Base-mediated N- And O-arylations of NH-containing heterocycles, heterocyclic amines and phenols

Article abstract of DOI:10.3184/174751915X14210808001753

Nucleophilic substitution reactions of N-heterocycles such as imidazole, benzimidazole, indole and pyrazole as well as NH₂ or OH containing heterocycles, with electron-deficient aryl halides in the presence of t-BuOK or K₂CO₃as base and DMSO as solvent are reported. A series of N-aryl azoles, unsymmetric diaryl ethers and diaryl amines were obtained in good yields.

Full text of DOI:10.3184/174751915X14210808001753

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 FEBRUARY, 73–75
RESEARCH PAPER 73
Base-mediated N- and O-arylations of NH-containing heterocycles,
heterocyclic amines and phenols
Zarrin Ghasemi*, Nasim Shahi Shahrak, Behzad Jalali Roomi and Ziba Zakeri
Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz 5166614766, Iran
Nucleophilic substitution reactions of N‑heterocycles such as imidazole, benzimidazole, indole and pyrazole as well as NH2
or OH containing heterocycles, with electron‑deficient aryl halides in the presence of t‑BuOK or K2CO3 as base and DMSO as
solvent are reported. A series of N‑aryl azoles, unsymmetric diaryl ethers and diaryl amines were obtained in good yields.
Keywords: Ullmann type reactions, metal free arylations, N‑aryl azoles, aryl‑heteroaryl ethers
The cross‑coupling N‑ and O‑arylations, which are known
as the Ullmann‑type reactions, have been among the most
relevant transformations in modern organic synthesis.1–4
Transition metal‑catalysed approaches, especially the most
commonly utilised copper and palladium based methodologies,
are the major synthetic protocols to form various C–N and
C–O bond‑containing compounds.5–8 Although extensive
research and notable advances focus on the transition metal‑
assisted cross‑coupling reactions, some drawbacks such
as long reaction times, high reaction temperatures and
expensive metal catalysts, have resulted in increasing interest
and demand for metal‑free techniques in recent years.9–13 In
these fields, organocatalytic14–16 and base‑promoted arylation
reactions17–21 as rapidly growing areas for chemical synthesis,
are of particular importance. Use of a super‑basic medium
such as potassium t‑butoxide or potassium hydroxide in DMSO
can play a critical role in many metal‑free Ullmann‑type
processes.22 In these conditions, the SNAr or benzyne‑mediated
mechanisms are proposed for couplings with activated and
unactivated aryl halides respectively.
Diaryl ethers and N‑aryl azoles which are accessible
through the above methodologies, have emerged as important
classes of organic compounds with extensive applications
in chemical, pharmaceutical, life sciences and polymer
industries.23–26 Through our interest in the synthesis of
polyaromatic heterocyclic frameworks,27–28 we now report the
base‑ mediated O‑arylation of some phenolic compounds for
preparing unsymmetrical diaryl ethers most of which contain
a heterocyclic motif, and also N‑arylation of NH‑containing
heterocycles and some heterocyclic amines. Both classes of
the reactions were carried out using active aryl halides with
electron‑withdrawing groups.
t-BuOK
Nu H
Br
NO2
+
Nu
NO2
1a–l
DMSO
O2N
N
O2N
N
N
O2N
N
N
O2N
N
CH3
N
N
1a
1b
1c
1d
(82%)
(76%)
(79%)
(75%)
CH3
CH3
O2N
N
N
O2N
N
O2N
N
O2N
N
CH3
N
N
N
a
a
1e
1f
1g
1h
(74%)
(80%)
(84%)
(78%)
H
N
H
N
H
N
H
N
S
N
S
N
N
N
N
O2N
O2N
O2N
O2N
1i (76%)
1j (85%)
1k (82%)
1l (79%)
Scheme 1 SNAr reactions of NH‑containing heteroaryls and heterocyclic amines with 4‑bromonitrobenzene. aPromoted by KOH/DMSO.
* Correspondent. E‑mail: z.ghasemi@tabrizu.ac.ir

