Hegedus indole synthesis

What is Hegedus indole synthesis?

The Hegedus reaction, also known as the Hegedus indole synthesis, involves two main types of reactions for creating indole derivatives: the oxidative N-heterocyclization of o-allylaniline or o-aminostyrenes catalyzed by palladium (II) complexes, and the intramolecular cyclization of o-halo N-allylaniline, which is also called the Hegedus cyclization.

Hegedus indole synthesis - general reaction scheme
Hegedus indole synthesis

R1 = H, Me, Ac, Ts
R2 = H, 5-Me, 5-CO2Et, 6-OMe, etc.

Hegedus indole synthesis - general reaction scheme
Hegedus indole synthesis

X = I, Br (2 eq. P(o-Tolyl)3 required)

Hegedus indole synthesis - general reaction scheme
Hegedus indole synthesis

To perform the Hegedus indole synthesis, one can add o-allylaniline to a tetrahydrofuran THF solution of PdCl2(CH3CN)2 to form a yellow-brown precipitate. Adding triethylamine will dissolve the precipitate and create a cherry red solution that will deposit metallic palladium. Once the palladium deposition is complete, the solution can be filtered and the filtrate concentrated to obtain 2-methylindole, which may be contaminated with a small amount of Et3N·HCl.

It is important to note that stoichiometric amounts of palladium dichloride PdCl2 are necessary for this reaction, but it can also be performed catalytically in the presence of an oxidant, such as benzoquinone, which can reoxidize Pd(0) to Pd(II). In some cases, higher yields of indoles can be obtained under catalytic conditions than those using a stoichiometric amount of catalyst. It should be noted that Pd(OAc)2 and lithium chloropalladate are not effective catalysts for this reaction.

The Hegedus indole synthesis is a versatile reaction that can accommodate a wide range of functional groups on the aromatic ring and alkyl groups at the 2 or 3 position of the allyl side chain. One advantage of this reaction is its general accessibility for the intramolecular amination of mono-olefin from primary amines and weakly basic amines like aniline. Unlike other reaction conditions, it is unnecessary to remove the amine to form the olefin-palladium complex. In addition, the reaction can also perform intramolecular amination of cyclohexene and 2-methylbutene moiety. However, the failure for the amination of mono-olefin from primary amines in other reaction conditions is probably due to the strong linkage between nitrogen and palladium that eliminates the amine as an effective nucleophile. The reaction is not restricted to nitrogen nucleophiles; it also works for oxygen nucleophiles.

For example, treatment of o-allylbenzoic acid with PdCl2 and Na2CO2 in THF affords 3-methylisocoumarin in good yield. Although p-toluenesulfonamides are not considered good nucleophiles, they are effective for the attack on Pd(II)-coordinated olefins. N-tosyl o-allylanilines cyclize much faster and more efficiently to give N-tosylindole derivatives.

In contrast, the preparation of an indole from o-halo N-allylaniline typically requires the use of Pd(OAc)2 and Et3N in CH3CN at 110 ºC for 72 h, with iodoaromatics usually giving good yields of indole. However, due to the deactivation of the palladium catalyst, it is necessary to add fresh catalyst periodically. For less reactive bromo aromatics, 2 equivalents of tris(o-tolyl)phosphine per Pd is necessary for an acceptable yield.

The Hegedus indole synthesis has been utilized for the production of various compounds such as: cycloprop[c]indol-5-ones

  • indole-3-acetic acids, and their hetero analogs
  • indole-3-pyruvic acid oxime ether
  • 5-(sulfamoylmethyl)indoles
  • CP-122288 (anti-migraine agent), N-methyl-1-[3-([(2R)-1-methylpyrrolidin-2-yl]methyl)-1H-indol-5-yl]methanesulfonamide
  • protected A-unit of antibiotic CC-1065

Moreover, the cyclization of o-vinylaniline has been employed in the preparation of o-vinyl-N-tosylanilines, o-vinylacetanilides, and o-vinyl-N-alkylanilines.

In summary, the Hegedus indole synthesis is a versatile reaction that can accommodate a wide range of functional groups and can perform intramolecular amination of various compounds.