Copper-catalyzed coupling of 1,2-dibromo-1-styrenes with sulfonamides for the preparation of ynamides

Article abstract of DOI:10.1016/j.tetlet.2012.09.092

Ynamides were prepared through an efficient copper-catalyzed coupling reaction. In the presence of copper iodide, 1,10-phenanthroline, and Cs ₂CO₃, the coupling reaction of 1,2-dibromo-1-styrenes with sulfonamides proceeded smoothly

Full text of DOI:10.1016/j.tetlet.2012.09.092

Tetrahedron Letters 53 (2012) 6557–6560
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed coupling of 1,2-dibromo-1-styrenes with sulfonamides
for the preparation of ynamides
⇑
Yuan Yang, Xiaoyun Zhang, Yun Liang
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of Resource Fine-Processing and Advanced Materials of
Hunan Province, Hunan Normal University, Changsha, Hunan 410081, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2012
Revised 18 September 2012
Accepted 21 September 2012
Available online 28 September 2012
Ynamides were prepared through an efficient copper-catalyzed coupling reaction. In the presence of cop-
per iodide, 1,10-phenanthroline, and Cs2CO3, the coupling reaction of 1,2-dibromo-1-styrenes with sul-
fonamides proceeded smoothly and generated the corresponding products with excellent isolated yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ynamide
1,2-Dibromo-1-alkene
Sulfonamide
Copper
As a result of excellent reactivity of ynamide in the aspect of
addition reactions, cycloadditions, cycloisomerization reactions,
metal-catalyzed cross-coupling reaction, reduction reaction, oxida-
tion reaction etc., ynamides have become useful synthons in organ-
ic synthesis.1,2 These useful transformations could be utilized to
synthesize a variety of nitrogen-containing molecules. Thus, many
useful methods have been developed.3–11 Traditional approaches
are focused on (1) the isomerization of propargyl amide,4 (2) the
elimination of halo-substituted enamides,5 (3) the coupling reac-
tion of alkynyliodonium salts with lithiated amine.6 Due to the re-
quired harsh reaction conditions and poor substrate scope, the
synthetic application of these approaches often lack generality.
At present, the copper-catalyzed coupling of alkynyl bromides with
amides to synthesize ynamides is the most widely applied meth-
od.7 However, this method is also limited to a certain extent be-
cause of instability of alkynyl bromides. In order to overcome
these limitations (such as harsh reaction conditions, poor substrate
scope, and difficulty of preparation of the starting substrate), some
new synthetic methods of ynamides are developed. For example,
Stahl and co-workers developed a copper-catalyzed method for
aerobic oxidative coupling of terminal alkynes with a variety of
nitrogen nucleophiles.8 Jiao and Jia reported a novel Cu-catalyzed
aerobic oxidative amidation of propiolic acids to synthesize yna-
mides via decarboxylation under air.9 Evano and co-workers used
potassium alkynyltrifluoroborates10a and alkynylcopper10b as
alkynylation reagents to prepare ynamides. Besides, Evano and
co-workers reported a more general copper-mediated synthesis
of ynamide derivatives starting from readily available 1,1-dibro-
mo-1-alkenes.11 Similar to the 1,1-dibromo-1-alkenes, 1,2-dibro-
mo-1-alkenes are possible alkynylation reagents too. Ranu et al.
reported a facile synthesis of (E)-2-alkene-4-ynoate system by
the coupling of 1,2-diiodo-1-alkenes with acrylic ester.12 Banerjee
et al. also reported a similar result.13 Our group developed an
approach for the highly selective synthesis of unsymmetrical
buta-1,3-diynes using 1,2-diiodo-1-alkenes as starting substrate.14
In this reaction, dehydroiodination of the starting 1,2-diiodo-1-
alkenes would generate alkynyl iodines as intermediate and
subsequent coupling with acrylic ester or terminal alkyne to form
corresponding alkynylation products. Thus, we envisioned that
1,2-dibromo-1-alkenes would be an efficient precursor of alkynyl
bromides which could be used to synthesize ynamides by coupling
with amides (Scheme 1). In addition, 1,2-dibromo-1-alkenes are
more inexpensive and more stable than the common alkynylation
reagent of alkynyl bromides.15 Herein, we reported the first
example of the preparation of ynamides from readily available
1,2-dibromo-1-alkenes.
