Rh(II)-Catalyzed Transannulation of N-Sulfonyl-1,2,3-Triazoles with 2,1-Benzisoxazoles or 1,2-Benzisoxazoles

Article abstract of DOI:10.1021/acs.orglett.6b02454

A Rh(II)-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles with 2,1-benzisoxazoles has been developed, which affords an efficient method for the synthesis of quinazoline derivatives. The transformation represents an unprecedented example which utilizes N-sulfonyl-1,2,3-triazole as an aza-[2C]-component in cycloadditions. Meanwhile, a Rh(II)-catalyzed formal [3 + 2] cycloaddition of N-sulfonyl-1,2,3-triazoles with 1,2-benzisoxazoles is also presented, which enables the rapid synthesis of functionalized imidazole derivatives.

Full text of DOI:10.1021/acs.orglett.6b02454

Letter
pubs.acs.org/OrgLett
Rh(II)-Catalyzed Transannulation of N‑Sulfonyl-1,2,3-Triazoles with
2,1-Benzisoxazoles or 1,2-Benzisoxazoles
Xiaoqiang Lei,† Mohan Gao,† and Yefeng Tang*,†,‡,§
†School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
‡Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Medical
School, Sichuan University, Chengdu 610041, China
§Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing 100190, China
S
* Supporting Information
ABSTRACT: A Rh(II)-catalyzed transannulation of N-
sulfonyl-1,2,3-triazoles with 2,1-benzisoxazoles has been
developed, which affords an efficient method for the synthesis
of quinazoline derivatives. The transformation represents an
unprecedented example which utilizes N-sulfonyl-1,2,3-triazole
as an aza-[2C]-component in cycloadditions. Meanwhile, a
Rh(II)-catalyzed formal [3 + 2] cycloaddition of N-sulfonyl-
1,2,3-triazoles with 1,2-benzisoxazoles is also presented, which enables the rapid synthesis of functionalized imidazole derivatives.
uinazoline and related scaffolds (e.g., quinazolin-4-one)
has also shown keen interest in this emerging area of research,
and several mechanistically interesting and synthetically useful
cycloaddition reactions have been developed by us.9a,b,10 For
example, we recently disclosed a novel Rh(II)-catalyzed
cycloaddition of N-sulfonyl 1,2,3-triazoles with isoxazoles,
which enables the efficient synthesis of polysubstituted 3-
aminopyrroles (Scheme 1a).9b In continuation of the above-
mentioned study, we present herein another interesting Rh(II)-
catalyzed cycloaddition of N-sulfonyl-1,2,3-triazoles with 2,1-
benzisoxazoles, which results in the formation of functionalized
quinazoline derivatives (Scheme 1b). Of note, in this reaction
the N-sulfonyl-1,2,3-triazole formally serves as an aza-[2C]-
Q are widespread structural units in bioactive natural
products, therapeutic agents, and agrochemicals.1 For example,
gefitinib and erlotinib are known drugs for the treatment of
lung cancer (Figure 1).2 Prazosin, an α-adrenergic blocker, is
Scheme 1. Rh(II)-Catalyzed Cycloadditions of N-Sulfonyl-
1,2,3-triazoles with Isoxazoles and Benzisoxazoles
Figure 1. Representative quinazoline-containing compounds.
used to treat high blood pressure, anxiety, and panic disorder.3
Rutaecarpine, an alkaloid isolated from Evodia rutaecarpa,
displays diverse therapeutic effects including anticancer, anti-
inflammatory, and analgesic activities.4 Not surprisingly, in view
of their importance in organic synthesis and drug research, the
development of a novel method to access quinazoline and
related scaffolds has been a subject of intense interest in organic
chemistry.5
Recently, Rh-azavinylcarbene (Rh-AVC) has emerged as a
versatile intermediate for the synthesis of nitrogen-containing
heterocycles.6 Readily generated from N-sulfonyl 1,2,3-triazoles
through denitrogenation with the action of a Rh(II)-catalyst,
Rh-AVC has been successfully employed as a [1C]-, [2C]-, or
aza-[3C]-component in various transformations.7−9 Our group
Received: August 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02454
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Letter
component instead of the commonly seen [1C]-, [2C]-, or aza-
[3C]-component. In addition, a formal [3 + 2] cycloaddition of
N-sulfonyl-1,2,3-triazoles with 1,2-benzisoxazoles is also pre-
sented, which provides a rapid entry to imidazole derivatives
(Scheme 1c).
