NBS-mediated dinitrogen extrusion of diazoacetamides under catalyst-free conditions: practical access to 3-bromooxindole derivatives

Abstract

A synthetically useful transformation arises from NBS-mediated dinitrogen extrusion of N-aryl diazoacetamides under catalyst-free conditions, which gives 3-bromooxindoles in high to excellent yields with high selectivity via a non-carbene process.

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3,3-Disubstituted oxindoles and indoles are pervasive structural motifs in bioactive compounds,¹ including Citrinadin A and B,^1c,2 Gelsemine,³ Chitosenine,⁴ Spirotryprostatin A and B⁵ etc. Over the past several years, effective methods have been developed for 3-position functionalization on existing indole frameworks,⁶ including nucleophilic addition with oxindole units (Scheme 1, Path A)⁷ and electrophilic addition with 3-bromooxindoles (Path B).⁸ Among these reports, examples using 3-bromooxindole as an electrophile for the construction of 3-substituted or 3,3-disubstituted derivatives are limited. The main obstacle in this context is the underdeveloped access to 3-bromooxindole derivatives with diversified functional groups.^8,9 Here, we report a practical method for accessing these building blocks under catalyst-free conditions with broad substrate tolerance.¹⁰

Scheme 1 General approaches to 3,3-disubstituted oxindoles.

Diazo compound is a useful material in organic synthesis and its typical utility is metal-catalyzed carbene transformation.¹¹ In the last few years, Hu and co-workers have reported a three-component reaction,¹² in which various electrophiles, including aldehydes,¹³ α,β-unsaturated aldehydes/ketones¹⁴ and imines,¹⁵ are utilized to trap the active ylide intermediate and give the vicinal difunctionalized products in highly selective fashion (Scheme 2a). Recently, Yu's group disclosed a cascade reaction via trapping the diketonate complex with N-chlorosuccinimide (NCS) (Scheme 2b).¹⁶ Inspired by these works, a direct 3-halogenated oxindole derivatives formation could be envisioned via a zwitterionic intermediate trapping transformation with halogenating agent (NCS or NBS) (Scheme 2c).^15b Here, we report our recent progress on this direction, and the results turned out that the reaction did not go through carbene intermediate; instead, it was a direct electrophilic addition on the carbon of the diazo group followed by an F–C type reaction with dinitrogen extrusion simultaneously to give the final product (Scheme 2d). Besides the numerous reports on metal- or organo-catalysis, photolysis and thermolysis in carbene transformations with diazo compounds,^11,17 this report presents the rare example of substrate promoted reaction pathway.

Scheme 2 Designed transformation to 3-bromooxindoles.

Our study of designed approach to 3-bromooxindoles began by evaluating the model reaction of diazoacetamide 1a with NBS catalyzed by Rh₂(OAc)₄ in DCM at room temperature, and only 42% of desired product 3a was obtained contaminated with 54% of direct intramolecular aromatic substitution product 4 (Table 1, entry 1). The structure of 3a was confirmed spectroscopically^8b and single-crystal X-ray diffraction analysis.¹⁸ Next, we examined several of copper-catalysts, including Cu(I) and Cu(II), and all of them worked very well to predominantly give 3 in >90% yields (entries 2–4). Interestingly, when the control reaction was carried out in the absence of catalyst, it gave the brominated product in 82% yield (entry 5), which suggested a non carbene process of this reaction. Various solvents were screened for further optimization of reaction conditions in the absence of catalyst (entries 5–9), and CH₃CN turned out to give the higher yields due to it better solubility for NBS (entry 6, in 97%). In addition, the synthetic practicability of the present method was demonstrated through a gram–scale reaction, which generated the 3-bromooxindole in 70% yield combined with another 10% of 3,5-dibromooxindole byproduct (entry 10).

Table 1 Condition optimization^a

Entry	Cat (X mol%)	Solvent	3a^b (%)	4^b (%)
a Reactions were carried out at room temperature on a 0.2 mmol scale in 2.0 mL solvent with corresponding catalyst for 1 h.b Isolated yield.c Reaction carried out in 7.0 mmol scale and 1.1 g of 3a was isolated combined with 10% corresponding 3,5-dibromooxindole byproduct. TBME = tert-butyl methyl ether; DMB = 2,2-dimethylbutane.
1	Rh2(OAc)4 (1.0%)	DCM	42	54
2	Cu(CH3CN)4PF6 (5.0%)	DCM	90	—
3	CuI (5.0%)	DCM	93	—
4	Cu(OTf)2 (5.0%)	DCM	97	—
5	—	DCM	82	—
6	—	CH3CN	97	—
7	—	TBME	80	—
8	—	Toluene	73	—
9	—	DMB	62	—
10^c	—	CH3CN	70	—

