Synthesis of Cyclohepta[b]indoles by (4 + 3) Cycloaddition of 2-Vinylindoles or 4H-Furo[3,2-b]indoles with Oxyallyl Cations

Abstract

The synthesis of cyclohepta[ b ]indole derivatives through the dearomative (4 + 3) cycloaddition reaction of 2-vinylindoles or 4 H -furo[3,2- b ]indoles with in situ generated oxyallyl cations is reported. Oxyallyl cations are generated from α-bromoketones in the presence of a base and a perfluorinated solvent. Cyclohepta[ b ]indole scaffolds are obtained under mild reaction conditions, in the absence of expensive catalysts, starting from simple reagents, in good to excellent yields and with complete diasteroselectivity. Preliminary expansion of the scope to 3-vinylindoles and to aza-oxyallyl cations is reported.

An Update on Cyclohepta[b]indoles

“…[26] Substituted 2,3dimethyleneindolines 40 and the trimethylene methane zwit-terion precursor 41 were subjected to a chiral catalyst complex generated in situ from Pd 2 (dba) 3 In 2020, Rossi et al described the synthesis of racemic ethano-bridged cyclohepta[b]indoles 46 by intermolecular (4 + 3) cycloaddition (Figure 13). [27] Product formation was accomplished by reacting 2-vinylindoles 44 and α-bromocyclopentanone 45 in the presence of 2,2,2-trifluoroethanol and Hünig's base in toluene. Constitutionally, the accessible bicyclo[4.2.1] nonane-derived building block is loosely related to the bicyclo [4.2.1]nonane-derived core carbon structure of the vincamaginine alkaloids (Figure 5).…”

“…When using acyclic α-bromoketones 47, racemic cyclohepta [b]indoles 48 were made accessible by diastereoselective (4 + 3) cycloaddition (Figure 14). [27] Subjecting furo[3,2-b]indoles 49 and 2-bromo cyclopentanone 45 to the (4 + 3) cycloaddition protocol afforded racemic ethano-and oxo-bridged cyclohepta[b]indoles 50 as single diastereomers (Figure 15). [27] Racemic cyclohepta[b]indoles 51 highlighting a 8-oxabicyclo[3.2.1]octane core structure were synthesized by diastereoselective (4 + 3)-cycloaddition between furo[3,2-b]indole-derived dienes 49 and acyclic α-bromo ketones 47 (Figure 16).…”

“…[27] Subjecting furo[3,2-b]indoles 49 and 2-bromo cyclopentanone 45 to the (4 + 3) cycloaddition protocol afforded racemic ethano-and oxo-bridged cyclohepta[b]indoles 50 as single diastereomers (Figure 15). [27] Racemic cyclohepta[b]indoles 51 highlighting a 8-oxabicyclo[3.2.1]octane core structure were synthesized by diastereoselective (4 + 3)-cycloaddition between furo[3,2-b]indole-derived dienes 49 and acyclic α-bromo ketones 47 (Figure 16). [27] 3-(4-Methylstyryl)-substituted indole 52 was also susceptible to (4 + 3) cycloaddition with 2-bromo cyclopentanone 45 under previously optimized conditions (Figure 17).…”

“…[27] Racemic cyclohepta[b]indoles 51 highlighting a 8-oxabicyclo[3.2.1]octane core structure were synthesized by diastereoselective (4 + 3)-cycloaddition between furo[3,2-b]indole-derived dienes 49 and acyclic α-bromo ketones 47 (Figure 16). [27] 3-(4-Methylstyryl)-substituted indole 52 was also susceptible to (4 + 3) cycloaddition with 2-bromo cyclopentanone 45 under previously optimized conditions (Figure 17). [27] The substituent pattern of the bicyclo[4.2.1]nonane core of the ethano-bridged cyclohepta[b]indole 53 loosely related to the bicyclo[4.2.1] nonane segment of the vincamaginine core carbon structure (Figure 5).…”

“…When using acyclic α‐bromoketones 47 , racemic cyclohepta[ b ]indoles 48 were made accessible by diastereoselective (4+3) cycloaddition (Figure 14). [27] …”