Cs2CO3-mediated synthesis of terminal alkynes from 1,1-dibromo-1-alkenes

Article abstract of DOI:10.1016/j.tetlet.2010.12.071

An unprecedented route to prepare terminal alkynes from 1,1-dibromo-1-alkenes mediated by Cs₂CO₃ was proven. 1,1-Dibromo-1-alkenes bearing various functional groups were efficiently converted to corresponding terminal alkynes in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.12.071

Tetrahedron Letters 52 (2011) 992–994
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cs2CO3-mediated synthesis of terminal alkynes from 1,1-dibromo-1-alkenes
Ming Zhao a, Chunxiang Kuang a, , Qing Yang b, , Xuezhi Cheng a
⇑
⇑
a Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, China
b Department of Biochemistry, School of Life Sciences, Fudan University, Handan Road 220, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedented route to prepare terminal alkynes from 1,1-dibromo-1-alkenes mediated by Cs2CO3
was proven. 1,1-Dibromo-1-alkenes bearing various functional groups were efficiently converted to cor-
responding terminal alkynes in moderate to excellent yields.
Received 9 October 2010
Revised 1 December 2010
Accepted 17 December 2010
Available online 23 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cesium
Alkynes
Dibromoalkenes
Cycloaddition
1. Introduction
Cesium salts have been utilized with good results in the Heck,
Suzuki, and Sonogashira reactions12 because of their softness and
Terminal alkynes are useful and versatile intermediates in the
synthesis of pharmaceuticals, agrochemicals, and functional mate-
rials.1 Their utilization as precursors in a wide range of copper-cat-
alyzed azide-alkyne cycloaddition reactions2 and C–C bond
formation reactions3 has stimulated a significant level of interest
from chemists. The preparation of alkynes from carbonyl com-
pounds via a one-carbon homologation is a very important strategy
to gain access to terminal alkynes.4 The most frequently used meth-
ods to convert aldehydes to terminal alkynes are Corey–Fuchs reac-
tion,5 Colvin rearrangement,6 Gilbert–Seyferth homologation,7 and
their modifications.8–10 However, the excessive employment of
superbases (BuLi, NaHMDS, t-BuOK, etc.) combined with low tem-
peratures in these procedures not only hampered the scope of sub-
strates, but also increased the difficulty of the procedure in open-air
condition. Subsequently, the Ohira–Bestmann procedure11 was rec-
ognized as the most popular methodology in transforming alde-
hydes into terminal alkynes. In this procedure, mild reaction
conditions tolerated a wide range of functionalized substrates.
susceptibility to dissolution in organic solvents, such as DMSO,
DMF, and alcohols. We have previously reported a facile method
for the preparation of (E)-vinyl bromides from 1,1-dibromo-1-al-
kenes using a diethyl phosphonate/EtONa/EtOH system.13 In order
to investigate the effect of cesium ion on 1,1-dibromo-1-alkenes,
we performed the reaction by treating 1,1-dibromo-1-alkenes with
Cs2CO3 in DMSO at 115 °C. The result was surprising in the sense
that terminal alkynes were produced selectively, but no eliminated
bromoacetylene products were detected (Scheme 1).
2. Results and discussion
We report a novel synthetic method of deriving terminal
alkynes from 1,1-dibromo-1-alkenes by adopting a Cs2CO3/DMSO
system. We initially designated 2-(p-methylphenyl)-1,1-dibromo-
1-alkene 1a as the model substrate to screen the reaction condi-
tions (Table 1). Several inorganic bases were examined including
However, in this method, a,b-unsaturated aldehydes could not be
Corey-Fuchs reaction
transformed into corresponding enynes; and the requirement for
expensive and complex phosphonate (dimethyl-1-diazo-2-oxopro-
pyl phosphonate) makes this procedure economically and experi-
mentally unreasonable. Thus, the preparation of terminal alkynes
is generally inconvenient and lacks adherence to environmental
safety.
H
Br
H2O
n-BuLi
R
H
THF, -78 oC
R
Br
This work
H
Br
Br
Cs2CO3
R
H
DMSO, 115 o
C
⇑
Corresponding authors.
E-mail addresses: kuangcx@tongji.edu.cn (C. Kuang), yangqing68@fudan.edu.cn
R
(Q. Yang).
Scheme 1. Access to terminal alkynes from 1,1-dibromo-1-alkenes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.071

