Zinc in acetic acid

Trichloro- and 2,2,2-tribromoethoxycarbonyl (Tceoc and Tbeoc) protecting groups are introduced with the commercially available 2,2,2-trihaloethyl chloroformates. These derivatives are stable towards CrOj and acids, but can smoothly be cleaved by reduction with zinc in acetic acid at 20 °C to yield 1,1-dihaloethene and CO. Several examples in lipid (F.R. Pfeiffer, 1968, 1970) and nucleotide syntheses (A.F. Cook, 1968) have been described. 

The blocking and deblocking of carboxyl groups occurs by reactions similar to those described for hydroxyl and amino groups. The most important protected derivatives are /-butyl, benzyl, and methyl esters. These may be cleaved in this order by trifluoroacetic acid, hydrogenolysis, and strong acid or base (J.F.W. McOmie, 1973). 2,2,2-Trihaloethyl esters are cleaved electro-lytically (M.F. Semmelhack, 1972) or by zinc in acetic acid like the Tbeoc- and Tceoc-protected hydroxyl and amino groups. 

Phenylpyridazin-4-oxime is transformed into 5-methyl-2-phenylpyrrole when treated with zinc in acetic acid. 

The iV-hydroxypyrazoles (523 R = H) and the pyrazole iV-oxides (268 Section 4.04.2.1.3 (xiii)) have been reduced to pyrazoles by means of zinc in acetic acid and catalytic hydrogenation, respectively (75MI40402). 

Many carbamates have been used as protective groups. They are arranged in this chapter in order of increasing complexity of stmcture. The most useful compounds do not necessarily have the simplest stmctures, but are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hy-drogenolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by /3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid and ally], readily cleaved by Pd-catalyzed isomerisation. 

The TCBOC group is stable to the alkaline hydrolysis of methyl esters and to the acidic hydrolysis of r-butyl esters. It is rapidly cleaved by the supemucleophile lithium cobalt(I)phthalocyanine, by zinc in acetic acid, and by cobalt phthalocy-anine (0.1 eq., NaBH4, EtOH, 77-90% yield). 

A reaction which is of considerable importance for the selective labeling of a position adjacent to a carbonyl group is the treatment of a-halo ketones (mainly bromides) with zinc in acetic acid-OD, or deuteriobromic acid at... 

The isotopic purity of the product is usually about 48-62%, the rest of the material being mainly undeuterated. (An alternate preparation of a-mono-deuterio ketones of high configurational and isotopic purity is the mild oxidation of cis- or tra 5-deuterated alcohols under Jones conditions, see sections V-D and VII-A.) Treatment with zinc in acetic acid-OD has also been applied to the deiodination of 2a-iodoandrost-4-ene-3,17-dione. In a slightly modified version the iodine in 19-iodocholesterol acetate has been replaced with tritium by using tritium oxide as the isotope source/... 

Displacement of aromatic halogen in 2,4-diiodo-estradiol with tritiated Raney nickel yields 2,4-ditritiated estradiol. Aromatic halogen can also be replaced by heating the substrate with zinc in acetic acid-OD or by deuteration with palladium-on-charcoal in a mixture of dioxane-deuterium oxide-triethylamine, but examples are lacking for the application of these reactions in the steroid field. Deuteration of the bridge-head position in norbornane is readily accomplished in high isotopic purity by treatment of the... 

Deuteration at C-9 by Treatment of a 9a-Bromo-11 -keto Steroid with Zinc in Acetic Acid-OD... 

Zinc in acetic acid at room temperature reduces a,j6-unsaturated ketones,... 

The nitrate group is stable to the dilute alkaline conditions required for saponification of secondary acetates although it is cleaved during Wolff-Kishner reduction.Nitrates are stable to chromic acid oxidation in acetic acid, to organic peracids, and to lead tetraacetate.This group is readily split by reduction with zinc in acetic acid. 

Deuteration at C-9 by treatment of a 9a-bromo-ll-keto steroid with zinc in acetic acid-OD, 204... 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Norcoralyne (113) was reduced with zinc in acetic acid and 1% hydrochlorid acid in 88% yield to give the 13-hydroxy-norcoralynium... 

The oxygen atom at 21 is similarly an expendable group. Reaction of 241 (obtained from 185 by the usual procedure for introduction of the 9a-fluoro group) with methanesulfonyl chloride affords the 21 mesylate (242a). Replacement of the leaving group at 21 with iodine by means of potassium iodide in acetone followed by reduction of the halogen with zinc in acetic acid leads to fluorometholone (243). ... 

An isoindol1 none moiety forms part of the aromatic moiety of yet another antiinflammatory propionic acid derivative. Carboxylation of the anion from -nitro-ethylbenzene (45) leads directly to the propionic acid (46). Reduction of the nitro group followed by condensation of the resulting aniline (47) with phthalic anhydride affords the corresponding phthalimide (48). Treatment of that intermediate with zinc in acetic acid interestingly results in reduction of only one of the carbonyl groups to afford the isoindolone. There is thus obtained indoprofen (49). ... 

