Efficient copper-catalyzed N-arylation of NH-containing heterocycles and sulfonamides with arenediazonium tetrafluoroborates

Article abstract of DOI:10.1080/00397911.2017.1284239

A practical copper-catalyzed N-arylation of NH-containing heterocycles with arenediazonium tetrafluoroborates has been developed using CuCl as catalyst and K₂CO₃ as additive under ligand-free conditions. This reaction system has wide substrate scope including imides, 1H-pyrazole, 1H-tetrazoles, 1,2-benzisothiazol-3(2H)-one, and related sulfonamides and gives moderate to excellent yields (up to 95%) of the desired products. This strategy is very general, simple, environmentally friendly, and tolerant of oxygen.

Full text of DOI:10.1080/00397911.2017.1284239

An Efficient Copper-Catalyzed N-Arylation of NH-Containing Heterocycles and
Sulphonamides with Arenediazonium Tetrafluoroborates
Yu-Qing Ouyang1, Zhen-Hua Yang1, Zhong-Hui Chen1, Sheng-Yin Zhao1
1Department of Chemistry, Donghua University, Shanghai, P. R. China
Corresponding author Sheng-Yin Zhao E-mail: syzhao8@dhu.edu.cn
Abstract
A practical copper-catalyzed N-arylation of NH-containing heterocycles with
arenediazonium tetrafluoroborates has been developed using CuCl as catalyst, K2CO3 as
additive under ligand-free conditions. This reaction system has wide substrate scope
including imides, 1H-pyrazole, 1H-tetrazoles, 1,2-benzisothiazol-3(2H)-one and related
sulfonamides and gives moderate to excellent yields (up to 95%) of the desired products.
This strategy is very general, simple, environmentally friendly, and tolerant of oxygen.
Graphical Abstract
KEYWORDS: N-arylation; arenediazonium tetrafluoroborate; NH-containing
heterocycle; copper chloride
INTRODUCTION
N-arylated aliphatic and aromatic amines are important substituent in many biologically
active compounds(Scheme 1).They are versatile building blocks in organic synthesis.[1]
1

They serve as key precursors in the synthesis of a variety of natural products,
pharmaceuticals and functional materials.[2] Therefore, the development of efficient
methods for their synthesis has continuously attracted the attentions of many chemists.
In recent years, transition-metal catalyzed C-N bond formation reactions have been
widely explored and emerged as a powerful tool for synthesis of amines, amides and
nitrogen-containing molecules such as Ullmann reaction, Suzuki coupling, Heck,
Sonogashira reaction and so on.[3] Several transition metals have been studied as catalysts
in the sp2 C-H bond activation and oxidative amination reactions such as Cu,[2a] Ni,[4]
Pd,[5] Ru,[6] Rh,[7] Co,[8]and Fe.[9] The arylation agents that have been used are aryl
halides, arylboronic acids, arylbismuth compounds,[10] diaryliodonium salts,[11] aryllead
compounds,[12] and so on. Copper-mediated cross-coupling reactions initiated by the
pioneering work of Ullmann and Goldberg have drawn much interest due to their C-N
bond formations via direct C-N functionalization. Indeed, they have been widely utilized
in the synthesis of nitrogen-containing heterocycles through cross-coupling of aromatic
halides with NH-containing heterocycles.[13] In addition, it should be noticed, however,
that saccharin, tetrazoles, sucinimides, phtalimides and non-heterocyclic sulfonamides
were previously shown to be N-arylated by copper catalysis under oxidative conditions
using boronic acids.[14] However, the above methods have many disadvantages such
as low or moderate yield, long reaction times, expensive and hazardous reagents, high
catalyst loadings and special reaction conditions to enhance reactivity such as high
reaction temperature and visible light photoredox catalysis.[15] Thus, an efficient,
2

