Copper-catalyzed cross-dehydrogenative coupling (CDC) of Alkynes and Benzylic C-H bonds

Article abstract of DOI:10.1002/adsc.201000066

The activation of benzylic C-H bonds and subsequent coupling with terminal alkynes in the presence of 2,3-dichloro-5,6-dicyanoquinone (DDQ) and a catalytic amount of copper(I) triflate is presented. Good to moderate yields of disubstituted alkynes are obtained for this cross-dehydrogenative coupling (CDC) reaction between a variety of aromatic alkynes and diphenylmethane derivatives.

Full text of DOI:10.1002/adsc.201000066

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DOI: 10.1002/adsc.201000066
Copper-Catalyzed Cross-Dehydrogenative Coupling (CDC) of
À
Alkynes and Benzylic C H Bonds
Camille A. Correiaa and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A2K6, Canada
Fax : (+1)-514-398-3797; e-mail: cj.li@mcgill.ca
Received: January 26, 2010; Published online: June 8, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000066.
À
À
Abstract: The activation of benzylic C H bonds
Metal-catalyzed C H functionalization remains one
of the most efficient but challenging areas for C C
À
and subsequent coupling with terminal alkynes in
the presence of 2,3-dichloro-5,6-dicyanoquinone
(DDQ) and a catalytic amount of copper(I) triflate
is presented. Good to moderate yields of disubsti-
tuted alkynes are obtained for this cross-dehydro-
genative coupling (CDC) reaction between a varie-
ty of aromatic alkynes and diphenylmethane deriva-
tives.
bond formation in organic chemistry.[7] With the need
for highly functionalized groups eliminated, the
number of steps in the synthetic process and conse-
quently the amount of toxic waste is reduced, making
the overall process greener.[8] In the past, we[9] and
others[10] have been involved in the synthesis of com-
plex molecules via metal-catalyzed oxidative reactions
À
which directly couple two C H bonds in the starting
À
À
Keywords: alkynes; C C coupling; C H activation;
materials; a reaction we termed cross-dehydrogena-
tive coupling (CDC) (Scheme 1). In our continued
effort to find novel CDC reactions, we wish to report
the unprecedented copper-catalyzed alkynylation of
copper; diphenylmethanes
À
benzylic C H bonds.
Disubstituted acetylenes are traditionally synthesized
through elimination[1] or substitution reactions under
harsh conditions. The metal-catalyzed substitution re-
actions generally employ a palladium catalyst and a
highly active metal acetylide,[2] all of which have the
disadvantage of generating a stoichiometric amount
Scheme 1. Cross-dehydrogenative coupling.
One of the well known oxidizing agents in organic
of metal waste. Another widely utilized method is the chemistry is 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
Sonagashira reaction in which the terminal C H bond none (DDQ).[11] Previously we[12] and others[13] have
of the alkyne is activated in the presence of a catalytic reported the efficient use of DDQ for C C bond for-
À
À
amount of copper.[3] This method reduces the amount mations through activation of benzylic C H bonds.
of metal waste due to the in-situ generated copper The benzylic C H bond lacking an adjacent hetero-
acetylide but it is still performed under rigorous con-
À
À
atom is more difficult to activate;[14] however, Shi re-
ditions. Alternatively, there is growing interest in the cently disclosed the use of DDQ for the arylation of
direct substitution of benzylic alcohols owing to them diphenylmethane derivatives.[15]
being more environmentally friendly, readily available
With this in mind, we began our study using the
and less costly than benzylic halides. Initial studies in copper/indium system that we previously reported for
this field involved the use of highly functional alky- the alkylation of benzylic ethers[16] but with DDQ as
nylsilane[4] and alkynylboron[5] reagents. More recent- the oxidant in chlorobenzene (C6H5Cl). We were
ly Jiao reported the FeACHTNUGTRENUNG(OTf)3/TfOH co-catalyzed pleased to note that the reaction provided us with a
cross-coupling of terminal alkynes and benzylic alco- 34% yield of product (Table 1, entry 1); the removal
hols.[6] In the light of this, we envisioned the reaction of indium increased the yield (Table 1, entry 2). Other
being accessed through a cross-dehydrogenative cou- Lewis acid metal salts were screened (Table 1, en-
À
pling of the sp C H bond of a terminal alkyne and a tries 3–6) but copper(II) triflate was found to be the
3
À
benzylic sp C H bond.
best. Reduction of the amount of copper(II) triflate
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Copper-Catalyzed Cross-Dehydrogenative Coupling (CDC) of Alkynes and Benzylic C H Bonds
