Lithium aluminum hydride, reduction reactions with

An 80% yield of tetraphenylfuran is obtained by treatment of benzoyl chloride with active titanium generated by lithium aluminum hydride reduction of titanium trichloride (Scheme 84e) (8UOC2407). The reaction nroceeds via benzil and tetraphenylbut-2-ene-l,4-dione, both of which are minor products of the reaction. 

In contrast to alcohols with their- rich chemical reactivity, ethers (compounds containing a C—O—C unit) undergo relatively few chemical reactions. As you saw when we discussed Grignaid reagents in Chapter 14 and lithium aluminum hydride reductions in Chapter 15, this lack of reactivity of ethers makes them valuable as solvents in a number of synthetically important transfonnations. In the present chapter you will leain of the conditions in which an ether linkage acts as a functional group, as well as the methods by which ethers are prepared. 

On treatment of N-methylpapaverine, formed by the lithium aluminum hydride reduction of papaverine methiodide with phosphoric acid, N-methylpavine is formed which is identical with the racemic alkaloid argemonine. This reaction was used for the synthesis of the alkaloid (-h)-coreximine (268) (174) and similar compounds containing the proto-berberine grouping in the molecule (269,270). 

Woodward s strychnine synthesis commences with a Fischer indole synthesis using phenylhydrazine (24) and acetoveratrone (25) as starting materials (see Scheme 2). In the presence of polyphosphor-ic acid, intermediates 24 and 25 combine to afford 2-veratrylindole (23) through the reaction processes illustrated in Scheme 2. With its a position suitably masked, 2-veratrylindole (23) reacts smoothly at the ft position with the Schiff base derived from the action of dimethylamine on formaldehyde to give intermediate 22 in 92% yield. TV-Methylation of the dimethylamino substituent in 22 with methyl iodide, followed by exposure of the resultant quaternary ammonium iodide to sodium cyanide in DMF, provides nitrile 26 in an overall yield of 97%. Condensation of 2-veratryl-tryptamine (20), the product of a lithium aluminum hydride reduction of nitrile 26, with ethyl glyoxylate (21) furnishes Schiff base 19 in a yield of 92%. 

The homology between 22 and 21 is obviously very close. After lithium aluminum hydride reduction of the ethoxycarbonyl function in 22, oxidation of the resultant primary alcohol with PCC furnishes aldehyde 34. Subjection of 34 to sequential carbonyl addition, oxidation, and deprotection reactions then provides ketone 21 (31% overall yield from (—)-33). By virtue of its symmetry, the dextrorotatory monobenzyl ether, (/ )-(+)-33, can also be converted to compound 21, with the same absolute configuration as that derived from (S)-(-)-33, by using a synthetic route that differs only slightly from the one already described. 

Direct hydrogenation of key intermediate 248 over the Adams catalyst and subsequent lithium aluminum hydride reduction yielded the two stereoisomeric alcohols 256 and 257, which were separately transformed to ( )-corynantheal (258) and ( )-3-epicorynantheal (259), respectively, by Moffatt oxidation, followed by Wittig reaction with methyltriphenylphosphonium bromide and, finally, by demasking the aldehyde function (151, 152). 

A multi-stage synthesis of azocino[4,5,6-cd]indoles has been suggested (03M13519). From 4-bromoindole (84) with the help of successive transformations (among them the Vilsmeier-Haack reaction, Henry nitroaldole condensation, lithium aluminum hydride reduction and insertion of an allyl fragment), indole 85 has been produced in 18% yield. The cyclization of the latter on palladium... 

Benzofuranyl)butanoic acid readily forms the acid chloride, and this undergoes intramolecular Friedel-Crafts acylation on treatment with tin(IV) chloride in carbon disulfide at room temperature, providing 1,2,3,4-tetra-hydro-l-dibenzofuranone (54%). " This intermediate has been converted to dibenzofuran by lithium aluminum hydride reduction and subsequent dehydrogenation, to 1-methyldibenzofuran by Grignard reaction and dehydrogenation, and to 1-dibenzofuranol by reaction with iV-bromosuccinimide and subsequent dehydrobromination with pyridine. 

