Palladium-catalyzed oxidative cyclization of aniline-tethered alkylidenecyclopropanes with O₂: a facile protocol to selectively synthesize 2- and 3-vinylindoles

Abstract

A novel palladium-catalyzed oxidative cyclization of aniline-tethered alkylidenecyclopropanes using molecular oxygen as the terminal oxidant through β-carbon elimination of aminopalladation intermediates is disclosed. The reaction opens up an effective way to obtain a series of 2- and 3-vinylindoles which are important synthetic intermediates in many natural indole derivatives.

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Indole derivatives are important structural motifs in many natural products and pharmaceuticals which exhibit a wide range of promising biological activities.¹ Moreover, 2- and 3-vinylindoles are key intermediates for the synthesis of biologically interesting polycyclic products.² During the past few decades, great efforts have been devoted to the development of efficient and practical strategies for the synthesis of these synthetic intermediates.^3–7 Although vinylindoles could be accessed through a variety of reactions such as Wittig,³ cross-coupling,⁴ S_N2′-type,⁵ elimination⁶ or others,⁷ current synthetic methodologies lack substrate diversity as functional indoles such as formylindole or haloindole or related species, possessing a leaving group, require an advanced preparation. Therefore, the development of novel strategies leading to a broad range of 2- and 3-substituted vinyl-indoles is still an on-going challenge that one needs to address.

Palladium-catalyzed aza-Wacker-type cyclization has been proved to be an effective approach for the preparation of indoles.⁸ In this context, two distinct strategies have been explored to establish the indole structures: (a) using terminal alkenes followed by a β-hydride elimination (Scheme 1, eqn (a))^8,9 and (b) using aryl substituted alkenes followed by an 1,2-aryl migratory reaction of the aminopalladated intermediate (Scheme 1, eqn (b)).¹⁰ Inspired by these methodologies, and with the hope to construct at the same time the indole framework and the vinyl group, we hypothesized that the aminopalladated intermediate may undergo a β-carbon and a β-hydride eliminations continuously to form the required vinylindole in a single-pot operation bypassing the abovementioned two-step pathway. Based on this hypothesis and our ongoing efforts to explore novel synthetic routes to indole-fused scaffolds,¹¹ we decided to prepare ortho-aminoaryl-tethered alkylidenecyclopropanes from the important building blocks alkylidenecyclopropanes (ACPs),¹² with aniline.¹³ Fortunately, we were delighted to observe that these substrates could undergo the above proposed cyclization to selectively give the desired 2- or 3-vinylindoles as described below (Scheme 1, eqn (c)).

Scheme 1 Pd-catalyzed aza-Wacker-type cycloaddition for the synthesis of indole.

We initially investigated the reaction of 1a, as a model substrate, by employing Pd(OAc)₂ as a palladium source and K₂CO₃ as an additive in toluene at 100 °C under an atmosphere of O₂ (balloon). Although in low yield (28%), we were pleased to observe that the reaction proceeded as expected to give 2-vinylindole 2a (Table 1, entry 1). We then further screened different Pd-catalysts, such as Pd₂(dba)₃·CHCl₃, PdCl₂, Pd(dppb)Cl₂, Pd(PPh₃)₂Cl₂ (Table 1, entries 2–5), and various typical aza-Wacker oxidants including BQ, CuCl₂ and AgOAc (Table 1, entries 6–8), but none of these conditions could offer a yield better than 39% (Table 1, entry 5). Additional screening of the nature of solvents and additives (for further details, see the ESI†) revealed that the presence of 1.0 equiv. of KHCO₃ in toluene provided the best result (55%, Table 1, entry 9). Next, the nature of ligands on palladium was tested, such as N-heterocyclic carbene and phosphine ligands with either electron-donating or electron-withdrawing substituents, and we were pleased to observe the formation of 2a in 74% yield when the complex Pd[P(4-CF₃C₆H₄)₃]₂Cl₂ was used in the presence of KHCO₃ (1.0 equiv.) in toluene under molecular oxygen at 100 °C within 12 h (Table 1, entry 13, for further details, see the ESI†).

