2
4
NR2
I2Sm R3
R3
I
II
Table 3. Synthesis of tetrasubstituted a,b-unsaturated amides 2 (R3 ˆ Me
and R4 ˆ Et).
Entry
2
R1
R2
t [h]
T [8C][a]
de[b]
Yield [%][c]
H
H
O
R1
R1
R3
O
1
2
3
4
5
6
7
8
9
2l
Et
(CH2)5
Et
Et
Et
nPr
nPr
C5H11
Ph
Ph
PhCH2
Et
1
1
25
25
25
±
±
70
80
70
O
O
2m
2n
2n
2n
2o
2o
2p
2q
2r
Sm
4
R2
Me
Me
Me
Me
Me
Me
Me
Et
2.5
12
72
2.5
72
2.5
2.5
2.5
2.5
42
50
60
40
46
44
78
91
94
Sm
NR2
4N
R3
R2
R2
50[d]
78[d]
25
41[e]
36[e]
73
78[d]
25
46[e]
70
A
B
Scheme 3. Proposed mechanism of the b-elimination reaction.
25
25
25
71
75
96
10
11
2s
Me
is chelated with the oxygen atom of the alcohol group
producing a six-membered ring.[16] We surmise that the
chairlike transition state model A might be involved with
the bulkier group R1 (comparatively to R2) in the equatorial
orientation (to avoid 1,3-diaxial interactions). As depicted in
B (C2 ± C3 Newman projection of A), R1 and R3 show a cis
relationship and, consequently, elimination from A affords
(E)-a,b-unsaturated amides.
[a] Unless otherwise noted, reactions were carried out with four equiv-
alents of SmI2. [b] Diastereoisomeric excess (de) determined by GC-MS
and 300 MHz 1H and 13C NMR analysis of the crude products 2. [c] Yield of
isolated product after column chromatography (based on compound 1).
[d] Five equivalents of SmI2 were used. [e] Approximately 50% of starting
product was recovered.
Synthesis of 2, with total stereoselection, from a mixture of
diastereoisomer of 1 could be explained by assuming that
after reaction of 1 with SmI2, the C ± R3 center suffers
epimerization affording only a diastereoisomer with the
appropriate conformation for coordination of the samarium
center with the alcohol oxygen.
The stereoselection in the synthesis of tetrasubstituted a,b-
unsaturated amides (determined on the crude reaction
products by GC-MS) was studied by using the amides 1,
obtained from unsymmetrical ketones and 2-chloro-N,N-
diethylpropanamide, as starting compounds.
At 258C the stereoselection of the elimination reaction
was lower when R1 and R2 were alkyl groups and the
stereoselectivity was not affected by the difference of size
between R1 and R2. The usual stereoselectivity/temperature
trend was observed: on decreasing the temperature ( 50 or
788C), a higher de value was observed,[15] but significant
amounts of starting compound 1 (50%) were recovered
(Table 3, entries 4, 5, and 7), even using long reactions times (3
days). When R1 was phenyl or benzyl, high stereoselection
(de > 78%) was obtained. The described preparation is
general and aliphatic or aromatic a,b-unsaturated amides in
which the C C double bond is tetrasubstituted can be
prepared in high yield and with moderate to high stereo-
selectivity (Table 3).
Conclusion
Herein we have presented an easy, simple and general
methodology for the preparation of di-, tri-, or tetrasubsti-
tuted a,b-unsaturated amides starting from 2-chloro-3-hy-
droxyamides and promoted by samarium diiodide. The
elimination reaction proceeds with total or high E diaster-
eoselectivity. The starting compounds are easily available. A
mechanism to explain the high stereoselectivity has been
proposed based on the chelation of the SmIII center with both
oxygen atoms.
The E stereochemistry of the C C double bond of
tetrasubstituted a,b-unsaturated amides 2 was assigned by
NOESY experiments (compound 2r).
Experimental Section
It is noteworthy that although 1:1 mixtures of diaster-
eoisomers of starting compounds 1 were used in all the
General: Reactions which required an inert atmosphere were conducted
under dry nitrogen, and the glassware was oven dried (1208C). THF was
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Chem. Eur. J. 2001, 7, No. 14

(E)-a,b-Unsaturated Amides
3062±3068
distilled from sodium/benzophenone 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.[17] 2-Chloroamides 3 were prepared by treatment of
different 2-chloroacid chlorides with amines and, in turn, 2-chloroacid
chlorides were obtained according to literature methods from the
corresponding carboxylic acids.[18] Silica gel for flash chromatography was
purchased from Merck (230 ± 400 mesh), and compounds were visualized
on analytical 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 (HP-5973) and HRMS (finnigan mat-MAT
95) were measured at 70 eV. Only the most important IR absorptions
(cm 1) and the molecular ions and/or base peaks in MS are given.
4.81 ± 4.69 (m, 2H), 3.49 ± 3.35 (m, 4H), 1.72 (s, 6H), 1.63 ± 1.18 (m, 24H);
13C NMR (50 MHz, CDCl3): d ˆ 170.4 (C), 167.2 (C), 137.6 (C), 129.6 (CH),
129.3 (CH), 127.5 (CH), 127.2 (CH), 127.0 (CH), 78.5 (CH), 68.2 (C), 50.9
(CH), 49.1 (CH), 47.4 (CH), 46.0 (CH), 20.9 (CH3), 20.3 (CH3), 20.2 (CH3),
19.9 (CH3), 19.8 (CH3), 19.7 (CH3), 19.6 (CH3), 19.2 (CH3), 18.7 (CH3); IR
(neat): nÄ ˆ 3410, 1650cm 1; elemental analysis calcd (%) for C16H24ClNO2:
C 64.53, H 8.12, N 4.70; found: C 64.44, H 8.22, N 4.86; Rf ˆ 0.4, 0.3 (two
diastereoisomers) (hexane/AcOEt 3:1).
2-Chloro-N,N-diethyl-3-hydroxy-2-methyldecanamide (1 f): 1H NMR
(200 MHz, CDCl3): d ˆ 4.05 ± 4.00 (m, 1H), 3.85 ± 3.80 (m, 1H), 3.72 ±
3.30 (m, 10H), 1.76 (s, 3H), 1.73 (s, 3H), 1.65 ± 1.01 (m, 30H), 0.96 ± 0.81
(m, 12H); 13C NMR (50 MHz, CDCl3): d ˆ 170.8 (C), 170.0 (C), 77.9 (CH),
76.7 (CH), 71.9 (C), 69.1 (C), 42.6 (CH2), 41.3 (CH2), 31.6 (CH2), 31.0
(CH2), 30.1 (CH2), 29.3 (CH2), 29.0 (CH2), 26.7 (CH2), 26.6 (CH2), 24.7
(CH3), 22.4 (CH2), 20.2 (CH3), 13.9 (CH3), 13.4 (CH3), 12.0 (CH3); HRMS
calcd for C15H30ClNO2 291.1965, found 291.1961; IR (neat): nÄ ˆ 3460,
1618 cm 1; elemental analysis calcd (%) for C15H30ClNO2: C 61.73, H 10.36,
N 4.80; found: C 61.69, H 10.39, N 4.96; Rf ˆ 0.4 (hexane/AcOEt 5:1).
