1.3- Dioxanes reduction

The methyl substituent of 2-methyl-4,8-dihydrobenzo[l,2- 5,4-. ]dithiophene-4,8-dione 118 undergoes a number of synthetic transformations (Scheme 8), and is therefore a key intermediate for the preparation of a range of anthraquinone derivatives <1999BMC1025>. Thus, oxidation of 118 with chromium trioxide in acetic anhydride at low temperatures affords the diacetate intermediate 119 which is hydrolyzed with dilute sulfuric acid to yield the aldehyde 120. Direct oxidation of 118 to the carboxylic acid 121 proceeded in very low yield however, it can be produced efficiently by oxidation of aldehyde 120 using silver nitrate in dioxane. Reduction of aldehyde 120 with sodium borohydride in methanol gives a 90% yield of 2-hydroxymethyl derivative 122 which reacts with acetyl chloride or thionyl chloride to produce the 2-acetoxymethyl- and 2-chloromethyl-4,8-dihydrobenzo[l,2-A5,4-3 ]-dithiophene-4,8-diones 123 and 124, respectively. 

Zinc-silver acetic acid Protection of carbonyl groups as 5,5-dibromo-l,3-dioxanes Reductive removal of tbe protective group... 

The best results are obtained with freshly prepared xanthhydrol (reduction of xanthone with sodium amalgam. Section VII,16). Dissolve 0 -25 g. of xanthhydrol and 0 -25g. of the primary sulphonamide in 10 ml. of glacial acetic acid. Shake for 2-3 minutes at the laboratory temperature and allow to stand for 60-90 minutes. Filter oflf the derivative, recrystallise it from dioxan-water (3 1), and dry at room temperature under water pump suction for 30 minutes. 

Recent investigation of the effect of substituents in the para position of the phenylalanine ligand on the stability of the ternary complexes has revealed the secpience Br > OH > Q NH2 > H > F". Interestingly, analysis of CD spectra indicates a reduction of the arene-arene interaction" upon addition of 1,4-dioxane to aqueous solutions of the mixed-ligand complexes, in disagreement with previous observations by Sigel" . 

Lithium hydride is perhaps the most usehil of the other metal hydrides. The principal limitation is poor solubiUty, which essentially limits reaction media to such solvents as dioxane and dibutyl ether. Sodium hydride, which is too insoluble to function efficiently in solvents, is an effective reducing agent for the production of silane when dissolved in a LiCl—KCl eutectic at 348°C (63—65). Magnesium hydride has also been shown to be effective in the reduction of chloro- and fluorosilanes in solvent systems (66) and eutectic melts (67). 

Acetic acid, 3-ethoxycarbonyl-l-methyl-2-pyrrolyl-ethyl ester reduction, 4, 287 Acetic acid, 9-hydroxyethoxy-as metabolite of dioxane, 1, 245... 

The nitrobenzyl caibonates were prepared to protect a secondary hydroxyl group in a thienamycin precursor. The o-nitrobenzyl carbonate was prepared from the chloroformate (DMAP, CH2CI2, 0° - 20°, 3 h) and cleaved by irradiation, pH 7. The p-nitrobenzyl carbonate was prepared from the chloroformate (—78°, n-BuLi, THE, 85% yield) and cleaved by hydrogenolysis (H2/Pd-C, dioxane, H2O, EtOH, K2HP04). It is also cleaved by electrolytic reduction. ... 

The o-nitrobenzyl ester, used in this example to protect penicillin precursors, can be cleaved by irradiation (H20/dioxane, pH 7). Reductive cleavage of benzyl or p-nitrobenzyl esters occurred in lower yields. 

The picolyl ester has been prepared from amino acids and picolyl alcohol (DCC / CH2CI2, 20°, 16 h, 60% yield) or picolyl chloride (DMF, 90-100°, 2 h, 50% yield). It is cleaved by reduction (H2/Pd-C, aq.= FtOH, 10 h, 98% yield Na/NH3, 1.5 h, 93% yield) and by basic hydrolysis (1 NaOH, dioxane, 20°, 1 h, 93% yield). The basic site in a picolyl ester allows its ready separation by extraction into an acidic medium. ... 

The Npys group can be. cleaved reductively with BU3P, H2O or mercaptoethanol. It is stable to CF3COOH (24 h), 4 M HCl/dioxane (24 h), and HF (1 h). The related reagent, 2-pyridinesulfenyl chloride, has also been proposed as a useful reagent for the deprotection of the 5-trityl, 5-diphenylmethyl, 5-acetamidomethyl, 5-/-butyl, and S-r-butylsulfenyl groups, but this reagent is very susceptible to hydrolysis. ... 

Aromatic steroids are virtually insoluble in liquid ammonia and a cosolvent must be added to solubilize them or reduction will not occur. Ether, ethylene glycol dimethyl ether, dioxane and tetrahydrofuran have been used and, of these, tetrahydrofuran is the preferred solvent. Although dioxane is often a better solvent for steroids at room temperature, it freezes at 12° and its solvent effectiveness in ammonia is diminished. Tetrahydrofuran is infinitely miscible with liquid ammonia, but the addition of lithium to a 1 1 mixture causes the separation of two liquid phases, one blue and one colorless, together with the separation of a lithium-ammonia bronze phase. Thus tetrahydrofuran and lithium depress the solubilities of each other in ammonia. A tetrahydrofuran-ammonia mixture containing much over 50 % of tetrahydrofuran does not become blue when lithium is added. In general, a 1 1 ratio of ammonia to organic solvents represents a reasonable compromise between maximum solubility of steroid and dissolution of the metal with ionization. 

A widely used procedure for the reduction of conjugated enones to saturated ketones is that of Bowers, Ringold and Denot, Procedure 5 (section V). Ether-dioxane (1 1) is used as the organic co-solvent and solid ammonium... 

