Facile route for N1-aryl benzotriazoles from diazoamino arynes via CuI-mediated intramolecular N-arylation

Article abstract of DOI:10.1016/j.tetlet.2010.08.083

A facile and high-yielding protocol for diverse benzotriazoles through intramolecular N-arylation of different o-chloro-1,2,3-benzotriazenes using CuI/Cs₂CO₃ has been developed.

Full text of DOI:10.1016/j.tetlet.2010.08.083

Tetrahedron Letters 51 (2010) 5740–5743
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile route for N1-aryl benzotriazoles from diazoamino arynes
via CuI-mediated intramolecular N-arylation
⇑
Raju R. Kale, Virendra Prasad, H. A. Hussain, Vinod K. Tiwari
Department of Chemistry, Centre of Advanced Study, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and high-yielding protocol for diverse benzotriazoles through intramolecular N-arylation of dif-
ferent o-chloro-1,2,3-benzotriazenes using CuI/Cs2CO3 has been developed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 June 2010
Revised 25 August 2010
Accepted 27 August 2010
Keywords:
Diazonium salt
Benzotriazole
Amines
CuI
N-Arylation
There is an increased demand for significant amount of benzo-
traizole-containing molecules because of their interesting chemis-
try and tremendous chemotherapeutic values.1–4 Potential drugs
like Vorozole1a and Alizapride1b contain a benzotriazole skeleton.
Several simple benzotriazole derivatives have been identified as
agonists of the human orphan G-protein-coupled receptor
GPR109b (HM74),2a inhibitors against different kinases,2b inactiva-
tors of severe acute respiratory syndrome 3CL protease,2c light-
activable DNA cleaving agents2d and are also known to display
an interesting selectivity profile in radio ligand-binding experi-
ments.2e Furthermore, benzotriazole has proved to be a versatile
synthetic auxiliary due to several advantages over other methodol-
ogies including inexpensive, non-toxic, highly stable, and opera-
tional simplicity.3 Thus the methodology nowadays recognized as
the most successful synthetic protocol has grown from an obscure
level to the level of very high popularity, since it can easily be
introduced into the molecules by a variety of reactions, activates
molecules toward numerous transformations, recognized as suffi-
ciently stable during the course of the reaction, and finally can eas-
ily be removed too at the end of the reaction sequence.3,4 In light of
this importance, a facile and efficient method for the synthesis of
benzotriazoles is an attractive objective.
tion of these reactions.5 Recently 1,2,3-triazoles6 were obtained by
the reaction of aromatic amines with t-butyl nitrite and azidotri-
methylsilane followed by CuI-catalyzed azide-alkyne 1,3-dipolar
cycloaddition (click chemistry), and later on, similar chemistry
has successfully been extended for an easy access to functionalized
benzotriazoles.7 Nowadays, fluoride-triggered azide-benzyne
cycloaddition strategies are being used for the synthesis of various
benzotriazoles by treating substituted azides with 2-(trimethyl-
silyl) phenyl triflate in the presence of CsF.8–10
A similar strategy was employed to obtain the triazoles with
fused aromatic skeleton via 2,3-didehydronaphthalene intermedi-
ate.11 Solid-phase synthesis of 1H-benzotriazoles using Hartwig–
Buchwald amination is another recent development in this
promising area.12 Recently, Pereira et al. has described the ultra-
sound-assisted synthesis of 1-acylbenzotriazoles from diazotiza-
tion of o-phenylenediamine.13 Carta constructed the triazole ring
of 4-aminotriazolo[4,5-f]quinolines from 8-acetylamino-6-chloro-
5-nitroquinoline through the reaction with ammonia or hydrazines
at 150 °C14a and later on the method was extended for the synthe-
sis of related heterocyclic skeletons.14b,c
The common synthetic methods for benzotriazole and their
derivatives (Scheme 1)5–12 generally involve the reaction of azides
with diazotized anthranilic acid as the benzyne precursor which
suffers the harsh reaction condition and thus limiting the explora-
N
Benzyne
N3
R
Organic Azide
N
N
R
Click Reaction
N1-Benzotriazoles
⇑
Corresponding author. Tel.: +91 542 6702466; fax: +91 542 2368174.
E-mail addresses: vtiwari@ucdavis.edu, tiwari_chem@yahoo.co.in (V.K. Tiwari).
Scheme 1. Synthesis of N1-benzotriazole under Click reaction condition.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.083