Synthesis of 2-chloro-3-hydroxyamides (1): To a stirred solution of the
corresponding 2-chloroamide 3 (9 mmol) at 858C in dry THF (4 mL) was
added dropwise lithium diisopropylamide [prepared from MeLi (6.4 mL of
1.5 m solution in diethyl ether, 10 mmol) and diisopropylamine (1.4 mL,
10 mmol) in THF (50 mL)at 08C]. After the mixture had been stirred for
10 min, a solution of the corresponding carbonyl compound (4.5 mmol) in
dry THF (4.5 mL) was added dropwise at 788C. The reaction mixture was
stirred for 1 h, then the reaction was quenched with an aqueous saturated
solution of NH4Cl (5 mL). Usual workup provided crude 2-chloro-3-
hydroxyamides 3, which were purified by column flash chromatography
over silica gel (10:1 hexane/ethyl acetate) to provide pure compounds 1.
2-Chloro-N,N-diethyl-3-hydroxy-3-phenylpropanamide (1a): 1H NMR
(200 MHz, CDCl3): d ˆ 7.49 ± 7.27 (m, 10H), 5.26 ± 5.10 (m, 2H), 4.91 (br
s, 1H), 4.70 (br s, 1H), 4.46 (d, J ˆ 4.1 Hz, 1H), 4.42 (d, J ˆ 6.2 Hz, 1H),
3.48 ± 3.11 (m, 8H), 1.17 ± 1.05 (m, 12H); 13C NMR (50 MHz, CDCl3): d ˆ
167.7 (C), 167.5 (C), 139.4 (C), 138.7 (C), 129.2 (CH), 128.5 (CH), 127.8
(CH), 127.7 (CH), 126.4 (CH), 75.2 (CH), 73.5 (CH), 57.9 (CH), 54.1 (CH),
41.9 (CH2), 40.5 (CH2), 40.4 (CH2), 13.8 (CH3), 12.0 (CH3), 11.9 (CH3); IR
(neat): nÄ ˆ 3400, 1633 cm 1; elemental analysis calcd (%) for C13H18ClNO2:
C 61.05, H 7.09, N 5.48; found: C 60.92, H 7.12, N 5.51; Rf ˆ 0.2 (hexane/
AcOEt 5:1).
2-Chloro-N,N-diethyl-3-hydroxydecanamide (1b): 1H NMR (200 MHz,
CDCl3): d ˆ 4.73 (br s, 2H), 4.23 ± 3.90 (m, 4H), 3.50 ± 3.16 (m, 8H), 1.85 ±
0.90 (m, 36H), 0.76 ± 0.74 (m, 6H); 13C NMR (50 MHz, CDCl3): d ˆ 168.7
(C), 167.8 (C), 72.4 (CH), 71.0 (CH), 55.8 (CH), 54.2 (CH), 42.1 (CH2), 41.9
(CH2), 40.4 (CH2), 40.3 (CH2), 32.9 (CH2), 32.7 (CH2), 31.5 (CH2), 29.1
(CH2), 28.9 (CH2), 25.2 (CH2), 22.3 (CH2), 14.3 (CH3), 14.2 (CH3), 13.8
(CH3), 12.2 (CH3), 12.1 (CH3); IR (neat): nÄ ˆ 3330, 1615cm 1; elemental
analysis calcd (%) for C14H28ClNO2: C 60.52, H 10.16, N 5.04; found: C
60.44, H 10.20, N 5.12; Rf ˆ 0.4, 0.2 (two diastereoisomers) (hexane/AcOEt
3:1).
2-Chloro-N,N-diethyl-3-hydroxy-4-phenylpentanamide (1c): 1H NMR
(200 MHz, CDCl3): d ˆ 7.56 ± 7.05 (m, 10H), 4.15 ± 3.86 (m, 4H), 3.57 ±
2.65 (m, 12H), 1.65 ± 0.55 (m, 18H); 13C NMR (50 MHz, CDCl3): d ˆ
169.2 (C), 168.3 (C), 143.4 (C), 142.6 (C), 128.5 (CH), 128.4 (CH), 128.3
(CH), 128.2 (CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.1 (CH), 127.0
(CH), 126.9 (CH), 126.7 (CH), 78.3 (CH), 75.7 (CH), 75.3 (CH), 55.1 (CH),
52.5 (CH), 51.4 (CH), 43.8 (CH), 43.0 (CH), 41.4 (CH2), 41.0 (CH2), 40.4
(CH2), 40.2 (CH2), 18.5 (CH3), 18.3 (CH3), 17.5 (CH3), 13.6 (CH3), 13.3
(CH3), 12.0 (CH3); IR (neat): nÄ ˆ 3450, 1620cm 1; elemental analysis calcd
(%) for C15H22ClNO2: C 63.48, H 7.81, N 4.94; found: C 63.39, H 7.96, N
5.01; Rf ˆ 0.5, 0.4 (two diastereoisomers) (hexane/AcOEt 3:1).
2-Chloro-N,N-diisopropyl-3-hydroxy-2-methyl-3-(4-methoxyphenyl)pro-
1
panamide (1g): H NMR (200 MHz, CDCl3): d ˆ 7.29 (d, J ˆ 7.0 Hz, 4H),
6.73 (d, J ˆ 7.0 Hz, 4H), 5.09 (s, 2H), 4.70 ± 4.60 (m, 2H), 3.66 (s, 6H), 3.34 ±
3.27 (m, 4H), 1.59 ± 1.06 (m, 30H); 13C NMR (50 MHz, CDCl3): d ˆ 170.1
(C), 158.7 (C), 130.3 (CH), 129.6 (CH), 112.1 (CH), 77.8 (CH), 68.5 (C),
54.6 (CH3), 50.6 (CH), 48.8 (CH), 47.1 (CH), 45.6 (CH), 20.6 (CH3), 20.5
(CH3), 20.0 (CH3), 19.9 (CH3), 19.7 (CH3), 19.5 (CH3), 19.4 (CH3), 19.4
(CH3), 19.3 (CH3), 19.1 (CH3); IR (Nujol): nÄ ˆ 3283, 1650 cm 1; elemental
analysis calcd (%) for C17H26ClNO3: C 62.28, H 7.99, N 4.27; found: C 62.24,
H 8.08, N 4.20; m.p. ˆ 1048C; Rf ˆ 0.4, 0.3 (two diastereoisomers) (hexane/
AcOEt 3:1).
2-Chloro-3-(4-chlorophenyl)-N,N-diisopropyl-3-hydroxy-2-methylpropan-
amide (1h): 1H NMR (200 MHz, CDCl3): d ˆ 7.44 (d, J ˆ 1.7 Hz, 4H), 7.27
(d, J ˆ 1.7 Hz, 4H), 5.27 (d, J ˆ 3.0 Hz, 1H), 5.21 (d, J ˆ 2.2 Hz, 1H), 4.79 ±
4.65 (m, 2H), 3.46 ± 3.34 (m, 4H), 1.67 (s, 6H), 1.63 ± 1.09 (m, 24H);
13C NMR (50 MHz, CDCl3): d ˆ 170.4 (C), 136.2 (C), 135.5 (C), 133.5 (C),
131.0 (CH), 130.8 (CH), 127.5 (CH), 127.2 (CH), 78.0 (CH), 68.1 (C), 51.0
(CH), 49.2 (CH), 47.6 (CH), 46.1 (CH), 21.0 (CH3), 20.4 (CH3), 20.3 (CH3),
20.0 (CH3), 19.9 (CH3), 19.8 (CH3), 19.7 (CH3), 19.1 (CH3); IR (neat): nÄ ˆ
3422, 1645 cm 1; Rf ˆ 0.5, 0.4 (two diastereoisomers) (hexane/AcOEt 3:1).
