Synthesis of Isoindolo[2,1-a]indoles by the Palladium-Catalyzed Annulation of Internal Acetylenes

Abstract

A wide variety of substituted isoindolo[2,1-alpha]indoles have been prepared via annulation of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This methodology provides an extremely efficient route for the synthesis of these tetracyclic heterocycles from readily available starting materials. The mechanism of this interesting annulation process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) addition of the resulting vinylic palladium intermediate to the C-N double bond of the imine, (4) either electrophilic palladation of the resulting sigma-palladium intermediate onto the adjacent aromatic ring derived from the internal alkyne or oxidative addition of the neighboring aryl carbon-hydrogen bond, and (5) reduction of the tetracyclic product and Pd(0). A variety of internal acetylenes have been employed in this annulation process in which the aromatic ring of the alkyne contains either a phenyl or a heterocyclic ring.

A Novel Water‐Soluble m‐TPPTC Ligand: Steric and Electronic Features –Recent Developments in Pd‐ and Rh‐Catalyzed CC Bond Formations

“…[11] Using only 1 mol % palladium at 70 8C in acetonitrile/water mixture and without a copper co-catalyst (Scheme 6), the 2-(1-hexynyl)pyridine were isolated in good yields (75 -85%). The 2-(1-phenyl)thiophene 13a [31] and 2-(1-hexynyl)thiophene 13b [32] were also obtained in good to excellent yields and in shorter reaction time and temperature.…”

Copper‐Catalyzed Enantioselective Intramolecular Conjugate Addition/Trapping Reactions: Synthesis of Cyclic Compounds with Multichiral Centers

“…Substrate S2: The Swern oxidation of 6-phenylhex-5-yn-1-ol [24] (15 mmol, 2.61 g) under standard conditions with oxalyl chloride (23.6 mmol, 2 mL), dimethylsulfoxide (DMSO; 59.6 mmol, 4.2 mL), and triethyl amine (74.6 mmol, 10.4 mL) in CH 2 Cl 2 gave quantitatively the corresponding aldehyde 6-phenylhex-5-ynal, which is used directly without further purification. A mixture of the 6-phenylhex-5-ynal and 1-triphenylphosphoranylidene-2-propanone (19.5 mmol, 6.20 g) in CH 2 Cl 2 (40 mL) was stirred at room temperature for 60 h under argon.…”

“…1 Substrate S3: A mixture of 4,6-heptadienal [25] (17 mmol, 1.87 g) and (benzoylmethylene)triphenylphosphorane (20 mmol, 7.6 g) in CH 2 Cl 2 (20 mL) was stirred at room temperature for 48 h. The solvent was evaporated and the residue was purified by flash chromatography to give the product S3 (2.28 g, 63 % yield) as a light yellow oil. Substrate S4: [24] Glutaric dialdehyde (2 mmol, 0.35 mL) was added to a solution of 1-triphenylphosphoranylidene-2-propanone (5 mmol, 1.59 g) in CH 2 Cl 2 (10 mL). The resulting solution was stirred at room temperature for 70 h and was then washed with water and dried over MgSO 4 .…”

Recent Uses of Palladium Chemistry in Indole Synthesis

“…isoindolo[2,1-a]indoles (80) have been synthesized by Larock et al [78] using three different methods employing Pd(OAc) 2 (catalyst), Na 2 CO 3 or i Pr 2 NEt (base) and LiCl or n-Bu 4 NCl (chloride source). Itahara and others [79][80][81][82][83][84][85][86] have reported the palladium-assisted synthesis of these indoles.The heteroannulation of N-tosyl-2-iodoaniline with a variety of oxygen substituted 1,3 dienes has been described by Larock and Guo [87].…”