Practical and efficient synthesis of (E)-α,β-unsaturated amides bearing (S)-α-methylbenzylamine from 2-phosphonamides via Horner-Wadsworth-Emmons reaction

Article abstract of DOI:10.1055/s-2006-926265

The highly stereoselective synthesis of (E)-α,β-unsaturated amides bearing (S)-α-methylbenzylamine was achieved from 2-phosphonamides via Horner-Wadsworth-Emmons reaction. The starting phosphonamides are easily prepared in two steps with excellent yields

Full text of DOI:10.1055/s-2006-926265

440
LETTER
Practical and Efficient Synthesis of (E)-a,b-Unsaturated Amides Bearing
(S)-a-Methylbenzylamine from 2-Phosphonamides via Horner–Wadsworth–
Emmons Reaction
(
E
)-
a
,
b
-Unsatur
u
atedAmides
g
Bearing
(
S
)
e
-
a
-Methylb
n
e
nzylamine io Hernández-Fernández,a Mario Fernández-Zertuche,a Oscar García-Barradas,b Omar Muñoz-Muñiz,b
Mario Ordóñez*a
a
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad No. 1001, 62209 Cuernavaca,
Morelos, Mexico
b
Unidad de Servicios de Apoyo en Resolución Análitica de la Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala S/N.,
91190 Xalapa, Veracruz, Mexico
Fax +52(77)73297998; E-mail: palacios@ciq.uaem.mx
Received 27 October 2005
The experimental procedure for the preparation of (S)-2
Abstract: The highly stereoselective synthesis of (E)-a,b-unsatur-
was very simple following the standard Arbuzov reac-
ated amides bearing (S)-a-methylbenzylamine was achieved from
2-phosphonamides via Horner–Wadsworth–Emmons reaction. The
starting phosphonamides are easily prepared in two steps with
tion.10 The trimethyl phosphite and a-bromoamide 1 were
mixed together without solvent and heated at 100 °C, and
excellent yields via the standard Arbuzov reaction of trimethyl- undesired products were removed by distillation to afford
the phosphonamide (S)-2 in quantitative yield.11,12
phosphite and a-bromoamides.
Enolization of (S)-2 with lithium bis(trimethylsilyl)amide
in THF at –78 °C, followed by the addition of methyl
iodide, afforded the monomethylated phosphonamide 3 in
good yield, but with a low diastereoselectivity of 53:47
(Scheme 1).12
Key words: a,b-unsaturated amides, chiral phosphonamides,
Horner–Wadsworth–Emmons reaction, (S)-a-methylbenzylamine
The synthesis of chiral a,b-unsaturated amides is an area
of growing interest in synthetic organic chemistry,1 since
several natural compounds containing an amide bond
show biological activity. For example, chiral (E)-a,b-un-
saturated amides bearing (S)-a-methylbenzylamine and
their derivatives have attracted considerable attention in
recent years for their role in biologically relevant process-
es as exemplified by the novel KCNQ2 potassium channel
opener which exhibits excellent oral bioavailability.2 Ad-
ditionally, the a,b-unsaturated amides 5 are useful build-
ing blocks in organic synthesis. They can be transformed
to a variety of compounds,3 and also have been used as
Michael acceptors4 or Diels–Alder dienophiles.5
O
O
O
Me
Me
(MeO)3P
Br
(MeO)2P
N
H
N
H
Ph
100 °C
98%
Ph
(S)-1
(S)-2
1. LHMDS
2. CH3I
THF, –78 °C
78%
O
O
Me
(MeO)2P
N
H
Ph
Me
3
The chiral a,b-unsaturated amides 5 bearing (S)-a-meth-
ylbenzylamine can be synthesized by the enzymatic ami-
nolysis of cinnamic ester with racemic amines,6 or by the
reaction of chiral amines with acrylic acids and their chlo-
rides.3b,4b,5a However, an important limitation of the last
method is the difficulty in accessing the corresponding
acrylic acid and its derivatives; therefore this process can-
not be considered as a general methodology for their prep-
aration. For this reason, more general methods are
desirable, and in this letter we wish to describe a new
practical and efficient methodology for the synthesis of
a,b-unsaturated amides 5 and 6 bearing (S)-a-methylben-
zylamine, as an extension of the Horner–Wadsworth–
Emmons (HWE) reaction7,8 using the phosphonamides 2
and 3.9
Scheme 1 Preparation of phosphonamides 2 and 3
In an effort to increase the chemical yield of 2-phos-
phonamide 3, we carried out the reaction of 2-bromo-
propionyl bromide with (S)-a-methylbenzylamine and
triethylamine at room temperature, obtaining a diastereo-
meric mixture of a-bromoamides 4 in excellent yield