2-Chloro-N,N-diethyl-3-cyclohexyl-3-hydroxy-2-methylpropanamide (1i):
1H NMR (200 MHz, CDCl3): d ˆ 4.37 (d, J ˆ 6.7 Hz, 1H), 4.30 (d, J ˆ
6.4 Hz, 1H), 3.34 ± 3.03 (m, 10H), 2.42 (br d, J ˆ 7.20 Hz, 1H), 1.73 ± 0.78
(m, 38H); 13C NMR (50 MHz, CDCl3): d ˆ 170.6 (C), 170.0 (C), 81.2 (CH),
80.0 (CH), 72.8 (C), 70.7 (C), 42.6 (CH2), 41.6 (CH2), 40.0 (CH), 39.1 (CH),
33.3 (CH2), 32.6 (CH2), 27.9 (CH2), 27.8 (CH2), 26.5 (CH2), 26.3 (CH2), 26.1
(CH2), 26.0 (CH2), 25.9 (CH2), 25.4 (CH3), 22.1 (CH3), 13.4 (CH3), 11.8
(CH3); IR (neat): nÄ ˆ 3440, 1618cm 1; elemental analysis calcd (%) for
C14H26ClNO2: C 60.96, H 9.50, N 5.08; found: C 60.92, H 9.56, N 5.15; Rf ˆ
0.5 (hexane/AcOEt 3:1).
2-Chloro-N,N-diethyl-3-hydroxy-2,5,9-trimethyldec-8-enamide
(1j):
1H NMR (200 MHz, CDCl3): d ˆ 4.95 ± 4.86 (m, 3H), 4.01 ± 3.05 (m,
18H), 1.81 ± 0.71 (m, 48H), 1.44 (s, 3H), 1.41 (s, 6H), 1.05 (t, J ˆ 7.2 Hz,
9H), 0.94 (t, J ˆ 7.2 Hz, 9H); 13C NMR (50 MHz, CDCl3): d ˆ 170.3 (C),
169.6 (C), 167.6 (C), 130.2 (C), 130.1 (C), 124.5 (CH), 124.3 (CH), 75.4
(CH), 74.8 (CH), 74.4 (CH), 72.1 (C), 72.0 (C), 69.0 (C), 42.4 (CH2), 41.6
(CH2), 41.1 (CH2), 40.2 (CH2), 38.4 (CH2), 38.1 (CH2), 37.7 (CH2), 37.6
(CH2), 37.2 (CH2), 37.1 (CH2), 29.6 (CH), 29.0 (CH), 28.9 (CH), 25.3 (CH3),
25.2 (CH3), 24.9 (CH2), 24.8 (CH2), 24.5 (CH2), 24.4 (CH2), 20.7 (CH3), 20.3
(CH3), 20.2 (CH3), 20.1 (CH3), 18.5 (CH3), 18.4 (CH3), 17.2 (CH3), 14.2
1
(CH3), 13.2 (CH3), 12.1 (CH3), 11.8 (CH3); IR (neat): nÄ ˆ 3487, 1650cm
;
2-Chloro-N,N-diethyl-3-hydroxy-2-methyl-3-phenylpropanamide
(1d):
1H NMR (200 MHz, CDCl3): d ˆ 7.50 ± 7.26 (m, 10H), 5.25 (d, J ˆ 3.0 Hz,
1H), 5.16 (d, J ˆ 3.0 Hz, 1H), 3.67 ± 3.19 (m, 10H), 1.64 (s, 6H), 1.43 ± 1.08
(m, 12H); 13C NMR (50 MHz, CDCl3): d ˆ 170.9 (C), 170.1 (C), 137.4 (C),
129.4 (CH), 129.0 (CH), 127.8 (CH), 127.6 (CH), 127.2 (CH), 127.0 (CH),
78.6 (CH), 78.4 (CH), 67.8 (C), 42.8 (CH2), 41.8 (CH2), 40.5 (CH2), 20.9
(CH3), 19.9 (CH3), 13.4 (CH3), 12.3 (CH3), 12.0 (CH3); IR (neat): nÄ ˆ 3317,
1604 cm 1; elemental analysis calcd (%) for C14H20ClNO2: C 62.63, H 7.47,
N 5.19; found: C 62.47, H 7.49, N 5.14; Rf ˆ 0.2 (hexane/AcOEt 5:1).
Rf ˆ 0.5, 0.3, 0.2 (three diastereoisomers) (hexane/AcOEt 3:1).
2-Chloro-N,N-diethyl-2-ethyl-3-hydroxyheptanamide (1k): 1H NMR
(200 MHz, CDCl3): d ˆ 4.08 ± 4.04 (m, 1H), 3.88 ± 3.25 (m, 5H), 2.41 ±
2.22 (m, 2H), 2.21 ± 1.97 (m, 2H), 1.80 ± 1.17 (m, 10H), 1.01 (t, J ˆ 7.6 Hz,
3H), 0.89 (t, J ˆ 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): d ˆ 169.3 (C),
76.5 (CH), 75.8 (C), 42.5 (CH2), 41.9 (CH2), 32.4 (CH2), 29.8 (CH2), 28.9
(CH2), 22.5 (CH2), 13.9 (CH3), 13.7 (CH3), 12.2 (CH3), 10.2 (CH3); IR
(neat): nÄ ˆ 3464, 1649cm 1; elemental analysis calcd (%) for C13H26ClNO2:
C 59.19, H 9.93, N 5.31; found: C 59.25, H 9.87, N 5.36; Rf ˆ 0.4 (hexane/
AcOEt 5:1).
2-Chloro-N,N-diisopropyl-3-hydroxy-2-methyl-3-phenylpropanamide
(1e): 1H NMR (200 MHz, CDCl3): d ˆ 7.52 ± 7.27 (m, 10H), 5.25 (s, 2H),
Chem. Eur. J. 2001, 7, No. 14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0714-3065 $ 17.50+.50/0
3065

Â
J. M. Concellon et al.
FULL PAPER
2-Chloro-N,N-diethyl-3-ethyl-3-hydroxy-2-methylpentanamide
(1l):
amides 1 (0.4 mmol) in THF (2 mL) at room temperature or 258C. After
the time indicated in the corresponding Table, the reaction was quenched
with aqueous HCl (5 mL of 1m solution). Usual workup provided crude
a,b-unsaturated amides 2, which were purified by column flash chroma-
tography over silica gel (3:1 hexane ethyl acetate) to provide pure
compounds 2.
1H NMR (200 MHz, CDCl3): d ˆ 5.25 ± 5.17 (br s, 2H), 4.11 ± 3.81 (m,
4H), 3.50 ± 3.15 (m, 4H), 1.88 ± 1.62 (m, 8H), 1.83 (s, 6H), 1.22 ± 1.11 (m,
12H), 0.97 (t, J ˆ 7.44 Hz, 6H), 0.95 (t, J ˆ 7.44 Hz, 6H); 13C NMR
(50 MHz, CDCl3): d ˆ 171.6 (C), 78.2 (C), 74.3 (C), 42.9 (CH2), 41.5 (CH2),
28.3 (CH2), 27.8 (CH2), 23.0 (CH3), 13.0 (CH3), 11.4 (CH3), 8.8 (CH3), 8.1
(CH3); IR (neat): nÄ ˆ 3405, 1611cm 1; Rf ˆ 0.4 (hexane/AcOEt 5:1).
