A ligand-free copper (1) catalysed intramolecular N-arylation of diazoaminobenzenes in PEG-water: An expeditious protocol towards regiospecific 1-aryl benzotriazoles

Article abstract of DOI:10.1039/c0ob00177e

An efficient and highly versatile method for the synthesis of diverse regiospecific 1-arylbenzotriazoles being important medicinal scaffolds, by the copper (1) catalysed intramolecular N-arylation of diazoaminobenzenes of 2-haloaryldiazonium salts in PEG-water has been developed. A very simple reaction protocol, large number of substrate affordability and excellent yields are the main features of this methodology.

Full text of DOI:10.1039/c0ob00177e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A ligand-free copper (1) catalysed intramolecular N-arylation of
diazoaminobenzenes in PEG-water: an expeditious protocol towards
regiospecific 1-aryl benzotriazoles†
Chhanda Mukhopadhyay,*a Pradip Kumar Tapaswia and Ray J. Butcherb
Received 27th May 2010, Accepted 14th July 2010
DOI: 10.1039/c0ob00177e
An efficient and highly versatile method for the synthesis of diverse regiospecific 1-arylbenzotriazoles
being important medicinal scaffolds, by the copper (1) catalysed intramolecular N-arylation of
diazoaminobenzenes of 2-haloaryldiazonium salts in PEG-water has been developed. A very simple
reaction protocol, large number of substrate affordability and excellent yields are the main features of
this methodology.
Introduction
Results and Discussion
Substituted benzotriazoles, one of the most privileged heterocyclic
subunit display many interesting properties including anticancer,
antifungal, anti-inflammatory, anti-depressant activities1 and ex-
hibit utility as synthetic auxiliaries.2 Many methods have been
developed to synthesize 1,2,3-benzotriazoles till date.3 Tradition-
ally, 1,3-dipolar cycloaddition of organic azides with terminal
alkynes commonly known as click chemistry4 proved to be a very
useful and extremely applicable method.5 However, the synthetic
efficiency of this methodology is largely dependant on the steric
and electronic properties of the alkynes and the regioselectivities
of these reactions are normally low using unsymmetrical alkynes
leading to the regioisomeric mixture of triazoles.6 Again, the
preparations of arynes as well as handling of low molecular
weight azides are hazardous.7 Therefore, it is extremely desirable
to develop more efficient, eco-friendly methodologies for synthe-
sizing this important heterocyclic nucleus particularly, the 1-aryl
substituted ones by one-step procedure.
In continuation of our search for the synthesis of biologically
important heterocycles,24 we, here for the first time, describe
the synthesis of 1-aryl benzotriazoles by copper(I)iodide catal-
ysed intramolecular N-arylation of diazoaminobenzenes of 2-
haloaryldiazonium chlorides in PEG-water at moderate tempera-
ture in excellent yields (Scheme 1).
Although synthesis of various heterocycles from aryl halides
with copper catalysts8–20 has become one of the most popular
synthetic methodologies in the last few decades, yet there is
no report for the synthesis of 1-aryl benzotriazoles using this
strategy. Moreover, all previous syntheses of 1-aryl benzotriazoles
generally proceed by N-arylation of the simple benzotriazole.3a,b
Recently, the synthesis of diverse organic compounds maintaining
an environmentally benign pathway has emerged as a powerful
alternative to the use of volatile, toxic and hazardous organic
solvents.21 PEG, a biologically acceptable polymer has been used
as an inexpensive, thermally stable, recoverable and non-toxic
reaction medium22 as well as a solid-liquid phase transfer catalyst
(PTC) with Cs2CO3 or K2CO3 as a base.23 In addition, a probable
complexation of PEG with copper(I) might result in the prevention
of the hydrolysis of copper species.
Scheme 1 Synthesis of 1-aryl benzo and pyridotriazoles.
Initially, the diazoaminobenzene (1a) (formed by the reaction
of 2-iodobenzene diazonium chloride and aniline) was chosen
as the model substrate (Scheme 1, X I, Y CH, R1 R2 H)
in order to optimize the reaction conditions like the amount of
bases, solvents, copper catalysts, reaction temperature etc. It was
observed that in the absence of either the base or the copper source,
the reaction failed completely (Table 1, entries 1–3). Bases such as
K2CO3, Cs2CO3, K3PO4 were activated this reaction and K2CO3 (2
equivalents) proved to be the best (Table 1, entry 4) among them.