M. Zhao et al. / Tetrahedron Letters 52 (2011) 992–994
993
Table 1
Table 2
Screen for optimal reaction conditions
Synthesis of terminal alkynes 2a–w from 1,1-dibromo-1-alkenes 1a–wa
Br
Br
Cs2CO3(2.5 equiv)
DMSO, 115 oC, 12h
base
solvent
R
R
Br
Br
1a-w
2a-w
1a
2a
Entry
Base
Solvent
Temperature (°C)
Time (h)
Yielda (%)
1
2
Cs2CO3
Cs2CO3
K2CO3
CsF
Cs2CO3
Cs2CO3
DMF
115
115
115
115
95
12
12
12
12
24
24
56
92
Trace
85
92
DMSO
DMSO
DMSO
DMSO
DMSO
2a, 92%
2b, 89%
3
2c, 94%
4b
5
O
BnO
O
6
25
0
MeO
Br
2d, 86% (p)
2e, 96% (m)
2f, 90% (o)
2g, 88%
Reaction conditions: 1.0 equiv of 1a and 2.5 equiv of base were stirred in DMSO.
a
2h
, 92%
Isolated yield.
4.0 Equiv of CsF was used.
b
Cl
Cl
Cl
Cs2CO3 when DMSO was engaged as solvent at 115 °C (entries 2–
4). Cs2CO3 was the most effective reagent and facilitated a yield
of 92% for product 2a. A similar yield was achieved when CsF
was used. In contrast, K2CO3 was inefficient in this reaction. When
DMF was employed as solvent, the yield dropped significantly to
56% (entry 1). Notably, terminal alkyne 2a was also obtained with
92% yield at 95 °C after 24 h when using Cs2CO3 as base (entry 5).
However, no desired product was obtained at room temperature
(entry 6).
2j, 90% (p)
2i
, 91%
2m
, 85%
2k
, 97% (m)
2l, 92% (o)
F
F3C
MeO2C
2n
2o
2p
, 78%
, 89%
, 86%
O2N
H2N
2s, 95%c
2q, 50%b
2r, 75%
With the optimized conditions (Table 1, entry 2) in hand, the
scope of dibromide substrates was examined and summarized in
Table 2. Aromatic, heteroaromatic, aryl vinyl, and alkyl dibromides
were studied and converted to corresponding terminal alkynes
efficiently. Unfunctionalized aromatic substrates (1b–c) and elec-
tron-rich aromatic substrates (1a, 1d–h) were converted to the
corresponding terminal alkynes in excellent yields (86–96%). Aro-
matic halides (1i–n) furnished parallel exceptional yields of 85–
97%. It is worth noting that steric congestion did not depress the
yields in this reaction as the substrates with ortho substituent on
aromatic vinyl dibromides (1f, 1l–m) also worked effectively
(90%, 92%, and 85%, respectively). For electron-deficient aromatic
substrates (1o–q), however, decreased yields were obtained (86%,
78%, and 50%, respectively). Challenging functionalized substrates,
such as free amine (1r), bifunctional dibromide (1s), pyridine (1t),
and vinyl dibromide (1u) were also investigated and found compe-
tent in this reaction, producing corresponding terminal alkynes in
good to excellent yields (75%, 95%, 88%, and 98%, respectively). Fi-
nally, alkyl substrates (1v–w) were also compatible with this reac-
tion, and corresponding terminal alkynes (2v–w) were isolated in
81% and 76% yields, respectively. This was a notable result.
Recently, the reaction of azides and terminal alkynes catalyzed
by Cu(I), a process known as ‘click chemistry,’ was used and conse-
quently gained wide acceptance in the preparation of N-substi-
tuted 1,2,3-triazoles for a variety of purposes. We applied this
transformation to a one-pot synthesis of 1,4-substituted 1,2,3-tria-
zoles. Reaction of 1a with Cs2CO3 in DMSO at 115 °C for 12 h, and
the subsequent reaction of the mixture in the presence of CuI and
(azidomethyl)benzene achieved the desired product 3 in 80% yield
(Scheme 2).
N
2v
, 81%
2u
2t
, 98%
, 88%
2w
, 76%
Reaction conditions: a mixture of 1 (0.5 mmol) and Cs2CO3 (407 mg, 1.25 mmol)
was stirred in 6 mL of DMSO at 115 °C for 12 h.
Yields of isolated product.
Run at 80 °C.
5.0 Equiv of Cs2CO3 was used.
a
b
c
N
N
N
1) Cs2CO3(2.5 equiv)
DMSO, 115 oC, 12h
Br
Br
2) BnN3(1.1 equiv)
1a
20% CuI, 80 oC, 10h
3, 80%
Scheme 2. One-pot CuAAC reaction from 1a.
show that a small amount of water in DMSO rather than DMSO
may be the hydrogen source for the protonation of acetylenyl
bromide.
3. Conclusion
The mechanism is not yet clear, however, elimination of hydro-
gen bromide from 1,1-dibromo-1-alkenes under base may initially
occur.14 As shown in Scheme 3, when 1-bromo-2-phenylethyne 4
was used instead of 1b under the optimal reaction conditions,
desired product 2b was also isolated in 90% yield. Subsequently a
In summary, we have developed a convenient and efficient
route to the synthesis of terminal alkynes from 1,1-dibromo-1-al-
kenes. The reaction is carried out using Cs2CO3 only, proceeds effi-
ciently, and tolerates a broad range of functional groups. Various
terminal alkynes were prepared with moderate to excellent yields.
Furthermore, one-pot CuAAC reaction from 1,1-dibromo-1-alkenes
was achieved as well, which provided a novel way to construct
1,2,3-triazoles.
deuterium-labeling experiment was performed, when
4 was
treated in DMSO-d6 under similar reaction conditions, no 1-deute-
ro-2-phenylalkyne D-2b was detected. Another experiment under-
taken in dry DMSO did not afford product 2b either. These results

