Copper mediated oxidative coupling between terminal alkynes and CuCN

Article abstract of DOI:10.1016/j.tetlet.2014.11.108

A direct oxidative cross coupling between terminal alkynes and CuCN to form 1-cyanoalkynes was reported. FeCl₃ was employed as the sole additive. The reaction could be carried out under mild conditions, with moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.11.108

Accepted Manuscript
Copper mediated oxidative coupling between terminal alkynes and CuCN
Yihang Li, Dunfa Shi, Pengqi Zhu, Hongxing Jin, Shuo Li, Feng Mao, Wei Shi
PII:
S0040-4039(14)02022-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.108
TETL 45492
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 September 2014
18 November 2014
23 November 2014
Please cite this article as: Li, Y., Shi, D., Zhu, P., Jin, H., Li, S., Mao, F., Shi, W., Copper mediated oxidative coupling
between terminal alkynes and CuCN, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.11.108
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Copper Mediated Oxidative Coupling between Terminal Alkynes and
CuCN
Yihang Li, Dunfa Shi, Pengqi Zhu, Hongxing Jin, Shuo Li, Feng Mao and Wei Shi*
College of Science, Huazhong Agricultural University, Wuhan 430070, China
* Corresponding author. Tel./fax: +86 27 87284018. e-mail address: shiwei@mail.hzau.edu.cn
Abstract
A direct oxidative cross coupling between terminal alkynes and CuCN to form 1-cyanoalkynes
was reported. FeCl3 was employed as the sole additive. The reaction could be carried out under
mild conditions, with moderate to good yields.
Keywords
iron; cyanoalkyne; oxidative coupling; terminal alkyne
Oxidative coupling reactions have been an important synthetic route in the latest decades.1
Tremendous efforts have been devoted to this area and great achievements have been made.
Of these examples, bonding between two sp hybridized carbon centers may be the earliest
oxidative coupling reactions since 1869, by Carl Glaser.2 Besides, there are at least two other
forms of oxidative Csp-Csp coupling reactions, as described in Scheme 1. Path A shows the most
common form, the coupling between two terminal alkynes (or alkynyl metallic reagents). Typical
procedure include the Cu(I) catalyzed Glaser-Eglinton-Hay homocoupling reactions.3 It is
noteworthy that Csp species are not limited to alkynes, but should also include the cyano
group.1c Path B and Path C have shown other possibilities of Csp-Csp type oxidative couplings
involving cyano groups.
Scheme 1 Possible forms of oxidative coupling reactions between two Csp centers
Path B in Scheme 1 has represented a new synthetic strategy towards the cyanoalkynes, an
important structure in both synthetic and mechanistic studies.4 Cyanoalkynes have also
constituted a prominent homologous series of complex interstellar molecules identified by
radioastronomy.5 To the best of our knowledge, only a few reports have focused on the
1

synthesis of cyanoalkynes. Xie and Kato have reported a method from aldehyde through
biosynthesis.6 Gough and Trippett have reported the synthesis through pyrolysis.7 Apart from
these methods, the direct cross coupling of terminal alkynes with cyano groups would be more
efficient.
Ricci et al. reported one example of the bis(trimethylsilyl)peroxide (BTMSPO) promoted reaction
of phenylacetylene with CuCN.8 In this report, 30% of homo-coupled 1,4-diphenyl-1,3-butadiyne
was formed, which limited its application. Luo et al. have reported the iodide-catalyzed
cyanation of terminal acetylenes with CuCN in the presence of excess chlorotrimethylsilane
(TMSCl).9 10 mol% of NaI and 3 eq. of TMSCl as well as CuCN were required to obtain the
cyanoalkynes in moderate to good yields. Recently, Okamoto et al. have used cyanogen iodide
as cyanation reagent.10 However, BTMSPO, cyanogen iodine or other cyanogroup sources are
usually toxic, expensive or difficult to handle in laboratories, and the excessive use of them may
limit the application of these methods therefore.
Inspired by the concept of oxidative coupling, we have started the investigation of direct
oxidative coupling between terminal alkynes and the relatively low toxic CuCN (due to the low
Ksp) to form the cyanoalkynes. At first, we have used 2 mmol% of Pd(OAc)2 as catalyst with 2 eq.
of CuCN to investigate the reactions. After 3 days in MeOH under 50oC, 33% of the desired
product was obtained. Other solvents, including toluene, DMSO, MeCN and amine systems
showed less reactivity, as the low solubility of iron salts in them.
We have then optimized the reaction conditions, as shown in Table 1. It is shown that 6 hours
was enough for the reaction. Increasement of Pd catalyst loading did not improve the yield
obviously. It was noteworthy that considerable yield of cyanoalkyne was obtained without the
addition of Pd salt (entry 9, table 2). More importantly, 1,4-diphenyl-1,3-butadiyne, a commonly
observed byproduct in terminal alkynes involved systems, was not determined in this case
without Pd salt. This discovery indicated us that Pd was not necessary for this reaction.
Table 1 Cyanoalkynes from terminal alkynesa
2

Further investigations were then carried out without Pd catalyst. Considering the toxicity of
CuCN, we have used excess of alkynes to promote the transformation of CuCN, as shown in
Table 2. Different additives were explored, while sole FeCl3 under air atmosphere (Entry 6, Table
2) performed the best.
Table 2 Different additivesa
3

We have then applied this oxidative cross coupling method to various terminal alkynes. Table 3
has listed the preliminary results. Moderate to good yields were observed in both electron rich
and poor aryl alkynes. Importantly, among all these reactions, diynes were almost not
determined even under the air atmosphere. 1-chloroalkynes were determined as the main
byproduct and could be easily removed by column chromatography. It is also interesting that 3h
was obtained in high yield, which has a longer Csp chain. However, aliphatic alkynes showed
relatively low activity under this condition, with less than 40% of isolated yields (entry 12, Table
3. For 1-octyne, only trace product was observed).
Table 3 Oxidative coupling using different alkynesa
4

In further studies, we have found that 1-chloroalkynes do not react with CuCN under this
condition, indicating that they do not act as the intermediate. No reaction occurs under this
condition in the absence of iron or copper. Interestingly, 30% of 1-chloroalkynes was observed
when catalytic amount of CuCN (10%) was added to the system. Further investigations including
broader substrate scope and detailed mechanism studies are currently carrying out in our team
and more results will be reported in due course.
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In conclusion, an Iron-mediated oxidative coupling between terminal alkynes and CuCN to form
the cyanoalkynes under mild reaction conditions was discovered. Low cost could be achieved
since FeCl3 was employed as the sole additive and the reaction may be carried out in air. This
method provides an efficient way to form cyanoalkynes, which will greatly promote the studies
in this research area.
Acknowledgments
This work was supported by NSFC (21202050) and the Natural Science Foundation of Hubei
Province of China (2014CFB930).
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