Oxidative Rearrangement of 3-Aminoindazoles for the Construction of 1,2,3-Benzotriazine-4(3 H)-ones at Ambient Temperature

Article abstract of DOI:10.1021/acs.orglett.8b02813

A novel oxidative rearrangement of 3-aminoindazoles is reported, enabling the production of diverse functionalized 1,2,3-benzotriazine-4(3H)-ones in good yields at room temperature. The key success of this unprecedented transformation of 3-aminoindazoles is the use of water as cosolvent, which could facilitate the halogen-induced ring expansion of 3-aminoindazoles under oxidative conditions.

Full text of DOI:10.1021/acs.orglett.8b02813

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxidative Rearrangement of 3‑Aminoindazoles for the Construction
of 1,2,3-Benzotriazine-4(3H)‑ones at Ambient Temperature
Yao Zhou,† Ya Wang,† Yixian Lou,‡ and Qiuling Song*,†,‡
†Institute of Next Generation Matter Transformation, College of Chemical Engineering, College of Material Sciences Engineering,
Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P.R. China
‡Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou, Zhejiang 310000, P.R. China
S
* Supporting Information
ABSTRACT: A novel oxidative rearrangement of 3-amino-
indazoles is reported, enabling the production of diverse
functionalized 1,2,3-benzotriazine-4(3H)-ones in good yields
at room temperature. The key success of this unprecedented
transformation of 3-aminoindazoles is the use of water as
cosolvent, which could facilitate the halogen-induced ring
expansion of 3-aminoindazoles under oxidative conditions.
of such progress on halogen-induced migration rearrangement
reactions, the rearrangement reactions in which the migration
groups are N-centered rather than C-centered groups have been
sparsely documented to date. 3-Aminoindazoles have thus far
proven to be effective cyclization partners for the construction of
various functionalized pyrimido[1,2-b]indazole derivatives.8 To
our knowledge, the rearrangement reaction of 3-aminoindazoles
has not been explored thus far.
alogen-induced rearrangement reactions represent a
Hpromising avenue that can give rise to a vast array of
synthetically useful transformations.1−4 The earliest study
involving halogen-mediated rearrangements can be dated back
to Hofmann rearrangement,2 which provides a reliable approach
to access diverse primary amines from their corresponding
amide derivatives via the 1,2-C-to-N migrations. Recently,
Fujioka and co-workers developed a train of NXS-induced
oxidative rearrangements of secondary amines to afford a wide
range of fused aliphatic N-heterocycles in good yields (Scheme
1a).3,6l In contrast to these NXS-promoted rearrangements,3,4
hypervalent iodine reagents have also frequently been used to
accomplish a series of rearrangement reactions,5,6 due to their
high electrophilicity and good leaving group capability.7 In spite
1,2,3-Benzotriazine-4(3H)-ones have emerged as privileged
core structural motifs in a diverse array of bioactive molecules
and agrochemicals (Figure 1).9 Meanwhile, 1,2,3-benzotriazine-
Scheme 1. Halogen-Induced Rearrangement Reactions
Figure 1. Some examples of biologically active benzo-1,2,3-triazin-
4(3H)-ones.
4(3H)-ones can serve as pre-eminent building blocks to afford a
range of valuable heterocycles through metal-catalyzed deni-
trogenative reactions.10 Traditionally, 1,2,3-benzotriazine-
4(3H)-ones are prepared from 2-aminobenzamide or methyl
anthranilate via the diazotization using strong acid (HCl or
H2SO4) and NaNO2 at 0 °C.11,12 Although this method arguably
represents an effective strategy, it often suffers from narrow
Received: September 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02813
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrate scope. In addition, this stepwise protocol for synthesis
of benzotriazinones proceeds in an acidic condition. The
substrates bearing acid-sensitive functional groups are not
compatible with this transformation. As an alternative strategy,
Liu and co-workers demonstrated a novel oxidative annulation
of 2-aminobenzamides to access various N-substituted 1,2,3-
benzotriazine-4(3H)-ones using nitromethane as the nitrogen
synthon.13 Although the targeted N-substituted 1,2,3-benzo-
triazine-4(3H)-ones could be obtained in good yields, acid
(HOAc), high temperature (120 °C), and inert gas protection
were prerequisite for this protocol. In 2016, the same group
reported another efficient and mild TBAI-catalyzed synthesis of
1,2,3-benzotriazine-4-(3H)-ones from 2-aminobenzamides
using tert-butyl nitrite as the nitrogen source.14 Later,
Sankararaman developed a Pd-catalyzed annulation reaction of
1,3-diaryltriazenes to afford diverse 3-arylbenzo-1,2,3-triazin-
4(3H)-ones using CO as one carbon source in 2017.15 Despite
these undisputed advances, some weaknesses in the known
methods still remain to be addressed for the construction of
1,2,3-benzotriazine-4-(3H)-ones. The development of a new
and mild route to assemble these significant benzotriazinones is
still in demand. Herein, we disclose an expedient halo-mediated
rearrangement reaction to forge these important 1,2,3-
benzotriazine-4-(3H)-ones starting from 3-aminoindazoles
under mild conditions, which represents the first example of
oxidative rearrangement of 3-aminoindazoles.