(E)-N,N-Diethyl-3-phenylpropenamide (2a):[12] 13C NMR (75 MHz,
CDCl3) d ˆ 165.5 (C), 142.1 (CH), 135.2 (C), 129.2 (CH), 128.2 (CH),
127.5 (CH), 117.5 (CH), 42.1 (CH2), 40.9 (CH2), 14.8 (CH3), 13.0 (CH3); MS
2-Chloro-N,N-diethyl-2-(1-hydroxycyclohexyl)ethanamide (1m): 1H NMR
(200 MHz, CDCl3): d ˆ 4.98 (br s, 2H), 3.93 ± 3.31 (m, 8H), 2.03 ± 1.53 (m,
20H), 1.82 (s, 6H), 1.50 ± 1.13 (m, 12H); 13C NMR (50 MHz, CDCl3): d ˆ
171.1 (C), 77.1 (C), 73.2 (C), 43.2 (CH2), 41.7 (CH2), 30.8 (CH2), 30.1 (CH2),
25.2 (CH2), 22.6 (CH3), 21.2 (CH2), 21.1 (CH2), 13.2 (CH3), 11.6 (CH3); IR
(neat): nÄ ˆ 3416, 1605cm 1; Rf ˆ 0.4 (hexane/AcOEt 5:1).
‡
(70 eV): m/z (%): 203 (25) [M] , 131 (100), 103 (67), 77 (55); HRMS calcd
for C13H17NO 203.1301, found: 203.1308; IR (neat): nÄ ˆ 3056, 2950,
1620 cm 1; Rf ˆ 0.3 (hexane/AcOEt 1:1).
(E)-N,N-Diethyldec-2-enamide (2b): 1H NMR (200 MHz, CDCl3): d ˆ
6.88 ± 6.74 (m, 1H), 6.10 (d, J ˆ 14.9 Hz, 1H), 3.35 ± 3.24 (m, 4H), 2.12 (q,
J ˆ 6.8 Hz, 2H), 1.37 ± 1.02 (m, 16H), 0.79 (t, J ˆ 6.7 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d ˆ 165.7 (C), 146.0 (CH), 120.1 (CH), 41.8 (CH2), 40.5
(CH2), 32.2 (CH2), 31.5 (CH2), 28.9 (CH2), 28.8 (CH2), 28.1 (CH2), 22.3
(CH2), 14.5 (CH3), 13.8 (CH3), 12.9 (CH3); MS (70 eV): m/z (%): 225 (10)
2-Chloro-N,N-diethyl-3-hydroxy-2,3-dimethylpentanamide (1n): 1H NMR
(200 MHz, CDCl3): d ˆ 5.09 (br s, 1H), 4.99 (br s, 1H), 3.95 ± 3.00 (m, 8H),
1.71 ± 1.45 (m, 4H), 1.67 (s, 3H), 1.62 (s, 3H), 1.20 (s, 3H), 1.04 (s, 3H),
1.04 ± 0.86 (m, 12H), 0.79 (t, J ˆ 7.4 Hz, 3H), 0.77 (t, J ˆ 7.4 Hz, 3H);
13C NMR (50 MHz, CDCl3): d ˆ 171.8 (C), 171.4 (C), 78.5 (C), 78.1 (C), 73.7
(C), 73.1 (C), 42.3 (CH2), 41.8 (CH2), 28.7 (CH2), 28.0 (CH2), 23.2 (CH3),
22.9 (CH3), 21.2 (CH3), 19.7 (CH3), 13.3 (CH3), 11.7 (CH3), 7.6 (CH3), 7.4
(CH3); IR (neat): nÄ ˆ 3404, 1605cm 1; elemental analysis calcd (%) for
C11H22ClNO2: C 56.04, H 9.41, N 5.94; found: C 56.09, H 9.35, N 6.02; Rf ˆ
0.5 (hexane/AcOEt 5:1).
‡
[M] , 196 (5), 153 (39), 126 (100); HRMS calcd for C14H27NO 225.2092,
found: 225.2086; IR (neat): nÄ ˆ 2956, 2928, 1659 cm 1; Rf ˆ 0.2 (hexane/
AcOEt 3:1).
(E)-N,N-Diethyl-4-phenylpent-2-enamide (2c): 1H NMR (300 MHz,
CDCl3): d ˆ 7.33 ± 7.20 (m, 5H), 7.07 (dd, J ˆ 15.2, 7.0 Hz, 1H), 6.13 (d,
J ˆ 15.2 Hz, 1H), 3.68 ± 3.65 (m, 1H), 3.41 (q, J ˆ 7.0 Hz, 2H), 3.32 (q, J ˆ
7.0 Hz, 2H), 1.43 (d, J ˆ 7.0 Hz, 3H), 1.32 ± 0.94 (m, 6H); 13C NMR
(75 MHz, CDCl3): d ˆ 165.7 (C), 149.5 (CH), 143.9 (C), 128.4 (CH), 127.2
(CH), 126.4 (CH), 119.3 (CH), 42.1 (CH), 42.1 (CH2), 40.7 (CH2), 20.7
2-Chloro-N,N-diethyl-3-hydroxy-2,3-dimethylhexanamide (1o): 1H NMR
(200 MHz, CDCl3): d ˆ 5.09 (br s, 1H), 4.98 (br s, 1H), 3.95 ± 2.95 (m, 8H),
1.61 (s, 3H), 1.58 (s, 3H), 1.55 ± 0.65 (m, 26H), 1.17 (s, 3H), 1.01 (s, 3H);
13C NMR (50 MHz, CDCl3): d ˆ 171.6 (C), 171.3 (C), 78.3 (C), 77.9 (C), 73.5
(C), 73.0 (C), 43.2 (CH2), 41.7 (CH2), 38.6 (CH2), 37.7 (CH2), 22.9 (CH3),
22.8 (CH3), 21.8 (CH3), 20.3 (CH3), 16.6 (CH2), 16.2 (CH2), 14.2 (CH3), 14.1
(CH3), 13.2 (CH3), 11.6 (CH3); IR (neat): nÄ ˆ 3410, 1610 cm 1; elemental
analysis calcd (%) for C12H24ClNO2: C 57.70, H 9.68, N 5.61; found: C 57.76,
H 9.71, N 5.55; Rf ˆ 0.5 (hexane/AcOEt 5:1).
‡
(CH3), 14.7 (CH3), 13.0 (CH3); MS (70 eV): m/z (%): 231 (89) [M] , 159
(92), 131 (85), 126 (100), 91 (81), 77 (36); HRMS calcd for C15H21NO
231.1623, found 231.1627; IR (neat): nÄ ˆ 3008, 2945, 1647 cm 1; Rf ˆ 0.1
(hexane/AcOEt 5:1).