Solvents such as DMF, DMSO, ACN, 1,4-dioxane, MeOH were
investigated and it was found that the best results were obtained
both in cases of DMF and DMSO (Table 1, entries 4, 5). Readily
available copper salts such as CuI, CuCl, CuBr, CuSO4, Cu(OAc)2
were surveyed and CuI proved to be the best choice without any
ligand (Table 1, entries 3–12). Next, we thought it worthwhile to see
if the same reaction can be performed in water keeping in mind its
green impact. We were rather disappointed to find that the reaction
proceeded very poorly in water (Table 1, entry 11) which may be
due to the poor solubility of the diazoaminobenzenes in aqueous
aDepartment of Chemistry, University of Calcutta, 92 APC Road, Kolkata-
700009, India. E-mail: cmukhop@yahoo.co.in; Tel: +91-33-23371104
bDepartment of Chemistry, Howard University, Washington DC, 20059, USA
† Electronic supplementary information (ESI) available: Materials and
methods, synthesis of diazoaminobenzenes, analytical data of compounds,
NMR of compounds. CCDC reference numbers 773428–773429. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00177e
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Table 1 Optimization of reaction condition for copper (1) catalyzed
(2 mL), the desired product was obtained in excellent yield after
2.5 h (Table 1, entry 12) which was even better than in DMF or in
DMSO. The great enhancement in yield using PEG compared to
water must be surely due to the phase transfer catalytic properties
of PEG.23
ligand-free intramolecular N-arylation of diazoaminobenzenesa
With the above optimizations in hand, the scope of this
methodology was explored using different diazoaminobenzenes
of 2-haloaryldiazonium chlorides and substituted anilines (Table
2). The results show that almost all the tested diazoaminobenzenes
successfully produced the desired benzotriazoles in excellent
yields. The reaction was also well tolerated using varieties of
diazoaminobenzenes of quinoline amines. It was noteworthy
that diazoaminobenzenes of less reactive 2-bromoanilines could
successfully react under the present reaction condition to produce
the desired benzotriazoles but in the case of diazoaminobenzenes
of 2-chloroanilines which is obviously much less reactive, the
temperature had to be elevated to 130 ◦C for 6–8 h (Table 2,
entries 9–12, 15, 18–22) to obtain the best yields. In addition, the
same protocol worked well for the diazoaminobenzenes from 3-
amino-2-chloropyridine to produce the pyridotriazoles (Table 2,
entries 18–22).
The final structure for 2e has been confirmed by an X-ray
crystallography of its single crystal and is shown below in Fig. 1.
Interestingly, in case of diazoaminobenzenes of anilines both
possessing halogen atom (I, Br, Cl) at 2-position of the amines, we
obtained the single product indicating the absence of tautomerism
in diazoaminobenzenes under the present reaction conditions
(Table 3).
Catalyst (10
mol%)
Entry Base
Solvent
DMF
Conversion (%)
1
2
3
none
K2CO3 DMF
none DMF
none
none
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
nil
nil
nil
100
100
95
85
70
60
20
05
100
45
75
50
4
5
6
7
8
9
K2CO3 DMF
K2CO3 DMSO
Cs2CO3 DMSO
K3PO4 DMSO
K2CO3 1,4 – dioxane
K2CO3 ACN
10
11
12
13
14
15
16
K2CO3 MeOH
K2CO3 H2O
K2CO3 H2O - PEG – 400 CuI
K2CO3 H2O - PEG – 400 CuCl
K2CO3 H2O - PEG – 400 CuBr
K2CO3 H2O - PEG – 400 CuSO4
K2CO3 H2O - PEG – 400 Cu(OAc)2
60
The final structure for 2d has been confirmed by an X-
ray crystallography of its single crystal and is shown below in
Fig. 2.
a Reaction conditions: diazoaminobenzene 1a (1 mmol), CuI (0.1 mmol),
base (2 mmol) in H2O+PEG-400 (2 mL+0.2 mL) at 110 ◦C for 2.5 h.
