Nickel-catalyzed cross-coupling reaction of acetylenic sulfones with alkynyl Grignard reagents: A facile method for the preparation of unsymmetrical 1,3-diynes

Article abstract of DOI:10.1016/j.tetlet.2013.05.049

The cross-coupling reaction of acetylenic sulfones with acetylenic Grignard reagents was realized by using Ni(acac)₂ as catalyst to afford unsymmetrical 1,3-diynes under mild conditions without homocoupling byproducts. By using this method, 1,4-diaryl-1,3-diynes could be obtained in moderate to good yields (59-83%), whereas, the yields for alkyl substituted 1,3-diynes are lower (30-54%).

Full text of DOI:10.1016/j.tetlet.2013.05.049

Tetrahedron Letters 54 (2013) 3819–3821
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nickel-catalyzed cross-coupling reaction of acetylenic sulfones with
alkynyl Grignard reagents: a facile method for the preparation of
unsymmetrical 1,3-diynes
⇑
Kuang Fang, Meihua Xie , Zhannan Zhang, Peng Ning, Guanying Shu
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key Laboratory of Molecular Based Materials, College of Chemistry and Materials Science, Anhui
Normal University, Wuhu 241000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The cross-coupling reaction of acetylenic sulfones with acetylenic Grignard reagents was realized by
using Ni(acac)2 as catalyst to afford unsymmetrical 1,3-diynes under mild conditions without homocou-
pling byproducts. By using this method, 1,4-diaryl-1,3-diynes could be obtained in moderate to good
yields (59–83%), whereas, the yields for alkyl substituted 1,3-diynes are lower (30–54%).
Ó 2013 Elsevier Ltd. All rights reserved.
Received 31 January 2013
Revised 28 April 2013
Accepted 10 May 2013
Available online 20 May 2013
Keywords:
Acetylenic sulfone
Grignard reagent
Cross-coupling reaction
1,3-Diyne
1,3-Diynes are useful starting materials in organic synthesis1
and the conjugation functionality is widely occurring in natural
products, pharmaceuticals,2 and carbon-rich materials, such as
and has versatile reactivities.9 We have achieved the stereoselec-
tive synthesis of polysubstituted alkenes by the conjugate addi-
tion of organometallic reagents to acetylenic sulfones.10 As an
macrocyclic annulenes,
p-conjugated acetylenic oligomers, and
polymers.3 Some compounds containing the 1,3-diyne structure
have been recognized for their antitumor, antibacterial, anti-
inflammatory, and anti-HIV activities.4 Consequently, the synthesis
of 1,3-diynes has attracted considerable attention for decades.
Methods for the synthesis of symmetrical 1,3-diynes have already
been well-developed, mainly by transition-metal-catalyzed homo-
coupling reaction of terminal alkynes and their derivatives.5 In
contrast, methods for the synthesis of unsymmetrical 1,3-diynes
are still under-represented. Until now, the Cadiot–Chodkiewicz
reaction, copper-catalyzed cross-coupling of 1-bromoalkynes with
terminal alkynes with aliphatic amines as bases, still represents
the major protocol for preparing unsymmetrical 1,3-diynes.6 Lei
and co-workers recently reported a Pd-catalyzed version of this
cross-coupling.7 Jiao and co-workers developed a Cu-catalyzed
decarboxylative cross-coupling of propiolic acids with terminal al-
kynes.8 However, in these reaction systems, the homo-coupling
byproducts were formed concomitantly with the desired unsym-
metrical diynes, which would inevitably add to the difficulty in
the purification of the product.
Table 1
Screening of desulfonylation cross-coupling of acetylenic sulfone 1a with Grignard
reagent 2aa
Ph
MgBr
SO2Tol
catalyst
+
Ph
THF
CH3
3a
Yieldb (%)
1a
2a
CH3
Entry
Catalyst
None
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(PPh3)2Cl2
FeCl3
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ratio of 1a:2a
T (°C)
Time (min)
1
2
3
4
5
6
7
8
1:1.2
1:1.2
1:1.5
1:2.0
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
25
25
25
25
25
25
0
45
25
25
40
40
30
30
40
40
240
20
30
30
45
59
78
80
64
30
71
60
60
70
9c
10d
Acetylenic sulfone has shown great potential in organic syn-
thesis because the sulfone group is strongly electron-withdrawing
a
The reaction was carried out with 1a (1.0 mmol), 2a, and 10 mol % catalyst in
5 mL of THF.
b
Isolated yield based on 1a.
5 mol % Ni(acac)2 was used.
15 mol % Ni(acac)2 was used.
c
⇑
Corresponding author. Tel.: +86 0553 3869310; fax: +86 0553 3883517.
E-mail address: xiemh@mail.ahnu.edu.cn (M. Xie).
d
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.049