(96%), which were separated by column chromatography
to provide the a-bromoamides (R,S)-4 and (S,S)-4 diaste-
reomerically pure. The reaction of the a-bromoamide
(S,S)-4 with trimethyl phosphite without solvent at 140 °C
gave the phosphonamide 3 in good yield (81%), but with
total racemization of C2 (determined by 1H and 31P NMR
spectroscopy). In order to avoid racemization, the Arbu-
zov reaction was performed at 100–130 °C; however, un-
der these conditions the reaction did not afford the desired
product. Therefore we decided to carry out the reaction
of trimethyl phosphite with the diastereomeric mixture of
SYNLETT 2006, No. 3, pp 0440–0444
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926265; Art ID: S10905ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
(E)-a,b-Unsaturated Amides Bearing (S)-a-Methylbenzylamine
441
Me
phonamide 2 with isobutyraldehyde under the same
conditions gave a,b-unsaturated amides 5d with low
selectivity (Table 1, entry 4), while the reaction of 2 with
isovaleraldehyde proceeded with only moderate E selec-
tivity (Table 1, entry 5).16 However, the reaction of 2 with
pivalaldehyde was highly E-selective and only the (E)-
a,b-unsaturated amide 5f was detected by 1H NMR spec-
troscopy (Table 1, entry 6). The E/Z selectivity was deter-
mined on the crude reaction products by 1H NMR
spectroscopy.17 The stereochemistry of the C=C double
bond of the disubstituted a,b-unsaturated amide was as-
signed on the basis of the value of the 1H NMR coupling
constant between the olefinic protons.18
O
Me
O
H2N
Ph
Br
Br
N
H
Ph
Br
Et3N, CH2Cl2
96%
Me
Me
4
(MeO)3P
140 °C
81%
O
O
Me
(MeO)2P
N
H
Ph
Me
As temperature can affect the selectivity in these reac-
tions,19 we performed several control experiments for the
reaction of the phosphonamide 2 with isobutyraldehyde
and isovaleraldehyde. The results are summarized in
Table 2. Under reflux conditions in THF, the reaction of
phosphonamide 2 with isobutyraldehyde proceeded in an
E-selective manner (E/Z, 64:36), while at –78 °C, the E/Z
ratio was 43:57 (Table 2, entries 1 and 2). An identical in-
crement in the selectivity was also observed for isovaler-
aldehyde (Table 2, entries 4 and 5). In the same way, an
improvement in the selectivity was observed when the re-
action of the phosphonamide 2 with isobutyraldehyde and
isovaleraldehyde was carried out under reflux conditions
in toluene, where the E/Z ratio was 81:19 and 86:14, re-
spectively (Table 2, entries 3 and 6). These results suggest
that the HWE reaction occurred under thermodynamic
control.
3
Scheme 2 Preparation of phosphonamide 3
a-bromoamides 4 without solvent at 140 °C, obtaining the
phosphonamide 3 in good yield (Scheme 2).
With the phosphonamides 2 and 3 in hand, and following
the Masamune–Roush procedure,13,14 the HWE reaction
of phosphonamide 2 with aromatic and alkyl aldehydes
was carried out using DBU as a base in the presence of
lithium chloride in anhydrous THF at room temperature,
and furnished a,b-unsaturated amides 5 (Table 1).
As shown in Table 1, the HWE reaction of 2 with benzal-
dehyde at room temperature was highly E-selective and
only the (E)-a,b-unsaturated amide 5a was detected by 1H
NMR spectroscopy (Table 1, entry 1). Identical results
were obtained when the reaction was carried out with
p-chlorobenzaldehyde and p-methoxybenzaldehyde
(Table 1, entries 2 and 3). The stereoelectronic factors on
the ring affected neither the E/Z selectivity nor the reac-
tion time. On the other hand, the HWE reaction of phos-
We have recently described a useful methodology for the
preparation of both diastereomers of a,a-disubstituted b-
phosphonamides from 3, by changing the amount of LDA
used.11 Therefore, we decided to evaluate the selectivity
of the HWE reaction of phosphonamide 3 with benzalde-
hyde by changing the amount of LDA, since it is known
that variables such as the base, metal cation, crown ether,
and solvent can affect the selectivity of the HWE reaction
(Scheme 3, Table 3).20,21
Table 1 The HWE Reaction of Phosphonamide 2 with Several
Aldehydes at Room Temperature15
O
Me
RCHO
(S)-2
+ (Z)-(S)-5a–f
R
N
H
Ph
DBU, LiCl
THF, r.t.
