Synthesis of diverse benzotriazoles from aryne precursors bearing an azido group via inter- and intramolecular cycloadditions

Article abstract of DOI:10.1246/cl.160349

A diverse range of benzotriazoles were synthesized from various 3-(azidoalkoxy)aryne precursors, which were easily prepared by Mitsunobu etherification. Various bis-1,2,3-triazoles containing a benzotriazole skeleton were obtained via sequential azide-alkyne and azide-aryne cycloadditions. Intramolecular azido-aryne cycloaddition, conducted using the same starting materials, afforded new types of ring-fused benzotriazoles. In the latter case, the reaction proceeded efficiently even though the regioorientation of the azido group was the reverse of that usually observed in intermolecular reactions between 3-alkoxyarynes and an azide.

Full text of DOI:10.1246/cl.160349

CL-160349
Received: April 9, 2016 | Accepted: April 22, 2016 | Web Released: April 29, 2016
Synthesis of Diverse Benzotriazoles from Aryne Precursors
Bearing an Azido Group
via Inter- and Intramolecular Cycloadditions
Suguru Yoshida, Takamoto Morita, and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University,
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(E-mail: thosoya.cb@tmd.ac.jp)
A diverse range of benzotriazoles were synthesized from
various 3-(azidoalkoxy)aryne precursors, which were easily
prepared by Mitsunobu etherification. Various bis-1,2,3-triazoles
containing a benzotriazole skeleton were obtained via sequential
azide-alkyne and azide-aryne cycloadditions. Intramolecular
azido-aryne cycloaddition, conducted using the same starting
materials, afforded new types of ring-fused benzotriazoles. In the
latter case, the reaction proceeded efficiently even though the
regioorientation of the azido group was the reverse of that usually
observed in intermolecular reactions between 3-alkoxyarynes and
an azide.
A
Previous work: an aryne precursor bearing an alkyne moiety
N
N
R2
N
O
O
O
I
N3–R2
N3–R1
N
N
R1
N
aryne
Cu cat.
OTf
A
pro-A
B
permutable
N
B
This work
N
R1
R1 N3–R2
N
O
*
N3
N
N
N3
O
aryne
sequential
Cu cat.
O
N
I
cycloadditions
Keywords: Aryne
| Azide | Benzotriazole
R2
D
*
OTf
O
pro-C
Benzotriazole is a heterocyclic compound that often forms part
of the core skeleton of bioactive compounds, including clinical
drugs and drug candidates.1 To address the increasing demand for
chemical libraries that facilitate efficient drug discovery, we have
constructed a chemical library comprising benzotriazoles bearing
various pharmacophores.2 Since benzotriazoles are easily prepared
by cycloaddition reactions between arynes and azides,3 arynes
bearing a latently transformable group serve as useful intermedi-
ates for preparing a diverse range of benzotriazoles.2,4,5 In this
context, we recently reported a modular synthetic method for the
preparation of diverse bis- and tris-1,2,3-triazoles, including the
benzotriazole skeleton.2b This approach was based on the use of
aryne precursors pro-A bearing a clickable terminal alkyne moiety
(Figure 1A). Various bis-1,2,3-triazoles B were prepared from
pro-A via sequential azide-aryne and azide-alkyne cycloadditions.
Herein, we show that the azido-functionalized 3-alkoxyaryne
precursors pro-C also serve as useful common platform molecules
for the synthesis of diverse benzotriazoles such as bistriazoles D
and new types of ring-fused benzotriazoles E, which were
obtained via sequential intermolecular cycloadditions and an
intramolecular cycloaddition, respectively (Figure 1B).
Various 3-(azidoalkoxy)aryne precursors, the starting materi-
als used in this study, were easily prepared in a convergent manner
using the Mitsunobu reaction6 (Scheme 1). Commercially avail-
able resorcinols 1 were easily converted to 2-iodo-3-triflyloxy-
phenols 2 according to Suzuki’s three-step protocol.7,8 Dehydra-
tive etherification of 2 with separately prepared azido-substituted
alcohols 3 proceeded efficiently upon treatment with triphenyl-
phosphine and diethyl azodicarboxylate to afford the correspond-
ing aryne precursors 4a-4g without damaging the azido group
stemmed from iminophosphorane formation.8
C
N
N
aryne
N
intramolecular
cycloaddition
E
Figure 1. Versatile synthetic methods for the preparation of
benzotriazoles. (A) Our previous work based on sequential cyclo-
additions of an aryne bearing an alkyne moiety. (B) This work based
on the use of aryne precursors bearing an azido group. Tf = CF3SO2.
R3
R2
R3
R2
1. Iodination
2. Tf2O
i-Pr2NEt
N3
OH
OH
N3
3
HO
I
O
3. Cs2CO3
DEAD
PPh3
toluene, –20 °C
I
R1
OTf
R1
OH
2
1
R1
OTf
53–89%
4
Scheme 1. Preparation of 3-(azidoalkoxy)aryne precursors.
tion (CuAAC),9 followed by silylmethyl Grignard-triggered2b,2c,5v
regioselective azide-aryne cycloaddition (Figure 2). This method
enabled the facile synthesis of bistriazoles such as 8a-8c bearing
various functional groups, including silyl, ester, bromo, and
pyridyl moieties, in moderate to high yield without isolation of the
monotriazole intermediates.
During our attempt to perform the sequential cycloadditions
in reverse order, we observed that a new type of ring-fused
benzotriazole was also produced (Figure 3). From the reaction of
an aryne generated from 4a in the presence of excessive benzyl
azide (7a), a small amount of tetracyclic compound 10a was
obtained in addition to the intermolecular cycloadduct 9a
(Figure 3A). This compound must be formed via an intramolecular
The modular synthesis of benzotriazole-containing bis-1,2,3-
triazoles was accomplished via sequential cycloadditions to the
aryne precursors 4: a copper(I)-catalyzed azide-alkyne cycloaddi-
726 | Chem. Lett. 2016, 45, 726–728 | doi:10.1246/cl.160349
© 2016 The Chemical Society of Japan