3820
K. Fang et al. / Tetrahedron Letters 54 (2013) 3819–3821
extension of our continued research interest in the synthetic
applications of acetylenic sulfone, we report herein the facile syn-
thesis of unsymmetrical 1,3-diynes by nickel-catalyzed desulfony-
lation cross-coupling of alkynyl Grignard reagent with acetylenic
sulfone at room temperature without the formation of homo-cou-
pling byproducts.
Initially, the reaction of 1-phenyl-2-(p-tolylsulfonyl)ethyne (1a)
and (p-tolylethynyl)magnesium bromide (2a) in THF was investi-
gated. The results are summarized in Table 1. In the absence of a cat-
alyst, the unsymmetrical 1,3-diyne 3a could be obtained in 45%
yield when 1a was reacted with 1.2 equiv of 2a in THF at 25 °C (Ta-
ble 1, entry 1).11 The yield of 3a was improved to 59% when 10 mol %
of Ni(acac)2 was added (Table 1, entry 2). When 1.5 equiv of 2a was
used, the yield could be further improved to 78% (Table 1, entry 3).
Similar result was obtained when the amount of 2a was increased to
2.0 equiv (Table 1, entry 4). When Ni(PPh3)2Cl2 was used as the
catalyst, the yield decreased to 64% (Table 1, entry 5). With FeCl3
as catalyst, only 30% yield of 3a was isolated (Table 1, entry 6).
The reaction proceeded sluggishly at 0 °C (Table 1, entry 7), while
a reduction in the yield was observed when the reaction tempera-
ture was raised to 45 °C (Table 1, entry 8). Neither reducing the cat-
alyst loading amount to 5 mol % nor increasing it to 15 mol % could
improve the yield (Table 1, entries 9 and 10). Notably, in all these
cases examined, no homocoupling by-product was detected, though
some unidentifiable complex mixtures of polar side products were
detected.12 To summarize, we choose the use of 1.5 equiv of 2a,
10 mol % Ni(acac)2 in THF at room temperature as the optimized
reaction conditions for further study.
Under the optimized reaction conditions, the scope of the cross-
coupling reaction was investigated. The results were compiled in
Table 2. Using different combinations of acetylenic sulfones and
Grignard reagents, a series of unsymmetrical 1,4-disubstituted
Table 2
The desulfonylation cross-coupling of acetylenic sulfone and Grignard reagent
Ni(acac)2
(10 mol %)
R1
SO2Tol
+ R2
MgBr
R1
R1
R2
THF, RT
1
3
2
R2
Entry
1
1
2
Yielda (%)
78
(3)
CH3
1a
2a
(3a)
OCH3
2
3
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1d
1d
1e
1f
2b
2c
2d
2e
2b
2c
2d
2e
2c
2d
2e
2d
2e
2a
67
83
42
30
59
66
54
33
63
36
40
35
36
30
(3b)
F
(3c)
C5H11-n
(3e)
4
(3d)
5
CH3
CH3
CH3
CH3
CH3O
CH3O
F
OCH3
F
6
(3f)
7
(3g)
C5H11-n
(3i)
8
(3h)
9
F
10
11
12
13
14
(3j)
C5H11-n
(3k)
C5H11-n
(3l)
F
(3m)
n-C5H11
CH3
(3h)
CH3
15
(3i)
a
Isolated yield based on 1.

K. Fang et al. / Tetrahedron Letters 54 (2013) 3819–3821
3821
Ni(acac)2
(Ni0)
Supplementary data
R2
MgBr
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.05.049.
R1
R1
R2
R1
SO2Tol
References and notes
R1
Ni-SO2Tol
MgBr
Ni
(II)
+ BrMgSO2Tol
R2
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(I)
R2
Scheme 1. A tentative catalytic cycle for the cross-coupling reaction.
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1,3-diynes were synthesized in 30–78% yields. When R1 and R2
were aryl groups, the desired diyne products were obtained in
good yields, regardless of the electronic nature of the substituents
on the benzene ring (Table 2, entries 1–3, 6, 7, and 10). However,
when either R1 or R2 was an alkyl group, the yield dropped signif-
icantly (Table 2, entries 4, 5, 8, 9, 11–15), and the reaction failed to
produce the desired 1,3-diynes when both R1 and R2 were alkyl
groups.
The catalytic mechanism for this cross-coupling might be simi-
lar to that of the previously reported Ni-catalyzed cross-coupling
of aryl sulfone and arylmagneusium bromide.13 A tentative cata-
lytic cycle is shown in Scheme 1. First, in the presence of Grignard
reagents, Ni(acac)2 would be reduced to Ni(0) species, which
would undergo oxidative addition to the acetylenic sulfone to form
intermediate (I). Subsequent transmetallation with the Grignard
reagent would give intermediate (II) followed by reductive elimi-
nation to furnish the diyne products and regenerate the catalytic
active Ni(0) species.
8. Yu, M.; Pan, D. L.; Jia, W.; Chen, W.; Jiao, N. Tetrahedron Lett. 2010, 51, 1287.
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In conclusion, we have developed a facile method for the syn-
thesis of unsymmetrical 1,3-diynes by nickel-catalyzed desulfony-
lation cross-coupling reactions of acetylenic sulfones with
Grignard reagents. The cross-coupling reaction could be run at
room temperature, and no homo-coupling byproduct was de-
tected. Further studies on the reaction are ongoing in our
laboratory.
11. For
a
related direct reaction between aryl lithium reagents and
arylsulfonylacetylenes without any transition metal catalysts, see: Ruano, J.
L. G.; Alemán, J.; Marzo, L.; Alvarado, C.; Tortosa, M.; Díaz-Tendero, S.; Fraile, A.
Angew Chem., Int. Ed. 2012, 51, 2712.
Acknowledgments
12. 1H NMR analysis of these mixtures suggested the probable presence of
products derived from the conjugate addition of the Grignard reagent to the
acetylenic sulfone. For a relevant report, see: Cheng, C. Y.; Isobe, M. Tetrahedron
2011, 67, 9957.
The authors are grateful to the National Natural Science Foun-
dation of China (Nos. 20772001 and 21272004) for financial sup-
port of this work. We are also grateful to Professor Jiping Hu,
Professor Gaosheng Yang and Dr. Zhuo Chai for their helpful
assistance.
13. (a) Clayden, J.; Julia, M. J. Chem. Soc., Chem. Commun. 1993, 1682; (b) Clayden,
J.; Cooney, J. J. A.; Julia, M. J. Chem. Soc., Perkin Trans. 1 1995, 7.