Synthesis of Aromatic (E)- or (Z)-α,β-Unsaturated Amides with Total or Very High Selectivity from α,β-Epoxyamides and Samarium Diiodide

Article abstract of DOI:10.1021/jo0349577

Highly stereoselective synthesis of aromatic α,β-unsaturated amides was achieved by treatment of aromatic α,β-epoxyamides with samarium diiodide. The starting compounds 1 and 3 are easily prepared by the reaction of enolates derived from α-chloroamides wi

Full text of DOI:10.1021/jo0349577

Recently, we reported several highly diastereoselective
â-elimination reactions, promoted by samarium diiodide,8
leading (Z)-vinyl halides,9 (E)-R,â-unsaturated esters,10
or (Z)-vinylsilanes.11 We also published the preparation
of (E)-R,â-unsaturated amides from 2-chloro-3-hydroxy-
amides.12 In addition, more recently we described the
transformation of aromatic R,â-epoxyamides into R-hy-
droxyamides by reaction with SmI2 in the presence of
H2O.13
Syn th esis of Ar om a tic (E)- or
(Z)-r,â-Un sa tu r a ted Am id es w ith Tota l or
Ver y High Selectivity fr om
r,â-Ep oxya m id es a n d Sa m a r iu m Diiod id e
J ose´ M. Concello´n* and Eva Bardales
Departamento de Qu´ımica Orga´nica e Inorga´nica,
Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a, 8, 33071 Oviedo, Spain
In this work we wish to describe a new synthesis of
aromatic R,â-unsaturated amides starting from the easily
available R,â-epoxyamides 1 and 3 by using SmI2. Thus,
aromatic (Z)-R,â-unsaturated amides were obtained from
aromatic R,â-epoxyamides, in which the oxirane ring is
trisubstituted, and (E)-R,â-unsaturated amides from
aromatic di- and tetrasubstituted R,â-epoxyamides. These
preparations take place with total or very high stereo-
selectivity. A mechanism is proposed to account for the
different stereochemistries.
Starting R,â-epoxyamides 1 were prepared by reaction
of the corresponding potassium enolates of R-chloroam-
ides14 (generated by treatment of R-chloroamides with
potassium hexamethyldisilazide at -78 °C) with different
aldehydes at temperatures ranging from -78 to 25 °C.
Disubstituted epoxyamides, compounds 3a and 3b, were
prepared by reaction of lithium enolate of chloroacet-
amide (generated by treatment of R-chloroacetamide with
LDA at -78 °C) with different aldehydes at -78 °C and
further treatment with sodium hydride. Tetrasubstituted
epoxyamides, compounds 3c-e, were obtained by reac-
tion of lithium enolate of chloropropanamide with dif-
ferent ketones at temperatures ranging from -78 to 25
°C (Scheme 1 and Table 1).
jmcg@sauron.quimica.uniovi.es
Received J uly 3, 2003
Abstr a ct: Highly stereoselective synthesis of aromatic R,â-
unsaturated amides was achieved by treatment of aromatic
R,â-epoxyamides with samarium diiodide. The starting com-
pounds 1 and 3 are easily prepared by the reaction of eno-
lates derived from R-chloroamides with carbonyl compounds
at -78 °C. A mechanism to explain this transformation is
proposed.
R,â-Unsaturated amides have been used as building
blocks in organic synthesis1 to prepare natural products.2
Moreover, R,â-unsaturated amides show both biological3
and insecticide activities.4 Consequently, several prepa-
rations of R,â-unsaturated amides have been described.
However, the described methodologies afford (E)-R,â-
unsaturated amides and, to the best of our knowledge,
only a paper describing the synthesis of (Z)-R,â-unsatur-
ated amides has been published to date.5 An important
limitation of this last method is that the preparation of
the starting phosponate occurs in low yield (33%).
