Palladium-catalyzed stereoselective synthesis of (E)-β,γ -unsaturated amides

Article abstract of DOI:10.1016/j.tetlet.2003.08.011

A facile Suzuki type cross-coupling reaction of alkenylborane with 2-bromo-N,N-dimethylacetamide in the presence of a catalytic amount of tricyclohexylphosphine as the ligand has been demonstrated to be a convenient way for the synthesis of (E)-β,γ-unsaturated amides.

Full text of DOI:10.1016/j.tetlet.2003.08.011

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7249–7251
Palladium-catalyzed stereoselective synthesis of
(E)-b,g-unsaturated amides
Fen-Tair Luo,a,* Ting-Yi Lub and Cuihua Xuea
aInstitute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529
bDepartment of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, Taiwan 621
Received 30 June 2003; revised 2 August 2003; accepted 6 August 2003
Abstract—A facile Suzuki type cross-coupling reaction of alkenylborane with 2-bromo-N,N-dimethylacetamide in the presence of
a catalytic amount of tricyclohexylphosphine as the ligand has been demonstrated to be a convenient way for the synthesis of
(E)-b,g-unsaturated amides.
© 2003 Elsevier Ltd. All rights reserved.
b,g-Unsaturated amides are synthetically important key
intermediates;1 yet their synthesis is a tedious task.
Nonetheless, a few methods for their preparation have
been hitherto described. For example, the preparation
of b,g-unsaturated amides have involved palladium-cat-
alyzed carbonylation of allylamines,2 rhodium-cata-
a mixture of Pd(dba)2 (0.3 mmol), PCy3 (0.6 mmol),
K3PO4 (34 mmol) in 10 mL of dry THF was added
2-bromo-N,N-dimethylacetamide9 (10 mmol) at 70°C.
After stirring for 20 min, the alkenylborane prepared in
situ in THF10 was added and the mixture was stirred
for another 16 h at 70°C. The mixture was quenched
with water, extracted with EtOAc, and purified by
column chromatography (hexane/EtOAc=3/1). The
(E)-configuration stereochemistry of target molecules
lyzed
azacarbonylation
of
allyl
phosphates,3
ruthenium-catalyzed carbonylation of allylic alkyl car-
bonates,4 conversion from allyl alcohol by the use of
N,N-dimethylformamide acetals,5 and cross-coupling
reaction of alkenylborane with N,N-dialkyl(dimethyl-
sulfuranylidene)acetamide.6 In addition, Deng has
reported6 that (E)-b,g-unsaturated amides could not be
obtained from (E)-9-alkenyl-9-borabicyclo[3,3,1]nonane
and a-bromoacetamide by Brown’s procedure.7 We
have recently reported that the Suzuki type cross-cou-
pling reaction of aryldioxaborolane and 2-bromo-N,N-
dimethylacetamide could provide a convenient and
simple way to the synthesis of a-arylacetamide in mod-
erate to good yields.8 Interestingly, we discovered that
our Suzuki type cross-coupling conditions could be
simply employed to the cross-coupling of alkenylbo-
ranes with 2-bromo-N,N-dimethylacetamide. Herein,
we wish to report the results of preparing highly
1
were determined by means of either H NMR or 2D
NOESY spectral analysis.
The palladium-catalyzed cross-coupling reactions of
various alkenylborane with 2-bromo-N,N-dimethylac-
etamide were studied and the results are summarized in
Table 1. Alkenylborane obtained from hydroboration
by using dicyclohexylborane is expected to give satisfied
yields and no difficulty to isolate the desired products
in the above Suzuki type cross-coupling reaction. How-
ever, the use of alkenylborane obtained from the com-
mercial 9-BBN in THF gave the desired products in
moderate yields, but it was found difficult to remove
other unidentified by-products. On the other hand, the
stereoselectivity of the carbonꢀcarbon double bond
could reach to 30:1 for (E)/(Z) by using 9-BBN and to
25:1 for (E)/(Z) by using dicyclohexylborane. 1-Alkyne
with or without methoxyl group at propargyl position
could give good results (entries 1, 2 and 3). The two
vinylic protons of the b,g-unsaturated products from
1-alkyne are accidentally equivalent in 400 MHz NMR
spectrum. For comparison, we have run the 2D
NOESY of the mixture of (E)- and (Z)-N,N-
dimethyldec-3-enamide11 and that of pure (E)-isomer.
The (Z)-isomer does have cross peaks between the two
stereoselective
a-alkenylacetamide
from
the
stereodefined alkenylboranes, which can be easily
obtained via hydroboration of terminal or internal
acetylenes. Following is a representative procedure: To
Keywords: Suzuki coupling reactions; alkenylborane; 2-bromo-N,N-
dimethylacetamide.
* Corresponding author: Tel.: +886-2-27898576; fax: +886-2-
27888199; e-mail: luoft@chem.sinica.edu.tw
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.011

