2-Hydrazino- -ester

Scheme 18 Synthesis of an a-Hydrazino Ester by Asymmetric Hydrogenation of an iV-Benzoylhydrazone1"71...

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

A stirred solution of 0.10 mmol of the protected hydrazino ester 4 in 2 mL of CH2C12 is treated with 2.0 mL of CP jCOOH at 25 °C under N2. After 30 min, Raney nickel is added and the stirred mixture is hydrogenated... 

Azodicarboxylates undergo Michael addition to the electron-rich 5-position. The intermediate hydrazino ester is converted with bases to fervenu-lones or converted with Vilsmeier reagent (POCl3-DMF) to fervenulins, which are available by oxidation of the corresponding hydrazone using lead tetraacetate [75JOC2321 76JCS(P 1)2398] (Scheme 82). 

This reaction is arguably the most useful and certainly the most widely used application of the electrophilic C-amination of enolates in organic synthesis. A number of 4- and 4,5-substituted 2-oxazolidinones are commercially available in both enantiomeric forms and the chiral auxiliary is easily recovered.430 Reactions of A-acyloxazolidinonc enolates with azo esters431,432 and arenesulfonyl azides433 are rapid even at very low temperatures (—100°) and the diastereochemical outcome is reliably predictable. The facile removal of the chiral auxiliary and ready conversion of the azide or hydrazino ester functionalities into amines makes these reactions a standard method for the preparation of d- and L-a-amino acids. 

Unfortunately, the hydrazino esters or amides required inconveniently high pressures for their hydrogenolysis (500 psi Schemes 8.25a and b). An improvement involved the direct azidation of the same enolates using arylazide derivatives, which were found to undergo reactions with enolate nucleophiles to provide a C-sulfonyltriazene intermediate which could be decomposed to the a-azido ester (Scheme 8.25c) [110]. Alternatively, azides may be obtained by enolate bromination followed by Sn2 azide displacement note that these techniques are stereochemically complementary. Similar chemistry has also been accomplished using 10-suIfonamidoisobomyl chiral auxiliaries (Scheme 8.25d) [111]. 

Ethyl hydrazinoacetate 535 Chloroacetic acid (94.5 g, 1 mole) is added in portions to aqueous 32 % hydrazine solution (500 g, 5 moles), followed after 48 h by sodium hydroxide (8 5g, ca. 2 moles). Distillation in a vacuum then enables much (4 moles) of the hydrazine to be recovered. The distillation residue is heated with 30% alcoholic hydrochloric acid (650ml) to gentle reflux, then cooled and saturated with gaseous hydrogen chloride (ca. 2 h). Next, dry ethanol (500 ml) is added and the mixture is boiled and filtered hot. The hydrazino ester hydrochloride (103 g, 66.5%), m.p. 150-153°, crystallizes. 

In 2013, the Smith group reported asymmetric a-amination through an NHC-catalyzed redox reaction of a-aroyloxyaldehydes with A/-aryl-AI-aroyldi-azenes to form a-hydrazino esters with high enantioselectivity (up to 99% ee). The hydrazide products are readily converted into enantioen-riched A -aryl amino esters through Sml2-mediated N—N bond cleavage (Scheme 7.83). 

Ethyl N-benzyl-L-phenylalaninate treated 0.5 hr. at 80° with 1.2 equivalents NaNOg in 2 equivalents 1N HCl N-nitroso deriv. (Y ca. 100%) treated with Zn-dust in 3 1 acetic acid-acetic anhydride N -acetyl-Na-benzyl-L-a-hydrazino ester (Y 80%) hydrogenated with 5%-Pd-C in ethanol containing p-toluenesulfonic acid debenzylated compd. (Y 85%) heated 0.5 hr. at 110° in 6 N HCl under Ng L-a-hydrazino-j -phenylpropionic acid (Y 87%). F. e. s. K. Achiwa and S. Yamada, Tetrah. Let. 1975, 2701. 

Finally, a direct Mannich-type approach has been developed for the enantioselective synthesis of hydrazines and amines (Scheme 16.40). Thus, by trapping with alkyl diazoacetates some in s/iw-generated acyclic azomethine imines, in the presence of axially chiral dicarboxylic acids, a series of a-diazo-(3-hydrazino esters were obtained with excellent enantioselectivities [86]. 

Bowman RK, Brown AD, Cobb JH. Synthesis of HCV rephcase inhibitors base-catalyzed synthesb of protected a-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde. J Org Chem. 2013 78 11680-11690. 

The resolving of a variety of a-substituted carboxyHc acid esters by a previously undescribed enzyme, Candida lipolytica esterase, has been reported (64). a-Methyl-a-amino (49) and a-methyl-a-hydrazino (48) esters, which function as inhibitors of acid decarboxylase enzymes, are obtained on a multigram scale in optically pure form. 

A formal enantioselective synthesis of the antibiotic L-azatyrosine was developed. The asymmetric ally lation of hydrazono esters with ally lsilanes in the presence of a catalytic amount of ZnF2-chiral diamines in aqueous media generated (benzoyl)hydrazino-4-pentenoates in high enantioselec-tivity(Eq. 11.46).77... 

This ring system is represented by tricyclic ring system 533 (76JHC1249). Reaction of 3-hydrazino[l,2,4]triazin-5-ones 531 with 3-imi-nobutyronitrile afforded 6-methyl- (or phenyl-) 3-[3-methyl-5-aminopyra-zolyl]-2,5-dihydro[l,2,4]triazin-5-ones 532A, which may exist in tautomeric form 532B. Its reaction with diethoxymethyl acetate (DEMA) or ortho-esters afforded the tricyclic compounds 533. 

Furo[2, 3 4,5]pyrrolo[l,2-d][l,2,4]triazolo[3,4-/][l,2,4]triazines 667 were prepared by reaction of 664 with phosphorus pentasulfide to give 665 followed by conversion to the hydrazino derivative 666 and subsequent cyclization with ortho-esters (84CCC65, 84M13). Similarly, the indolo analogue 670 was prepared from 668 by sulfurization and hydrazinolysis to give 669, which cyclized with ortho-esters (84CCC1529). 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Amination. Three laboratories2-4 have reported use of esters of azodicarbox-ylic acid for amination of chiral substrates to provide a synthesis of optically active a-hydrazino and a-amino acids. The di-r-butyl ester is particularly useful because the diastereoselectivity improves with increasing size of the ester group, and in addition these esters are hydrolyzed by TFA at 25°. Two laboratories21 used the lithium enolates of chiral N-acyloxazolidones (2) as the chiral precursors. A typical procedure is outlined in equation (I). Thus reaction of the lithium enolate of 2... 

Diethyl N-phenylaminothiocarbonylmalonate was reacted with hydrazine hydrate in boiling ethanol for 4 hr to give a mixture of 5-phenylamino-2-pyrazolin-5-one and monoethyl ester, a hydrazide of hydrazino(phe-nylamino)methylenepropanedioic acid (77G555). 

It has been found that triamcinolone [101] and the 21-phosphate esters [102] do not under go the Porter-Silber reaction. It was also shown that an increased sensitivity for this procedure can be obtained using the p-hydrazino-benzenesulfonic acid-phosphoric acid reagent [103],... 

Die Cyclisierung von Dithiokohlensaure-ester-hydraziden, die durch Alkylierung von Kalium-C-(2-acyl-hydrazino)-dithiocarbonaten erhaltlich sind, vcrlauft unter Alkanthiol-Abspaltung zu 2-Mercapto-l,3,4-oxadiazolen. Die Methode bietet gegeniiber dem zumeist praktizierten obigen Verfahren keine Vorteile. 

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