Mild and efficient TBAI-catalyzed synthesis of 1,2,3-benzotriazine-4-(3H)-ones from tert-butyl nitrite and 2-aminobenzamides under acid-free conditions

Article abstract of DOI:10.1016/j.tetlet.2016.07.102

A facile and efficient annulation of 2-aminobenzamides and tert-butyl nitrite was developed, affording 1,2,3-benzotriazine-4-(3H)-ones in good yields under mild conditions. Notably, the reaction was carried out in the absence of strong acid and tert-butyl

Full text of DOI:10.1016/j.tetlet.2016.07.102

Accepted Manuscript
Mild and efficient TBAI-catalyzed synthesis of 1,2,3-benzotriazine-4-(3H)-
ones from tert-butyl nitrite and 2-aminobenzamides under acid-free conditions
Yizhe Yan, Hongyi Li, Bin Niu, Changrui Zhu, Ting Chen, Yanqi Liu
PII:
S0040-4039(16)30970-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.102
TETL 47964
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 June 2016
21 July 2016
30 July 2016
Please cite this article as: Yan, Y., Li, H., Niu, B., Zhu, C., Chen, T., Liu, Y., Mild and efficient TBAI-catalyzed
synthesis of 1,2,3-benzotriazine-4-(3H)-ones from tert-butyl nitrite and 2-aminobenzamides under acid-free
conditions, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.102
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Mild and efficient TBAI-catalyzed synthesis
of 1,2,3-benzotriazine-4-(3H)-ones from tert-
butyl nitrite and 2-aminobenzamides under
acid-free conditions
Leave this area blank for abstract info.
Yizhe Yan ∗, Hongyi Li, Bin Niu, Changrui Zhu, Ting Chen, Yanqi Liu∗

1
Tetrahedron Letters
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Mild and efficient TBAI-catalyzed synthesis of 1,2,3-benzotriazine-4-(3H)-ones from
tert-butyl nitrite and 2-aminobenzamides under acid-free conditions
Yizhe Yan a, b∗ , Hongyi Li a, Bin Niua, Changrui Zhua, Ting Chena, Yanqi Liua∗
a School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou, 450000, P. R. China.
bCollaborative Innovation Center of Food Production and Safety, Henan Province, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and efficient annulation of 2-aminobenzamides and tert-butyl nitrite was developed,
affording 1,2,3-benzotriazine-4-(3H)-ones in good yields under mild conditions. Notably, the
reaction was carried out in the absence of strong acid and tert-butyl nitrite was employed as the
nitrogen source.
Received in revised form
Accepted
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
1,2,3-Benzotriazine-4-(3H)-ones
tert-Butyl nitrite
2-Aminobenzamides
Tetrabutylammonium iodide
Acid-free
1,2,3-Benzotriazine-4-(3H)-ones have attracted considerable
attention because of potential pharmacological properties, such as
sedative, diuretic, anesthetic, antiarthritic, antitumor and
antitubercular activities in the field of bioorganic and medicinal
chemistry.1,2 Traditionally, 1,2,3-benzotriazine-4-(3H)-ones were
formed from methyl anthranilates3 or 2-aminobenzamides4 via
diazotization in the presence of strong acid (HCl or H2SO4) and
NaNO2 at 0°C (Scheme 1a and 1b). However, strong acid and
low temperature were required and substrate scope was limited,
giving the products in moderate yields. Recently, we have
developed an efficient KI/TBHP-mediated oxidative annulation
of 2-aminobenzamides with nitromethane via C−N cleavage and
N−N bond formation, affording 1,2,3-benzotriazine-4-(3H)-ones
in moderate to excellent yields under transition-metal-free
conditions (Scheme 1c).5 In this protocol, nitromethane was used
as the nitrogen synthon. Although the yield of product was good
and the substrate scope was broad, acid (HOAc) and high
temperature (120°C) remained required, which limited further
applications in organic synthetic industry. Therefore, the
development of mild and efficient protocol for the synthesis of
1,2,3-benzotriazine-4-(3H)-ones in the absence of acid is highly
desirable.
Scheme 1. Synthetic routes to 1,2,3-benzotriazine-4-(3H)-
ones
synthesis of 1,2,3-benzotriazine-4-(3H)-ones from tert-butyl
nitrite and 2-aminobenzamides under acid-free conditions
(Scheme 1d)
We began our study with the reaction of 2-amino-N-
phenylbenzamide (1a, 0.2 mmol) and tert-butyl nitrite (2, 0.6
mmol) in the presence of tetrabutylammonium iodide (TBAI, 10
mol%) as the catalyst. After the reaction mixture was heated in 2
mL of CH3CN at 60 °C for 12 h, 3-phenylbenzo[d][1,2,3]triazin-
4(3H)-one (3a) was obtained in almost quantitative yield (Table
1, entry 1). When tetrabutylammonium bromide (TBAB) and
tetrabutylammonium chloride (TBAC) were used as the catalyst,
the reaction yields slightly decreased (Table 1, entries 2 and 3).
When lowering reaction temperature from 60 °C to 50 °C or 40
Recently, tert-butyl nitrite (TBN) has emerged as a useful
nitrogen synthon in organic synthesis.6 Especially, TBN has been
widely used for efficient synthesis of nitrogen containing
heterocycles under mild conditions.7 Inspired by these reports,
herein we demonstrate a mild and efficient TBAI-catalyzed
———
∗ Corresponding author. e-mail: yanyizhe@mail.ustc.edu.cn
∗ Corresponding author. e-mail: liuyanqi@zzuli.edu.cn

