Copper-catalyzed cross-coupling of amides and potassium alkenyltrifluoroborate salts: A general approach to the synthesis of enamides

Article abstract of DOI:10.1016/j.tet.2010.03.076

Potassium alkenyltrifluoroborate salts undergo coupling with amides to give enamides using a catalytic amount of Cu(OAc)₂ under mild oxidative conditions. The air and water stable alkenyltrifluoroborate salts offer a practical alternative to the use of alkenyl halides and alkenylboronic acids as cross-coupling partners. A range of amides participate in the cross-coupling, including heterocyclic amides, imides, carbamates, benzamides, and acetamides. Optimization studies established two sets of conditions, best suited to either high PK_a or low PK_a amide substrates. Lower PK amide substrates worked best using a dichloromethane solvent system in the presence of 4 ? molecular sieves, 10 mol % Cu(OAc)₂, and 20 mol % N-methylimidazole. Higher PK_a amide substrates worked best using a ligandless protocol using a 1:1 dichloromethane/DMSO solvent system in the presence of 4 ? molecular sieves and 10 mol % Cu(OAc)₂. The cross-coupling reactions occur stereospecifically with retention of alkene configuration from the alkenyltrifluoroborate salt. The mild reaction conditions employed are tolerant of various functionalities, including nitro, acetals, alkyl and aryl halides, and α,β-unsaturated carbonyls. Finally, the importance of copper sources and the presence of minor impurities were investigated.

Full text of DOI:10.1016/j.tet.2010.03.076

Tetrahedron 66 (2010) 5283–5294
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed cross-coupling of amides and potassium alkenyltrifluoroborate
salts: a general approach to the synthesis of enamides
y
*
Yuri Bolshan , Robert A. Batey
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5R 3H6
a r t i c l e i n f o
a b s t r a c t
Article history:
Potassium alkenyltrifluoroborate salts undergo coupling with amides to give enamides using a catalytic
amount of Cu(OAc)2 under mild oxidative conditions. The air and water stable alkenyltrifluoroborate salts
offer a practical alternative to the use of alkenyl halides and alkenylboronic acids as cross-coupling
partners. A range of amides participate in the cross-coupling, including heterocyclic amides, imides,
carbamates, benzamides, and acetamides. Optimization studies established two sets of conditions, best
suited to either high pKa or low pKa amide substrates. Lower pKa amide substrates worked best using
a dichloromethane solvent system in the presence of 4 Å molecular sieves, 10 mol % Cu(OAc)2, and
20 mol % N-methylimidazole. Higher pKa amide substrates worked best using a ‘ligandless’ protocol using
a 1:1 dichloromethane/DMSO solvent system in the presence of 4 Å molecular sieves and 10 mol %
Cu(OAc)2. The cross-coupling reactions occur stereospecifically with retention of alkene configuration
from the alkenyltrifluoroborate salt. The mild reaction conditions employed are tolerant of various
Received 7 February 2010
Received in revised form 18 March 2010
Accepted 22 March 2010
Available online 31 March 2010
Keywords:
Enamide synthesis
Copper catalysis
Oxidative cross-coupling reaction
Organoboron compounds
Organotrifluoroborate salt
functionalities, including nitro, acetals, alkyl and aryl halides, and
importance of copper sources and the presence of minor impurities were investigated.
Ó 2010 Elsevier Ltd. All rights reserved.
a,b-unsaturated carbonyls. Finally, the
1. Introduction
Perhaps the most widely applicable metal-catalyzed method to
have been developed to date is the copper-catalyzed coupling24 of
alkenyl halides with amides (Fig. 2b), a modern variant of the
Goldberg reaction.1 This approach has addressed some of the
problems with other methods, since it permits good control of E/Z
stereoselectivity, and does not require the use of expensive cata-
lysts or harsh reaction conditions. Ogawa25 originally reported the
coupling of potassium amides and alkenyl bromides using stoi-
chiometric amounts of copper, but Porco, Buchwald, Ma and others
have since shown that the method can be rendered catalytic in
copper.26 Lam and co-workers also extended their studies on the
amidation of arylboronic acids,27 with a limited study on the use of
(E)-1-hexenylboronic acid as an alternative coupling partner
(Fig. 2c).28,29 More recently, Liebeskind and co-workers showed
that hydroxamic acid derivatives react with alkenylstannanes in the
presence of a stoichiometric amount copper salt to afford enamides
in moderate yields. Alkenylboronic acids, however, were unreactive
under the same set of conditions.30
In contrast to the arylation of amides, originally reported by
Goldberg,1 the transition metal-catalyzed alkenylation of amides
remained an unexplored area until the end of twentieth century.
However, the utility of enamides as synthetic precursors,2–4 and the
discovery of several new families of enamide-containing natural
products has sparked an interest in the development of new
methodologies for the synthesis of the enamide functionality.5,6
Representative enamide antitumor natural products include sali-
cylihalamide A and B,7 apicularen A and B,8 aspergillamide A,9
oximidine I and II,10 TMC-95A,11 and frangufoline12 (Fig. 1).
There are a number of methods that have traditionally been
employed for the synthesis of enamides, including acid-catalyzed
condensation of amides and aldehydes,13 Curtius rearrangement
of
of
a,b
-unsaturated acyl azides,14 acylation of imines,15 elimination
b
-hydroxy-a
-silyl amides,16 and condensation of aldehydes or
ketones with nitriles.17 More recently Re,18 Ni,19 Rh and Fe,20,21 and
Pd22 catalyzed methods for the synthesis of enamides have
emerged. Ru catalysis has been used for the amidation of alkynes to
give both (E) and (Z)-enamides (Fig. 2a).23
Despite these advances there is still a need for general methods
for enamide formation, particularly since existing methods often
have limited substrate scope and typically require elevated tem-
peratures, rigorous exclusion of air and water, and the use of two or
more equivalents of strong base.
Our interest in the use of organoboron compounds as reagents
for organic synthesis, particularly organotrifluoroborate salts, led
us to consider their utility for the cross-coupling with amides. The
previous studies by Lam using hexenylboronic acid had lacked
* Corresponding author. Tel.: þ1 416 978 5059; fax: þ1 416 978 6033; e-mail
address: rbatey@chem.utoronto.ca (R.A. Batey).
y
Present address: Graduate School of Pharmaceutical Sciences, University of
Tokyo, Tokyo 113-0033, Japan.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.076

5284
Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
alkenyltrifluoroborate salts are effective coupling partners in
copper-catalyzed cross-coupling reactions with a variety of amides
under mild base-free conditions (Scheme 1).39
R5
R3
BF3K
O
R5
O
R4
R3
R2
R1
N
R1
N
H
CuX2 (cat.)
4Å MS, air or O2
R2 R4
Scheme 1. Copper-catalyzed cross-coupling approach to the synthesis of enamides
using alkenyltrifluoroborate salts.
2. Results and discussion
The previous investigations of Lam and co-workers had utilized
phthalimide as one of the cross-coupling partners in couplings with
hexenylboronic acid, giving a high product yield (79%) in the pres-
ence of a stoichiometric amount of Cu(OAc)2, and a low yield (13%) in
the presence of a catalytic amount (10 mol %) of Cu(OAc)2 and
2 equiv of triethylamine.28 Since our aim was to develop a robust
catalytic method, phthalimide was chosen as the substrate of choice
for an initial cross-coupling optimization study (Table 1). Initially,
phthalimide was submitted to the reaction conditions developed by
Lam and co-workers, except that potassium hexenyltrifluoroborate
2a was used as the coupling partner, and an elevated temperature of
40 ꢀC rather than room temperature was used. The desired product
3a was obtained in a low yield (Table 1, entry 1). Reaction in the
absence of external base and ligand resulted in no detectable
product formation (Table 1, entry 2). The addition of the bidentate
ligand 1,10-phenanthroline (10 mol %) did not improve the yield of
3a, and further increasing the amount of 1,10-phenanthroline to
20 mol % (i.e., 2 equiv with respect to copper) inhibited the reaction
(Table 1, entries 3 and 4). Reaction in the absence of triethylamine
using 1,10-phenanthroline (10 mol %) as ligand led to a significant
improvement in the yield of 3a (Table 1, entry 5). Reaction using 2,20-
dipyridyl (10 mol %) was less successful (Table 1, entry 6). Further
screening of a variety of monodentate ligands (20 mol %) led to
good to excellent yields of 3a (Table 1, entries 7–10). Thus, reaction
yields increased along the series pyridine, dimethylaminopyridine
(DMAP), imidazole, and N-methylimidazole, with the latter
achieving quantitative formation of 3a. Tothe bestof ourknowledge,
Figure 1. Enamide synthetic targets.
Table 1
Ligand optimization for the cross-coupling of phthalimide with potassium hex-
enyltrifluoroborate to yield enamide 3a
Bu
BF3K (2 eq.)
Figure 2. Metal-catalyzed cross-coupling approaches to the synthesis of enamides.
O
O
Cu(OAc)2 (10 mol%)
Bu
generality, and only three examples of amide-like substrates (1-
ethyl-1,3-dihydro-benzoimidazol-2-one, 2-pyridone, and phthali-
mide) were reported, with variable yields under five different sets
of reaction conditions.28 We reasoned that one of the potential
problems with this route, compared to similar chemistry employed
with arylboronic acids,27,29 is the lower stability of alkenylboronic
acids, particularly under oxidative conditions. Previous studies in
our group have demonstrated that the use of potassium organo-
trifluoroborate salts in copper-catalyzed cross-couplings with al-
cohols31 and amines32 provides several advantages over the use of
the boronic acids. The tetracoordinate organotrifluoroborate salts
possess increased stability toward air and water, and are readily
prepared.33 Their commercial availability34 and low toxicity35 have
contributed to growing recognition within the synthetic com-
munity of the value of these reagents for other classes of metal-
catalyzed transformations.34,36–38 We now report that potassium
NH
N
Ligand / Base
4Å MS, CH2Cl2,
O2, 40 °C 20 h
O
O
Entry
Additive
Ligand
Yielda (%)
1
2
3
4
5
6
7
8
9
Et3N (2.0 equiv)
None
None
None
13
d
Et3N (2.0 equiv)
Et3N (2.0 equiv)
None
1,10-Phenanthroline (10 mol %)
1,10-Phenanthroline (20 mol %)
1,10-Phenanthroline (10 mol %)
2,20-Dipyridyl (10 mol %)
Pyridine (20 mol %)
12
3
39
10
51
65
85
None
None
None
None
DMAP (20 mol %)
Imidazole (20 mol %)
1-Methylimidazole (20 mol %)
10
None
Quant.
a
Isolated product after column chromatography.

Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
5285
this is the first time N-methylimidazole has been used as a ligand for
a copper-catalyzed reaction, and its success may be due to its high
affinity for binding to copper40 and potentially for stabilization of
copper at higher oxidation state.41
Benzamide was chosen as an appropriate starting point for re-
action optimization, since this prototypical amide had failed to give
any of the desired product under the initial conditions (method A).
An initial optimization screen of solvents (DMSO, acetonitrile, and
dichloromethane) and ligands (monodentate and bidentate), using
benzamide as a starting material with Cu(OAc)2 (10 mol %), 4 Å
molecular sieves, in dichloromethane under an atmosphere of ox-
ygen at 40 ꢀC, was unsatisfactory giving low yields (0–14%) of 3f.
Similar observations were made with couplings using 2-pyrrolidi-
none, although reaction using either dichloromethane or DMSO as
solvent, gave modest yields of 3e, of 22% and 24%, respectively
(Table 3, entries 1 and 7). The use of DMSO alone improved reactant
solubility, but we were concerned that DMSO may be too strongly
coordinating with copper. Therefore, the use of varying dichloro-
methane/DMSO co-solvent mixtures was investigated (Table 3,
entries 2–6). The yield of 3e improved in each case, with the highest
yield occurring with a 1:1 ratio of dichloromethane/DMSO (Table 3,
entry 6). Reaction of benzamide with potassium hexenyltri-
fluoroborate under the same conditions led to 3f in 62% yield,
a substantial improvement over the 14% yield obtained in pure
DMSO (Table 3, entries 10 and 9).
A diverse set of amides were screened using the optimized
conditions (method A) of Cu(OAc)2 (10 mol %), N-methylimidazole
(20 mol %), 4 Å molecular sieves, in dichloromethane under an at-
mosphere of oxygen at 40 ꢀC (Table 2). Unfortunately, the reaction
scope was not general. Thus, while 2-hydroxypyridine and isatin
gave the desired enamides in 78% and 82%, respectively, lower
yields were obtained for the couplings of oxazolidinone and pyr-
rolidinone, and only starting material was recovered when benza-
mide was submitted to the optimized reaction conditions. Two
factors may be responsible for this behavior. Firstly, the lower sol-
ubility of the latter amides in dichloromethane may be problematic.
Secondly, there was a rough correlation of lower yields with the
amides having higher pKa values. Thus, good yields were obtained
with the more acidic amides, such as phthalimide (pKa¼13.4 in
DMSO),42 isatin, and hydroxypyridine (pKa¼17.0 in DMSO).43
Whereas, lower yields of the enamide products 3 were obtained
with the less acidic amides, oxazolidinone (pKa¼20.8 in DMSO),
pyrrolidinone (pKa¼24.2 in DMSO),43 and benzamide (pKa¼23.3 in
DMSO).44 The unsatisfactory results obtained with these amides,
required a re-examination of reaction conditions in order to ach-
ieve the goal of a more generally applicable method.
Table 3
Optimization of the solvent and ligand for the cross-couplings of 2-pyrrolidinone
and benzamide with potassium hexenyltrifluoroborate
O
O
Bu
BF3K
(2.0 eq)
Bu
Table 2
NH
O
N
O
Examination of the scope of the optimized copper-catalyzed cross-coupling reaction
using N-methylimidazole as a ligand (method A)
Cu(OAc)2 (10 mol%)
Bu
(2.0 eq)
BF3K
Cu(OAc)2 (10 mol%)
or
or
O
O
-methylimidazole ( mol%)
4Å MS, solvent
R2
Bu
R1
N
H
R1
N
Bu
NH2
N
O2, 40 °C, 20 h
R2
H
-methylimidazole (20 mol%)
4Å MS, CH2Cl2
O2, 40 °C, 20 h
Entry Substrate
DMSO/CH2Cl2 Ligand (mol %) Product Yielda (%)
1
2
3
4
5
6
7
8
2-Pyrrolidinone 0:1
20
20
20
20
20
20
20
0
3e
3e
3e
3e
3e
3e
3e
3e
3f
22
68
69
71
78
84
24
86
14
62
70
80
Entry
1
Amide
pKa
Product
Yielda (%)
Quant.
2-Pyrrolidinone 1:9
2-Pyrrolidinone 1:4
2-Pyrrolidinone 1:3
2-Pyrrolidinone 1:2
2-Pyrrolidinone 1:1
2-Pyrrolidinone 1:0
2-Pyrrolidinone 1:1
13.4
9
Benzamide
Benzamide
Benzamide
Benzamide
1:0
1:1
1:1
1:1
20
20
5
10
11
12
3f
3f
3f
2
3
17.0
78
82
0
a
Isolated product after column chromatography.
Finally, a further iteration of the ligand to copper ratio was
attempted using the 1:1 ratio of dichloromethane/DMSO (Table 3,
entries 11 and 12). Surprisingly, it appeared that not only was the
N-methylimidazole ligand not necessary for the reaction, but that
the highest yield of 3f was observed in its absence. This was
completely unexpected based upon the preliminary optimization
studies using phthalimide, for which 20 mol % of N-methyl-
imidazole was optimal (Table 1). The ‘ligandless’ set of conditions
(i.e., in the absence of N-methylimidazole) using a 1:1 solvent ratio
of dichloromethane/DMSO (method B) was similarly applied to
pyrrolidinone, and led to 3e in 86% yield (Table 3, entry 8).
Application of the ‘ligandless’ method B using phthalimide and
isatin, afforded the corresponding products 3a and 3c in much lower
yields than were obtained using method A (Table 4, entries 1 and 2).
Moreover, 2-hydroxypyridine did not react at all using method B
(Table 4, entry 3). The two methods thus complement each other,
with method A appearing to work better for lower pKa substrates,
while method B is better suited for the higher pKa substrates.
d
4
5
20.8
24.2
40
22
6
23.3
0b
a
Isolated product after column chromatography.
Only starting material was recovered.
b