Toluene is a useful co-solvent in metal-ammonia reductions as first reported by Chapman and his colleagues. The author has found that a toluene-tetrahydrofuran-ammonia mixture (1 1 2) is a particularly useful medium for various metal-ammonia reductions. Procedure 8a (section V) describes the reduction of 17-ethyl-19-nortestosterone in such a system. Ethylene dibromide is used to quench excess lithium. Trituration of the total crude reduction product with methanol affords an 85% yield of 4,5a-dihydro-17-ethyl-19-nortestosterone, mp 207-213° (after sintering at 198°), reported mp 212-213°. For the same reduction using Procedure 5 (section V), Bowers et al obtained a 60% yield of crude product, mp, 196-199°, after column chromatography of the total reduction product. A similar reduction of 17-ethynyl-19-nortestosterone is described in Procedure 8b (section V). The steroid concentration in the toluene-tetrahydrofuran-ammonia system is 0.05 M whereas in the ether-dioxane-ammonia system it is 0.029 M. 

NaBH4 is soluble in water, alcohols, pyridine, dioxane, dimethoxyethane, diglyme and triglyme. All these solvents, as well as aqueous tetrahydrofuran and aqueous dimethylformamide, have been used for reductions. The reductions go very slowly in di- and triglyme so these solvents are not suitable for preparative work. In some reductions in dry pyridine and dry dimethyl sulfoxide, reaction only takes place on aqueous work-up. This... 

The isotopic purity of the products from a lithium aluminum deuteride reduction is usually equivalent to that of the reagent. The presence of moisture has little effect on the isotope composition of the products, causing only the decomposition of some of the reagent. For the best results, however, it is advisable to distill the solvent— usually ether, tetrahydrofuran or dioxane depending on the desired reaction temperature—from lithium aluminum hydride directly into the reaction flask. In this manner the reduction of 3-keto-5a-steroids (60), for example, gives the corresponding 3a-di alcohols (61) in 98% isotopic purity. ... 

As a general procedure, a mixture of the steroidal ketone (50 mg) and lithium aluminum deuteride (20 mg) in dry ether (5 ml, freshly distilled from lithium aluminum hydride) is heated under reflux until the reduction is complete according to thin layer chromatography test. The excess deuteride is then decomposed by the careful addition of a few drops of water and the reaction mixture is worked up by the usual procedure. For hindered ketones or esters the use of other solvents, such as tetrahydrofuran or dioxane, may be preferable to allow higher reaction temperatures. 

Thus, the reduction of tosylhydrazones with sodium borodeuteride in dioxane provides only monodeuterated analogs. For the insertion of two deuteriums it is necessary to first exchange the hydrazone proton and to carry out the reduction in aprotic or deuterated solvents. Under these conditions the reduction of the tosylhydrazone derivatives of 7- and 20-keto... 

The following general procedure has been used for the reduction of the tosylhydrazone derivatives of various steroidal ketones. A mixture of the tosylhydrazone (50 mg) and sodium borodeuteride (50 mg) in dry dioxane (3 ml) is heated under reflux for 2 hr, and then the excess deuteride is decomposed by the addition of a few drops of acetic acid. Ether is added and the resulting solution is washed with 2 N sodium bicarbonate solution and... 

A novel reaction of perchloryl fluoride with aromatic substrates was discovered by Neeman and Osawa, the oxofluorination reaction. These authors found that reaction of indene with perchloryl fluoride in dioxane-water yields five products, the major product being, 2-fluoroindanone. When applied to 6-dehydroestradiol diacetate (24) there is obtained as the major product the 7a-fluoro-6-ketone (25). Borohydride reduction of the... 

Reductive Opening of a 17a,20-Epoxide 17a,20-Oxidopregn-4-en-3-one (0.7 g) in 90 ml of dioxane (previously distilled over sodium) is added gradually to a solution of 1 g of lithium aluminum hydride in 50 ml of dry ether. 

Amino acids are protected as the 4-nitrophenyl carbonate (H2O, dioxane, 54-85% yield) and cleaved by reduction of the azide with SnCl2. The group is stable to the conditions normally used to cleave a BOC group, but it is not expected to be stable to a large number of strongly reducing conditions. ... 

The perhydroisoindole system can be prepared by high-pressure hydrogenation of the isoindole over nickel on alumina at elevated temperatures. The use of Raney nickel with dioxane in the reduction of l,3-diphenyl-2-methylisoindole (47) gives the perhydro product (96), accompanied by the isoindoline (97). An alternative route to partially hydrogenated isoindoles has been described in Section III, D. 

Reductive cleavage of phenylhydrazones of carbonyl compounds provides a route to amines. The reduction is carried out conveniently in ethanol containing ammonia over palladium-on-carbon. Ammonia is used to minimize formation of secondary amines, derived by addition of the initially formed amine to the starting material (160). Alternatively, a two-phase system of benzene, cyclohexane, toluene, or dioxane and aqueous hydrochloric acid can be used. 

The lithium cnolate generated by deprotonation of 2-/m-butyl-6-methyl-l,3-dioxan-4-onc, readily available from polyhydroxybutyric acid (PHB), predominantly affords the diastereo-mers 7 when reacted with aldehydes. The diastereomeric ratios of aldol adducts 7/8, produced by reactions with aliphatic aldehydes, range from 87.5 12.5 to >99 1. Pure diastereoiners7are obtained by recrystallization in 25-74% yield116-118. Only marginal diastereoselectivities with respect to the carbinol center are obtained with aromatic aldehydes111-119. Benzoylation of the dioxanones 7, followed by reduction with lithium aluminum hydride, affords enan-tiomerically and diastereomerically pure triols 9 in >85% yield 11. ... 

---