Synthesis of Tryptophol from
Dihydrofuran and Phenylhydrazine

Among the diverse and creative approaches that have been discovered, the Fischer indole reaction remains the benchmark to which other methods are compared. Despite being quite versatile, the Fischer indole reaction with aldehydes often suffers from low yields and involves a two-step process (i.e., hydrazone formation, [3+3] rearrangement). We herein wish to report a convenient and practical one-pot synthesis of 3-substituted indoles from commercially available cyclic enol ethers and enol lactones and the extension of this procedure to the regioselective synthesis of 2,3-disubstituted indoles. In our pursuit of an efficient synthesis of tryptophol homologs, we were intrigued with the possibility of using dihydropyran as an aldehyde equivalent in the Fischer indole reaction. We suspected that suitable conditions could be developed that would not only generate the hydrazone from the aryl hydrazine and dihydropyran in situ but also catalyze the [3+3] rearrangement in the same pot.

We chose 4% aqueous sulfuric acid as the solvent because of its documented success in promoting the Fisher indole reaction involving the in situ hydrolysis of an aldehyde protected as its dimethyl acetal². When dihydropyran was added to a solution of phenylhydrazine hydrochloride in 4% aqueous sulfuric acid at 100°C, indole 2a [homotryptophol] was obtained in 50% isolated yield. The major byproduct of the reaction was triol 1, resulting from further reaction of 2a with dihydropyran (Eq. 1 ).

We suspected that 1 was produced due to the high concentration of dihydropyran relative to indole product during the reaction; however, slow addition of dihydropyran did not decrease the level of 1 (49%).^{Note 1} After considerable study, it was discovered that addition of a cosolvent to the reaction significantly improved the reaction profile, producing less than 5% of byproduct 1.^{Note 2} Of the solvents investigated, acetonitrile (MeCN) and N,N-dimethylacetamide (DMAc) were optimal, affording indole 2a in 85 and 90% yields, respectively.^{Note 3}

The utility of this method was highlighted in the synthesis of Glaxo's antimigraine drug, sumatriptan. Despite the documented difficulty of Fischer indole reactions with hydrazine 3 [4-(MeNHSO₂CH₂)C₆H₄-NH₂NH₂] due to the instability of the product under acidic conditions³, the one-pot reaction could be accomplished to cleanly afford the desired hydroxyindole 4 [5-(MeNHSO₂CH₂)-2a]. Activation of the hydroxyl group as the mesylate followed by displacement in the presence of excess dimethylamine according to previously disclosed methodology^3b (Eq. 3) afforded sumatriptan in three steps and 45% overall yield (unoptimized).

The reaction of phenylhydrazine with other cyclic enol ethers was then investigated further. For example, reaction of phenylhydrazine with dihydrofuran (5) afforded tryptophol (6) in 72% yield (Eq. 2).

In conclusion, a general, one-pot method for the synthesis of highly functionalized indoles from commercially available cyclic enol ethers and enol lactones has been demonstrated. The procedure is general with respect to both the aryl hydrazine and the enol ether that are used. The method was especially useful for the regioselective synthesis of 2,3-disubstituted indoles. Cyclic enol lactones could be used in this coupling to afford substituted indole propionic acids and indole acetic acid derivatives in an efficient manner.

Notes:

1. Excess hydrazine (2 equiv) slightly reduced the amount of 1 (40%).
2. Importance of the cosolvent is due to the homogenization of the reaction mixture. In purely aqueous systems, the product and dihydrofuran are insoluble, creating a highly concentrated "organic layer" that leads to increased formation of 1.
3. Performing the reaction at 100°C was optimal. Lower temperatures gave significantly lower yields of 2a (50°C, 33% yield; 25°C, 18% yield). However, in the case of more electron-rich hydrazines such as p-methoxyphenylhydrazine, lower temperatures (55°C) were needed to prevent the formation of the methoxy-substituted analogue of 1.

N,N-Disubstituted Tryptamines from Tryptophols⁴

Abstract⁴
N-disubstituted tryptamines are obtained in high yield on boiling a solution of tryptophols in benzene or xylene with secondary amines and a nickel catalyst.

(Lilienthal's voice:) Mechanism⁵: The alcohol is catalytically dehydrogenated to the aldehyde, which reacts with the amine to an imine, which is subsequently hydrogenated to the amine. Usually this gives moderate yields and needs high temperatures (very uncool for the low-boiling dimethylamine).

From Indole-3-Acetic Acid via Tryptophol to DMT

Some notes on this route by 'Know Conscience'

Main Step One:

Diborane is a newer (than LAH), more selective reducing agent specific for carboxylic acids. It reduces them to primary alcohols quickly and in high yield at room temperature in an ether solvent such as diglyme or THF. LAH will also get the job done, but it is difficult to work with and apparently only gives a 65% yield in this instance.

Main Step 2:

Once you've got the 3-(2-hydroxyethyl)-indole made, PBr₃ is a better way to brominate it than HBr. This is because HBr is a stronger acid than PBr₃ and will therefore tend to favor an unwanted dehydration side reaction on this primary alcohol.

That is, 3-(2-hydroxyethyl)-indole + HBr → 3-(2-bromoethyl)-indole + 3-ethenyl-indole.

Also, every one PBr₃ molecule has the potential to brominate three 3-(2-hydroxyethyl)-indole molecules to form three 3-(2-bromoethyl)-indole molecules plus one H₃PO₄ (phosphoric acid) molecule. So if you have X moles of 3-(2-hydroxyethyl)-indole, you will only need to use X/3 moles PBr₃.

Phosphorus acid is water soluble and has a high boiling point, so it can therefore be separated from the brominated indole product by means of an acid-base extraction or by simple distillation after basification.