Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Domino Cyclization/Alkylation of Terminal Alkynes: Synthesis of Alkynyl-Functionalized Azaindoline Derivatives Xin-Xing Wu,* Anjia Liu,† Shuai Xu,† Junxia He,† Wei Sun, and Shufeng Chen* Department of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot 010021, P.R. China S Supporting Information *
ABSTRACT: A novel palladium-catalyzed domino cyclization/alkylation of terminal alkynes was achieved for the synthesis of alkynyl-functionalized 3,3-disubstituted azaindoline derivatives under air atmosphere conditions. Various types of terminal alkynes, including aromatic alkynes, aliphatic alkynes, and ferrocene acetylene, can undergo the process successfully. The protocol provides a range of alkynyl-functionalized azaindoline scaffolds bearing a quarternary carbon center.
A
functionalities into organic molecules to form new C(sp)− C(sp3) bonds is highly desirable and urgent. Heterocyclic compounds, especially those containing nitrogen, are valuable structural fragments of a variety of natural products.4 Among them, 3,3-disubstituted azaindoline units as the key skeletons show prominent biological and pharmaceutical activities in numerous biologically active compounds.5 In past decades, numerous synthetic methods to build up 3,3disubstituted indoline frameworks were developed,6 and reports for constructing 3,3-disubstituted azaindolines are comparatively scarce.7 In 2015, an intramolecular reductive cyclization to synthesize 3,3-dimethylazaindolines was reported.8 Recently, a transition-metal-catalyzed domino Heck cyclization/Suzuki coupling process to prepare substituted azaindolines was developed by Stivala and co-workers.9 To expand the diversity of functionalized azaindolines, we report here a new practical synthetic method to construct azaindolines bearing alkyne functionalities via palladium-catalyzed domino cyclization followed by alkylation of terminal alkynes with a transient alkylpalladium(II) intermediate.10 Notably, the scope of terminal alkynes can be expanded to aryl, alkyl, and ferrocenyl substituents. Significantly, this protocol can be used to easily construct the structural framework of 3,3-disubstituted azaindolines under air atmosphere conditions (Scheme 1b). We commenced our optimization studies using tosylprotected aminopyridine (1a) and phenyl acetylene (2a) as model substrates (Table 1). First, various palladium catalysts were evaluated, and different palladium sources affected the reaction outcome: Pd(TFA)2 was better than Pd(OAc)2, Pd(PPh3)2Cl2, Pd(PPh3)4, and Pd2(dba)3, affording the desired
lkynes are important structural motifs found in a wide range of natural products, pharmaceutical agents, and materials. The inherent characteristics make them useful building blocks in organic syntheses.1 Transition-metal-catalyzed alkylation of alkynes has recently emerged as a powerful strategy to access valuable molecules via the construction of C(sp)−C(sp3) bonds. The groups of Fu and Hu reported alkyne coupling with primary alkyl halides by employing Pd/Cu and Ni/Cu cocatalyst systems, respectively.2 Afterward, significant progress was achieved in this area (Scheme 1a).3 The reported methods commonly use Scheme 1. Strategies for Alkylation of Alkynes
terminal alkynes, haloalkynes, alkynyl carboxylic acids, and other alkynyl analogues or precursors as the substrates. However, the reaction conditions often have some limitations; for instance, bimetal catalytic systems or other activators were required to realize alkynylation by a transmetallization reaction (e.g., Sonogashira-type cross-coupling); an inert atmosphere was usually necessary to avoid side reactions. Therefore, developing mild and efficient methods for the introduction of alkyne © XXXX American Chemical Society
Received: January 25, 2018
A
DOI: 10.1021/acs.orglett.8b00106 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 2. Substrate Scope of Aromatic Alkynes and Aminopyridinesa,b
entry
catalyst
ligand
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11c 12 13c 14c 15d 15e 16f
Pd(OAc)2 Pd(PPh3)2Cl2 Pd(PPh3)4 Pd2(dba)3 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
PPh3 PPh3 PPh3 PPh3 PPh3 P(2-furyl)3 DPEphos Xantphos Sphos dppb PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3
toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene MeCN dioxane DME DCE toluene toluene toluene
31 26 61 63 75 67 69 24 38 33 49 46 58 66 61
