Copper(I) 3-methylsalicylate mediates the Chan-Lam N-arylation of heterocycles

Article abstract of DOI:10.1080/00397911.2014.961196

Copper(I) 3-methylsalicylate (CuMeSal) mediates N-arylation reactions between aryl boronic acids and aromatic heterocycles (Chan-Lam coupling) under moderate reaction conditions (K₂CO₃, methanol, 65 °C, in air, 3-5 h). Both electron-rich and electron-deficient aryl boronic acids and a diverse set of N-heterocycles were allowed to react and gave N-arylation products in reasonable yields, which demonstrate the utility of this catalyst.

Full text of DOI:10.1080/00397911.2014.961196

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Copper(I) 3-Methylsalicylate Mediates
the Chan–Lam N-Arylation of
Heterocycles
Abdelbasset A. Farahat a b & David W. Boykin a
a Department of Chemistry , Georgia State University , Atlanta ,
Georgia , USA
b Department of Pharmaceutical Organic Chemistry, Faculty of
Pharmacy , Mansoura University , Mansoura , Egypt
Accepted author version posted online: 25 Sep 2014.Published
online: 26 Nov 2014.
To cite this article: Abdelbasset A. Farahat & David W. Boykin (2015) Copper(I) 3-Methylsalicylate
Mediates the Chan–Lam N-Arylation of Heterocycles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 45:2, 245-252, DOI:
10.1080/00397911.2014.961196
To link to this article: http://dx.doi.org/10.1080/00397911.2014.961196
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Synthetic Communications1, 45: 245–252, 2015
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.961196
COPPER(I) 3-METHYLSALICYLATE MEDIATES THE
CHAN–LAM N-ARYLATION OF HETEROCYCLES
Abdelbasset A. Farahat1,2 and David W. Boykin1
1Department of Chemistry, Georgia State University, Atlanta, Georgia, USA
2Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy,
Mansoura University, Mansoura, Egypt
GRAPHICAL ABSTRACT
Abstract Copper(I) 3-methylsalicylate (CuMeSal) mediates N-arylation reactions between
aryl boronic acids and aromatic heterocycles (Chan–Lam coupling) under moderate
reaction conditions (K2CO3, methanol, 65 ꢀC, in air, 3–5 h). Both electron-rich and electron-
deficient aryl boronic acids and a diverse set of N-heterocycles were allowed to react and
gave N-arylation products in reasonable yields, which demonstrate the utility of this catalyst.
Keywords C-N bond formation; Chan–Lam coupling; copper(I) 3-methylsalicylate;
N-arylation
INTRODUCTION
The ability to directly form heterocyclic aryl C-N bonds is of importance to
synthetic chemists engaged in medicinal and natural product chemistry research. In
recent years significant attention has been focused on metal-mediated reactions,
leading to the formation of C-N bonds. These studies have primarily concentrated
on Ullmann (Cu-mediated)[1] and Buchwald–Hartwig (Pd-mediated)[2] coupling reac-
tions. Considerable attention has been given to optimization of the copper-mediated
processes because it is the more economical and less toxic of the two metals. The
preponderance of these studies has focused on reactions between N-heterocycles
and aryl halides with extensive efforts directed toward optimization of the copper
source, ligand, base, and solvent.[3] As a consequence, a number of attractive alter-
natives to the original Ullman process for coupling with aryl halides are available.
Received April 16, 2014.
Address correspondence to David W. Boykin, Department of Chemistry, Georgia State University,
Atlanta, GA 30303, USA. E-mail: dboykin@gsu.edu
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
245