Conclusion
medium. Therefore, we used a phase transfer catalyst (PTC) in
water in order to enhance the solubility of diazoaminobenzenes
in this solvent. Moreover, we tried several well known PTCs such
as CTAB, TBAB, 18-Crown-6 and PEG-400. Among them, PEG-
400 turned out to be the best. Using PEG-400 (0.2 mL) in water
In summary, a simple, efficient and expeditious synthetic protocol,
for the synthesis of benzotriazoles and pyridotriazoles through
ligand-free copper(I) iodide catalyzed intramolecular N-arylation
of diazoaminobenzenes of 2-halo anilines or 2-halo pyridoamines
Fig. 1 Ortep plot of 2e showing the crystallographic numbering (CCDC 773428).
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Table 2 Investigation on the scope of diazoaminobenzenes of 2-haloanilines for the formation of benzotriazoles and pyridotriazoles
Entry
1
Diazoaminobenzene
Product
Time/h
2.5
Yields (%) (isolated)
92
Reference
3(c)
2
2.5
92
3(c)
3
4
5
3.0
2.5
3
90
92
89
3(c)
—
—
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Table 2 (Contd.)
Entry
6
Diazoaminobenzene
Product
Time/h
3
Yields (%) (isolated)
90
Reference
—
7
2.5
92
—
8
3
91
—
9
6.0
91
—
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Table 2 (Contd.)
Entry
10
Diazoaminobenzene
Product
Time/h
6.5
Yields (%) (isolated)
84
Reference
—
11
6.0
84
—
12
6.0
82
—
13
2.5
92
25
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Table 2 (Contd.)
Entry
14
Diazoaminobenzene
Product
Time/h
3.0
Yields (%) (isolated)
82
Reference
26
15
16
17
6.5
3.0
3.0
88
90
75
—
—
—
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Table 2 (Contd.)
Entry
18
Diazoaminobenzene
Product
Time/h
6.0
Yields (%) (isolated)
86
Reference
27
19
6.0
88
27
20
6.0
88
—
21
6.5
75
—
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Table 2 (Contd.)
Entry
22
Diazoaminobenzene
Product
Time/h
6.5
Yields (%) (isolated)
84
Reference
—
23
3.0
85
—
Fig. 2 Ortep plot of 2d showing the crystallographic numbering (CCDC 773429).
in PEG-H2O medium are described. The methodology worked
well for all the diazoaminobenzenes of 2-iodo, 2-bromo, 2-chloro
anilines. This synthetic strategy allows the construction of a
wide range of different benzo and pyrido-triazoles both being
important medicinal scaffolds in excellent yields maintaining a
green protocol. We sincerely hope that this methodology should
find great applications in the near future both in academia and in
industry.
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Table 3 Selective formation of 1-aryl benzotriazoles with the CuI catalyzed intramolecular N-arylation of diazoaminobenzenes of 2-halo anilines
Diazoaminobenzene
Product
References
3(c)
—
—
—
flask and the resulting mixture was heated at 110 ◦C (130 ◦C for
diazoaminobenzenes of 2-chloroanilines) until the disappearance
of reacting materials (monitored by TLC). The reaction mixture
was then cooled and poured into a beaker containing crushed
ice. After stirring the mixture for 10 min with a glass-rod, it was
Experimental section
General procedure for the synthesis of 1-aryl benzotriazoles.
Diazoaminobenzene (1 mmol), CuI (0.1 mmol), K2CO3 (2 mmol),
PEG-400 (0.2 mL), H2O (2 mL) were taken in an Erlenmayer
4728 | Org. Biomol. Chem., 2010, 8, 4720–4729
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filtered and extracted through celite by EtOAc. The solvent was
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1
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Acknowledgements
One of the authors (PKT) thanks the University Grants Com-
mission, New Delhi for his fellowship (SRF). We thank the CAS
Instrumentation Facility, Department of Chemistry, University of
Calcutta for spectral data. We also acknowledge grant received
from UGC funded Major project, F. No. 37-398/2009 (SR) dated
11-01-2010.
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