Copper(I) 3-methylsalicylate, an efficient catalyst for N-arylation of heterocycles under moderate reaction conditions

Article abstract of DOI:10.1016/j.tetlet.2014.03.117

Copper(I) 3-methylsalicylate mediates N-arylation reactions of both aliphatic and aromatic heterocycles under moderate reaction conditions. Both electron rich and electron poor aryl bromides and a diverse set of N-heterocycles were allowed to react and gave N-arylation products in high yields which demonstrated the efficiency and utility of this catalyst.

Full text of DOI:10.1016/j.tetlet.2014.03.117

Accepted Manuscript
Copper (I) 3-Methylsalicylate, an efficient catalyst for N-arylation of heterocy-
cles under moderate reaction conditions
Abdelbasset A. Farahat, David W. Boykin
PII:
S0040-4039(14)00549-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.117
TETL 44439
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 March 2014
24 March 2014
26 March 2014
Please cite this article as: Farahat, A.A., Boykin, D.W., Copper (I) 3-Methylsalicylate, an efficient catalyst for N-
arylation of heterocycles under moderate reaction conditions, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.03.117
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Copper (I) 3-Methylsalicylate, an efficient catalyst for N-arylation of
heterocycles under moderate reaction conditions
Abdelbasset A. Farahata,b and David W. Boykina*.
aDepartment of Chemistry, Georgia State University, Atlanta, GA, 30303.
bDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy,
Mansoura University, Mansoura 35516, Egypt.
Tel: +1404 413 5498, E-mail: dboykin@gsu.edu
Abstract
Copper (I) 3- methylsalicylate mediates N-arylation reactions of both
aliphatic and aromatic heterocycles under moderate reaction conditions.
Both electron rich and electron poor aryl bromides and a diverse set of N-
heterocycles were allowed to react and gave N-arylation products in high
yields which demonstrated the efficiency and utility of this catalyst.
Keywords.
Ullmann type coupling, Copper (I) 3-methylsalicylate, N-arylation, C-N
bond formation.
The direct formation of aryl C-N bonds between aryl halides and N-
heterocycles, amides and related compounds represents an important
approach for synthesis of more complex molecules. In the past two decades,
the use of metal mediated reactions to achieve aryl C-N bond formation has
1

been the focus of extensive research efforts due to the importance of such
structures in medicinal chemistry and natural products research. The work
has centered in large part on Pd (Buchwald-Hartwig coupling1,2) and Cu
(Ullmann type coupling3,4) based catalysis. Approaches employing both
metals have limitations, although those using copper are generally less
expensive and the reagents are less toxic. The importance of copper
mediated arylation is attested to by the extensive number of publications
describing the search for improvements in copper reagents and reaction
conditions.5 This rapidly expanding field has led to the regular appearance of
comprehensive reviews.6 We note that a great deal of attention has been
given to searching for effective ligands to use with copper salts to provide
efficient copper catalyst systems in situ, including assessment of libraries of
ligands7, whereas relatively less attention has been given to the use of
defined copper complexes.5,6 Copper complexes containing aryl amines have
been reported to react with aryl iodides to form further arylated amines.8
Copper (I) thiophene-2-carboxylate (CuTC), which has been successfully
used as a cofactor in Liebeskind-Srogl protocols for Suzuki type coupling
reactions9, has seen moderate results when used for N-arylation of 2-
imidazolines10 and very good results when used at high loading (25 mol%)
to mediate the reaction between aryl bromides and imidazole and other
2

similar N-heterocycles.11 To our knowledge the use of the related complex
copper(I) 3-methylsalicylate (CuMeSal) has not been reported for N-
arylation reactions using aryl halides. This report describes, for the first
time, the efficient arylation of various N-heterocycles mediated by CuMeSal.
To initiate these studies we used similar conditions to those optimized for
the CuTC meditated N-arylation of imidazole11; DMSO as solvent, open to
air, potassium carbonate as base, relatively high loading of CuMeSal ( 25
mol%) and heating at 110oC for 24 h (CuTC methodology was under
o
11
nitrogen atmosphere at 135 C ). Using both 4-nitrobromobenzene and 4-
methoxybromobenzene we were pleased to find complete conversion to the
respective N-arylimidazoles.
Having determined that CuMeSal effectively mediates N-arylation of
imidazole we then set out to explore the scope of the reaction. First, we
examined the effect of catalyst load using 4-nitrobromobenzene as the
arylating agent as outlined in Table 1 and Scheme 1, where isolated yields
serve as the indicator of conversion to product. As can be seen 10 mol % of
CuMeSal seems to be the lowest amount of catalyst that should be used to
form high yields of product in a relatively short time period. Consequently,
in the subsequent optimization studies we employed 10 mol % of CuMeSal.
Insert scheme 1 and Table 1 here
3

Next we explored the use of a range of different type of solvents at or near
their boiling points as shown in Table 2 and Scheme 2, which shows
reaction temperature, reaction time and isolated yield. In those cases in
which TLC analysis indicated little conversion to product after 3h the
reaction times were extended up to 24 h. It is clear from Table 2 that heating
in DMSO for 3 h at 110oC is the condition of choice. NMP and DMF are
acceptable solvents to use however the reaction times must be extended
beyond that required of DMSO to obtain reasonable yields. The remaining
six solvents studied are ineffective for this reaction.
Insert scheme 2 and Table 2 here
We then examined the effect of base on the course of the reaction as can
be found in Table 3 and Scheme 3. These results indicate that cesium and
potassium carbonate are essentially equally effective, consequently for
economic reasons we used potassium carbonate in subsequent studies. We
examined the effect of base concentration by using one equivalent of
potassium carbonate which, gave a significantly lower yield (42%).
Potassium phosphate is moderately effective, however sodium carbonate is
essentially ineffective for this reaction.
Insert scheme 3 and Table 3 here
4