Our study was initiated from a seminal discovery depicted in
Scheme 2. When 1,2,3-triazole 1a and 2,1-benzisoxazole 2a
Table 1. Optimization of Reaction Conditions
b
yield (%)
a
entry
catalyst
other conditions
5a
46
3a
1
2
Rh2(oct)4
DCE, 140 °C, 40 min
DCE, 140 °C, 90 min
DCE, 140 °C, 40 min
DCE, 140 °C, 40 min
DCE, 140 °C, 10 min
CHCl3, 140 °C, 90 min
PhMe, 140 °C, 10 min
DCE, 160 °C, 5 min
DCE, 120 °C, 30 min
DCE, 60 °C, 12 h
17
Rh2(OAc)4
Rh2(S-DOSP)4
Rh(S-PTAD)4
Rh2(esp)2
30
29
Scheme 2. Initial Discovery
3
trace
trace
63
trace
trace
11
4
5
6
Rh2(esp)2
21
9
7
Rh2(esp)2
35
34
8
Rh2(esp)2
80
−
24
9
Rh2(esp)2
59
10
Rh2(esp)2
trace
trace
a
Reaction conditions: 1a (0.20 mmol), 2a (0.26 mmol), and Rh(II)-
b
cat. (3.0 μmol) in 1,2-DCE (1.0 mL); DBU (1.5 equiv). Isolated
yield. DCE = dichloroethane, oct = octanoate, (S)-DOSP = 4-
(dodecylphenyl)sulfonyl-(2S)-prolinate, (S)-PTAD = N-phthaloyl-
(S)-adamantylglycine, esp = α,α,α′,α′-tetramethyl-1,3-benzene-
dipropanoate.
ab
,
were treated with the conditions (1.5 mol % Rh2(esp)2, 1,2-
DCE, 140 °C, 10 min) employed in the previous work,9b the
expected cycloadduct was not observed (for details, see Scheme
S-1, Supporting Information). Instead, two new products were
detected, among which the minor one was determined to be 3a
by X-ray crystallographic study (Scheme 2),11 and the major
one was assigned to be 4a on the basis of extensive
spectroscopic study. 4a was unstable and readily transformed
to 3a upon exposure to high temperature (140 °C, 4 h).
Besides, 4a could also convert to the quinazoline derivative 5a
in nearly quantitative yield upon treatment with DBU. The
above discoveries appeared encouraging, since the resulting
quinazoline derivative represents an important class of
heterocycles in organic and medicinal chemistry. Moreover,
in the reaction N-sulfonyl-1,2,3-triazole formally serves as an
aza-[2C]-component, which represents a mechanistically
interesting reaction that has not been fully explored.
Scheme 3. Scope of 1,2,3-Triazoles
To improve the efficiency of the reaction, we conducted a
systematic condition screening (Table 1). In consideration of
the fragile nature of 4a, we chose to convert it to the more
stable and synthetically useful product 5a through a two-step
one-pot procedure. As shown, among the several commonly
used Rh(II)-catalysts, Rh2(esp)2 exhibited superior reactivity by
affording the best yield of 5a (entries 1−5). This observation
was in agreement with our previous results.9b The solvent effect
was also examined. Both CHCl3 (entry 6) and toluene (entry
7) were less effective than DCE. A notable improvement was
obtained when the reaction was conducted at 160 °C (entry 8),
which afforded 5a in 80% yield. In contrast, the lower reaction
temperature (entries 9 and 10) gave inferior results.
With the optimal conditions in hand, the scope of triazole
was examined. As illustrated in Scheme 3, a wide range of 4-
aryl-triazoles reacted smoothly with 2a to afford the
corresponding quinazolines in good yields. Substrates possess-
ing electron-rich (5b−d) or electron-deficient (5e−f) aryl
substitutes at the C4 position showed comparable efficiency.11
The orientation of the substituents exerted notable impact on
the reaction. While both the para- and meta-substituted
substrates provided satisfying results (5b−i), the ortho-
substituted ones displayed inferior reactivity (e.g., 5l). More-
a
Reaction conditions: 1 (0.20 mmol), 2a (0.26 mmol), and Rh2(esp)2
(3.0 μmol) in 1,2-DCE (1.0 mL) at 160 °C; then DBU (1.5 equiv).
Isolated yield. 120 °C, 10 min.
b
c
over, some other aryl- or heteroaryl-substituted triazoles were
tolerated well in the reaction (5m and 5n).
