Palladium-catalyzed intramolecular C–H amination using aluminum nitrate as the oxidant

Abstract

A palladium catalyzed intramolecular C(sp²)–H amination using a readily available aluminum nitrate (Al(NO₃)₃·9H₂O) as the oxidant is reported. The C–H amination is promoted by in situ nitration of the quinoline directing group (DG). The oxindole products can be efficiently converted into novel polycyclic compounds (up to 7 fused rings) via a sequential reduction/cyclization involving the DG. Mechanistic studies indicate that nitration of the quinoline DG favors the following activation of γ-aryl C(sp²)–H bonds over β-methyl C(sp³)–H bonds.

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Introduction

Intramolecular C–N bond formation via the activation of the C–H bond¹ has become a general and practical tool for the synthesis of N-based molecules including important heterocycles such as lactams,² indoles,³ indolines,⁴ oxindoles,⁵ carbozoles,⁶etc. The straightforward approach could simplify substrate preparation and facilitate novel retrosynthetic planning in view of atom economy and synthetic simplicity. Oxindoles have attracted a lot of interest as important structural motifs present in natural products and pharmacologically active compounds (Scheme 1a).⁷ The synthesis of oxindoles via C–H amination was first reported by Yu in 2008 through the palladium-catalyzed intramolecular amination of ortho C(sp²)–H bonds of N-methoxyhydroxamic acids using a combination of CuCl₂/AgOAc as the oxidant (Scheme 1b).^5a In 2009, Murakami and co-workers reported a C–H amination of N-tosylphenylacetamide derivatives with Cu(OAc)₂.^5b Since then, a few examples have been reported where oxindoles have been synthesized through C(sp²)–H amination using palladium,^2a,h copper^2b and cobalt catalysts^2c with PhI(OAc)₂ or copper/silver based oxidants. In addition, a ligand-assisted enantioselective amination of C(sp²)–H bonds was reported recently by Wang using Ag₂O as the oxidant.^5c Nevertheless, the selectivity between the methyl sp³ C–H bonds and the aryl sp² C–H bonds has always caused an issue in these methods. Herein, we report a simple and efficient reaction for the synthesis of oxindoles promoted by in situ directing group (DG) modification using Al(NO₃)₃·9H₂O as a readily available oxidant⁸ (Scheme 1c). The oxindole products can be efficiently converted into novel polycyclic compounds involving the DG.

Scheme 1 Oxindole containing molecules and transition-metal catalyzed C(sp²)–H amination.

The 8-aminoquinoline (AQ) group, first introduced by Daugulis et al.,⁹ has shown great ability and success in a variety of C–H functionalization reactions.¹⁰ A number of reactions on AQ itself were discovered during these studies,¹¹ and the use of modified/substituted AQ was also reported to avoid AQ reactions or to enhance its directing ability for C–H functionalization reactions.¹² In our study, the 5-chloro AQ auxiliary on the substrate was nitrated¹³in situ at its C7 position prior to the C–H amination reaction, and a reduction/cyclization with the nitro group could efficiently convert the oxindole products to novel polycyclic compounds involving the DG (Scheme 1c). In the past few decades, DGs have played an important role in transition metal-catalyzed site-selective C–H activations, and a variety of mono- or bidentate chelating groups have been identified as powerful DGs.¹⁴ However, the installation and removal of these DGs add additional steps, compromising the step-economical nature of the overall C–H activation strategy.¹⁵ Our work demonstrated an in situ DG modification strategy to enhance its directing ability for C–H functionalization and to incorporate DGs into the targeted products¹⁶ for an efficient synthesis of complex molecules.

