Tetrahedron Letters
Palladium-free Sonogashira-type cross-coupling reaction of
bromoisoxazolines or N-alkoxyimidoyl bromides and alkynes
⇑
N. P. Probst, B. Deprez, N. Willand
Univ. Lille, Inserm, Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, F-59000 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A Cu(I)-catalysed Sonogashira-type cross coupling reaction with aliphatic or aromatic bromoisoxazolines
or N-alkoxyimidoyl bromides and alkynes is reported. The protocol we developed employs catalytic
amount of copper(I), non-toxic ligand bathophenanthroline and is tolerant to a wide range of functional
groups and is therefore particulary adapted in the context of drug discovery.
Received 17 December 2015
Revised 12 January 2016
Accepted 19 January 2016
Available online 21 January 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Sonogashira-type
Copper catalysis
Catalysis
Isoxazoline
Introduction
Here, we describe the first palladium-free cross-coupling reac-
tion between bromoisoxazolines and alkynes in the presence of a
Palladium and copper co-catalysed Sonogashira-Hagihara
cross-coupling reaction is widely used for the formation of sp2–
sp carbon–carbon bonds under mild conditions with aryl or vinyl
halides (or triflate) and is frequently employed for the synthesis
of biologically active molecules, heterocycles, natural products
and in other chemical fields such as electronics or polymers.1 Typ-
ical procedures involve the use of palladium phosphine complexes
with CuI as the co-catalyst and large amounts of amines as the sol-
vents or co-solvents.2 To circumvent the high cost and relative
higher toxicity of palladium compared to copper, catalytic systems
without palladium have been successfully reported in the litera-
ture, combined with ligands such as phosphines,3 nitrogen4 and
oxygen-containing molecules.5 Even coupling reactions without
the use of any transition metal have been published.6
Nevertheless, coupling partners such as acid chlorides and imi-
doyl halides have received less attention, with only few examples
of catalytic coupling reaction between N-alkoxybenzimidoyl
halides, and alkynes are described in the literature.7 Those exam-
ples were restricted to aromatic groups attached to the sp2 carbon
and with the use of catalytic amount of palladium(II) complex
(Scheme 1A).8
catalytic amount of copper bromide and phenanthroline based-
ligand (Scheme 1B). An extension to N-alkoxylalkylimidoyl bro-
mides is also reported.
Results and discussion
At the outset of our investigations, we carried out the Sono-
gashira cross-coupling reaction between bromospiroisoxazoline
1a and phenylacetylene 2a under standard Sonogashira condi-
tions.9 Unfortunately, the desired cross-coupling product was not
obtained, and
observed.
a considerable amount of side products was
Solvents were first screened (Table 1) with CuBr as a cheap cop-
per(I) source. For the first time the desired product was observed
with the combination of Na2CO3 and DMF. (HPLC yield: 4% yield
with Bn2O as the internal standard, Table 1, entry 1), whereas with
toluene, THF or 1,4-dioxane as solvents no desired coupled product
was detected, suggesting a dissociative pathway.
To reduce the catalytic charge of copper (in our first experiment
loaded at 50 mol %) while trying to increase significantly the yield,
we investigated different ligands, bases, copper sources (Table 2).
At 100 °C, only ligands L1 and L8 containing aromatic nitrogen as
donor groups (Table 2, entries 1 and 5) yielded the desired com-
pound 3aa with more than 10% HPLC yield, compared to those
bearing secondary and tertiary amines (Table 2, entries 2–4).
At higher temperature (120 °C), phenanthroline L1 and 2,20-
bipyridyl L8 (Table 2, entries 6 and 7) associated with CuBr were
⇑
Corresponding author at present address: Faculté de Pharmacie, 3 rue du
Professeur Laguesse, 59000 Lille, France. Tel.: +33 3 20 96 49 91; fax: +33 3 20 96 47
09.
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.