Nickel-catalyzed oxidative coupling reactions of two different terminal alkynes using O2 as the oxidant at room temperature: Facile syntheses of unsymmetric 1,3-diynes

Article abstract of DOI:10.1021/ol8027863

(Formula Presented) Two different terminal alkynes now can be coupled together in the presence of NiCl₂-6H₂O/Cul by using an excess of one of the terminal alkyne substrates. The new method employed 20 mol % TMEDA as the ligand and environmentally benign O₂ or air as the oxidant. It is the first example using Ni-salt as catalyst by employing air or O₂ as oxidant, which led to efficient heterocoupling of two different alkynes.

Full text of DOI:10.1021/ol8027863

ORGANIC
LETTERS
2009
Vol. 11, No. 3
709-712
Nickel-Catalyzed Oxidative Coupling
Reactions of Two Different Terminal
Alkynes Using O2 as the Oxidant at
Room Temperature: Facile Syntheses of
Unsymmetric 1,3-Diynes
Weiyan Yin, Chuan He, Mao Chen, Heng Zhang, and Aiwen Lei*
College of Chemistry and Molecular Sciences, Wuhan UniVersity, P.R. China
aiwenlei@whu.edu.cn
Received December 3, 2008
ABSTRACT
Two different terminal alkynes now can be coupled together in the presence of NiCl2·6H2O/CuI by using an excess of one of the terminal
alkyne substrates. The new method employed 20 mol % TMEDA as the ligand and environmentally benign O2 or air as the oxidant. It is the
first example using Ni-salt as catalyst by employing air or O2 as oxidant, which led to efficient heterocoupling of two different alkynes.
Conjugated diynes are recurring building blocks in natural
products, industrial and pharmaceutical intermediates, elec-
tronic and optical materials, etc.1-3 Homocoupling of
terminal alkynes was pioneered by Glaser4,5 in 1869, and
nowadays, Cu-salt mediated Glaser coupling and related
modified methods6-13 are still widely applied in the synthesis
of conjugated diynes.14 Recently, Pd-catalyzed oxidative
homocouplings of alkynes with a stoichiometric amount of
oxidant such as O2,15-18 R-halocarbonyl compounds,19-21
I2,22,23 and others24-30 have emerged as efficient means.
Currently, the major methods for constructing unsymmetric
conjugated diynes are Cadiot-Chodkiewicz coupling and its
modifications,31-34 which are Cu-catalyzed couplings be-
tween a haloalkyne and a terminal alkyne. Heterocoupling
of a haloalkyne and a terminal alkyne using palladium
catalysis are also known.35-37 Haloalkynes are usually
prepared from terminal alkynes by halogenation. Thus from
an environmental and economical viewpoint, this protocol
is inferior to a method directly coupling two different
terminal alkynes.
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oxidant is environmentally and economically benign and has
.
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10.1021/ol8027863 CCC: $40.75
Published on Web 12/24/2008
2009 American Chemical Society

attracted much attention during the past century.42,43 Oxida-
tion of low valent transition metals by readily available O2,
as a fundamental reaction in chemistry, plays an important
role in many oxygenase enzyme functions and catalytic
processes.44-46 For example, catalytic chemistry of Pd with
O2 as an oxidant has made great strides recently,47-54 and
several new processes have been introduced to organic
syntheses.55-61 Oxidation of Ni(0)-complexes by O2 similar
to that of Pd and Pt has been investigated in stoichiometric
and catalytic reactions, and side-on NiO2 was identified or
invoked as the outcome of the oxidation in several
cases.46,62-64 Although the inexpensive Ni possesses the
potential of being an effective catalyst, applications of Ni
catalyst with O2 as oxidant in organic syntheses are still
limited compared to the well-established Pd/O2 chemistry
and have yet to be explored.65,66 Herein, we report our
observation of a Ni-catalyzed oxidative coupling reaction of
terminal alkynes to form unsymmetric conjugated diynes
under aerobic conditions.
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(Figure 1). Unexpectedly, addition of 5 mol % of NiCl2·6H2O
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Org. Lett., Vol. 11, No. 3, 2009

