Microwave-assisted benzyne-click chemistry: preparation of 1H-benzo[d][1,2,3]triazoles

Article abstract of DOI:10.1016/j.tetlet.2009.06.004

The benzotriazoles were prepared by three-component and two-component microwave-assisted [3+2] cycloadditions of various azides to benzyne, 3-methoxybenzyne, and 4,5-difluorobenzyne. In the three-component reaction, the aryne is generated, in the presence of an azide prepared in situ, by the reaction of an o-(trimethylsilylaryl) triflate with either CsF or KF/18-Crown-6. However, in the two-component reactions, a freshly prepared azide is added to the reaction vessel prior to aryne generation. Good to excellent yields of benzotriazoles were obtained in 15-20 min when the microwave-assisted reactions were carried out at 125 °C. These reaction times are significantly faster than similar reactions carried out using conventional heating.

Full text of DOI:10.1016/j.tetlet.2009.06.004

Tetrahedron Letters 50 (2009) 4677–4682
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted benzyne-click chemistry: preparation
of 1H-benzo[d][1,2,3]triazoles
*
Haribabu Ankati, Ed Biehl
Department of Chemistry, Southern Methodist University, Dallas, TX 75275, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The benzotriazoles were prepared by three-component and two-component microwave-assisted [3+2]
cycloadditions of various azides to benzyne, 3-methoxybenzyne, and 4,5-difluorobenzyne. In the three-
component reaction, the aryne is generated, in the presence of an azide prepared in situ, by the reaction
of an o-(trimethylsilylaryl) triflate with either CsF or KF/18-Crown-6. However, in the two-component
reactions, a freshly prepared azide is added to the reaction vessel prior to aryne generation. Good to
excellent yields of benzotriazoles were obtained in 15–20 min when the microwave-assisted reactions
were carried out at 125 °C. These reaction times are significantly faster than similar reactions carried
out using conventional heating.
Received 29 April 2009
Accepted 1 June 2009
Available online 6 June 2009
Keywords:
Benzyne
Microwave-assisted reactions
Click reaction
1H-Benzo[d][1,2,3]triazoles
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
a [3+2] cycloaddition of an azide to an aryne. Accordingly, various
azides were first prepared in situ, which was followed by the gener-
The [3+2] cycloaddition of azides with alkynes,1 termed ‘click’
chemistry,2 has been extensively studied and applied to several
areas of chemistry. Recently, Larock et al.3 reported the first ben-
zyne click chemistry which involved the room temperature reac-
tion of an azide with benzyne, generated by the reaction of o-
(trimethylsilyl)-aryl triflate and CsF,4 to give the corresponding
1H-benzo[d][1,2,3]triazoles (hereafter referred to as benzotriaz-
oles). The benzotriazoles were obtained in 51–100% yields, but
reaction times ranging from 18 to 24 h were required. Subse-
