Hydrazine surrogate

Like the use of the imine as an ammonia surrogate, the hydrazone of benzophenone can be used as a hydrazine surrogate (Scheme 2.165). The coupling product 2.564 may be diverted directly into a Fischer indole synthesis via hydrazone exchange with an added ketone. This pathway gives an indole 2.565 with a free N-H. Alternatively, the available nitrogen atom may be alkylated or coupled a second time, and then diverted into a Fisher indole synthesis. In this way, indoles with no nitrogen substituent, or an A-alkylated indole 2.566 or an iV-arylated indole 2.567 can be formed. 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

In addition to 1,3-dicarbonyl as a reactant for the Knorr pyrazole synthesis, several variants exist as the 1,3-dicarbonyl group surrogate. Enaminone is one example. Reaction between ethyl-4-iodobenzylacetate and I. N-dimethylformamide dimethylacetal (DMFDMA) provided the enaminone. Subsequent condensation between the enaminone and 2,4-dichlorophenyl-hydrazine afforded the pyrazole as an advanced intermediate for 1,5-diarylpyrazole derivatives as CBi receptor antagonists. 

In this reaction, acylhydrazones were chosen as imine surrogates because they could be more easily handled than imines. Products were obtained as hydrazines, which could be used as unique building blocks as well as be transformed to the corresponding free amines after N—N bond cleavage under reductive conditons. The reaction also proceeded smoothly in pure water with excellent enantioselectivity (entry 5). 

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