5286
Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
Table 4
very similar steric and electronic properties of the acetate and pro-
Application of method B to low pKa substrates
pionate counter ions. Other copper(II) salts showed inferior catalytic
activity to copper acetate, with Cu(OTf)2 achieving the closest result,
giving 3f in 70% yield (Table 5, entry 4). Cu(acac)2 was completely
inactive, presumably due to the strong coordinating character of the
bidentate acac ligand (Table 5, entry 5). Copper(I) and copper(II)
chloride also gave modest yields of 3f (Table 5, entries 6 and 7). It is
worth mentioning that all of these salts were soluble under the re-
action conditions. Although not unexpected, it is clear that the na-
ture of the counter ionplays a key role in the ability of the complexes
to catalyze the reaction.
Bu
(2.0 eq)
BF3K
O
O
R2
Bu
Cu(OAc)2 (10 mol%)
R1
N
H
R1
N
R2
DMSO/CH2Cl2 (1:1)
4Å MS, O2, 40 °C, 20 h
Entry
1
Amide
Product
Yielda (%)
35
Table 5
The influence of copper salts for the cross-couplings of benzamide with potassium
hexenyltrifluoroborate
BF3K
(2.0 eq)
O
O
Copper (II) propionate
(10 mol%)
2
56
Bu
NH2
N
H
4Å MS, O2, 40 °C, 20 h
DMSO/CH2Cl2 (1:1)
3
0
Entry
Cu(II) source
Purity (%)
Yielda (%)
1
2
3
4
5
6
7
Cu(OAc)2
Cu(OAc)2
Cu(O2C3H5)2
Cu(OTf)2
Cu(acac)2
CuCl2
97
99.999
98
98
97
80
60
49
70
d
a
Isolated product after column chromatography.
The origin of the difference in success of the two sets of con-
ditions, ‘ligand-based’ method A and ‘ligandless’ method B, is not
clear. The poor performance of method B with lower pKa substrates
may occur because of their decreased ability to stabilize copper at
a higher oxidation state, presumably Cu(III). For method A it is
possible that N-methylimidazole also serves as a base, leading to
deprotonation of the lower pKa substrates and coordination of the
deprotonated cross-coupling partner to copper. With higher pKa
substrates the N-methylimidazole may not serve this role, and in-
stead its direct coordination to copper may have a deleterious role.
The strikingly different results obtained on variation of the
dichloromethane/DMSO ratio using 20 mol % of N-methylimidazole
(Table 3, entries 1–7, 9, and 10) are not easily rationalized. The
solubility of substrate 1 may be less important, since although
benzamide has much lower solubility than either phthalimide or
pyridin-2(1H)-one at room temperature, it was found to be com-
pletely soluble at 40 ꢀC in dichloromethane at the concentrations
being employed for method A (approximately 0.25 M). With in-
creasing amounts of DMSO, the benzamide substrates were found
to have higher solubility. The solubility of the copper salts or
organotrifluoroborate salts 2 may be more important. Salts 2 were
found to be only partially soluble in dichloromethane at 40 ꢀC, but
completely soluble in DMSO at 40 ꢀC. The copper salts were also
only partially soluble in dichloromethane, but completely soluble in
the dichloromethane/DMSO solvent mixtures. Perhaps, the success
of the 1:1 dichloromethane/DMSO solvent ratio can be attributed to
achieving an appropriate ‘Goldilocks’ modulation of organo-
trifluoroborate salt solubility, i.e., not too low (as for dichloro-
methane) and not too high (as for DMSO). Of course, DMSO may
also serve as a ligand to copper.45
ꢁ99
54
30
CuCl
ꢁ99
a
Isolated product after column chromatography.
The interesting differences achieved for the reactions using
copper(II) propionate and copper(II) acetate, and the effect of pu-
rity, inspired us to look more carefully at the copper salts. An
analysis using Inductively Coupled Plasma Atomic Emission Spec-
trometry (ICP AES) for the presence of 28 different metal ions was
run on both anhydrous copper(II) acetate (97% purity, Strem
Chemicals) and copper(II) propionate (98% purity, Alfa Aesar) (Table 6).
The results showed that the sample of anhydrous copper(II) acetate
contained approximately 10 mg of chromium, 0.8 mg of iron. and
0.6 mg of calcium per gram of sample. The sample of anhydrous
copper(II) propionate on the other hand did not contain any de-
tectable amounts of other metal ions.
Table 6
Metal analysis of copper(II) acetate and copper(II) propionate
Entry
Element
Copper(II) acetate
Copper(II) propionate
1
2
3
4
5
Ca
Cr
Cu
Fe
0.574a
9.96
402
0.789
BDL
BDLb
BDL
360
BDL
BDL
Other metalsc
a
Numbers are milligram per gram of sample.
BDLdbelow detection limit.
Ag, Al, As, B, Ba, Be, Cd, Co, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Sb, Se, Si, Sr, Ti, Tl, V, Zn.
b
c
For the sample of copper(II) acetate (97% purity), which gave the
best results in the cross-coupling reactions, the presence of calcium
ions is unlikely to exert a significant effect on the reaction, although
the presence of iron and chromium metal ions may influence the
reaction, especially considering the oxidative reaction conditions
and the redox active nature of these two metals. The presence of
chromium was of particular interest, because of its high concen-
tration in the copper(II) acetate (97% purity) sample and its absence
in the copper(II) propionate or copper(II) acetate (99.999% purity)
sample. According to the ICP AES analysis of copper(II) acetate (97%
purity), the addition of 10 mol % of Cu is accompanied by 0.35 mol %
Further attempts at improving the reaction conditions (method
B) focused upon the influence of the copper catalyst on the cross-
coupling of benzamide (Table 5). Copper(II) acetate (97% or
99.999% purity) and copper(II) propionate (98%) reproducibly gave
3f in 80%, 60%, and 49% yields, respectively (Table 5, entries 1–3). The
wide variation in these results was unexpected, and showed that the
purity of the copper source was playing a role. The lower yield
obtained with copper(II) propionate compared to copper(II) acetate
was particularly surprising, given their similar solubilities and the

Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
5287
Table 8
of Cr, with respect to the starting material. To test whether chro-
mium or iron had an effect on the reactions, reactions were run
with copper(II) propionate doped with Cr(II) or Fe(II) (Table 7).
Reactions with copper(II) propionate (10 mol %) doped with chro-
mium(II) chloride in small amounts (0.175 or 0.35 mol % relative to
starting material) led to a modest improvement in the yields of 3f
(Table 7, entries 3 and 4). However, lower yields of 3f were obtained
with a higher amount of chromium(II) chloride (0.60 mol %) dopant
(Table 7, entry 5). The use of a chromium(II) chloride doped sample
of Cu(OAc)2 (99.999% purity) increased the yield of the reaction,
beyond that obtained with Cu(OAc)2 (99.999% purity) alone (Table
7, entry 6). The use of an iron(II) acetate (0.028 mol %) doped
sample of copper(II) propionate led to a modest decrease in yield
(Table 7, entry 7). Finally, the use of catalytic quantities of CrCl2
alone afforded no product. These results suggest that the presence
of a chromium impurity may have a modest effect on the reaction,
but further investigation is required before this can be confirmed,
and an understanding of these observations made.
Re-examination of temperature, copper, and potassium hexenyltrifluoroborate salt
2a stoichiometry
BF3K
(2.0 eq.)
Cu(OAc)2
O
O
Bu
NH2
N
H
4Å MS, O2, 40 °C, 20 h
DMSO/CH2Cl2 (1:1)
Entry Copper source
Temperature Yielda (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (10 mol %)
Cu(OAc)2 (5 mol %)
Cu(OAc)2 (20 mol %)
40 ꢀ
40 ꢀ
40 ꢀ
C
C
C
C
C
C
80
46
16
47
78
69
d
Cu(OAc)2 (10 mol %)/myristic acid (20 mol %) 40 ꢀ
Cu(OAc)2 (10 mol %)
Cu(OAc)2 (10 mol %)
Cu(OAc)2 (10 mol %)
50 ꢀ
30 ꢀ
rt
Cu(OAc)2 (10 mol %) using 2a (1.2 equiv)
40 ꢀ
C
16
a
Isolated product after column chromatography.
Table 7
The influence of metal ion additives on the cross-coupling reaction of benzamide
and 2a catalyzed by copper(II) propionate and copper(II) acetate
with an oil bubbler, with the oxygen gas supplied from a cylinder
passed through a gas drying unit filled with DRIERITE desiccant.
Attempts to utilize a balloon filled with oxygen or air led to lower
yields of 3f.
BF3K
(2.0 eq)
O
O
Cu catalyst (10 mol%)
+ Additive
With an optimized ‘ligandless’ protocol developed, the next step
was to evaluate its effectiveness with a range of amide substrates.
In general, the resultant enamides 3 are of particular interest since
they provide easy excess to functionalized systems that can further
undergo transition metal47 and organocatalyzed transformations.48
In general, various benzamide derivatives participated in the re-
action to afford enamides 3 in good yields using method B (Table 9).
In all cases the reactions were highly stereoselective, and only the
trans-enamides 3 were observed (ꢁ97:3 by 1H NMR spectroscopy).
Electron-deficient benzamides afforded the corresponding enam-
ides 3g–l (Table 9, entries 2–7) in higher yields than was for the
case with the electron-rich amides (Table 9, entries 8 and 9).
Chlorosubstituted benzamides reacted well, regardless of the po-
sition of the chloride on the ring (Table 9, entries 4–6), with even
the di-ortho-chloro substituted product 3k being formed in good
yield. The difference in yield between the electron-rich and
electron-deficient benzamides is quite different to the observations
of Buchwald and Altman,49 who noted that while pyridin-2(1H)-
one underwent a copper(I) catalyzed coupling with aryl iodide
under mild conditions, the more electron-deficient nitro-
substituted pyridin-2(1H)-one was unreactive, even at 150 ꢀC.
In addition to benzamides, acetamide underwent cross-
coupling in good yield to give enamide 3o (Table 10, entry 1). As
for the cross-coupling reactions of benzamides, more electron-
deficient acetamides afforded the corresponding enamides 3p–r
in higher yields (Table 10, entries 2–4). These results are in agree-
ment with Ogawa’s results where trifluoroacetamide gave a much
higher yield of the enamide than was observed for the cross-
Bu
NH2
N
H
4Å MS, O2, 40 °C, 20 h
DMSO/CH2Cl2 (1:1)
Entry
Cu (II) source (purity)
Additive
Added metal
Yielda (%)
ion (mol %)
1
2
3
4
5
6
7
Cu(OAc)2 (97%)
d
d
80
49
55
64
40
69
40
Cu(O2C3H5)2 (98%)
Cu(O2C3H5)2 (98%)
Cu(O2C3H5)2 (98%)
Cu(O2C3H5)2 (98%)
Cu(OAc)2 (99.999%)
Cu(O2C3H5)2 (98%)
d
d
CrCl2
CrCl2
CrCl2
CrCl2
Fe(OAc)2
0.175
0.350
0.600
0.350
0.028
a
Isolated product after column chromatography.
As a final optimization step, the effect of temperature, catalyst
loading, and the amount of potassium hexenyltrifluoroborate and
myristic acid was probed (Table 8). The catalyst loading of 10 mol %
copper(II) acetate (97% purity) was found to be optimal, since lower
(5 mol %) and higher (20 mol %) catalyst loadings led to 46% and 16%
yields of 3f, respectively (Table 8, entries 1–3). It is particularly
interesting that a higher catalyst loading leads to lower product
yields. The addition of myristic acid has been reported to improve
the yields in oxidative cross-couplings of amines and arylboronic
acids.46 It was proposed that the role of the myristate carboxylate
side-chain (a long aliphatic chain) was to improve the solubility of
the copper salt in the aprotic non polar solvent (toluene). In our
case, however, the yield of 3f decreased to 47% when myristic acid
(20 mol %) was added to the reaction, probably, due to the fact that
the copper salt is soluble in dimethylsulfoxide and the myristate
only acted as a ligand to copper, thus inhibiting the coordination of
an amide and transmetalation of organotrifluoroborate (Table 8,
entry 4). Elevating the reaction temperature to 50 ꢀC did not cause
an improvement in the yield of 3f (Table 8, entry 5). A slightly lower
yield was observed when the temperature was lowered to 30 ꢀC,
and no product was observed when the reaction was run at am-
bient temperature (Table 8, entries 6 and 7). The use of just
1.2 equiv of trifluoroborate salt 2a, rather than the 2.0 equiv usually
employed, resulted in significantly lower amounts of isolated
product 3f (Table 8, entry 8). Finally, it should be noted that all of
the reactions described in this manuscript were conducted under
a slightly positive oxygen pressure using a gas manifold equipped
coupling of acetamide with trans-b
-bromostyrene.25 In the case of
(S)-(ꢂ)-lactamide an interesting example of chemoselective cou-
pling was observed, with the alcohol group undergoing selective
O-alkenylation in the presence of the amide, to give the
corresponding enol ether 4 (Table 10, entry 5). Acrylamide and
cinnamamide were also effective cross-coupling partners giving 3s
and 3t, respectively (Table 10, entries 6 and 7). Reaction of heter-
oaromatic substituted substrates gave mixed results with 2-thio-
phenecarboxamide affording 3u in good yield (Table 10, entry 8),
whereas coupling of nicotinamide was unsuccessful. The reaction
of pyrrolidinone gave 3e in 86% yield, and the reaction of methyl
(S)-(þ)-2-pyrrolidone-5-carboxylate gave 3v in 80% yield (Table 10,
entries 9 and 10). Reaction of cyclic oxazolidinones occurred in
good yields to give 3d and 3w (Table 10, entries 11 and 12). Again in

