One‐Pot Synthesis of Polyheterocycles by a Palladium‐Catalyzed Intramolecular N‐Arylation/CH Activation/Aryl–Aryl Bond‐Forming Domino Process

Abstract

There has been considerable interest in developing novel cyclization methodologies for organic synthesis.[1] Indeed, many complex natural products and drugs are cyclic in nature, and a ring closure reaction is very often the crucial step in a multistep synthesis. In connection with our ongoing project on the synthesis of macrocycles with an endo aryl-aryl bond, [2] we examined the cyclization of diamide 1 under modified Miyaura-Suzuki conditions.[3] However, heating a solution of 1 in DMSO in the presence of [PdCl 2 (dppf)] (5.0 mol %; dppf = 1,1'-bis(diphenylphosphanyl)ferrocene), KOAc (3.0 equiv), and bis-(pinacolato)diboron (2, 1.2 equiv) did not provide macrocycle 4. Instead, polyheterocycle 3 was produced in about 50 % yield (Scheme 1). Formally, one C aryl À N and one C aryl À C aryl bond were created with concurrent formation of a nine-membered and a six-membered ring. While intramolecular N-arylation leading to five-and six-membered rings is well-established, attempts to access mediumsized and macrocyclic ring systems by the same reaction were, to the best of our knowledge, unsuccessful. [4,5] Intrigued by the potential synthetic power of this novel catalytic domino process, [6] we set out to examine in detail this unprecedented transformation and report herein our preliminary results.

Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis

“…231 This methodology has provided a wide variety of alkaloids, such as indoles, 232 indazoles, 233 benzimidazoles, 234 benazepines, 235 phenazines, 236 carbapenems, 237 the mitomycin ring system, 238 R-carbolines, 239 and polyheterocycles. 240 Pharmacologically active natural products, such as (-)-asperlicin (550) (Scheme 167), 241 dehydrobufotenine (553) (Scheme 168), 242 …”

Heterocycle Synthesis Based on Palladium-Catalyzed C-H Bond Functionalization Methods

“…In 2002, Bedford developed a sequential synthesis of carbazoles from 2-chloroanilines and arylbromides [(Pd(OAc) 2 /PtBu 3 and NaOtBu, toluene] [11]. Later, Zhu reported the synthesis of dihydroazaphenanthrenes fused with a benzodiazepine ring by double cyclization of a substrate bearing two diiodide functions, using [PdCl 2 (dppf)], as catalyst, KOAc, as base, in DMSO [12] Recently, some trialkylphosphines such as tricyclohexylphosphine (PCy 3 ) and di-tert-butylmethylphosphine [PMe(t-Bu) 2 ] turned out to be highly efficient and robust catalysts in the synthesis of a variety of tricyclic heterocycles from aromatic halides [13].…”

Recent Developments in Palladium-Catalyzed Heterocycle Synthesis and Functionalization

“…For example, Zhu has reported the conversion of 35 to 36 in the presence of a catalytic amount of Pd(dppf)Cl 2 (eq 48) [77]. This transformation affords a polycyclic product that results from tandem N-arylation/C-H activation/aryl-aryl bond formation.…”

“…This transformation is believed to proceed via oxidation of an intermediate aryl or alkyl Pd(II) intermediate (77) to a Pd(IV) species (78), which then undergoes carbonheteroatom bond-forming reductive elimination.…”