R'–N3
R
Table 1. Optimization of the reaction conditions
6
7
(1.2 equiv)
(1.2 equiv)
4
bis-1,2,3-triazole
R–Mtl
N3
(1.2 equiv)
(MeCN)4CuBF4 Me3SiCH2MgCl
O
8
(5 mol %)
(1.2 equiv)
THF
O
N
TBTA (5 mol %)
CH2Cl2, rt, 12 h
THF
Temp., Time
I
N
–78 °C, 1.5 h
N
OTf
4a
10a
N
Br
N
N
N
O
N
N
N
Entry
R-Mtl
Temp./°C
Time
Yield/%
Ph
N
N
N
N
58a
24b
16b
8b
27a
30a
57b
71b
92a
N
N
1
2
3
4
5
6
7
8
9
Me3SiCH2MgCl
n-BuLi
¹78
¹78
¹78
¹78
¹78
¹78
¹40
0
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
O
O
N
N
N
N
CO2Me
N
N
i-PrMgCl
CO2Me
i-PrMgCl¢LiCl
n-BuMgCl
Bn
SiMe3
Br
8a
95%
(2 steps)
8b
66%
(2 steps)
8c
39%
(2 steps)
PhMgBr
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Figure 2. Synthesis of bistriazoles from 4 via sequential intermo-
lecular azide-alkyne and azide-aryne cycloadditions.
rt
5 min
b
1
aIsolated yields. Yields determined by H NMR analysis.
A
Bn–N3
N3
7a
N3
N3
(10 equiv)
O
Me3SiCH2MgCl
(1.2 equiv)
O
O
+
O
O
N
N
I
N
N
Me3SiCH2MgCl
(1.2 equiv)
THF
I
N
N
N
9a
85%
N
THF
rt, 5 min
N
R1
OTf
R1
OTf
4a
–78 °C, 1.5 h
4
10
Bn
10a
9%
OMe
Br
OMe
CF3
Cl
B
O
O
O
O
N3
N3
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
Bn
N
N
N
N
N
N
10b
83%
10c
78%
10d
94%
10e
85%
N
N
N
Bn
distal
proximal
proximal
O
O
intermolecular
cycloaddition
intermolecular
cycloaddition
intramolecular
cycloaddition
O
O
N
N
N
N
N
N
N
favored
disfavored
favored?
disfavored?
N
N
N
MeO2C
Me
N
N
10h
28%
10f
94%
10g
87%
10i
21%
Figure 3. Inter- versus intramolecular azide-aryne cycloaddition.
azide-aryne cycloaddition. Similar to the formation of 9a,
intermolecular [3+2] cycloaddition between 3-alkoxybenzyne
and an azide generally proceeds in a regioselective manner,
owing to the inductive electron-withdrawing effect of the alkoxy
group. This affords a cycloadduct, wherein the alkoxy group and
the substituent on the azide are placed distal to each other
(Figure 3B).2b-2d,3a,3b Because we were interested in the formation
of new types of compact ring-fused heterocycles obtained through
the proximal mode of cycloaddition, which is usually disfavored,
we further examined this unusual intramolecular reaction.
We optimized the reaction conditions for the intramolecular
cycloaddition using aryne precursor 4a (Table 1). In the absence of
an arynophile, treating 4a with (trimethylsilylmethyl)magnesium
chloride (1.2 equiv) in THF at ¹78 °C for 1 h provided the desired
intramolecular cycloadduct 10a in moderate yield (Entry 1). The
use of n-butyllithium or other Grignard reagents returned poorer
results, indicating that the silylmethyl Grignard reagent was a
suitable activator for this purpose (Entries 2-6). The yield of
10a was improved when the reaction was performed at higher
temperatures (Entries 7-9). The best result was obtained when
the reaction was conducted at room temperature for 5 min, which
afforded 10a in excellent yield (Entry 9).8
Figure 4. Synthesis of various ring-fused benzotriazoles.
The optimized conditions were applied to the intramolecular
cycloadditions of various 3-(azidoalkoxy)arynes generated from
precursors 4 (Figure 4).8 Arynes generated from the precursors
bearing electron-rich and -deficient substituents on the azido-
substituted benzene rings also participated in the 7-membered ring-
forming intramolecular cycloaddition to afford benzotriazoles 10b
and 10c in high yields. Chloro- and bromo-substituted benzotria-
zoles 10d and 10e were also obtained, efficiently keeping the
halogen atoms intact. The presence of an additional methyl or ester
group on the 3-alkoxybenzyne ring did not affect the efficacy of
intramolecular cycloaddition, to afford 10f and 10g, respectively
in high yields. Unfortunately, benzotriazole 10h, which contained
a fused 8-membered ring, was only obtained in low yield. In this
case, an undesired side-product, formed via an intermolecular
reaction, was also obtained. Considering that the yield of
benzotriazole 10i, which does not bear a tethering benzene ring,
was also low, the presence of an aromatic azido group must favor
this reaction, although the details are yet to be investigated.
The synthesis of a wider range of benzotriazole derivatives
was easily achieved using a combination of intramolecular azide-
Chem. Lett. 2016, 45, 726–728 | doi:10.1246/cl.160349
© 2016 The Chemical Society of Japan | 727