Table 2 The HWE Reaction of 2 with i-PrCHO and i-BuCHO –
Temperature Effect on the E/Z Ratio
(E)-(S)-5a–f
Entry
Product
5a
R
Yield (%)a (E)-5/(Z)-5b
Entry
R
Conditions
Yield (%)a (E)-5/(Z)-5b
1
2
3
4
5
6
C6H5
96
94
90
92
92
93
>98:<02
>98:<02
>98:<02
55:45
1
2
3
4
5
6
i-Pr
i-Pr
i-Pr
i-Bu
i-Bu
i-Bu
THF, –78 °C
THF, 60 °C
86
95
90
92
90
91
43:57
64:36
81:19
70:30
82:18
86:14
5b
p-ClC6H4
p-MeOC6H4
i-Pr
5c
Toluene, 100 °C
THF, –78 °C
THF, 60 °C
5d
5e
i-Bu
73:27
5f
t-Bu
>98:<02
Toluene, 100 °C
a Isolated yields after purification by column chromatography.
b The E/Z ratio was determined by 1H NMR spectroscopy of the crude
product.
a Isolated yields after purification by column chromatography.
b The E/Z ratio was determined by 1H NMR spectroscopy of the crude
product.
Synlett 2006, No. 3, 440–444 © Thieme Stuttgart · New York

442
E. Hernández-Fernández et al.
LETTER
O
Table 3 Preparation of a,b-Unsaturated Amides 6a–f under Differ-
Me
ent Conditionsa,15
RCHO
Base
3
+ (Z)-(S)-6a–f
R
N
H
Ph
Entry Conditions
Product Yield (%) (E)-6/(Z)-6
Me
(E)-(S)-6a–f
1
2
LDA, THF, –78 °Cb
6a
6a
6a
6a
6b
6c
6d
6e
6f
91
90
47
90
96
86
86
91
38
90
96
86
86
89
77
91
93
>98:<02
>98:<02
>98:<02
45:55
a: R = C6H5, b: R = p-ClC6H4, c: R = p-CH3OC6H4,
d: R = i-Pr, e: R = i-Bu, f: R = t-Bu
LDA, THF, –78 °Cc
LDA, THF, –78 °Cd
KH, THF, –78 °Ce
LDA, THF, –78 °Cb
LDA, THF, –78 °Cb
LDA, THF, –78 °Cb
LDA, THF, –78 °Cb
LDA, THF, –78 °Cb
DBU, THF, 25 °Cf
DBU, THF, 25 °Cf
DBU, THF, 25 °Cf
DBU, THF, 25 °Cf
DBU, THF, 60 °Cf
3
Scheme 3 HWE reaction of phosphonamide 3 with several alde-
hydes under a variety of conditions
4
5
>98:<02
>98:<02
68:32
Initially, phosphonamide 3 in anhydrous THF was treated
at –78 °C with LDA (3 equiv) followed by the addition of
benzaldehyde, and the a,b-unsaturated amide 6a was ob-
tained with high E selectivity and chemical yield (Table 3,
entry 1). An identical result was obtained when the reac-
tion was carried out using two equivalents of LDA
(Table 3, entry 2). However, when one equivalent of LDA
was used, the (E)-a,b-unsaturated amide 6a was obtained
with high E selectivity, but with low yield, since the reac-
tion did not reach completion even though the reaction
temperature was allowed to rise to room temperature
(Table 3, entry 3). These results show that the selectivity
of 6a was unaffected by the amount of LDA used for the
enolization of 3. The stereochemistry of the C=C double
bond of the trisubstituted a,b-unsaturated amide 6a was
assigned on the basis of the coupling constant between the
olefinic proton and the methyl group at C2, and was con-
firmed by X-ray analysis.
6
7
8
62:38
9
55:45
10
11
12
13
14
15
16
17
18
19
20
6a
6b
6c
6d
6d
>98:<02
>98:<02
>98:<02
70:30
74:26
DBU, toluene, 100 °Cf 6d
55:45
DBU, THF, 25 °Cf
DBU, THF, 60 °Cf
6e
6e
73:27
78:22
Furthermore, we examined the HWE reaction of 3 with
benzaldehyde and potassium hydride in anhydrous THF
in combination with 18-crown-6 at –78 °C, and the a,b-
unsaturated amide 6a formed in excellent chemical yield,
but with a poor E/Z selectivity of 45:55 (Table 3, entry 4).
With these results, we decided to evaluate the selectivity
of the HWE reaction of phosphonamide 3 with several ar-
omatic and alkyl aldehydes using three equivalents of
LDA in anhydrous THF at –78 °C. The results in Table 3
show that the reaction of phosphonamide 3 with p-chlo-
robenzaldehyde and p-methoxybenzaldehyde proceeded
with excellent E selectivity and good chemical yield
(Table 3, entries 5 and 6). On the other hand, the reaction
of 3 with isobutyraldehyde and isovaleraldehyde afforded
only moderate E selectivity, and when pivalaldehyde was
used poor selectivity was observed (Table 3, entries 7–9).
DBU, toluene, 100 °Cf 6e
87
93:07
DBU, THF, 25 °Cf
DBU, THF, 60 °Cf
6f
6f
g
g
g
g
a Isolated yields after purification by column chromatography.