(E)-N,N-Diethyl-3-phenyl-2-methylpropenamide
(2d):
1H
NMR
2-Chloro-N,N-diethyl-3-hydroxy-2,3-dimethyloctanamide (1p): 1H NMR
(200 MHz, CDCl3): d ˆ 5.13 (br s, 1H), 5.03 (br s, 1H), 3.90 ± 2.90 (m, 8H),
1.80 ± 0.65 (m, 34H), 1.67 (s, 3H), 1.63 (s, 3H), 1.23 (s, 3H), 1.07 (s, 3H);
13C NMR (50 MHz, CDCl3): d ˆ 171.7 (C), 171.4 (C), 78.4 (C), 78.1 (C), 73.6
(C), 73.1 (C), 43.3 (CH2), 41.8 (CH2), 36.3 (CH2), 35.5 (CH2), 32.2 (CH2),
(300 MHz, [D6]DMSO, 373 K): d ˆ 7.57 ± 7.27 (m, 5H), 6.52 (s, 1H), 3.48
(q, J ˆ 6.7 Hz, 4H), 2.09 (s, 3H), 1.24 (t, J ˆ 6.7 Hz, 6H); 13C NMR
(75 MHz, [D6]DMSO, 373 K): d ˆ 171.9 (C), 135.9 (C), 134.0 (C), 128.4
(CH), 128.0 (CH), 127.1 (CH), 126.8 (CH), 39.8 (CH2), 15.4 (CH3), 13.1
‡
(CH3); MS (70 eV): m/z (%): 217 (72) [M] , 202 (41), 117 (100), 91 (51), 89
32.0 (CH2), 23.1 (CH2), 22.9 (CH2), 22.7 (CH3), 22.3 (CH3), 21.9 (CH3), 20.4
(9); HRMS calcd for C14H19NO 217.1466, found: 217.1475; IR (neat): nÄ ˆ
3081, 3023, 2974, 1625, 1427, 1381 cm 1; Rf ˆ 0.4 (hexane/AcOEt 1:1).
1
(CH3), 13.6 (CH3), 13.3 (CH3), 11.7 (CH3); IR (neat): nÄ ˆ 3409, 1611 cm
;
(E)-N,N-Diisopropyl-2-methyl-3-phenylpropenamide (2e): 1H NMR
(300 MHz, [D6]DMSO, 373 K): d ˆ 7.50 ± 7.31 (m, 5H), 6.44 (s, 1H),
3.97 ± 3.84 (m, 2H), 2.08 (s, 3H), 1.40 (d, J ˆ 6.7 Hz, 12H); 13C NMR
(75 MHz, [D6]DMSO, 373 K): d ˆ 172.0 (C), 136.3 (C), 135.7 (C), 128.6
(CH), 128.3 (CH), 127.0 (CH), 126.0 (CH), 47.3 (CH), 20.5 (CH3), 15.6
Rf ˆ 0.5 (hexane/AcOEt 3:1).
2-Chloro-N,N-diethyl-3-hydroxy-2-methyl-3-phenylbutanamide
(1q):
1H NMR (200 MHz, CDCl3): d ˆ 7.98 ± 7.26 (m, 10H), 6.31 (br s, 2H),
3.89 ± 2.97 (m, 8H), 1.99 (s, 3H), 1.94 (s, 3H), 1.77 (s, 3H), 1.67 (s, 3H),
1.22 ± 1.01 (m, 12H); 13C NMR (50 MHz, CDCl3): d ˆ 172.0 (C), 171.0 (C),
144.0 (C), 142.2 (C), 127.2 (CH), 126.9 (CH), 126.7 (CH), 79.9 (C), 78.6 (C),
74.0 (C), 71.7 (C), 43.6 (CH2), 42.8 (CH2), 42.4 (CH2), 27.3 (CH3), 25.3
(CH3), 24.1 (CH3), 23.8 (CH3), 13.5(CH3), 12.0 (CH3), 11.5 (CH3); IR
(neat): nÄ ˆ 3386, 1606 cm 1; Rf ˆ 0.4, 0.3 (two diastereoisomers) (hexane/
AcOEt 5:1).
‡
(CH3); MS (70 eV): m/z (%): 245 (30) [M] , 230 (21), 168 (8), 145 (100), 91
(27); HRMS calcd for C16H23NO 245.1779, found: 245.1770; IR (neat): nÄ ˆ
3059, 1626, 1532, 1471, 1369cm 1; Rf ˆ 0.3 (hexane/AcOEt 3:1).
(E)-N,N-Diethyl-2-methyldec-2-enamide (2 f): 1H NMR (200 MHz,
CDCl3): d ˆ 5.46 (t, J ˆ 7.4 Hz, 1H), 3.34 (q, J ˆ 7.2 Hz, 4H), 2.04 (q, J ˆ
6.9 Hz, 2H), 1.78 (s, 3H), 1.50 ± 1.22 (m, 10H), 1.11 (t, J ˆ 7.2 Hz, 6H), 0.84
(t, J ˆ 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 173.7 (C), 130.8 (C),
130.3 (CH), 41.5 (CH2), 31.6 (CH2), 29.1 (CH2), 29.0 (CH2), 28.8 (CH2), 27.3
(CH2), 22.4 (CH2), 14.2 (CH3), 13.9 (CH3), 12.8 (CH3); MS (70 eV): m/z
2-Chloro-N,N-diethyl-3-hydroxy-2-methyl-3-phenylpentanamide
(1r):
1H NMR (200 MHz, CDCl3): d ˆ 7.62 ± 7.16 (m, 10H), 6.08 (br s, 1H),
5.59 (br s, 1H), 4.0 ± 2.5 (m, 8H), 1.89 (s, 3H), 1.53 (s, 3H), 1.20 ± 1.12 (m,
12H), 0.9 (t, J ˆ 6.7 Hz, 6H), 0.67 (q, J ˆ 6.7 Hz, 4H); 13C NMR (50 MHz,
CDCl3): d ˆ 172.0 (C), 171.0 (C), 140.7 (C), 139.9 (C), 128.8 (CH), 127.9
(CH), 126.8 (CH), 126.6 (CH), 126.5 (CH), 82.5 (C), 80.5 (C), 75.0 (C), 72.0
(C), 43.4 (CH2), 42.8 (CH2), 27.4 (CH2), 26.8 (CH2), 23.9 (CH3), 13.7 (CH3),
13.2 (CH3), 11.8 (CH3), 11.2 (CH3), 7.8 (CH3), 7.4 (CH3); IR (neat): nÄ ˆ
3356, 1604 cm 1; Rf ˆ 0.5 (hexane/AcOEt 3:1).
‡
(%): 239 (2) [M] , 167 (27), 140 (100), 55 (40), 41 (40); HRMS calcd for
C15H29NO 239.2249, found: 239.2242; IR (neat): nÄ ˆ 2928, 2856, 1624, 1460,
1379 cm 1; Rf ˆ 0.5 (hexane/AcOEt 1:1).
(E)-N,N-Diisopropyl-3-(4-methoxyphenyl)-2-methylpropenamide (2g):
1H NMR (300 MHz, [D6]DMSO, 373 K): d ˆ 7.36 (d, J ˆ 8.9 Hz, 2H), 7.03
(d, J ˆ 8.9 Hz, 2H), 6.37 (s, 1H), 3.96 ± 3.80 (m, 2H), 3.88 (s, 3H), 2.06 (s,
3H), 1.38 (d, J ˆ 6.7 Hz, 12H); 13C NMR (75 MHz, [D6]DMSO, 373 K):
d ˆ 172.3 (C), 158.7 (C), 133.9 (C), 130.0 (CH), 129.0 (C), 125.7 (CH), 114.2
(CH), 55.3 (CH3), 47.3 (CH), 20.6 (CH3), 15.8 (CH3); MS (70 eV): m/z (%):
2-Chloro-N,N-diethyl-3-hydroxy-2,3-dimethyl-4-phenylbutanamide (1s):
1H NMR (200 MHz, CDCl3): d ˆ 7.36 ± 7.18 (m, 10H), 5.52 (br s, 1H),
5.30 (br s, 1H), 4.14 ± 2.96 (m, 12H), 1.94 (s, 3H), 1.93 (s, 3H), 1.31 ± 1.19 (m,
12H), 1.31 (s, 3H), 1.19 (s, 3H); 13C NMR (50 MHz, CDCl3): d ˆ 171.9 (C),
171.3 (C), 137.8 (C), 137.4 (C), 130.9 (CH), 130.8 (CH), 127.3 (CH), 125.8
(CH), 125.7 (CH), 79.1 (C), 78.6 (C), 73.3 (C), 72.7 (C), 43.5 (CH2), 42.1
(CH2), 41.5 (CH2), 23.3 (CH3), 23.2 (CH3), 22.2 (CH3), 20.6 (CH3), 13.5
(CH3), 11.9 (CH3); IR (neat): nÄ ˆ 3410, 1606 cm 1; Rf ˆ 0.5 (hexane/AcOEt
3:1).