quently, Campbell-Verduyn et al.5 developed a copper-free ‘click’
1,3-dipolar-cycloaddition of azide and arynes (also generated by
the reaction of o-(trimethylsilyl)-aryl triflate and KF in the pres-
ence of 18-crown-6) in which benzotriazoles were formed rapidly
(0.5–2 h) at room temperature in yields ranging from 59% to 82%.
In our continuing interest in microwave-assisted reactions, we
recently reported the first microwave-assisted reaction6 involving
benzyne, namely, the copper-catalyzed benzyne-acetylene cou-
pling reaction. We have extended the use of microwave heating
to benzyne click chemistry and report the results herein. To our
knowledge this is the first example of a microwave-assisted ben-
zyne click reaction.7
ation of benzyne, 3-methoxybenzyne, or 3,4-difluorobenzyne by the
reaction of an o-trimethylsilylaryl triflate with either CsF or KF/18-
crown-6. The reagents were charged into a sealed tube which was
placed in a CEM Discover Model and subjected to microwave radia-
tion at a power of 200 W while being rapidly stirred. By varying the
solvent, temperature, and reaction time, best yields were obtained
when the two successive reactions were run in MeCN at 125 °C for
10 min each. The reaction scheme and results are listed in Table 1
(see Ref. [8] for typical example). As shown, 1-benzyl and 1-substi-
tuted benzotriazoles are formed via benzyne itself (entries 1–10)
in yields ranging from 51% to 85% (CsF) and 63% to 88% (KF/18-
crown-6). In most cases, the yields were slightly higher when ben-
zyne was generated from KF/18-crown-6. Similar treatment of the
unsymmetric 3-methoxybenzyne intermediate gave 4-methoxy-1-
substituted benzotriazoles (entries 11–14) in yields ranging from
63% to 77% using CsF as benzyne inducer and from 69% to 79% using
KF/18-crown-6 as benzyne inducer. The structures of these products
were confirmed by 1D and 2D NOE experiments. Presumably the
4-methoxy group sterically hinders the formation of the 7-meth-
oxy-1-substituted product. As expected the symmetric 4,5-dif-
luorobenzyne gave 1-benzyl-5,6-di-fluorobenzotriazole (entries 15
and 16) as sole product in very similar yields, that is, 76–79% versus
78–80%. Importantly, the, C@O, CF3, NO2, CN, OMe, and COOH groups
tolerated microwave heating. Further, the reaction times of the CsF
and KF/18-crown-6-induced benzyne reactions were significantly
faster than similar reactions carried out using conventional heating.
Interestingly, attempts to prepare aryl azides by various in situ aryl
amine diazotization reactions prior to benzyne formation gave com-
plex mixture of products.
2. Results
Initially, benzotriazoles were prepared by benzyne-click chemis-
try using a microwave-assisted three-component reaction involving
* Corresponding author. Tel.: +1 214 768 1280; fax: +1 214 768 4089.
E-mail addresses: ebiehl@mail.smu.edu, ebiehl@att.net (E. Biehl).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.004