The E/Z ratio was determined by 1H NMR spectroscopy of the crude
product.
b LDA (3 equiv).
c LDA (2 equiv).
d LDA (1 equiv).
e The reaction was carried out in the presence of 18-crown-6.
f The reaction was carried out in the presence of LiCl (3 equiv).
g No reaction observed.
valeraldehyde was carried out under the same conditions,
the a,b-unsaturated amides 6d and 6e were obtained with
moderate E/Z selectivity, 70:30 and 73:27, respectively
(Table 3, entries 13 and 16). However, under reflux
conditions in THF, a better selectivity was obtained and
the E/Z ratio increased to 74:26 for 6d and 78:22 for 6e
(Table 3, entries 14 and 17). Interestingly, an improve-
ment in the selectivity was observed when the reaction of
phosphonamide 3 with isovaleraldehyde was carried out
under reflux conditions in toluene, where the E/Z ratio
was 93:07 (Table 3, entry 18). However, for the reaction
of 3 with isobutyraldehyde the selectivity was lower, and
when pivalaldehyde was used, the desired product was not
obtained, in spite of long reaction times at room tempera-
ture and at 60 °C (Table 3, entries 19 and 20).
In an effort to obtain the (E)-a,b-unsaturated amides 6 un-
der a practical and efficient experimental procedure, we
carried out the HWE reaction of the phosphonamide 3
with aromatic and alkyl aldehydes using DBU in the pres-
ence of lithium chloride in anhydrous THF at different
temperatures. As shown in Table 3, when the HWE
reaction of phosphonamide 3 was performed with benzal-
dehyde, p-chlorobenzaldehyde, and p-methoxybenzalde-
hyde at room temperature, good chemical yield and
excellent E selectivity were obtained and only the (E)-a,b-
unsaturated amides 6a–c were detected by 1H NMR spec-
troscopy (Table 3, entries 10–12). On the other hand,
when the reaction of 3 with isobutyraldehyde and iso-
Synlett 2006, No. 3, 440–444 © Thieme Stuttgart · New York

LETTER
(E)-a,b-Unsaturated Amides Bearing (S)-a-Methylbenzylamine
(12) The non-chiral diethoxyphosphoryl-N-(1-methyl-
443
In conclusion, we have developed an efficient methodol-
ogy for the synthesis of (E)-a,b-unsaturated amides, both
disubstituted and trisubstituted, bearing the (S)-a-methyl-
benzylamine moiety.
benzyl)acetamide has been obtained from diethoxyphos-
phorylacetyl chloride and 1-methylbenzylamine and used in
the preparation of (E)-N-(1-methylbenzyl)-4-phenyl-2-
butenamide via the HWE reaction: Janecki, T.; Bodalski, R.;
Wieczorek, M.; Bujacz, G. Tetrahedron 1995, 51, 1721.
(13) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
Acknowledgment
We wish to thank CONACYT of Mexico, for financial support via
grants 41657-Q and 44704-Q for this work. We also thank Victoria
Labastida for her valuable technical help in obtaining MS spectra,
and M. A. Muñoz-Hernández for valuable technical help in the
acquisition of the X-ray structure. One of us, E.H.F., also wishes to
thank CONACYT for a Graduate Scholarship (170288).
(14) Similar HWE reactions using NaI, NaBr, and KI in the
presence of DBU have been reported: Ando, K. J. Org.
Chem. 2000, 65, 4745.
(15) HWE Reaction Using DBU/LiCl in Anhydrous THF;
General Procedure A solution of phosphonamides 2 or 3 (1
equiv) in anhyd THF (30 mL) was treated under nitrogen
with DBU (3 equiv) and LiCl (3 equiv) at r.t. After stirring
for 5 min, the aldehyde (1 equiv) was added and the reaction
mixture was stirred for 4 h at r.t. The reaction was quenched
by the addition of a sat. soln of NH4Cl and extracted with
EtOAc (3 × 40 mL). The combined extracts were washed
with H2O (30 mL) followed by brine (30 mL), dried over
Na2SO4, and concentrated. The E/Z ratio was determined by
1H NMR spectroscopy of the crude product, and then the
(E)-a,b-unsaturated amides 5a–f and 6a–f were purified by
flash chromatography.
References
(1) (a) Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K. J. Soc.
Chem., Chem. Commun. 2000, 1795. (b) Fortin, S.;
Duppont, F.; Deslongchamps, P. J. Org. Chem. 2002, 67,
5437. (c) Concellón, J. M.; Bardales, E. J. Org. Chem. 2003,
68, 9492; and references therein.
(2) (a) L’Heureux, A.; Martel, A.; He, H.; Chen, J.; Sun, L. Q.;
Starrett, J. E. Jr.; Natale, J.; Dworetzky, S. I.; Knox, R. J.;
Harden, D. G.; Weaver, D.; Thompson, M. W.; Wu, Y. J.
Bioorg. Med. Chem. Lett. 2005, 15, 363. (b) Wickenden, A.
