Palladium-free Sonogashira-type cross-coupling reaction of bromoisoxazolines or N-alkoxyimidoyl bromides and alkynes

Article abstract of DOI:10.1016/j.tetlet.2016.01.070

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.

Full text of DOI:10.1016/j.tetlet.2016.01.070

Tetrahedron Letters 57 (2016) 1066–1070
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Tetrahedron Letters
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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.
E-mail address: nicolas.willand@univ-lille2.fr (N. Willand).
URL: http://www.deprezlab.fr (N. Willand).
http://dx.doi.org/10.1016/j.tetlet.2016.01.070
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

N. P. Probst et al. / Tetrahedron Letters 57 (2016) 1066–1070
1067
2c) and electron poor aromatic alkynes (4-fluorophenylacetylene
2b and 2-ethynylpyridine 2e) afforded the coupling products in
excellent yields but no conversion was observed with 1-ethynyl-
4-nitrobenzene (2d). Interestingly 2-ethynylpyridine 2e showed a
remarkable reactivity, affording complete consumption of the
starting bromoisoxazoline 1a within 3 h.
The phenylacetylene derivatives (2a to 2e) afforded in general
better yields compared to aliphatic or functionalized alkynes 2f
to 2i. Aliphatic alkynes 2g and 2h also afforded the targeted com-
pounds in good yields however to overcome the Castro-Stephens
homocoupling reaction, ten equivalents of cyclohexylacetylene 2f
and cyclopropylacetylene 2i were used for the synthesis of the cor-
responding isoxazolines 3af and 3ai. To broaden the scope of the
reaction, we performed the reaction with bromoisoxazolines bear-
ing an ester (1b and 1c), a free alcohol (1e) or a tert-butylcarba-
mate group (1f) and we also succeeded in isolating the desired
compounds in good yields. The cis-fused ring isoxazoline 3da
was also easily obtained following the same protocol (Table 3).
Scheme 1.
Table 2
Ligand optimization of the Sonogashira-type cross-coupling reaction with bromoisox-
azoline 1a and phenylacetylene 2aa
able to catalyse the reaction, affording respectively 61% and 40%
HPLC yield. At 140 °C (Table 2, entry 8) the formation of the desired
compound was not improved. The use of K2CO3 afforded a signifi-
cant better yield (Table 2, entry 9). When phenanthroline based-
ligands (L1 to L4) were used, we were allowed to halve the cat-
alytic loadings of CuBr and ligands respectively to 10 and 25 mol
%. 4,7-dihydroxy-1,10-phenanthroline L2 (Table 2, entry 10) failed
to catalyse the reaction while neocuproin L3 (Table 2, entry 11)
was less effective than phenanthroline L1 (Table 2, entry 12). Inter-
estingly, the reaction was as efficient with CuI (Table 2, entry 13)
and CuBr (Table 2, entry 12) as copper sources, whereas CuCl
(Table 2, entry 14) was less efficient for this transformation. When
the reaction was carried out at 120 °C using 25 mol % of
bathophenanthroline L4 (Table 2, entry 15), 200 mol % of K2CO3
and 10 mol % of CuBr, a quantitative HPLC yield was obtained
and the desired compound was isolated with a 84% yield after flash
chromatography. The copper free reaction (entry 16) did not lead
to any formation of the cross-coupling product, excluding a com-
petitive addition-elimination reaction pathway catalysed by the
phenanthroline alone.
Next, we explored the scope of this reaction starting with substi-
tuted terminal alkynes. Electron rich (4-methoxyphenylacetylene
Table 1
Entry Base
Cu source
(mol %)
Ligand
(mol %)
Time
(h)
Temp.
(°C)
Yield b
Solvent optimization of the Sonogashira-type cross-coupling reaction with bro-
moisoxazoline 1a and phenylacetylene 2aa
1
2
3
4
5
6
7
8
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
Na2CO3 CuBr (20)
L1 (50)
L5 (50)
L6 (50)
L7 (50)
L8 (50)
L1 (50)
L8 (50)
L1 (50)
L1 (50)
L2 (25)
L3 (25)
L1 (25)
L1 (25)
L1 (25)
L4 (25)
14
14
14
14
14
20
20
20
3
9
9
9
9
100
100
100
100
100
120
120
140
120
120
120
120
120
120
120
16
8
9
Br
N
O
Phenylacetylene 2a (300 mol-%)
CuBr (50 mol-%)
Base (200 mol-%)
5
15
61
40
65
84
nrc
20
73
72
57
91
(84d)
nrc
N
O
Solvent
100 °C, 14 h
N
Boc
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CuBr (20)
CuBr (10)
CuBr (10)
CuBr (10)
CuI (10)
10
11
12
13
14
15
3aa
1a
N
Boc
Entry
Base
Solvent
Yieldb (%)
CuCl (10)
CuBr (10)
9
9
1
2
3
4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMF
THF
Toluene
1,4-Dioxane
4
nrc
nrc
nrc
16
K2CO3
—
L1 (50)
20
120
a
Conditions: bromoisoxazoline 1a (0.157 mmol, 100 mol %), phenylacetylene 2a
a
Conditions: bromoisoxazoline 1a (0.157 mmol, 100 mol %), phenylacetylene 2a
(300 mol %), base (200 mol %), copper source, ligand, DMF (1.5 mL).
b
(300 mol %), base (200 mol %), CuBr (50 mol %) in DMF (1.5 mL) at 100 °C for 14 h.
HPLC yield of 3aa relative to Bn2O as the internal standard.
No reaction.
b
c
HPLC yield of 3aa relative to Bn2O as the internal standard.
No reaction.
c
d
Isolated yield after flash chromatography.