Reactions of 4,7-phenanthroline-5,6-dione have been the subject of considerable study. It is reduced to 5,6-dihydroxy-4,7-phenanthroline by Raney nickel hydrogenation226,249 or by aromatic thiols in benzene,262 and oxidized by permanganate to 3,3 -bipyridyl-2,2 -dicarboxylic acid.263 It forms bishemiketals with alcohols226 and diepoxides with diazomethane.226 The diepoxides by reaction with hydrochloric acid form diols of type 57, R = Cl, which on oxidation with lead tetraacetate give 3,3 -bipyridyl diketones of type 58, R = Cl. Methyl ketones of type 58, R = H, are also obtained by lead(IV) acetate oxidation of the diol 57, R = H, obtained by lithium aluminum hydride reduction of 57, R = Cl. With phenyldiazomethane and diphenyldiazomethane the dione forms 1,3-dioxole derivatives,264,265 which readily hydrolyze back to the dione with concomitant formation of benzaldehyde and benzophenone, respectively. 

The reduction of tosylhydrazones can also be performed with sodium borodeuteride in boiling methanol or dioxane, but the mechanism of this reaction (in boiling dioxane at least) is radically different from that of the lithium aluminum deuteride reductions.82 With sodium borohydride the first step is apparently hydride attack on the carbon atom of the C=N bond which is probably concerted with the elimination of the tosylate anion (110 - 111). Migration of the hydrogen from nitrogen to C-3 in (111) concerted with expulsion of nitrogen, provides the corresponding methylene derivative (100).82... 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

By lithium aluminum hydride. The reaction at several dpi-sulfides with lithium aluminum hydride has been shown to proceed with reductive ring cleavage to give thiols as their lithium mercaptidea in about 75% yields. The secondary thiols, rather than the corresponding 1 -thiols, wore obtained from the reduction of propylene sulfide and 1-hexene sulfide ... 

An esoteric attempt to synthesize cis-dianthrylethylene 38a via the cyclobutanol derivative 128 involved as starting material l,2-di-9-anthrylethanol 127, which was reportedly formed in good yield in a one-pot reaction by lithium aluminum hydride reduction of 9-anthraldehyde 129. Again, we had to abandon this route to cis-dianthrylethylene when the dianthrylethanol of the literature was found to be the 9,10-dihydroanth-racene derivative 130. However, dianthrylethanol 130 did form the acetate 131, which upon treatment with base afforded, via elimination product 114, hydrocarbon 113, viz. lepidopterene [147], whose structure, fortunately, had been established in 1975 [129,130]. 

An important example of this type of reaction is the formation of esters, which was discussed previously in connection with the reactions of alcohols in Section 15-4D. Similar addition-elimination mechanisms occur in many reactions at the carbonyl groups of acid derivatives. A less obvious example of addition to carboxyl groups involves hydride ion (H 0) and takes place in lithium aluminum hydride reduction of carboxylic acids (Sections 16-4E and 18-3C). 

Thiiranes can be formed directly and stereospecifically from 1,2-disubstituted alkenes by addition of trimethylsilylsulfenyl bromide, formed at -78 C from reaction of bromine with bis(trimethylsilyl) sulfide (Scheme 7).12 A two-step synthesis of thiiranes can be achieved by addition of succinimide-A/-sulfe-nyl chloride or phthalimide-A -sulfenyl chloride to alkenes followed by lithium aluminum hydride cleavage of the adducts (Scheme 8).13 Thiaheterocycles can also be formed by intramolecular electrophilic addition of sulfenyl chlorides to alkenes, e.g. as seen in Schemes 914 and 10.13 Related examples involving sulfur dichloride are shown in Schemes 1116 and 12.17 In the former case addition of sulfur dichloride to 1,5-cyclooctadiene affords a bicyclic dichloro sulfide via regio- and stereo-specific intramolecular addition of an intermediate sulfenyl chloride. Removal of chlorine by lithium aluminum hydride reduction affords 9-thiabicyclo[3.3.1]nonane, which can be further transformed into bicyclo[3.3.0]oct-1,5-ene.16... 

