Iodine-catalysed N-centered [1,2]-rearrangement of 3-aminoindazoles with anilines: efficient access to 1,2,3-benzotriazines

Abstract

A straightforward and synthetically valuable approach for the synthesis of 1,2,3-benzotriazines has been developed via iodine-catalysed N-centered [1,2]-rearrangement of 3-aminoindazoles with anilines. This reaction tolerated a wide scope of substrates under simple reaction conditions employing I₂ as a cheap catalyst.

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Introduction

1,2,3-Benzotriazine and its derivatives, as an important class of nitrogen-containing heterocycles, have been widely used in organic synthesis because of their unique chemical properties¹ and biological activities.² Particularly, 4-substituted-1,2,3-benzotriazines are fundamental structural motifs in biologically active molecules that possess significant antitumor, and anti-inflammatory activities and are inhibitors of vascular endothelial growth factor.³ The traditional synthesis approaches to 4-substituted-1,2,3-benzotriazines are roughly divided into three categories: (1) coupling reaction of diazonium salts with alkylamines;⁴ (2) intramolecular cyclization of o-bromobenzyl azides in the presence of BuLi in THF at −78 °C;⁵ and (3) diazotization of 2-aminobenzonitrile by treating with a strong acid and NaNO₂ at 0 °C.⁶ However, tedious steps, unstable reagents and harsh reaction conditions are required in these procedures. Consequently, the development of a simple and efficient method to construct such a motif is of great significance.

Rearrangement reactions are extremely useful in organic synthesis since they provide complicated molecules from simple and readily available reactants.⁷N-Haloamine, as an easily available and highly reactive electrophilic nitrogen source, was ingeniously utilized to synthesize nitrogen-containing molecules.⁸ Generally, an effective pathway to construct substituted amines has become available by the use of N-haloamines together with nucleophilic reagents.⁹ However, the use of in situ generated N-haloamines directly as electrophilic nitrogen sources in a one-pot manner to carry out rearrangement reactions avoiding prefunctionalization of amines prior to the reaction was still a challenge.¹⁰ In 2012, the Fujioka group reported an oxidative rearrangement of spiro cyclobutane cyclic aminals to form bicyclic amidines in one pot and N-halosuccinimides as halogenated reagents that involved initial N-halogenation (Scheme 1a).¹¹ Subsequently, they prepared fused tetrahydroisoquinolines by generating N-chloroamine in situ to participate in oxidative rearrangement reactions in 2016 (Scheme 1b).¹² These reactions were limited to the starting materials containing cyclobutane moieties, where releasing a ring strain is an important driving force and an excessive halogenated reagent is essential. On the other hand, iodine-catalysed organic reactions have attracted much attention due to their low cost, high efficiency and green nature of progress.¹³ Hence, as part of our ongoing efforts to develop clean procedures to heterocycles,¹⁴ we reported an iodine-catalysed oxidative N-centered [1,2]-rearrangement reaction of 3-aminoindazoles with anilines for the synthesis of N-phenyl-1,2,3-benzotriazin-4(3H)-imines under simple reaction conditions (Scheme 1c). This transformation involved the formation of the C=N and N–N bonds simultaneously, and employed I₂ as a cheap catalyst to form N-haloamine in situ.

Scheme 1 The N-haloamines rearrangement reactions.