D.; Roeloffs, R.; McNaughton-Smith, G.; Rigdon, G. C.
Expert Opin. Ther. Pat. 2004, 14, 1. (c) Wu, Y.-J.; He, H.;
Sun, L.-Q.; L’Heureux, A.; Chen, J.; Dextraze, P.; Starrett,
J. E. Jr.; Boissard, C. G.; Gribkoff, V. K.; Natale, J.;
Dworetzky, S. I. J. Med. Chem. 2004, 47, 2887. (d) Wu, Y.-
J.; Davis, C. D.; Dworetzky, S.; Fitzpatrick, W. C.; Harden,
D.; He, H.; Knox, R. J.; Newton, A. E.; Philip, T.; Polson, C.;
Sivarao, D. V.; Sun, L.-Q.; Tertyshnikova, S.; Weaver, D.;
Yeola, S.; Zoeckler, M.; Sinz, M. W. J. Med. Chem. 2003,
46, 3778; and references therein.
(3) (a) Meth-Cohn, O.; Williams, D. J.; Chen, Y. J. Chem. Soc.,
Chem. Commun. 2000, 495. (b) Meth-Cohn, O.; Chen, Y.
Tetrahedron Lett. 1999, 40, 6069. (c) Bremand, N.; Marek,
I.; Normant, J. F. Tetrahedron Lett. 1999, 40, 3383.
(d) Kishikawa, K.; Furusawa, A.; Kohmoto, S.; Yamamoto,
M.; Yamada, K. J. Org. Chem. 1993, 58, 7296.
(E)-(S)-N-(1-Methylbenzyl)-3-phenylpropenamide 5a
Yield: 96%; white solid; mp 146 °C; [a]D –21.7 (c 2.2,
CHCl3).22
(E)-(S)-N-(1-Methylbenzyl)-3-(p-chlorophenyl)propen-
amide (5b) Yield: 94%; white solid; mp 164–165 °C; [a]D
+2.1 (c 2.60, CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.53
[d, J = 6.8 Hz, 3 H, CH3(CH)Ph], 5.24 [quint, J = 6.8 Hz, 1
H, CH(CH3)Ph], 6.38 (d, J = 6.8 Hz, 1 H, NH), 6.42 (d,
J
trans = 15.6 Hz, 1 H, =CHCO), 7.24–7.36 (m, 9 H, Harom)
7.55 [d, Jtrans = 15.6 Hz, 1 H, =CH(p-ClC6H4]. 13C NMR
(100 MHz, CDCl3): d = 21.9 [CH3(CH)Ph], 49.2
[CH(CH3)Ph], 121.5, 126.4, 127.6, 128.9, 129.1, 129.2,
133.5, 135.6, 139.9, 143.2, 164.9 (C=O). HRMS (CI+): m/z
calcd for C17H17ClNO (MH+): 286.0999; found: 286.0989.
Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90.
Found: C, 71.09; H, 5.60; N, 9.94.
(E)-(S)-N-(1-Methylbenzyl)-3-(p-methoxyphenyl)prop-
enamide (5c) Yield: 90%; white solid; mp 149 °C; [a]D
+13.2 (c 2.43, CHCl3). 1H NMR (400 MHz, CDCl3): d =
1.52 [d, J = 6.8 Hz, 3 H, CH3(CH)Ph], 3.79 (s, 3 H, CH3O),
5.25 [quint, J = 6.8 Hz, 1 H, CH(CH3)Ph], 6.31 (d, J = 6.8
Hz, 1 H, NH), 6.33 (d, Jtrans = 15.6 Hz, 1 H, =CHCO), 6.83
(AA¢BB¢ system, J = 8.8 Hz, 2 H, Harom), 6.23–6.38 (m, 5 H,
Harom), 7.39 (AA¢BB¢ system, J = 8.8 Hz, 2 H, Harom), 7.58
[d, Jtrans = 15.6 Hz, 1 H, =CH(p-MeOC6H4]. 13C NMR (100
MHz, CDCl3): d = 21.9 [CH3(CH)Ph], 49.0 [CH(CH3)Ph],
55.5 (CH3O), 114.3, 118.6, 126.4, 127.4, 127.7, 128.8,
129.5, 140.9, 143.4, 160.9, 165.6 (C=O). HRMS (EI): m/z
calcd for C18H19NO2 (M+): 281.1416; found: 281.1408.
Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98.
Found: C, 76.88; H, 6.80; N, 5.06.
