Copper as a powerful catalyst in the direct alkynylation of azoles

Article abstract of DOI:10.1002/anie.200904776

[Chemical equation presented] Copper-bottomed catalysis! The direct alkynylation of azoles through a copper-based C - H bond activation, using alkynylbromides as the coupling partner, has been developed (see scheme). The method is very rapid, is functional-group tolerant, and provides a straightforward entry to diverse alkynyl heterocycles that is complementry to the Sonogashira reaction.

Full text of DOI:10.1002/anie.200904776

Angewandte
Chemie
DOI: 10.1002/anie.200904776
À
C H Bond Activation
Copper as a Powerful Catalyst in the Direct Alkynylation of Azoles**
Franꢀois Besseliꢁvre and Sandrine Piguel*
The widespread use of heteroarenes in medicinal chemistry
and in materials science has driven the development of a
plethora of new synthetic strategies to prepare appropriately
substituted heterocyclic cores. In particular, transition-metal-
catalyzed direct functionalization has gained enormous
attention over the past decade as an effective and straightfor-
ward method for creating aryl/alkenyl–heteroaryl linkages
because it presents many advantages over traditional cross-
coupling reactions.[1] Clearly, major time and atom economies
can be achieved once the need to prepare a suitably activated
heteroarene has been eliminated. A wide range of metal
catalysts, including palladium, rhodium, and ruthenium, and
to a lesser extent copper and nickel, have been exploited for
these processes, providing a toolbox of tunable reaction
conditions for a large range of substrates.[2,3] However, one
key reaction remains largely unexplored, namely the creation
of an alkynyl–heteroaryl linkage between an sp2-hybridized
Table 1: Optimization of the direct alkynylation reaction of 5-phenyl-
oxazole.[a]
Entry
Catalyst
(mol%)
Ligand
(20 mol%)
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuI (15)
CuI (15)
CuI (15)
CuBr (15)
dmeda
1,10-phen
dpm
dpm
dpm
dpm
dpm
PPh3
24 h
24 h
7 h
4 h
3 h
24 h
5 h
3 h
3 h
5 h
1 h
2 h
1 h
2 h
2 h
24
–
–
43
–
56
22
15
64[c]
–
Cu(OTf)2 (5)
CuSO4·5H2O (10)
Cu(OAc)2 (10)
Cu(OTf)2 (15)
Cu(OTf)2 (15)
Cu(OTf)2 (10)
CuI (10)
CuBr·SMe2 (10)
CuBr·SMe2 (10)
CuBr (10)
heteroaryl carbon and an sp-hybridized carbon of an alkynyl
[4]
À
halide using C H bond activation.
The few known examples of direct alkynylation deal
principally with benzene derivatives bearing an ortho direct-
ing group, using gallium salts as the catalyst and silylated
haloethynes as the coupling partner.[5] Recently, two notable
exceptions were reported by Gevorgyan and later by Gu and
Wang in which two classes of electron-rich heterocycles were
alkynylated using various bromoalkynes.[6] In the former case,
high dilution conditions were required, whilst the latter case
was limited by substrate scope. Given that these two methods
rely on the use of palladium catalysis, we decided to explore
the development of an efficient, general, copper-catalyzed
procedure for the direct alkynylation of various heterocycles
that exploits the minimal cost and toxicity of copper.
P(tBu)3
DPEPhos
PPh3
57
71
69
89
70
24
<5
PPh3
DPEPhos
DPEPhos
–
–
–
CuBr·SMe2 (10)
Pd(PPh3)4
PdCl2(PPh3)2
Pd(PPh3)4/CuI
[d]
4 h
24 h
–
[e]
–
–
[a] All reactions were performed using 0.35m of 5-phenyloxazole 1a
(1 equiv), 1-bromophenylacetylene 2a (2 equiv) and LiOtBu (2 equiv) in
dioxane at 1208C. [b] Yields are calculated from isolated products.
[c] 58% for 15 h. [d] KOAc and toluene were used (Gevorgyan con-
ditions). [e] Cs2CO3 used as base, and N,N-dimethyl formamide as
solvent; 1508C.
To test this possibility, and based on our previous work on
heteroarene direct alkenylation, we began with the reaction
between 5-phenyloxazole (1a) and bromophenylacetylene
(2a). We screened a series of copper/ligand sources, beginning
with CuI/trans-N,N’-dimethyl ethylene-1,2-diamine (dmeda);
LiOtBu was added as base and the mixture was heated in
dioxane to 1208C (Table 1, entry 1).[3b,7] Unfortunately, the
only isolated product was the symmetrical diyne (4) resulting
from the rapid homocoupling of the alkynylbromide through
an Ullmann-type reaction. A satisfactory result was obtained
when dipivaloylmethane (dpm) was used as ligand instead of
dmeda to afford the alkynyloxazole (3a) in 43% yield
(Table 1, entry 3).
A subsequent screen of copper sources, using dpm as the
ligand, gave only modest improvement of the yield; the best