R. R. Kale et al. / Tetrahedron Letters 51 (2010) 5740–5743
5741
Intramolecular
N-Arylation
intramolecular N-arylation of different o-chloro-1,2,3-benzotriaz-
enes using CuI/base has been described.
N
NH2
Cl
N
HCl+NaNO2
N
N
ArNH2 (2a-f)
NHAr
Further to our ongoing research on benzotriazole-mediated
novel synthetic methodologies,15 we commenced our synthetic
strategy with environmentally benign o-chloroaniline, which on
diazotization and in situ treatment with different aromatic amines
including p-anisidine, 2-napthylamine, p-toluedine, and aniline
afforded the intermediates o-chloro-1,2,3-benzotriazenes in good
yields. The benzotriazenes (3a–f) on further treatment with CuI
in the presence of Cs2CO3 led to the formation of various N1-subsi-
tuted benzotriazoles (4a–d, f) in good yields (Scheme 2). Thus, the
synthesis of N1-subsutituted benzotriazoles was achieved in two
steps. Step 1 includes the formation of intermediate 3a through
diazotization and in situ coupling of amines whereas, step 2 in-
volves the formation of desired N1-substituted benzotriazoles
through N-arylation of the intermediates. In our early attempts
to synthesize N1-substituted benzotriazole, we did not succeed in
converting the benzotriazene intermediates into the desired
N
Cl
1
3a-f
4a-f
Ar
Scheme 2. Synthesis of N1-substituted benzotriazoles via intramolecular N-
arylation.
Despite the advantages of the above described protocols for the
synthesis of functionalized benzotriazoles, there are still some
shortcomings like the use of hazardous chemicals, long reaction
times, low reaction yields, requirement of absolute anhydrous con-
ditions, limited availability of starting materials, harsh reaction
conditions, and limited stability of the benzyne intermediate.
Moreover, the hazardous nature of low molecular weight azides,
warrant the search for a simple, short, and high-yielding alternate
protocol to synthesize substituted benzotriazoles. Herein, a facile
and high-yielding protocol for diverse benzotriazoles through
Table 1
Benzotriazole derivatives (4a–f) via intramolecular N-arylation
Entry
Amine (2a, 1, 2c–f)
Condition
Product (4a–f)
Yielda (%)
NH
2
N
N
N
Me
1
CuI, Cs2CO3, DMF, 8 h
80
2a
4a12
Me
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
NH2
CuI, Cs2CO3, DCM, 10 h
CuI, Cs2CO3, toluene, 8 h
CuI, K2CO3, DMF, 10 h
CuI, DABCO, 1, 10-phenanthroline, DMF, 8 h
CuI, DABCO , 1,8-naphthyridine, DMF, 8 h
CuI, DBU, DMF, 8 h
4a
70
—
72
30
NPb
4a
4a
4a
4a
28
Trace amount
Trace amount
—
DIB, DMF, 24 h
Cs2CO3, DMF, 10 h
4a
NPb
N
N
N
Cl
Cl
10
CuI, Cs2CO3, DMF, 8 h
78
76
1
12
4b
NH2
N
N
N
MeO
11
CuI, Cs2CO3, DMF, 8 h
2c
12
4c
OMe
NH
N
N
N
2
12
13
CuI, Cs2CO3, DMF, 8 h
CuI, Cs2CO3, DMF, 8 h
78
—
2d
4d12
NH
2
NRb
2e
NH2
N
N
N
14
CuI, Cs2CO3, DMF, 8 h
75
2f
4f
a
The reaction yield refers to product isolated through column chromatography (SiO2).
No desired product formation, confirmed by comparison with known compound.
b

