Green Protocols in Heterocycle Syntheses via 1,3-Dipolar Cycloadditions

Abstract

The aim of this review is to provide an overview of green protocols for the organic synthesis of heterocycles via 1,3-dipolar cycloaddition. Particular attention has been devoted to the use of green solvents; reactions performed in ionic liquids, fluorinated solvents and water have been included. Also explored are several protocols that make use of catalyst-free reaction conditions, the use of microwave irradiation and activation by light exposure. Improvements over commonly used organic solvents will be underlined in order to highlight environmental protection aspects and enhancements in regio- and stereo-selectivity.

Keywords: Ionic liquids; aqueous medium; dipolar cycloadditions; green chemistry; heterocycles.

Scheme 1

Synthesis of N-methylpyrrol[2,3-a]pyrrolizidine.

Scheme 2

Synthesis of dispirooxindolopyrrolidines.

Scheme 3

Possible mechanism of the synthesis of dispirooxindolopyrrolidine regioisomers.

Scheme 4

Synthesis of 9-arylmethylene-10-anthrone and following 1,3-dipolar cycloaddition to bis-spiro compound.

Scheme 5

Synthesis of dispiropyrrolidine derivatives.

Scheme 6

Schematic representation of plausible secondary orbital interaction of azomethine ylide.

Scheme 7

Synthetic route of diazapoycyclic cage compounds.

Scheme 8

Synthesis of dispiropyrrolidine derivatives.

Scheme 9

Synthesis of benzo[1,4]oxazine (X = O) and benzo[1,4]thiazine (X = S) based dispiroheterocycles via azomethine ylides.

Scheme 10

Plausible transition state.

Figure 1

Reprinted with permission from Butler et al. (2004). Copyright (2018) American Chemical Society.

Figure 2

Schematic representation of nitrones synthesis in micelle.

Scheme 11

1,3-dipolar cycloaddition with furanoside-5-aldehydes derivatives and phenyl hydroxylamine.

Scheme 12

1,3-dipolar cycloaddition of N-methyl-α-chloronitrone.

Scheme 13

Dipolar cycloaddition of β-phosphonium (or ammonium) allenolates to obtain isoxazolidine derivatives.

Scheme 14

Schematic representation of synthesis of 3,5-diarylisoxazolidines via the 1,3-dipolar cycloaddition in presence of γ-CD and plausible transition stage to obtain the major E-endo derivative. The image was reprinted adapted with permission from Floresta et al. (2017). Copyright (2018) American Chemical Society.

Scheme 15

Synthesis of 5-substituted isoxazolidines with nitrones in water under microwave irradiation.

Scheme 16

Schematic representation of spiro-indole synthesis from 3-diazooxindole derivatives.

Scheme 17

Proposed mechanism.

Scheme 18

Synthesis of spiroindole by 1,3-dipolar cycloaddition with TiO₂ in water and with CAN in solvent.

Scheme 19

Synthesis of benzopyranopyrazole from propargylated salicylaldehydes and tosyl hydrazine.

Scheme 20

Enantioselective synthesis of substituted isoxazolidine.

Scheme 21

Schematic representation of iminoesters as the precursors of stabilized azomethine ylides.

Scheme 22

Enantioselective synthesis of substituted pyrrolidines.

Scheme 23

One pot Three component catalytic asymmetric synthesis of pyrazolidine.

Scheme 24

Organocatalytic synthesis of spiro[pyrrolidin-3,3′-oxindoles].

Scheme 25

Polysubstituted pyrazoles synthetic route from diazoacetates and carbonyl compounds.

Scheme 26

Postulated reaction pathway.

Scheme 27

Synthesis of polycyclic tetrahydroisoquinoline derivatives.

Figure 3

“Metal-free” and “azide-free” syntheses of triazoles.

Scheme 28

Synthesis of bicyclic 1,2,4-oxadiazolines.

Scheme 29

Plausible mechanism for the synthesis of 1,2,4-oxadiazolines.

Scheme 30

Visible-light mediated synthesis of pyrroles and isozazoles from of 2H-azirines and 2H-oxazirine.