Direct N-vinylation of aryl and hetaryl carboxamides with trimethoxyvinylsilane

Article abstract of DOI:10.1016/j.tetlet.2008.06.117

A general method for direct N-vinylation of aryl and hetaryl carboxamides with trimethoxyvinylsilane using a copper(II) acetate-TBAF system as catalyst is elaborated. The yield of N-vinyl amides depends strongly on the initial amide and nature of the solvent.

Full text of DOI:10.1016/j.tetlet.2008.06.117

Tetrahedron Letters 49 (2008) 5255–5257
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct N-vinylation of aryl and hetaryl carboxamides
with trimethoxyvinylsilane
*
Pavel Arsenyan , Alla Petrenko, Sergey Belyakov
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for direct N-vinylation of aryl and hetaryl carboxamides with trimethoxyvinylsilane
using a copper(II) acetate–TBAF system as catalyst is elaborated. The yield of N-vinyl amides depends
strongly on the initial amide and nature of the solvent.
Received 20 February 2008
Revised 18 June 2008
Accepted 25 June 2008
Available online 1 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The development of new methods for catalytic C–N bond
formation is highly challenging.1 Notably, copper-promoted
nitrogen–carbon bond cross-coupling reactions of amides with
organometalloids have received a great deal of attention since
initial reports.2 This method is convenient for the preparation of
useful substrates in pharmaceutical chemistry and material
sciences. Recently, Lam reported very impressive results for the
arylation of hetarylcarboxamides with phenyl trimethoxysilane
and tributylphenyltin under mild conditions.3 Lam’s method is
In the first step of our investigation, we performed the vinyla-
tion of 2-picolinamide in DMF at rt in the presence of various fluo-
rine donors such as CsF/18-crown-6, TBAF, ZnF2, CuF2, SmF3, NdF3,
TbF3, NH4BF4 and NH4PF6. According to experimental data, the use
of TBAF led to the formation of N-vinyl-2-picolinamide (11a) in
good yield (64%). Also, under the same reaction conditions, com-
pound 11a was obtained in low yields using ZnF2 or CuF2 (10–14%).
Lam’s group reported that benzamide on reaction with trimeth-
oxyphenylsilane gave only a 9% yield in DMF of N-phenylbenza-
mide even after heating at 70 °C for 2 days.3a Surprisingly,
N-vinylation of benzamide proceeded in DMF at room temperature
to yield 8a (36%) (Scheme 1, Table 1). Due to the inconvenience of
using DMF as a solvent, we ran the same reaction in dichlorometh-
ane and dioxane. It was found that the desired N-vinylbenzamide
(8a) was formed smoothly in 51% yield in CH2Cl2 in 10 h at room
temperature. Notably, the same reaction in dioxane proceeded
much faster at 50 °C (47% yield of 8a). In our opinion, in the viny-
lation reaction, the chelating effect of the nitrogen alpha to the
amide group is not a necessary requisite as has been reported for
the N-arylation reaction of 2-picolinamide with trimethoxy-
phenylsilane.3a
based on the
a-nitrogen activating effect in the copper(II) ace-
tate-promoted N-arylation. Buchwald’s group presented an effi-
cient copper iodide–DMEDA vinylation of amides and imides
using various substituted vinyl bromides and iodides.4 Moreover,
according to the literature, no methods are available for direct
replacement of amide protons by an unsubstituted vinyl group.
N-Vinyl benzamide can be obtained by treating vinyl isocyanate
with phenylmagnesium bromide,5a by thermal decomposition of
N,N0-ethylidene-bis-benzamide at 250 °C5b or 4-methyl-2-phenyl-
4H-oxazol-5-one at 550 °C5c or under reduced pressure. Also,
N-vinyl benzamide was obtained in the reaction of S-phenyl-N-
benzoylthioethanolamine with O-mesitylenesulfonylhydroxyl-
amine by elimination of a thiophenol molecule in the presence of
potassium carbonate.5d
Motivated by the importance of developing direct and facile
methods for the synthesis of N-vinyl amides using commercially
available and inexpensive reagents, we examined the copper-med-
iated vinylation of primary aryl and hetaryl carboxamides with
trimethoxyvinylsilane as the source of a vinyl group. Herein, we re-
port a convenient method for the preparation of N-vinylcarboxa-
mides under mild base-free conditions.