(Z)-(S)-N-(1-Methylbenzyl)-4-methyl-2-pentenamide
(5d) Yield: 42%; white solid; mp 80–81 °C, [a]D –167
(c 3.13, CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.94 [d,
J = 6.4 Hz, 3 H, (CH3)2CH], 1.00 [d, J = 6.4 Hz, 3 H,
(CH3)2CH], 1.50 [d, J = 6.4 Hz, 3 H, CH3(CH)Ph], 3.61–
3.70 [m, 1 H, (CH(CH3)2], 5.15 [quint, J = 6.4 Hz, 1 H,
CH(CH3)Ph], 5.55 (dd, Jcis = 11.6 Hz, J1,4 = 0.8 Hz, 1
H, =CHCO), 5.78 [dd, Jcis = 11.6 Hz, J1,3 = 10.0 Hz, 1
H, =CHCH(CH3)2], 5.80 (br, 1 H, NH), 7.22–7.36 (m, 5 H,
Harom). 13C NMR (100 MHz, CDCl3): d = 22.0 [CH3(CH)Ph],
22.8 [2 C, (CH3)2CH], 27.5 [CH(CH3)2], 48.7 [CH(CH3)Ph],
(4) (a) Braschi, I.; Cardillo, G.; Tomasini, C. Tetrahedron 1994,
50, 2955. (b) Cardillo, G.; Hashem, M. A.; Tomasini, C. J.
Chem. Soc., Perkin Trans. 1 1990, 1487.
(5) (a) Bell, A. S.; Fishwick, C. W. G.; Reed, J. E. Tetrahedron
1998, 54, 3219. (b) Bell, A. S.; Fishwick, C. W. G.; Reed, J.
E. Tetrahedron Lett. 1996, 37, 123.
(6) Gotor, V.; Menéndez, E.; Mouloungui, Z.; Gaset, A. J.
Chem. Soc., Perkin Trans. 1 1993, 2453.
(7) For reviews on the HWE reaction, see: (a) Maryanoff, B.
E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. (b) Kelly, S. E.
In Comprehensive Organic Synthesis, Vol. 1; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 755.
(8) For an asymmetric version of the HWE reaction, see:
(a) Rein, T.; Pedersen, T. M. Synthesis 2002, 579. (b) Rein,
T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369.
(9) For the HWE reaction of chiral phosphonamides, see:
(a) Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein, T.;
Tanner, D.; Bodmann, K.; Reiser, O. Org. Lett. 2000, 2,
535. (b) Rzasa, R. M.; Shea, H. A.; Romo, D. J. Am. Chem.
Soc. 1998, 120, 591. (c) Abiko, A.; Masamune, S.
Tetrahedron Lett. 1996, 37, 1077.
(10) Bhattachrya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81,
415.
(11) Ordóñez, M.; Hernández-Fernández, E.; Xahuentitla, J.;
Cativiela, C. J. Chem. Soc., Chem. Commun. 2005, 1336.
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444
E. Hernández-Fernández et al.
LETTER
120.0, 126.4, 127.5, 128.8, 143.5, 153.0, 165.7 (C=O).
HRMS (EI): m/z calcd for C14H19NO (M+): 217.1467; found
217.1467. Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N,
6.45. Found: C, 76.88; H, 8.84; N, 6.39.
Found: C, 77.76; H, 9.08; N, 6.12.
(E)-(S)-N-(1-Methylbenzyl)-2-methyl-3-phenyl-
propenamide (6a) Yield: 90%; white solid; mp 113–
114 °C; [a]D –4.0 (c 1.94, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 1.57 [d, J = 6.8 Hz, 3 H, CH3(CH)Ph], 2.08 (d,
J = 1.6 Hz, 3 H, CH3C=CH), 5.25 [quint, J = 6.8 Hz, 1 H,
CH(CH3)Ph], 6.21 (d, J = 6.8 Hz, 1 H, NH), 7.25–7.39 (m,
11 H, 10 × Harom, Hvinyl). 13C NMR (100 MHz, CDCl3): d =
14.6 (CH3C=CH), 21.9 [CH3(CH)Ph], 49.3 [CH(CH3)Ph],
126.4, 127.5, 127.9, 128.4, 128.8, 129.4, 132.1, 134.0,
136.2, 143.3, 168.7 (C=O). HRMS (CI+, CH4): m/z calcd for
C18H19NO (M+): 265.1466; found: 265.1479. Anal. Calcd
for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.56;
H, 7.22; N, 5.38.
(E)-(S)-N-(1-Methylbenzyl)-4-methyl-2-pentenamide
(5d) Yield: 50%; white solid; mp 94–95 °C, [a]D –123
(c 3.30, CHCl3). 1H NMR (200 MHz, CDCl3): d = 1.00 [d,
J = 7.0 Hz, 3 H, (CH3)2CH], 1.01 [d, J = 7.0 Hz, 3 H,
(CH3)2CH], 1.45 [d, J = 7.0 Hz, 3 H, CH3(CH)Ph], 2.33–
2.42 [m, 1 H, (CH(CH3)2], 5.17 [quint, J = 7.0 Hz, 1 H,
CH(CH3)Ph], 5.80 (dd, Jtrans = 15.6 Hz, J1,4 = 1.2 Hz, 1
H, =CHCO), 6.62 (br, 1 H, NH), 6.79 [dd, Jtrans = 15.6 Hz,
J1,3 = 6.8 Hz, 1H, =CHCH(CH3)2], 7.21–7.30 (m, 5 H,
H
arom). 13C NMR (100 MHz, CDCl3): d = 21.6 [2 C,
(CH3)2CH], 21.9 [CH3(CH)Ph], 30.9 [CH(CH3)2], 48.7
[CH(CH3)Ph], 121.0, 126.2, 127.1, 128.5, 143.4, 150.9,
165.5 (C=O). HRMS (EI): m/z calcd for C14H19NO (M+):
217.1467; found: 217.1460. Anal. Calcd for C14H19NO: C,
77.38; H, 8.81; N, 6.45. Found: C, 77.28; H, 8.79; N, 6.38.