We next turned our attention to the effect of structure of both the aryl
bromide and the N-heterocycle on the course of the CuMeSal mediated N-
arylation using our optimized conditions.12 These results can be found in
Table 4 and Scheme 4. First, we compared the reactivity of bromobenzene
and both o- and p- nitro and methoxybromobenzene with imidazole under
the optimized conditions.12 There appears essentially no electronic effect of
substituents on the aryl bromide on the reaction under these conditions as
both p-nitro and p-methoxybromobenzene give nearly equivalent isolated
yields of the N-arylimidazoles. The results using the o-isomers show a
modest steric effect; the yields of the N-arylimidazoles using o-nitro and o–
methoxybromobenzene are reduced to 90 and 87%, respectively. As an
initial probe of the effect of changing the aryl halide from bromo to chloro
we allowed 4-nitrochlorobenzene to react with imidazole under the
optimized conditions12 and observed a 76% yield of 1-(4-nitrophenyl)-1H-
imidazole after 6h reaction time (not shown in Table 1). This suggests that
conditions may be found for optimization of N-arylation with aryl chlorides
using CuMeSal, however such studies are beyond the scope of the present
investigation. In addition to coupling reactions with imidazole, Table 4
contains the results for coupling three aryl bromides with pyrazole, 1,2,4-
triazole, pyrrolidine, indole and benzimidazole. All of the five ring
5

heterocycles gave isolated coupling yields of 90% or higher. The results
with pyrrolidine show that CuMeSal mediated coupling reactions are not
limited to N-heteroaromatics and likely can be used for other aliphatic
amines. In general, the isolated yields for the benzimidazole and indole
coupling reactions were somewhat lower (mostly high 80s %) than noted for
the simple 5-ring analogues. The lower yields may be a result of steric
interactions arising from the peri-like 7-proton of both benzimidazole and
indole which is consistent with the modest steric effect noted above for the
o-substituted aryl bromides.
Insert scheme 4 and Table 4 here
In summary we have shown, for the first time, that CuMeSal mediates N-
arylation of N-heterocycles, including aliphatic ones, in high yields under
moderate conditions. The protocol developed provides efficient and
economical methodology for performing Ullmann type N-arylations.
Acknowledgment
This work was supported in part by the Ministry of Higher Education, Egypt
(AAF).
Supplementary data
6

Supplementary data associated with this article, which includes
compound characterization results, can be found, in the online version, at
http:
References and notes
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53.
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754.
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Ghorbani-Vaghei, R.; Hemmati, S.; Veisi, H. Tetrahedron Lett. 2013, 54,
7095. c) Yang, Q.; Wang, Y.; Yang, L.; Zhang, M. Tetrahedron 2013,
69, 6230. d) Wang, X.; Guram, A.; Ronk, M.; Milne, J. E.;Tedrow, J. S.;
Faul, M. M. Tetrahedron Lett. 2012, 53, 7. e) Liu, H-Y.; Yu, Z-T.; Yu,
T.; Zou, Z-G. Tetrahedron 2010, 66, 9141. f) Chen, H.; Wang, D.; Wang,
X.; Huang, W.; Cai, Q.; Ding, K. Synthesis 2010, 1505. g) Haldon, E.;
Alvarez, E.; Nicasio, M. C.; Perez, P. J. Organometallics, 2009, 28,
3815.
7

6. a) Lin, H.; Sun, D. Org. Prep. Proced. Int. 2013, 45, 341. b)
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8. Giri, R.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 2185.
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12. General method of N-arylation. A dry flask was charged with a
nitrogen containing heterocycle (1.5 mmol), aryl halide (1 mmol),
potassium carbonate (2 mmol) and CuMeSal (0.01 mmol) then
anhydrous DMSO (5 ml) was added. The reaction mixture was stirred
o
at 110 C, open to air, for 3 h , cooled to rt, filtered, and the
precipitate was washed with DMSO (2 ml) then stirred with ice water
8

(30 ml) and extracted with ethyl acetate (3 x 50 ml), dried over
sodium sulfate and the solvent was removed under reduced pressure.
The residue was purified by chromatography or recrystallization as
indicated with each compound (see supplementary information).
9

Table 1. Effect of Mol % of catalyst.
Mol % Catalyst
Time (h)
% Isolated yield
5
6
3
3
3
3
72
97
97
97
97
10
15
20
25
10

Table 2. Effect of solvent, temperature and reaction time.
Temp. (oC)
Solvent
DMSO
NMP
Time (h)
% Isolated yield
110
110
110
110
110
101
82
3
97
89
6
DMF
6
93
DMA
24
24
24
24
24
24
No reaction
No reaction
10
Toluene
Dioxane
Isopropanol
Acetonitrile
THF
No reaction
5
81
66
No reaction
11

Table 3. Effect of base.
Base
CsCO3
K2CO3
K3PO4
Na2CO3
Time (h)
% Isolated yield
3
3
98
97
86
15
12
24
12

Table 4. Reaction of different N-containing heterocycles with different
aryl bromides under the optimized reaction conditions12.
N-
%Isolated
yield
A
Product
heterocycle
H
95
98
p-NO2
NO2
N
90
94
o-NO2
p-OMe
N
87
o-OMe
90
97
96
H
p-NO2
p-OMe
13

H
93
98
92
90
96
93
p-NO2
p-OMe
H
p-NO2
p-OMe
N
H
89
99
88
85
92
N
H
N
p-NO2
p-OMe
H
N
H
N
N
H
p-NO2
14

p-OMe
89
15