Initially, the coupling reaction of (1,2-dibromovinyl)benzene
(1a) with N-benzyl-tosylamine was selected for optimization of
reaction conditions, and the results are summarized in Table 1.
Our investigation started by an attempted amination of substrate
1a with 2a in THF at 80 °C in the presence of CuI as catalyst, and
the desired product 3a could be isolated in 35% yields (entry 1).
This result encouraged us to develop an efficient catalytic sys-
tem to synthesize ynamides using (1,2-dibromovinyl)benzene as
a starting substrate. A variety of N,N-bidentate ligands, such as
1,10-phenanthroline (1,10-phen), N,N0-dimethylethanediamine
⇑
Corresponding author. Tel.: +86 10 8887 2576; fax: +86 10 8887 2531.
E-mail address: liangyun1972@126.com (Y. Liang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.092

6558
Y. Yang et al. / Tetrahedron Letters 53 (2012) 6557–6560
(DMEDA), cyclohexane-1,2-diamine, 2,20-bipyridine, and N,N,N0,N0-
R2
R1
Evano's work
Br
tetramethylethylenediamine (TMEDA) were screened. Results indi-
cated that the ligand (1,10-phen) is the best for this coupling reac-
tion (entries 2–6). Subsequently, the effects of base (including
Cs2CO3, NaOt-Bu, K2CO3, and K3PO4) (entries 7–9) and solvent
(including THF, toluene, dioxane, and DMF) (entries 10–12) were
examined. Cs2CO3 was found to give the best result and THF was
found to be the best solvent for the reaction. Finally, the amount
of catalyst and the reaction temperature were evaluated. Relatively
low yields were found when the reaction was carried out in 60 or
100 °C (entries 13 and 14), and the yield of 3a was the highest
when using 10 mol % loading of CuI and 20 mol % of 1,10-phen (en-
try 15). Thus, the optimized reaction conditions were as follows: 1a
(0.39 mmol), 2a (0.3 mmol), CuI (10 mol %), 1,10-phen (20 mol %),
Cs2CO3 (1.2 mmol), in THF (2 mL) at 80 °C.
HN
Br
R2
R1
Cu
Br
Cu
R
N
R
Br
R
This work
Br
R2
R1
HN
Base
R2
R1
R
R
N
R
Br
Cu
Scheme 1. Synthesis of ynamides by copper-catalyzed coupling of 1,1-dibromo-1-
alkenes or 1,2-dibromo-1-alkenes with nitrogen nucleophiles.
Table 1
Optimization of reaction conditionsa
With the standard reaction conditions in hand, the coupling
reaction of 1,2-dibromo-1-styrenes with various nitrogen nucleo-
philes were investigated, and the results are summarized in Table 2.
First, we found arylsulfonamides were better nitrogen nucleophiles
than carbamates in the coupling reaction with 1,2-dibromovi-
nyl)benzene (3a–e). Then, we examined the scope of the coupling
reaction of (1,2-dibromovinyl)benzene with various tosylamines.
As expected, N-benzyl substituted tosylamine bearing electron-
withdrawing groups such as F or Cl (3f,3g) or electron-donating
group such as OMe (3h,3i) afforded the corresponding ynamides
in perfect yields. Interestingly, N-(2-bromobenzyl)-4-methylben-
zenesulfonamide could selectively react with (1,2-dibromovinyl)
benzene to gain 3j in 87% yield and no competitive amination or
reduction was observed. In addition, 2-furfuryl and phenemyl
substituted tosylamines both work well and afforded the corre-
sponding ynamides (3l,3m) in 90% yield. Under the standard reac-
tion conditions, N-alkyl substituted N-(phenylethynyl) tosylamine
including cycloalkyl (3n) and linear-chain (3o–q) groups could all
be obtained in high yields. However, N-aryl substituted tosylam-
ines were not suitable substrates for such reaction to form
ynamide under the reaction conditions. In this case, tosylamines
remained. Meanwhile, the scope and reactivity of 1,2-dibromo-
1-styrenes were also examined under the optimized conditions.
