Masked 1-difunctional compounds

Reaction of 2-methylene-1,3-dithietanes (256) with hydrazines affords 5-thiolpyrazoles (257) 90JHC567 . These last products were converted into 5-S-methyl pyrazoles (258) by methyliodide. Other authors 87JCS(P1)1945 have used a-aroyl-a-bromoketenedithioacetals to prepare 3(5),4-bis(alkylthio)pyrazoles. 

Transformation of (l,3-dioxolan-2-ylidene)methylphosphonates (or phosphinates) to 5-amino-A -substituted-3-(2-hydroxyethoxy)-4-phosphono (or phosphino)pyrazoles occurs by reaction with hydrazines, R —NH—NH2 (R = CH3, CsHj, OEt) 92HCA124 . Similarly, dioxolanes (259) are transformed into 5-hydroxypyrazoles (260) by reaction with hydrazine and into pyrazolium betaines (261) by reaction with 1,1-disubstituted hydrazines 92HCA1039 . 

Reaction of hydrazines with 3-unsubstituted isoxazolium salts (262) yield 3-aminopyrazoles (263 X = H, NO2, Cl, Br, COMe, COjEt, = H, Me, Ph, CONHj) 88S203 . 

In order to study estrogen synthetase inhibitors, it was necessary to prepare the carbinol (267). This compound was obtained from the corresponding A -methylpyrimidinium salt (266 Ar=p-chlorophenyl) 90JMC416 . 

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A simplified synthesis relies on the potential to protect difunctional compounds as cyclic derivatives. For example, 1,2-diols are masked as cyclic acetals (Section 24-8), hydroxy acids as lactones (Section 19-9), amino acids as lactams (Section 19-10), and dicarboxylic acids as anhydrides (Section 19-8). The last two possibilities merit consideration as applied to Asp. However, direct lactam formation can be quickly ruled out because of the complications of ring strain (although /3-lactams have been used in the preparation of aspartame). This problem is absent with respect to dehydration to the five-membered ring anhydride. Because anhydrides are activated carboxylic acid derivatives (Section 20-3), the Asp anhydride can be coupled directly with Phe-OCHa without the help of added DCC. Nucleophilic attack of the amino end of Phe-OCHs occurs preferentially at the desired position, albeit not completely so 19% of the product derives from peptide-bond formation at the /3-carboxy group of Asp. 

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