| Bartoli indole synthesis | |
|---|---|
| Named after | Giuseppe Bartoli[1] |
| Reaction type | Ring forming reaction |
| Identifiers | |
| RSC ontology ID | RXNO:0000494 |
TheBartoli indole synthesis (also called theBartoli reaction) is thechemical reaction of ortho-substitutednitroarenes andnitrosoarenes withvinylGrignard reagents to form substitutedindoles.[2][3][4][5]
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.[6][7] TheLeimgruber-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 ringand thepyrrole ring, which is difficult to do with the Leimgruber-Batcho indole synthesis.
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 begins by the addition of the Grignard reagent (2) onto the nitroarene (1) to form intermediate3. Intermediate3 spontaneously decomposes to form anitrosoarene (4) and amagnesium salt (5). (Upon reaction workup, the magnesium salt will liberate acarbonyl compound (6).) Reaction of the nitrosoarene (4) with a second equivalent of the Grignard reagent (2) forms intermediate7. The steric bulk of the ortho group causes a[3,3]-sigmatropic rearrangement forming the intermediate8. Cyclization andtautomerization give intermediate10, which will react with a third equivalent of the Grignard reagent (2) to give a dimagnesium indole salt (12). Reaction workup eliminateswater and gives the final desired indole (13).
Therefore, three equivalents of the Grignard reagent are necessary, as one equivalent becomes carbonyl compound6, one equivalent deprotonates10 forming analkene (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]
Adrian Dobbs greatly enhanced the scope of the Bartoli indole synthesis by using an ortho-bromine as a directing group, which is subsequently removed byAIBN andtributyltin hydride.[10]
The synthesis of 4-methylindole (3) highlights the ability of this technique to produce highly substituted indoles.