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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01618 • Publication Date (Web): 13 Aug 2018 Downloaded from http://pubs.acs.org on August 13, 2018
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The Journal of Organic Chemistry
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.
ABSTRACT: Vinly azides feature as electrophile, nucleophile and radical acceptor in synthetic chemistry, which have emerged as rapid and versatile synthon 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 furnishs the vesatile 2-arylindoles with high efficieny and excellent regioselectivity. INTRODUCTION Indole is not only widely found in natural products, but 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 compounds in the field of skeletal modification.2 Among them, 2-arylindoles are the important moiety of many natural products as well as drug components.3 Consequently, chemists have thus far been pursuing the 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 the past decades, transition-metal-catalyzed direct C―H bond activations proves to be 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 2-arylation reactions (Scheme 1c).7
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Alternatively, 2-arylindoles could be obtained through transition-metal-catalyzed cyclization of ortho-N-substituted styrene or phenylacetylene derivatives, which would take multi-steps and therefore increases the synthetic costs (Scheme 1d).8 Palladium-catalyzed oxidative cyclization of N-aryl enamines derived from anilines and ketones represents more promising protocol along with the pioneering contributions from Glorius and Yoshikai (Scheme 1e).9 More recently, alternative appealing strategy involving the direct intermolecular dehydrogenation coupling of anilines with C2 fragments, such as alkenes10 and their analogs11 was explored (Scheme 1f). However, some challenges still remain, such as chemo- or regioselectivity and relatively harsh reaction conditions. Therefore, it is would be highly desirable to explore more efficiently and regioselectively 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 construction
of
various
N-heterocyclies.12,13
With
our
ongoing
efforts
to
the
transition-metal-catalyzed C―H bond functionalisations,14 we reported 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 2-arylindoles under mild reaction conditions. Moreover, the thermal decomposition of vinyl azides to 2H-azirines ensured an inducing migratory insertion process, which promised the 2-arylindole transformations with excellent chemo- and regioselectivities. Scheme 1. Strategies for the regioselective 2-arylindole syntheses
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The Journal of Organic Chemistry
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 exhibit 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). Besides, supplementary investigation of the reaction temperature revealed that 75 °C was most suitable, giving 3aa in 58% yield (entries 9-10). 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 14-15). The yield of the target product 3aa
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declined 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*RhCl2]2, [Cp*CoI2(CO)], [Cp*IrCl2]2 and [(p-Cymene)RuCl2]2 were explored as well, however, failed to promote this reaction. It should be noteworthy that pyrimidine as directing group had a detrimental effect for the current transformation comparing 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 Table 1. Optimization of various reaction parametersa
Entry
Catalyst
Oxidant
Additive
T
(10 mol%)
(equiv)
(equiv)
(°C)
1 2 3 4 5 6 7 8 9 10 11
Pd(OAc)2 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 ) 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)
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)
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Yield%
90 90 90 90 90 90 90 90 60 75 75
19% 31% 30% 41% 30% 32% 49% 36% 22% 58% 65%
75
83%
75
55%
75
trace
75
46%
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The Journal of Organic Chemistry
16d
Pd(TFA)2
K2S2O8(2.0)
TFA (1.5) DABCO (0.2)
75
66%
17
/
BQ (2.0)
HOAc (1.5)
90
NR
18
Pd(TFA)2
/
/
90
NR
19
Pd(TFA)2
BQ (2.0 )
/
90
NR
20
Pd(TFA)2
/
HOAc (1.5)
90