‡
275 (10) [M] , 260 (15), 175 (79), 91 (57); HRMS calcd for C17H25NO2
1
275.1885, found: 275.1874; IR (neat): nÄ ˆ 3002, 2967, 1621, 1441, 1369 cm
;
Rf ˆ 0.2 (hexane/AcOEt 3:1).
(E)-3-(4-Chlorophenyl)-N,N-diisopropyl-2-methylpropenamide
(2h):
1H NMR (300 MHz, [D6]DMSO, 373 K): d ˆ 7.48 (d, J ˆ 8.4 Hz, 2H), 7.43
(d, J ˆ 8.4 Hz, 2H), 6.40 (s, 1H), 3.94 ± 3.83 (m, 2H), 2.06 (s, 3H), 1.38 (d,
J ˆ 6.7 Hz, 12H); 13C NMR (75 MHz, [D6]DMSO, 373 K): d ˆ 171.7 (C),
136.6 (C), 135.1 (C), 131.8 (C), 130.4 (CH), 128.3 (CH), 124.7 (CH), 47.3
Synthesis of a,b-unsaturated amides (2): A solution of SmI2 (1 or 1.6 mmol)
in THF (12 mL) was added very slowly dropwise, under a nitrogen
atmosphere, to a stirred solution of the corresponding 2-chloro-3-hydroxy-
3066
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0714-3066 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 14

(E)-a,b-Unsaturated Amides
3062±3068
‡
(CH), 20.5 (CH3), 15.6 (CH3); MS (70 eV): m/z (%): 281 (9) [M‡2] , 279
125.7 (C), 41.9 (CH2), 37.6 (CH2), 35.7 (CH2), 31.9 (CH2), 27.4 (CH2), 22.4
(CH2), 16.4 (CH3), 16.0 (CH3), 14.1 (CH3), 13.9 (CH3), 12.5 (CH3); MS
(70 eV): m/z (%): 225 (18) [M] , 210 (10), 196 (17), 153 (100); HRMS calcd
‡
(26) [M] , 264 (20), 179 (100), 168 (9); HRMS calcd for C16H22ClNO
279.1389, found: 279.1384; IR (neat): nÄ ˆ 1626, 1490, 1440, 1370 cm 1; Rf ˆ
‡
0.4 (hexane/AcOEt 3:1).
for C14H27NO 225.2092, found: 225.2094; IR (neat): nÄ ˆ 2963, 2933, 1629,
1458, 1425, 1380cm 1; Rf ˆ 0.3 (hexane/AcOEt 3:1).
(E)-N,N-Diethyl-2-methyl-3-phenylbut-2-enamide
(E)-3-Cyclohexyl-N,N-diethyl-2-methylpropenamide (2i): 1H NMR
(300 MHz, [D6]DMSO, 373 K): d ˆ 5.33 (dq, J ˆ 1.7, 8.9 Hz, 1H), 3.39 (q,
J ˆ 7.0 Hz, 4H), 2.43 ± 2.30 (m, 1H), 1.84 (d, J ˆ 1.7 Hz, 3H), 1.81 ± 1.68 (m,
5H), 1.50 ± 1.21 (m, 5H), 1.17 (t, J ˆ 7.0 Hz, 6H); 13C NMR (75 MHz,
[D6]DMSO, 373 K): d ˆ 172.5 (C), 134.0 (CH), 130.4 (C), 40.4 (CH2), 36.0
(CH), 32.0 (CH2), 25.6 (CH2), 25.1 (CH2), 14.0 (CH3), 13.4 (CH3); MS
(2q):
1H
NMR
(200 MHz, [D6]DMSO, 350 K): d ˆ 7.38 ± 7.30 (m, 5H), 3.48 (q, J ˆ
7.22 Hz, 4H), 2.14 (s, 3H), 2.02 (s, 3H), 0.92 (t, J ˆ 7.22 Hz, 6H);
13C NMR (75 MHz, CDCl3): d ˆ 172.2 (C), 142.2 (C), 132.6 (C), 128.6
(C), 127.8 (CH), 127.4 (CH), 126.8 (CH), 41.7 (CH2), 37.5 (CH2), 19.3 (CH3),
‡
‡
17.4 (CH3), 13.7 (CH3), 11.6 (CH3); MS (70 eV): m/z (%): 231 (12) [M] , 216
(70 eV): m/z (%): 223 (9) [M] , 208 (2), 151 (57), 140 (100); HRMS calcd
(40), 202 (10), 159 (68), 131 (96), 91 (100); HRMS calcd for C15H21NO
231.1623, found: 231.1627; IR (neat): nÄ ˆ 3055, 2975, 2933, 1614, 1458,
1380 cm 1; Rf ˆ 0.2 (hexane/AcOEt 3:1).
for C14H25NO 223.1936, found: 223.1944; IR (neat): nÄ ˆ 2974, 1623, 1457,
1380 cm 1; Rf ˆ 0.2 (hexane/AcOEt 3:1).
(E)-N,N-Diethyl-2,5,9-trimethyldec-2,8-dienamide
(2j):
1H
NMR
(E)-N,N-Diethyl-2-methyl-3-phenylpent-2-enamide (2r): 1H NMR
(200 MHz, [D6]DMSO, 350 K): d ˆ 7.35 ± 7.33 (m, 5H), 3.19 (q, J ˆ
6.89 Hz, 4H), 2.56 (q, J ˆ 7.55 Hz, 2H), 2.02 (s, 3H), 1.04 (t, J ˆ 7.55 Hz,
3H), 0.92 (t, J ˆ 6.89 Hz, 6H); 13C NMR (75 MHz, CDCl3): d ˆ 172.0 (C),
140.8 (C), 138.7 (C), 127.9 (CH), 127.6 (CH), 127.0 (C), 126.6 (CH), 41.5
(CH2), 37.1 (CH2), 26.0 (CH2), 16.5 (CH3), 13.7 (CH3), 12.2 (CH3), 11.4
(300 MHz, [D6]DMSO, 373 K): d ˆ 5.53 ± 5.48 (m, 1H), 5.21 ± 5.17 (m,
1H), 3.41 (q, J ˆ 7.3 Hz, 4H), 2.21 ± 0.93 (m, 7H), 1.83 (s, 3H), 1.75 (s, 3H),
1.68 (s, 3H), 1.17 (t, J ˆ 7.3 Hz, 6H), 0.99 (d, J ˆ 6.7 Hz, 3H); 13C NMR
(75 MHz, [D6]DMSO, 373 K): d ˆ 172.4 (C), 132.9 (C), 130.5 (C), 127.3
(CH), 124.6 (CH), 40.4 (CH2), 36.4 (CH2), 34.2 (CH2), 32.5 (CH), 25.2
(CH2), 19.3 (CH3), 17.3 (CH3), 14.2 (CH3), 13.4 (CH3); MS (70 eV): m/z
‡
‡
(CH3); MS (70 eV): m/z (%): 245 (45) [M] , 230 (19), 216 (89), 173 (100),
(%): 265 (6) [M] , 250 (10), 193 (<1), 182 (67), 154 (12); HRMS calcd for
145 (63), 91 (25); HRMS calcd for C16H23NO 245.1779, found: 245.1781; IR
(neat): nÄ ˆ 3054, 3019, 2968, 2873, 1617, 1459, 1379 cm 1; Rf ˆ 0.2 (hexane/
AcOEt 3:1).
