Trisubstituted hydrazines

Aminonaphthalene (775) reacts with diethyl azodicarboxylate to give the trisubstituted hydrazine (776) which can be cyclized in wet piperidine to l,4-dihydro-3-oxonaphtho-[2,1 -e][ 1,2,4]triazine-1 -carboxylate (777) (21CB213). 

Electrophilic N-aminations have been performed with hydroxylamine-O-sulfonic acid (HOSA)," O-(2,4-dinitrophenyl)hydroxylamine and C>-mesitylenesulfonylhydroxylamine. The use of HOSA is mainly restricted to aqueous reaction media. Imide sodium salts of some heterocycles such as theobromine (88) can be converted to hydrazine derivatives by treatment with 0-(diphenylphosphinyl)hydroxylamine (equation 35)." This reaction has been extended to synthesis of N-arylhyd ines, where R and R are hydrogen, alkyl or aryl (equation 36)." Similarly, trisubstituted hydrazines can be prepared by the use of N-aryl-O-acetylhy oxylamines and secondary amines." A recent publication" concerning the synthesis of l-acyl-2-dkylhydrazines from hydroxamic acids and amines in the presence of activating agents has been found to be erroneous no N—N bond formation occurs under these conditions." ... 

Aryl Azo Compounds. Alkyl- (including tert-butyl) and aryllithium reagents add to azo benzene to give trisubstituted hydrazines in fair to excellent yields (see Eqs. 44 and 45) alkylation of the intermediate anion in situ leads to tetra-substituted hydrazines.211 Benzyl and heteroarylmethyl (see Eq. 54) anions and the enolate of phenylacetamide add to azo benzene in fair to excellent yields.212 Aromatic Grignard reagents are reported to reduce azo benzene and its derivatives to the hydrazo compounds (cf. also Eq. 20).213 The only other aryl azo compound investigated in animations appears to be benzo[c]cinnoline.214... 

The formation of pentagonal-bipyramidal complexes with a coordinated hydrazido(l-) ligand is also observed upon the interaction of WOF4 with other di- and trisubstituted hydrazines in the presence of triethylamine [65]. This is indicated both by the high values of /( Fa- Fc) and 7( Fa- Fm), and by the positions of the signals in the F NMR spectra. 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

Because of the ease of ring synthesis, symmetrically trisubstituted s-triazines have been more thoroughly studied, but a few nucleophilic substitutions of derivatives bearing a single leaving group are known. 2-Chloro-4,6-diphenyl- and 2-chloro-4,6-dimethyl-s-triazines (318) undergo facile nucleophilic displacements with ammonia, amines, and hydrazine, with alkoxide, or with hydrosulfide... 

Pyridazines 160 were obtained by microwave-assisted reaction of 1,4-dicarbonyl compounds and hydrazine in AcOH and in the presence of DDQ as oxidant in order to obtain the aromatic compound in a one pot reaction [ 105]. The yields reported were relatively low although the method can be applied to the preparation of arrays of trisubstituted pyridazines with high molecular diversity (Scheme 57). 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

As depicted in Scheme 21, subjection of 86 with 20 mol% of freshly prepared 2 after 4 h at 22 °C indeed afforded 87 in 92% yield after silica gel chromatography (>98% Z). Stereocontrolled hydrogenation of the trisubstituted olefin (72% yield) and removal of the acetate and trifluroacetate groups, effected by subjection of the hydrogenated adduct with hydrazine in MeOH, delivered Sch 38516 (1) in 96% yield to complete the total synthesis. 

A robust catch, cyclize, and release preparation of 3-thioalkyl-1,2,4-triazoles mediated by the polymer-bound base P-BEMP has been described <02TL5305>. Reaction of solid-supported hydrazides 103 with isocyanates or isothiocyanates followed by base-induced cyclization/cleavage afforded 1,2,4-trisubstituted urazoles and thiourazoles 104 <02JCO491, 02TL3899>. Polymer-supported V-acyl-1 //-benzotriazole- 1-carboximidamides 105 reacted with hydrazines followed by acidic cyclizative release to give 3-alkylamino-l,2,4-triazoles 106 <02OL1751>. 

Recently, Muller and co-workers [145] have reported a series of 3,5-disubstituted and 1,3,5-trisubstituted pyrazoles 104 and 105 by reacting an acyl chloride, a terminal alkyne and a hydrazine via a consecutive one-pot three-component Sonogashira coupling/Michael addition/cyclocondensation sequence under microwave irradiation. The desired products were obtained in good to excellent yields. These obtained pyrazoles are highly fluorescent, both in solution and in the solid state (Scheme 81). 

The orientation of the substituent gtoups in 1,2,4-oxadiazole substituted pyrazoles 39, formed by reaction of benzonittile oxides with an unsymmetrically substituted hydrazine, has been determined by C NMR assignments <1998JHC161>. The scope and limitations in the regioselective synthesis of 1,3,5-trisubstituted pyrazoles from / -amino enones and hydrazine derivatives were investigated by C chemical-shift prediction mles for 1,3,5-trisubstituted pyrazoles <2001H(55)331>. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Aminopyrazoles were prepared from the reaction of hydrazines with a resin-supported /3-ketonitrile <1997TL9065>. Cyanoacetophenone has been employed as a synthon for the assembly of 1,4,5-trisubstituted pyrazoles <1998M1207>. 2-Tosylethylhydrazine 559 could be condensed with either / -ketonitriles 557 or /3-aminoacrylonitriles 558 to give 5-aminopyrazoles 560, which were deprotected with sodium ethoxide to give 3(5)-aminopyrazoles 561 (Scheme 69)... 

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, A -alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocon-densation process (Equation 131) <2002J(P1)207>. A -Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition-decyclization-cyclocondensation process (Equation 132) <2003H(60)2499>. 

Dihydropyrazoles can be prepared under microwave irradiation conditions. /3-Alkyl chalcones 649 reacted with hydrazines under microwave conditions followed by addition of acid chlorides to yield 1-acyl-3,5-diaryl-5-alkyl-4,5-dihydropyrazoles 650 (Scheme 82) <2004TL1489>. l,3,5-Trisubstituted-2-pyrazolines 652 were obtained from chalcones 651 and phenylhydrazine on silica gel and with microwave irradiation (Equation 135) <2005JHC157>. 

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