(Z)-(S)-N-(1-Methylbenzyl)-5-methyl-2-hexenamide (5e)
Yield: 25%; colorless oil; [a]D –156.9 (c 3.06, CHCl3). 1H
NMR (200 MHz, CDCl3): d = 0.91 [d, J = 6.8 Hz, 3 H,
(CH3)2CH], 0.92 [(d, J = 6.8 Hz, 3 H, (CH3)2CH], 1.49 [d,
J = 6.8 Hz, 3 H, CH3(CH)Ph], 1.69 [m, J = 6.8 Hz, 1 H,
CH(CH3)2], 2.54 [dddd, Jgem = 14.6, J1,3 = 7.4 Hz, J1,4 = 1.8
Hz, 2 H, CH2CH(CH3)2], 5.15 (quint, J = 6.8 Hz, 1 H,
CH(CH3)Ph], 5.72 (dt, Jcis = 11.6 Hz, J1,4 = 1.8 Hz, 1
H, =CHCO), 5.92 (br, 1 H, NH), 5.99 (dt, Jcis = 11.6 Hz,
J1,3 = 7.4 Hz, 1 H, =CHCH2i-Pr), 7.26–7.36 (m, 5 H, Harom).
13C NMR (100 MHz, CDCl3): d = 22.0 [CH3(CH)Ph], 22.5
[2 C, (CH3)2CH], 28.8 [CH2CH(CH3)2], 37.6 [CH(CH3)2],
48.6 [CH(CH3)Ph], 123.0, 126.4 (Cortho), 127.4 (Cpara),
128.8 (Cmeta), 143.5 (Cipso), 144.9, 165.9 (C = O). HRMS
(EI): m/z calcd for C15H21NO (M+): 231.1623; found:
231.1625.
(E)-(S)-N-(1-Methylbenzyl)-2-methyl-3-(p-chloro-
phenyl)propenamide (6b) Yield: 96%; white solid;
mp 118–119 °C; [a]D +5.9 (c 2.34, CHCl3). 1H NMR (400
MHz, CDCl3): d = 1.57 [d, J = 6.8 Hz, 3 H, CH3(CH)Ph],
2.06 (d, J = 1.2 Hz, 3 H, CH3C=CH), 5.24 [quint, J = 6.8 Hz,
1 H, CH(CH3)Ph], 6.18 (d, J = 6.8 Hz, 1 H, NH), 7.23
(AA¢BB¢ system, J = 8.4 Hz, 2 H, Harom), 7.26–7.37 (m, 8 H,
7 × Harom, Hvinyl). 13C NMR (100 MHz, CDCl3): d = 14.6
(CH3C=CH), 21.9 [CH3(CH)Ph], 49.4 [CH(CH3)Ph], 126.3,
127.5, 128.7, 128.8, 130.7, 132.7, 132.8, 133.7, 134.6,
143.2, 168.4 (C=O). HRMS (CI+, CH4): m/z calcd for
C18H19ClNO (MH+): 300.1155; found: 300.1146. Anal.
Calcd for C18H18ClNO: C, 72.11; H, 6.05; N, 4.67. Found: C,
71.89; H, 6.07; N, 4.83.
(E)-(S)-N-(1-Methylbenzyl)-2-methyl-3-(p-methoxy-
phenyl)propenamide (6c) Yield: 86%; white solid;
mp 117–118 °C; [a]D +14.8 (c 2.0, CHCl3). 1H NMR (400
MHz, CDCl3): d = 1.56 [d, J = 6.8 Hz, 3 H, CH3(CH)Ph],
2.09 (d, J = 1.2 Hz, 3 H, CH3C=CH), 3.81 (s, 3 H, CH3O),
5.24 [quint, J = 6.8 Hz, 1 H, CH(CH3)Ph], 6.16 (d, J = 6.8
Hz, 1 H, NH), 6.89 (AA¢BB¢ system, J = 8.4 Hz, 2 H, Harom),
7.28 (AA¢BB¢ system, J = 8.4 Hz, 2 H, Harom), 7.29–7.39 (m,
6 H, 5 × Harom, Hvinyl). 13C NMR (100 MHz, CDCl3): d = 14.5
(CH3C=CH), 21.9 [CH3(CH)Ph], 49.3 [CH(CH3)Ph], 55.5
(CH3O), 114.0, 126.5, 127.5, 128.9, 129.0, 130.5, 131.1,
133.7, 143.6, 159.5, 169.1 (C=O). HRMS (CI+, CH4): m/z
calcd for C19H22NO2 (MH+): 296.1651; found: 296.1653.