In addition, transformations of epoxides6 into alkenes
with high diastereselectivity are very scarce.7
Our first attempts were performed by using N,N-
diethyl-2-methyl-3-phenyl-2,3-epoxypropanamide as a
model substrate, and several reaction conditions were
tested. When the elimination reaction was carried out
with 4 equiv of SmI2, without cosolvents, a mixture of
(Z) and (E)-R,â-unsaturated amides was obtained (roughly
(1) (a) Caramella, P.; Reami, D.; Falzoni, M.; Quadrelli, P. Tetra-
hedron 1999, 55, 7027-7042. (b) Cardillo, G.; Hashem, M. A.; To-
masini, C. J . Chem. Soc., Perkin Trans. 1 1990, 1587-1490. (c) J urczak,
J .; Bauer, T.; Chapuis, C. In Stereoselective Synthesis (Houben-Weyl);
Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;
Thieme Verlag: Stuttgart, 1995; Vol E 21c, p 2735. (d) Gothelf, R. F.;
J orgensen, K. A. Chem. Rev. 1998, 98, 863-909.
(6) To see synthetic applications of epoxides: (a) Gansa¨uer, A.;
Bluhm, H. Chem. Rew. 2000, 100, 2771-2788. (b) Li, J . J . Tetrahedron
2001, 57, 1-24. (c) Rao, A. S.; Panikar, S. K.; Kirtane, J . G.
Tetrahedron 1983, 39, 2323-2365. (d) Gorzynski-Smith, J . Synthesis
1984, 629-656.
(7) Synthesis of alkenes from epoxides can be carried out with very
low diastereoselectivity by using SmI2: Girard, P.; Namy, J . L.; Kagan,
H. B. J . Am. Chem. Soc. 1980, 102, 2963-2968.
(8) To see several reviews of synthetic applications of SmI2: (a)
Molander, G. A. Chem. Rew. 1992, 92, 29-68. (b) Molander, G. A.;
Harris, C. R. Chem. Rew. 1996, 96, 307-338. (c) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321-3354. (d) Krief, A.; Laval,
A. M. Chem. Rew. 1999, 99, 745-777. (e) Still, P. G. J . Chem. Soc.,
Perkin Trans. 1 2001, 2727-2751.
(2) Takai, K.; Tezuka, M.; Utimoto, K. J . Org. Chem. 1991, 56,
5980-5982.
(3) (a) Crombie, L.; Krasinski, A. H.; Manzoor-I-Khuda, M. J . Chem.
Soc. 1963, 4970-4976. (b) Bohlmann, F.; Miethe, R. Chem. Ber. 1967,
3861-3868. (c) Hirayama, N.; Shimizu, K.; Shirahata, K.; Ueno, K.;
Tamura, G. Agric. Biol. Che. 1980, 44, 2083-2087. (d) Onda, M.;
Konda, Y.; Hinottozawa, K.; Omura, S. Chem. Pharm. Bull. 1982, 30,
1210-1214. (e) Cho, H.; Beale, J . M.; Graff, C.; Mocek, U.; Nakagawa,
A.; Omura, S.; Floss, H. G. J . Am. Chem. Soc. 1993, 115, 12296-12304.
(f) Ojika, M.; Niwa, H.; Shizuri, Y.; Yamada, K. J . Chem. Soc., Chem.
Commun. 1982, 628-629. (g) Grote, R.; Zeeck, A.; Drautz, H.; Za¨hner,
H. J . Antibiot. 1988, 41, 1275-1276. (h) Werner, G.; Hagenmaier, H.;
Drautz, H.; Baumgartner, A.; Za¨hner, H. J . Antibiot. 1984, 37, 110-
117. (i) Omura, S.; Imamura, N.; Hinitizawa, K.; Otoguro, K.; Lukacs,
G.; Faghih, R.; Tolmaann, R.; Arison, B. H.; Smith, J . L. J . Antibiot.
1983, 36, 1783-1786.
(9) Concello´n, J . M.; Bernad, P. L.; Pe´rez-Andre´s, J . A. Angew. Chem.
1999, 111, 2528-2530; Angew. Chem., Int. Ed. Engl. 1999, 2384-2386.
(10) (a) Concello´n, J . M.; Bernad, P. L.; Pe´rez-Andre´s, J . A.;
Rodr´ıguez-Solla, H. Angew. Chem. 2000, 112, 2773-2775; Angew.
Chem., Int. Ed. Engl. 2000, 112, 2866-2868. (b) Concello´n, J . M.;
Bardales, E. Org. Lett. 2002, 4, 189-191.