5288
Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
Table 9
Table 10
Substrate scope of the cross-coupling reactions of primary amides with 2a under
Substrate scope of the cross-coupling reactions of amides, lactams, and ox-
‘ligandless’ conditions (method B)
azolidinones with 2a under ‘Ligandless’ conditions (method B)
BF3K
BF3K
(2.0 eq)
Cu(OAc)2 (10 mol%)
(2.0 eq)
Cu(OAc)2 (10 mol%)
O
O
O
O
R2
Bu
Bu
R1
N
R1
N
H
R
N
H
R
NH2
DMSO/CH2Cl2 (1:1)
4Å MS, O2, 40 °C, 20 h
DMSO/CH2Cl2 (1:1)
4Å MS, O2, 40 °C, 20 h
R2
Entry
Product
Yielda (%)
81
Entry
1
Amide
Product
Yielda (%)
67
1
2
2
3
4
86
88
79
86
72
66
71
70
3
4
5
6
5
6
68
74
7
8
9
75
76
86
7
8
66
55
65
10
11
80
97
9
a
Isolated product after column chromatography.
all cases the reactions were highly diastereoselective, and only the
trans-enamides 3 were observed (ꢁ97:3 by 1H NMR spectroscopy).
Other potassium alkenyltrifluoroborate salts can also be
employed using the ligand-free protocol to give enamides 5 (Fig. 3).
For example, reactions of benzamide, a substituted acetamide and
oxazolidinone with potassium trans-styryltrifluoroborate 2b, affor-
ded the products 5a, 5b, and 5c in good yields. In the case of reactions
with potassium cis-styryltrifluoroborate salt 2c, however, the iso-
lation of the cis-enamide 5d proved to be difficult. Even though the
product was observed by TLC, the enamide decomposed on the silica
gel column. These observations are in agreement with observations
12
71
a
Isolated product after column chromatography.
by Fu¨rstner and co-workers.16c The product was isolated by
employing alumina column chromatography. Reaction of potassium
vinyltrifluoroborate 2d with benzamide was similarly problematic,
giving 5e in low yield. Several attempts to improve the yield by
increasing the amount of vinyltrifluoroborate were fruitless.

Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
5289
hydrogen fluoride afforded cis-styryltrifluoroborate salt 2c in 52%
yield without any loss of stereochemical fidelity.
There are several proposed mechanisms concerning the cou-
plings of alkenyl and arylboronic acids that have appeared in the
literature. Evans and co-workers proposed a mechanism for the
cross-coupling of arylboronic acids and phenols.52 They suggested
that tetracoordinated Cu(II) intermediate, which resulted after the
coordination and deprotonation of phenol, and transmetalation of
arylboronic acid, can either undergo reductive elimination directly
or be initially oxidized to Cu(III) and then proceed to reductive
elimination. Lam and co-workers proposed a similar pathway for
the arylation and alkenylation of nitrogen nucleophiles, where
oxidation of a Cu(II) to a Cu(III) intermediate and reductive elimi-
nation are fast compared to slow reductive elimination of Cu(II)
species.38 Collman and Zhong proposed a similar mechanism in
more detail for the arylation of imidazoles in the presence of
[Cu(OH)$TMEDA]2Cl2 complex.53 Collman also outlined the im-
portance of ligands on copper as a means of reducing oxidation
potential. More recently, Stahl and co-workers have reported the
reactions of a defined copper(III) complex 7 with various amides
affording coupling product 8 (Scheme 3).42 A byproduct 9 was
observed when complex 7 was heated in the absence of external
nucleophile and when less reactive amides were employed. After
performing kinetic studies for different amides it was observed that
amides with lower pKa values reacted more rapidly than those with
high pKa values. As a result, Stahl and co-workers suggested that
this trend was a result of an amide being deprotonated prior to or in
the rate-determining step. The C–N bond formation event was
suggested to proceed via a three-centered Cu(III) intermediate,
which was not observed, or by the bimolecular attack of an amidate
on the ipso carbon of the aryl ligand. Stahl has subsequently pro-
posed a Cu(I)/Cu(II)/Cu(III) mechanistic scheme for the coupling of
boronic esters with methanol, where transmetalation is the rate-
determining step.54
Figure 3. Substrate scope of the cross-coupling reactions of amides and oxazolidinones
with potassium alkenyltrifluoroborate salts under ‘ligandless’ conditions (method B).
Coupling of potassium trans-3-methoxy-1-propenyltrifluoroborate
salt 2e with benzamide and chloroacetamide gave the products 5f
and 5g in good and excellent yields. Coupling of trans-cinnamamide
with potassium trans-styryltrifluoroborate gave a 56% yield of 5h.
Increasing the amount of the alkenyltrifluoroborate salt used led to
improved yields of 5h, with almost quantitative formation when
using 5 equiv of the potassium trans-styryltrifluoroborate salt.
Enamide 5h has been reported to be the key intermediate in the
synthesis of a natural product lansamide I, which was prepared in
three steps in 42% yield using an alternative route.50
The developed methodology relies upon ready access to potas-
sium alkenyltrifluoroborate salts 2. The salts can be synthesized
from the corresponding boronic acids and potassium hydrogen
fluoride using the standard procedure developed by Vedejs and co-
workers.33 Potassium trans-styryltrifluoroborate 2b was prepared
from commercially available trans-styrylboronic acid. The corre-
sponding cis-styryltrifuoroborate salt 2c was prepared using a met-
alation approach, which was initially used for the synthesis of
boronic acids, and later adopted for the synthesis of organo-
trifluoroborate salts (Scheme 2). Thus, cis-styryliodide 6 was formed
in 60% yield in a 10:1 diastereomeric ratio (cis/trans), from the re-
action of benzaldehydewith an in situ preformed phosphoniumylid,
according to the protocol of Stork and Zhao.51 Lithium–halogen ex-
change of 6 in the presence of tert-butyllithium, and trapping of the
resultant organolithium species with triisopropylborate, followed
by reaction of the boronate ester intermediate with potassium
2+
HNRZ
+
HN
NH
Cu
N
Me
HN
NH
NRZ
HN
NH
+
CH3CN,
50 °C
N
N
Me
Me
Scheme 3. Stahl’s studies on the reactivity of copper(III) complex 7.
It is clear that enamide formation is very sensitive to changes in
the ligand, solvent, and the structures of the substrate amides and
alkenyltrifluoroborate salts. While the specific copper oxidation
states, spatial orientation of the complexes, and the sequence of
events in a catalytic cycle are not known, a general mechanistic
scheme can be made (Fig. 4), based upon some of the generally
L = N-methylimidazole,
I
(i) NaHMDS, THF,
amide or solvent
R3 = alkenyl
20 °C, 1 min
Ph3PCH2I2
+
R3ŠNR2COR1
14
CuIL2
12
(ii) HMPA,
PhCHO, 30 min
1
2 O2
+
L
L
III
13
+
Cu
60%
:
R1CONHR2
R3
NR2COR1
10:1 (
)
KF3B
1
(i) BuLi
(ii) B(O Pr)3
Š
Š
Š
R3ŠBFx(OH)y
11
R3ŠBF3
2
(iii) KHF2 (aq.)
BFx(OH)y+1
, 52%
:
10:1 (
)
Figure 4. Mechanistic overview for the copper-catalyzed cross-coupling between
Scheme 2. Synthesis of potassium cis-styryltrifluoroborate salt 2c.
amides and potassium alkenyltrifluoroborate salts.