Next, we investigated the influence of substituents on the phe-
nyl ring. Vinylation of 3,4,5-trimethoxybenzamide (2) in DMF led
to the formation of N-vinyl-3,4,5-trimethoxybenzamide (9a, entry
5) in a low 17% yield after 5 h of stirring. Vinylation in CH2Cl2 gave
O
N
O
N
O
R
R
O
+
R
NH2
H
H
1–7
8a–14a
8b–14b
* Corresponding author. Tel.: +371 29849464.
E-mail address: pavel.arsenyan@lycos.com (P. Arsenyan).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.117

5256
P. Arsenyan et al. / Tetrahedron Letters 49 (2008) 5255–5257
Table 1
N-Vinylation of aryl carboxamides 1–7 with trimethoxyvinylsilane
Amide
Entry
Temperature
Solvent
Time (h)
Vinyl amide (%)
(1-Methoxyethyl) amide (%)
O
1
2
3
rt
rt
50
CH2Cl2
DMF
Dioxane
10
5
2
8a, 51
8a, 36
8a, 47
—
—
—
Ph
NH2
1
MeO
4
5
6
7
rt
rt
rt
50
CH2Cl2
DMF
DMAc
Dioxane
2
5
2
2
—
9b, 40
—
9b, 33
9b, 22
O
9a, 17
9a, 15
—
MeO
O2N
NH2
2
MeO
O
8
9
rt
rt
CH2Cl2
DMF
2
2
10a, 45
10a, 34
—
—
NH2
3
O
10
11
12
rt
rt
50
CH2Cl2
DMF
Dioxane
10
10
10
—
—
—
—
11a, 64
—
N
NH2
4
O
13
14
15
rt
rt
50
CH2Cl2
DMF
Dioxane
2
2
2
12a, 60
12a, 44
12a, 41
12b, 21
—
12b, 4
N
NH2
5
O
16
17
rt
rt
CH2Cl2
DMF
2
4
13a, 57
13a, 10
13b, 5
—
N
NH2
6
O
18
19
20
rt
50
50
CH2Cl2
DMF
Dioxane
2
2
5
14a, 7
14a, 30
14a, 47
14b, 35
14b, 3
14b, 25
S
NH2
7
3,4,5-trimethoxy-N-(1-methoxyethyl)-benzamide 9b in 40% yield
(entry 4).6 The initially formed N-vinyl-3,4,5-trimethoxybenza-
mide (9a) reacts with a methanol molecule, which results from
partial trimethoxyvinylsilane polymerization under the reaction
conditions, to yield derivative 9b. The same compound 9b was ob-
served as the sole product during the vinylation in dioxane (entry
7). According to our experimental data, the use of dimethylacet-
amide (DMAc) as solvent leads to the formation of a mixture of
products 9a and 9b (15% and 33%, respectively). No solvent influ-
ence on the reaction of 4-nitrobenzamide (3) was observed, 4-ni-
tro-N-vinyl benzamide (10a) was obtained in good yields as a
single product (entries 8 and 9). It should be noted that electron-
withdrawing substituents on the phenyl ring of benzamide acti-
vate the vinyl group for the subsequent addition of methanol;
however, in the case of a benzamide with an electron-accepting
substituent, the reaction stopped after N-vinylation.
complex with the a-nitrogen of initial compound 4. Similarly, N-vi-
nyl-nicotinamide (12a) was obtained in 44% yield as a single prod-
uct from nicotinamide (5) in DMF in 2 h. Notably, vinylation of 5 in
CH2Cl2 gave the desired vinyl amide 12a in 60% yield as a mixture
with N-(1-methoxyethyl)-nicotinamide 12b (21%). Use of dioxane
as the solvent resulted in a 41% yield of N-vinylpicolinamide 12a
and only 4% of 12b. N-Vinyl-isonicotinamide (13a) was formed in
low yield in DMF (10%); however, a mixture of 13a and N-(1-
methoxyethyl)-isonicotinamide 13b was obtained in CH2Cl2 (57%
and 5% yields, respectively).
Reaction of 2-thiophenecarboxamide (7) with trimethoxyvi-
nylsilane in DMF in the presence of copper(II) acetate and TBAF
led to the formation of N-vinyl-2-thiophenecarboxamide (14a) in
moderate yield (30%), along with traces of N-(1-methoxyethyl)-2-
thiophenecarboxamide (14b) at 50 °C in 2 h (entry 19).6 In dichlo-
romethane, the N-methoxyethyl derivative 14b was the major
product (35% yield), whereas dioxane gave a mixture of both prod-
ucts 14a and 14b (47% and 25% yields, respectively).
