Hydrazines solid support

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. ... 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

The hydrazone was subsequently treated with KOH under the action of MW to undergo Wolff-Kishner reduction (leading to PhCH2Ph) within 25-30 min in excellent yields (95 %). As an extension, the reaction of neat 5- or 8-oxobenzopyran-2(lH)-ones with a variety of aromatic and heteroaromatic hydrazines is substantially accelerated by irradiation in the absence of any catalyst, solid support, or solvent [66] (Eq. 14). 

Baxendale IR, Ley SV Sneddon H (2002a) A clean conversion of aldehydes to nitriles using a solid-supported hydrazine. Synlett 775-777 Baxendale IR, Lee A-L, Ley SV (2002b) A concise synthesis of carpanone using solid-supported reagents and scavengers. J Chem Soc Perkin Trans 1 1850-1867... 

Hence, the implication of combinatorial chemistry for high throughput generation of structurally diverse hydroxamic acids is self-evident. Several solid-phase approaches for their syntheses have been reported,1 7-11 the majority of which are based on the anchoring of iV-hydroxyphthalimide onto an appropriate solid support. After hydrazine-mediated /V-dcprotcction, /V-acylation of the resin-bound hydroxylamine would yield the desired O-anchored hydroxamic acid, which is typically released by acidolysis. 

A-Hydroxyphthalimide 178 was used as a source of the hydroxylamine reacting with trityl chloride resin 182 in the presence of triethylamine to obtain the A-hydroxyphth-alimide derivative 183. This intermediate is transformed to the desired hydroxylamine resin 184 by treatment with hydrazine. The peptidic and peptidomimetic hydroxamic acids 185 and 186 were synthesized using the described solid-supported reagent (Scheme 82). 

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 combination of iron(III) salts with solid-supported hydrazine hydrate (preabsorbed on AI2O3) were successfully used in reductions of aromatic nitro groups (Scheme 4.33). The nature of the solid support plays a crucial role in this reaction and alumina was found to be most effective. In the absence of a solid support, the reaction... 

To accelerate the reactions rates and to increase their yields, sometimes microwave-assisted procedures are applied. The first mention of using a solvent-free microwave procedure was in [55]. The authors described the synthesis of 1,3,5-triarylpyrazoline by the cyclization of chalcones with phenylhydrazine on a basic alumina solid support. The target heterocycles were synthesized under microwave irradiation in high yields (up to 85%) in 1-2 min instead of 3 h in the case of thermal activation. Another publication [56] deals with the rapid (2-12 min) solvent-phase cyclization of naphthyl-substituted chalcones 41 and hydrazines 42 in a microwave field yielding the appropriate pyrazolines 43 quantitatively (Scheme 2.10). 

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>. 

Isonicotinic acid hydrazide (isoniazid 275), a drug used in treating tuberculosis269, has been 1 -labelled264 by introduction of a [nC]cyano group at the 2-position of the pyridine ring of l-methoxy-4-methoxcarbonyl pyridinium methyl sulphate and subsequent treatment of the 1 -labelled methyl ester 276 with hydrazine hydrate. The reaction has been carried out on a solid support (silica gel) to yield methyl 2[11C]cyano-isonicotinate in 32.4+12% (EOB) yield. 275 was obtained in 10% (EOB), radiochemical... 

The iV-l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl linker has also been introduced between the C2-amino group of the glucosamine and a solid-support [5]. This linker was stable during glycosylation with thioglycoside in the presence of methyl trifluoromethane sulfonate, but readily cleaved by hydrazine, primary amines, or even ammonia. 

These linkers are based on the acetyldimedone (Dde) protecting group for amines originally developed by Bycroft et al. [33]. Linker 29 can be coupled to an amino-modified support, and the attachment of the amine to give 30 proceeds without an activating reagent. Alternatively, the linker can be first coupled to the amine, after which the adduct is attached to the solid support. The linker is stable towards acidic conditions as well as moderately basic conditions, but the amine can be cleaved from the linker by treatment with a 2% solution of hydrazine in DMF... 

Solid-Supported Surface Catalysis by Metal Complexes. Hong et al. (1987a, b, in press) have prepared a variety of hybrid catalysts between Co(II) phthalocyanine complexes and the surfaces of silica gel, polystyrene-divinylben-zene, and Ti02 and tested these hybrids for catalytic activity with respect to the autoxidation of hydrogen sulfide, sulfur dioxide, 2-mercaptoethanol, cysteine, and hydrazine ... 

Figure 18.3. H spectra (region of amide protons) of a polystyrene/1 % divinylbenzene resin (0.5 mmol/g in d7-DMF) allow fast and reliable controls of synthesis and cleavage conditions. Top H spectra of the pure HMPA-PS resin center H spectra after the synthesis of an letra-peptidc Gly-Asn-Leu-Ile bottom H spectra after the cleavage of the tetrapeptide with hydrazine. The latter spectrum shows some small amounts of product still attached to the solid support.

Polymer-bound chiral hydrazines have been synthesized to furnish a-branched amides (Scheme 12.17) [13, 23], Enantiopure (i-methoxyamines 37 and 38, derived from readily available hydroxyproline and N,N-dibenzylleucinol, respectively, have been attached to solid support and transformed into the corresponding hydrazine auxiliaries 39 and 40 via several steps. The synthesis of a series of enantiomerically enriched a-branched amides required the coupling of aliphatic and aromatic aldehydes to form hydrazones 41 and 42 followed by the addition of different nucleophiles. Cleavage of the N-N bond of the resulting hydrazines 43 and 44 led to a-branched amines 45. Further conversion with benzoyl chloride or acetyl chloride furnished amides 46 in yields of 24—51% and 50-83% ee. 

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