(4) (a) Baldwin, J . E.; Dupont, W. A. Tetrahedron Lett. 1980, 21,
1881-1182. (b) Mpango, G. B.; Mahalanabis, K. K.; Mahdavi-
Damghani, Z.; Snieckus, V. Tetrahedron Lett. 1980, 21, 4823-4826.
(c) Greger, H.; Grentz, M.; Bohlmann, F. Phytochemistry 1981, 20,
2579-2581. (d) Greger, H.; Grentz, M.; Bohlmann, F. Phytochemistry
1982, 21, 1071-1074. (e) Bohlmann, F.; Gancer, M.; Kruger, M.;
Nordhoff, E. Tetrahedron 1983, 39, 123-128.
(11) Concello´n, J . M.; Bardales, E. Org. Lett. 2001, 3, 937-939.
(12) Concello´n, J . M.; Pe´rez-Andre´s, J . A.; Rodr´ıguez-Solla, H. Chem.
Eur. J . 2001, 7, 3062-3068.
(13) Concello´n, J . M.; Bardales, E.; Go´mez, C. Tetrahedron Lett.
2003, 44, 5323-5326.
(5) Fortin, S.; Dupont, F.; Deslongchamps, P. J . Org. Chem. 2002,
67, 5437-5439.
(14) Chloroamides were prepared by treatment of 2-chloro acid
chlorides with amines.
10.1021/jo0349577 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/28/2003
9492
J . Org. Chem. 2003, 68, 9492-9495

TABLE 2. Syn th esis of Tr isu bstitu ted Ar om a tic
(Z)-r,â-Un sa tu r a ted Am id es 2
SCHEME 1. Syn th esis of r,â-ep oxya m id es 1 a n d 3
2
Ar
R1
R2
Et
Et
Et
i-Pr
i-Pr
ed (%)
yield (%)a
2a
2b
2c
2d
2e
Ph
Ph
Me
Bu
Me
Me
Me
>98
>98
97
>98
>98
75
87
67
70
78
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
a
Isolated yield after flash column chromatography based on
compound 1.
SCHEME 3. Syn th esis of Di- a n d Tetr a su bstitu ted
(E)-r,â-Un sa tu r a ted Am id es 4
TABLE 1. Syn th esis of r,â-Ep oxia m id es 1 a n d 3
product
Ar
R1
R2
R3
yield (%)a
1a
1b
1c
1d
1e
3a
3b
3c
3d
3e
Ph
Ph
Me
Bu
Me
Me
Me
H
Et
Et
Et
i-Pr
i-Pr
Et
Et
Et
H
H
H
H
H
H
H
Me
Et
Et
83
65
79
72
74
67
69
90
95
93
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
Ph
p-MeOC6H4
Ph
TABLE 3. Syn th esis of Di- a n d Tetr a su bstitu ted
Ar om a tic (E)-r,â-Un sa tu r a ted Am id es 4
4
Ar
R1
R2
R3
ed (%)
yield (%)a
H
Me
Me
Me
4a
4b
4c
4d
4e
Ph
H
H
Me
Me
Me
Et
Et
Et
Et
H
H
Me
Et
Et
>98
>98
>98
>98
>98
75
80
95
84
91
Ph
Ph
Et
i-Pr
p-MeOC6H4
Ph
Ph
Ph
a
Isolated yield after flash column chromatography based on
starting carbonyl compound.
i-Pr
a
Isolated yield after flash column chromatography or vacumm
SCHEME 2. Syn th esis of Tr isu bstitu ted Ar om a tic
(Z)-r,â-Un sa tu r a ted Am id es 2
distillation based on compound 3.
However, when tetrasubstituted R,â-epoxiamides 3c-e
were used as starting compounds, (E)-R,â-unsaturated
amides were isolated with total stereoselectivity (Scheme
3 and Table 3), instead of (Z)-unsaturated amides. When
the reactions were performed without MeOH, no differ-
ences were observed and similar yields and de were
obtained. It is noteworthy that tetrasubstitution of CdC
with total diastereoselectivity is very difficult to achieve.
In the case of N,N-diethyl-3-phenyl-2,3-epoxypropan-
amide (disubstituted R,â-epoxyamide), a mixture of N,N-
diethyl-3-phenyl-2-hydroxypropanamide and its corre-
sponding reduction product (N,N-diethyl-3-phenyl-
propanamide) was obtained. On the basis of these results,
the reaction was carried out without MeOH (to avoid both
the reduction of the double bond CdC of the R,â-un-
saturated amide and the synthesis of R-hydroxyamides).