C17H31NO 265.2405, found: 265.2415; IR (neat): nÄ ˆ 2966, 1624, 1459, 1430,
1379cm 1; Rf ˆ 0.2 (hexane/AcOEt 3:1).
(E)-N,N-Diethyl-2-ethylhept-2-enamide (2k): 1H NMR (300 MHz,
CDCl3): d ˆ 5.37 (t, J ˆ 7.2 Hz, 1H), 3.33 (q, J ˆ 7.2 Hz, 4H), 2.25 (q, J ˆ
7.4 Hz, 2H), 2.04 (q, J ˆ 7.2 Hz, 2H), 1.32 ± 1.18 (m, 4H), 1.08 (t, J ˆ 7.2 Hz,
6H), 0.93 (t, J ˆ 7.4 Hz, 3H), 0.84 (t, J ˆ 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d ˆ 172.9 (C), 136.9 (C), 129.1 (CH), 40.4 (CH2), 31.1 (CH2), 26.7
(CH2), 22.1 (CH2), 21.7 (CH2), 13.6 (CH3), 13.4 (CH3), 12.4 (CH3); MS
(E)-N,N-Diethyl-2,3-dimethyl-4-phenylbut-2-enamide (2s): 1H NMR
(200 MHz, [D6]DMSO, 350 K): d ˆ 7.42 ± 7.26 (m, 5H), 3.45 (q, J ˆ
6.56 Hz, 4H), 2.93 (d, J ˆ 13.46 Hz, 1H), 2.72 (d, J ˆ 13.46 Hz, 1H), 1.87
(s, 3H), 1.63 (s, 3H), 1.21 (q, J ˆ 6.56 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d ˆ 172.5 (C), 139.1 (C), 131.4 (C), 128.8 (CH), 128.0 (CH), 127.3 (C), 125.7
(CH), 42.1 (CH2), 41.5 (CH2), 37.9 (CH2), 16.2 (CH3), 16.0 (CH3), 14.0
‡
(70 eV): m/z (%): 211 (10) [M] , 182 (10), 154 (82), 139 (51), 69 (100);
‡
(CH3), 12.4 (CH3); MS (70 eV): m/z (%): 245 (23) [M] , 230 (3), 216 (17),
HRMS calcd for C13H25NO 211.1936, found: 211.1940; IR (neat): 2963,
1610, 1460, 1431, 1380 cm 1; Rf ˆ 0.5 (hexane/AcOEt 1:1).
173 (46), 145 (23), 91 (44); HRMS calcd for C16H23NO 245.1779, found:
1
245.1783; IR (neat): nÄ ˆ 3060, 3025, 2973, 2932, 1623, 1494, 1427, 1380 cm
;
(E)-N,N-Diethyl-3-ethyl-2-methylpent-2-enamide
(2l):
1H
NMR
Rf ˆ 0.2 (hexane/AcOEt 3:1).
(200 MHz, [D6]DMSO, 350 K): d ˆ 3.43 (q, J ˆ 7.22 Hz, 4H), 2.20 (q, J ˆ
7.55 Hz, 2H), 2.09 (q, J ˆ 7.55 Hz, 2H), 1.83 (s, 3H), 1.21 (t, J ˆ 7.22 Hz,
6H), 1.11 (t, J ˆ 7.55 Hz, 3H), 1.06 (t, J ˆ 7.55 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d ˆ 172.8 (C), 139.6 (C), 125.3 (C), 42.0 (CH2), 37.7 (CH2), 25.9
(CH2), 22.5 (CH2), 15.5 (CH3), 14.1 (CH3), 12.6 (CH3), 12.5 (CH3), 12.3
Acknowledgements
‡
(CH3); MS (70 eV): m/z (%): 197 (12) [M] , 182 (8), 165 (92), 125 (100), 97
Â
We thank II Plan Regional de Investigacion del Principado de Asturias
(25); HRMS calcd for C12H23NO 197.1779, found: 197.1778; IR (neat): nÄ ˆ
Â
(PB-PGI99 ± 01) and the Ministerio de Educacion y Cultura (PB97 ± 1278)
2986, 2936, 1616, 1461, 1425, 1380 cm 1; Rf ˆ 0.2 (hexane/AcOEt 3:1).
Â
for financial support, Dra. Cecilia Gomez (Universidad de Alicante) for
(E)-2-Cyclohexylidene-N,N-diethylpropanamide
(2m):
1H
NMR
Â
spectrometric mass determination, and Dr. Francisco J. Gonzalez for
(200 MHz, CDCl3): d ˆ 3.47 ± 3.12 (m, 4H), 2.05 ± 1.93 (m, 4H), 1.68 (s,
3H), 1.56 ± 1.35 (m, 6H), 1.07 ± 1.00 (m, 6H); 13C NMR (75 MHz, CDCl3):
d ˆ 172.9 (C), 136.1 (C), 122.2 (C), 41.8 (CH2), 37.6 (CH2), 31.9 (CH2), 28.8
(CH2), 27.2 (CH2), 27.0 (CH2), 26.2 (CH2), 15.0 (CH3), 14.1 (CH3), 12.4
Â
Â
valuable discussions. J.M.C. thanks Carmen Fernandez-Florez for her time.
H.R.S. thanks the Universidad de Oviedo and the Principado de Asturias
for a predoctoral fellowship.
‡
(CH3); MS (70 eV): m/z (%): 209 (31) [M] , 194 (12), 180 (51), 137 (89), 109
(89); HRMS calcd for C13H23NO 209.1779, found: 209.1780; IR (neat): nÄ ˆ
2929, 2854, 1625, 1447, 1426, 1380cm 1; Rf ˆ 0.2 (hexane/AcOEt 3:1).
[1] a) L. Crombie, A. H. Krasinski, M. Manzoor-I-Khuda, J. Chem. Soc.
1963, 4970 ± 4976; b) F. Bohlmann, R. Miethe, Chem. Ber. 1967, 3861 ±
3868; c) N. Hirayama, K. Shimizu, K. Shirahata, K. Ueno, G. Tamura,
Agric. Biol. Chem. 1980, 44, 2083 ± 2087; d) M. Onda, Y. Konda, K.
Hinottozawa, S. Omura, Chem. Pharm. Bull. 1982, 30, 1210 ± 1214;
e) H. Cho, J. M. Beale, C. Graff, U. Mocek, A. Nakagawa, S. Omura,
H. G. Floss, J. Am. Chem. Soc. 1993, 115, 12296 ± 12304; f) M. Ojika,
H. Niwa, Y. Shizuri, K. Yamada, J. Chem. Soc. Chem. Commun. 1982,
628 ± 629; g) R. Grote, A. Zeeck, H. Drautz, H. Zähner, J. Antibiot.
1988, 41, 1178 ± 1185; h) G. Werner, H. Hagenmaier, H. Drautz, A.