Results and discussion

We started our investigation with aniline (1a) and 3-aminoindazole (2a) as model substrates to optimize various reaction parameters (Table 1). To our delight, the desired N-phenyl-1,2,3-benzotriazin-4(3H)-imine 3aa was obtained in 20% yield in the presence of I₂ and H₂O₂ in MeOH (methanol) at 80 °C under air for 12 h (Table 1, entry 1). No product could be detected when other iodine sources including NIS (N-iodosuccinimide) and KI, served as a catalyst (entries 2 and 3). Subsequently, a variety of oxidants were investigated (entries 4–7) and TBHP (tert-butyl hydroperoxide) gave the best result. After introduction of TBAI (tetrabutylammonium iodide) as an additive, the yield of 3aa was provided up to 47% (entry 8). Inspired by this interesting result, other additives, including KF, NH₄Cl and Na₂HPO₄ were tested, but resulted in lower yields (entry 9–11). Evaluation of solvents disclosed that 1-propanol was the best choice (entries 12–15). Gratifyingly, when TBHP was increased to 2 equiv., the desired product could be afforded in 78% yield (entry 16). Meanwhile, the higher yield was obtained by increasing the amount of TBAI to 1.5 equiv. (entry 17). When the ratio of 1a and 2a was 1.2 : 1, the yield of the desired product 3aa was obtained in an excellent yield of 86% (entry 18). Finally, the optimal reaction conditions were identified as follows: aniline (0.12 mmol), 3-aminoindazole (0.1 mmol) in the presence of I₂ (10 mol%), TBHP (2 equiv.) and TBAI (1.5 equiv.) in 1-propanol (2 mL) at 80 °C under an air atmosphere for 12 h.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Oxidant	Additive	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), catalyst (10 mol%), oxidant (1 equiv.), additive (1 equiv.) and solvent (2 mL), 80 °C, 12 h, air. b Isolated yields. NR: no reaction. c TBHP (2 equiv.). d TBAI ( 1.5 equiv). e 1a (0.12 mmol).
1	I2	H2O2	—	MeOH	20%
2	NIS	H2O2	—	MeOH	NR
3	KI	H2O2	—	MeOH	NR
4	I2	K2S2O8	—	MeOH	15%
5	I2	BPO	—	MeOH	21%
6	I2	TBHP	—	MeOH	35%
7	I2	O2	—	MeOH	Trace
8	I2	TBHP	TBAI	MeOH	47%
9	I2	TBHP	KF	MeOH	24%
10	I2	TBHP	NH4Cl	MeOH	NR
11	I2	TBHP	Na2HPO4	MeOH	17%
12	I2	TBHP	TBAI	DCM	37%
13	I2	TBHP	TBAI	CH3CN	32%
14	I2	TBHP	TBAI	1-Propanol	53%
15	I2	TBHP	TBAI	THF	NR
16^c	I2	TBHP	TBAI	1-Propanol	78%
17^d	I2	TBHP	TBAI	1-Propanol	82%
18	I 2	TBHP	TBAI	1-Propanol	86%

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With the optimized reaction conditions in hand, the applicability of this reaction system was investigated (Scheme 2). We firstly examined the effect of the substituents in anilines. Satisfyingly, it was observed that anilines with both electron-withdrawing and electron-donating groups at the para-position all coupled smoothly with 3-aminoindazole to deliver the corresponding products in 61–90% yields (3aa–3ia). However, only trace amounts of the desired products were obtained for 4-CF₃ and 4-NO₂ substituted anilines, perhaps due to their strong electron-withdrawing ability (3ja–3ka). The meta- and ortho-substituted (including F, Me and OMe) anilines were all compatible in this transformation, affording the corresponding products in moderate yields (3la–3qa). Meanwhile, the polysubstituted anilines were also coupled with 2a to provide products in 70–94% yields (3ra–3ta). This result indicated that the steric hindrance on the benzene had no significant effect on this reaction. In addition, the transformation showed an excellent tolerance toward benzylamine and 4-aminobiphenyl (3ua–3va). The secondary amines were also applicable as in the isolation of products in 63–72% yields (3wa–3xa).

Scheme 2 Scope of the anilines. Reaction conditions: 1 (0.12 mmol), 2a (0.1 mmol), I₂ (10 mol%), TBHP (2 equiv.), TBAI (1.5 equiv.) and 1-propanol (2 mL) at 80 °C for 12 h under air.

Furthermore, a series of substituted 3-aminoindazoles were employed to probe the scope of the reaction (Scheme 3). When halogen (including Cl and Br), Me and OMe were at the C-4 position of 3-aminoindazoles, this transformation showed satisfactory tolerance in 47–91% yields (3ab–3ae). The C-5 position of 3-aminoindazoles also proceeded smoothly to afford the desired products in moderate yields (3af–3ag). This catalytic system was not applied to 5-nitro-1H-indaol-3-amine, perhaps due to the low electron density (3ah). In addition, 4-methoxy-1H-indaol-3-amine also performed well, affording the product in 82% yield (3ai). These results indicated that steric hindrance of 3-aminoindazoles did not dramatically influence this transformation. However, it was unsuccessful to synthesize product 3aj from N-methyl-1H-indaol-3-amine, which indicated that the N-protected 3-aminoindazole was not applied to the reaction.