coupled conjugated diyne 2a was obtained. When the ratio
changed to 1:5 (Table 1, entry 2), 50% 2a was obtained while
3a was only 8%. When the ratio of 1a:1b was changed to
Scheme 1. Speculated Reaction Pathways of Alkyne Couplings
Figure 2. Time profiles of homocoupling of 1a (100 mmol)
catalyzed by Ni(II)/Cu(I) with TMEDA in THF in 500-mL Schlenk
flask. Red line represents the amount of 3a versus time; black line
represents the consumed O2 versus time.
and functional groups such as OR, OH, NHR, TBS, etc. were
tolerated well (Table 2, entries 1-6, 8, 10, 11). The reaction
between 1c and 1h resulted in product 2g in 85% isolated yield,
and that between 1b and 1i furnished 81% of the product (Table
2, entries 7 and 9).
5:1 (Table 1, entry 3), the yield of 2a was 86%. The reaction
proceeded smoothly without NEt3 and gave 2a in 82% yield
(Table 1, entry 5). If the statistical distribution controlled
the formation of cross-coupled and homocoupled diynes, the
ratio of 1:5 will lead to 83% of the cross-coupled diyne.
However, under the same reaction conditions, the reaction
without the nickel catalyst only yielded 30% cross-coupled
diyne (Table 1, entry 4), which exhibited the crucial role of the
nickel catalyst during the formation of cross-coupled diynes.
The substrate scope of the syntheses of unsymmetric diynes
was further examined, and the results are compiled in Table 2.
All reactions proceeded smoothly at room temperature under
aerobic conditions. By utilizing the different polarity between
these alkyne substrates, we could overcome the problem of
separation. Phenylacetylene 1a successfully cross-coupled with
a variety of alkynes based on propargylic alcohols and amines,
Further investigations revealed that aryl bromides could
be tolerated under the reaction conditions, and the couplings
between 1k and 1e or 1f furnished the corresponding
products in good yields (Table 3, entries 1 and 2). It is
noteworthy that even aryl iodides could be retained, and the
substrates bearing a 2-iodophenyl group or a 4-iodophenyl
group readily cross-coupled with another terminal alkyne in
good yields (Table 3, entries 3-6). The results were
significant because aryl bromides and iodides are reactive
building blocks in many transition metal catalytic systems
and thus are usually difficult to be tolerated; moreover, the
halo groups retained in the products provided opportunities
for further transformation.
Homocoupling of terminal alkynes under the above
conditions had been examined, and good to excellent yields
were obtained under mild conditions (for details, see Sup-
porting Information, pp 9 and 10).
Nickel alkynyl complexes have been reported to be
prepared by CuI-catalyzed reaction of Ni(0) with terminal
alkynes,67-74 implying that Cu(I) was more reactive toward
terminal alkynes than the Ni(0) species. Therefore, the
reaction is proposed to initiate from oxidation of the Ni-
complex by O2 to generate a Ni(O2) intermediate,46,62 which
is transmetalated stepwise with an copper alkynyl species
to generate a dialkynyl-Ni intermediate. The final reductive
Table 1. Heterocoupling of Alkynes Catalyzed by Ni/Cu
2a
yield yield yield
entry (mmol) (mmol) NiCl26H2O NEt3 (%)a (%)b (%)c
3a
3b
1a
1b
5 mol
%
5 mol
%
5 mol
%
3.0
equiv (0.46) (0.21)
3.0 50
equiv (0.50) (0.04)
3.0 86 64
46
41
54
(67) Matsumoto, F.; Chujo, Y. Pure Appl. Chem. 2006, 78, 1407–1411
.
1
1.0
1.0
5.0
5.0
5.0
1.0
5.0
1.0
1.0
1.0
(027)
(68) Butler, P.; Gallagher, J. F.; Manning, A. R.; Mueller-Bunz, H.;
8
63
(1.6)
5
2d
3
McAdam, C. J.; Simpson, J.; Robinson, B. H. J. Organomet. Chem. 2005,
690, 4545–4556.
equiv (0.86) (1.6) (0.025)
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Inorg. Chim. Acta 2005, 358, 1673–1682
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Commun. 1978, 446–447
3.0
equiv (0.30) (0.5) (0.035)
82 64
none (0.82) (1.6) (0.035)
30
20
7
.
4e
none
5 mol
%
7
.
5
a GC yields based on 1.0 mmol of reactant (naphthalene as the internal
standard); the numbers in the parentheses are amounts of 2a (mmol). b Yields
based on 1a; the numbers in the parentheses are amounts of 3a (mmol).
c Yields based on 1b; the numbers in the parentheses are amounts of 3b
(mmol). d 42% of 1a was not converted. e 60% of 1b remained.
.
.
.
.
Org. Lett., Vol. 11, No. 3, 2009
711