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After identifying the optimized reaction conditions, we evaluated the substrate scope of this method. As shown in Table 2, all the tested diazoacetamides were tolerated in these reaction conditions to give moderate to high yields. Substrates carrying neutral or electronic rich groups on the aryl ring showed higher reactivity compared to the ones with electronic deficient substitutions (3a, 3b vs. 3c, 3d). Ortho- or meta-position substituted compounds were both effective and the F–C type addition occurred at the position with less steric hindrance to give the corresponding products 3e and 3f in 70% and 50% yields, respectively. Due to steric effect, using excess amount of NBS was necessary to ensure the full conversion of 1f; however, considerable amount of multi-brominated byproduct 3f′ was also obtained under these conditions. To extensively explore the substrates scope, diazoacetamides 1 with various R² groups were investigated and it did not make any obvious differences in the yields. It is worth mentioning that the reaction was highly selective. Diversified substitutions or functional groups were tolerated under these mild catalyst-free reaction conditions, including compounds with benzyl group (3i–3n, >90% yields), propargyl group (3o, 90% yield), ether group (3p, 87% yield) and allyl group (3q, 80% yield), which were all perfect reacting partners in typical carbene transformations and they were all untouched in this reaction. What's more, α-substituted diazoacetamides 1, either with methyl, phenyl, or electronic deficient Ts groups, all performed well and yielded the 3,3-disubstituted oxindoles with >70% yields (3r–3t).

Table 2 Substrate scope^a

a Reactions were carried out on a 0.2 mmol scale.b 0.2 mmol of NBS was added slowly to the reaction mixture with 0.4 mmol of 1d.c 3.0 eq. of NBS was used and 23% byproduct 3,3,7-tribormooxindole 3f′ was obtained.d Reaction was carried out at 0 °C with 2.0 eq. of NBS.

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The possibility of applying the developed reaction conditions to the formation of other 3-halogenated oxindoles could be expected (eqn (1)), and the corresponding chlorooxindoles 5a and

5b were produced in 53% and 59% yields, respectively. The corresponding iodination product 5c was obtained in 67%. The reaction with fluoro reagent (N-fluorobenzenesulfonimide, NFSI) was much slower under current conditions and only 25% of corresponding product was obtained even after 2 days and with majority of the material recovered.¹⁹

To gain insight into the mechanism details, a few control reactions were carried out. Reaction pathways through metal carbene or carbene intermediates were first excluded; otherwise byproducts could be envisioned from 1i–1q with most possibilities. The other possibility of via intermediate 4 could be ruled out, which only gave the aryl brominated product 6 under standard conditions (eqn (2)). Photolysis was also

not the case since the same result was obtained when the reaction was carried out in the dark (eqn (3)). Although it was possible to form the 3-halogenated oxindoles starting from α-halogenation of diazoacetamides 1 followed by aromatic substitution with the thermolysis generated carbene species;²⁰ this could not occur in our case because no base was presented in these conditions, and more importantly, all the α-substituted diazoacetamides (1r–1t), which couldn't go through this way to give the final products, all performed well under these conditions. Radical process was also ruled out by carrying out the reaction in the presence of TEMPO (see ESI† for details). Based on these observations, we proposed our reaction pathway in Scheme 3. Initially, the in situ generated bromonium ion attacked the nucleophilic carbon on the diazo compound to form a procarbonium intermediate I (ref. 21) followed by intramolecular F–C type addition with the aryl group, and releasing a N₂ synchronously to give the final products. This mechanism was also consistent with the results that substrates with more electronic rich group on the aryl ring gave higher yields (Table 2, 3a and 3b vs. 3c and 3d).

Scheme 3 Proposed reaction pathway.

The generated 3-bromooxindoles is an important synthon in the synthesis of bioactive indole and oxindole derivatives.^9,10 Here, two general protocols were carried out for the further derivation of the obtained products (Scheme 4). The 3-position of 3c could be easily brominated to give 3,3,5-tribromooxindole 7 in 78% yield. Dimerized product 8 could be obtained under basic condition with 85% yields from 3a.

Scheme 4 Derivation.

Conclusions

In this work, a practical catalyst-free reaction for the synthesis of 3-bromooxindole derivatives with N-aryl diazoacetamides and NBS has been developed.²² The reaction initiates from the electrophilic addition of bromonium ion with the carbon on the diazo group followed by intramolecular F–C type addition with the aryl ring, and releasing a N₂ synchronously to give the final products in high yield. In addition, this non carbene process shows high selectivity and tolerates diversified substitutions and functional groups, which are competitive reactive sites in typical carbene transformations and are untouched in this process.

Acknowledgements

We thank the grants from the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); and Natural Science Foundation of China Jiangsu province (SBK20150315 and 15KJD150004).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1425225. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16868j

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