Baumgartner, H. Zähner, J. Antibiot. 1984, 37, 110 ± 117; i) S. Omura,
N. Imamura, K. Hinitizawa, K. Otoguro, G. Lukacs, R. Faghih, R.
Tolmaann, B. H. Arison, J. L. Smith, J. Antibiot. 1983, 36, 1782 ± 1788.
[2] a) J. E. Baldwin, W. A. Dupont, Tetrahedron Lett. 1980, 21, 1881 ±
1882; b) G. B. Mpango, K. K. Mahalanabis, Z. Mahdavi-Damghani,
V. Snieckus, Tetrahedron Lett. 1980, 21, 4823 ± 4826; c) H. Greger, M.
Grentz, F. Bohlmann, Phytochemistry 1981, 20, 2579 ± 2581; d) H.
Greger, M. Grentz, F. Bohlmann, Phytochemistry 1982, 21, 1071 ±
1074; e) F. Bohlmann, M. Gancer, M. Kruger, E. Nordhoff, Tetrahe-
dron 1983, 39, 123 ± 128.
(E)-N,N-Diethyl-2,3-dimethylpent-2-enamide (2n): 1H NMR (200 MHz,
CDCl3): d ˆ 3.71 ± 3.00 (m, 4H), 1.96 ± 1.89 (m, 2H), 1.71 (s, 3H), 1.59 (s,
3H), 1.28 ± 0.77 (m, 9H); 13C NMR (75 MHz, CDCl3): d ˆ 172.7 (C), 133.9
(C), 125.4 (C), 41.8 (CH2), 37.5 (CH2), 28.4 (CH2), 15.8 (CH3), 15.7 (CH3),
‡
14.0 (CH3), 12.4 (CH3), 12.0 (CH3); MS (70 eV): m/z (%): 183 (20) [M] ,
168 (11), 154 (57), 111 (100), 83 (57); HRMS calcd for C11H21NO 183.1623,
1
found: 183.1623; IR (neat): nÄ ˆ 2968, 2936, 1630, 1461, 1426, 1380 cm
;
Rf ˆ 0.2 (hexane/AcOEt 3:1).
(E)-N,N-Diethyl-2,3-dimethylhex-2-enamide (2o): 1H NMR (200 MHz,
[D6]DMSO, 350 K): d ˆ 3.41 (q, J ˆ 7.22 Hz, 4H), 2.00 (t, J ˆ 7.22 Hz, 2H),
1.80 (s, 3H), 1.73 (s, 3H), 1.58 ± 1.39 (m, 2H), 1.18 (t, J ˆ 7.22 Hz, 6H), 0.94
(t, J ˆ 7.22 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 172.7 (C), 132.9 (C),
132.5 (C), 41.8 (CH2), 37.6 (CH2), 37.5 (CH2), 20.7 (CH2), 16.2 (CH3), 15.7
(CH3), 14.0 (CH3), 13.9 (CH3), 12.3 (CH3); MS (70 eV): m/z (%): 197 (18)
‡
[M] , 182 (11), 168 (20), 125 (100), 97 (12); HRMS calcd for C12H23NO
197.1779, found: 197.1782; IR (neat): nÄ ˆ 2962, 2934, 2872, 1626, 1460, 1426,
1380cm 1; Rf ˆ 0.2 (hexane/AcOEt 3:1).
(E)-N,N-Diethyl-2,3-dimethyloct-2-enamide (2p): 1H NMR (200 MHz,
[D6]DMSO, 350 K): d ˆ 3.41 (q, J ˆ 7.22 Hz, 4H), 2.04 (t, J ˆ 7.22 Hz, 2H),
1.81 (s, 3H), 1.75 (s, 3H), 1.52 ± 1.36 (m, 6H), 1.20 (t, J ˆ 7.22 Hz, 6H), 0.98
(t, J ˆ 6.89 Hz, 3H); 13C NMR (75 MHz, CDCl3): d ˆ 172.9 (C), 133.2 (C),
[3] a) P. Caramella, D. Reami, M. Falzoni, P. Quadrelli, Tetrahedron 1999,
55, 7027 ± 7044; b) G. Cardillo, M. A. Hashem, C. Tomasini, J. Chem.
Soc. Perkin Trans. 1 1990, 1587 ± 1590; c) J. Jurczak, T. Bauer, C.
Chem. Eur. J. 2001, 7, No. 14
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0714-3067 $ 17.50+.50/0
3067

Â
J. M. Concellon et al.
FULL PAPER
Chapuis in Stereoselective Synthesis, (Houben-Weyl) Vol E 21c (Eds.:
G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme,
Stuttgart, 1995, p. 2735; d) R. F. Gothelf, K. A. Jorgensen, Chem. Rev.
1998, 98, 863 ± 909.
[11] The coupling constant between the olefinic protons of compounds 2a,
2b and 2c were J ˆ 15.3, 14.9 and 15.2 Hz, respectively, from the
average literature values.
[12] The 1H NMR spectrum of 2a has been described by: C. C. Tung, A. J.
Speziale, H. W. Frazier, J. Org. Chem. 1963, 28, 1514 ± 1521.
[4] K Takai, M. Tezuka, K. Utimoto, J. Org. Chem. 1991, 56, 5980 ± 5982.
[5] a) M. K. Tay, E. About-Jaudet, N. Collignon, P. Savignac, Tetrahedron
1989, 45, 4415 ± 4430; b) T. Janecki, R. Bodalski, M. Wieczorek, G.
Bujacz, Tetrahedron 1995, 51, 1721 ± 1740.
[6] S. Kojima, H. Inai, T. Hidaka, K. Ohkata, Chem. Commun. 2000,
1795 ± 1796.
[7] a) I. Matsuda, K. Takeuchi, K. Itoh, Tetrahedron Lett. 1999, 40, 2553 ±
2556; b) M. Shindo, S. Oya, R. Murakami, Y. Sato, K. Shishido,
Tetrahedron Lett. 2000, 41, 5947 ± 5950.
[13] 2-Chloroamides
3 were prepared by treatment of 2-chloroacid
chlorides with amines.
[14] A mixture of the corresponding a,b-unsaturated ester and b-hydrox-
yester was isolated. See reference [10].
[15] However, this ªusualº trend is not always followed in samarium-
promoted reactions (see reference [9] and references cited therein).
[16] A similar transition state model with a chair transition state was
proposed to explain the selectivity in other reactions with SmI2:
a) G. A. Molander, J. B. Etter, P. W. Zinke, J. Am. Chem. Soc. 1987,
109, 453 ± 463; b) D. Urban, T. Skrydstrup, J. M. Beau, J. Org. Chem.
1998, 63, 2507 ± 2516.
Ã
[8] F. Tellier, R. Sauvetre, Tetrahedron Lett. 1993, 34, 5433 ± 5436.
Â
Â
Â
[9] J. M. Concellon, P. L. Bernad, J. A. Perez-Andres, Angew. Chem.
1999, 111, 2528 ± 2530; Angew. Chem. Int. Ed. 1999, 38, 2384 ± 2386.
Â
Â
Â
[10] J. M. Concellon, J. A. Perez-Andres, H. Rodríguez-Solla, Angew.
Chem. 2000, 112, 2866 ± 2868; Angew. Chem. Int. Ed. 2000, 39, 2773 ±
2775.
[17] J. L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chem. 1981, 5, 479 ± 484.
[18] D. N. Harpp, L. Q. Bao, C. J. Black, J. G. Gleason, R. A. Smith, J. Org.
Chem. 1975, 40, 3420 ± 3426.
Received: December 8, 2000 [F2919]
3068
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0714-3068 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 14