Table 1 Optimization of conditions for the Pd-catalyzed oxidative cyclization of 1a

Entry^a	Catalyst	Additive (equiv.)	Solvent	Oxidant	Yield^b (%)
a Reactions were performed with 1a (0.2 mmol), additive and 10 mol% of catalyst in solvent (2.0 mL) under O2 (1 atm; balloon) at 100 °C in 12 h. b Yields were determined by ^1H NMR using 1,3,5-trimethoxybenzene as an internal standard. c Yield of the isolated products. d Using 2.0 equiv. BQ under Ar. e Using 2.0 equiv. CuCl2 under Ar. f Using 2.0 equiv. AgOAc under Ar. g The reaction was performed in air.
1	Pd(OAc)2	K2CO3 (2.0)	Toluene	O2	28 (24)^c
2	Pd2(dba)3·CHCl3	K2CO3 (2.0)	Toluene	O2	8
3	PdCl2	K2CO3 (2.0)	Toluene	O2	0
4	Pd(dppb)Cl2	K2CO3 (2.0)	Toluene	O2	12
5	Pd(PPh3)2Cl2	K2CO3 (2.0)	Toluene	O2	39^c
6^d	Pd(PPh3)2Cl2	KaCO3 (2.0)	Toluene	BQ	19
7^e	Pd(PPh3)2Cl2	K2CO3 (2.0)	Toluene	CuCl2	13
8^f	Pd(PPh3)2Cl2	K2CO3 (2.0)	Toluene	AgOAc	13
9	Pd(PPh3)2Cl2	KHCO3 (1.0)	Toluene	O2	55
10	PdIPrCl2	KHCO3 (1.0)	Toluene	O2	38
11	Pd[P(4-MeOC6H4)3]2Cl2	KHCO3 (1.0)	Toluene	O2	52
12	Pd[P(4-FC6H4)3]2Cl2	KHCO3 (1.0)	Toluene	O2	64
13	Pd[P(4-CF3C6H4)3]2Cl2	KHCO3 (1.0)	Toluene	O2	74 (63)^c
14	Pd[P(C6F5)3]2Cl2	KHCO3 (1.0)	Toluene	O2	8
15^g	Pd[P(4-CF3C6H4)3]2Cl2	KHCO3 (1.0)	Toluene	Air	50

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Under the optimized conditions, we next surveyed the substrate scope of this reaction and the results are shown in Scheme 2. We first examined the effect of the position of substituents on the benzene ring. As for substrates 1b–1e, the reactions proceeded smoothly to furnish the corresponding 2-vinylindoles 2b–2e in yields ranging from 56% to 65% regardless of the positions of the substituents (ortho-, meta-, or para-position on the benzene ring). Then, the electronic effect at the para-position of the benzene ring was examined. Substrates with both electron-donating and electron-withdrawing groups could afford the desired products 2f–2k in yields ranging from 33% to 70%. The structure of 2f has been confirmed by X-ray diffraction analysis.¹⁴ When substrates 1l (R¹ = Ph and R² = 5-Cl) and 1m (R¹ = 2-ClC₆H₄ and R² = 5-Cl) were tested, the corresponding products 2l and 2m were obtained in 59% and 60% yields, respectively. To further investigate the scope of this reaction, we prepared functionalized substrates with a heteroaromatic group (furan 1n and thiophene 1o) or with an alkyl chain (methyl group 1p and n-butyl group 1q). The experimental results showed that 1o and 1q were suitable substrates for this reaction under the current reaction conditions, giving the corresponding products 2o and 2q in 40% and 45% yields, respectively. However, the yields of 2n and 2p were low, probably due to the formation of byproducts (for detailed information, see the ESI†). Other N-sulfonyl protecting groups such as 4-bromobenzene sulfonyl (Bs) 1r, 4-nitrobenzene sulfonyl (Ns) 1s and the N-carbonyl protecting group (Ac) 1t were compatible under these reaction conditions. To our delight, when using the substrate 1u without the protecting group on the nitrogen atom, the reaction still proceeded smoothly giving 2u in 31% yield. We also got the product 2u through detosylation of 2a in 81% yield.

Scheme 2 Substrate scope for the synthesis of 2-vinylindoles 2.^a

However, when using the substrate 3a, which has no substituent on the alkylidene moiety, the reaction proceeded to furnish the 3-vinylindole 4a in 48% yield (Table 2, entry 5) rather than the 2-vinylindole. Taking into account the lessons from the previous transformation (1 into 2), we reinvestigated this reaction in detail. After screening the ligands of the catalysts and the additives, we found that when 10 mol% of Pd[P(4-MeOC₆H₄)₃]₂Cl₂ and 1.0 equiv. of KHCO₃ were used in toluene under O₂ at 100 °C, the yield of 4a could reach 60% (Table 2, entry 2).

