Hydrazine-epoxide

Scheme 6 Rearrangement of a bicyclic hydrazine-epoxide by an aziridiniiun cation intermediate...

Micouin et al. found that the nucleophilic substitution of bicycUc hydrazine-epoxide 7 using alkynylaluminum reagent led to the formation of hydroxy group-rearranged product 8 (Scheme 6) [20]. The plausible mechanism of this unique reaction involves (1) the initial formation of aziridinium cation intermediate catalyzed by aluminum Lewis acid and (2) the intramolecular nucleophilic migration of alkynyl group, as in transition state 9. 

HydroxyethyUiydrazine (11) is a plant growth regulator. It is also used to make a coccidiostat, furazoHdone, and has been proposed, as has (14), as a stabilizer in the polymerization of acrylonitrile (72,73). With excess epoxide, polysubstitution occurs and polyol chains can form to give poly(hydroxyaLkyl) hydrazines which have been patented for the preparation of cellular polyurethanes (74) and as corrosion inhibitors for hydrauHc fluids (qv) (75). DialkyUiydrazines, R2NNH2, and alkylene oxides form the very reactive amineimines (15) which react further with esters to yield aminimides (16) ... 

Other methods of generating a-aminoketones in situ are common, if somewhat less general than the methods already described. 2-Nitrovinylpyrrolidine, which is readily available, yields 2,3-bis(3-aminopropyl)pyrazine on reduction and this almost certainly involves ring opening of the intermediate enamine to an a-aminoketone which then dimerizes under the reaction conditions (Scheme 59) (78TL2217). Nitroethylene derivatives have also served as a-aminoketone precursors via ammonolysis of the derived epoxides at elevated temperatures (Scheme 60) (76S53). Condensation of 1,1-disubstituted hydrazine derivatives with a-nitro-/3-ethoxyethylene derivatives has been used in the synthesis of l,4-dialkylamino-l,4-dihydropyrazines (Scheme 61) (77S136). 

The azidohydrins obtained by azide ion opening of epoxides, except for those possessing a tertiary hydroxy group, can be readily converted to azido mesylates on treatment with pyridine/methanesulfonyl chloride. Reduction and subsequent aziridine formation results upon reaction with hydrazine/ Raney nickel, lithium aluminum hydride, or sodium borohydride/cobalt(II)... 

The potential of such reaction sequences for the generation of molecular diversity was also demonstrated by the synthesis of a library of heterocycles. Epoxide ring-opening with hydrazine and subsequent condensation with (3-diketones or other bifunctional electrophiles gave rise to a variety of functionalized heterocyclic structures in high purity [34]. A selection based on the substrate derived from cyclohexene oxide is shown in Scheme 12.12. 

Displacement of the 3-hydroxyl group of 74 was carried out with Et2NSF3 (DAST) (DAST - diethylaminosulfur trifluoride) in dichloromethane. The expected fluorinated product 75 on treatment with aqueous perchloric acid led to regioselective epoxide ring opening to give 76, which on treatment with hydrazine hydrate at 100 °C for 18 h yielded 3,4-dihydroxy-8-oxo-octahydropyridazino[l,6-r/][l,2,4]triazine-l-carboxylic acid phenylamide 77 (Scheme 3) <1997T9357>. 

Pyrazoles were synthesized in the authors laboratory by Le Blanc et al. from the epoxy-ketone as already stated in Sect. 3.1.1a, Scheme 35 [80]. The synthetic strategy employed by Le Blanc et al. [80] was based upon that the strategy published by Bhat et al. [81] who also described the synthesis of pyrazoles but did not report cytotoxic evaluation on the synthesized compounds. Scheme 48 shows the synthesis of the most active compound (178). Dissolution of the epoxide (179) with a xylenes followed by treatment with p-toluenesulfonic acid and hydrazine hydrate produced the pure nitro-pyrazole 180 in good yield (60%). Catalytic hydrogenation with palladium on activated carbon allowed the amino-pyrazole (178) to be obtained in a pure form. This synthesis allowed relatively large numbers of compounds to be produced as the crude product was sufficiently pure. Yield, reaction time, and purification compared to reported approaches were improved [50, 61, and 81]. Cytotoxicity of these pyrazole analogs was disappointing. The planarity of these compounds may account for this, as CA-4, 7 is a twisted molecule. 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

The successful synthesis of 2-thienyl and substituted 2- and 3-thienyl-acetylenes in yields as high as 60-80% opened a wide variety of synthetic applications. Various addition reactions with carbonyl compounds or epoxides could be carried out with ease. Aliphatic as well as aromatic amine addition reactions, or condensation reactions with hydrazine or hydroxylamine could be easily performed. 

Hemminki, K., Falck, K. Vainio. H. (1980) Comparison of alkylation rates and mutagenicity of directly acting industrial and laboratory chemicals. Epoxides, glycidyl ethers, methylating and ethylating agents, halogenated hydrocarbons, hydrazine derivatives, aldehydes, thiuram and dithiocarbamate derivatives. Arch. Toxicol., 46, 277-285... 

Esckenmoser fragmentation (2, 419 422). This hydrazine can be more effective than tosylhydrazine for this fragmentation.2 Thus reaction of 1 with the a-keto epoxide 2 results in formation of l-cyclononyn-5-one (3) in about 43% yield. Another example is the preparation of 2,2-dimcthyl-5-hexynal (5) from 4. These relictions proceed in about 15- 20% yield with tosylhydrazine. 

The treatment of a N-substituted hydrazine hydrobromide successively with the a,a-dicyano-epoxide 91 and with TV-methyl hydrazine results in the racemic a-hydrazino hydrazide 92 (Scheme 29)/111 Repeating the above two reactions allows the elongation of 92 into the racemic (hydrazide) peptide 93/1121 A derived procedure, with ClCH2COCl instead of 91, is applied to the synthesis of the first (hydrazide) cyclotripeptide 94 (R1 = 4-C1C6H4 or 4-MeQlLi) (Scheme 30), by coupling of the N-terminal chloroacetyl and C-terminal hydrazine groups/113 It has been later extended to the synthesis of linear (hydrazide) polypeptides/114 It is noteworthy that the a-carbon is racemic in all of the above cases. 

Verazine (358), the steroidal alkaloid of Viscum album, has been synthesized,188 starting from the pregnadiene ketone (354) (Scheme 17), itself available by a hydrazine reduction (Wharton-Bohlen reaction) of the 16a, 17a-epoxide of 16-dehydropregnenolone. Condensation of (354) with (2S)-methyl-5-nitropentanoate (355) gave a mixture of C-22 epimers from which the (C-22S)-compound (356) was... 

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