74 JOURNAL OF CHEMICAL RESEARCH 2015
Table 1 O‑Arylations of some phenolic compounds with electron poor aryl halides
R
Base / DMSO
Ar OH
+
X
2a–i
O
Ar
R
Entry
1
Ar–OH
Aryl halide
Base
Time/h
12
Product
2a–i
Yield%
72
O
3‑Pyridinol
4‑Bromo‑nitrobenzene
2‑Iodo‑nitrobenzene
4‑Bromobenzonitrile
2‑Bromobenzaldehyde
t‑BuOK
2a
NO2
N
NO2
O
2
3
4
“
“
“
K2CO3
K2CO3
K2CO3
6
12
10
2b
2c
2d
63
58
70
N
O
CN
N
CHO
O
N
N
O
NO2
5
8‑Hydroxyquinoline
4‑Bromo‑nitrobenzene
t‑BuOK
6
2e
85
O
6
7
2‑Naphthol
“
4‑Bromo‑nitrobenzene
2‑Bromonaphthalene
t‑BuOK
t‑BuOK
12
24
2f
74
54
NO2
O
2g
NO2
O
8
9
“
2‑Iodo‑nitrobenzene
K2CO3
K2CO3
24
24
2h
2i
65
67
CHO
O
O
O
Kojic acid
2‑Bromobenzaldehyde
OH
were obtained. Furthermore, heterocyclic amines such as
2‑aminopyridine, 2‑aminopyrimidine, 2‑aminothiazole and
2‑aminobenzothiazole also produced the related secondary
amines 1i–l, using the above optimised conditions.
Results and discussion
We first examined the nucleophilic reactions of imidazole with
4‑bromonitrobenzene in the presence of t‑BuOK (1.1 equiv.) in
dry DMSO. The N‑substitution was completed within 4 h at
60 °C (Scheme 1), and the coupling product 1a was obtained
after a very simple workup and in good yield. Fulfilment of
a similar reaction with benzimidazole needed 7–8 h heating
at 60 °C. Utilisation of K2CO3 as the base in these reactions
resulted in the desired products after 24 h at 85 °C.
Other azoles such as pyrazole, 3‑methylpyrazole,
4‑methylpyrazole, and benzotriazole were also subjected
to the t‑BuOK promoted conditions of this reaction and the
corresponding N‑(4‑nitrophenyl) derivatives 1c–f, were
obtained after 4–5 h. in excellent yields (Scheme 1). Under
the same conditions, indole and 3,5‑dimethylpyrazole
showed two major products on TLC, but by using KOH
instead of t‑BuOK, the major N‑arylated products 1g and 1h
We then examined the reactivity of specific phenolic
compounds towards electron poor aryl halides by using
basic media. Table 1 shows the best results from these
investigations. Treatment of 3‑pyridinol, 8‑hydroxyquinoline
and 2‑naphthol with 4‑bromonitrobenzene in the presence
of t‑BuOK (1.1 equiv.) in dry DMSO at 100°C (entries 1, 5
and 6), gave the related O‑(4‑nitrophenyl) derivatives 2a, 2e
and 2f. However the reactions of 2‑iodonitrobenzene with
3‑pyridinol and 2‑naphthol were optimised by using K2CO3
as base, and the 2‑nitrophenoxy compounds 2b and 2h were
obtained in good yields (entries 2 and 8). Clean reactions using
2‑bromobenzaldehyde and 4‑bromobenzonitrile were also
achieved in the presence of K2CO3, so that 3‑pyridinol and

JOURNAL OF CHEMICAL RESEARCH 2015 75
kojic acid were converted to corresponding ethers containing
cyano or formyl groups in these conditions (entries 3, 4 and
9). Finally, t‑BuOK promoted the reaction of 2‑naphthol with
2‑bromonaphthalene, resulting in the bis(2‑naphthyl) ether as
the sole product (entry 7).
Electronic Supplementary Information
1
Spectral and characterisation data (IR, H, and 13C NMR)
of compounds (1a–l) and (2a–i) as well as literature
references to melting point values are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp‑data.
www.jchemres.co.uk.
Conclusions
In conclusion, nucleophilic substitution reactions of
NH‑containing heteroaryls with 4‑bromonitrobenzene in the
presence of t‑BuOK or KOH in DMSO have been reported,
the N‑(4‑nitrophenyl) derivatives were obtained in good yields.
Furthermore, the base‑mediated (t‑BuOK or K2CO3) reactions
of some NH2 or OH containing heterocycles with electron poor
aryl halides, yielded the heteroaryl‑aryl amines or heteroaryl‑
aryl ethers respectively. 2‑Naphthol, also showed good
reactivity with such activated aryl halides under these basic
conditions.
The authors gratefully acknowledge the Iran National Science
Foundation (INSF) for financial support. The research work of
the University of Tabriz is also gratefully appreciated.
Received 6 November 2014; accepted 4 January 2015
Paper 1403004 doi: 10.3184/174751915X14210808001753
Published online: 13 February 2015
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