A novel and regiospecific synthesis of 1-aryl-1H-benzotriazoles via copper(I)-catalyzed intramolecular cyclization reaction

Article abstract of DOI:10.1002/hlca.200900384

1-Aryl-1H-benzotriazole derivatives were synthesized via intramolecular cyclization of easily obtained triazenes, using CuI as the catalyst, DMSO as the solvent, t-BuONa as the base, and 1,10-phenanthroline as the ligand, in up to 97% yield. The synthesis is regiospecific and functional grouptolerant.

Full text of DOI:10.1002/hlca.200900384

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A Novel and Regiospecific Synthesis of 1-Aryl-1H-benzotriazoles via
Copper(I)-Catalyzed Intramolecular Cyclization Reaction
by Qi-Lun Liu, Di-Di Wen, Chen-Chen Hang, Qiu-Lian Li, and Yong-Ming Zhu*
School of Pharmacy, Soochow University, Suzhou, 215123, P. R. China
(phone: þ 86-512-62880109; fax: þ 86-512-67166591; e-mail: zhuyongming@suda.edu.cn)
1-Aryl-1H-benzotriazole derivatives were synthesized via intramolecular cyclization of easily
obtained triazenes, using CuI as the catalyst, DMSO as the solvent, t-BuONa as the base, and 1,10-
phenanthroline as the ligand, in up to 97% yield. The synthesis is regiospecific and functional group-
tolerant.
Introduction. –The structure of 1-aryl-1H-benzotriazole is an important moiety in
compounds that possess antibacterial [1], antimalarial [2], and potassium channel-
activating properties [3], and in selective small-molecule agonists of the human orphan
G-protein-coupled receptor GPR109b (HM74) [4]. In addition, the special character-
istics, due to the tautomerism of the molecule, had attracted many researchersꢀ and
entrepreneursꢀ attention [5]. Some methodologies for the synthesis of these 1-aryl-1H-
benzotriazoles have been developed; the most important are: 1) reaction of
benzotriazoles with aryl halides [6], 2) diazotization and then coupling of benzene-
1,2-diamines [7], and 3) azide – benzyne cycloaddition [8]. Either harsh reaction
conditions or hazardous materials are employed in the above strategies, and difficulties
in directing the newly introduced substituents as a result of the tautomerism of
benzotriazoles still exist.
Recently, transitional metal-catalyzed coupling reactions have gained much interest
due to their high regiospecificity and broad compatibility regarding functional groups
[9]. Zimmermann and Brꢀse [10] obtained a wide range of benzotriazoles by a
combinatorial-chemistry approach using the Hartwig – Buchwald amination reaction.
However, the strategy has to be performed on solid supports and is thus confined to
academic uses. This, together with our previous efforts [11] at the construction of
heterocycles via CuI catalyzed intramolecular cyclization reactions, prompted us to
investigate the feasibility of establishing a regiospecific benzotriazole synthesis strategy
using the corresponding triazenes (Scheme).
Scheme
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Results and Discussion. – To explore the feasibility of the proposed reaction, we
first focused on a brief optimization of the reaction conditions for the synthesis of 2a
from 1a (Table 1), which was easily obtained according to the protocols described in
[12]. In the light of the work of Bulgakova and Gornostaev [13], we considered it
possible to obtain benzotriazoles from the corresponding triazenes. However, no target
compound was obtained, when the reaction was carried out in the absence of either
catalyst or ligand (Entries 13 and 14). When Pd(OAc)2 was utilized as the catalyst, only
small amounts of product were identified (Entry 12). Addition of Cu improved the
yield significantly (Entry 3), suggesting that CuI was a catalyst superior to Pd, and CuI
was much more efficient than CuBr (Entries 1 and 7). To improve the yield further, we
surveyed a series of reaction conditions, and found that all ligands gave 2a in as good a
yield as with 1,10-phenanthroline (La; Entries 8 – 11). Among the solvents employed,
DMSO gave the best result (Entries 1, 5, and 6) due to its better solubility. The base
used played a critical role in the present coupling reaction. When weaker bases were
utilized, 1-(2-bromophenyl)-1H-benzotriazole was isolated apart from the desired
product. The mechanism remains unclear. However, its ratio decreased with increasing
base strength, and the optimal result was achieved with t-BuONa (Entries 1 – 4).
Table 1. Optimization of the Reaction Conditionsa)
b
Entry
Base
Catalyst
Solvent
Ligand
)
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
t-BuONa
K2CO3
Cs2CO3
KOH
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
Cs2CO3
K2CO3
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuI
CuI
CuI
CuI
Pd(OAc)2
CuI
–
DMSO
DMSO
DMSO
DMSO
Toluenec)
1,4-Dioxanec)
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
DMSO
DMSO
La
La
La
La
La
La
La
Lc
Ld
Le
Lf
90
52
58
60
73
75
80
50
80
85
83
18
–
c
)
Lb
–
La
K2CO3
–
a) Reaction conditions: a mixture of 1a, catalyst, ligand, base (1 : 2.5%: 5%: 2) reacted at 135 – 1408
under Ar for 10 h. b) La: 1,10-phenanthroline, Lb: bis[2-(diphenylphosphino)phenyl]ether. Lc: l-
proline, Ld: ethane-1,2-diamine, Le: N,N’-dimethylethane-1,2-diamine, Lf: (ꢀ)-trans-cyclohexane-1,2-
diamine. c) Reflux.
On the basis of the above results, the scope of the reaction was explored with
different substrates. As shown in Table 2, the catalyst system was of quite general
character and tolerant of a wide range of functionalities. The yield was almost

