Article Cite This: J. Org. Chem. 2018, 83, 10974−10984
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Synthesis of 2‑Arylindoles through Pd(II)-Catalyzed Cyclization of Anilines with Vinyl Azides Lianghua Jie, Lianhui Wang,* Dan Xiong, Zi Yang, Di Zhao, and Xiuling Cui* Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen 361021, P.R. China
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ABSTRACT: Vinly azides are featured as electrophiles, nucleophiles, and radical acceptors in synthetic chemistry and have emerged as rapid and versatile synthons in the preparation of N-heterocyclic systems. Herein, a novel approach to 2-arylindoles via Pd(II)-catalyzed cyclization reaction of anilines with vinyl azides has been achieved, which furnishes the versatile 2arylindoles with high efficieny and excellent regioselectivity.
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INTRODUCTION Indoles are widely found in natural products and are also a key structural unit in a large number of synthetic drugs.1 By this token, indole and its derivatives are one kind of heterocyclic compound in the field of skeletal modification.2 Among them, 2-arylindoles are an important moiety of many natural products as well as drug components.3 Consequently, chemists have thus far been pursuing efficient methods for the regioselective synthesis of 2-arylindoles, such as the Fischer4 and Larock5 indole synthesis (Scheme 1a,b). However, these methods possess poor chemoselectivity, especially with unsymmetrical carbonyl and alkyne substrates. In previous decades, transition-metal-catalyzed direct C−H bond activations have proven to be a powerful protocol in the preparation of indole derivatives.6 In this context, the easiest way was to decorate the core indole structure itself through metal-catalyzed direct 2arylation reactions (Scheme 1c).7 Alternatively, 2-arylindoles could be obtained through transition-metal-catalyzed cyclization of ortho-N-substituted styrene or phenylacetylene derivatives, which would take multiple steps, therefore increasing the synthetic costs (Scheme 1d).8 Palladiumcatalyzed oxidative cyclization of N-aryl enamines derived from anilines and ketones represents a more promising protocol along with the pioneering contributions from Glorius and Yoshikai (Scheme 1e).9 More recently, an alternative appealing strategy involving the direct intermolecular dehydrogenation coupling of anilines with C2 fragments, such as alkenes10 and their analogues,11 was explored (Scheme 1f). However, some challenges still remain, such as chemo- or regioselectivity and relatively harsh reaction conditions. © 2018 American Chemical Society
Scheme 1. Strategies for the Regioselective 2-Arylindole Syntheses
Therefore, it is would be highly desirable to explore more efficient and regioselective synthetic protocols. The divergent modes of reactivity of vinyl azides, which occur due to their distinct azide-appended olefin motif, have been explored in various annulation reactions for the Received: June 27, 2018 Published: August 13, 2018 10974
DOI: 10.1021/acs.joc.8b01618 J. Org. Chem. 2018, 83, 10974−10984
Article
The Journal of Organic Chemistry
Table 1. Optimization of Various Reaction Parametersa
construction of various N-heterocycles.12,13 With our ongoing efforts in transition-metal-catalyzed C−H bond functionalizations,14 we report herein an efficient strategy for the synthesis of 2-arylindoles via Pd(II)-catalyzed cyclization of anilines with vinyl azides as the coupling partner (Scheme 1). This protocol features good functional group tolerance and provides 2arylindoles under mild reaction conditions. Moreover, the thermal decomposition of vinyl azides to 2H-azirines ensured an inducing migratory insertion process, which generated the 2-arylindole transformations with excellent chemo- and regioselectivities.
