Lactam with lithium aluminum hydride

Partial reductions of N-alkylated lactams with lithium aluminum hydride (107) or sodium and butanol (108,109) and electrolytic reductions of N-methylglutarimide (110) have been reported. 

Heating XXIV in polyphosphoric acid gave the tetracyclic lactam XXV in 71 % yield. Reduction of the lactam with lithium aluminum hydride gave racemic XX. The racemic base was resolved with dibenzoyltartaric acid and the ( — )-enantiomorph was shown to be identical with XX from natural sources. 

The ethylene ketal of 168 was reduced with lithium aluminum hydride in dioxane and then hydrolysed to the amino ketone 169. Treatment of 169 with acrylyl chloride and triethylamine gave the acrylamide 170 containing all the carbons of the lycopodine system. Oyclization to the tetracyclic system shown in 171 occurred when 170 was refluxed in toluene containing p-toluenesulfonic acid. Reduction of the lactam with lithium aluminum hydride in THE followed by Jones oxidation of the product gave racemic 12-epilycopodine (4) identical in spectroscopic properties with the enantiomer derived by reduction of anhydrolycodoline. 

Cleavage of the oxazoline ring can be achieved by treatment of bicyclic lactams with lithium aluminum hydride and aluminum trichloride to obtain a-substituted pyrrolidines (187) (Equation (19)) <91JOC2294, 92T3945). 

Lhommet s team has reported a second synthesis of (—)-lupinine (926) based on a convenient multicomponent condensation of the 5-ketoester 1024, (S)-phenylglycinol (1025) and acrolein (Scheme 127). That the reaction yielded a 2 1 mixture of chiral tetrahydro[l,3]oxazolo[3,2-mixture—effectively a masked iminium ion—with sodium triacetoxyborohydride led to the piperidine (—)-1027 as a single isomer. Hydrogenolysis of 1027 followed by treatment with p-toluenesulfonic acid brought about cyclization to the bicycHc lactam (- -)-1028, which underwent reduction of both the ester and the lactam with lithium aluminum hydride to complete this short synthesis of (—)-926. 

The lactam is then reduced to amine 49 with lithium aluminum hydride, and the resulting amine is methylated to obtain elantrine (50). ... 

Preparation of nefopam starts with the acylation of aminobenzhydrol 1 (obtainable by reduction of the corresponding benzoylbenzamide) with chloroacetyl chloride treatment of the chloroamide (2) with potassium tertiary butoxide results in internal alkylation to give the eight-membered ring (3). Reduction of the lactam function with lithium aluminum hydride gives the amine and, thus, nefopam (4). ... 

Reduction of o /i-unsatin-ated lactams, S,6-dihydro-2-pyridones, with lithium aluminum hydride, lithium alkoxyaluminum hydrides and alane gave the corresponding piperidines. 5-Methyl-5,6-dihydro-2-pyridone (with no substituent on nitrogen) gave on reduction with lithium aluminum hydride in tetrahydrofuran only 9% yield of 2-methylpiperidine, but l,6-dimethyl-5,6-dihydro-2-pyridone and 6-methyl-l-phenyl-5,6-dihydro-2-pyridone afforded 1,2-dimethylpiperidine and 2-methyl-1-phenylpiperidine in respective yields of 47% and 65% with an excess of lithium aluminum hydride, and 91% and 92% with alane generated from lithium aluminum hydride and aluminum chloride in ether. Lithium mono-, di- and triethoxyaluminum hydrides also gave satisfactory yields (45-84%) [7752]. 

Reductions of alkyl pyridones with lithium aluminum hydride or alane are very complex and their results depend on the position of the substituents and on the reducing reagent. Since the pyridones can be viewed as doubly unsaturated lactams with a,/J- and )i, -conjugated double bonds, the products result from all possible additions of hydride ion 1,2,1,4 or 1,6. Consequently the products of reduction are alkylpiperidines and alkylpiperideines with double bonds in 3,4 or 4,5 positions [449, 7755]. 

Lithium hydroxide hydrolysis of the ester of pyrrolo[l,2-l7][l,2,5]benzothia-diazepine 5,5-dioxide 346 afforded the acid, subsequently reduced with lithium aluminum hydride-aluminum chloride to alcohol 348 (Scheme 73, Section 4.2 (2006JMC5840)). Pyrrolo[l,2- 7][l,2,5]benzothiadiazepine acid 347 gives easy access to a variety of esters and amides 407, while treatment with TFAA produces fused lactam 408 (Scheme 85 (1996FES425)). 

Oxo- and 3,5-dioxo-pyrrolizidines can be regarded as mono- and di-lactams, respectively, and hence exhibit typical amide properties. They are readily reduced to amines electrochemically (see, e.g. refs. 29 and 31) or with lithium aluminum hydride (see, e.g., refs. 30 and 33). 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

Sodium borohydride is an effective reductant for the imine bond of dihydro-1,3-oxazines affording tetrahydro derivatives, but predictably where lactam or sultam functions form part of the heterocycle, treatment with lithium aluminum hydride is necessary. Dihydro-1,3-benzothiazinones for instance are reduced by this reagent to the corresponding dihydroben-zothiazines (Scheme 29) <77ACH(92)317). 

The diversity of the products obtained by the three-component domino-Knoevenagel-hetero-Diels-Alder reaction can be further increased by a different work-up of the formed cycloadduct 141. Thus, hydrogenolytic removal of the Cbz-group in 141 led to 151 with a lactam and an aldehyde moiety by reaction of the formed secondary amine with the lactone moiety followed by elimination of benzyl alcohol. Reduction of 151 with lithium aluminum hydride gave benzoquinolizidine 152 (Scheme 5.30). Alkaloids of this type have so far not been found in nature, but it can be assumed that they might exist, since they could easily be formed from deacetylisopecoside 153, which is an intermediate in the biosynthesis of emetine 111. 

Alternatively, yohimban and alloyohimban were also synthesized via the route of reduction with lithium aluminum hydride of the conjugated lactam (193), followed by catalytic hydrogenation. 

In 1973 Koda el al. 122) exposed pilocarpine to aminolysis and lithium aluminum hydride reduction, and then obtained several analogs. Treatment with ammonia or with aqueous methylamine or isopropylamine at room temperature gave the hydroxy amides 64-66. Reaction of pilocarpine with ammonia at 200-210°C yielded a lactam, the pilocarpine analog 67. Similarly, the /V-methyllactam 68 was prepared by reaction with liquid methylamine at 225°C. Reduction of pilocarpine with lithium aluminum hydride (LAH) in tetrahydrofuran yielded the tetrahydrofuran analog 69. Preliminary pharmacological studies indicated interesting cholinergic activity. 

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