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Helvetica Chimica Acta – Vol. 93 (2010)
quantitative where R2 was 4-Me, followed by where R1 was 4-Cl, H, and 4-Br
(Entries 1 – 3 and 8). Interestingly, where R1 was 4-Cl, only intramolecular cyclization
product was isolated, and no intermolecular coupling product was identified, whereas
traces of intermolecular coupling product were detected, when R1 was 4-Br. This
observation was indicative of and in accord with the reported reactivity order of
IꢁAr> BrꢁAr> ClꢁAr [14]. Entries 1 – 8 suggested that electron-donating or elec-
tron-withdrawing functional groups were also well-tolerated. However, the yields
dropped drastically with a F-substituent in either of the rings (Entries 9 and 12) due to
its special electronic features. As can be seen from Entries 10, 11, and 13, steric
hindrance led to slightly lower yields.
Table 2. Cyclization of Triazenesa)
Entry
Substrate
R1
R2
Product
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
4-Cl
4-Br
3-NO2
3-Me
H
H
H
H
2-Me
4-Cl, 2-Me
4-F
2-Me, 4-NO2
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
90
92
88
73.5
75.3
65.7
72.1
97
40
88
63.6
41.8
78
H
x-MeOc)
x-Brc)
x-Mec)
x-Fc)
H
1j
1k
1l
2j
H
H
H
2kd)
2l
1m
2m
a) Reaction condition: 1 (0.5 mmol), La (25 mmol), t-BuONa (1 mmol), CuI (12.5 mmol), DMSO
(5 ml). b) La: 1,10-Phenanthroline. c) For 1, x ¼ 4; for 2, x ¼ 6. d) 15 h.
Conclusions. – A new protocol that involves CuI-catalyzed intramolecular
amination cyclization in DMSO in the presence of 1,10-phenanthroline and t-BuONa
for the synthesis of benzotriazoles is reported. As a regiospecific synthetic strategy, the
present methodology, using easily accessible starting materials, shows wide functional
group tolerance.
Experimental Part
General. Reagents and chemicals were purchased from commercial suppliers and used without
further purification. Flash chromatography (FC): silica gel (SiO2; 200 – 300 mesh) from Qingdao Ocean
Chemicals, P. R. China. TLC: Silica-gel GF 254 plates. M.p.: XT5 Digital melting-point apparatus from
Beijing Keyi Elec-opti Instrument Factory; uncorrected. IR: ProStarLC240; KBr pellets; ˜n in cmꢁ1. NMR