The reduction of phenanthridine to 5,6-dihydrophenanthridine (90, R = H) was readily accomplished by reaction with lithium aluminum hydride in ethereal solution.118 The same dihydrophenanthridine resulted from the lithium aluminum hydride reduction of 6-chloro-phenanthridine or phenanthridone,1180 thus confirming the position of saturation of the product.119 It is of interest to note that molecular complexes of phenanthridine and dihydrophenanthridine were not observed as products in this reduction as was the case in the metal hydride reduction of phenazine.119... 

The apparently simple procedures of partial dehydrogenation of pyrrolidines and partial hydrogenation of pyrroles afford Zl1-pyr-rolines. However, the reaction is complex and is of little preparative value.97-98 A 1-Pyrrolines may be obtained by isomerization of A 3-pyrrolines.100 From the preparative point of view, partial hydrogenation of quaternary pyridine salts in strongly alkaline media to give 1-alkyl-id 2-piperideines is more important.101 Formation of heterocyclic enamines was observed in the reduction of i -methyl-pyrrolidone with lithium aluminum hydride,102 -alkylpiperidones with sodium in ethanol,103,104 and in the electrolytic reduction of N-methylglutarimide.106... 

The synthesis of the zero-valent, 1,3-cyclohexadiene benzene ruthenium complex 196a has been mentioned as a coproduct of the cyclohexadienyl complex 236a in the reduction of the benzene ruthenium dication 235 with lithium aluminum hydride. Reduction of 235 with sodium borohydride in THF, however, gives only the air-sensitive, yellow-green ruthenium(O) complex 196a (118). This reaction has been generalized to... 

The alkaloid behaved similarly to voaeangine, since on the one hand its dihydro derivative was readily decarbomethoxylated to 4-epi-ibogamine (XLIII), mp 162°-164°, [a]D + 86° (hydrochloride in MeOH), and on the other its lithium aluminum hydride reduction product, catharanthinol, afforded an acetonide (XXXVII), mp 188°-191°. To account for the difficulty with which catharanthine eliminated the carbomethoxy group, it has been suggested that an intermediate in this reaction (XLIV) is highly strained (40). Since XLIV can be readily constructed from Dreiding Atomic Models, this explanation may not be correct. In actual fact, it is probable that the acid-catalyzed decomposition of catharanthine takes a different course. It has more recently... 

Lithium aluminum hydride reduction of epiquinamine, as expected, afforded 3-epicinchonamine, mp 168°, [a]D +48° (EtOH), also obtainable along with cinchonamine by the sodium-ethanol reduction of apoquinamine (23). Finally, it was shown in 1945 that, on heating quinamine or dihydroquinamine above its melting point, formaldehyde was evolved, and this was taken as evidence for the presence of a 2-hydroxymethyl on an indole a-carbon (15). In the light of the true structure, the writer would like to suggest that this aldehyde is formed by pyrolysis of a 1,3-glycol, that is, a retro Prins reaction (25). 

Z-Eburnamonine (XXXVI) has been produced by other reactions of vincamine. Oxidation of vincaminic acid (XL R = H) by means of ammoniacal silver nitrate was one way, and periodic acid fission of vincaminol was another (16). A different group of workers, who had probably attempted to prepare vincaminol by lithium aluminum hydride reduction of vincamine, obtained instead Z-ebumamonine in excellent yield (18). This has been rationalized as illustrated (partial formulas) by analogy with the base-induced decomposition of formic esters to carbon monoxide and alkoxide ion ... 

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