result was achieved with Cu(OTf)2, although conversion was
still incomplete (Table 1, entries 3–7). A drastic improvement
was observed by switching to phosphine ligands (Table 1,
entries 8–13), with the highest yield (89%) obtained using
bis[(2-diphenylphosphino)phenyl] ether (DPEPhos) in com-
bination with CuBr·SMe2 after only 1 h (Table 1, entry 13).[8]
Interestingly, the use of uncomplexed CuBr led to a decrease
in the yield of 3a (70%; Table 1, entry 14) and enhanced
[*] F. Besseliꢀvre, Dr. S. Piguel
Institut Curie/CNRS, UMR 176, Bꢁt. 110–112
Centre Universitaire, Orsay F-91405 (France)
Fax: (+33)1-69-07-53-81
E-mail: sandrine.piguel@curie.u-psud.fr
[**] The Rꢂgion Ile-de-France (doctoral grant for F. B.) and the Agence
Nationale de la Recherche are thanked for financial support. We
acknowledge the Institut de Chimie des Substances Naturelles—
CNRS (Gif sur Yvette) for use of the X-ray facility and thank Dr.
Pascal Retailleau from the Service de Cristallochimie for the crystal
structure solution.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904776.
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formation of the by-product 5-phenyloxazole dimer 5 (5% to
which makes it available immediately for coordination in the
reaction medium. A brief survey of bases was therefore
undertaken in which optimal results were achieved using
LiOtBu, with weaker bases (K2CO3, Cs2CO3, and K3PO4)
resulting in no product formation. 1,4-Dioxane was found to
be the preferred solvent, as reactions in N,N-dimethyl
formamide or acetonitrile resulted in no conversion into the
product 3a. Palladium catalysts were also tested but, in
contrast to the copper system, these were found to be
ineffective. Therefore, we identified CuBr·SMe2 (15 mol%)/
DPEPhos (15 mol%)/LiOtBu (2 equiv)/dioxane/1208C as the
best conditions for the coupling of 5-phenyloxazole with
bromoalkyne; product 3a was synthesized in 1h and in 89%
yield.
30%). In the absence of DPEPhos, a lower conversion into
product 3a (24%) and increased yield of the homocoupling
product 5 was observed (42%, Table 1, entry 15). Clearly,
CuBr alone is still able to catalyze the formation of 5, and so
to prevent this unwanted side reaction, rapid generation of
the CuBr/DPEPhos species is required. The greater success of
the copper bromide/dimethyl sulfide complex lies in the
increased solubility over the uncomplexed copper bromide,
Table 2: Scope of direct alkynylation of 5-phenyloxazole with alkynyl
bromides.[a]
This optimized procedure was subsequently used to
investigate the scope of the direct alkynylation reaction of
5-phenyloxazole using various readily accessible 1-bromoal-
kynes (Table 2). Two methods are commonly used for their
preparation: 1) bromination of terminal alkynes using NBS/
AgNO3; or 2) a two-step sequence involving formation of 1,1-
dibromoalkenes from their corresponding commercially
available aldehydes, followed by a DBU/DMSO-promoted
dehydrobromination.[9] Both electron-rich (Table 2, entries 1–
5) and electron-deficient (Table 2, entries 6–8) alkynyl bro-
mides reacted regioselectively at the C2 position of 1a in good
yields, with substitution being tolerated at each of the ortho,
meta, and para positions. The reaction proceeds equally well
with heteroaryl- and alkenyl-susbtituted alkynes (Table 2,
entries 9 and 10); however, alkyl-substituted 3l was obtained
in a disappointing 26% yield (Table 2, entry 12). Noteworthy
is the (triisopropylsilyl)bromoacetylene, which underwent
coupling to afford the silyl-substituted alkynyloxazole 3k in
84% yield; alkynyloxazole 3k is a precursor to the versatile
terminal acetylene, and has potential for further elaboration
(Table 2, entry 11).[10] The C2 regioselectivity of the reaction
Entry Alkynyl bromide
Product
Yield
[%][b]
1
3a 89 (81)[c]
2
3b 84
3
4
5
6
3c 74
3d 82
3e 89
3 f 76
À
was in agreement with that reported for the C H bond
functionalization of 5-substituted oxazoles, and was unam-
biguously confirmed by single-crystal X-ray diffraction anal-
ysis of compound 3 f, in which the unit cell was composed of
two molecules (Figure 1).[11]
7
3g 73
These reaction conditions were also successfully applied
to electron-rich and electron-poor oxazoles (Table 3, entries 1
and 2). Remarkably, oxazole itself was regioselectively
8
3h 66
3i 73
3j 73
3k 84
3l 26
9
10
11
12
[a] 5-Phenyloxazole (0.35m, 1 equiv), alkynyl bromide (2 equiv), dioxane,
1208C for 1 h. [b] Yields are calculated based on isolated products.
