Pyridine lithium aluminium hydride

It is quite difficult to reduce benzene or pyridine, because these are aromatic stmctures. However, partial reduction of the pyridine ring is possible by using complex metal hydrides on pyridinium salts. Hydride transfer from lithium aluminium hydride gives the 1,2-dihydro derivative, as predictable from the above comments. Sodium borohydride under aqueous conditions achieves a double reduction, giving the 1,2,5,6-tetrahydro derivative, because protonation through the unsaturated system is possible. The final reduction step requires catalytic hydrogenation (see Section 9.4.3). The reduction of pyridinium salts is of considerable biological importance (see Box 11.2). 

Pyridine is difficult to reduce (as is benzene ), but pyridinium salts, e.g. alkylpyridinium halides, are partly reduced by hydride transfer reagents such as lithium aluminium hydride (LiAlH ) and sodium borohydride (NaBH4). LiAlH, which must be used in anhydrous conditions, only gives the 1,2-dihydro derivative, but the less vigorous reductant NaBH in aqueous ethanol yields the 1,2,5,6-tetrahydro derivative (Scheme 2.30)1... 

The aldehyde (163), which was prepared from 160 by periodic acid oxidation, was further converted into pseudo-a-D-mannopyranose as follows. Dehydration of 163 with mesyl chloride and pyridine, and subsequent reduction with lithium aluminium hydride gave (3S, 4R, 5S)-3,4,5-tris(benzyloxy)-l-cyclohexene-1-methanol (164). Hydroxyla-tion of 164 with diborane and hydrogen peroxide yielded 4,6-di-0-acetyl-l,2,3-tri-0-... 

The starting compound 251 was reduced to 252 with sodium borohydride. The latter was heated under reflux in 6% sulfuric acid in methanol to afford compound 253. Treatment of the latter with maleic anhydride at 170° for 3 hr afforded compound 254. Bisdecarboxylation of 254 with dicarbonyl bistriphenylphosphinenickel in anhydrous diglyme under nitrogen at reflux temperature for 6 hr afforded the olefin 255 in 69% yield (171). The latter was reduced with lithium aluminium hydride to the primary alcohol 256, which was oxidized to the aldehyde 257 with Ar,A -dicyclohexylcarbodiimide, dimethyl sulfoxide and pyridine in dry benzene. Treatment of the aldehyde 257 with an excess of the Grignard reagent prepared from l-bromo-3-benzyloxybutane afforded a mixture of diastereoisomers represented by the structure 258. 

Lithium aluminium hydride reduction of lucidusculine (35) afforded napelline (34) in quantitative yield. Napelline was hydrogenated with platinum oxide in acetic acid to afford dihydronapelline (286). Treatment of 286 with mercuric acetate in aqueous acetic acid followed by oxidation with chromium trioxide in pyridine afforded 287 in 16.5% yield. Ketalization of 287 yielded 285 in a yield of 71%. On refluxing 285 with methanolic base, a 4 6 equilibrium mixture of 285 and 288 was obtained. These compounds... 

Compound 85 was dehydrogenated at 300° over palladium black under reduced pressure to a pyridine derivative 96 which was independently synthesized by the following route. Anisaldehyde (86) was treated with iodine monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde (88). The Knoevenagel condensation with malonic acid yielded the unsaturated diacid 91. The methyl ester (92) was also prepared alternatively by a condensation of 3-iodoanisaldehyde with malonic acid to give the iodo-cinnamic acid (89), followed by the Ullmann reaction of its methyl ester (90). The cinnamic diester was catalytically hydrogenated and reduced with lithium aluminium hydride to the diol 94. Reaction with phosphoryl chloride afforded an amorphous dichloro derivative (95) which was condensed with 2,6-lutidine in liquid ammonia in the presence of potassium amide to yield pyridine the derivative 96 in 27% yield (53). 

Cyclization of enone (9) in hexane with boron trifluorideetherate in presence of 1,2-ethanedithiol, followed by hydrolysis with mercury (II) chloride in acetonitrile, yielded the cis-isomer (10) (16%) and transisomer (11) (28%). Reduction of (10) with lithium aluminium hydride in tetrahydrofuran followed by acetylation with acetic anhydride and pyridine gave two epimeric acetates (12) (32%) and (13) (52%) whose configuration was determined by NMR spectroscopy. Oxidation of (12) with Jones reagent afforded ketone (14) which was converted to the a, 3-unsaturated ketone (15) by bromination with pyridinium tribromide in dichloromethane followed by dehydrobromination with lithium carbonate and lithium bromide in dimethylformamide. Ketone (15), on catalytic hydrogenation with Pd-C in the presence of perchloric acid, produced compound (16) (72%) and (14) (17%). The compound (16) was converted to alcohol (17) by reduction with lithium aluminium hydride. 