Table 2 Optimization of conditions for the Pd-catalyzed oxidative cyclization of 3a

Entry^a	Catalyst	Additive (1.0 equiv.)	Solvent	Oxidant	Yield^b (%)
a Reactions were performed with 1a (0.2 mmol), additive and 10 mol% of catalyst in solvent (2.0 mL) under O2 (1 atm; balloon) at 100 °C in 12 h. b Yields were determined by ^1H NMR using 1,3,5-trimethoxybenzene as an internal standard. c Yield of the isolated products. d Using 2.0 equiv. KHCO3.
1	Pd(PPh3)2Cl2	KHCO3	Toluene	O2	41
2	Pd[P(4-MeOC6H4)3]2Cl2	KHCO3	Toluene	O2	60 (58)^c
3	PdIPrCl2	KHCO3	Toluene	O2	24
4	Pd[P(4-FC6H4)3]2Cl2	KHCO3	Toluene	O2	56
5	Pd[P(4-CF3C6H4)3]2Cl2	KHCO3	Toluene	O2	48
6	Pd[P(C6F5)3]2Cl2	KHCO3	Toluene	O2	17
7	Pd[P(4-MeOC6H4)3]2Cl2	NaHCO3	Toluene	O2	39
8	Pd[P(4-MeOC6H4)3]2Cl2	Na3PO4	Toluene	O2	50
9	Pd[P(4-MeOC6H4)3]2Cl2	NaOAc	Toluene	O2	8
10^d	Pd[P(4-MeOC6H4)3]2Cl2	KHCO3	Toluene	O2	45

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With these optimized reaction conditions in hand, the substrate scope for 3 was explored and the results are shown in Scheme 3. Substrates 3 having both electron-donating and electron-withdrawing substituents (R¹) at different positions of the aromatic ring were tolerated, providing the 3-vinylindole derivatives (4b–4g) in moderate yields ranging from 39% to 58%. In addition, when methyl sulfonyl and 2,4-dimethoxybenzene sulfonyl were used as the N-protecting groups, the reactions took place efficiently to afford the corresponding 3-vinylindoles 4h and 4i in 55% and 48% yields, respectively.

Scheme 3 Substrate scope for the synthesis of 3-vinylindoles 4.^a

To further investigate the reaction mechanism, two control experiments were performed and the results are shown in Scheme 4. 2-Vinylindole 5 could not be transformed into 3-vinylindole 6 under our standard reaction conditions, suggesting that 5 was not an intermediate in this reaction. Subsequently, a deuterium-labeling experiment was conducted to obtain more information on the mechanism. The treatment of [D]-7 with Pd[P(4-MeOC₆H₄)₃]₂Cl₂ produced [D]-8 in 60% yield with 66% D content. The deuterium atom at the double bond of the ACP moiety was therefore transferred to the 2-position of the 3-vinylindole, shedding some light on the reaction mechanism.

Scheme 4 Control experiments to investigate the mechanism.

On the basis of previous reports^8,9 and our control experiments, a plausible mechanism¹⁵ for this reaction is outlined in Scheme 5. First, the electrophilic Pd(II) species coordinated with the substrate 1 or 3 activates the double bond of the ACPs to form complexes A or D. If R ≠ H, A could undergo a 5-endo-aminopalladation to form B. Then following a β-carbon elimination, the Pd-alkyl intermediate C is obtained. Finally, the intermediate C undergoes a β-hydride elimination to form the product 2. The reduced Pd catalyst was then oxidized directly by molecular oxygen to regenerate the Pd(II) catalyst. However, if R = H, complex D would undergo a 4-exo-aminopalladation to yield E. Following a β-aryl elimination, the Pd-aryl intermediate F would be formed and this process transfers the alkylidene cyclopropane to the aniline nitrogen and places Pd on the ortho-position of the aniline. Next, F undergoes a 5-endo-carbonpalladation to generate G. Subsequently, G could undergo a β-carbon elimination and a β-hydride elimination to form the product 4a. Another possible mechanism for the generation of 4a is outlined in the ESI.†

Scheme 5 Proposed mechanism.

In conclusion, a facile and versatile palladium-catalyzed oxidative cyclization of aniline-tethered alkylidenecyclopropanes with molecular oxygen could selectively provide either 2- or 3-vinylindoles in moderate to good yields. Different reaction mechanisms have also been proposed on the basis of control experiments. Further investigations on expanding the scope of this reaction toward a variety of novel and potentially useful polycyclic indole derivatives as well as the application of this protocol to natural product synthesis are in progress.

This work was supported by the Joint NSFC-ISF Research Program, jointly funded by the National Natural Science Foundation of China and the Israel Science Foundation. We are also grateful for the financial support from the National Basic Research Program of China ((973)-2015CB856603) and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127, 21421091, 21372250, 21121062, 21302203, 20732008 and 21572052).

Notes and references

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14. The crystal data of 2f have been deposited in CCDC with number 1491285.
15. We appreciate the referee's important suggestion for the generation of product 4 during the peer-review process.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data of new compounds. CCDC 1491285. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6cc08731k

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