Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
One-Pot Access to peri-Condensed Heterocycles via Manganese-Catalyzed Cascade C−N and C−C Bond Formation Yunliang Yu, Yadong Feng, Remi Chauvin,*,† Shuangshuang Ma, Lianhui Wang, and Xiuling Cui* Engineering Research Center of Molecular Medicine of 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
Downloaded via TUFTS UNIV on July 2, 2018 at 17:39:29 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: A Mn(III)-catalyzed three-component cascade C−H/N−H functionalization of 2-aminopyridines with 2 equiv of dialkyl butyndioates leads to peri-condensed tricylic azines through a selective, but partly destructive, stoichiometry. A wide range of 2,11-diazatricyclo[5.3.1.04,11]undeca1(10),4,6,8-tetraen-3-ones were thus obtained with moderate to high yields in a step-economical fashion under mild conditions. This transformation can serve as a concise method for constructing valuable precursors of functional materials and biologically active compounds.
T
remendous progress in transition-metal-catalyzed C−H bond functionalization has been achieved in the past decade,1 with the main breakthroughs relying on the use of noble metals, such as Rh, Ru, Pd, or Ir.2 The focus is, however, currently shifting toward first-row transition metals for their high natural abundance, low cost, low toxicity, and recently disclosed promising catalytic activities.3 Among them, manganese has been raised in the field of C−H functionalizations.4−7 In 2007, pioneering results were reported by the group of Takai in an insertion reaction of aldehyde carbonyl groups into aromatic C−H bonds.4 Subsequently, in 2013, Wang reported a Mn-catalyzed aromatic C−H alkenylation starting from arylpyridines and terminal alkynes.5a The same group also developed a Mn-catalyzed dehydrogenative [4 + 2] annulation of N−H imines with alkynes to furnish isoquinolines.5c Simultaneously, Ackermann reported a Mn-catalyzed synthesis of cis cyclic β-amino acid esters via ortho-directed C−H bond activation of arylketimines with alkenes.6i Also noteworthy is a manganese and Brønsted acid catalyzed synthesis of substituted alkenylindoles by C−H alkenylation of indoles with alkynes, reported by the group of Li.7a On the other hand, condensed heterocycles receive considerable attention due to their application prospects in the fields of electrochemistry, photochemistry, biochemistry, and functional materials science.8 Among them, the cycl[3.2.2]azine, a nitrogen-pericondensed [10]annulene (named 11-azatricyclo[5.3.1.04,11]undeca-1(11),7,9-triene by the official IUPAC nomenclature), is particularly promising for the high fluorescence efficiency and biological activity of several derivatives (Figure 1).9 Conventional protocols for the preparation of 2,11-diaza representatives are based on reactions of imidazo[1,2-a]pyridines or imidazo[1,2-a]pyrimidines with alkynes.10 These procedures, however, suffer from remaining challenges, such as the requirement of noble metal catalysts, complicated starting materials, and multistep overall transformations. © XXXX American Chemical Society
Figure 1. Selected examples illustrating the importance of the compounds with cycl[3.2.2]azine.
As part of our continued efforts for the development of economically and ecologically valuable strategies for the synthesis of functional aromatic heterocycles,11 we herein present a novel Mn(III)-catalyzed three-component cyclizing cascade C−H/N−H functionalization of 2-aminopyridines with dialkyl butynedioates to prepare 2,11-diazatricyclo[5.3.1.04,11]undeca1(10),4,6,8-tetraen-3-one and its derivatives (Scheme 1). Scheme 1. One-Pot Preparation of Azacycl[3.2.2]azines from 2-Aminopyridines and 2 equiv of Dialkyl Acetylene Dicarboxylates
In this protocol, nitrogen atoms not only serve as directing groups but also ultimately become involved in two new C−N bonds, with parallel formation of two C−C bonds in a one-pot manner, using a manganese salt as catalyst. At the outset, N-benzyl-3-methylpyridin-2-amine 1a and diethyl acetylenedicarboxylate 2a were selected as model Received: May 19, 2018
A
DOI: 10.1021/acs.orglett.8b01586 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of the Substratesa
reactants to optimize the reaction parameters (Table 1). The product 3aa was isolated in 31% yield after treatment of 1a Table 1. Optimization of Reaction Conditionsa
entry
[M]
ligand
oxidant
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13c 14
Mn(OAc)3·2H2O none Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O MnO2 MnBr(CO)5 Mn(OAc)3·2H2O Mn(OAc)3·2H2O
none none none none none none none bipy phen BINAP bipy bipy bipy bipy
TBHP none none Cu(OAc)2 K2S2O8 PhI(OAc)2 DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMSO DCE
31 trace 24 46 no 5 55 85 44 49 26 25 50 43
a Reaction conditions: 1 (0.1 mmol), 2 (0.5 mmol), Mn(OAc)3·2H2O (20 mol %), 2,2′-dipyridyl (20 mol %), di-tert-butyl peroxide (DTBP, 2.0 equiv), CH3CN (2 mL), 16 h, under air, 70 °C; isolated yields. b Reaction run at 100 °C.
a
Reaction conditions: 1a (0.1 mmol), 2a (0.5 mmol), [Mn] (20 mol %), ligand (20 mol %), oxidant (2.0 equiv), solvent (2 mL), 16 h, under air, 70 °C. bIsolated yields. c120 °C. TBHP: tert-butyl hydroperoxide. DTBP: di-tert-butyl peroxide. bipy: 2,2′-dipyridyl. phen: 1,10phenanthroline. BINAP: 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl. DCE: 1,2-dichloroethane.
3′-Br, 3′-CF3) also gave the anticipated products 3ia−3ma in 50−83% yields, confirming a minor influence of the electron density on the benzyl group. Introduction of a methyl or methoxy group at the ortho-position of the benzyl moiety resulted in poor conversion, imputable to steric hindrance effects (3na, 24% and 3oa, 27%). Nevertheless, ortho-halogenated substrates gave the products 3pa, 3qa in relatively higher yields (56%, 50%). When the 3-pyridyl substituent R2 was changed from a methyl group in 1a to a methoxy group in 1r, the targeted product 3ra was obtained in 60% yield (vs 85% for 3aa). However, when R2 was H, the anticipated product 3sa was only provided in 27% yield. Other substitutions at the pyridyl ring, such as 4-methyl, 5-methyl, and electron-withdrawing groups (e.g., −CF3), did not favor this catalytic system (yields