7250
F.-T. Luo et al. / Tetrahedron Letters 44 (2003) 7249–7251
allylic protons at C-5 position (2.02 ppm) and the two
protons at C-2 position (3.10 ppm), while there is no
such corresponding cross peaks [the two allylic protons
at C-5 position (2.02 ppm) and the two protons at C-2
position (3.08 ppm)] for the (E)-isomer. As such, the
stereochemistry of the (E)-isomer was confirmed. The
method could also be employed to the synthesis of
g-aryl-substituted b,g-unsaturated acetamides with or
without electron-donating substituents on the aryl
groups (entries 4–11). Thus, the highly stereoselective
(E)-alkenylborane generated from the hydroboration of
terminal acetylenes with dicyclohexylborane gave
stereoselective (E)-b,g-unsaturated amides in moderate
to good yields. The internal (Z)-styrylborane prepared
from the hydroboration of 1,2-diphenylacetylene with
dicyclohexylborane also underwent the Suzuki type
cross-coupling reaction to give the desired product in
about 54% yield (Eq. (1)). The plausible reaction mech-
anism could be similar to the one we have already
described.8 Thus, dibenzylideneacetone ligand was
replaced initially by tricyclohexylphosphine to the pal-
ladium(0) catalyst, after oxidative addition with 2-
bromo-N,N-dimethylacetamide to form bromo-
palladium enolate complex, the palladium complex was
activated in the presence of a base. Another equivalent
of base activated the alkenylborane to form a borate
complex, which will undergo transmetallation with the
activated palladium species to form alkenylpalladium
enolate complex and a stablilized borate complex.
Reductive elimination of the alkenylpalladium enolate
complex afforded the cross-coupling product and
regenerate Pd(0) catalyst.
(1)
Table 1. Synthesis of (E)-b,g-unsaturated amides from terminal acetylenes