Table 1. Optimization of Reaction Conditions
a
b
entry
Br source
oxidant
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
solvent
CH3CN
CH3CN/H2O (10:1)
CH3CN/H2O (3:1)
CH3CN/H2O (2:1)
CH3CN/H2O (1.25:1)
H2O
yield of 2a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
TBAB
NBP
DBDMH
DBA
PTT
LiBr
trace
17%
49%
63%
56%
22%
53%
38%
45%
41%
38%
trace
58%
67%
68%
39%
55%
trace
DCM/H2O (2:1)
DCE/H2O (2:1)
CAN
EtOAc/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
CH3CN/H2O (2:1)
K2S2O8
Na2S2O8
(NH4)2S2O8
CAN
CAN
CAN
CAN
CAN
CAN
a
Reaction and conditions: 1a (0.3 mmol), Br source (0.3 mmol),
b
To commence the study, commercial 1H-indazol-3-amine
(1a) was chosen as a model substrate for screening of the
reaction conditions. The initial experiment was conducted in the
presence of N-bromosuccinimide (NBS) and ceric ammonium
nitrate (CAN) at room temperature (Table 1, entry 1). A trace
amount of the rearrangement product benzo[d][1,2,3]triazin-
4(3H)-one 2a was indeed detected by GC-MS. To our suprise,
the yield of 2a was slightly increased to 17% when 0.1 mL of
H2O was added to the reaction (Table 1, entry 2). Inspired by
this result and the importance of H2O, we further screened the
amount of water, and 0.5 mL of H2O was proven to be the best
choice to afford the desired product 2a in 63% yield. We
wondered if this transformation could be accomplished in water.
However, when the model reaction proceeded in water without
another solvent, only 22% yield of 2a was achieved (Table 1,
entry 6). Subsequently, we investigated several common
solvents. Only marginal improvements were obtained when
other solvents were employed instead of CH3CN (Table 1,
entries 7−9). We also inspected a number of oxidants (Table 1,
entries 10−12). However, no superior results were gained. As
part of a subsequent optimization, the model reaction was
submitted to a series of bromide reagents to test the effects of
different bromide sources (Table 1, entries 13−18). Among the
bromide reagents investigated, 1,3-dibromo-5,5-dimethylhy-
dantoin (DBDMH) displayed the optimal one, furnishing the
expected product 2a in 68% yield (Table 1, entry 15).
With the optimal reaction conditions available, the scope and
generality of this oxidative rearrangement of 3-aminoindazoles
were assessed, which was summarized in Scheme 2. A range of
functionalized 3-aminoindazoles having different electronic
properties were proven to be good candidates to afford the
desired 1,2,3-benzotriazine-4(3H)-ones (2b−2m) in decent
yields. A suite of susceptive functional groups, such as chloro,
bromo, iodo, ester, and nitro groups, were well compatible under
this oxidative rearrangement reaction, which could provide an
opportunity for further diversification to access various
functionalized 1,2,3-benzotriazine-4(3H)-ones. To our delight,
oxidant (0.45 mmol), CH3CN (1 mL), air, rt, 16 h. Isolated yields.
the borneo-(−)-derived 3-aminoindazole 1n could also be
engaged under the established conditions, enabling the
production of 2n in 66% yield. In addition to monosubstituted
3-aminoindazoles, the disubstituted 3-aminoindazoles 1o and
1p were also found to react smoothly in this transformation,
delivering the targeted products 2o and 2p in 75 and 68% yields,
respectively.
The scalability of this oxidative rearrangement reaction was
also evaluated. When 3 mmol of 1a was submitted to this
transformtion, the desired 1,2,3-benzotriazine-4(3H)-ones 2a
could be readily obtained in 61% yield without loss of the
efficacy (Scheme 3a). Further applications and transformations
of this rearrangement product were also implemented. Treat-
ment of 2a with propargyl bromide gave the 3-(prop-2-yn-1-
yl)benzo[d][1,2,3]triazin-4(3H)-one 3 in good yield under
basic conditions. Very recently, our group developed a novel Cu-
catalyzed synthesis of 5-aryl-substituted 1,2,3-triazoles via an
oxidative interrupted click reaction.16 We wondered if this
benzotriazinone-derived terminal alkyne 3 could be engaged in
this transformation. To our delight, this N-propargyl-substituted
1,2,3-benzotriazine-4(3H)-one 3 was amenable to this oxidative
interrupted click reaction, rendering the desired 1,2,3-triazoles 4
in 88% yield. The 1,2,3-benzotriazine-4(3H)-ones 2a could also
undergo the Cu-catalyzed Ullmann condensation of arylboronic
acid17 to deliver the N-aryl-substituted 1,2,3-benzotriazine-
4(3H)-ones 5 in high yield, which could be utilized as versatile
building blocks for the assembly of a series of N-heterocycles.