The benzene ring of 1,2-dibromo-1-styrene bearing either elec-
tron-withdrawing groups such as F (1b) or electron-donating
groups such as Me (1c) or OMe (1d) gave the corresponding
ynamides in high to perfect isolated yields. Unfortunately, aliphatic
1,2-dibromo-1-decene and 1,2-dibromo-1-hexene only afforded
corresponding 29% of 3u and 25% of 3v.
Ts
Bn
Ts
Bn
Br
CuI, Ligand
Ph
N
HN
+
Base, Solvent
80 oC, 24 h
Ph
Br
3a
1a
2a
Entry
Ligand
Base
Solvent
Yield of 3ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
14d
15e
16f
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOt-Bu
K2CO3
THF
THF
THF
THF
THF
THF
THF
THF
35
96
93
81
23
20
90
40
43
82
86
71
84
88
99
84
1,10-Phen
DMEDA
Cyclohexane-1,2-diamine
2,20-Bipyridine
TMEDA
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
K3PO4
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
Dioxane
DMF
THF
THF
THF
1,10-Phen
1,10-Phen
THF
a
Reaction conditions: 1a (0.39 mmol), 2a (0.3 mmol), CuI (20 mol %), ligand
(40 mol %), base (1.2 mmol), solvent (2 mL), 80 °C, under N2 atmosphere for 24 h.
b
Isolated yields.
100 °C.
60 °C.
c
d
e
CuI (10 mol %), ligand (20 mol %).
CuI (5 mol %), ligand (10 mol %).
f
Table 2
Copper-catalyzed coupling of 1,2-dibromo-1-styrenes with nitrogen nucleophilesa,b
CuI (10 mol%)
R1
R2
R1
R2
Br
1,10-phen (20 mol%)
HN
Ph
N
+
R
1
Br
Cs2CO3 (4 equiv)
THF, 80 oC, 24 h
2
3
F
O
S
O
O
N
Ph
Ph
N
S
O
Ph
Ph
(3b, 99%)
(3c, 94%)
O
N
Boc
N
OBn
(3e, 40%)
(3d, 65%)c

Y. Yang et al. / Tetrahedron Letters 53 (2012) 6557–6560
6559
Ts
Ts
Ts
Ts
Ph
Ph
N
Ph
N
Cl
F
(3g, 96%)
(3f, 93%)
N
Ph
N
OMe
OMe
(3i, 99%)d
(3h, 88%)
OMe
Ts
Ts
N
Ph
N
Ph
(3k, 55%)c
(3j, 87%)d
Br
Ts
Ts
Ph
N
O
Ph
N
(3l, 90%)
(3m, 90%)
Ts
Ts
Ts
Ph
N
Ph
N
Ph
F
N
C8H17
C5H11
(3p, 85%)
(3n, 98%)
(3o, 92%)
Ts
Ts
Ph
N
N
C3H7
Bn
(3q, 87%)
(3r, 99%)
Ts
Bn
Ts
Me
N
MeO
C4H9
N
Bn
(3t, 90%)e
(3s, 81%)e
Ts
Ts
N
C8H17
N
Bn
Bn
(3u, 25%)
(3v, 29%)
a
Reaction conditions: 1 (0.39 mmol), 2 (0.3 mmol), CuI (10 mol %), 1,10-phenanthroline (20 mol %), Cs2CO3 (1.2 mmol), THF
(2 mL), 80 °C, under N2 atmosphere for 24 h.
b
Isolated yields.
35 h.
27 h.
28 h.
c
d
e
Importantly, a selective amidative cross-coupling of ortho-
bromo-2-(1,2-dibromovinyl)benzene could be readily established
as shown in Scheme 2. By employing 10 mol % of CuI and
20 mol % of 1,10-phenanthroline, ynamide 3w was attained in
65% yields. Then, the tandem amination-5-endo-dig cyclization of
as-prepared o-bromoaryl-substituted ynamide 3w was tested,
which is particularly useful in the synthesis of 2-sulfonamido-
indoles.16 One example is the tandem cyclization catalyzed by
2.5 mol % Pd2dba3 and 5 mol % X-phos to form 2-sulfonamido-
indole 4 in a good yield of 85% (Scheme 2). Reactions of this type
could have been used in the synthesis of 2-sulfonamido-indoles
with unique structures.