Table 2. Syntheses of Unsymmetric Conjugated Diynesa
Table 3. Syntheses of Unsymmetric Conjugated Diynesa
a Reaction conditions: NiCl2·6H2O (5.0 mol %), CuI (5.0 mol %),
TMEDA (20 mol %) in THF at room temperature under aerobic conditions.
The ratio of R1CCH:R2CCH was 1:5. Isolated yields.
In summary, we have developed a Ni/Cu-cocatalyzed
aerobic oxidative coupling reaction that efficiently promoted
heterocouplings between two different terminal alkynes and
provided a variety of unsymmetric conjugated diynes under
mild conditions. Although the limitation for heterocouplings
was evident, the obtained yields might be under statistical
control. However, this method for constructing unsymmetric
conjugated diynes though two different terminal alkynes,
which were usually readily available, were environmentally
benign. In addition, it is the first example using a Ni-salt as
a catalyst by employing air or O2 as oxidant, which led to
efficient heterocoupling of two different alkynes. Further
mechanistic studies are currently undergoing in our labora-
tory and will be reported in due course.
a Reaction conditions: NiCl2·6H2O (5.0 mol %), CuI (5.0 mol %),
TMEDA (20 mol %) in THF at room temperature under aerobic conditions.
The ratio of R1CCH:R2CCH was 5:1. Isolated yields.
elimination would release the coupling product and regener-
ate the Ni(0) complex75,76 (Scheme 1). The proposed reaction
mechanism in Scheme 1 indicated that the role of CuX was
to form the copper acetylide, which further transmetalated
as the nucleophile with a Ni(O2) complex. When zinc
acetylide ((phenylethynyl)zinc(II) chloride) was employed
as the nucleophile, without the CuI additive, the reaction in
the presence of NiCl2·glyme produced 93% homocoupled
product (eq 1). Furthermore, the homocoupling of pheny-
lacetylene could occur smoothly in the presence of NaOtBu
and ZnCl2, and 90% homocoupled diyne was obtained (eq
2). This result supported the role of nickel catalyst, proposed
in Scheme 1, in the oxidative coupling of alkynes.
Acknowledgment. This work was supported by National
Natural Science Foundation of China (20772093, 20502020,
20832003), the Excellent Youth Foundation of Hubei
Scientific Committee, Specialized Research Fund for the
Doctoral Program of Higher Education (20060486005), and
a startup fund from Wuhan University.
In the above mechanism, the formation of 1 mol of
coupling product would consume 1 mol of O2. On the other
hand, in Cu-catalyzed homocoupling of alkynes, consumption
of 1 mol of O2 was reported to result in 2 mol of coupling
product.6,14 To gain some preliminary understanding of the
reaction, a 100 mmol scale homocoupling of 1a was carried
out. The kinetic profiles of the reaction clearly revealed that
the formation of 3a was accompanied by the consumption
of an equal molar amount of O2 (Figure 2).77 Therefore, the
observation supported the hypothesis shown in Scheme 1.
Note Added after ASAP Publication. Red bonds were
missing in Tables 2 and 3 in the version published ASAP
December 24, 2008; the corrected version was published
ASAP January 7, 2009.
Supporting Information Available: Detailed experimental
procedure and spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL8027863
(77) This reaction time was longer than the one in the Figure 1, in which
the size and shape of reactors for these two reactions were different. We
speculated that the different reaction rate might be due to the reactors, which
could affect the uptaking of O2.
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712
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