F.-T. Luo et al. / Tetrahedron Letters 44 (2003) 7249–7251
7251
Since the highly stereoselective (E)-alkenylboranes are
easily available, this method is useful for the synthesis
of (E)-N,N-dimethyl-b,g-unsaturatedacetamides.
(Z)-N,N-Dimethyl-3-decenamide: 1H NMR (CDCl3,
TMS) l 0.88 (t, J=7.1 Hz, 3H), 1.20–1.37 (m, 8H), 2.02
(m, 2H), 2.98 (s, 6H), 3.10 (d, J=4.1 Hz, 2H), 5.52–5.55
(m, 2H) ppm.
(E)-N,N-Dimethyl-4-phenyl-3-butenamide: 1H NMR
(CDCl3, TMS) l 2.98 (s, 3H), 3.07 (s, 3H), 3.31 (d, J=6.5
Hz, 2H), 6.36 (dt, J=16.0, 6.5 Hz, 1H), 6.47 (d, J=16.0
Hz, 1H), 7.20–7.39 (m, 5H); 13C NMR (CDCl3, TMS) l
35.50, 37.44, 38.06, 123.17, 126.19, 127.35, 128.46, 132.59,
136.98, 170.93 ppm.
Acknowledgements
The authors thank the National Science Council and
Academia Sinica of ROC for financial supports.
(E)-N,N-Dimethyl-4-naphthalen-1-yl-3-butenamide: 1H
NMR (CDCl3, TMS) l 3.00 (s, 3H), 3.12 (s, 3H), 3.42 (d,
J=6.8 Hz, 2H), 6.38 (dt, J=15.7, 6.8 Hz, 1H), 7.21 (d,
J=15.7 Hz, 1H), 7.41–8.11 (m, 7H) ppm; 13C NMR
(CDCl3, TMS) l 35.57, 37.51, 38.44, 123.79, 123.99,
125.63, 125.67, 125.94, 126.41, 127.78, 128.49, 129.95,
131.07, 133.60, 134.79, 170.97 ppm.
References
1. Murahashi, S.-I.; Imada, Y.; Nishimura, K. J. Chem.
Soc., Chem. Commun. 1988, 1578.
2. Murahashi, S.-I.; Imada, Y.; Nishimura, K. Tetrahedron
1994, 50, 453.
3. Imada, Y.; Shibata, O.; Murahashi, S.-I. J. Organomet.
Chem. 1993, 451, 183.
4. Mitsudo, T.-A.; Suzuki, N.; Kondo, T.; Watanabe, Y. J.
Org. Chem. 1994, 59, 7759.
5. Bu¨chi, G.; Cushman, M.; Wu¨est, H. J. Am. Chem. Soc.
1974, 96, 5563.
(E)-N,N-Dimethyl-4-thiophen-2-yl-3-butenamide:
1H
NMR (CDCl3, TMS) l 2.97 (s, 3H), 3.05 (s, 3H), 3.26 (d,
J=6.8 Hz, 2H), 6.18 (dt, J=15.8, 6.8 Hz, 1H), 6.59 (d,
J=15.8 Hz, 1H), 6.91–7.13 (m, 3H) ppm; 13C NMR
(CDCl3, TMS) l 35.54, 37.48, 37.82, 122.79, 123.94,
125.10, 125.80, 127.19, 142.06, 170.68 ppm.
6. Deng, M.-Z.; Li, N.-S.; Huang, Y.-Z. J. Chem. Soc.,
(E)-N,N-Dimethyl-5-methoxy-3-pentenamide: 1H NMR
(CDCl3, TMS) l 2.95 (s, 3H), 3.02 (s, 3H), 3.15 (d, J=6.6
Hz, 2H), 3.33 (s, 3H), 3.91 (d, J=6.0 Hz, 2H), 5.65 (dt,
J=15.6, 6.0 Hz, 2H), 5.88 (dt, J=15.6, 6.6 Hz, 2H) ppm;
13C NMR (CDCl3, TMS) l 35.45, 37.31, 37.38, 72.77,
126.97, 129.50, 170.85 ppm.
Chem. Commun. 1993, 65.
7. Brown, H. C.; Cho, B. T.; Park, W. S. J. Org. Chem.
1986, 51, 3398.
8. Lu, T.-Y.; Xue, C.; Luo, F.-T. Tetrahedron Lett. 2003,
44, 1587.
9. (a) Hand, E. S.; Johnson, S. C.; Baker, D. C. J. Org.
Chem. 1997, 62, 1348; (b) Bartlett, P. A.; Carruthers, N.
I.; Winter, B. M.; Long, K. P. J. Org. Chem. 1982, 47,
1284.
10. To a 100 mL round-bottomed flask with a rubber sep-
tum, from which was removed moisture and air under
low pressure first and then flushed with dry nitrogen, was
sequentially and slowly added 20 mL of dry THF,
Me2S·BH3 (10 mmol) and cyclohexene (20 mmol) at 0°C.
The reaction mixture was stirred for another 3 h at 0°C.
Terminal acetylene (10 mmol) was then slowly added to
the above white reaction mixture at 0°C. The reaction
mixture was stirred for another 3 h at rt until it became
clear.
11. NMR spectral data of selected products:
(E)-N,N-Dimethyl-3-decenamide: 1H NMR (CDCl3,
TMS) l 0.88 (t, J=7.1 Hz, 3H), 1.20–1.37 (m, 8H), 2.02
(m, 2H), 2.98 (s, 6H), 3.08 (d, J=4.1 Hz, 2H), 5.52–5.55
(m, 2H) ppm, 13C NMR (CDCl3, TMS) l 14.07, 22.60,
28.84, 29.24, 31.70, 32.55, 35.45, 37.41, 37.91, 122.62,
134.04, 171.62 ppm.
(E)-N,N-Dimethyl-3-dodecenamide: 1H NMR (CDCl3,
TMS) l 0.88 (t, J=7.0 Hz, 3H), 1.26–1.38 (m, 12H), 2.02
(m, 2H), 2.94 (s, 3H), 3.01 (s, 3H), 3.07 (d, J=4.7 Hz,
2H), 5.52–5.54 (m, 2H) ppm; 13C NMR (CDCl3, TMS) l
14.05, 22.64, 29.17, 29.25, 29.27, 29.43, 31.86, 32.53,
35.44, 37.39, 37.89, 122.60, 134.04, 171.63 ppm.
1
(E)-N,N-Dimethyl-4-(4-methoxyphenyl)-3-butenamide: H
NMR (CDCl3, TMS) l 2.97 (s, 3H), 3.05 (s, 3H), 3.27 (d,
J=6.8 Hz, 2H), 3.79 (s, 3H), 6.19 (dt, J=15.9, 6.8 Hz,
1H), 6.41 (d, J=15.9 Hz, 1H), 6.83 (d, J=6.7 Hz, 2H),
7.29 (d, J=6.7 Hz, 2H) ppm; 13C NMR (CDCl3, TMS) l
35.51, 37.45, 38.07, 55.26, 113.94, 120.92, 127.35, 129.92,
132.05, 159.09, 171.17 ppm.
(E) - N,N - Dimethyl - 4 - (4 - methylsulfanylphenyl) - 3 - bute-
1
namide: H NMR (CDCl3, TMS) l 2.47 (s, 3H), 2.97 (s,
3H), 3.05 (s, 3H), 3.28 (d, J=6.4 Hz, 2H), 6.30 (dt,
J=16.0, 6.4 Hz, 1H), 6.41 (d, J=16.0 Hz, 1H), 7.18 (d,
J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H) ppm; 13C NMR
(CDCl3, TMS) l 15.86, 35.48, 37.41, 37.94, 122.66,
126.59, 126.68, 131.94, 134.06, 137.42, 170.90 ppm.