5742
R. R. Kale et al. / Tetrahedron Letters 51 (2010) 5740–5743
products. The reaction was investigated carefully and we noticed
that the intermediate formed after the coupling of diazonium salt
of o-chloroaniline with amine 1 was not sufficiently stable. It
was getting converted into p-aminoazoaryne, a thermodynami-
cally favoured rearranged product after keeping at 45 °C for a short
period of time. Hence, the reaction was carried out at 20 °C initially
for 1 h to avoid decomposition and then allowed further to con-
tinue at 55 °C.
Acknowledgments
We thank CISC, BHU, and RSIC, CDRI for providing spectroscopic
and analytical data of synthesized compounds; Dr. R. P. Tripathi,
CDRI, Lucknow for useful suggestions and Professor K. N. Singh,
BHU for providing MW facility. Grant-in-Aid from University Grant
Commission, New Delhi, India is gratefully acknowledged.
Having established a protocol for the synthesis of benzotriazole
derivatives, we shifted our focus toward the role of solvents like
CH2Cl2, CHCl3, DMF, and toluene upon yield and the reaction time.
The results illustrated that the reaction in toluene did not give the
desired benzotriazole, whereas, the reaction in CHCl3 was slow and
did not proceed smoothly. However, for this cyclization CH2Cl2 was
found to be good in terms of yield and handling but took a slightly
longer time to afford the products. Eventually, DMF emerged as a
solvent of choice for N-arylation of o-chloro-1,2,3-benzotriazenes
by affording the desired product in very good yield. N-Arylation
reactions are greatly influenced by the base used, therefore, to find
out the appropriate base, we examined K2CO3 and Cs2CO3 in the
cyclization reaction of 3a and found that the reaction in the pres-
ence of K2CO3 afforded the N1-substituted benzotriazole in 72%
yield after a prolonged reaction (10 h) whereas Cs2CO3 gave this
product in 80% yield. We believe that carbonate with a bigger
counter cation may be more dissociated in aprotic solvents and
consequently is more reactive. In order to enhance the yield fur-
ther, we reviewed some more bases and noticed that for a similar
type of cyclization, DABCO with ligand 1,10-phenanthroline has
been successfully used.16 When the cyclization reaction 3a was
carried out with DABCO in presence of 1,10-phenanthroline ligand,
the yield of N1-substituted benzotriazole dropped drastically from
80% to 30% (Table 1). Therefore we explored another ligand, 1,8-
naphthyridine which provides a 1,3 chelating site but this also gave
a poor yield of the product.
The cyclization reaction of 3a in anhydrous DMF in the presence
of Cs2CO3 without CuI was investigated and it resulted in the for-
mation of undesired rearranged product. The failure of the reaction
to afford the desired product confirmed the feasibility of this cycli-
zation only under the catalysis of CuI. Then the cyclization of 3a
through diacetoxyiodobenzene17 was tried and the reaction again
did not occur smoothly and yielded the compound 4a in trace
amounts. All the above studies suggest that CuI in combination
with Cs2CO3 in anhydrous DMF is well suited for intramolecular
N-arylation reaction. In another reaction, o-chloroaniline 1 was
coupled in situ with its own diazonium salt to afford intermediate
o-chloro-1,2,3-benzotriazene 3b in good yield which on treatment
with CuI/Cs2CO3 in anhydrous DMF afforded 2-cholorophenyl ben-
zotriazole 4b in good yield (78%). Unfortunately similar CuI-cata-
lyzed cyclization reaction with benzyl-substituted compound did
not provide the desired benzotriazole. Under similar reaction con-
ditions a series of diverse N1-substituted benzotriazoles (4a–d, and
f) were obtained in good to high yields using different amines such
as p-toluedine, o-chloroaniline, p-anisidine, aniline, and 2-napthyl-
amine (Scheme 2).18
References and notes
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2007, 4, 43–46.
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60, 833–842; (c) Corona, P.; Piras, S.; Palomba, M.; Carta, A. Mini-Rev. Org.
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Tiwari, V. K. Trends Carbo. Res. 2009, 1, 80–85; (e) Tiwari, V. K.; Singh, D. D.;
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18. Typical experimental procedure for the synthesis of functionalized benzotriazoles
(4): 2-Chloroaniline 1 (1 mmol), concd HCl (0.1 ml) and 0.5 ml of water were
mixed in a R.B. flask and stirred for 10 min followed by the addition of 0.4 g of
crushed ice. Then a precooled solution of NaNO2 (1 mmol) in 1 ml of ice cold
water was added dropwise for 5 min with constant stirring at 0 °C. After
complete addition of precooled NaNO2 solution, the reaction was further
stirred for 15 min. The diazonium salt thus precipitated was added slowly into
the solution of p-toludine 2a (1 mmol) and CH3COONa (2 mmol) over a period
of 5–10 min with constant stirring at 0–5 °C. The solution was stirred for
another 1 h maintaining the same reaction temperature. The solid product o-
chloro-1,2,3-benzotriazenes (3a) obtained in quantitative yield was filtered
immediately at below 10 °C and kept for drying in desiccator.
In conclusion, a simple, efficient and novel method has been
developed for an easy access to diverse N1-aryl benzotriazoles
through intramolecular N-arylation of different o-chloro-1,2,3-
benzotriazenes using CuI/Cs2CO3. The protocol offers several
advantages including (a) mild reaction conditions; (b) simple
work-up procedure; (c) moderately high yields of the desired prod-
ucts; and finally (d) the use of explosive azides is avoided. To the
best of our knowledge this is the first report of this kind of intra-
molecular N-arylation reaction for an easy access to functionalized
benzotriazoles. Efforts to widen the scope of the process on fused
heterocycles as well as carbohydrate-based molecules of great che-
motherapeutic value are under progress in our laboratory.
CuI (0.2 mmol) was added to a solution of freshly prepared o-chloro-1,2,3-
benzotriazines (3a, 1 mmol) in anhydrous DMF (2 ml) and the solution was
stirred maintaining the temperature at 20 °C for 15 min. Cs2CO3 (2 mmol) was
added and the reaction was stirred magnetically initially for 1 h at 20 °C and
then allowed to warm up to 55 °C for another 7 h. The progress of the reaction
was monitored by TLC using 12% EtOAc in n-hexane. The reaction mixture was
filtered through Celite, the solvent was evaporated under reduced pressure.
The residue was washed with water (and then extracted with EtOAc
(2 Â 100 ml). The organic layer was dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure. The crude mass thus obtained
was subjected to flash column chromatography that furnished the pure
product, 1-(4-methylphenyl-1H-benzo[d][1,2,3] triazole (4a): Yield 80%; IR
(KBr): mmax 2928, 2847, 1452, 1101 cmÀ1 1H NMR (CDCl3, 300 MHz): d = 8.01
;