economical and environmentally synthetic methodology is highly desirable for this
process.
Arenediazonium salts have been increasingly used by organic chemists in cross-coupling
reactions due to both their wide availability and high reactivity as arylation reagents.[16]
Notably, the superelectrophile properties of arenediazonium salts allows the reaction to
proceed under mild conditions, without the need of the ligands, and occasionally base.
The simple and efficient experimental procedure these reagents enable features many
advantages including lower energy, cost, waste, all of which are of interest for the
development of sustainable processes. In 2014, Taillefer and coauthor reported the
arylation of pyrazole derivatives can be achieved by coupling arenediazonium species
(formed in situ from anilines and tBuONO) by using copper acetate in the presence of
NBu4I as an additive.[17] These results represent the first examples of C-N bond formation
from arenediazonium species. The same year, Bhojane described inexpensive copper(I)
iodide catalyzes the formation of N-aryl amides from arenediazonium salts and primary
amides via in situ formation of iodoarenes in the presence of NBu4I and N1,N2-
dimethylethane-1,2-diamine as ligand.[18] However, a limited substrates were used in
these methodology. In our continuing research program directed toward the chemistry of
arenediazonium salts,[19] herein, we wish to present a practical copper-catalyzed N-
arylation of NH-containing heterocycles and sulfonamides with arenediazonium
tetrafluoroborates using CuCl as catalyst under ligand-free conditions.
RESULTS AND DISCUSSION
3

Our studies were initiated by examining catalyst usefulness and reaction conditions using
succinimide (3a) and PhN2BF4 (2a) as substrates, because the product is easy to detect
and isolate (Table 1). Firstly, benzenediazonium tetrafluoroborate was prepared from
aniline, fluoroboric acid and sodium nitrite following by the classic procedure, because it
is more stable than the corresponding chlorides and avoids side reactions induced by
halogens. Initial tests were performed in DMSO at 25℃under air conditions. When the
experiments were undertaken with catalyst-free and base-free condition, no reaction took
place (Table 1, entry 1). Then, our research plans turn to screen various copper sources
for the N-arylation reaction (Table 1, entries 2-5). We found that compound 4a was
obtained with 63% yield using CuCl as catalyst. When using CuI as catalyst, the yield
decreased to 33%. Fortunately, the yield increased up to 76% in the presence of NEt3 as
additive. Several parameters were altered in an attempt to improve the yield of desired
product. Under the same conditions, we found 93% yield was obtained when working
with K2CO3. Subsequently, we also examined the effect of solvent on the product yield
(Table 1, entries 9-13). Using DMF, CH3COCH3/H2O, THF or CH3CN as solvent, gave
unsatisfactory low yields of product. One possible reason was that the solubility of
reagents is higher in the DMSO system. The above results demonstrated that CuCl is a
more effective catalyst in comparison with other metallic reagents. It should be noted that
without any catalyst, the reaction did not generate the desired product at all.
To further illustrate the utility of this method for NH-containing heterocycles and various
arenediazonium salts, a series of substrates were applied to this protocol. The results are
summarized in Table 2. In some cases, isolated yields were good and ranged from 43 to
4

95%. The aryl rings with electron-withdrawing and donating moieties gave an acceptably
yield. The former led to slightly lower yields than the latter, because of the difference of
nucleophilicity. The yields of products 4i, 4j, 4m and 4o are lower because of the
negative inductive effect of nitro and CF3 groups (Table 2, entry 9,10,13,15).
Additionally, we also tested the different NH-containing heterocycles including imides,
1H-pyrazole,1H-tetrazoles, 1,2-benzisothiazol-3(2H)-one and related sulfonamides for
adaptability of this protocol. These reactions could be run under moderate condition and
gave satisfied yield.
According to the reported literature [16a,19], a possible mechanism for N-arylation is
proposed in Scheme 2. No production was obtained in the presence of TEMPO as free
radical scavenger. It indicated that free radical reaction was carried out in this condition.
First of all, arenediazonium tetrafluoroborate 2a was decomposed to aryl radical 5 and
nitrogen by Cu(I). At the same time, Cu(I) converts to Cu(II). Compound 3a was treated
with K2CO3 to generate 6. The aryl radical coupling with compound 6 generates
intermediate 7. Finally, the resulting intermediate7undergoes reduction by Cu(II) to give
the desired product 4a and the Cu(I) catalyst.
CONCLUSIONS
In summary, we have reported a mild and efficient method for copper-catalyzed N-
arylation of NH-containing heterocycles and sulfonamides by using arenediazonium
tetrafluoroborates as coupling agents under ligand-free conditions. The reactions were
preformed smoothly to generate the desired products in moderate to excellent yields. This
5