Two experiments were carried out to investigate the reaction
mechanism. (1) Phenylethynyl bromide was probed from crude
reaction mixtures of the coupling reaction of (1,2-dibromovinyl)
benzene (1a) with N-benzyl-tosylamine (2a) by using GC–MS anal-
ysis; (2) in the absence of amide 2, phenylethynyl bromide was
also obviously detected by using GC–MS analysis. Based on the
present experimental results and the previous reported mecha-
nism,3–17 a proposed catalytic cycle for the formation of ynamides
3 from 1 and 2 is given in Scheme 3. First, dehydrobromination of
the starting 1,2-dibromo-1-alkenes would generate intermediate
alkynyl bromides.12–14 Next, oxidative addition of 5 to the alkynyl
bromides presumably generates a copper(III) intermediate 6. Final-
ly, reductive elimination of 6 would furnish the desired ynamide
and regenerate the active Cu(I) species for the catalytic cycle (Path
I).17 According to Evano’s work,11 another mechanism involving
the formation of b-bromoenamide by amination of the starting
1,2-dibromo-1-alkenes and its subsequent dehydrobromination
to form ynamides could also account for the formation of ynamides
from 1,2-dibromo-1-alkenes. Since all attempts to evidence the
Br
CuI (10 mol%)
Ts
R
Ts
R
1,10-phen (20 mol%)
Br
Br
HN
N
+
Cs2CO3 (4 equiv)
THF, 80 oC, 26 h
Br
3w-z
1e
Ts
Ts
Ts
N
N
O
Br
Br
(3w, 65%)
Ts
(3x, 48%)
N
N
C8H17
Br
Br
(3z, 55%)
(3y, 53%)
Ts
NH2
N
Pd2dba3 (2.5 mol%)
X-phos (5 mol%)
Ts
N
Bn
N
Bn
+
Cs2CO3 (3 equiv)
Toluene, 110 oC, 11 h
Br
3w
4 (85%)
Scheme 2. Synthesis of 2-sulfonamido-indole 4.

6560
Y. Yang et al. / Tetrahedron Letters 53 (2012) 6557–6560
H
N
2
References and notes
+ Cs2CO3
L2CuI
R1
R2
1. For reviews, see: (a) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010,
Br
Br
R
Cs2CO3
HBr
49, 2840; (b) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.;
Hsung, R. P. Chem. Rev. 2010, 110, 5064; (c) Zificsak, C. A.; Mulder, J. A.; Hsung,
R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
R
Br
R
Br
Br
1
1
2. For selected recent references on the application of ynamides: (a) Smith, D. L.;
Goundryb, W. R. F.; Lam, H. W. Chem. Commun. 2012, 48, 1505; (b) Compain, G.;
Jouvin, K.; Martin-Mingot, A.; Evano, G.; Marrot, J.; Thibaudeau, S. Chem.
Commun. 2012, 48, 5196; (c) Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Angew. Chem.,
Int. Ed. 2012, 51, 113; (d) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011,
50, 3072; (e) Kramer, S.; Odabachian, Y.; Overgaard, J.; Rottländer, M.; Gagosz,
F.; Skrydstrup, T. Angew. Chem., Int. Ed. 2011, 50, 5090; (f) DeKorver, K. A.;
Wang, X.-N.; Walton, M. C.; Hsung, R. P. Org. Lett. 2012, 14, 1768; (g)
Greenaway, R. L.; Campbell, C. D.; Holton, O. T.; Russell, C. A.; Anderson, E. A.
Chem. Eur. J. 2011, 17, 14366; (h) Saito, N.; Saito, K.; Shiro, M.; Sato, Y. Org. Lett.
2011, 13, 2718; (i) Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2007, 9, 3245;
(j) Davies, P. W.; Cremonesi, A.; Martin, N. Chem. Commun. 2011, 47, 379; (k) Al-
Rashid, Z. F.; Hsung, R. P. Org. Lett. 2008, 10, 661.
CuL2
N
R1
R2
5
R1
R2
R1
R2
N
N
Br
CuL2
Br
Path II
Path I
R
CuL2
Br
R
7
6
L2CuBr
R1
3. For the synthesis of ynamides, see: Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.
Synlett 2003, 1379.
Br
N R2
R2
N
Cs2CO3
HBr
4. (a) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T.