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 77.40; H, 7.23; N, 4.91.
(E)-(S)-N-(1-Methylbenzyl)-5-methyl-2-hexenamide (5e)
Yield: 67%; white solid; mp 95 °C; [a]D –118.5 (c 2.23,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.89 [d, J = 6.8
Hz, 3 H, (CH3)2CH], 0.90 [d, J = 6.8 Hz, 3 H, (CH3)2CH],
1.51 [d, J = 6.8 Hz, 3 H, CH3(CH)Ph], 1.73 [m, J = 6.8 Hz,
1 H, CH(CH3)2], 2.04 [td, J1,3 = 7.4 Hz, J1,4 = 1.4 Hz, 2 H,
CH2CH(CH3)2], 5.20 [quint, J = 6.8 Hz, 1 H, CH(CH3)Ph],
5.76 (dt, Jtrans = 15.2 Hz, J1,4 = 1.4 Hz, 1 H, CHC=O), 5.84
(d, J = 6.8 Hz, 1 H, NH), 6.83 [dt, Jtrans = 15.6 Hz, J1,3 = 7.4
(16) The E and Z isomers for 5d and 5e were easily separable by
flash chromatography.
Hz, 1 H, CHCH2CH(CH3)2], 7.24–7.34 (m, 5 H, Harom). 13
C
NMR (100 MHz, CDCl3): d = 21.9 [CH3(CH)Ph], 22.7 [2 C,
(CH3)2CH], 28.1 [CH2CH(CH3)2], 41.6 [CH(CH3)2], 48.9
[CH(CH3)Ph], 124.6, 126.4, 127.4, 128.8, 143.3, 144.1,
165.1 (C=O). HRMS (EI): m/z calcd for C15H21NO (M+):
231.1623; found: 231.1627. Anal. Calcd for C15H21NO: C,
77.88; H, 9.15; N, 6.05. Found: C, 77.91; H, 9.14; N, 6.15.
(E)-(S)-N-(1-Methylbenzyl)-4,4-dimethyl-2-pentenamide
(5f) Yield: 93%; white solid; mp 94–95 °C; [a]D –120 (c 2.5,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.05 [s, 9 H,
(CH3)3C], 1.51 [d, J = 6.8 Hz, 3 H, CH3(CH)Ph], 5.21 [quint,
J = 6.8 Hz, 1 H, CH(CH3)Ph], 5.67 (d, Jtrans = 15.6 Hz, 1
H, =CHCO), 5.92 [d, J = 6.8 Hz, 1 H, NH], 6.85 [d,
(17) When the minor diastereomer was not detected, an E/Z ratio
98:02 is shown in Tables 1 and 3.
(18) The coupling constant between the olefinic protons of
compound 5a–f was J = 15 Hz for E and J = 11 Hz for Z;
this is in agreement with the average literature values.
(19) Sano, S.; Takemoto, Y.; Nagao, Y. Arkivoc 2003, (viii), 93.
(20) Thompson, S. K.; Heathcock, C. H. J. Org. Chem. 1990, 55,
3386.
(21) Phosphonamides bearing amino acids have been used in the
HWE reaction: (a) Ordóñez, M.; Bustos-Salgado, P.;
Bautista-de la Cruz, R.; Hernández-Fernández, E.; Rojas-
Cabrera, H. manuscript in preparation (b) Coutrot, Ph.;
Grison, C.; Gérardin-Charbonnier, C.; Lecouvey, M.
Tetrahedron Lett. 1993, 34, 2767.
Jtrans = 15.6 Hz, 1 H, =CHC(CH3)3], 7.25–7.34 (m, 5 H,
Harom). 13C NMR (100 MHz, CDCl3): d = 21.9 [CH3(CH)Ph],
29.1 [(CH3)3C], 33.7 [C(CH3)3], 48.9 [CH(CH3)Ph], 119.0,
126.5, 127.6, 128.9, 143.5, 155.1, 165.7 (C=O). HRMS (EI):
m/z calcd for C15H21NO (M+): 231.1623; found: 231.1635.
Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05.
(22) For the R enantiomer: mp 144–146 °C, [a]D +20.2 (c 1.0,
CHCl3), see: Gotor, V.; Menéndez, E.; Mouloungui, Z.;
Gaset, A. J. Chem. Soc., Perkin Trans. 1 1993, 2453.
Synlett 2006, No. 3, 440–444 © Thieme Stuttgart · New York