Thus, treatment of disubstituted R,â-epoxyamides 3a and
3b in THF (4 mL) with a solution of SmI2 (2.5 equiv) in
THF for 30 min at room temperature afforded, after
hydrolysis, the corresponding disubstituted (E)-R,â-
unsaturated amides 4a -b with total stereoselectivity
(Scheme 3 and Table 3)
10:1). When 2.5 equiv of SmI2 was used in the presence
of MeOH as a cosolvent,15 a mixture of the (Z)-unsatur-
ated amide and the corresponding 2-hydroxyamide were
isolated (roughly 5:1). The best yields and the highest
(Z)-diastereoselectivity were obtained by using 4 equiv
of SmI2 and MeOH as a cosolvent.16
Thus, treatment of R,â-epoxyamides 1a -e in THF (4
17
mL) and MeOH (0.5 mL) with a solution of SmI2 (4
equiv) in THF for 30 min at room temperature afforded,
after hydrolysis, the corresponding trisubstituted (Z)-R,â-
unsaturated amides 2 with total stereoselectivity (Scheme
2 and Table 2).18
This â-elimination reaction was general, and trisub-
stituted aromatic R,â-unsaturated amides 2 could be
obtained bearing electron rich or deficient groups at
the aromatic ring or bulky groups R2 (iPr) on nitrogen
(Table 2).
It is noteworthy that, although 3:1 mixtures of dia-
stereoisomers of starting compounds 1 and 3 were used
in all described reactions, the corresponding R,â-unsatur-
ated amides 2 and 4 were obtained with high stereose-
lectivity.
The diastereoisomeric excess was determined on the
crude reaction products by GC-MS and 1H NMR spec-
troscopy.19 The stereochemistry in the double bond CdC
of disubstituted R,â-unsaturated amides 4a ,b was as-
signed on the basis of the value of 1H NMR coupling
(15) Proton-donor solvents increase the oxidative potential of
SmI2: Hasegawa, E.; Curran, D. P. J . Org. Chem. 1993, 58, 5008-
5010.
(16) Elimination reactions of 1,2-dibromoalkanes to alkenes are
accelerated in a methanolic medium: Yamada, R.; Negoro, N.; Yanada,
K.; Fujita, T. Tetrahedron Lett. 1996, 37, 9313-9316.
(17) SmI2 was very rapidly prepared by sonication of a mixture of
samarium powder and diiodomethane in THF: Concello´n, J . M.;
Rodr´ıguez-Solla, H.; Bardales, E.; Huerta, M. Eur. J . Org. Chem. 2003,
1775-1778.
(18) Minor amounts of 2-hydroxy-2-methyl-3-phenylpropanamide
were obtained (11:1). In the other preparations of aromatic trisubsti-
tuted R,â-unsaturated amides, no 2-hydroxyamides were detected.
J . Org. Chem, Vol. 68, No. 24, 2003 9493

SCHEME 4. Mech a n istic P r op osa l for th e
Syn th esis of Tr isu bstitu ted Ar om a tic
(Z)-r,â-Un sa tu r a ted Am id es 2
F IGURE 1. Transition states proposal for the synthesis of
trisubstituted aromatic (Z)-R,â-unsaturated amides 2.
produced with the appropriate conformation for a double
coordination of the samarium center with the alcohol
oxygen.
constant between the olefinic protons20 or by NOESY
experiments in the case of the trisubstituted (compounds
2b and 2d ) and tetrasubstituted (compound 4d ) amides.
In addition, in the case of compounds 4c,d , a comparison
with the 1H and 13C NMR values described in the
literature for the corresponding (E)-R,â-unsaturated
amides12 was also carried out.
The synthesis of products 2 could be explained (Scheme
4) by assuming the initial double coordination of sa-
marium with both oxygen atoms of 1. The coordination
of samarium with the oxirane ring produces an effect
similar to that of a Lewis acid and can open the oxirane
ring by reduction of the Câ-O bond. The cleavage of the
Câ-O bond in aromatic R,â-epoxyamides is favored, since
it gives rise to a benzylic radical, which is stabilized by
resonance.