Scheme 3 Scope of the 3-aminoindazoles. Reaction conditions: 1a (0.12 mmol), 2 (0.1 mmol), I₂ (10 mol%), TBHP (2 equiv.), TBAI (1.5 equiv.) and 1-propanol (2 mL) at 80 °C for 12 h under air.

To evaluate the utility of this method in organic synthesis, a gram-scale synthesis of N-phenyl-1,2,3-benzotriazin-4(3H)-imine 3aa was performed under the standard reaction conditions in 75% yield (Scheme 4a). In addition, a series of chemical transformations of 3aa and 1a were carried out. The aryl boronic acid was coupled with 3aa to give the corresponding N-arylated product 4aa, which can be exploited as a precursory platform for the synthesis of other nitrogen-containing heterocycles (Scheme 4b). Homo-coupling of 3-aminoindazole gave product 5aa in 90% yield (Scheme 4c). The structure of compound 5aa was unambiguously confirmed by X-ray crystallographic analysis (see the ESI†). In the presence of I₂ (20 mol%), TBHP (4 equiv.), 2-aminopyridine (2.4 equiv.) and TBAI (3.0 equiv.) in 1-propanol (2 mL) at 80 °C for 12 h, the secondary amine of 3-aminoindazole took part in the reaction to get product 6aa in 84% yield (Scheme 4d). We deduced that 2-aminopyridine might act as the base in this transformation. These results confirmed the practicability of this current developed protocol to afford N-phenyl-1,2,3-benzotriazin-4(3H)-imines.

Scheme 4 Scale-up reaction and chemical transformations.

In order to understand the reaction mechanism, a series of control experiments were carried out. N-Phenyl-1,2,3-benzotriazin-4(3H)-imine 3aa could be obtained in 68% yield when TEMPO (3 equiv., TEMPO = 2,2,6,6-tetramethylpiperidinyl) as a radical trapper was added to the reaction of 1a and 2a (Scheme 5a). This result indicated that a radical process might not be involved in the reaction. In addition, the reaction proceeded smoothly to afford the desired product in 59% yield in the absence of TBAI (condition a). Meanwhile, when NH₄I (1.5 equiv.) instead of TBAI was added to the reaction of 1a and 2a, 3aa was obtained in 41% yield (condition b), which implied that the iodine ion of TBAI was not the initial step of the reaction and TBAI might act as the phase transfer catalyst in this transformation. Moreover, no product was observed when the reaction was performed in the absence of I₂ or TBHP (conditions c and d), which suggested that I₂ and oxidant were crucial for the initial step of the reaction.

Scheme 5 Control experiments.

On the basis of the above discussion and previous reports,^12,13d a plausible mechanism of the [1,2]-rearrangement reaction is proposed in Scheme 6. First, the iodination of 2a with TBHP would lead to the formation of N-iodoaminoindazole A and HI.^12,13d Then, intermediate A underwent an intramolecular nucleophile to generate intermediate B and the electron-rich nucleophile of 1a attacked B to afford intermediate C. Subsequently, intermediate C underwent intramolecular C–N bond cleavage to deliver D. Finally, with the aid of the oxidant, D was oxidized to the desired product 3aa. In addition, the molecular iodine as the catalyst can be regenerated by the oxidation of hydrogen iodide and TBHP.^13d

Scheme 6 Proposed reaction mechanism.

Conclusions

In conclusion, we have successfully developed a novel and straightforward iodine-catalysed N-centered [1,2]-rearrangement reaction of 3-aminoindazoles with anilines. A broad range of 1,2,3-benzotriazines were conveniently obtained in moderate to excellent yields with good functional group tolerance under simple reaction conditions. Significantly, the formation of the C=N and N–N bonds was simultaneously involved and I₂ was used as a cheap catalyst to form N-haloamine in situ. Further studies on the application of this strategy are in progress in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We greatly acknowledge partial financial support from the Ministry of Science and Technology of China (2016YFE0123600).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1955883. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9gc03567b

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