For instance, 81% yield of isoquinolones 6 could be expediently
obtained via the photoinduced denitrogenative alkyne insertion
of 5.10h As noted in the literature,10c,d compound 5 was also
B
DOI: 10.1021/acs.orglett.8b02813
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Letter
underlying the identified conditions, 77% of 18O-labeled product
2a was detected (eq 1), which indicated that the oxygen of the
carbonyl group should come from the water.
Scheme 2. Substrate Scope
On the basis of previous work,3,6l N-haloamines could be
generated in situ in such halo-induced rearrangement reactions.
However, 3-aminoindazoles have two types of N−H, both of
1
which could undergo the halogenation. With this in mind, H
NMR experiments were executed to confirm which N−H was
halogenated first. When 1a reacted with DBDMH under the
standard conditions for 25 min without CAN, the primary NH2
of 3-aminoindazoles disappeared. The signals of N-halogenated
aminoindazoles were observed in the spectra (Figure 2b), which
*
Reaction and conditions: 1 (0.3 mmol), DBDMH (0.3 mmol), CAN
a
(0.45 mmol), MeCN/H2O = 2:1 (1.5 mL), air, rt, 16 h. NBP (0.3
mmol). CAN (0.6 mmol).
b
Figure 2. 1H NMR experiments.
Scheme 3. Synthetic Applications and Transformations
showed that the primary NH2 of 3-aminoindazoles was
preferentially halogenated under these oxidative conditions.
Not surprisingly, the signals of 1,2,3-benzotriazine-4(3H)-ones
2a could be identified when 1a reacted with DBDMH and CAN
at room temperature for 25 min (Figure 2c).
Based on previous work and primary mechanism inves-
tigations, a plausible reaction mechanism of this oxidative
rearrangement of 3-aminoindazoles is proposed in Scheme 4.
First, 3-aminoindazole 1a reacts with the electrophilic bromide
reagent, leading to the formation of N-haloaminoindazole A in
situ, which undergoes an intramolecular nucleophilic attack to
provide the active intermediate B. This incipient iminium
intermediate B is further attacked by water to afford the
intermediate C, which goes through the ring expansion process
Scheme 4. Plausible Reaction Mechanism
reported to achieve the 3,4-dihydroisoquinolin-1(2H)-ones 7
and 3-(imino)isoindolin-1-ones 8 in excellent yields via the
transition-metal-catalyzed denitrogenative annulation reactions.
As a follow-up study, a sequence of experiments were
performed to gain mechanistic insight into this oxidative
rearrangement reaction. To clarify the origination of the
carbonyl oxygen atom of the desired 1,2,3-benzotriazine-
4(3H)-ones, an isotope labeling experiment was carried out.
When the reaction was conducted with 10 equiv of H218O
C
DOI: 10.1021/acs.orglett.8b02813
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Organic Letters
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to deliver the compound D. With the aid of an oxidant,
compound D is oxidized to furnish the desired product 1,2,3-
benzotriazine-4(3H)-ones 2a.
In conclusion, we have disclosed a novel oxidative rearrange-
ment reaction of 3-aminoindazoles at room temperature. This
newly discovered reactivity of 3-aminoindazoles enables the
production of a range of functionalized 1,2,3-benzotriazine-
4(3H)-ones in good yields. The current protocol is charac-
terized by features such as acid-free, no inert gas protection,
simple operation, mild conditions, good yields, and a broad
spectrum of functional group tolerance. In addition, this
oxidative rearrangement reaction can be readily scaled up
without loss of the efficacy. Further mechanism investigation
and synthetic applications of this novel rearrangement reaction
are in progress in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02813.
General experimental procedures and spectroscopic data
for the corresponding products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qsong@hqu.edu.cn.
ORCID
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Yao Zhou: 0000-0002-3500-7355
Qiuling Song: 0000-0002-9836-8860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Founda-
tion of China (21202049), the Recruitment Program of Global
Experts (1000 Talents Plan), the Natural Foundation of Fujian
Province (2016J01064), Fujian Hundred Talents Plan, the
Program of Innovative Research Team of Huaqiao University
(Z14X0047), and Subsidized Project for Cultivating Post-
graduates’ Innovative Ability in Scientific Research of Huaqiao
University (for Y.Z.) is gratefully acknowledged. We also thank
the Instrumental Analysis Center of Huaqiao University for
analysis support.
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