Reduction With Zinc

Zinc has been, and still is, after sodium the most abundantly used metal reductant. It is available mainly in form of zinc dust and in a granular form referred to as mossy zinc. 

Zinc dust is frequently covered with a thin layer of zinc oxide which deactivates its surface and causes induction periods in reactions with compounds. This disadvantage can be removed by a proper activation of zinc dust immediately prior to use. Such an activation can be achieved by a 3-4-minute contact with very dilute (0.5-2%) hydrochloric acid followed by washing with water, ethanol, acetone and ether [/55]. Similar activation is carried out in situ by a small amount of anhydrous zinc chloride [156 or zinc bromide [157 in alcohol, ether or tetrahydrofuran. Another way of activating zinc dust is by its conversion to a zinc-copper couple by stirring it (180g) with a solution of 1 g of copper sulfate pentahydrate in 35 ml of water [/55]. 

Mossy zinc is activated by conversion to zinc amalgam by brief immersion in a dilute aqueous solution of mercuric chloride and decantation of the solution before the reaction proper (40 g of mossy zinc, 4g of mercuric chloride, 4 ml of concentrated hydrochloric acid and 40 ml of water [759]). This type of activation is especially used in the Clemmensen reduction which converts carbonyl groups to methylene groups [160 Procedure 31, p. 213). 

Reductions with zinc are carried out in aqueous [160 as well as anhydrous solvents [163 and at different pHs of the medium. The choice of the reaction conditions is very important since entirely different results may be obtained under different conditions. While reduction of aromatic nitro groups in alkali hydroxides or aqueous ammonia gives hydrazo compounds, reduction in aqueous ammonium chloride gives hydroxylamines, and reduction in acidic medium amines (p. 73). Of organic solvents the most efficient seem to be dimethyl formamide [164 and acetic anhydride [755]. However, alcohols have 

Reductions with zinc are usually performed in hot or refluxing solvents, and some take many hours to complete. After the reaction is over the residual zinc, if any, is filtered off, and the products are isolated in ways depending on their chemical nature. If zinc dust has been used care must be taken in disposing of it since it may be pyrophoric in the dry state. 

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Treatment with PCI5 gives phthalyl chloride reduction with zinc and ethanoic acid or NaOH gives phthalide. Fusion with urea gives phthalimide. 

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 Gassman synthesis has been a particularly useful method for the synthesis of oxindolcs[lb,8]. Use of methylthioacetate esters in the reactions leads to 3-(methylthio)oxindoles which can be desulfurized with Raney nickel. Desulfurization can also be done by reduction with zinc or tin[10,ll]. 

Thiophene-2-sulfonic acid is a strong acid, similar to benzenesulfonic acid. It forms a sulfonyl chloride with phosphoryl chloride which on reduction with zinc yields thiophene-2-sulfinic acid. 

In the thiophene and selenophene series, a-halogens are preferentially removed by reduction with zinc and acetic acid, as is illustrated by the preparation of 3-bromothiophene... 

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. 

This, on reduction with zinc dust and acetic acid, yielded the corresponding oxime, which was further reduced by sodium amalgam to -3 4 5-trimethoxyphenylethylamine, CgHjj(OMe)3. CH. CH. NHg, and this proved to be identical with mezcaline (I). Like the latter, it behaves on analysis as if it contained the grouping —NHMe but this had already been disproved by Heffter. Interest in the remarkable physiological properties attributed to mezcaline has led to many syntheses of this alkaloid and of its isomerides and analogues. ... 

Meroquinenine, CgHjjOaN (meroquinene), formed by the oxidation of all four alkaloids and of cinchoninone or quininone and by the hydrolysis of quinenine or cinchenine (p. 489), crystallises from methyl alcohol in needles, m.p. 223-4° (dee.), [ajp -f- 27-5° (H2O). It gives a nitrosoamine, m.p. 67°, and a monoacetyl derivative, m.p. 110°, and can be esterified the ethyl ester hydrochloride has m.p. 165°. When oxidised by chromic acid it yields formic and cincboloiponic acids. On reduction with zinc dust and hydriodic acid, it adds on two atoms of hydrogen forming cincholoipon, CgH jOaN, and when heated with hydrochloric acid at 250-60° gives 3-ethyl-4-methylpyridine ()3-collidine). 