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H. Ankati, E. Biehl / Tetrahedron Letters 50 (2009) 4677–4682
Table 1
Three-component microwave-assisted benzyne click chemistry
CsF, MeCN
RI
RI
N
N
TMS
OTf
MW, 20 min, 125 ºC
N
R-X
+
+
NaN3
or KF/18-Crown-6, MeCN
MW, 20 min, 125 ºC
R
Entry
1
RX
R1
H
Producta
CsF % yieldb
KF/18-Crown-6 % yieldb
N
N
N
BnBr
79
86
Bn
N
N
2
BnCl
H
80
88
N
Bn
N
N
MeO
MeO
Cl
N
OMe
3
4
5
H
H
H
85
76
62
88
78
66
OMe
OMe
OMe
N
N
N
N
Br
O2N
NO2
N
N
NO2
NO2
Cl
N
O
O
N
Cl
N
6
H
51
63
Cl
Cl
N
N
N
N
N
N
Br
7
8
H
78
81
75
68
70
81
83
78
71
76
F
F
N
N
Br
H
F3C
CF3
CN
N
N
Br
9
H
NC
N
N
Br
10
11
H
HOOC
COOH
OMe
N
N
BnBr
3-OMe
N
Bn

H. Ankati, E. Biehl / Tetrahedron Letters 50 (2009) 4677–4682
4679
Table 1 (continued)
Entry
RX
R1
Producta
CsF % yieldb
KF/18-Crown-6 % yieldb
OMe
N
12
13
14
15
BnCl
3-OMe
72
79
79
69
N
N
Bn
OMe
OMe
N
Br
N
N
3-OMe
3-OMe
77
63
N
O2N
NO2
N
N
NO2
Cl
NO2
F
F
N
N
N
BnBr
BnCl
4,5-F2
4,5-F2
76
79
78
80
Bn
F
F
N
N
16
N
Bn
a
All the compounds were characterized by 1H and 13C NMR spectroscopies.
Isolated yields.
b
We next studied the microwave-assisted 2-component benzyne
microwave-assisted reaction of primary halides with NaN3 and cat-
alytic amount of 18-Crown-6, in nearly quantitative yields (see Ref.
9 for typical example) whereas the aryl azides were synthesized by
click synthesis of benzotriazoles in which freshly prepared ali-
phatic and aryl azides were added to the reaction vessel prior to ar-
yne generation. The aliphatic azides were prepared by the
Table 2
Two-component microwave-assisted benzyne click reaction
CsF, MeCN
MW, 15 min, 125 C
RI
RI
N
N
TMS
OTf
º
N
+
RN3
or KF/18-Crown-6, MeCN
MW, 15 min, 125 C
R
º
R1
H
Productb
CsF % yieldc
KF/18-Crown-6 % yieldc
a
Entry
1
RN3
N
N
N
BnN3
81
89
Bn
N
N
N
N3
2
H
83
92
OMe
OMe
N
N
N
N3
Cl
3
H
81
85
Cl
(continued on next page)

