Grandberg synthesis

An interesting extension of the Grandberg synthesis was utilized in reaction of the hydrazines 355 with the aldehyde 356, followed by N-functionalization, to provide the systems 357, via the conceivable intermediates 358 (Equation 99) <2002H(58)587>. 

An exceptionally nsefnl adaptation is the Grandberg synthesis of tryptamines from 4-halo-butanals, or more often in practice their acetals, in which the nitrogen nsnally lost dnring the Fischer process is incorporated as the nitrogen of the aminoethyl side-chain. 

When phenylhydrazine and 4-chlorobutanal are reacted in refluxing ethanol, a 70% yield of tryptamine is obtained after the usual workup (Grandberg synthesis). 

Scheme 21. Synthesis of almotriptan (5) using the Grandberg modification of the Fischer indole reaction.

For a review, sec Przheval skii Grandberg Russ. Chem. Rev. 1987,56, 477-491. For reviews of (3.3 sigmatropic rearrangements with hctcro atoms present, sec Blcchert Synthesis 1989, 71-82 Wintcrfcldt Fortschr. Chem. Forsch. 1970,16. 75-102. For a review of [3,3) rearrangements of iminium salts, sec Hcimgartncr Hansen Schmid Adv. Org. Chem. 1979, 9, pt. 2, 655-731. 

The ketone component can be replaced by cyclic enol ethers, which react with phenylhydrazines to give phenylhy-drazones, as has been demonstrated by a large-scale synthesis of 5-fluorohomotryptophol derivatives from 4-fluorophe-nylhydrazine hydrochloride and tetrahydropyran <19970PD300>. The Grandberg modification of the Fischer synthesis involves the use of an acetal as the ketone equivalent <2001T1041>. 

F. Reynolds, J. Pitha, P. M. Pitha, and D. Grandberg, Inhibition of Cell-Free Protein-Synthesis by Poly(9-Vinyladenine), Poly (1-Vinyluracil), and Corresponding Vinyl Copolymer, Biochemistry, vol. 11, no. 17, pp. 3261-3266, 1972. 

Singh and coworkers demonstrated the power of the Grandberg method for the preparation of both tryptophols and homotryptophols (equations 1-3) [393], whereas Bosch applied the Grandberg tryptamine synthesis to the preparation of 5-(suIfamoylmethyl)indoles (equation 4) [394],... 

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