Table 1. Optimization of the alkynylation of diphenylmethane with phenylacetylene.
Entry[a]
Catalyst (mol%)
Solvent (mL)
Yield[b] [%]
1
2
3
4
5
6
7
8
Cu
Cu
Cu
InCl (5)
FeCl2 (5)
CuI (5)
N
E
C6H5Cl (0.2)
C6H5Cl (0.4)
C6H5Cl (0.2)
C6H5Cl (0.2)
C6H5Cl (0.2)
C6H5Cl (0.2)
C6H5Cl (0.2)
C6H5Cl (0.4)
DCE (0.2)
34
52
NP
21
Trace
NP
57
64
49
NP
18
71
CuACTHNGUTREN(UNG OTf)2 (2.5)
CuOTf·toluene (2.5)
CuOTf·toluene (2.5)
CuOTf·toluene (2.5)
CuOTf·toluene (2.5)
CuOTf·toluene (1)
CuOTf·toluene (1)
none
9
10
11
12
13[c]
14
15[d]
16[e]
DMF (0.2)
MeNO2 (0.2)
C6H5Cl (0.4)
C6H5Cl (0.4)
C6H5Cl (0.4)
C6H5Cl (0.4)
C6H5Cl (0.4)
78
NP
67
CuOTf·toluene (1)
CuOTf·toluene (1)
70
[a]
Reaction conditions: 0.2 mmol phenylacetylene, 5 equiv. diphenylmethane, 1.5 equiv. of DDQ at 1058C and under nitro-
gen unless otherwise noted.
NMR yields using mesitylene as an internal standard.
Reaction run for 24 h at 1208C.
Reaction run for 24 h at 1258C.
Reaction run for 24 h at 1208C and 2 equiv. DDQ.
[b]
[c]
[d]
[e]
was found to be beneficial to the reaction (Table 1, flourophenylacetylene (Table 2, entry 4) can be attrib-
entry 7). Increasing the amount of chlorobenzene al- uted to the lower nucleophilicity of an electron-defi-
lowed for better stirring of the reaction mixture and cient alkyne.[19] Aliphatic alkynes such as n-hexyne
likewise increased the yield (entry 8). The reaction were not amenable to this system (Table 2, entry 9).
did not proceed as efficiently in dichloroethane Substitutions on the phenyl ring of diphenylmethane
(DCE), dimethylformamide (DMF) or nitromethane were well tolerated (Table 2, entries 10–14). 1,3-Di-
(MeNO2) (Table 1, entries 9–11).[17] During these in- phenylpropene (4) was also found to be a feasible
vestigations we noticed that copper(I) triflate was starting material for this reaction (Scheme 2).
more active than copper(II) triflate for this reaction
A tentative mechanism for this reaction is proposed
(Table 1, entry 12). Increasing the reaction time to in Scheme 3. The benzylic radical (6) could be formed
24 h and the temperature to 1208C proved to be our through single-electron transfer (SET) with DDQ and
best reaction conditions (Table 1, entry 13). The metal copper. This radical can be further oxidized to the
catalyst was critical for the reaction and its removal benzylic cation (8) through a second SET. The re-
provided no product (entry 14). Further increasing duced hydroquinone would then have the ability to
the temperature or the amount of DDQ did not aid abstract the acidic proton from the alkyne forming
the reaction (Table 1, entries 15 and 16).[18] With our the copper acetylide (7) which adds to the benzylic
optimized conditions in hand (Table 1, entry 13) we carbocation (8) forming the desired product (3a).
then turned our attention to the scope of the reaction.
In summary, we have developed a novel copper-cat-
Phenylacetylene was found to be the most effective alyzed CDC method for the synthesis of disubstituted
alkyne for this reaction providing the desired product alkynes. To the best of our knowledge this is the first
in good yields. The reaction was sensitive to electronic report of the metal-catalyzed alkynylation of the
À
changes on the phenyl group of the alkyne (Table 2, more challenging benzylic C H bonds which are not
entries 2–8). It is thought that the electron-rich al- adjacent to nitrogen atom.[20] This method provides a
kynes were more prone towards the competing oxida- greener alternative to the nucleophilic substitution of
tive dimerization, whereas the very low yield of 3- diphenylmethanol since there is no need for pre-func-
Adv. Synth. Catal. 2010, 352, 1446 – 1450
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Camille A. Correia and Chao-Jun Li
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Table 2. Cross-dehydrogenative coupling of various alkynes and diphenylmethane de-
rivatives.[a]
[a]
Reaction conditions: 0.1 mmol 2, 5 equiv. 1, 1.5 equiv. of DDQ, 1 mol% CuOTf·to-
luene, 0.2 mL chlorobenzene under nitrogen at 1208C unless otherwise noted.
Isolated yield.
[b]
Scheme 2. Alkynylation of diphenylpropene.
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Copper-Catalyzed Cross-Dehydrogenative Coupling (CDC) of Alkynes and Benzylic C H Bonds
Scheme 3. Proposed mechanism for the CDC reaction.
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was performed without DDQ.
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after the reaction. Increasing the reaction time to 30 h
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À
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