Helvetica Chimica Acta – Vol. 93 (2010)
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Spectra: UNITY INOVA 400 MHz, CDCl3 soln., unless otherwise noted; d in ppm and J in Hz. MS:
Micromass.
General Procedure. A mixture of 1 (0.5 mmol), CuI (2.4 mg, 12.5 mmol), t-BuONa (96.0 mg,
1 mmol), 1,10-phenanthroline (4.5 mg, 25.0 mmol), and anh. DMSO (5 ml) in a flask filled with Ar was
stirred at 135 – 1408 for 10 h. After removal of the solvent, the cyclized product 2 was obtained by FC
(hexane/AcOEt). For anal. data for compounds 2a, 2b, 2c, and 2l, see [10].
1-(3-Nitrophenyl)-1H-benzotriazole (2d). Pale brown solid (88 mg, 73.5%). M.p. 187 – 1898. IR:
3069, 1598, 1501, 1468, 1270, 1061, 927, 814, 755, 690. 1H-NMR: 8.72 (s, 1 H); 8.37 (d, J ¼ 8.26, 1 H); 8.24
(d, J ¼ 8.06, 1 H); 8.20 (d, J ¼ 8.38, 1 H); 7.80 – 7.87 (m, 2 H); 7.66 (t, J ¼ 7.67, 1 H); 7.51 (t, J ¼ 7.67, 1 H).
13C-NMR ((D6)DMSO): 148.7; 145.9; 137.1; 131.73; 129.26; 128.74; 125.1; 123.2; 119.9; 117.5; 110.9. HR-
MS: 240.0646 (Mþ, C12H8N4Oþ2 ; calc. 240.0647).
1-(3-Methylphenyl)-1H-benzotriazole (2e). Pale yellow liquid (78 mg, 74.3%). IR: 3058, 2921, 1612,
1
1593, 1496, 1064, 786, 746, 693. H-NMR: 8.14 (d, J ¼ 8.35, 1 H); 7.74 (d, J ¼ 8.37, 1 H); 7.39 – 7.63 (m,
5 H); 7.31 (d, J ¼ 7.53, 1 H); 2.49 (s, 3 H). 13C-NMR: 146.9; 140.6; 137.3; 132.8; 130.0; 129.9; 128.6; 124.8;
124.0; 120.7; 120.3; 110.9; 21.9. HR-MS: 209.0953 (Mþ, C13H11N3þ ; calc. 209.0953).
6-Methoxy-1-phenyl-1H-benzotriazole (2f). White solid (74 mg, 65.7%). M.p. 65 – 678. IR: 3058,
2968, 2839, 1494, 1460, 1265, 1051, 833, 804, 761. 1H-NMR: 7.98 (d, J ¼ 9.05, 1 H); 7.75 (d, J ¼ 7.49, 2 H);
7.62 (t, J ¼ 7.84, 2 H); 7.51 (t, J ¼ 7.44, 1 H); 7.04 – 7.09 (dd, J ¼ 9.06, 2.21, 1 H); 7.01 (d, J ¼ 1.75, 1 H); 3.87
(s, 3 H). 13C-NMR: 160.5; 141.6; 136.9; 133.3; 129.7; 128.4; 122.8; 120.7; 116.4; 90.5; 55.7. HR-MS:
225.0902 (Mþ, C13H11N3Oþ; calc. 225.0902).
6-Bromo-1-phenyl-1H-benzotriazole (2g). White solid (99 mg, 72.1%). M.p. 129 – 1308. IR: 3068,
1599, 1501, 1469, 1269, 1061, 814, 755, 691. 1H-NMR: 8.02 (d, J ¼ 8.81, 1 H); 7.93 (s, 1 H); 7.75 (d, J ¼ 8.04,
2 H); 7.64 (t, J ¼ 7.81, 2 H); 7.50 – 7.58 (m, 2 H). 13C-NMR: 145.1; 136.3; 133.2; 129.9; 128.9; 128.0; 122.8;
122.5; 121.3; 113.1. HR-MS: 272.9903 (Mþ, C12H8BrN3þ ; calc. 272.9902).