246
A. A. FARAHAT AND D. W. BOYKIN
In 1998 researchers[4–6] reported a variation in the Ullmann process that replaced the
aryl halides with aryl boronic acids, which significantly expands the scope of this
reaction. The Chan–Lam process has been the subject of intensive investigations with
similar goals of optimizing the reaction.[7] Many of these studies have focused on the
pairing of effective copper ion sources with various ligands, whereas relatively limited
attention has been given the use of defined copper complexes. The reaction of imidaz-
ole and aryl boronic acids mediated by a synthetic sulfonato-Cu-salen complex in
water at 100 ꢀC gave good to excellent yields of N-arylimidazoles[8] and a more recent
report has shown that a related synthetic Cu–salen complex mediated the N-arylation
of imidazole and benzimidazole with aryl boronic acids in good yields at room tem-
perature in 2-propanol.[9] We recently reported that commercially available copper(I)
3-methylsalicylate (CuMeSal) mediated the reaction between aryl bromides and
various N-heterocycles in excellent yields.[10] To our knowledge the use of CuMeSal
for Chan–Lam coupling has not been reported for N-arylation. This report describes
our efforts to evaluate CuMeSal as a possible Chan–Lam coupling mediator.
RESULTS AND DISCUSSION
Previously, we had determined that dimethylsulfoxide (DMSO) was the most
effective solvent for the CuMeSal-mediated reaction between aryl bromides and
N-heterocycles;[10] hence in our initial experiment using aryl boronic acids as the aryl
donor we used DMSO as the solvent. When 4-cyanophenyl boronic acid and imidaz-
ole was allowed to react for 3 h in DMSO, in air, at 110 ꢀC in the presence of 15 mol%
CuMeSal and 2 eqv of K2CO3, we were pleased to see that a moderate isolated yield
(55%) of 1-(4-cyanophenyl)-1-H-imidazole was obtained (Scheme 1). Seeking to
improve the yield we explored the same reaction in a number of different solvents
(Table 1). We found that alcohols were the most effective solvents with methanol
(77% yield), giving a slightly greater yield than i-propanol (74% yield).
Next we examined the impact of catalyst load (ranging from 5 to 25 mol%) on
the yield of the reaction between 4-cyanophenyl boronic acid and imidazole in
methanol (Table 2). The two lowest loads of CuMeSal (5 and 10 mol%) gave lower
isolated yields (53% and 61%, respectively) than the 15 mol% load (77% isolated
yield). Raising the catalyst load to 20 or 25 mol% did not significantly change the
yield (79%) obtained compared to that obtained with 15 mol%. Consequently, in
subsequent experiments we used 15 mol% for all the coupling reactions.
In additional efforts to improve the yield we examined the use of several other
bases as shown in Table 3. Cesium and potassium carbonate gave the greatest yields,
Scheme 1. Reaction of imidazole with 4-cyanophenylboronic acid.

COPPER 3-METHYLSALICYLATE CHAN–LAM N-ARYLATION
Table 1. Effects of solvent, temperature, and reaction time
247
Solvent
Temp. (ꢀC)
Time (h)
Isolated yield (%)
DMSO
NMP
DMF
110
110
110
110
110
101
82
3
3
55
43
3
51
DMA
12
12
12
3
Trace
Trace
28
Toluene
Dioxane
Isopropanol
Methanol
Ethanol
74
77
65
78
3
3
69
with the former giving slightly greater value. Because the two bases were essentially
equally effective, we used potassium carbonate in the subsequent studies for
economic reasons.
Table 4 contains the results of the effects of structures of both the aryl boronic
acid and the N-heterocycle on the yield of the CuMeSal-mediated Chan–Lam
process. The electronic effects of substituents on the aryl boronic acid when coupled
with imidazole show a modest effect on the yield of the N-aryl imidazoles. The
isolated yields range from a high of 82% for the electron-attracting p-nitro group
Table 2. Effects of mol% of catalyst
Amount (mol%) catalyst
Isolated yield (%)
5
53
61
77
79
79
10
15
20
25

248
A. A. FARAHAT AND D. W. BOYKIN
Table 3. Effects of base
Base
Time (h)
Isolated yield (%)
Cs2CO3
K2CO3
K3PO4
Na2CO3
Et3N
3
3
80
77
12
12
12
15
58
Trace
to a low of 69% for the electron-donating p-methoxy group. A similar trend was
noted for the CuMeSal-mediated coupling of aryl bromides and imidazole,[10] and
the original Lam conditions using Cu(OAc)2 for coupling imidazole with aryl boro-
nic acids showed a similar substituent effects trend.[6] However, other studies using
various copper salt=ligand combinations for formation of N-arylimidazoles show
no clear substituent effect trend.[11] On examination of the results for the imidazole
coupling reaction with o-nitrophenyl boronic acid and o-methoxyphenyl boronic
acid we note that steric effects play an important role on the yield under our
conditions. In comparison to the results obtained with the p-isomers a greater than
2-fold reduction in yield was noted; the isolated yield for the o-nitro isomer is 35%
and that for the o-methoxy one is 24%. The steric effect for the CuMeSal-mediated
reaction of imidazole with related o-substituted aryl bromides was significantly
less.[10] However, Chan–Lam couplings using [Cu(OH)TMEDA]2Cl2 showed a
similar sensitivity to steric effects.[12] In contrast, a study using CuCl as the copper
source showed essentially no sensitivity to steric interactions.[13] To gain a better
understanding of both substituent electronic and steric effects on the course of
Chan–Lam reactions, careful studies employing a range of substituted aryl boronic
acids, hindered N-heterocycles, and different copper sources under standardized
conditions are needed.
Catalyst systems have been reported which successfully use alkyl boronic acids in
Chan–Lam coupling processes with N-heterocycles.[14] However, under the conditions
presented here we failed to detect the formation of coupling between imidazole and
methyl, cyclopropyl, or cyclopentyl boronic acids. Cross-coupling between boronic
esters and N-heterocycles under various Chan–Lam conditions have been reported,
although the yields are often poor.[15] However, under our conditions no evidence
of coupling was found between imidazole and p-nitrophenylboronic acid pinacol ester.
In the case of the CuMeSal-mediated reactions of aryl bromides with N-heterocycles
we also found that nonaromatic heterocycles such as pyrrolidine were also coupled in
good yields.[10] However, under our standard conditions here we did not detect the
formation of a coupling product between pyrrolidine and p-nitrophenylboronic acid.