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H. Ankati, E. Biehl / Tetrahedron Letters 50 (2009) 4677–4682
Table 2 (continued)
R1
Productb
CsF % yieldc
KF/18-Crown-6 % yieldc
a
Entry
RN3
N
N
N3
Cl
N
4
H
69
78
Me
Me
O
Cl
O
N
N
O
O
N
N
N3
5
6
H
H
H
H
H
H
H
H
H
H
H
68
66
81
82
69
83
76
72
73
71
71
73
71
83
87
73
86
77
79
75
74
76
Cl
Cl
Cl
OH
OH
N
N
N3
Cl
F
N
N
N3
N
7
F
N
N
N
N
N3
8
O2N
NO2
N
N
NO2
NO2
9
N3
N
N
N
N
N
N3
10
11
12
13
14
15
F3C
CF3
CN
N
N
N3
NC
N
N
N3
HOOC
COOH
N
OH
OH
OH
OH
N
N
N3
Cl
Cl
F
Cl
Cl
F
N
N
N
N3
N
OH
N
OH
N3
N

H. Ankati, E. Biehl / Tetrahedron Letters 50 (2009) 4677–4682
4681
Table 2 (continued)
R1
Productb
CsF % yieldc
KF/18-Crown-6 % yieldc
a
Entry
RN3
F
F
N
N
N
16
17
18
BnN3
BnN3
4,5-F2
73
86
81
75
89
88
Bn
OMe
N
3-OMe
3-OMe
N
N
Bn
OMe
OMe
N
N3
N
N
N
O2N
NO2
N
N
NO2
19
3-OMe
74
79
N3
NO2
OMe
N
N
N3
Cl
N
20
3-OMe
73
79
Me
Me
O
Cl
O
a
All the aliphatic azides were prepared in a CEM microwave synthesizer at 125 °C except entry 6 which was prepared by sodium borohydride reduction of ketone at 0 °C
and all the aryl azides were prepared by diazonium reaction of aromatic amines using t-BuONO followed by treatment with TMSN3.8
b
All the compounds were characterized by 1H and 13C NMR spectroscopies.
Isolated yields.
c
a newly reported novel diazonium reaction of aromatic amines
with t-BuONO followed by treatment with TMSN3.10
In conclusion, we have developed a rapid (15–20 min) micro-
wave-assisted, two-component (aryne precursor and freshly pre-
pared primary or aryl azide) and three-component benzyne
(primary halide, NaN3, and benzyne precursor) click reaction for
the preparation of 1-substituted benzotriazoles. In each case, ben-
zyne intermediates were generated by either CsF or KF/18-Crown-
6. Benzotriazoles possessing a 1-primiary azide group can be pre-
pared by either method with best yields and fastest reaction times
(15 min) being achieved by the 2-component reaction in which
benzyne is generated by KF/18-Crown-6. On the other hand 1-aryl
benzotriazoles are best prepared by the 2-component reaction in
which the benzynes are generated by KF/18-Crown-6. The C@O,
CF3, NO2, CN, OMe, OH, and COOH functional groups tolerate the
conditions of the microwave reactions. Further, it has been shown
that the rate determining step in the fluoride ion-induced aryne
formation from o-trifluoromethysilylaryl triflates involves the very
slow loss of triflate from the anionic phenyl triflate intermediate.4
Under mild, conventional conditions, these arynic reactions can
take as long as 15–22 h. That the arynic reactions reported here
are complete within 15–20 min under microwave heating is truly
remarkable.
As shown in Table 2, good to excellent yields of both 1-aryl-(en-
tries 2–4) and 1-benzylbenzotriazoles (entries 1, 5–15) were ob-
tained in 15 min at 125 °C using either CsF and KF/18-Crown-6 to
generate the aryne intermediates (see Ref. [11] for typical example).
As in the case of the 3-component reactions, the yields of the KF/
18-Crown-6-initiated reactions were higher than those of the CsF-
initiated reactions. For example, the reaction of benzyne with aryl
azides (entries 2–4) gave the corresponding 1-arylbenzotriazoles
in yields ranging from 69% to 83% and from 78% to 92% when benzyne
was generated by CsF and KF/18-Crown-6, respectively. Addition-
ally, 1-benzylbenzotriazoles were prepared in yields ranging from
66% to 83% and from 74% to 89% when benzyne was generated by
the respective fluoride-generating bases. Interestingly, (S)-2-azi-
do-1-(4-fluorophenyl)ethanol (entry 15) was converted to (S)-2-
(1H-benzo[d][1,2,3triazol-1yl)-1-(4-fluorophenyl)-ethanol in 71%
and 74% yields demonstrating that the chiral carbon is retained
and thealcohol functionalgroup toleratedmicrowaveheating. Addi-
tionally, 3-methoxybenzyne (entries17–20) gave the corresponding
4-methoxybenzotriazolesin 73–86% and 79–89% yield, respectively,
and 4,5-di fluorobenzyne (entry 16) reacted with benzyl azide to
give the 4,5-difluoro 1-benzylbenzotriazole in 73% and 75% yield,
respectively. Again the yields from the KF/18-Crown-6 reactions
were higher than those from the CsF. However, the convenience of
the 3-component method in which the aliphatic azides are prepared
in situ, may justify its use in certain cases.
Acknowledgment
We thank the Welch Foundation, Houston, TX, for financial
support.