6-Methyl-1-phenyl-1H-benzotriazole (2h). White solid (104 mg, 97%). M.p. 126 – 1278. IR: 3057,
2974, 2858, 1597, 1505, 1089, 1058, 804, 766, 697. 1H-NMR: 8.01 (d, J ¼ 8.53, 1 H); 7.78 (d, J ¼ 7.59, 2 H);
7.58 – 7.65 (t, J ¼ 7.83, 2 H); 7.48 – 7.54 (m, 2 H); 7.24 – 7.29 (m, 1 H); 2.54 (s, 3 H). 13C-NMR: 144.9; 138.8;
136.9; 132.5; 129.6; 128.3; 126.4; 122.7; 119.5; 109.4; 21.9. HR-MS: 209.0953 (Mþ, C13H11N3þ ; calc.
209.0953).
6-Fluoro-1-phenyl-1H-benzotriazole (2i). Pale yellow solid (43 mg, 40%). M.p. 102 – 1048. IR: 3103,
1625, 1506, 1487, 1450, 1249, 1148, 1112, 762, 694. 1H-NMR: 8.11 (dd, J ¼ 9.04, 4.66, 1 H); 7.75 (d, J ¼ 7.93,
2 H); 7.63 (t, J ¼ 7.81, 2 H); 7.53 (t, J ¼ 7.38, 1 H); 7.40 (dd, J ¼ 8.11, 2.14, 1 H); 7.22 (dt, J ¼ 9.03, 2.16,
1 H). 13C-NMR: 163.9; 161.5; 143.2; 136.5; 132.7; 132.5; 129.9; 128.8; 122.6; 121.7; 121.6; 114.4; 114.1;
96.3; 96.0. HR-MS: 213.0702 (Mþ, C12H8FN3þ ; calc. 213.0702).
1-(2-Methylphenyl)-1H-benzotriazole (2j). White solid (92 mg, 88%). M.p. 66 – 678. IR: 3059, 3030,
2918, 2855, 1502, 1269, 1079, 787, 754. 1H-NMR: 8.15 (d, J ¼ 8.33, 1 H); 7.24 – 7.59 (m, 7 H); 2.13 (s, 3 H).
13C-NMR: 145.3; 135.0; 134.9; 133.6; 131.4; 129.8; 127.8; 126.8; 126.6; 123.9; 119.8; 109.9; 17.5. HR-MS:
209.0952 (Mþ, C13H11Nþ3 ; calc. 209.0953).
1-(4-Chloro-2-methylphenyl)-1H-benzotriazole (2k). White solid (77 mg, 63.6%). M.p. 86 – 888. IR:
3065, 2980, 2856, 1602, 1497, 1454, 1272, 1078, 825, 756. 1H-NMR: 8.15 (d, J ¼ 8.33, 1 H); 7.53 (t, J ¼ 7.57,
1 H); 7.43 – 7.48 (m, 2 H); 7.41 (m, 2 H); 7.37 (t, J ¼ 7.45, 1 H); 2.11 (s, 3 H). 13C-NMR: 145.4; 135.8;
133.6; 133.5; 132.6; 132.1; 129.9; 128.2; 126.8; 124.2; 120.1; 109.7; 17.3. HR-MS: 243.0563 (Mþ,
C13H10ClNþ3 ; calc. 243.0563).
1-(2-Methyl-4-nitrophenyl)-1H-benzotriazole (2m). Pale yellow solid (99 mg, 78%). M.p. 153 – 1548.
IR: 3065, 2925, 1585, 1519, 1348, 1053, 747, 737. 1H-NMR: 8.38 (d, J ¼ 2.15, 1 H); 8.29 (dd, J ¼ 8.63, 2.46,
1 H); 8.20 (d, J ¼ 8.35, 1 H); 7.57 – 7.66 (m, 2 H); 7.50 (t, J ¼ 7.64, 1 H); 7.40 (d, J ¼ 8.31, 1 H); 2.36 (s,
3 H). 13C-NMR: 142.9; 140.6; 135.1; 131.9; 128.1; 123.7; 122.3; 121.8; 119.6; 117.1; 115.3; 104.5; 13.3. HR-
MS: 254.0805 (Mþ, C13H10N4Oþ2 ; calc. 254.0804).

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Received November 3, 2009