A very fast second reduction with another equivalent
of SmI2 affords the corresponding anion, which suffers a
â-elimination reaction (far faster than the hydrolysis of
the anion by MeOH), affording the corresponding R,â-
unsaturated amide 2. Tentatively, we propose an anti
elimination process, transition states I and II being
possible (Figure 1), in which the samarium(III) center is
coordinated with the oxygen atom of the amide group. I
would be preferred because there is no steric hindrance
between Ar and R1 and no 1,3-diaxial interactions of Ar
are present in the cyclic transition state. Elimination
from I affords a trisubstituted (Z)-R,â-unsaturated amide.
In the case of disubstituted epoxyamides, transition state
II would be preferred, with the bulkier group Ar in the
equatorial orientation and there is no steric hidrance
between Ar and R1 ) H.
The methodology herein described is complementary
to the previously reported elimination of aromatic 2-chloro-
3-hydroxyamides also promoted by SmI2.12 Thus, the
elimination reaction from R,â-epoxyamides to obtain
trisubstituted (Z)-R,â-unsaturated amides or tetrasub-
stituted (E)-R,â-unsaturated amides is recommendable,
while synthesis of trisubstituted (E)-R,â-unsaturated
amides can be achieved from 2-chloro-3-hydroxyamides.
Similar results are obtained from R,â-epoxyamides or
2-chloro-3-hydroxyamides to obtain aromatic disubsti-
tuted (E)-R,â-unsaturated amides.
In conclusion, we have presented an easy, simple, and
general methodology to obtain both (Z)-R,â-unsaturated
amides from aromatic trisubstituted R,â-epoxyamides
and (E)-R,â-unsaturated amides from di- or tetrasubsti-
tuted R,â-epoxyamides. These elimination reactions pro-
ceed with total or high diastereoselectity.
Exp er im en ta l Section
Gen er a l.21 Samarium diiodide was prepared by reaction of
CH2I2 with samarium powder.17
Gen er a l P r oced u r e for th e Syn th esis of 2,3-Ep oxy-
a m id es 1. To a -78 °C stirred solution of the corresponding
2-haloamide (2.5 mmol) in dry THF (4 mL) was added dropwise
potassium hexamethyldisilazide (6.5 mL of 0.5 m solution in
toluene, 3.25 mmol). After stirring for 10 min, a solution of the
corresponding aldehyde (2.5 mmol) in dry THF (4 mL) was added
dropwise at -78 °C and the mixture was allowed to warm to
room temperature. The resulting solution was quenched with
aqueous saturated solution of NH4Cl (20 mL). Usual workup
provided crude 2,3-epoxyamides 1, and purification by flash
column chromatography over silica gel (hexane/ethyl acetate)
provided pure compounds.
Gen er a l P r oced u r e of Syn th esis of r,â-Un sa tu r a ted
Am id es 2. A solution of 1 (0.4 mmol) in THF (2 mL) was added
to a stirred solution of SmI2 (1.6 mmol) and MeOH (0.4 mL),
under a nitrogen atmosphere, at 25 °C. The mixture was stirred
for 30 min at this temperature and then quenched with aqueous
HCl (0.1 M, 15 mL). Usual workup afforded crude R,â-unsatur-
ated amides 2, which were purified by flash column chromatog-
raphy on silica gel (hexane/AcOEt). Yields are given in Table 1.
(Z)-N,N-Dieth yl-2-m eth yl-3-p h en ylp r op en a m id e (2a ): 1H
NMR (400 MHz, [D6]DMSO, 373 K) δ ) 7.32-7.12 (m, 5 H),
6.34 (s, 1 H), 3.36 (q, J ) 6.9 Hz, 2 H), 3.14 (q, J ) 6.9 Hz, 2 H),
When the elimination is carried out from tetrasubstited
epoxyamides, transition state II would be also preferred
with the bulkier group Ar in the equatorial position.
Synthesis of 2 and 4, with total stereoselection, from
a mixture of diastereoisomers of 1 and 3 could be ex-
plained by assuming that after the reaction of epoxy-
amides 1 and 3 with SmI2, only one diastereoisomer is
(19) When the minor diastereoisomer was not detected, ed >98% is
showed in Tables 2 and 3.
