Synthesis of spiro[cycloalkane‐1,3′‐[3H]indoles] from cycloalkanecarbaldehydes. Acid‐catalyzed rearrangement to cycloalkano[b]indoles

Abstract

Spiro[cycloalkane‐1,3′‐[3H]indoles] 2 can be obtained from the cycloalkanecarbaldehydes 1 by the Fischer reaction of their phenylhydrazones. These cyclizations are sensitive to the acid catalyst, solvent and temperature employed. Rearrangement of the 2 to the homologous cycloalkane derivatives 3 can occur by an acid catalyst or by thermal treatment of 2 in ethyleneglycol.

Synthesis of Spirocyclic Indolenines

“…This was achieved using Lewis acid catalysis, as opposed to the previously used Brønsted acid catalysis, but the efficacy of this procedure cannot be judged as no yields were reported. Later, Rodriguez and co‐workers investigated the synthesis of a range of other cycloalkyl spirocyclic indolenines 31 from the corresponding hydrazones 30 . Through skilful optimisation of the reaction parameters (concentration, solvent, acid, temperature, time), the competing 1,2‐migration (to form fused ring system 32 ) could be inhibited to deliver the desired spirocycles 31 in modest to excellent yield.…”

“… Interrupted Fischer indolisations for the synthesis of simple carbocyclic spirocycles (Hughes, Lions; Witkop, Patrick; Jones, Stevens; Rodríguez et al …”

“…Before focusing on each synthetic strategy in detail, it is useful to considers omeo ft he challenges particulart ot he 3,3'-disubstitued indolenine motif (Scheme 2). First, this framework is known for its propensity to undergo 1,2-migrations under acidic conditions; [20][21][22] this is driven by the formation of an aromatic indole product, which is typically at hermodynamically favourable process.S econd, as is common with other imines, 3,3'-disubstitued indolenines are known to exist as an equilibrium between the imine and the imine trimer form (22$23). This equilibrium may not always affect their subsequentr eactivity (as the trimer 23 can usually collapse to the imine 22 in situ), but may serve to impede both their isolationa nd correct identification, as their analytical datai ss ignificantly complicated (note that this phenomenon is generally not observed with indolenines bearing as ubstituent at the 2-position).…”

“…Later, Rodriguez and co-workersi nvestigated the synthesis of ar ange of other cycloalkyl spirocyclic indolenines 31 from the corresponding hydrazones 30. [20] Through skilful optimisation of the reactionp arameters (concentration, solvent, acid, temperature, time), the competing 1,2-migration (to form fused ring system 32)c ould be inhibited to deliver the desired spirocycles 31 in modestt oe xcellent yield. More recently, Rodríguez, García-Mera and co-workerse xpanded upon these works with welcome additions to the substrate scope.…”

Formation of 3-acylamino-2-arylhydrazono-3-cyano-2,3-dihydro-1H-indoles in the reaction of 2-acylamino-3,3-dichloroacrylonitriles with arylhydrazines

“…Since the intermediate compounds 5a-d contain two substituents at the position 3 of the 2,3-dihydro-1H-indole system, the elimination of an ammonia molecule is accompanied by the formation of an exocyclic C=N bond in the final products 6a-d. The formation of similar 3,3-substituted indoles has been described in the literature [7][8][9].…”