method offers one of the important motifs for the synthesis of N-arylated heterocyclic
compounds as natural products, biologically active compounds, and pharmaceutical
agents. Further application of this method for the preparation of new potent bioactive
molecules is ongoing in our group.
EXPERIMENTAL
Melting points were uncorrected and were determined with RY-1 apparatus. Infrared (IR)
spectra were determined as KBr pellets on a Shimadzu model 470 spectrophotometer. 1H
NMR and 13C NMR spectra were recorded using a Bruker AV 400 MHz spectrometer in
CDCl3 with tetramethylsilane as internal standard. Chemical shifts (δ) are expressed in
ppm. EI mass spectra were recorded on Shimadzu QP-2010 GC-MS system and Waters
Micromass GCT system. Silica gel (100–200 microns) was used for all chromatographic
separations. All materials were obtained from commercial suppliers and were used as
received. The purity of substrates and the monitoring of reactions were performed by
TLC on silica gel polygram SILG/UV 254 plates.
General Procedure For The Synthesis Of Arenediazonium Tetrafluoroborates
Aniline (50 mmol) was dissolved in the 40% (V/V) fluoroboric acid (200 mmol). After
cooling to 0 ℃, an aqueous solution of sodium nitrite (3.6 g, 51 mmol) in 15 mL H2O was
added dropwise for 20 min. The mixture was stirred for 3 h and the thick precipitate was
collected and washed with diethyl ether (2×10 mL). The arenediazonium
tetrafluoroborate was dried in vacuo (10-3 mbar) for 10 minutes and was then directly
used without further purification.
6

General Procedure For The Synthesis Of Nitrogen-Containing Heterocycles
To a mixture of NH-containing heterocycles(1.0 mmol), K2CO3 (1.0 mmol), CuCl
catalyst (0.2 mmol), and 8 mL DMSO, arenediazonium tetrafluoroborates (1.2 mmol)
was added dropwise for one hour at 25℃under air condition. The reaction mixture was
stirred for 12 h. After completion of the reaction, the catalyst was filtered off, and
H2O(15mL) was added. The mixture was extracted with ethyl acetate (3×15 mL). The
combined extracts were washed with saturated sodium chloride solution, dried,
evaporated to dryness, and chromatographed on silica gel (eluting with ethyl acetate and
petroleum ether=8:1) to yield specified products 4a~4l. All of the products were known
compounds, and the data of mp and 1HNMR were in accord with those reported in the
literature.
SUPPLEMENTARY MATERIAL
Experimental details and 1H and 13C NMR spectral data for this article can be accessed
on the publisher’s website
ACKNOWLEDGEMENTS
The authors acknowledge financial support from Shanghai Municipal Natural Science
Foundation (Grant 15ZR1401400).
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Table 1 Optimization of the Reaction Conditionsa
Entry Catalyst(equiv.) Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
Time(h) Yield(%)b
1
None
None
None
12
12
12
12
12
12
12
12
12
0
2
CuI (0.2)
33
3
Cu(OAc)2 (0.2) None
trace
trace
63
4
CuCl2(0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.1)
CuCl (0.2)
CuCl (0.2)
None
None
5
6
CH3COONa DMSO
41
7
Et3N
DMSO
DMSO
CH3OH
76
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
93
9
45
10
11
12
13
14
15
16c
17d
Acetone/ H2O 12
trace
53
DCM
12
12
12
8
DMF
trace
trace
83
THF
DMSO
DMSO
DMSO
DMSO
16
12
12
87
72
65
11

a Unless noted otherwise, the reactions were carried out with 1a (1.0 mmol),2a
(1.2mmol), catalyst (0.2mmol), and base (1.0mmol) at 25℃ for 12 h in solvent (8 mL)
under air condition.
bIsolated yields.
c Base (0.5 mmol).
d Base (1.5 mmol).
12

Table 2 Copper-Catalyzed N-arylation of NH-containing heterocycles and sulfonamidesa
Entry Amine
1
ArN2BF4
Product
Yield(%)b
93
4a
2
95
4b
3
4
5
88
91
83
4c
4d
4e
6
81
4f
7
8
85
76
4g
4h
13

9
72
67
4i
4j
10
11
12
67
73
4k
4l
13
14
15
56
71
63
4m
4n
4o
16
17
51
43
4p
4q
14

aReaction condition: NH-containing heterocycles(1.0mmol), arenediazonium
tetrafluoroborates (1.2mmol), CuCl (0.2 mmol), and K2CO3 (1.0 mmol) in DMSO at 25
℃under air condition for 12 hours.
bIsolated yield.
15

Scheme 1. Examples of N-arylated compounds as pharmaceutical targets
16

Scheme 2. Proposed catalytic cycle for the reaction of arenediazonium tetrafluoroborate
and NH-containing heterocycles catalyzed by CuCl.
17