[c] Yield in parentheses is obtained for a reaction performed on a gram-
scale.
Figure 1. ORTEP of the two independent molecules compound 3 f.
Ellipsoids set at 50% probability; the fluorine atoms on C18 are
disordered.[12]
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Table 3: Testing the scope of the heterocycle substrate.[a]
of heterocycles.[15] Oxidative addition of B onto the alkynyl
bromide presumably gives a four-coordinate copper(III)
complex (C). Subsequent reductive elimination would lead
to the expected alkynylated compound 3, and regenerate the
catalytic copper(I) species A in the process. Furthermore, this
mechanism rationalizes the beneficial effect of using a bulky
chelating ligand (compare Table 1, entries 12 and 13), as it is
the DPEPhos, rather than the monodentate triphenylphos-
phine, that gives a lower conversion into the product (89%
and 69% respectively). Indeed, formation of the mixed
copper(III)(alkynylate)(oxazolate) intermediate C is thought
to compete directly with activation of a second equivalent of
oxazole, which would afford bis(oxazolate) copper(I) species
D, and subsequently the undesired bis(oxazole) dimer 5.
However, steric hindrance about the copper center blocks
access of the second oxazolate that would generate D; the less
sterically demanding alkyne enters more freely, thus prefer-
entially forming C. Finally, with B generated quickly in the
reaction medium, thanks to the solubility of the dimethylsul-
fide complex and a strong preference for the formation of C
because of the bulky bidentate ligand, the equilibrium is
Entry
Heterocycle
Product
Yield [%][b]
85
1
6
7
2
92
3
4
5
8
9
50
75
10 90
11 71
6
7
12 80
13 50
À
driven toward the formation of the desired product 3. This C
8
H alkynylation can be considered as a “reverse Sonogashira”
reaction because a) the first organocopper species formed
derives from the heterocycle and not from the acetylene, and
b) the acetylene, rather than the heterocycle, is involved in
the oxidative addition step.
[a] Heterocycle (1 equiv), 2 equiv of phenylacetylene bromide (2a),
CuBr·SMe2 (15 mol%), DPEPhos (15 mol%) and LiOtBu (2 equiv), in
dioxane at 1208C for 1 h. [b] Yields are calculated based on isolated
products.
À
In summary, we have developed new conditions for a C H
bond functionalization that enables the first entirely copper-
catalyzed direct alkynylation of heterocycles. This reaction is
very rapid, is functional group tolerant, and provides a
straightforward entry to diverse alkynyl heterocycles that is
alkynylated at the C2 position, albeit in moderate yield (50%;
Table 3, entry 3). Other heterocycles, such as benzoxazole,
benzothiazole, 1,3,4-oxadiazole, and 1,2,4-triazole were also
found to be suitable substrates
(Table 3, entries 4–7).
Whilst compounds with higher
pKa values (ꢀ 30), such as imida-
zoles, gave mediocre results (not
shown), the reaction proceeded in
satisfactorily yield with N-benzyl-
6-chloropurine (50%; Table 3,
entry 8). This result is particularly
À
noteworthy as it leaves the C Cl
bond untouched; it therefore
allows subsequent functionaliza-
tion at this position to access
biologically interesting 6,8,9-tri-
substituted purines.[13]
Although the precise mecha-
nism of this new process is unclear
Scheme 1. Mechanistic proposal for copper-catalyzed direct alkynylation of heterocycles with alkynyl
at this stage, the reaction probably bromides.
proceeds through the formation of
a
copper(III) complex (C;
Scheme 1), because such species are commonly speculated
as intermediates in the copper-mediated Ullmann reaction
complementary to the well-established Sonogashira reaction.
This work illustrates once again that inexpensive copper salts
[14]
À
À
and recently in the C H bond arylation reaction.
The
are able to supplement palladium catalysis in the field of C H
bond activation.
sequence begins with deprotonation of the oxazole by
LiOtBu, followed by lithium–copper transmetallation to
generate copper(I)(oxazolate) intermediate B, as illustrated
by Do and Daugulis for the copper-catalyzed direct arylation
Received: August 26, 2009
Published online: November 9, 2009
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www.angewandte.org
9555

Communications
À
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Keywords: alkynes · alkynylation · C H activation · copper ·
heterocycles
.
tion of our manuscript, Tobisu and Chatani published
a
À
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