COPPER 3-METHYLSALICYLATE CHAN–LAM N-ARYLATION
249
Table 4. Reactions of different N-containing heterocycles with different aryl boronic acids under the
optimized reaction conditions
N-Heterocycle
Ar
Product
Isolated yield (%)
p-Nitrophenyl
82
o-Nitrophenyl
35
p-Cyanophenyl
77
69
p-Methoxyphenyl
o-Methoxyphenyl
24
71
Phenyl
p-Nitrophenyl
78
74
p-OMe
p-Nitrophenyl
84
(Continued )

250
A. A. FARAHAT AND D. W. BOYKIN
Table 4. Continued
N-Heterocycle
Ar
Product
Isolated yield (%)
p-Methoxyphenyl
p-Nitrophenyl
77
75a
65a
72a
67a
p-Methoxyphenyl
p-Nitrophenyl
p-Methoxyphenyl
aReaction time ¼ 5 h.
In contrast, Chan–Lam coupling of aliphatic amines with aryl boronic acids using
copper acetate[16] or copper oxide[17] gave good to excellent yields.
In addition to coupling aryl boronic acids with imidazole we obtained the results
of reaction conditions with the coupling of p-nitrophenyl and p-methoxyphenyl boro-
nic acid with pyrazole, 1H-2,4-triazole, benzimidazole, and indole (Table 4). The
results with pyrazole and 1H-2,4-triazole were similar to those noted with imidazole,
and in all cases the coupling with p-nitrophenylboronic acid gave a somewhat greater
yield than obtained with p-methoxyphenylboronic acid. A similar result was found for
the coupling with benzimidazole and indole, although the reaction times needed to be
increased from our standard 3 h time to 5 h to achieve the indicated yields. This
difference may reflect a moderate steric effect from the peri-like 7-protons of the
two fused ring heterocycles.
In conclusion we have shown, for the first time, that commercially available
CuMeSal mediates Chan–Lam arylation of N-heterocycles in reasonable yields under
moderate conditions. This methodology is not as robust as the similar one using aryl
bromides[10] and it appears less efficient than the Chan–Lam protocols employing
the synthetic Cu-salens.[8,9] Nevertheless, the methodology reported here provides a
useful alternative for performing Ullmann-type N-arylations.

COPPER 3-METHYLSALICYLATE CHAN–LAM N-ARYLATION
251
EXPERIMENTAL
All commercial reagents were used without purification. Melting points were
determined on a Mel-Temp 3.0 melting-point apparatus and are uncorrected.
Thin-layer chromatographic (TLC) analysis was carried out on silica gel 60 F254
1
precoated aluminum sheets using ultraviolet light for detection. H NMR spectra
were recorded on a 400-MHz spectrometer using the indicated solvents. High-
resolution mass spectra (HRMS) were obtained from the Georgia State University
Mass Spectrometry Laboratory, Atlanta, GA.
General Method of N-Arylation
A dry flask was charged with the nitrogen-containing heterocycles (1 mmol),
aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol), and CuMeSal
(0.015 mmol) and then anhydrous methanol (10 ml) was added. The reaction mixture
was stirred at 65 ꢀC, open to air, for 3 h (5 h in case of indole and benzimidazole),
cooled to room temperature, and filtered, and the precipitate was washed with meth-
anol (2 ml). The filtrate was concentrated under vacuum, then stirred with ice water
(30 ml), extracted with ethyl acetate (3 ꢁ 50 ml), and dried over sodium sulfate, and
the solvent was removed under reduced pressure. The residue was purified by chroma-
tography or recrystallization as indicated with each compound in the Supplementary
Material. Spectral data and references to previously reported data for each compound
are also provided in the Supplementary Material.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
FUNDING
This work was supported in part by the Ministry of Higher Education, Egypt
(AAF).
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