Synthesis of Fused Imidazoles, Pyrroles, and Indoles with a Defined Stereocenter α to Nitrogen Utilizing Mitsunobu Alkylation Followed by Palladium-Catalyzed Cyclization

• Published in: Journal of organic chemistry Vol. 76; no. 20; pp. 8477 - 8482
• Main Authors: Laha, Joydev K, Cuny, Gregory D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.10.2011; Amer Chemical Soc
• Subjects: Alkylation; Anxiety - drug therapy; Catalysis; Chemistry; Chemistry, Organic; Chemistry, Pharmaceutical - methods; Cyclization; Etomidate - analysis; Etomidate - chemistry; Etomidate - pharmacology; Exact sciences and technology; GABA Agonists - analysis; GABA Agonists - chemical synthesis; GABA Agonists - pharmacology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Hypnotics and Sedatives - analysis; Hypnotics and Sedatives - chemical synthesis; Hypnotics and Sedatives - pharmacology; Imidazoles - analysis; Imidazoles - chemical synthesis; Indoles - analysis; Indoles - chemical synthesis; Magnetic Resonance Spectroscopy; Molecular Structure; Nitrogen - chemistry; Organic chemistry; Palladium - chemistry; Physical Sciences; Preparations and properties; Pyrroles - analysis; Pyrroles - chemical synthesis; Science & Technology; Stereoisomerism; Structure-Activity Relationship; ETOMIDATE; ANESTHESIA; RESPONSES; DIRECT ARYLATION; HETEROCYCLES; ACIDS; INDUCTION; DERIVATIVES; HYDRIDE; Imidazole derivatives; Catalytic reaction; Nitrogen heterocycle; Ligand; Mitsunobu reaction; Palladium complex; Dissociation constant; Transition metal; Palladium; Stereochemistry; Biological activity; Alkylation; Pyrrole derivatives; Cyclization; Carboxylate; Optical purity; Secondary alcohol; Indole derivatives; Chemical synthesis; Platinoid; Functional group
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo201237h

Nitrogen-containing fused heterocycles comprise many compounds that demonstrate interesting biological activities. A new synthetic approach involving Mitsunobu alkylation of imidazoles, pyrroles, and indoles followed by palladium-catalyzed cyclization has been developed providing access to fused heterocycles with a defined stereochemistry α to nitrogen. While ethyl imidazole or indole carboxylates are good substrates for Mitsunobu alkylation with optically pure secondary benzylic alcohols, the corresponding pyrroles are poor substrates presumably due to the increased pK a of the NH. The presence of a synthetically versatile trichloroacetyl functional group on the pyrroles significantly reduces the pK a and thereby facilitates Mitsunobu alkylation. Subsequent cyclization of the alkylated products mediated by palladium in the presence or absence of a ligand gave fused heterocycles in good to excellent yields.