Potassium Iodide/tert-Butyl Hydroperoxide-Mediated Oxidative Annulation for the Selective Synthesis of N-Substituted 1,2,3-Benzotriazine-4(3H)-ones Using Nitromethane as the Nitrogen Synthon

Article abstract of DOI:10.1002/adsc.201500619

A novel and efficient oxidative annulation of 2-aminobenzamides with nitromethane has been developed for the chemoselective synthesis of N-substituted 1,2,3-benzotriazine-4(3H)-ones in moderate to excellent yields under transition metal-free conditions. T

Full text of DOI:10.1002/adsc.201500619

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DOI: 10.1002/adsc.201500619
Potassium Iodide/tert-Butyl Hydroperoxide-Mediated Oxidative
Annulation for the Selective Synthesis of N-Substituted
1,2,3-Benzotriazine-4(3H)-ones Using Nitromethane as the
Nitrogen Synthon
Yizhe Yan,a,b,* Bin Niu,a Kun Xu,c Jianhua Yu,a Huanhuan Zhi,a and Yanqi Liua,*
a
School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450000, Peopleꢀs
Republic of China
E-mail: yanyizhe@mail.ustc.edu.cn or liuyanqi@zzuli.edu.cn
Collaborative Innovation Centre of Food Production and Safety, Henan Province, Peopleꢀs Republic of China
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, Peopleꢀs Republic
b
c
of China
Received: June 28, 2015; Revised: October 17, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500619.
Abstract: A novel and efficient oxidative annula-
tion of 2-aminobenzamides with nitromethane has
been developed for the chemoselective synthesis of
N-substituted 1,2,3-benzotriazine-4(3H)-ones in
moderate to excellent yields under transition metal-
action between 1,2,3-benzotriazine-4(3H)-ones and
aryl iodide (or arylboronic acids) has been used for
the synthesis of 3-aryl-1,2,3-benzotriazine-4(3H)-ones
(Scheme 1c).[7,10] However, these methods require te-
dious steps or transition metal catalysts, and they gen-
erally give low yields and have a limited substrate
À
free conditions. Two N N bonds were constructed
À
in one pot via C N cleavage of nitromethane,
which was selectively employed as the nitrogen syn-
thon. The preliminary mechanistic studies revealed
that this protocol proceeded under hypoiodite catal-
ysis generated in situ.
À
Keywords: 1,2,3-benzotriazine-4(3H)-ones; C N
cleavage; hypoiodite catalysis; nitromethane; oxida-
tion
1,2,3-Benzotriazine-4(3H)-ones represent an impor-
tant class of nitrogen-containing heterocycles and
have attracted much attention in the fields of bioor-
ganic and medicinal chemistry.[1] For example, many
pharmacological properties for this class of com-
pounds have been reported, including drugs having
sedative,[2] diuretic,[3] anesthetic,[4] antiarthritic,[5] anti-
tumor[6] and antitubercular activities.[7] Traditionally,
1,2,3-benzotriazine.-4(3H)-ones were synthesized
from methyl anthranilates via a multi-step process
(Scheme 1a).[8] The diazotization of 2-aminobenz-
amides as an alternative general method also afforded
1,2,3-benzotriazine-4(3H)-ones in the presence of
a strong acid and sodium nitrite (Scheme 1b).[9] Re-
Scheme 1. Approaches for the construction of 1,2,3-benzo-
cently, a copper-catalyzed Ullmann-type coupling re- triazine-4(3H)-ones.
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Potassium Iodide/tert-Butyl Hydroperoxide-Mediated Oxidative Annulation
Table 1. Optimization of reaction conditions[a]
scope. Therefore, the development of a transition
metal-free and efficient protocol for the synthesis of
1,2,3-benzotriazine-4(3H)-ones using readily available
starting materials is highly desirable.
Nitromethane has emerged as a useful nucleophilic
carbon synthon in organic reactions such as Henry re-
actions,[11] Michael additions,[12] cross dehydrogenation
coupling (CDC) reactions[13] and multicomponent re-
actions (MCRs)[14] as well as being a common solvent.