(20) The coupling constant between the olefinic protons of com-
pounds 4a and 4b were J ) 15.3 and 15.5 Hz, respectively, according
with the average literature values.
(21) Concello´n, J . M.; Bardales, E. J . Org. Chem. 2003, 68, 1585-
1588.
9494 J . Org. Chem., Vol. 68, No. 24, 2003

1.99 (s, 3 H), 1.05 (t, J ) 6.9 Hz, 3 H), 0.84 (t, J ) 6.9 Hz, 3 H);
13C NMR (75 MHz, CDCl3) δ ) 171.2 (C), 135.8 (C), 133.4 (C),
128.0 (CH), 127.5 (CH), 127.1 (CH), 126.7 (CH), 41.9 (CH2), 38.0
(CH2), 22.4 (CH3), 13.5 (CH3), 11.9 (CH3); MS (70 eV) m/z (%)
217 [M+] (81), 202 (32), 145 (100), 117 (97), 91 (40); HRMS calcd
for C14H19NO 217.1467, found 217.1461; IR (neat) ν˜ ) 2973,
1620, 1431 cm-1; Rf ) 0.2 (hexane/AcOEt 3/1). Anal. Calcd for
C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.51; H, 8.79;
N, 6.41.
in dry THF (4.5 mL) was added dropwise at -78 °C and the
mixture was stirred for 1 h. In the case of 2,3-epoxyamides 3a ,b,
the reaction mixture was quenched with an aqueous saturated
solution of NH4Cl (20 mL). Usual workup provided crude 2-halo-
3-hydroxyamides, which were diluted with CH2Cl2 (20 mL) and
treated with sodium hydride (1 g, 45 mmol) at 25 °C. The
mixture was stirred for 2.5 h at this temperature and then
quenched with H2O. In the case of 2,3-epoxyamides 3c-e, the
mixture was allowed to warm to room temperature. The result-
ing solution was quenched with an aqueous saturated solution
of NH4Cl (20 mL). Usual workup afforded crude 2,3-epoxyamides
3a -e, and purification by flash column chromatography on silica
gel (hexane/AcOEt) provided pure compounds.
Gen er a l P r oced u r e of Syn t h esis of r,â-Un sa t u r a t ed
Am id es 4. A solution of 3 (0.4 mmol) in THF (2 mL) was added
to a stirred solution of SmI2 (1.0 mmol), in THF (12 mL), under
a nitrogen atmosphere, at 25 °C. The mixture was stirred for
30 min at this temperature and then quenched with aqueous
HCl (0.1 M, 15 mL). Usual workup afforded crude R,â-unsatur-
ated amides 4, which were purified by flash column chromatog-
raphy on silica gel (hexane/AcOEt). Yields are given in Table 2.
(E)-N,N-Dieth yl-3-p h en ylp r op en a m id e (4a ). See ref 12.
(E)-N,N-Dieth yl-3-[4-m eth oxyp h en yl]p r op en a m id e (4b):