Dibromo adducts have been used for many years for purifying olefins. Reduction with zinc or iodide has been the traditional way of regenerating the olefin, although occasionally other reagents, ferrous chloride, for example, have been employed. Zinc is usually effective and may be used in acetic acid in favorable cases. Milder conditions are necessary if sensitive groups are present (ref. 185, p. 51). A well known application of the protective function... 

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. 

These ethers can be removed from naphthohydroquinones either by elimination to the vinyl ether followed by hydrolysis or by Finklestein reaction with iodide followed by reduction with zinc. ... 

An interesting method for preparing 2,6-dioxo-l,3-oxazine derivatives was described by Wasserman and Koch who stated that the five-membered ring of an a-keto-lactam could be transformed into the 1,3-oxazine (22) by ozone followed by reduction with zinc. 

Ketalization of the aldehyde with neopentyl glycol (32) followed by reaction with dichloroketene gives the 2+2 cycloadduct, 33. The halogen is then removed by reduction with zinc... 

Treatment of the heterocycle, 38 (obtained from ethylene-diamine and carbon disulfide), with nitrous acid affords the N-nitroso compound, 39. Reduction with zinc leads to the corre-... 

Reduction with zinc dust in aqueous sulfuric acid gives 2-methyl-4-aminothiophenol (28) Condensation with 2-chlorobenzoic acid (Ullmann reaction) leads to 29, which can close to but one thiox-anthone (25) on treatment with sulfuric acid. Although this procedure is longer than the original, the yields are good and the sequence is regioselective. ... 

If the a-phellandrene nitrite be heated with an alcoholic solution of potash, it is converted into nitrophellandrene, Ck,Hi5(N02). This bodyis converted by reduction with sodium and alcohol into tetrahydrocarvone, or by less energetic reduction with zinc and acetic acid, into carvotan-acetone. The relationship between these bodies is shown by the following formulas —... 

By reduction with zinc-dust and acetic acid it yields the acetic ester of perillic alcohol, from which the alcohol itself is separated by saponification. 

Starting with cuminal, nitro-cuminal was prepared, the nitro group entering the para position, meta to the aldehyde group. This compound - when treated with phosphorus pentachloride was converted into nitro-cymyline chloride, which on reduction with zinc and hydrochloric acid... 

Alkenes are reduced by addition of H2 in the presence of a catalyst such as platinum or palladium to yield alkanes, a process called catalytic hydrogenation. Alkenes are also oxidized by reaction with a peroxyacid to give epoxides, which can be converted into lTans-l,2-diols by acid-catalyzed epoxide hydrolysis. The corresponding cis-l,2-diols can be made directly from alkenes by hydroxylation with 0s04. Alkenes can also be cleaved to produce carbonyl compounds by reaction with ozone, followed by reduction with zinc metal. 

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. 

For the reduction with zinc, render the chlorate solution strongly acid with acetic acid, add excess of zinc, and boil the mixture for 1 hour. Dissolve the excess of unused zinc with nitric acid, filter, and treat the filtrate with silver nitrate in the usual manner. 

The solutions of mer-OsCl3(PR3)3 undergo an interesting reduction with zinc amalgam [155] to form OsCl2(PR3)2L (Figure 1.62), where L is a molecule abstracted from the atmosphere in the reaction flask if a noble gas, incapable of coordination, is employed, coordinative saturation is obtained by dimerization to [(PR3)3OsCl3Os(PR3)3]+. 

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

If the carbonyl group must be regenerated under nonhydrolytic conditions, (3-halo alcohols such as 3-bromopropane-l,2-diol or 2,2,2-trichloroethanol can be used for acetal formation. These groups can be removed by reduction with zinc, which leads to (3-elimination. 

The isoindolobenzazepine 380 obtained readily from prechilenine (139), 13-hydroxyoxyberberine (134), or oxybisberberine (130) (223), was recently isolated and named as chilenine (225). On reduction with zinc in hydrochloric acid-acetic acid 380 gave chilenamine (458) along with the hydroxylated product 459 (Scheme 94). Reduction of 380 followed by methylation and elimination of methanol gave pictonamine (460). On treatment with sodium hydroxide in aqueous methanol, 380 was converted to the isoindole 461, exposure of which to trifluoroacetic acid promoted cyclization and decarboxylation to afford the isoindoloisoquinoline neuvanine (462) (226). Its structure was revised (227) from the one originally proposed 463 (228). 

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