5290
Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
accepted speculations outlined above, and the recent studies of
Stahl and co-workers. The transmetalation step probably does not
occur directly on the organotrifluoroborate salt 2. Instead re-
placement of at least one of the fluoride ions from 2 must occur to
give the boron intermediate 11, which contains a hydroxyl group(s).
The presence of the hydroxy group on 11 allows the formation of
a bridging M–O–B species that is required for transmetalation, as
for palladium55 and rhodium56 catalyzed reactions. Oxidation by
molecular oxygen of Cu(I) species 12 to Cu(III) is believed to occur in
a stepwise fashion via Cu(II).56 Transmetalation by 11 and co-
ordination of 1 may occur either at the Cu(II) or Cu(III) oxidation
states, leading to intermediate 13. Rapid reductive elimination of 13
then gives the product enamide 14 and regenerates Cu(I) complex
12. It is also possible that dinuclear Cu complexes may be involved
in the catalytic cycle. The role of 4 Å molecular sieves is not clear,
but they may serve as a catalyst for hydrogen peroxide de-
composition, or aid in the re-oxidation of copper by oxygen, per-
haps through the generation of a peroxo-copper species.57 In
addition, they may facilitate ligand exchange on boron (as for the
conversion of 2 to 11).
Elmer Spectrum 1000, with samples loaded as films on NaCl plates
or as KBr pellets. 1H and 13C NMR spectra were obtained on Varian
Mercury 300 or Unity 400 as solutions in deuterated solvents
(CDCl3, DMSO-d6, and acetone-d6, obtained from Cambridge Iso-
tope Labs) and referenced to their corresponding solvent peaks
(i.e., CHCl3 7.26 ppm; DMSO 2.54 ppm; acetone 2.09 ppm for
proton resonances, and CHCl3, 77.23 ppm; DMSO 40.45; acetone
205.87 ppm for carbon resonances). Chemical Shifts are expressed
in parts per million values. Peak multiplicities are designated by
the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; dd, doublet of doublets; dt, doublet of triplets; m, mul-
tiplet; J, coupling constant in hertz. Low-resolution mass spectra
(MS) were recorded on a Bell and Howell 21-490 spectrometer.
High-resolution mass spectra (HRMS) were recorded on an AEI
MS3074 spectrometer. Melting points were obtained on a Fisher-
Johns melting point apparatus and are uncorrected. Flash col-
umn chromatography on silica gel (60 Å, 230–400 mesh, low
acidity, obtained from Silicycle Inc.) and aluminum oxide (acti-
vated, neutral, Brockmann I, standard grade, w150 mesh, 58 Å,
obtained from Aldrich) was performed on reagent grade solvents.
Analytical thin-layer chromatography (TLC) was performed on
pre-coated aluminum-backed silica gel plates (Alugram SIL/G/
UV254 purchased from Silicycle Inc.), visualized with an UV lamp
(254 nm) and potassium permanganate (Aldrich). Spectral data are
provided for all new compounds and for compounds that lack full
characterization in the literature. Spectral data for compounds
3e,23b 3v,23b 5a,26a 5c,60 5d,23c 5e,61 and 5h62 were in agreement
with literature values.
3. Conclusions
In conclusion, two protocols for the cross-coupling reaction of
potassium alkenyltrifluoroborate salts with amides to give enam-
ides have been developed. The existing methods for the synthesis
of enamides often have limited substrate scope and typically re-
quire elevated temperatures, rigorous exclusion of air and water,
and the use of two or more equivalents of strong base. In contrast,
this protocol occurs at low temperature under neutral conditions,
providing an attractive alternative for the synthesis of the enam-
ide moiety. The cross-coupling reactions occur under an atmo-
sphere of molecular oxygen at 40 ꢀC in the presence of a copper
catalyst (10 mol %). For amide substrates with lower pKa values,
such as phthalimide, isatin, and 2-hydroxypyridine, the presence
of N-methylimidazole (20 mol %), was essential for the reaction to
take place, possibly due to the ability of N-methylimidazole to act
as a stabilizing ligand for higher oxidation states of copper, and/or
to facilitate deprotonation of the amides bound to copper. For less
acidic amide substrates (higher pKa’s), reaction in a DMSO/CH2Cl2
co-solvent mix occurred in the absence of N-methylimidazole or
other added external ligand. Under these conditions we speculate
that DMSO may serve as a ligand for copper, and that deproto-
nation of the copper bound amide may not be necessary for re-
ductive elimination to occur. Further investigations on the
applications of this reaction and of the utility of organo-
trifluoroborate salts in metal-catalyzed couplings will be reported
in due course.
4.2. Method A
To Cu(OAc)2 (0.05 mmol), amide (0.5 mmol), potassium alke-
nyltrifluoroborate salt (1.0 mmol), and 4 Å molecular sieves (0.38 g)
were added CH2Cl2 (2.0 ml) and N-methylimidazole (0.1 mmol). The
suspension was stirred for 20 h at 40 ꢀC under positive atmosphere
of oxygen (oxygen from a cylinder was passed through a gas drying
unit filled with DRIERITE), then through a manifold equipped with
an oil bubbler. The reaction flask was attached to the manifold. The
reaction mixture was then filtered through a plug of Celite, which
was washed with EtOAc (50 mL). The crude products were purified
by silica gel chromatography using EtOAc/hexanes/Et3N.
4.3. Method B
To Cu(OAc)2 (0.05 mmol), amide (0.5 mmol), potassium alke-
nyltrifluoroborate salt (1.0 mmol), and 4 Å molecular sieves (0.38 g)
were added CH2Cl2 (1.0 ml) and DMSO (1.0 ml). The suspension was
stirred for 20 h at 40 ꢀC under an atmosphere of oxygen (see method
A). The reaction mixture was then filtered through a plug of Celite,
which was washed with EtOAc (50 mL). The crude products were
purified by silica gel chromatography using EtOAc/hexanes/Et3N.
4. Experimental section
4.1. General
4.4. Characterization data
The following general experimental applies for all experiments
described in this paper. Unless otherwise stated, all reactions were
performed under oxygen. All reagents, unless otherwise stated
were used as received. Reaction solvents were distilled under an
inert atmosphere before use and transferred via syringe using
standard techniques unless otherwise stated. Dichloromethane
was distilled from CaH2 under nitrogen. DMSO was purchased as
anhydrous grade from Aldrich. All other solvents were obtained as
ACS grade (or better). All reagents, unless otherwise stated, were
used as received (Aldrich, Fischer Scientific Ltd., or Lancaster). cis-
Styryl iodide,53 potassium hexenyltrifluoroborate,58 and potassium
trans-styryl trifluoroborate37,59 were prepared according to the
literature procedures. FTIR spectra were obtained on a Perkin–
4.4.1. trans-2-Hex-1-enyl-isoindole-1,3-dione (3a)28. Synthesized
by method A. Isolated as yellow crystals (114 mg, quantitative);
crude product was purified by silica gel column chromatography
(eluting with EtOAc/hexanes/Et3N 33:66:1); 1H NMR (300 MHz,
CDCl3)
d
7.84 (dd, J¼5.5, 3.0 Hz, 2H), 7.72 (dd, J¼5.5, 3.0 Hz, 2H),
6.57–6.63 (m, 2H), 2.11–2.20 (m, 2H), 1.41–1.51 (m, 4H), 0.92 (t,
J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 166.9, 134.5, 131.9, 123.6,
123.1, 117.7, 31.8, 31.1, 22.4, 14.1.
4.4.2. trans-1-Hex-1-enyl-1H-pyridin-2-one (3b)28. Synthesized by
method A. Isolated as colorless crystals (89 mg, 78%); crude product
was purified by silica gel column chromatography (eluting with

Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
5291
EtOAc/hexanes/Et3N 33:66:1); 1H NMR (300 MHz, CDCl3)
d
7.47 (dd,
146.6, 133.8, 132.2, 130.8, 128.9, 124.6, 122.1, 116.1, 32.0, 29.7, 22.4,
14.1; MS (EI) m/z (rel intensity) 76 (27), 104 (17), 150 (100), 205 (18),
248 (14); HRMS (EI) m/z calcd for C13H16N2O3 (Mþ) 248.1161, found
248.1155.
J¼7.0, 2.0 Hz,1H), 7.31 (ddd, J¼9.0, 6.5, 2.0 Hz,1H), 7.24 (d, J¼4.5 Hz,
1H), 6.55 (d, J¼9.0 Hz, 1H), 6.19 (dd, J¼6.0, 6.0 Hz, 1H), 5.79 (dt,
J¼14.5, 7.0 Hz, 1H), 2.18–2.25 (m, 2H), 1.41–1.51 (m, 4H), 0.92 (t,
J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 161.7, 140.0, 134.0, 126.9,
123.6, 121.4, 106.5, 31.6, 29.9, 22.4, 14.0.
4.4.8. 4-Chloro-trans-N-hex-1-enyl-benzamide (3i). Synthesized by
method B. Isolated as colorless crystals (79 mg, 66%): mp¼110–
111 ꢀC; crude product was purified by silica gel column chroma-
4.4.3. trans-1-Hex-1-enyl-1H-indole-2,3-dione (3c)28. Synthesized
by method A. Isolated as red crystals (94 mg, 82%); crude product
was purified by silica gel column chromatography (eluting with
tography (eluting with EtOAc/hexanes/Et3N 20:80:1); IR (neat)
3318, 2967, 2928, 2473, 1679, 1631, 1594, 1529, 1486, 954 cmꢂ1; 1H
NMR (400 MHz, acetone-d6)
n
EtOAc/hexanes/Et3N 25:75:1); IR (KBr pellet)
n
3454, 2923, 1732,
d
9.47 (d, J¼7.0 Hz, NH), 7.94 (m, 2H),
1608, 1470, 1362, 1324, 1181, 1095, 755 cmꢂ1
;
1H NMR (400 MHz,
7.49 (m, 2H), 6.94 (ddt, J¼14.5, 10.0, 1.5 Hz), 5.45 (dt, J¼14.5, 7.5 Hz),
CDCl3)
d 7.59–7.63 (m, 2H), 7.12–7.18 (m, 2H), 6.31–6.42 (m, 2H),
2.07 (m, 2H), 1.34 (m, 4H), 0.90 (J¼7.5 Hz); 13C NMR (125 MHz,
2.20–2.25 (m, 2H), 1.40–1.50 (m, 4H), 0.94 (t, J¼7.0 Hz, 3H); 13C
acetone-d6) d 162.6, 137.0, 132.9, 129.1, 128.5, 123.5, 113.5, 32.1, 29.5,
NMR (100 MHz, CDCl3)
d
182.8, 157.2, 150.6, 138.5, 126.1, 125.6,
21.9, 13.3; MS (EI) m/z (rel intensity) 111 (20), 139 (100), 141 (30),
237 (18), 239 (6); HRMS (EI) m/z calcd for C13H16NOCl (Mþ)
237.0920, found 237.0925.
124.4, 118.7, 117.9, 111.1, 31.7, 30.7, 22.4, 14.1; MS (EI) m/z (rel in-
tensity) 77 (28), 130 (19), 145 (100), 158 (70), 229 (46); HRMS (EI)
m/z calcd for C14H15NO2 (Mþ) 229.1102, found 229.1105.
4.4.9. 2-Chloro-trans-N-hex-1-enyl-benzamide (3j). Synthesized by
method B. Isolated as colorless crystals (85 mg, 71%): mp¼54–
56 ꢀC; crude product was purified by silica gel column chroma-
4.4.4. trans-3-Hex-1-enyl-oxazolidin-2-one (3d). Synthesized by
method B. Isolated as a colorless oil (82 mg, 97%); crude product
was purified by silica gel column chromatography (eluting with
tography (eluting with EtOAc/hexanes/Et3N 25:75:1); IR (neat)
3277, 3081, 2965, 2934, 1650, 1592, 1530, 1430, 953, 744 cmꢂ1 1H
NMR (400 MHz, acetone-d6)
n
EtOAc/hexanes/Et3N 50:50:1); IR (thin film)
1669, 1416, 1247, 1289, 1082, 943, 755 cmꢂ1
CDCl3)
6.63 (d, J¼14.5 Hz, 1H), 4.82 (dt, J¼14.5, 7.0 Hz, 1H), 4.42 (t,
n
2924, 2362, 1751,
;
;
1H NMR (300 MHz,
d
9.24 (d, J¼6.0 Hz, NH), 7.50–7.36 (m,
d
4H), 6.89 (ddt, J¼14.5, 10.0, 1.5 Hz, 1H), 5.42 (dt, J¼14.5, 7.0 Hz, 1H),
J¼8.0 Hz, 2H), 3.69 (t, J¼8.0 Hz, 2H), 2.03–2.10 (m, 2H), 1.23–1.43
2.12–2.05 (m, 2H),1.41–1.33 (m, 4H), 0.92 (t, J¼3.5 Hz, 3H); 13C NMR
(m, 4H), 0.90 (t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
155.7,
(125 MHz, acetone-d6) d 163.4, 136.4, 130.7, 129.8, 129.1, 127.0,
124.0, 111.6, 62.3, 42.8, 32.4, 29.6, 22.2, 14.1; MS (EI) m/z (rel in-
tensity) 100 (100), 126 (29), 170 (70), 192 (49); HRMS (EI) m/z calcd
for C9H15NO2 (Mþ) 189.0793, found 189.0793.
122.9, 122.8, 113.6, 32.0, 29.4, 21.9, 13.3; MS (EI) m/z (rel intensity)
111 (18), 139 (100), 141 (30), 237 (12), 239 (4); HRMS (EI) m/z calcd
for C13H16NOCl (Mþ) 237.0920, found 237.0920.
4.4.5. trans-N-Hex-1-enyl-benzamide (3f). Synthesized by method
B. Isolated as colorless crystals (83 mg, 81%); crude product was
purified by silica gel column chromatography (eluting with EtOAc/
4.4.10. 2,6-Dichloro-trans-N-hex-1-enyl-benzamide (3k). Synthe-
sized by method B. Isolated as colorless crystals (95 mg, 70%):
mp¼178–179 ꢀC; crude product was purified by silica gel column
chromatography (eluting with EtOAc/hexanes/Et3N 25:75:1); IR
hexanes/Et3N 20:80:1); IR (thin film)
n
3278, 3025, 2923, 1651,
1543, 1423, 1323, 1024, 946, 707 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
(neat)
n 3252, 2928, 1652, 1548, 1432, 1317, 1119, 962, 800,
d
7.85–7.88 (m, 1H; NH), 7.79–7.84 (m, 2H), 7.50 (t, J¼7.5 Hz, 1H),
773 cmꢂ1; 1H NMR (400 MHz, acetone-d6)
d
9.39 (d, J¼7.0 Hz, NH),
7.41 (dd, J¼7.5, 7.5 Hz, 2H), 6.90–6.99 (m, 1H), 5.32 (dt, J¼14.5,
7.0 Hz, 1H), 2.04–2.10 (m, 2H), 1.29–1.42 (m, 4H), 0.90 (t, J¼7.0 Hz,
7.44–7.42 (m, 3H), 6.88 (ddt, J¼14.5, 10.0, 1.5 Hz), 5.41 (dt, J¼14.5,
7.0 Hz), 2.12–2.05 (m, 2H), 1.42–1.35 (m, 4H), 0.94–0.90 (m, 3H); 13C
3H); 13C NMR (75 MHz, CDCl3)
d
164.5, 134.1, 131.9, 128.8, 127.2,
NMR (125 MHz, acetone-d6) d 160.8, 136.3, 131.9, 131.0, 128.0, 122.5,
123.0, 114.6, 32.2, 29.7, 22.3, 14.1; MS (EI) m/z (rel intensity) 105
(100), 106 (7), 204 (4), 226 (17); HRMS (EI) m/z calcd for C13H18NO
(Mþþ1) 204.1382, found 204.1374.
114.2, 32.0, 29.4, 22.0, 13.3; MS (EI) m/z (rel intensity) 173 (100), 175
(70), 190 (28), 271 (12), 273 (7); HRMS (EI) m/z calcd for
C13H15NOCl2 (Mþ) 271.0531, found 271.0534.
4.4.6. trans-N-Hex-1-enyl-4-nitro-benzamide (3g). Synthesized by
method B. Isolated as yellow crystals (106 mg, 85%): mp¼124–
125 ꢀC; crude product was purified by silica gel column chroma-
tography (eluting with EtOAc/hexanes/Et3N 20:80:1); IR (KBr pel-
4.4.11. trans-N-Hex-1-enyl-3-trifluoromethyl-benzamide
(3l). Synthesized by method B. Isolated as colorless crystals (90 mg,
66%): mp¼43–44 ꢀC; crude product was purified by silica gel col-
umn chromatography (eluting with EtOAc/hexanes/Et3N 20:80:1);
let)
n
3296, 2928, 2420, 1641, 1599, 1515, 1297, 953, 866, 844,
IR (neat)
n 3259, 3202, 2963, 1644, 1544, 1348, 1320, 1163, 1120,
708 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
8.27 (d, J¼8.5 Hz, 2H), 8.07
920 cmꢂ1; 1H NMR (400 MHz, acetone-d6)
d
9.67 (d, J¼7.5 Hz, NH),
(d, J¼10.0 Hz, 1H; NH), 7.98 (d, J¼8.5 Hz, 2H), 6.91 (dd, J¼14.0,
10.0 Hz, 1H), 5.43 (dt, 1H, J¼14.0, 7.0 Hz, 1H), 2.05–2.12 (m, 2H),
1.26–1.43 (m, 4H), 0.90 (t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
8.24–8.21 (m, 2H), 7.88 (d, J¼8.0 Hz, 1H), 7.73 (t, J¼8.0 Hz, 1H), 7.0
(ddt, J¼14.5, 10.0, 1.5 Hz, 1H), 5.5 (dt, J¼14.5, 7.0 Hz, 1H), 2.11–2.04
(m, 2H), 1.40–1.28 (m, 4H), 0.90 (t, J¼7.0 Hz, 3H); 13C NMR
d
162.5, 149.9, 139.7, 128.5, 124.1, 122.5, 116.6, 32.1, 29.7, 22.3, 14.1;
(125 MHz, acetone-d6)
d
162.2, 135.2, 131.2, 129.9 (q, J¼32.5 Hz),
MS (EI) m/z (rel intensity) 104 (25), 150 (100), 167 (25), 205 (34),
248 (12); HRMS (EI) m/z calcd for C13H16N2O3 (Mþ) 248.1161, found
248.1167.
129.5, 127.9 (q, J¼3.5 Hz), 124.1 (q, J¼271.5 Hz), 124.0 (q, J¼4.0 Hz),
123.4, 114.1, 32.1, 29.5, 21.9 ,13.1; MS (EI) m/z (rel intensity) 145 (28),
173 (100), 190 (18), 228 (15), 271 (9); HRMS (EI) m/z calcd for
C14H16F3NO (Mþ) 271.1195, found 271.1184.
4.4.7. trans-N-Hex-1-enyl-2-nitro-benzamide (3h). Synthesized by
method B. Isolated as yellow crystals (89 mg, 72%); crude product
was purified by silica gel column chromatography (eluting with
4.4.12. trans-N-Hex-1-enyl-4-methoxy-benzamide (3m). Synthe-
sized by method B. Isolated as colorless crystals (65 mg, 56%); crude
product was purified by silica gel column chromatography (eluting
with EtOAc/hexanes/Et3N 25:75:1); 1H NMR (300 MHz, CDCl3)
EtOAc/hexanes/Et3N 50:50:1); 1H NMR (300 MHz, CDCl3)
d 8.13 (d,
J¼10.0 Hz, 1H, NH), 7.91 (d, J¼8.0 Hz, 1H), 7.57 (dd, J¼7.5, 7.5 Hz,
1H), 7.47 (dd, J¼7.5, 7.5 Hz, 1H), 7.39 (d, J¼7.0 Hz, 1H), 6.68 (dd,
J¼14.0, 10.0 Hz, 1H), 5.21 (dt, J¼14.0, 7.0 Hz, 1H), 1.29–2.00 (m, 2H),
d
7.95 (d, J¼10.0 Hz,1H; NH), 7.76 (d, J¼9.0 Hz, 2H), 6.94 (dd, J¼14.0,
10.0 Hz,1H), 6.87 (d, J¼9.0 Hz, 2H), 5.29 (dt, J¼14.0, 7.0 Hz,1H), 3.81
(s, 3H), 2.00–2.07 (m, 2H), 1.32–1.39 (m, 4H), 0.88 (t, J¼7.0 Hz, 3H);
1.31 (s, 4H), 0.89 (d, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 163.5,