1H NMR (400 MHz, [D6]DMSO, 373 K) δ ) 7.55 (d, J ) 8.5 Hz,
2 H), 7.42 (d, J ) 15.5 Hz, 1 H), 6.95 (d, J ) 8.5 Hz, 2 H), 6.84
(d, J ) 15.5 Hz, 1 H), 3.81 (s, 3 H), 3.45 (q, J ) 7.1 Hz, 4 H),
1.15 (t, J ) 7.1 Hz, 6 H); 13C NMR (50 MHz, CDCl3) δ ) 165.9
(C), 160.5 (C), 141.7 (CH), 129.1 (CH), 128.0 (C), 115.2 (CH),
114.0 (CH), 55.1 (CH3), 42.1 (CH2), 40.9 (CH2), 14.5 (CH3), 13.1
(CH3); MS (70 eV) m/z (%) 233 [M+] (21), 218 (6), 161 (100), 133
(25); IR (neat) ν˜ ) 2974, 1646, 1460 cm-1; Rf ) 0.3 (hexane/
AcOEt 1/1). Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N,
6.00. Found: C, 72.18; H, 8.29; N, 6.15.
(Z)-2-Bu tyl-N,N-d ieth yl-3-p h en ylp r op en a m id e (2b): 1H
NMR (200 MHz, CDCl3) δ ) 7.31-7.09 (m, 5 H), 6.32 (s, 1 H),
3.62-2.92 (m, 4 H), 2.41-2.31 (m, 2 H), 1.60-1.32 (m, 4 H), 1.08
(t, J ) 6.9 Hz, 3 H), 0.92 (t, J ) 6.9 Hz, 3 H), 0.73 (t, J ) 6.9 Hz,
3 H); 13C NMR (50 MHz, CDCl3) δ ) 170.9 (C), 138.0 (C), 136.0
(C), 128.0 (CH), 127.7 (CH), 127.1 (CH), 125.8 (CH), 41.8 (CH2),
37.8 (CH2), 36.0 (CH2), 29.7 (CH2), 22.4 (CH2), 13.7 (CH3), 13.3
(CH3), 11.8 (CH3); m/z (%) 259 [M+] (43), 216 (100), 202 (30),
100 (23); IR (neat) ν˜ ) 2959, 1619, 1430 cm-1; Rf ) 0.3 (hexane/
AcOEt 3/1). Anal. Calcd for C17H25NO: C, 78.72; H, 9.71; N, 5.40.
Found: C, 78.64; H, 9.79; N, 5.42.
(Z)-N,N-Dieth yl-3-[4-m eth oxyp h en yl]-2-m eth ylp r op en -
1
a m id e (2c): H NMR (400 MHz, [D6]DMSO, 373 K) 7.21 (d, J
) 8.8 Hz, 2 H), 6.84 (d, J ) 8.8 Hz, 2 H), 6.26 (s, 1 H), 3.74 (s,
3 H), 3.38 (q, J ) 6.9 Hz, 2 H), 3.17 (q, J ) 6.9 Hz, 2 H), 1.96 (s,
3 H), 1.08 (t, J ) 6.9 Hz, 3 H), 0.87 (d, J ) 6.9 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ ) 171.6 (C), 158.7 (C), 131.3 (C), 128.9
(CH), 128.7 (C), 126.3 (CH), 113.5 (CH), 55.0 (CH3), 41.9 (CH2),
38.1 (CH2), 22.3 (CH3), 13.7 (CH3), 12.0 (CH3); MS (70 eV) m/z
(%) 247 [M+] (69), 232 (20), 175 (100), 147 (45), 140 (18); HRMS
calcd for C15H21NO2 247.1572, found 247.1562; IR (neat) ν˜ )
2972, 1608, 1513 cm-1; Rf ) 0.3 (hexane/AcOEt 1/1). Anal. Calcd
for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.71; H,
8.50; N, 5.60.
(Z)-N,N-Diisop r op yl-3-[4-m eth oxyp h en yl]-2-m eth ylp r o-
p en a m id e (2d ): 1H NMR (300 MHz, CDCl3) 7.31 (d, J ) 8.8
Hz, 2 H), 6.80 (d, J ) 8.8 Hz, 2 H), 6.21 (s, 1 H), 4.95-4.12 (m,
1 H), 3.79 (s, 3 H), 3.37-3.23 (m, 1 H), 2.03 (s, 3 H), 2.02 (d, J
) 6.9 Hz, 6 H), 1.09 (d, J ) 6.7 Hz, 3 H), 0.56 (d, J ) 6.7 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ ) 171.4 (C), 158.7 (C), 133.0
(C), 129.2 (C), 129.1 (CH), 125.2 (CH), 113.4 (CH), 55.1 (CH3),
50.3 (CH), 45.3 (CH), 22.2 (CH3), 21.3 (CH3), 20.6 (CH3), 20.0
(CH3), 19.7 (CH3); MS (70 eV) m/z (%) 275 [M+] (8), 260 (13),
175 (75), 91 (53); HRMS calcd for C17H25NO2 275.3859, found
275.1876; IR (neat) ν˜ ) 2981, 1616, 1510 cm-1; Rf ) 0.4 (hexane/
AcOEt 3/1). Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N,
5.09. Found: C, 74.06; H, 9.20; N, 5.01.
(E)-N,N-Dieth yl-2-m eth yl-3-p h en ylbu t-2-en a m id e (4c).
See ref 12.
(E)-N,N-Dieth yl-2-m eth yl-3-p h en ylp en t-2-en a m id e (4d ).