P. Org. Lett. 2002, 4, 2417; (b) Klein, M.; König, B. Tetrahedron 2004, 60, 1087.
5. (a) Rodríguez, D.; Martínez-Esperón, M. F.; Castedo, L.; Saá, C. Synlett 2007,
1963; (b) Brückner, D. Tetrahedron 2006, 62, 3809; (c) Couty, S.; Barbazanges,
M.; Meyer, C.; Cossy, J. Synlett 2005, 905; (d) Wei, L.-L.; Mulder, J. A.; Xiong, H.;
Zificsak, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459; (e)
Janousek, Z.; Collard, J.; Viehe, H. G. Angew. Chem., Int. Ed. 1972, 11, 917.
6. (a) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281; (b) Rainier, J.
D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272; (c) Rainier, J. D.; Imbriglio, J. E.
Org. Lett. 1999, 1, 2037; (d) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998,
37, 489; (e) Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1255.
7. (a) DeKorver, K. A.; Walton, M. C.; North, T. D.; Hsung, R. P. Org. Lett. 2011, 13,
4862; (b) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74, 4630; (c)
Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org. Chem. 2008, 73,
9447; (d) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org.
Chem. 2006, 71, 4170; (e) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151; (f) Dunetz, J. R.; Danheiser, R. L. Org. Lett.
2003, 5, 4011; (g) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc. 2003, 125,
2368.
R
R1
R
8
3
Scheme 3. Proposed reaction pathway for the synthesis of ynamides from 1,2-
dibromo-1-alkenes.
formation of bromoenamides from crude reaction mixtures failed,
this hypothesis was possibly ruled out (Path II).
In summary, the first copper-catalyzed selective synthesis of
ynamides from the starting 1,2-dibromo-1-alkenes was developed.
In this reaction, dehydrobromination of the starting 1,2-dibromo-
1-alkenes would generate intermediate alkynyl bromides and then
couple with nitrogen nucleophiles to form ynamides. Further
studies on the applications of this method and the coupling
reaction with other nucleophiles are underway.
8. Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833.
9. Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000.
10. (a) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756; (b) Jouvin, K.;
Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272.
Acknowledgments
We thank the Natural Science Foundation of China (21072054),
New Teachers’ Fund for Doctor Stations, Ministry of Education of
China (20094306120003), Training Program Foundation for the
Young Talents by Hunan Normal University of China (ET21003),
Hunan Provincial Natural Science Foundation of China (12JJ2009),
Scientific Research Fund of Hunan Provincial Education Depart-
ment (12A095) and Aid Program for Science and Technology Inno-
vative Research Team in Higher Educational Institutions of Hunan
Province for financial support.
11. Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2009, 48,
4381.
12. (a) Ranu, B. C.; Chattopadhyay, K. Org. Lett. 2007, 9, 2409; (b) Ranu, B. C.; Adak,
L.; Chattopadhyay, K. J. Org. Chem. 2008, 73, 5609.
13. Banerjee, S.; Khatri, H.; Balasanthiran, V.; Koodali, R. T.; Sereda, G. Tetrahedron
2011, 67, 5717.
14. Liang, Y.; Tao, L.-M.; Xie, Y.-X.; Li, J.-H. Synthesis 2008, 3988.
15. Li, Z.-P.; Liu, J.-H.; Li, W.-J.; Wang, C.; Li, Y. Tetrahedron Lett. 2011, 52, 4320.
16. Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10, 4275.
17. For some recent examples, see: (a) Zhang, Y.; Yang, X.; Yao, Q.; Ma, D. Org. Lett.
2012, 14, 3056; (b) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552; (c) Diao,
X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang, H.; Guo, Y.; Ma, D. Org. Lett. 2011, 13, 6422;
(d) Wang, Y.; Liao, Q.; Xi, C. Org. Lett. 2010, 12, 2951; (e) Jones, G. O.; Liu, P.;
Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 6205; (f) Strieter, E. R.;
Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78; (g) Xie, Y.-X.; Pi, S.-
F.; Wang, J.; Yin, D.-L.; Li, J.-H. J. Org. Chem. 2006, 71, 8324.
Supplementary data
Supplementary data (experimental procedures and character-
ization data for all new compounds and copies of NMR spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.09.092.