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N. P. Probst et al. / Tetrahedron Letters 57 (2016) 1066–1070
Table 3
Scope of the Cu(I)-catalysed Sonogashira-type cross-coupling reactions between bromoisoxazolines 1a–g and alkynes 2a–ia
R
Alkyne 2a-i (300 mol-%)
CuBr (10 mol-%)
L4 (25 mol-%)
Br
N
O
N
O
K2CO3 (200 mol-%)
DMF, 120 °C
Time (h), yield (%)
1a-g
3aa-ga
F
MeO
O2N
N
O
N
O
N
O
N
O
N
N
N
N
Boc
Boc
Boc
Boc
3aa (9 h, 84%)
3ab (12 h, 93%)
3ac (6 h, 89%)
3ad (40 h, nr)
Ph
OTBDMS
N
N
O
N
O
N
O
N
O
N
N
N
N
Boc
Boc
Boc
Boc
3ae (3 h, 81%)
3af (16 h, 70%)b
3ag (6 h, 57%)
3ah (18 h, 76%)
N
O
N
O
N
O
N
O
N
CO2Et
3ba (23 h, 89%)
CO2Et
Boc
3ai (18 h, 82%)b
3ca (6 h, 79%)
3da (6 h, 90%)
N
O
N
N
O
O
HO
3ea (6 h, 40%)
BocHN
3fa (12 h, 58%)
3ga (3 h, 79%)
b 1000 mol % of alkyne was used.
nr = no reaction, Boc = tert-butylcarbamate, Ph = Phenyl, TBDMS = tert-butyldimethylsilyl.
a
Conditions: bromoisoxazoline 1a–g (100 mol %), alkyne 2a–i (300 mol %), K2CO3 (200 mol %), CuBr (10 mol %), bathophenanthroline L4 (25 mol %), in DMF (0.1 M) at
120 °C. Reaction time and isolated yields after flash chromatography are in brackets.
Once bromoisoxazolines 1a–g were shown to be excellent
reagents under our conditions, we turned our attention to the
Sonogashira-type coupling with N-benzyloxyimidoyl bromides
4a–c (Table 4). Interestingly, Miyata and co-workers pointed out
one example containing the cyclohexyl group attached to the
C@N double bond but the product was not isolated due to
blank;the decomposition of the substrate. The optimal conditions
were applied to cyclohexyl N-benzyloxyimidoyl bromides 4a to