R. R. Kale et al. / Tetrahedron Letters 51 (2010) 5740–5743
5743
(d, J = 6 Hz, 2 H), 7.70 (d, J = 9.9 Hz, 1 H), 7.49 (d, J = 7.8 Hz, 1 H), 7.38 (d,
J = 8.4 Hz, 2 H), 7.15 (two d merged and appeared as m, J = 8.1 Hz, 2 H), 2.32 (s,
3 H, CH3) ppm; 13C NMR (CDCl3, 75 MHz): d = 146.6, 138.8, 134.7, 132.5, 130.5,
128.2, 124.3, 123.0, 120.4, 110.4, and 21.3 ppm. 1-(2-Chlorolphenyl-1H-
123.8, 123.57, 123.53, 119.2, 114.1, 113.9, 112.4, 111.9, and 55.3 ppm. 1-
Phenyl-1H-benzo[d][1,2,3]triazole (4d): Yield 78%, brown solid: mp 84 °C; IR
(KBr):
m ;
2933, 2841, 1546 cmÀ1 1H NMR (CDCl3, 300 MHz): d = 8.13 (d,
J = 8.2 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.6 Hz, 1 H), 7.59 (t,
J = 7.5 Hz, 2 H), 7.46–7.54 (m, 2 H), 7.41 (t, J = 8.2 Hz, 1 H); 13C NMR (CDCl3,
75 MHz): d = 146.5, 136.9, 132.3, 129.9, 128.7, 128.3, 124.4, 122.8, 122.4, and
110.4 ppm. 1-(2-Naphthyl-1H-benzo[d][1,2,3]triazole (4f): Yield 75%; IR (KBr):
benzo[d][1,2,3]triazole (4b): Yield 78%; IR (KBr):
1H NMR (CDCl3, 300 MHz): d = 7.76 (d, J = 8.7 Hz, 1 H), 7.58 (m, 1 H), 7.41–7.35
(m, H), 7.14 (d, J = 8.6 Hz, H), 7.07 (m, J = 7.0 Hz, H) ppm. 1-(4-
Methoxyphenyl-1H-benzo[d] [1,2,3]triazole (4c): Yield 76%; IR (KBr): 2931,
2853, 1559 cmÀ1 1H NMR (CDCl3, 300 MHz): d = 7.67 (ddd, J = 8.2 Hz, 2 H),
m ;
2945, 2843, 1542 cmÀ1
4
1
1
m
m ;
2929, 2845, 1537 cmÀ1 1H NMR (CDCl3, 300 MHz): d = 8.67 (d, J = 8.4 Hz, 1
;
H), 8.09–7.85 (m, 3 H), 7.76 (d, J = 9.3 Hz, 1 H), 7.64–7.39 (m, 5 H), 6.94 (d,
J = 9.6 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d 142.8, 139.6, 133.7, 133.5, 132.8,
130.2, 129.8, 128.8, 128.2, 127.0, 126.4, 125.6, 124.4, 121.7, 118.4, 116.5 ppm.
7.53 (d, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 1 H), 7.07 (m, J = 7.5 Hz, 4 H), 3.84 (s,
3 H, OCH3) ppm; 13C NMR (CDCl3, 75 MHz): d = 142.3, 133.5, 129.6, 128.1,