Next, we examined the scope of the 2,1-benzisoxazole
partner. As shown in Scheme 4, a range of substrates bearing
electron-deficient or electron-rich substituents worked effec-
tively with 1a under the standard conditions, providing the
B
DOI: 10.1021/acs.orglett.6b02454
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Letter
a b
,
oxonium ylide D. Subsequently, the cleavage of the N−O bond
would give the intermediate 4 alone with the release of the
Rh(II)-catalyst. At this point, 4 could divert to two different
products. On one hand, it could convert to the quinazoline 5
via the elimination of TsH followed by tautomerization (path
a). This process plays a dominant role in the presence of DBU.
On the other hand, 4 could also undergo a formal 1,3-sulfonyl
migration13 to give the intermediate F,14 which, after
autoxidation with air, could advance to the quinazoline
derivative 4 (path b). Notably, while a concerted intramolecular
1,3-sulfonyl migration could not be completely excluded, a
stepwise mechanism involving a close ion pair intermediate
more likely accounts for the transformation from 4 to F based
on the result of crossover experiments (for details, see Scheme
S-3, Supporting Information).
Scheme 4. Scope of 2,1-Benzisoxazoles
As an extension of the above-mentioned study, the
cycloaddition of N-sulfonyl-1,2,3-triazoles (1) with 1,2-
benzisoxazoles (6) was also investigated (Scheme 6). To our
Scheme 6. Rh(II)-Catalyzed Cycloadditions of 1,2,3-
a b
,
Triazoles with 1,2-Benzisoxazoles
a
Reaction conditions: 1 (0.20 mmol), 2 (0.26 mmol), and Rh2(esp)2
(3.0 μmol) in 1,2-DCE (1.0 mL) at 160 °C; then DBU (1.5 equiv).
Isolated yield. 120 °C, 15 min. 120 °C, 5 min.
b
c
d
corresponding quinazolines (5o−t) in good yields. The
orientation of the substituents has little influence on the
outcomes. The transformation could also be applied to the
synthesis of a variety of quinazolines bearing two substituted
aromatic rings (5u−z and 5aa). However, the reaction was
sensitive to the R3-substituent of 2,1-benzisoxazoles 2. Actually,
both substrates bearing a H atom or a phenyl group at the C-3
position failed to give the desired products (5ab and 5ac).
The plausible mechanism of the above transformation is
illustrated in Scheme 5. Thus, the Rh-azavinylcarbene A, once
generated from triazole 1 upon treatment with a Rh(II)-
catalyst, could react with 2,1-benzisoxazole 2a to form the
intermediate B via an aza-[4 + 2] cycloaddition.12 B could
undergo ring opening to yield C which then evolves to the
a
Reaction conditions: 1 (0.20 mmol), 6 (0.60 mmol), and Rh2(esp)2
b
(3.0 μmol) in 1,2-DCE (1.0 mL) at 140 °C. Isolated yield.
surprise, this type of substrates displayed distinct reactivity from
that of 2,1-benzisoxazoles (2). Indeed, in all of the examined
cases, the imidazole derivatives (7a−f) were obtained as major
products in excellent yields. Mechanistically, a formal [3 + 2]
cycloaddition of N-sulfonyl-1,2,3-triazoles (1) with 1,2-
benzisoxazoles (6) would give the dihydroimidazoles H,
which then readily underwent aromatization via the cleavage
of the N−O bond to afford the imidazoles 7. Of note, a simple
survey of the substrate scope indicated that this transformation
was amenable to a wide range of triazoles and 1,2-
benzisoxazoles, thus offering a useful method for the access
of imidazole derivatives.
Scheme 5. Plausible Mechanisms
In summary, a novel Rh(II)-catalyzed transannulation of N-
sulfonyl-1,2,3-triazoles with 2,1-benzisoxazoles has been
developed, which provides an efficient method for the synthesis
of quinazoline derivatives. Besides its potential synthetic value,
the current work is also conceptually interesting since it
represents the first example of utilizing Rh(II)-AVC as an aza-
[2C]-component in the related cycloadditions, which further
enriches the versatile reactivity of Rh(II)-AVC. In addition, a
formal [3 + 2] cycloaddition of N-sulfonyl 1,2,3-triazoles with
1,2-benzisoxazoles is also reported, which enables the rapid
construction of diverse imidazole derivatives. We anticipate that
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02454.
■
S
Experimental procedures, spectra data, and copies of all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yefengtang@tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial supports from the National
Science Foundation of China (21272133, 21572112) and
Beijing National Laboratory for Molecular Sciences (BNLMS).
(11) X-ray CCDC 1498773 (3a) and CCDC 1498774 (5f) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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