Like the silyl ethers, the stability of the silyl esters parallels the steric bulk of the substituents on the silicon atom. Tris(2,6-diphenylbenzyl)siiy1 esters confer extraordinary steric protection upon the carboxyl group.234 For example, the tris(2,6-diphenylbenzyl)silyl ester of 4-phenylbutanoic acid 104.1 [Scheme 6.104] does not react with butyllithium (2.5 equiv) after 5 h at -78 °C or methylmag-nesium bromide (2,5 equiv) at room temperature. Nor did it react with lithium aluminium hydride after 30 min at 0 °C l M HC1 in THF at 40 °C, or aqueous sodium hydroxide at 50 °C after 5 h. Ester 104.1 was reduced with diisobutyl-aluminium hydride in 99% yield to give the 4-phenyl-l-butanol (99%) and HF pyridine in THF (1 2) at 50 aC cleaved it back to the acid after 5 h. Unfortunately, the penalty for such unusual stability is high the tris(2 6-diphenyl-... 

Pyridine reacts with nucleophiles under vigorous conditions at C-2 or C-4 by an addition limination mechanism. Thus pyridine reacts with sodamide (the Tschitschibabin reactiori Scheme 4.26a). Pyridine will also react with lithium aluminium hydride to give predominantly a 1,2-dihy-dropyridine (Scheme 4.26b), whereas sodium in ethanol gives mainly the 1,4-isomer (Scheme 4.26c). 

They have compositions corresponding to EcHg, structures are unknown. Copper hydride, CuH, has been made recently by mixing lithium aluminium hydride, dissolved in pyridine and ether, with copper (I) iodide in pyridine ... 

For the synthesis of (69), the enol ether (71) from the indanone (70) was carboxylated with COa-n-butyl-Iithium in THF at —70 C to yield (72). The methyl ester (73) was converted into (75) via the maleic anhydride adduct (74), essentially as described in earlier work. Lithium aluminium hydride reduction followed by oxidation with dicyclohexylcarbodi-imide afforded the aldehyde (76). This was condensed with excess (77) to yield a mixture of the diastereomers (78). Oxidation with chromium trioxide-pyridine in methylene dichloride gave (79), which could be converted into the diketone (80) by treatment with excess benzenesulphonylazide. The diketo-lactam (81) was prepared from (80) as described for the synthesis of the analogous intermediate used in the synthesis of napelline. Reduction of (81) with lithium tri-t butoxyaluminohydride gave the desired dihydroxy-lactam (82). Methylation of (82) with methyl iodide-sodium hydride gave (83). Reduction of this lactam to the amine (84) with lithium aluminium hydride, followed by oxidation with potassium permanganate in acetic acid, gave (69). 

Of the hydride reagents, sodium borohydride is without effect on pyridines, though it does reduce pyri-dinium salts (8.12.1), lithium aluminium hydride effects the addition of one hydride equivalent to pyridine,but lithium triethylborohydride reduces it to piperidine efficiently. ... 

Attention has been drawn to the remarkable stability of 21-bromo-17a,20-acetonides, but debromination occurred with lithium aluminium hydride and with sodium in propan-2-ol, although the main products with the latter reagent were the two olefins (534) and (535). Similar 17a,20-acetonides derived from cortisone have been prepared and oxidised with chromium trioxide in pyridine to the corresponding 21-aldehydes and 21-carboxylic acids. 

Disubstituted pyridines are an important group of substrates for the bispidine synthesis. Diethylpyridin-3,5-dicarboxylate can be converted to N-tosylpiperidine-3,5-dicarboxamide, which generates 2,4-dioxo-7-tosylbispidine upon heating in methylnaphthalene. Reduction with lithium aluminium hydride (LiAlH4) yields the bispidine 1 under simultaneous elimination of the p-tosyl... 

A catalyst system159 consisting of a mixture of boron trifluoride, acetic acid and pyridine gives rapid and reproducible total hydroxyl analysis (silanol plus water) in a variety of silicone materials. This method avoids many of the interferences, empirical calibration and miscellaneous problems such as poor solubility, incomplete reaction and interfering siloxane cleavage associated with many earlier methods. Results obtained by this procedure compare well with results obtained by the lithium aluminium hydride procedure160. 

Reactions of Pyridines. Treatment of 4-isopropylpyridine with lithium aluminium hydride, followed by electrophilic reagents, leads to side-chain- rather than ring-substitution products. For example, the 4-pyridylpropane (33) is formed... 

---