4682
H. Ankati, E. Biehl / Tetrahedron Letters 50 (2009) 4677–4682
5.83 (s, 2H), 13C NMR (125 MHz, CDCl3): 146.4 (C), 134.8 (C), 132.9 (C), 129.0
Supplementary data
(CH), 128.5 (CH), 127.7 (CH), 127.5 (CH), 124.0 (CH), 120.2 (CH), 109.8 (CH),
52.3 (CH2).
Supplementary data (preparation of azide starting materials,
experimental details, and characterization of the products by 1H
and 13C NMR spectra) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2009.06.004.
9. Preparation of (azidomethyl)benzene: Benzyl chloride (0.252 mg, 2 mmol),
sodium azide (0.162 mg, 2.5 mmol), 18-crown-6 (5.28 mg, 0.2 mmol), and
acetonitrile (3 mL) were placed in a microwave test tube. The tube was then
capped and charged into a CEM microwave instrument. The mixture was
irradiated with 250 psi pressure at a temperature of 125 °C for 10 min. At this
time, the product in the reaction mixture was confirmed by GC/MS. Then the
reaction mixture was diluted with ethyl acetate then washed with water
followed by brine solution. The separated organic layer was dried over Na2SO4
and concentrated under reduced pressure to obtain a yellow oily liquid product
(0.253 mg, 95% yield) that was directly used for the preparation of triazole
reaction. 1H NMR (500 MHz, CDCl3): 7.40–7.49 (m, 5H), 4.37 (br, 1H); 13C NMR
(125 MHz, CDCl3): 135.6 (C), 129.0 (CH), 128.8 (C), 128.5 (CH), 128.4 (CH), 54.9
(CH2): IR (cmÀ1): 3033.5, 2934.0, 2098.3, 1605.0, 1496.5, 1455.2, 1265.6,
1202.5, 877.0, 734.6, 701.6; GC/MS: 133 [M+].
10. Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809.
11. General procedure for the preparation of benzotriazoles by the two-component
method using KF/18-Crown-6: Substituted azide (0.30 mmol), 2-
(trimethylsilyl)phenyl triflate (0.35 mmol), potassium fluoride (0.60 mmol),
and 18-crown-6 (0.30 mmol) in acetonitrile (3 mL) were placed in a microwave
test tube. The tube was then capped and charged into a CEM microwave
References and notes
1. Huisgen, R. Helv. Chim. Acta 1967, 50, 2421.
2. For reviews, see: (a) Gil, M. V.; Arevalo, M. J.; Lopez, O. Synthesis 2007, 1589; (b)
Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249.
3. Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10, 2409.
4. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
5. Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.; Dierckx, R. A.; Feringa, B. L.
Org. Biomol. Chem. 2008, 6, 3461.
6. Akubathini, S. K.; Biehl, E. Tetrahedron Lett. 2009, 50, 1809.
7. Ankati, H. B.; Biehl, E. R. Abstract of Papers, 237th National Meeting of the
American Chemical Society, Salt Lake City, Ut., Mar. 22–26, 2009; American
Chemical Society: Washington, DC, 2009; ORG 98.
8. General procedure for the preparation of benzotriazoles by a three-component
system using CsF: Substituted benzyl halide (0.30 mmol), sodium azide
(0.45 mmol), and 18-Crown-6 (0.03 mmol) acetonitrile (3 mL) were placed in
a microwave test tube. The tube was then capped and charged into a CEM
microwave instrument. The mixture was irradiated with 250 psi pressure at a
temperature of 125 °C for 10 min. Then o-trimethylsilylphenyl triflate
(0.35 mmol) and cesium fluoride (0.6 mmol) were added and the reaction
mixture was stirred for 10 min under microwave heating at 125 °C and 250 psi
pressure. The reaction mixture was then washed with saturated NaHCO3
solution followed by saturated brine solution. The organic layer was removed,
dried over Na2SO4, and concentrated under reduced pressure to obtain a crude
product that was purified by preparative TLC using ethyl acetate/hexane (2:8)
system to get the pure compound. Physical and Spectra properties of a typical
benzotriazole produced by this method, that is, 1-benzyl-1H-benzo[d][1,2,3]-
triazole (entry 1, Table 1) is given here. Light yellow compound, mp 113–
115 °C; 1H NMR (500 MHz, CDCl3): 8.05 (d, 1H, J = 8.05 Hz). 7.27–7.35 (m, 8H),
instrument. The mixture was irradiated with 250 psi pressure and at
a
temperature of 125 °C for 15 min. Then the reaction mixture was washed with
saturated NaHCO3 solution followed by brine solution. The separated organic
layer was dried on Na2SO4 and concentrated under reduced pressure and thus
the obtained solid was purified by preparative TLC using ethyl acetate/hexane
(2:8) system to get the pure compound. A typical compound produced by this
method, that is, 1-(2-chloro-5-(4-methoxy-1H-benzo[d][1,2,3-triazol-1-
yl)phenyl)ethanone (entry 20, Table 2): yellow compound; mp 138–140 °C;
1H NMR (500 MHz, CDCl3): 7.99 (d, 1H, J = 2.5 Hz), 7.86 (dd, 1H, J = 8.60,
2.30 Hz), 7.66 (d, 1H, J = 8.0 Hz), 7.48 (t, 1H, J = 8.0 Hz), 7.25 (d, 1H, J = 7.45 Hz),
6.78 (d, 1H, J = 7.45 Hz), 4.14 (s, 3H), 2.73 (s, 3H) 13C NMR (125 MHz, CDCl3):
199.1 (CO), 152.1 (C), 140.4 (C), 138.5 (C), 136.0 (C), 132.3 (CH), 131.2 (C),
130.2 (CH), 125.8 (CH), 123.2 (CH), 104.3 (CH), 102.1 (CH), 56.5 (OCH3), 30.8
(CH3).