See ref 12.
(E )-N ,N -D i i s o p r o p y l-2-m e t h y l-3-p h e n y lp e n t -2-e n -
a m id e (4e): 1H NMR (200 MHz, CDCl3) 7.34-7.16 (m, 5 H),
3.97-3.84 (m, 1 H), 3.12-2.98 (m, 1 H), 2.32-1.95 (m, 2 H), 1.95
(s, 3 H), 1.36 (d, J ) 6.9 Hz, 3 H), 1.06 (d, J ) 6.9 Hz, 3 H), 0.99
(d, J ) 6.7 Hz, 3 H), 0.94 (t, J ) 6.7 Hz, 3 H), 0.37 (d, J ) 6.7
Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ ) 171.9 (C), 140.8 (C),
136.9 (C), 129.4 (C), 128.5 (CH), 127.6 (CH), 126.6 (CH), 49.7
(CH), 44.9 (CH), 25.8 (CH2), 21.4 (CH3), 20.4 (CH3), 19.7 (CH3),
19.4 (CH3), 16.7 (CH3), 12.4 (CH3); MS (70 eV) m/z (%) 273 [M+]
(2), 244 (49), 173 (100), 145 (70), 128 (21); IR (neat) ν˜ ) 2967,
1619, 1440 cm-1; Rf ) 0.5 (hexane/AcOEt 3/1). Anal. Calcd for
(Z)-N,N-Diisop r op yl-3-[4-ch lor op h en yl]-2-m et h ylp r o-
p en a m id e (2e): 1H NMR (200 MHz, CDCl3) 7.29 (d, J ) 8.2
Hz, 2 H), 7.19 (d, J ) 7.4 Hz, 2 H), 6.18 (s, 1 H), 3.99-3.85 (m,
1 H), 3.33-3.20 (m, 1 H), 2.00 (s, 3 H), 1.43 (d, J ) 5.9 Hz, 6 H),
1.06 (d, J ) 6.4 Hz, 3 H), 0.53 (d, J ) 6.4 Hz, 3 H); 13C NMR (50
MHz, CDCl3) δ ) 170.6 (C), 135.5 (C), 134.5 (C), 132.5 (C), 129.0
(CH), 128.0 (CH), 124.2 (CH), 50.2 (CH), 45.2 (CH), 22.1 (CH3),
21.0 (CH3), 20.2 (CH3), 19.8 (CH3), 19.4 (CH3); MS (70 eV)
m/z (%) 279 [M+] (47), 264 (29), 179 (100), 168 (11); HRMS calcd
for C16H22NOCl 279.1390, found 279.1425; IR (neat) ν˜ ) 2984,
1612, 1493 cm-1; Rf ) 0.4 (hexane/AcOEt 3/1). Anal. Calcd for
C
18H27NO: C, 79.07; H, 9.95; N, 5.12. Found: C, 79.19; H, 9.84;
N, 5.11.
Ack n ow led gm en t. We thank II Plan Regional de
Investigacio´n del Principado de Asturias (PB-EXP01-
11) and Ministerio de Ciencia y Tecnolog´ıa (BQU2001-
3807) for financial support. J .M.C. thanks Carmen
Ferna´ndez-Flo´rez for her time and E.B to Principado
de Asturias for a predoctoral fellowship. Thanks to
Robin Walker for his revision of the English.
C
16H22ClNO: C, 68.68; H, 7.93; N, 5.01. Found: C, 68.80; H,
7.89; N, 5.11.
Gen er a l P r oced u r e for th e Syn th esis of 2,3-Ep oxy-
a m id es 3a -e: To a -78 °C stirred solution of the corresponding
2-haloamide (4.5 mmol) in dry THF (4 mL) was added dropwise
lithium diisopropylamide [prepared from MeLi (3.2 mL of 1.5
m solution in diethyl ether, 5 mmol) and diisopropylamine (0.8
mL, 5 mmol) in THF 25 mL) at 0 °C]. After stirring for 10 min,
a solution of the corresponding aldehyde or ketone (3.5 mmol)
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 1 and 3 and 13C NMR spectra of compounds 2 and
4. This material is available free of charge via Internet at
http://pubs.acs.org.
J O0349577
J . Org. Chem, Vol. 68, No. 24, 2003 9495