N. P. Probst et al. / Tetrahedron Letters 57 (2016) 1066–1070
1069
Table 4
Scope of the Cu(I)-catalysed Sonogashira-type cross-coupling reactions between N-alkoxyimidoyl bromides 4a–c and phenylacetylidene 2aa
Alkyne 2a (300 mol-%)
CuBr (10 mol-%)
L4 (25 mol-%)
OBn
OBn
N
N
R
R
Br
K2CO3 (200 mol-%)
DMF, 120 °C
Time (h), yield (%)
Ph
4a-c
5a-c
OBn
OBn
N
OBn
N
N
O
Ph
Ph
Ph
5ba (6 h, 63%)
5ca (6 h,53%)
5aa (6 h, 81%)
a
Conditions: Reaction carried out with N-benzyloxyimidoyl bromides 4a–c (0.2 mmol, 100 mol %), alkyne 2a (300 mol %), K2CO3 (200 mol %), CuBr (10 mol %),
bathophenanthroline L4 (25 mol %), in DMF (1.5 mL) at 120 °C. Isolated yields after flash chromatography.
Reactivity of the associated ligands
Previous reports suggested that a stable chelate and strongly
donating ligands were required to actively catalyse the reac-
tion.10 We observed that the substituents on the phenanthroline
ring have a strong impact on the reaction rate as depicted in Fig-
ure 1 while copper source can be indifferently CuI or CuBr. 4,7-
Dihydroxy-1,10-phenanthroline L2 inhibits the coupling reaction
and neocuproin L3 slows the reaction compared to phenanthro-
line L1.
Moderate donating group such as phenyl rings on the 4 and 7
positions of the phenanthroline ring (bathophenanthroline L4)
seems to ideally balance the formation of the active monomeric
catalyst B and the C–C bond formation leading to D via the sup-
posed intermediate C. Detailed study of the actual mechanism is
in progress.
Scheme 2. Proposed reaction mechanism for the Sonogashira-type cross coupling.
afford the coupling product 5aa in a good yield (81%). N-Alkoxyimi-
doyl bromides bearing a phenyl (4b) or a furyl (4c) group afforded
respectively 5ba and 5ca in moderate yields from 53% to 63%.
Conclusions
We report the palladium-free Sonogashira-type cross-coupling
reaction between a large set of bromoisoxazolines and alkynes.
The protocol we developed allowed us to broaden this reaction
to alkyl and aromatic N-benzyloxyimidoyl bromide derivatives.
The protocol described herein demonstrates that copper can
replace the conventional, expensive and toxic Pd-catalysed for
Mechanism
A putative mechanism was proposed as outlined in Scheme 2 on
the basis of Bolm and co-workers work. They suggested that a rest-
ing state (form A) was a polymeric complex which was in equilib-
rium with an active monomeric complex (form B) which was
activated by the phenanthroline-based ligand by forming a soluble
[Cu(phenanthroline)(phenylacetylene)] complex.
the
catalysis
of
Sonogashira
cross-coupling
reactions.
Bathophenanthroline was used as a non-toxic ligand. The mild con-
ditions used allow the cross coupling to be carried out in the pres-
ence of functional groups. More importantly the catalytic system
tolerates
a range of electron-poor and electron-rich pheny-
lacetylene derivatives and aliphatic alkynes.
Acknowledgments
We are grateful to the institutions that support our laboratory:
Inserm, Université Lille Nord de France, Institut Pasteur de Lille, EU,
Région Nord-Pas de Calais, and PRIM, Pôle de Recherche Interdisci-
plinaire du Médicament. This project is funded by ANR (ANR-14-
CE14-0027).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.
070.
Figure 1. Benchmark of L1–4 and copper source by ex situ monitoring of formation
of 3aa by HPLC. (Sorted in order of reactivity.)

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2684–2687; (i) Santandrea, J.; Bédard, A.; Collins, S. Org. Lett. 2014, 16, 3892–
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