994
M. Zhao et al. / Tetrahedron Letters 52 (2011) 992–994
Budow, S. Org. Biomol. Chem. 2009, 7, 1374–1387; (e) Schulz, M.; Tanner, S.;
Cs2CO3(1.5 equiv)
undried DMSO, 115 oC, 12h
Barqawi, H.; Binder, W. H. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 671–680.
2. For reviews on copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition
reaction, see: (a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015;
(b) Amblard, F.; Cho, J. H.; Schinazi, R. F. Chem. Rev. 2009, 109, 4207–4220.
3. For reviews on alkynes C(sp)–C bonds formation reaction, see: (a) Chinchilla,
R.; Nájera, C. Chem. Rev. 2007, 107, 874–922; (b) Abu Sohel, Md. S.; Liu, S. R.
Chem. Soc. Rev. 2009, 38, 2269–2281.
H
2b, 90%
Cs2CO3(1.5 equiv)
Br
D
d6-DMSO, 115 oC, 12h
4. Review: (a) Habrant, D.; Rauhala, V.; Koskinen, A. M. P. Chem. Soc. Rev. 2010, 39,
2007–2017; (b) Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000, 185–213.
5. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
6. (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973, 151–152; (b)
Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1 1977, 869–874.
7. (a) Seyferth, D.; Hilbert, P.; Marmor, R. S. J. Am. Chem. Soc. 1967, 89, 4811–4812;
(b) Seyferth, D.; Hilbert, P.; Marmor, R. S. Tetrahedron Lett. 1970, 11, 2493–
2496; (c) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379–
1386.
4
D-2b,
0%
Cs2CO3(1.5 equiv)
dry DMSO, 115 oC, 12h
H
2b,
0%
8. For references to modifications of Corey–Fuchs reaction, see: (a) Michel, P.;
Gennet, D.; Rassat, A. Tetrahedron Lett. 1999, 40, 8575–8578; (b) Beshai, M.;
Dhudshia, B.; Mills, R.; Thadani, A. N. Tetrahedron Lett. 2008, 49, 6794–6796.
9. For references to modifications of the Colvin rearrangement, see: (a) Ohira, S.;
Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun. 1992, 721–722; (b) Miwa, K.;
Aoyama, T.; Shioiri, T. Synlett 1994, 107–108.
10. For references to modifications of the Seyferth–Gilbert homologation, see: (a)
Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997–4999; (b) Gilbert, J.
C.; Weerasooriya, U. J. Org. Chem. 1982, 47, 1837–1845.
11. (a) Zanatta, S. D. Aust. J. Chem. 2007, 60, 963; (b) Müller, S.; Liepold, B.; Roth, G.
J.; Bestmann, H. J. Synlett 1996, 521–522; (c) Meffre, P.; Hermann, S.; Durand,
P.; Reginato, G.; Riu, A. Tetrahedron 2002, 58, 5159–5162.
12. For a review, see: (a) Lehmann, F. Synlett 2004, 2447–2448; (b) Littke, A. F.; Fu,
G. C. J. Org. Chem. 1999, 64, 10–11; (c) Grasa, G. A.; Singh, R.; Stevens, E. D.;
Nolan, S. P. J. Organomet. Chem. 2003, 687, 269–279; (d) Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 1998, 37, 3387–3388; (e) Batey, R. A.; Shen, M.; Lough, J.
Org. Lett. 2002, 4, 1411–1414; (f) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 13642–13643.
Scheme 3. Reaction performed in undried DMSO, dry DMSO and DMSO-d6.
Acknowledgments
The work was supported by Natural Science Foundation of
China (No. 30873153), the Key Projects of Shanghai in Biomedical
(No.08431902700) and the Scientific Research Foundation of State
Education Ministry for the Returned Overseas Chinese Scholars.
We would like to thank the Center for Instrumental Analysis,
Tongji University, China.
References and notes
1. (a) Trost, B. M.; Sieber, J. D.; Qian, W.; Dhawan, R.; Ball, Z. T. Angew. Chem., Int.
Ed. 2009, 48, 5478–5481; (b) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010,
39, 1325–1337; (c) Soules, A.; Ameduri, B.; Boutevin, B.; Calleja, G.
Macromolecules 2010, 43, 4489–4499; (d) Seela, F.; Xiong, H.; Leonard, P.;
13. Kuang, C. X.; Senboku, H.; Tokuda, M. Tetrahedron 2002, 58, 1491–1496.
14. Sobha, P. G.; Björn, C. G. S.; Jeffrey, L. P.; Chet, R. H.; Shubhada, W. D.
Tetrahedron 2009, 65, 7357–7363.