RECENT ADVANCES

IN 1,3-DIPOLAR CYCLOADDITIONS

JAYANTA SAHA

IIT ROPAR

2015CHS1003

INTRODUCTION

The [3 + 2] 1,3-dipolar cycloaddition is a reaction where two organic

compounds, a dipolarophile, and a 1,3-dipole (or ylide), combine to

form a five membered heterocycle

B

A

C

R2

R1 R1

A

B

C

R2

+R3

R4

CB

AR2 R1

R4R3

This reaction is often used as a key step in many natural products and

pharmaceuticals synthesis

The asymmetric variants of this reaction using either chiral auxiliaries or chiral

catalysts are relatively new research fields and have attracted a continually

growing interest

The Dipolarophile

The dipolarophile in a 1,3-dipolar cycloaddition is a reactive

alkene moiety containing 2Π electrons.

Thus, depending on which dipole that is present, α,βunsaturated

aldehydes, ketones, and esters, allylic alcohols, allylic halides,

vinylic ethers and alkynes are examples of dipolarophiles that

react readily

The 1,3-dipole/ylide

The 1,3-dipole, also known as an ylide, bears a positive and a

negative charge distributed over three atoms and has 4 Π

electrons. The most common atoms incorporated in the 1,3-dipole

are nitrogen, carbon, oxygen or sulfur.

These are divided into two groups,

the allyl anion type which has a bent structure and

the propargyl/allenyl anion type with a linear

structure

Types of 1,3-Dipoles:-

Mechamisms for the 1,3-DC reaction

The 1,3-dipolar cycloaddition reaction of a 1,3-dipole with a dipolarophile

involves the 4Π electrons of the dipole/ylide and the 2Π electrons of the

dipolarophile. The reaction mostly proceeds in a concerted manner, which

means that all bonds are created simultaneously

Depending on the nature of the dipole and the dipolarophile, the 1,3-dipolar

cycloaddition reaction is controlled either by a LUMO(dipolarophile)-

HOMO(dipole)- or a LUMO(dipole)-HOMO(dipolarophile) interaction but insome

cases both interactions is involved.

Mechamisms for the 1,3-DC reaction

The classification of the 1,3-DC reactions onthe basis of the

FMOs

NITRONE

NITRILE

OXIDE

Azomethine imine

Diazoalkene

Nitosooxide

Ozone

The change in frontier orbitals by coordination

of a Lewis acid Type II

Recent Literature1,3-Dipolar cycloaddition reactions of azomethine ylides with aromatic

dipolarophiles

General reaction

Examples of isoindole-containing natural products, pharmaceuticals and dyes: (+)-staurosporine 4 (indolocarbazole alkaloid),

mitiglinide 5 (type 2 diabetes),46 lenalidomide 6 (anticancer, multiple myeloma), and Pigment Yellow 139 7 (dye).

1,3-Dipolar cycloaddition reactions of azomethine ylides with aromatic

dipolarophiles

Some products formed in this

manner

Main reaction

John H. Ryan,ARKIVOC 2015 (i) 160-183

Methods for asymmetric 1,3-DC reactions of Nitrones with Alkenes

Pellissier, H. Tetrahedron 2007, 63, 3235-3285

N

H

Ph

X

H

H

exo endo

Stereoselectivity

Regioselectivity

EDG

H

NPh

H

NPh

EWGhead-to-head head-to-tail

N

H

Ph

H

H

XN H

Ph N H

Ph

X X

N H

Ph

EDG

N H

Ph

EWG

General Approach to the Selectivity in 1,3-Dipolar Cycloadditions

Acylaziridines

Methods for asymmetric 1,3-DC reactions of Nitrones with Alkenes

J.Org. Chem. 1995, 60, 4999

+

Methods for asymmetric 1,3-DC reactions of Nitrones with Alkenes

Application of cycloaddition reaction in natural product synthesis