2
Tetrahedron
°C, the reaction yield obviously decreased (Table 1, entries 4
Table 2. 1,2,3-benzotriazine-4-(3H)-ones from various 2-
aminobenzamidesa
and 5), Moreover, reducing the amount of TBAI to 5 mol%
didn’t decrease the yield of 3a (Table 1, entry 6). However, 3a
was obtained in only 68% yield in absence of TBAI, which
indicated that TBAI played an important role in the
transformation (Table 1, entry 7). In addition, the yield of 3a
decreased gradually with reducing the amount of tert-butyl nitrite
(Table 1, entries 8 and 9). Expectedly, no desired 3a was
observed in the absence of tert-butyl nitrite. This result revealed
that the additional nitrogen atom of product 3a was derived from
tert-butyl nitrite (Table 1, entry 10). Thus, an optimal set of
conditions were determined as described in entry 6.
O
O
R1
R1
TBAI (5 mol%)
N
N
R2
+
tBuONO
R2
H
N
CH3CN (2 mL)
60 C,12 h
NH2
1a-1z
N
2
3a-3z
3a, R=H, 99%
O
N
3b, R= 4-Me, 94%
3c, R= 3-Me, 85%
3d, R= 2-Me, 75%
3e, R= 4-OMe, 88%
3f, R= 3-OMe, 84%
3g, R= 2-OMe, 70%
3h, R= 4-CF3, 85%
3o, 81%
N
N
O
N
R
N
3p, R1= Bn, 80%
N
O
N
, R1= n-Bu, 82%
3q
2
R1
Table 1. Optimization of reaction conditionsa
3i, R= 3-CF3, 84%
3r, R1= i-Pr 96%
3j, R= 2-CF3, 70%
3k, R= 4-F , 89%
3l, R= 4-Cl, 86%
3m, R= 4-I, 82%
3n, R= 4-t-Bu, 89%
3s, R1= cyclohexyl, 82%
3t, R1 = t-Bu, 96%
N
N
3u, R2= Me, 95%
3v, R2= OMe, 91%
N
O
N
O
N
N
Entry
Catalyst
TBAI
TBAB
TBAC
TBAI
TBAI
TBAI
None
TBN(equiv) Temp(°C) Yieldb(%)
R2
, R2= F, 91%
N
3w
3z, 73%
N
3x, R2= Cl, 87%
3y, R2= Br, 78%
N
N
O
1
2
3
4
5
6c
7
8
9
3
3
3
3
3
3
3
2
1
0
60
60
60
50
40
60
60
60
60
60
99
95
90
85
75
99
68
85
43
ND
N
a Reaction conditions: 1a-1z (0.2 mmol), 2 (0.6 mmol),
nBu4NI (5 mol%, 0.01mmol), CH3CN (2 mL), 60 °C, 12 h.
more complicated molecules, we tested this methodology for 2-
bis-{(2-aminobenzoyl-)amino}ethane (1z). Thus, the desired
1,2-bis-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-
yl)ethane (3z) containing two symmetrical 1,2,3-benzotriazine
rings was efficiently obtained in 73% yield (Table 2, entry 3z).
product
According to previous reports on tert-butyl nitrite as the
nitrogen source, a radical intermediate, such as NO radical, may
be generated via the decomposition of TBN.6,7 To gain insight
into the mechanism, a radical trappling experiments was
performed (Scheme 2). The reaction was not obviously inhibited
in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
and the expected trapping product 4 was also not detected. This
observation implies that the reaction may not undergo a radical
pathway, similar to our previous report. Moreover, when the
reaction was completed, tBuOH was detected as a main
byproduct by GC-MS anaylsis (See SI for details).
TBAI
TBAI
TBAI
10
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), nBu4NX
(10 mol%, 0.02mmol), CH3CN (2 mL), 60 °C, 12 h.
b Isolated yield
c 5 mol% of TBAI
With suitable reaction conditions in hand, we next
explored the generality of these reaction conditions for variously
substituted 2-aminobenzamides (Table 2). Various 2-
aminobenzamides (1a-1z) were employed in this reaction for the
synthesis of a variety of 1,2,3-benzotriazine-4-(3H)-ones in good
yields. First, 2-amino-N-arylbenzamides (1a-1n) with common
substituents such as Me, OMe, CF3, F, Cl, Br and t-Bu on phenyl
ring readily reacted with tert-butyl nitrite to give the
corresponding N-aryl-1,2,3-benzotriazine-4-(3H)-ones in good
Scheme 2. Radical trapping experiment
On the basis of results described above and previous reports6,7,
a plausible mechanism is proposed (Scheme 3). Initially, the
reaction of 2-aminobenzamide with tert-butyl nitrite generates a
unstable cation intermediate A via the nitrosation of primary
amino. Then A can be transformed to a diazonium salt B through
the dehydration, which generates a diazonium iodide C via the
anion exchange in the presence of TBAI. Finally, the direct
−
isolated yields (Table 2, entries 3a 3n). It is noted that the
reaction of 2-amino-N-arylbenzamides bearing electron-donating
groups (4-Me, 4-OMe or 4-tBu) on the phenyl ring gave higher
yields than that of electron-withdrawing groups (4-CF3) on the
phenyl ring. In addition, 2-amino-N-arylbenzamides bearing Me,
OMe or CF3 on ortho-position of phenyl ring gave lower yields
compared to para-position because of steric effect. This synthesis
was also applicable for the reaction of 2-amino-N-(naphthalen-1-
yl)benzamide with tert-butyl nitrite to produce 3o in 81% yield
(Table 2, entry 3o). Subsequently, substrates with aliphatic
groups as R1 substituent, such as Bn, n-Bu, i-Pr, cyclohexyl and
t-Bu, could also be employed to give the corresponding products
3p-3t in excellent yields (Table 2, entries 3p−3t). Furthermore,
2-aminobenzanilides with various R2 substituents such as Me,
OMe, F, Cl and Br were also employed in this reaction, giving
the desired products in good to excellent yields (Table 2, entries
3u−3y). Finally, to extend the applicability of this method in
Scheme 3. A proposed mechanism