Inspection of the reactivity of pyridine carboxamides showed
that picolinamide (4), as mentioned before, undergoes reaction
with trimethoxyvinylsilane in DMF at room temperature to form
the corresponding N-vinyl derivative 11a in 64% yield (entry 11).
Our attempts to run this vinylation in dichloromethane or dioxane
failed, due to possible formation of an insoluble copper(II) acetate
The structures of 14a and 14b were confirmed unambiguously
by X-ray diffraction (Figs. 1 and 2).7 The molecule of 14a is planar
due to the highly conjugated system. In the crystals of 14a there
are intermolecular NHꢀ ꢀ ꢀO hydrogen bonds. The length of the

P. Arsenyan et al. / Tetrahedron Letters 49 (2008) 5255–5257
5257
Acknowledgement
Financial support of this work by the Latvian Council of Science
(Grant No. 05.1757) is gratefully acknowledged.
References and notes
1. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5446.
2. (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K.; Chan, D. M. T.;
Combs, A. P. Synlett 2000, 674–676; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39,
2941–2944; (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940; (d) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936.
3. (a) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42,
2427–2429; (b) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett.
2002, 43, 3091–3094.
4. Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667–3669.
5. (a) Schulz, R. C.; Hartmann, H. Monatsh. Chem. 1961, 92, 303–309; (b) Ben-Ishai,
D.; Giger, R. Tetrahedron Lett. 1965, 4523–4526; (c) Jendrzejewski, S.; Steglich,
W. Chem. Ber. 1981, 114, 1337–1342; (d) Matsuo, J.-I.; Kozai, T.; Ishibashi, H. Org.
Lett. 2006, 8, 6095–6098.
Figure 1. ORTEP molecular structure of thiophene-2-carboxylic acid vinyl amide
(14a).
6. General
procedure: To
a
mixture of arylcarboxamide (1.0 mmol),
trimethoxyvinylsilane (2.0 mmol), and copper(II) acetate (1.0 mmol) in 10 mL
of the corresponding solvent, 1 M TBAF solution in dioxane (2 mmol) was added.
The reaction mixture was stirred and monitored by TLC until complete
disappearance of the starting compound. The pure product was isolated by
column chromatography on silica gel using chloroform/ethanol mixture 15:1 or
10:1 as eluent. The structures of all the products were confirmed by 1H
(400 MHz, CDCl3) and 13C (100.6 MHz, CDCl3) NMR data. (a) N-vinyl-3,4,5-
trimethoxybenzamide (9a) 1H NMR: 3.86 (6H, s), 3.87 (3H, s), 4.51 (1H, d,
J = 8.7 Hz), 4.79 (1H, dd, J = 0.6 Hz, J = 15.9 Hz), 7.03 (2H, s), 7.11–7.20 (1H, m),
8.06 (1H, br d, J = 9.8 Hz). 13C NMR: 56.3, 60.9, 96.2, 104.6, 128.8, 129.1, 141.3,
153.2, 164.5. Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C,
60.69; H, 6.38; N, 5.86. (b) 3,4,5-Trimethoxy-N-(1-methoxyethyl)-benzamide
(9b) 1H NMR: 1.43 (3H, d, J = 6.0 Hz), 3.39 (3H, s), 3.87 (6H, s), 3.89 (3H, s), 5.44–
5.52 (1H, m), 6.36 (1H, br d, J = 9.6 Hz) 7.02 (2H, s). 13C NMR: 21.7, 55.9, 56.3,
60.9, 78.4, 104.4, 129.2, 141.2, 153.2, 166.8. Anal. Calcd for C13H19NO5: C, 57.98;
H, 7.11; N, 5.20. Found: C, 58.02; H, 7.16; N, 5.22. (c) N-Vinyl-2-
thiophenecarboxamide (14a) 1H NMR: 4.49 (1H, d, J = 8.4 Hz), 4.77 (1H, dd,
J = 0.7 Hz, J = 15.8 Hz), 7.21 (1H, dd, J = 1.2 Hz, J = 4.8 Hz), 7.56 (1H, dd, J = 4.0 Hz,
J = 4.8 Hz), 7.63 (1H, dd, J = 1.2 Hz, J = 4.0 Hz). 13C NMR: 96.2, 127.8, 127.8, 128.7,
128.8, 129.4, 159.2. Anal. Calcd for C7H7NOS: C, 54.88; H, 4.61; N, 9.14; S, 20.93.
