Bartoli indole synthesis

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Bartoli indole synthesis
Named after Giuseppe Bartoli[1]
Reaction type Ring forming reaction
Identifiers
RSC ontology ID RXNO:0000494

The Bartoli indole synthesis (also called the Bartoli reaction) is the

arenes with vinyl Grignard reagents to form substituted indoles.[2][3][4][5]

The Bartoli indole synthesis
The Bartoli indole synthesis

The reaction is often unsuccessful without substitution ortho to the nitro group, with bulkier ortho substituents usually resulting in higher yields for the reaction. The steric bulk of the ortho group assists in the [3,3]-sigmatropic rearrangement required for product formation. Three equivalents of the vinyl Grignard reagent are necessary for the reaction to achieve full conversion when performed on nitroarenes, and only two equivalents when performed on nitrosoarenes.

This method has become one of the shortest and most flexible routes to 7-substituted indoles.

Leimgruber-Batcho indole synthesis gives similar flexibility and regiospecificity to indole derivatives. One advantage of the Bartoli indole synthesis is the ability to produce indoles substituted on both the carbocyclic ring and the pyrrole
ring, which is difficult to do with the Leimgruber-Batcho indole synthesis.

Reaction mechanism

The reaction mechanism[8] of the Bartoli indole synthesis is illustrated below using o-nitrotoluene (1) and propenyl Grignard (2) to form 3,7-dimethylindole (13).

The mechanism of the Bartoli indole synthesis
The mechanism of the Bartoli indole synthesis

The mechanism begins by the addition of the Grignard reagent (2) onto the nitroarene (1) to form intermediate 3. Intermediate 3 spontaneously decomposes to form a

water
and gives the final desired indole (13).

Therefore, three equivalents of the Grignard reagent are necessary, as one equivalent becomes carbonyl compound 6, one equivalent deprotonates 10 forming an alkene (11), and one equivalent gets incorporated into the indole ring.

The nitroso intermediate (4) has been isolated from the reaction. Additionally, reaction of the nitroso intermediate (4) with two equivalents of the Grignard reagent produces the expected indole.

The scope of the reaction includes substituted pyridines which can be used to make 4-azaindoles(left) and 6-azaindoles(right).[9]

Bartoli Indole Synth Scope

Variations

Dobbs modification

Adrian Dobbs greatly enhanced the scope of the Bartoli indole synthesis by using an ortho-

The Dobbs modification of the Bartoli indole synthesis
The Dobbs modification of the Bartoli indole synthesis

The synthesis of 4-methylindole (3) highlights the ability of this technique to produce highly substituted indoles.

See also

References