3
intramolecular substitution affords the intermediate D, which
further gives 3a by removing hydrogen ion. Notably, the residual
iodine anion regenerate the catalyst TBAI and hydrogen cation
References and notes
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with tert-butoxyl anion gives the byproduct tert-butyl alcohol.6b-
d,7a-b
In summary, a diverse array of 1,2,3-benzotriazine-4-(3H)-
ones were prepared from 2-aminobenzamides and tert-butyl
nitrite in good to excellent yields. Compared to previous reports,
this novel protocol is distinguished by (1) acid-free and mild
conditions, (2) operational simplicity, (3) high yields, (4) broad
substrate scope and (5) water and tert-butyl alcohol as green
byproducts. Further developments of tert-butyl nitrite based
novel synthesis of N-heterocycles are currently in progress in our
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Acknowledgments
We are grateful to the National Natural Science Foundation
of China (21502177), the Science and Technology Research Key
Project of the Department of Education of Henan Province
(15A150005), the Doctoral Research Foundation of Zhengzhou
University of Light Industry (2014BSJJ032) and Grants Program
of Youth Backbone Teachers Training Object of Zhengzhou
University of Light Industry.
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Supplementary data
Experimental procedures, compound characterization data
and copies of NMR spectra for all products are included in
Supplementary data. Supplementary data associated with this
article can be found in the online version.
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4
Tetrahedron
Mild and efficient TBAI-catalyzed
synthesis 1,2,3-benzotriazine-4-(3H)-ones
from tert-butyl nitrite and 2-
aminobenzamides under acid-free
conditions
Yizhe Yan ∗, Hongyi Li, Bin Niu, Changrui Zhu,
Ting Chen, Yanqi Liu∗

5
Highlights
· 1,2,3-benzotriazine-4-(3H)-ones was firstly
synthesized from tert-butyl nitrite
· The reaction was carried out under mild
conditions in the absence of strong acid
·tert-Butyl nitrite was employed as the nitrogen
source of the products
·A plausible mechanism is proposed based on
control experiment and GC-MS analysis