N3
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OH
N3
Me3SiCH2MgCl
HO
3f
O
I
O
N
N
DEAD
PPh3
toluene
–20 °C
THF
rt
I
N
Br
OTf
10j
72%
2d
Br
Br
OTf
4j
B(OH)2
S
63%
1,4-dioxane
H2O
11
100 °C
cat. L2PdCl2
K3PO4 ·n H2O
4
5
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N
N
N
N3
3 CO2Me
6b
O
cat. (MeCN)4CuBF4
cat. TBTA
O
N
N
N
CO2Me
N
N
N
CH2Cl2, rt
S
S
13
92%
12
91%
Scheme 2. Modular synthesis of bistriazole 13 from 2d, 3f, 11, and
6b.
aryne cycloaddition in conjunction with CuAAC conjugation9
and Suzuki-Miyaura cross-coupling reaction10 (Scheme 2). For
example, the Mitsunobu reaction between phenol 2d, bearing a
bromo group, and alcohol 3f, bearing two types of azido groups,
afforded aryne precursor 4j. Treatment of 4j with the silylmethyl
Grignard reagent afforded tetracyclic benzotriazole 10j, leaving
the bromo and azidomethyl groups untouched. These two groups
were subsequently coupled with boronic acid 11 and alkyne 6b to
yield bistriazole 13, which comprises the four module compounds
2d, 3f, 11, and 6b.8 This approach enabled the facile preparation
of a diverse range of tetracyclic benzotriazoles by substituting the
various components with new compounds.
In summary, we have developed a method for the synthesis of
new types of benzotriazole derivatives based on the cycloadditions
of aryne precursors bearing an azido group. From common starting
materials, a diverse range of bis-1,2,3-triazoles were prepared
via sequential intermolecular cycloadditions, and unique ring-
fused benzotriazoles were obtained via intramolecular azido-aryne
cycloaddition. Application of this method to the construction of a
unique benzotriazole library is now in progress.
6
7
a) O. Mitsunobu, M. Yamada, Bull. Chem. Soc. Jpn. 1967, 40, 2380.
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Miyamoto, Y. Yasui, T. Matsumoto, K. Suzuki, Helv. Chim. Acta 2002,
85, 3589.
The authors thank Central Glass Co., Ltd. for a generous gift
of Tf2O. This work was supported by Platform for Drug
Discovery, Informatics, and Structural Life Science from MEXT
and AMED, Japan; JSPS KAKENHI grant numbers 15H03118
(T.H.) and 26350971 (S.Y.); and the Cooperative Research
Program of the Network Joint Research Center for Materials and
Devices (IMCE, Kyushu University).
Supporting Information for characterization of new com-
pounds is available on http://dx.doi.org/10.1246/cl.160349.
8
9
See Supporting Information for details.
a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem., Int. Ed.
2001, 40, 2004. b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org.
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728 | Chem. Lett. 2016, 45, 726–728 | doi:10.1246/cl.160349
© 2016 The Chemical Society of Japan