Moreover, it is well-known that nitromethane can be
decomposed to a carbon synthon (HCHO) and a ni-
trogen synthon (HNO) via a Nef reaction.[15] There-
fore, nitromethane can likely be employed as
a carbon or nitrogen source for the synthesis of het-
erocycles. Recently, Zhang reported an interesting
radical approach to the synthesis of 3-(trifluorome-
thyl)quinoxalines from N-arylenamines with nitrome-
thane as an additional nitrogen source.[16] As part of
our efforts in developing new carbon and nitrogen
synthons for the transition metal-free synthesis of het-
erocycles,[17] herein we demonstrate an efficient potas-
sium iodide/tert-butyl hydroperoxide-mediated oxida-
tive annulation of 2-aminobenzamides with nitrome-
À
À
thane by C N bond cleavage and N N bond forma-
tion, which represents a simple and general approach
for the construction of 1,2,3-benzotriazine-4(3H)-ones
in moderate to excellent yields under transition
metal-free conditions (Scheme 1d). Notably, nitrome-
thane was selectively used as a nitrogen synthon
rather than a carbon synthon in this reaction.
We began our study with the reaction of 2-amino-
N-phenylbenzamide (1a, 0.2 mmol) in the presence of
potassium iodide (KI, 10 mol%) as a catalyst and tert-
butyl hydroperoxide (TBHP, 70% in water, 2.5 equiv.)
as an oxidant. When the reaction mixture was heated
in 2 mL of nitromethane at 1208C for 12 h, 3-phenyl-
benzo[d][1,2,3]triazin-4(3H)-one (2a) was obtained in
30% isolated yield, whereas a trace amount of 3-phe-
nylquinazolin-4(3H)-one (2a’) was detected (Table 1,
entry 1). To improve the yield of this reaction,
[a]
Reaction conditions: 1a (0.2 mmol), XI (0.02 mmol), oxi-
dant (0.5 mmol), additive (0.4 mmol), CH3NO2 (2 mL),
N2, 12 h.
Isolated yield.
Cs2CO3 (0.2 mmol) and HOAc (0.4 mmol) were used.
KI (0.01 mmol) was used.
[b]
[c]
[d]
[e]
2 equiv. of CH3NO2 in CH3CN (2 mL).
2 equiv. of HOAc were used in the reaction as an ad- as di-tert-butyl peroxide (DTBP) and H2O2 (30% in
ditive, affording 2a in moderate 50% yield (Table 1, water), did not give better results (Table 1, entries 8
entry 2). When 2 equiv. of Cs2CO3 or CsOAc were and 9). However, 2a was not detected in the absence
added, the reaction gave 2a in a 70% or 74% yield, of oxidant, which indicated that an oxidant is essential
respectively (Table 1, entries 3 and 4). This result indi- for this reaction (Table 1, entry 10). When the reac-
cated that both acids and bases could promote the re- tion temperature was decreased from 1208C to 1008C
action. Thus, we tried to use 1 equiv. of Cs2CO3 and or 808C, the reaction proceeded with a poor yield
2 equiv. of HOAc as combined additives. To our de- (Table 1, entries 11 and 12). Moreover, reducing the
light, 2a was obtained almost quantitatively (Table 1, loading of KI to 5% decreased the yield of 2a to 82%
entry 5) because Cs2CO3 could promote the decompo- (Table 1, entry 13). Unexpectedly, 2a was also ob-
sition of nitromethane to generate the NO anion; tained in a 65% yield in the absence of KI (Table 1,
then, HOAc could regulate the pH value of the reac- entry 14). When the loading of CH3NO2 was de-
tion system to generate HNO. When various iodine creased from 2 mL to 2 equiv., only a 43% yield of 2a
reagents, such as tetrabutylammonium iodide (TBAI) was obtained (Table 1, entry 15). Thus, the optimal set
and iodine, were used as catalysts, 2a was isolated in of conditions was determined as described in entry 5.
lower yields than with KI (Table 1, entries 6 and 7).
Under these optimized reaction conditions, the
Subsequently, examination of various peroxides, such scope of substrates that could be used and the versa-
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Yizhe Yan et al.
Table 2. Scope of 2-aminobenzamide substrates[a]
[a]
Reaction conditions: 1 (0.2 mmol), KI (0.02 mmol), TBHP (0.5 mmol), Cs2CO3 (0.2 mmol), HOAc (0.4 mmol), CH3NO2
(2 mL), 1208C, N2, 12 h.
tility of the reaction were investigated. As shown in such as benzyl, n-butyl, isopropyl, cyclohexyl and tert-
Table 2, various 2-aminobenzamides (1a–1z) were em- butyl as R1 substituents could also be employed to
ployed in this reaction to synthesize a variety of 1,2,3- give the corresponding products 2p–2t in 70–86%
benzotriazine-4(3H)-ones in good yields. First, when yields. Unfortunately, 2-aminobenzamide (2u) did not
R1 was an aromatic substituent, all of the desired give the desired product. Finally, 2-aminobenzanilides
products (2a–2n) were obtained in moderate to good with various R2 substituents such as methyl, methoxy,
yields. Notably, the reactions of 2-amino-N-arylbenza- fluoro, chloro and bromo were also employed in this
mides bearing electron-donating groups (4-Me, 4- reaction, giving the desired products 2v–2z in 68–85%
OMe or 4-t-Bu) on the phenyl ring of R1 gave higher yields. Among these reactions, substrates with elec-
yields than those of the substrates bearing electron- tron-rich substituents (1v or 1w) gave higher yields
withdrawing groups (4-CF3) on the phenyl ring. More- than those with electron-deficient ones (1x, 1y or 1z)
over, the substrates bearing methyl, methoxy or tri- because of the differences in amino nucleophilicity.