entry
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RESULTS AND DISCUSSION At the outset of our investigation, we chose the readily available N-phenyl-2-aminopyridine (1a) and (1-azidovinyl)benzene (2a) as model substrates to screen the reaction conditions (Table 1). The cyclization product 3aa was obtained in 19% yield when applying Pd(OAc)2 as the catalyst and 1,4-benzoquinone (BQ) as the oxidant (entry 1). The structure of 3aa was confirmed by X-ray single-crystal diffraction.15 Further studies showed that TFA exhibited a positive effect and led to the target product 3aa in 30% yield (entry 1 vs entry 2). Next, oxidants including BQ, TBHP, K2S2O8, and AgNO3 were explored, and K2S2O8 could efficiently facilitate the cyclization (entry 2 vs entries 3−5). Screening various palladium catalysts proved that Pd(TFA)2 was superior to other palladium salts in this transformation (entry 4 vs entries 6−8). In addition, supplementary investigation of the reaction temperature revealed that 75 °C was most suitable, giving 3aa in 58% yield (entries 9 and 10). Notably, addition of a catalytic amount of DABCO could efficiently accelerate this cyclization process (entries 11−13).16 With the combination of Pd(TFA)2, K2S2O8, and DABCO, organic solvents such as toluene, DMF, and THF were then screened, and toluene gave the optimal performance (entry 12 vs entries 14 and 15). The yield of the target product 3aa decreased by decreasing the loading of Pd(TFA)2 to 5.0 mol % (entry 16). In addition, control experiments indicated that the cyclization was completely inefficient in the absence of Pd(TFA)2, HOAc, and/or BQ (entries 17−20). Finally, several popular transition metal catalysts, including [Cp*RhCl 2 ] 2 , [Cp*CoI 2 (CO)], [Cp*IrCl 2 ] 2 , and [(pCymene)RuCl2]2, were explored as well; however, they failed to promote this reaction. It should be noted that pyrimidine as the directing group had a detrimental effect on the current transformation compared to the pyridine, probably due to its appropriate electron effect in the initial coordination with the palladium species and the following transfer processes (entry 12 vs entry 21).17 With the optimized catalytic system in hand, various anilines 1 were employed to examine the generality of the current methodology with (1-azidovinyl)benzene (2a) (Scheme 2). In general, incorporation of an electron-donating (1c−f) or an electron-withdrawing (1g−k) group at the para position on the benzene ring was well-tolerated. Substrates bearing an electron-rich substituent afforded good yields (3ca−3fa), whereas electron-deficient groups, such as halide (1g−i), trifluoromethyl (1j), and carbonyl (1k), led to the 2phenylindole products in moderate yields. Moreover, functional groups at the meta position were investigated. Notably, in the case of anilines with a meta-substituent (1h−n), excellent regioselectivities at the less hindered C−H bond were observed. The reaction of ortho-methylaniline (1o) smoothly
catalyst (10 mol %)
oxidant (equiv)
1
Pd(OAc)2
BQ (2.0)
2 3 4 5 6 7 8 9 10 11
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd(TFA)2 Pd(CH3CN)2Cl2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
BQ (2.0) TBHP (2.0) K2S2O8(2.0) AgNO3(2.0) K2S2O8 (2.0) K2S2O8 (2.0) K2S2O8 (2.0) K2S2O8 (2.0) K2S2O8 (2.0) K2S2O8 (2.0)
12
Pd(TFA)2
K2S2O8 (2.0)
13
Pd(TFA)2
K2S2O8 (2.0)
14b
Pd(TFA)2
K2S2O8 (2.0)
15c
Pd(TFA)2
K2S2O8 (2.0)
16d
Pd(TFA)2
K2S2O8 (2.0)
17
BQ (2.0)
18 19 20
Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
BQ (2.0)
21e
Pd(TFA)2
K2S2O8 (2.0)
additive (equiv) HOAc (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) TFA (1.5) DABCO (0.1) TFA (1.5) DABCO (0.2) TFA (1.5) DABCO (0.4) TFA (1.5) DABCO (0.2) TFA (1.5) DABCO (0.2) TFA (1.5) DABCO (0.2) HOAc (1.5)
HOAc (1.5) TFA (1.5) DABCO (0.2)
T (°C)
yield (%)
90
19
90 90 90 90 90 90 90 60 75 75
31 30 41 30 32 49 36 22 58 65
75
83
75
55
75
trace
75
46
75
66
90
NR
90 90 90
NR NR