The reduction of ,/S-unsaturated y-diketones can conveniently be done with zinc in acetic acid. The following procedure is applicable to the reduction of the Diels-Alder adduct of quinone and butadiene (Chapter 8, Section II). 

Compound A, C10H 8O, undergoes reaction with dilute H2S04 at 50 °C to yield a mixture of two alkenes, QpH ir>. The major alkene product, B, gives only cyclopentanone after ozone treatment followed by reduction with zinc in acetic acid. Identify A and B, and write the reactions. 

Oz.onide (Section 7.9) The product formed by addition of ozone to a carbon-carbon double bond. Ozonides are usually treated with a reducing agent, such as zinc in acetic acid, to produce carbonyl compounds. 

Ethyl 1-bromocyclohexanecarboxylate, when treated with magnesium in anhydrous ether-benzene with subsequent addition of cyclohexanone, yields ethyl l-(l-hydroxycyclohexyl)cyclo-hexanecarboxylate. Dehydration and saponification give rise to l-(l-cyclohexenyl)cyclohexanecarboxylic acid, which upon decarboxylation at 195° yields cyclohexylidenecyclohexane in 8% overall yield, m.p. 540.4 This olefin has also been prepared by the debromination of 1,1 -dibromobicyclohexyl with zinc in acetic acid. ... 

Cholest-3-ene has been prepared previously by deamination of 5/3-cholestan-3 -yl amine,by reduction of a mixture of 4 -bromo-5 -cholestan-3a-ol and its epimer with zinc in acetic acid, and as component of a mixture of cholestenes by Wolff-Kishner reduction of cholest-4-en-3-one. ... 

Reduction of Methylene Violet with zinc in acetic acid gives the air-sensitive leuco 20 which is further reacted with acetic anhydride in mild conditions to yield the acetylated leuco 21. The latter being air stable can be isolated and, the ring N-H being less reactive is not affected by acetylation at room temperature. The leuco 21 is again aroylated to produce the leuco 22. Selective hydrolysis provides the desired leuco dye 12 which regenerates the true Methylene Violet (6) on oxidation.83... 

Kondo et al. (182,183) reported a conversion of a fully aromatized phenolbetaine to a phthalide skeleton through photooxygenation. Reduction of norcoralyne (54) with zinc in acetic acid afforded dihydronorcoralyne (374), which was oxidized with m-chloroperbenzoic acid to the fully aromatized phenolbetaine 375 (Scheme 67). Photooxygenation of 375 in the presence of Rose Bengal, followed by reduction with sodium borohydride, gave rise directly to the phthalideisoquinoline 376 in 70% yield. The same phthalide (376) was also obtained from 2 -acetylpapaveraldine (129) (Section III,B,1). 

Reduction of berberinephenolbetaine (121) with zinc in acetic acid afforded tetrahydroberberine (26) and its isomer. The structure of the latter was shown to be the isoindolobenzazepine 458, commonly referred to as Schopf s base VI, and its formation mechanism was also postulated (Scheme 93) (224). Recently 458 was isolated and named as chilenamine. 

It was shown that 2,5-bis(phenoxy)-3,3aA4,4-trithia-l,6-diazapentalene 182 reacts with , v-diami nopolyether nucleophiles 183 in a 1 1 molar ratio to form novel pentaleno crown ethers 184 (see Scheme 21 and Table 24) <1997AG(E)1648>. Macrocycles 184 were readily reduced by treatment with zinc in acetic acid to form the corresponding thioureas 185. The reoxidation is quantitative in the presence of atmospheric oxygen. The complex formation of the starting pentalene 182 and the new crown ether compounds 184 and 185 was investigated (see Section 12.11.7.2). 

The concept of five-membered ring heterocyclic synthesis by transformation of the initial adduct of the ADC compound and substrate is not limited to cyclization of substitution products. l,3,4-Oxadiazol-2-ones (30, Scheme 3) result from heating the initial DEAZD-dichlorocarbene adduct.72 Treatment of the Diels Alder adducts 96 with zinc in acetic acid gives pyrroles in good yield (Eq. 17).151 The reaction has been extended to the synthesis of dipyrroles from the appropriate Diels-Alder adduct (96, R = pyrrol-2-yl). 

A highly stereoselective synthesis of ( )-deplancheine has been developed (121), utilizing a photocyclization process for the preparation of enelactam 181, which was reduced by zinc in acetic acid to lactam 182. In the latter, the double bond was shifted to the 19,20 position stereoselectively with an E geometry by the use of nonacarbonyldiiron catalyst to supply 159, previously synthesized and transformed to ( )-7 by Winterfeldt et al. (112). 

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