fluoromethyl groups at the ortho-position of the
Next, we examined using this novel approach for
phenyl ring of R1 gave lower yields compared with the synthesis of other 1,2,3-benzotriazines (Scheme 2).
the para- or meta-substituted reactants, perhaps due First, when nitroethane was used instead of nitrome-
to steric hindrance. When R1 was a 1-naphthyl sub- thane, the reaction of 1a afforded the product 2a in
stituent, product 2o was obtained in a 61% isolated a 45% yield, and no product with nitroethane as
yield. Subsequently, substrates with aliphatic groups, a carbon source was detected. When (nitromethyl)-
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Scheme 3. Control experiments for mechanistic studies.
2-aminobenzenesulfonamide was used instead of 2-
amino-N-phenylbenzamide, no desired product was
observed when nitromethane is used as the nitrogen
source. To extend the scope of substrates that could
be used in this reaction, 2-amino-N-phenylacetamide
containing an aliphatic amino group was used as the
substrate; however, no corresponding product was de-
tected.
Scheme 2. Syntheses of other 1,2,3-benzotriazines.
benzene was employed instead of nitromethane, the
To gain insight into the reaction mechanism, several
reaction of 1a afforded the product 2a in a 17% yield. control experiments were conducted (Scheme 3).
Meanwhile, a 24% yield of benzaldehyde was ob- First, the reaction of 1a with 2 equiv. of HNO2, gener-
tained (Scheme 2a). Subsequently, when 1,2-bis[(2- ated in situ from NaNO2 and HCl, gave 2a in a 62%
aminobenzoyl)amino]ethane (3) was used as the sub- yield, which indicated that HNO2 was probably the in-
strate, the desired product 1,2-bis(4-oxo-3,4-dihydro- termediate of this reaction (Scheme 3a). Subsequent-
1,2,3-benzotriazin-3-yl)ethane (4) containing two sym- ly, radical trapping experiments were performed
metrical 1,2,3-benzotriazine rings was obtained in (Scheme 3b). We observed that the reaction was not
a 63% yield (Scheme 2b). In addition, the reaction of completely inhibited in the presence of 2,2,6,6-tetra-
N-methylbenzene-1,2-diamine (5) under standard methylpiperidinyl 1-oxyl (TEMPO) or 1,1-diphenyl-
conditions also gave the desired 1-methyl-1H- ethylene. This observation implies that the reaction
benzo[d][1,2,3]triazole (6) in a 62% isolated yield may not proceed via a radical pathway. Moreover, the
(Scheme 2c). However, 4-phenylbenzo[d][1,2,3]tri- effect of iodine was also investigated (Scheme 3c).
azine (8) was not observed, and a 50% yield of 4-phe- When 2 equiv. of PhI(OAc)2 or IBX were employed
nylquinazoline (8a) was obtained when 2-aminoben- instead of our catalytic system, no 2a was obtained. In
zophenone (7) was employed as the substrate. Similar- contrast, when KIO generated in situ from I2 and
ly, when nitroethane was used instead of nitrome- KOH was used, the reaction gave 2a in a 51% yield.
thane, the reaction of 7 gave 2-methyl-4-phenylquina- This result indicates that hypoiodite plays an impor-
zoline (8b) with a 59% yield (Scheme 2d). These two tant role in the reaction process.
results indicated that nitromethane and nitroethane
On the basis of the results described above and pre-
were selectively used as carbon synthons in this reac- vious reports, a plausible mechanism is proposed
tion. When 2-amino-N-methyl-N-phenylbenzamide or (Scheme 4). Initially, the Nef reaction of CH3NO2
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Yizhe Yan et al.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (21502177, 21376228), the Science and Technology
Research Key Project of the Department of Education of
Henan Province (15A150005), and the Doctoral Research
Foundation of Zhengzhou University of Light Industry
(2014BSJJ032).
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General Procedure
Substrates 1 (0.2 mmol), KI (3.3 mg, 0.02 mol), Cs2CO3
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aqueous Na2SO3 solution and extracted with EtOAc (3”
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