Found: C, 54.87; H, 4.64; N, 9.11; S, 20.88. (d) N-(1-Methoxyethyl)-2-
thiophenecarboxamide (14b) 1H NMR: 1.42 (3H, d, J = 5.8 Hz), 3.37 (3H, s),
5.41–5.48 (1H, m), 6.37 (1H, br d, J = 8.4 Hz), 7.08 (1H, dd, J = 3.6 Hz, J = 4.9 Hz),
7.51 (1H, dd, J = 1.1 Hz, J = 4.9 Hz), 7.54 (1H, dd, J = 1.1 Hz, J = 3.6 Hz). 13C NMR:
21.7, 55.9, 78.3, 127.7, 128.3, 130.6, 138.5, 161.6. Anal. Calcd for C8H11NO2S: C,
51.87; H, 5.99; N, 7.56; S, 17.31. Found: C, 51.87; H, 6.02; N, 7.58; S, 17.25.
Figure 2. ORTEP molecular structure of thiophene-2-carboxylic acid (1-methoxy-
ethyl)amide (14b).
7. For compounds 14a and 14b diffraction data were collected on
KappaCCD diffractometer using graphite monochromated Mo K
a
Nonius
a
radiation
(k = 0.71073 Å). The crystal structures of 14a and 14b were solved by direct
methods8a,b and refined by full-matrix least squares.8c,d All non-hydrogen atoms
were refined anisotropically. Crystal data for 14a: C7H7NOS, orthorhombic,
a = 9.9242(3), b = 12.1227(5), c = 12.7055(6) Å; V = 1528.6(1) Å3, Z = 8,
hydrogen bonds is 2.926(3) Å (Hꢀ ꢀ ꢀO = 2.13 Å, N–Hꢀ ꢀ ꢀO = 163.4°).
These hydrogen bonds result in chains being formed in the crystal
structure along the crystallographic axis x. In the molecules of 14b,
the –CO–NH– group and the C9 carbon atom are in the plane of the
thiophene ring. The C10, C9, O11 and C12 atoms lie in the other
plane, which is almost perpendicular to the thiophene ring. In
the crystals, the intermolecular NHꢀ ꢀ ꢀO type hydrogen bonds form
chains along the crystallographic axis y. The length of these hydro-
gen bonds is 2.996(7) Å (Hꢀ ꢀ ꢀO = 2.02 Å, N–Hꢀ ꢀ ꢀO = 170.0°).
In summary, very simple reaction conditions [Cu(OAc)2, (MeO)3-
SiCH@CH2, TBAF, solvent] have been developed for the direct viny-
lation of aryl and hetaryl carboxamides. It should be noted that the
formation of N,N-divinyl carboxamides was not observed. It was
shown that the yields of the N-vinyl amides depend strongly on
the structure of the initial amide and solvent nature. Our future ef-
forts will focus on the application of this method to yield various
substituted N-vinyl amides, and the results will be reported in
due course.
l
= 0.35 mmꢁ1
,
Dcalc = 1.331 g cmꢁ3
;
space group is Pbca.
independent reflection intensities (2hmax = 60°) were collected at room
temperature. For structure refinement, 1178 reflections with I P 3 (I) were
used. The final R-factor is 0.058. Crystal data for 14b: C8H11NO2S, orthorhombic,
a = 8.3672(5), b = 9.5519(9), c = 11.8170(6) Å; Z = 4,
V = 944.5(1) Å3,
= 0.30 mmꢁ1 Dcalc = 1.303 g cmꢁ3
space group is Pc21a. total of 1144
independent reflection intensities (2hmax = 55°) were collected at room
temperature. For structure refinement, 762 reflections with I P 2 (I) were
A total of 2219
r
l
,
;
A
r
used. The final R-factor is 0.068. For further details, see crystallographic data for
14a and 14b deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Numbers CCDC 676987 and 676988.
8. (a) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.;
Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr.
1999, 32, 115–119; (b) Mishnev, A. F.; Belyakov, S. V. Krystallografia 1988, 33,
835; (c) Maskay, S.; Gilmore, C. J.; Edwards, C.; Stewart, N.; Shankland, K. MAXUS
.
Computer Program for the Solution and Refinement of Crystal Structures. Bruker
Nonius, The Netherlands; MacScience, Japan; The University of Glasgow, 1999.;
(d) Sheldrick, G. M. SHELXL97, Program for Crystal Structure Solution, University
of Göttingen, Germany, 2000.