Results and discussion

We began our research with α,α-dimethyl amide 1a with the 5-Cl AQ auxiliary as the model substrate. After a careful evaluation of various reaction parameters (see the ESI†), the C(sp²)–H amination product 2a was isolated in 80% yield under simple conditions with Pd(OAc)₂ as the catalyst, Al(NO₃)₃·9H₂O as the oxidant, and CH₃CN as the solvent (Table 1). No C(sp³)–H amination on the α-methyl group was observed in the reaction. Then, control experiments were conducted to understand the role of each reactant. The use of the 5-Cl AQ auxiliary was crucial for this transformation. Directing groups such as AQ (R¹ = H) or AQs with different substituents (R¹ = OMe or NO₂) all led to no desired product formation (entries 2–4). A range of other nitrates or nitrite-based oxidants were examined, and only the nitration intermediate 1a′ was observed (entries 5–8). As expected, the palladium catalyst was essential for this transformation, while the nitration of AQ could be promoted by the nitrate itself (entry 9). The yield decreased when the reaction was conducted at a lower temperature, while a higher temperature led to no improvement (entries 10 and 11). The addition of H₂O as the cosolvent was detrimental to the reaction and no desired product was observed in DCE (entries 12 and 13). Notably, the reaction gave a comparable yield under an argon atmosphere (entry 14).

Table 1 Selected optimization and control experiments^a

Entry	Variations from the ‘standard conditions’	1a′/2a ^b [%]
a Standard conditions: substrate 1 (0.2 mmol, 1.0 equiv.), Pd(OAc)2 (10 mol%), Al(NO3)3·9H2O (2.5 equiv.), CH3CN (2 mL), at 100 °C, 24 h, under air. b Yields determined by ^1H NMR spectroscopy using 1,3,5-trimethoxbenzene as the internal standard. c Isolated yield.
1	None	Trace/80^c
2	1aa, R^1 = H	Trace/0
3	1ab, R^1 = OMe	Trace/0
4	1ac, R^1 = NO2	<10/0
5	Fe(NO3)3·9H2O instead of Al(NO3)3·9H2O	75^c/trace
6	Cu(NO3)3·3H2O instead of Al(NO3)3·9H2O	42/0
7	Co(NO3)2·6H2O instead of Al(NO3)3·9H2O	45/0
8	t-BuONO instead of Al(NO3)3·9H2O	70/trace
9	Without Pd(OAc)2	55/0
10	At 90 °C	20/55
11	At 110 °C	Trace/78^c
12	CH3CN/H2O (2 : 1) as solvent	0/trace
13	DCE as solvent	70/0
14	Under Ar	Trace/77^c

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The scope of the C(sp²)–H amination reaction was then examined under the optimized conditions (Scheme 2). The structure of 2a was confirmed by X-ray crystallography. Substrates bearing diverse substituents at the para position on the phenyl ring furnished the desired oxindoles (2b–2h) in good yields. The electronic density of the phenyl ring did not affect the yields, and halogen or triflate groups were tolerated in the reaction (2b–2d). Biaryl substrates also reacted smoothly under these conditions (2f–2h). With meta substituents, the amination occurred exclusively at the less hindered 6-position (2i, 2j). For amides with different alkyl (ethyl, cyclopentyl, benzyl or butyl) or aryl substituents at the α-position, the desired oxindoles could be obtained in modest to good yields (2k–2p). Remarkably, α-cyclic substrates containing three- to six-membered rings all worked well to give the spiro-oxindole products (2q–2v). Further modification of the DG at the C3 position with a bromo substituent did not affect the reaction (2w). Unfortunately, α-nonsubstituted substrates failed to afford the C(sp²)–H amination product (2x), due to the gem-dialkyl effect, which was commonly observed in such cyclization reactions.¹⁷

Scheme 2 Substrate scope of the C(sp₂)–H amination. Conditions: substrate 1 (0.1 mmol, 1.0 equiv.), Pd(OAc)₂ (10 mol%), Al(NO₃)3·9H₂O (2.5 equiv.), CH₃CN (2 mL), at 100 °C, 24 h, under air, isolated yields. ^a Al(NO₃)₃·9H₂O (3.5 equiv.) was used. ^b 90 °C, 48 h. ^c Only the nitrated intermediate was formed.

