New Efficient Route to Fused Aryltetrahydroindolizinones via N‐Acyliminium Intermediates

Abstract

Straightforward routes to fused tetrahydroindolizinones by two routes A and B, starting either from 2-formylbenzoic acid and esters or from β-hydroxy lactones via acyl iminium ions, are described. A plausible mechanism and limitations are given.

Synthesis of Enantioenriched Phthalide and Isoindolinone Derivatives from 2-Formylbenzoic Acid

“…9,10,62 3-Alkoxyphthalides are building blocks for the synthesis of, for example 2-alkyl-3-hydroxy-1-isoindolinones 12 (Figure 4). 4,19,63 Notably, their synthesis is also possible directly from 1b as starting material. After heating 1b to reflux in SOCl 2 , the addition of primary amines directly led to substrates 12a-d in moderate yields.…”

Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-Ritter/Friedel–Crafts Type Reaction of Endocyclic N-Acyliminium Ions

“…Similarly in this class, pictamine, clavepictamines A and B ( 5 ) act as potent blockers for two neuronal nicotinic acetylcholine receptors, possessing significant cytotoxicity against murine leukemia and human solid tumor cell lines (P-388, A-549, U-251, and SN12K1) . More recently, tetrahydropyrido[1,2- a ]isoindolone derivatives (valmerins) 6 have been reported as potent cyclin-dependent kinase/glycogen synthase kinase-3 inhibitors and also show antitumor properties . Because of their remarkably rich biological activity, the search and development of newer methodologies to construct substituted azabicycles is desirable.…”

Stereoselective Synthesis of Pyrroloisoindolone and Pyridoisoindolone via aza-Prins Cyclization of Endocyclic N-Acyliminium Ions

“…Pyrroloisoindolone and pyridoisoindolone skeletons are found in many biologically active molecules and natural products. For example, N -[(9b S )-5-oxo-2,3,5,9b-tetrahydro-1 H -pyrrolo­[2,1- a ]-isoindol-9-yl]- N ′-[5-({[(2 S )-5-chloro-2,3-dihydro-1 H -inden-2-yl]­amino}- methyl)-1 H -pyrazol-3-yl]­urea is a potent Cdk4 inhibitor, whereas tetrahydropyrido­[1,2- a ]­isoindolone derivatives (valmerin vitamins) are potent cyclin-dependent kinase/glycogen synthase kinase-3 inhibitors and also exhibit antitumor activities . On the other hand, pyrroloisoindolone derivatives are urotensin-II receptor antagonists .…”

“…Due to the presence of the carbonyl group, the N -acyliminium ions are highly reactive electrophiles, and several groups have utilized this intermediate for the construction of a range of structurally diverse compounds via intra- and intermolecular nucleophilic substitution, cationic polycyclization, and ring expansions of β-lactams, leading to γ-lactams . There are different methods for the synthesis of isoindolones starting from 2-formylbenzoic acid and esters or from β-hydroxy lactones via acyl iminium ions; carboxybenzaldehyde; N -acyliminium ion cyclizations of trimethylsilylmethylallenes; cyclization of 2-bromo-3-nitrobenzoic acid, nitrophthalimide, and vinyl sulfides; and Aza-Nazarov cyclization cascades . Recently we have developed a methodology for the synthesis of amido- and tosylated aza-bicyclic compounds, including isoindolone derivatives using the aza-Prins cyclization reaction of the N -acyliminium ion intermediate .…”