5292
Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
13C NMR (75 MHz, CDCl3)
114.0, 55.6, 32.3, 29.7, 22.3, 14.1; MS (EI) m/z (rel intensity) 77 (7),
92 (6), 135 (100), 233 (18); HRMS (EI) m/z calcd for C14H19NO2 (Mþ)
233.1416, found 233.1419.
d
164.1, 162.6, 129.2, 126.3, 123.2, 114.1,
46 ꢀC; crude product was purified by silica gel column chroma-
tography (eluting with EtOAc/hexanes/Et3N 66:33:1); 1H NMR
(400 MHz, acetone-d6)
d
6.79–6.64 (m, NH2), 6.21 (dt, J¼12.5,
1.0 Hz, 1H), 4.91 (dt, J¼12.5, 7.5 Hz, 1H), 4.15(q, J¼7.0 Hz, 1H), 1.96–
1.88 (m, 2H), 1.35 (d, J¼7.0 Hz, 3H), 1.33–1.28 (m, 4H), 0.89–0.86 (m,
4.4.13. trans-N-Hex-1-enyl-2-methoxy-benzamide
(3n). Synthe-
3H); 13C NMR (125 MHz, acetone-d6)
d 174.0,144.6,106.7, 75.9, 32.5,
sized by method B. Isolated as a colorless oil (76 mg, 65%); crude
product was purified by silica gel column chromatography (elut-
26.9, 21.7, 17.8, 13.3; MS (EI) m/z (rel intensity) 55 (55), 57 (28), 72
(100), 73 (90), 171 (10); HRMS (EI) m/z calcd for C9H17NO2 (Mþ)
171.1259, found 171.1266.
ing with EtOAc/hexanes/Et3N 20:80:1); IR (thin film)
2356, 1644, 1519, 1298, 1248, 1021, 952, 755 cmꢂ1
(300 MHz, CDCl3)
n
3374, 2954,
;
1H NMR
d
9.37 (d, J¼9.5 Hz, 1H; NH), 8.20 (dd, J¼8.0,
4.4.19. trans-N-Hex-1-enyl-acrylamide (3s). Synthesized by method
B. Isolated as colorless oil (57 mg, 74%); crude product was purified
by silica gel column chromatography (eluting with EtOAc/hexanes/
2.0 Hz, 1H), 7.40–7.45 (m, 1H), 7.00–7.08 (m, 3H), 5.25 (dt, J¼14.5,
7.0 Hz, 1H), 3.96 (s, 3H), 2.03–2.10 (m, 2H), 1.29–1.40 (m, 4H), 0.89
(t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
162.4, 157.6, 133.3,
Et3N 50:50:1); IR (thin film)
n
3267, 3194, 2957, 2928, 1658, 1626,
9.07 (s,
132.7, 123.1, 121.6, 121.1, 114.4, 111.6, 56.2, 32.3, 29.8, 22.3, 14.1; MS
(EI) m/z (rel intensity) 57 (14), 77 (20), 92 (12), 135 (100), 233 (29);
HRMS (EI) m/z calcd for C14H19NO2 (Mþ) 233.1416, found
233.1420.
1533,1236, 954, 800 cmꢂ1; 1H NMR (400 MHz, acetone-d6)
d
NH), 6.81 (ddt, J¼14.5,10.5,1.5 Hz,1H), 6.26 (d, J¼2.0 Hz,1H), 6.25 (s,
1H), 5.63 (dd, J¼7.0, 5.5 Hz, 1H), 5.27 (dt, J¼14.5, 7.0 Hz, 1H), 2.06–
2.00 (m, 2H), 1.39–1.28 (m, 4H), 0.92–0.87 (m, 3H); 13C NMR
(125 MHz, acetone-d6)
d 161.8, 131.1, 125.8, 123.2, 112.8, 32.1, 29.4,
4.4.14. trans-N-Hex-1-enyl-acetamide (3o). Synthesized by method
B. Isolated as a colorless oil (47 mg, 67%); crude product was pu-
rified by silica gel column chromatography (eluting with EtOAc/
21.8, 13.3; MS (EI) m/z (rel intensity) 55 (28), 56 (15), 82 (19), 110
(100), 153 (60); HRMS (EI) m/z calcd for C9H15NO (Mþ) 153.1154,
found 153.1153.
hexanes/Et3N 75:25:1); 1H NMR (300 MHz, CDCl3)
d 7.59 (d,
J¼11.0 Hz, 1H; NH), 6.69 (m, 1H), 5.12 (dt, J¼14.5, 7.0 Hz, 1H), 1.94–
4.4.20. trans-N-Hex-1-enyl-3-phenyl-acrylamide (3t). Synthesized
by method B. Isolated as colorless crystals (86 mg, 75%); crude
product was purified by silica gel column chromatography (eluting
with EtOAc/hexanes/Et3N 25:75:1); 1H NMR (300 MHz, CDCl3)
2.00 (m, 5H), 1.24–1.35 (m, 4H), 0.85 (t, J¼7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 167.6, 122.6, 113.4, 32.2, 29.5, 23.3, 22.3, 14.1; MS
(EI) m/z (rel intensity) 56 (100), 60 (17), 70 (11), 98 (23), 141 (20);
HRMS (EI) m/z calcd for C8H15NO (Mþ) 141.1151, found 141.1154.
d
8.22 (d, J¼10.5 Hz, 1H, NH), 7.69 (d, J¼16.0 Hz, 1H), 7.44–7.47 (m,
2H), 7.26–7.33 (m, 3H), 6.93 (dd, J¼14.0, 1.5 Hz, 1H), 6.55 (d,
J¼16.0 Hz, 1H), 5.33 (dt, J¼14.5, 7.0 Hz, 1H), 2.00–2.07 (m, 2H), 1.32
4.4.15. 2,2,2-Trifluoro-trans-N-hex-1-enyl-acetamide
(3p). Syn-
thesized by method B. Isolated as a yellow oil (84 mg, 86%); crude
product was purified by silica gel column chromatography (eluting
with EtOAc/hexanes/Et3N 10:100:1); 1H NMR (300 MHz, CDCl3)
(m, 4H), 0.86 (t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 163.4,
142.1, 135.0, 130.0, 129.0, 128.1, 123.0, 120.5, 114.9, 32.2, 29.8, 22.4,
14.1; MS (EI) m/z (rel intensity) 103 (55), 131 (100), 132 (8), 230 (8),
252 (16); HRMS (EI) m/z calcd for C15H20NO (Mþþ1) 230.1541,
found 230.1539.
d
8.11 (br s, 1H), 6.61 (dd, J¼14.0, 10.0 Hz, 1H), 5.51 (dt, J¼14.5,
7.0 Hz, 1H), 2.02–2.09 (m, 2H), 1.24–1.41 (m, 4H), 0.88 (t, J¼7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3)
d
154.4 (q, 2J(C,F)¼38.0 Hz), 120.2,
120.0, 116 (q, 1J(C,F)¼287.0 Hz), 31.6, 29.5, 22.2, 14.0; MS (EI) m/z
(rel intensity) 57 (32), 69 (17), 82 (17), 152 (100), 195 (14); HRMS
(EI) m/z calcd for C8H12F3NO (Mþ) 195.0871, found 195.0871.
4.4.21. Thiophene-2-carboxylic acid trans-hex-1-enylamide
(3u). Synthesized by method B. Isolated as colorless crystals
(80 mg, 66%): mp¼134–135 ꢀC; crude product was purified
by silica gel column chromatography (eluting with EtOAc/
hexanes/Et3N 33:66:1); ; 1H NMR (400 MHz, acetone-d6)
4.4.16. 2-Chloro-trans-N-hex-1-enyl-acetamide (3q). Synthesized
by method B. Isolated as colorless crystals (77 mg, 88%): mp¼34–
35 ꢀC; crude product was purified by silica gel column chroma-
tography (eluting with EtOAc/hexanes/Et3N 33:66:1); 1H NMR
d
9.40 (d, J¼6.5 Hz, NH), 7.78 (dd, J¼4.0, 1.0 Hz, 1H), 7.71
(dd, J¼5.0, 1.0 Hz, 1H), 7.13 (dd, J¼5.0, 4.0 Hz, 1H), 6.88 (ddt,
J¼14.5, 10.0, 1.5 Hz), 5.39 (dt, J¼7.5, 14.5 Hz, 1H), 2.08–2.03
(m, 2H), 1.38–1.30 (m, 4H), 0.89 (t, J¼7.0 Hz, 3H); 13C NMR
(400 MHz, acetone-d6)
d
9.11 (s, NH), 6.68 (ddt, J¼14.0, 10.0, 1.5 Hz,
1H), 5.38 (dt, J¼14.0, 7.5 Hz, 1H), 2.06–2.00 (m, 2H), 1.37–1.29 (m,
(125 MHz, acetone-d6) d 158.5, 139.6, 130.9, 128.0, 127.7,
4H), 0.89 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, acetone-d6)
d
163.2,
123.1, 113.0, 32.1, 29.5, 21.9, 13.3; MS (EI) m/z (rel intensity)
83 (5), 111 (100), 128 (12), 166 (14), 209 (17); HRMS (EI)
m/z calcd for C11H15NOS (Mþ) 209.0874, found 209.0879.
122.6, 113.9, 42.3, 31.9, 29.3, 21.8, 13.3; MS (EI) m/z (rel intensity) 56
(45), 132 (100), 140 (30), 175 (20), 177 (7); HRMS (EI) m/z calcd for
C8H14NOCl (Mþ) 175.0764, found 175.0769.
4.4.22. trans-4-Benzyl-3-hex-1-enyl-oxazolidin-2-one (3w). Synth-
esized by method B. Isolated as a yellow oil (92 mg, 71%); crude
product was purified by silica gel column chromatography (eluting
4 . 4 .17 . t ra n s - 2 , 2 - D i e t h o x y - N - h e x - 1 - e nyl - a c e t a m i d e
(3r). Synthesized by method B. Isolated as colorless oil (90 mg,
79%); crude product was purified by silica gel column chromato-
with EtOAc/hexanes/Et3N 20:80:1); IR (thin film)
1672, 1417, 1234, 1088, 1029, 949, 758 cmꢂ1 1H NMR (300 MHz,
CDCl3)
n 3427, 2927,1769,
graphy (eluting with EtOAc/hexanes/Et3N 33:66:1); IR (thin film)
3300, 2976, 2958, 2874, 1670, 1514, 1166, 1128, 1064, 956 cmꢂ1; 1H
NMR (400 MHz, acetone-d6)
n
;
d
7.23–7.35 (m, 3H), 7.16 (d, J¼7.0 Hz, 2H), 6.56 (d, J¼14.5 Hz,
d
8.80 (d, J¼5.5 Hz, NH), 6.67 (ddt,
1H), 5.08 (dt, J¼14.5, 7.0 Hz, 1H), 4.12–4.29 (m, 3H), 3.19 (dd, J¼14.0,
3.0 Hz, 1H), 2.76 (dd, J¼14.0, 8.5 Hz, 1H), 2.09–2.15 (m, 2H), 1.31–
1.44 (m, 4H), 0.92 (t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
J¼14.5, 10.5, 1.5 Hz, 1H), 5.42 (dt, J¼14.5, 7.0 Hz, 1H), 4.78 (s, 1H),
3.68–3.55 (m, 4H), 2.09–1.99 (m, 2H), 1.36–1.31 (m, 4H), 1.18 (t,
J¼7.0 Hz, 6H), 0.91–0.87 (m, 3H); 13C NMR (125 MHz, acetone-d6)
d
155.4, 135.7, 129.5, 129.2, 127.5, 122.8, 112.5, 66.5, 55.2, 36.3, 32.5,
d
164.9, 122.3, 114.0, 98.9, 62.3, 32.3, 29.6, 22.1, 14.7, 13.5; MS (EI) m/
30.0, 22.3, 14.1; MS (EI) m/z (rel intensity) 117 (16), 190 (21), 216 (9),
260 (100), 282 (28); HRMS (EI) m/z calcd for C16H22NO2 (Mþþ1)
260.1645, found 260.1646.
z (rel intensity) 37 (75), 103 (100), 229 (5); HRMS (EI) m/z calcd for
C12H23NO3 (Mþ) 229.1678, found 229.1676.
4.4.18. trans-2-Hex-1-enyloxy-propionamide (4). Synthesized by
method B. Isolated as colorless crystals (58 mg, 68%): mp¼44–
4.4.23. 2,2-Diethoxy-trans-N-styryl-acetamide (5b). Synthesized by
method B. Isolated as yellow crystals (80 mg, 65%): mp¼64–65 ꢀC;

Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
5293
crude product was purified by silica gel column chromatography
(eluting with EtOAc/hexanes/Et3N 50:50:1); 1H NMR (400 MHz,
acetone-d6)
References and notes
1. (a) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691–1692; (b) Goldberg, I. Ber.
Dtsch. Chem. Ges. 1907, 40, 4541–4546.
2. (a) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517–536; (b) Hickmott, P. W.
Tetrahedron 1982, 38, 1975–2050; (c) Hickmott, P. W. Tetrahedron 1982, 38,
3363–3446.
3. Larock, R. L. Comprehensive Organic Transformations: A Guide to Functional Group
Preparations, 2nd ed.; Wiley-VCH: New York, NY, 1999; p 1507.
4. (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973–986; (b) Carbery,
D. R. Org. Biomol. Chem. 2008, 6, 3455–3466.
5. For reviews, see: (a) Yet, L. Chem. Rev. 2003, 103, 4283–4306; (b) Joullie´, M. M.;
Richard, D. J. Chem. Commun. 2004, 2011–2015; (c) Tan, N.-H.; Zhu, J. Chem. Rev.
2006, 106, 840–895.
6. For selected references of total syntheses of enamide natural products, see: (a)
Wu, Y. S.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed. 2000, 39, 4308–4310;
(b) Fu¨rstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731–3734; (c) Bhatta-
charjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron Lett. 2001, 42,1217–1220;
(d) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040–6041; (e) Shen, R.;
Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125,
7889–7901; (f) Yang, K. L.; Blackman, B.; Diederich, W.; Flaherty, P. T.; Mossman,
C. J.; Roy, S.; Ahn, Y. M.; Georg, G. I. J. Org. Chem. 2003, 68, 10030–10039; (g)
Nicolaou, K. C.; Kim, D. W.; Baati, R.; O’Brate, A.; Giannakakou, P. Chem.dEur. J.
2003, 9, 6177–6191; (h) Su, Q. B; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425–
2430; (i) Herb, C.; Bayer, A.; Maier, M. E. Chem.dEur. J. 2004, 10, 5649–5660; (j)
Shen, R.; Inoue, T.; Forgac, M.; Porco, J. A., Jr. J. Org. Chem. 2005, 70, 3686–3692; (k)
Dias, L. C.; de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F. J. Org. Chem. 2005, 70,
2225–2234; (l) Cristau, P.; Temal-Lay¨b, T.; Bois-Choussy, M.; Martin, M.-T.; Vors,
J.-P.; Zhu, J. Chem. Eur. J 2005, 11, 2668–2679; (m) Toumi, M.; Couty, F.; Evano, G.
Angew. Chem., Int. Ed. 2007, 46, 572–575; (n) He, G.; Wang, J.; Ma, D. Org. Lett. 2007,
9,1367–1369; (o) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc.
2007, 129, 6386–6387.
d
9.30 (d, J¼9.5 Hz, NH), 7.49 (dd, J¼10.5, 14.5 Hz, 1H),
7.37–7.34 (m, 2H), 7.31–7.26 (m, 2H), 7.19–7.14 (m, 1H), 7.47 (d,
J¼14.5 Hz, 1H), 3.73–3.60 (m, 4H), 1.21 (t, J¼7.0 Hz, 6H); 13C NMR
(125 MHz, acetone-d6)
d 165.7, 137.0, 128.9, 126.6, 125.6, 122.6,
113.9, 98.9, 62.5, 14.8; MS (EI) m/z (rel intensity) 75 (45), 91 (40),
103 (100), 118 (40), 249 (23); HRMS (EI) m/z calcd for C14H19NO3
(Mþ) 249.1365, found 249.1353.
4.4.24. trans-N-(3-Methoxy-propenyl)-benzamide (5f). Synthesized
by method B. Isolated as a colorless oil (86 mg, 60%); crude
product was purified by silica gel column chromatography
(eluting with EtOAc/hexanes/Et3N 50:50:1); IR (KBr pellet)
3334, 2935, 2340, 1724, 1567, 1301, 1207, 1098, 714 cmꢂ1 1H
NMR (300 MHz, CDCl3)
n
;
d
8.26 (d, J¼10.5 Hz, 1H, NH), 7.80 (dd,
J¼7.0, 1.0 Hz, 2H), 7.51 (tt, J¼7.5, 1.0 Hz, 1H), 7.42 (t, J¼7.5 Hz, 2H),
7.20 (dd, J¼14.0, 10.5 Hz, 1H), 5.43 (dt, J¼7.0, 14.0 Hz, 1H), 3.95
(dd, J¼7.0, 1.0 Hz, 2H), 3.31 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
165.1, 133.6, 132.3, 128.9, 127.4, 127.2, 109.2, 71.4, 57.6; MS (EI)
m/z (rel intensity) 105 (100), 106 (6), 160 (22), 178 (2), 214 (4);
HRMS (EI) m/z calcd for C11H13NO2Na (MþþNa) 214.0838, found
214.0840.
4.4.25. 2-Chloro-trans-N-(3-methoxy-propenyl)-acetamide
(5g). Synthesized by method B. Isolated as colorless crystals
(80 mg, 98%): mp¼47–48 ꢀC; crude product was purified by silica
gel column chromatography (eluting with EtOAc/hexanes/Et3N
7. (a) Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J. Org. Chem.
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M. R. J. Org. Chem. 2001, 66, 1532.
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ꢂ78 ꢀC was slowly added tBuLi (6.06 mL, 1.7 M in pentane,
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1 h at room temperature. It was then cooled to ꢂ20 ꢀC and an
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the literature.63
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Acknowledgements
The Natural Science and Engineering Research Council (NSERC)
of Canada funded this work. Y.B. acknowledges receipt of an NSERC
postgraduate scholarship (PGSD3) and the Walter C. Sumner Me-
morial Fellowship for funding. We thank Dr. A.B. Young for mass
spectrometric analysis, Dr. Tim Burrow for NMR assistance, and Mr.
Dan Mathers for the ICP AES study.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.076.

5294
Y. Bolshan, R.A. Batey / Tetrahedron 66 (2010) 5283–5294
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