The practical transformation could be scaled up to the gram scale using substrate 1a as an example; the auxiliary group in the oxindole products could be removed through nitro reduction with Fe/AcOH (2aa) followed by oxidation with ceric ammonium nitrate (CAN) to afford the free amide 4 (Scheme 3, see the ESI†).¹⁸ Cyclization of 2aa with TsOH efficiently led to a novel polycyclic compound 3a. Derivatization of the 5-chloro-7-nitro AQ auxiliary could be achieved through the nucleophilic substitution of the nitro group to obtain sulphide 5¹⁹ and Suzuki coupling with arylboric acid to obtain the biaryl compound 6.²⁰

Scheme 3 Auxiliary group removal and derivatization.

The synthesis of 3a demonstrated the power of C–H activation and the strategy of embedding the DG in the targeted product. 3a could be produced in just 4 steps starting from α,α-dimethylphenylacetic acid. Then we studied the scope of this reduction/cyclization sequence with more oxindole products (Scheme 4). With different substituents on the phenyl (3b, 3e) and quinolinyl (3g) rings, at the α-position (3h), and α-cyclic substrates (3c–3f), the reaction gave good to excellent yields of the polycyclic products. The structure of 3a was confirmed by X-ray crystallography.

Scheme 4 Synthesis of novel polycyclic compounds. Isolated yields are given.

To understand the mechanism of the C(sp²)–H amination reaction, especially the selectivity of the C–H activation of different C–H bonds, some control experiments, a kinetic isotope effect (KIE) study and the trapping of palladacycle intermediates were conducted (Scheme 5). A stepwise control of the reaction showed that the nitration intermediate 1a′ could be obtained in 84% yield with 1.0 equivalent of Al(NO₃)₃·9H₂O and the palladium catalyst at 90 °C for 8 hours. When 1a′ was isolated and subjected again to 1.5 equivalents of Al(NO₃)₃·9H₂O with the palladium catalyst at 100 °C for 12 hours, the targeted product 2a was obtained in 77% yield. The results indicated that the nitration of the quinolinyl ring might occur prior to the amination step. When the nitro group in 1a′ was replaced with chlorine (1ad), no desired amination product was observed, which showed the importance of the nitro group in enhancing the directing ability of the DG and improving the reactivity of the C–H amination. The intramolecular competitive KIE study was carried out with 1a-d₁ to obtain a value of 1.33, which suggested that the cleavage of the C(sp²)–H bond was probably not involved in the rate-determining step. This result inspired us to characterize the C–H insertion palladium complex using the strategy of ligand stabilization to gain more insights into the selectivity of C–H activation between the γ-aryl sp² C–H bonds and the β-methyl sp³ C–H bonds. Gratifyingly, the sp³ C–H insertion palladium complex 7 was isolated by treating 1a with Pd(OAc)₂ and Bu₃P in CH₃CN at room temperature, while the sp² C–H insertion palladium intermediate 8 was detected when 1a′ was used under the same conditions. The structures of both complexes were confirmed by X-ray crystallography. These intermediates provided direct evidence for the role of the nitro group on the DG in favoring the sp² C–H bond cleavage over the sp³ C–H bond cleavage. We anticipated that the oxidation of 8 by the nitrate^8a would afford the high-valence Pd(IV) intermediate, which would undergo reductive elimination to form a C–N bond and release the oxindole product. The reductive elimination might be the rate-determining step and the high-valence Pd(IV) intermediate generated from 7 would be unfavorable for delivering the β-lactam product.

Scheme 5 Control experiments, KIE study and characterization of C–H insertion palladium complexes.

Conclusions

In summary, a palladium-catalyzed intramolecular C(sp²)–H amination reaction utilizing aluminum nitrate as the oxidant is reported. The in situ modification of the DG and the incorporation of the DG into the final product might provide some insights into the development and application of new C–H functionalization reactions.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (grant no. 21772092 and 22075144).

References

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2192355–2192358. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2qo01562e

‡ These authors contributed equally.

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