Amides with lithium aluminium hydride

Indole-fused, or indole-benzo-fused azepinone derivatives have attracted synthetic attention and examples include the preparation of 85 in 84% yield from 84 by intramolecular Heck coupling [01SL848], as well as the preparation of paullone 87 (a CDK inhibitor) by cyclisation of 86 under basic conditions borylation/Suzuki coupling technology was used to access 86 [02JOC1199]. Acid-catalysed cyclisation with polyphosphoric acid was used to prepare the racemic reduced azepino[4,5-6]indoles 92a,b from the precursors 91, which were obtained in turn from CDl-mediated coupling of 88 and 89, followed by reduction of the amide with lithium aluminium hydride [01H1455]. 

We ve talked about reduction of iminium ions formed from carbonyl compounds plus amines. Iminium ions can also be formed by reducing amides with lithium aluminium hydride. A tetrahedral intermediate is formed that collapses to the iminium ion. 

EDCI), the nitrogen and hydroxy] groups were protected as the N,0-acetal 123.3 by reaction of 1232 with 2 2-dimethoxylpropane in acetone in the presence of trifluoroborane e the rate. Finally, reduction of the N me thoxy amide with lithium aluminium hydride afforded Garner s aldehyde in 88% overall yield for the 4-step sequence. Epimerisation of the stereogenic centre is negligible under these conditions. 

The alpha-aMy substituted derivatives are conveniently prepared by reducing the corresponding amides with lithium aluminium hydride. 

The seco amide alkaloids have been subjected to various transformations, mainly for structure elucidation purposes. When treated with lithium aluminium hydride, arnottianamide (206) was converted to the tertiary amine, deoxyarnottianamide (224), which on methylation with the Rodionow reagent gave deoxy-O-methylarnottianamide (225) (172,175). Arnottianamide (206) could be O-acetylated (174) as well as O-methylated with diazomethane in HMPA (172). Isoarnottianamide (208) was O-methylated to trimethoxy derivative 226, which under Bischler-Napieralski conditions recyclized to the benzophenantridine alkaloid, chelilutine (227) (176) (Scheme 33). 

The amides on reduction with lithium aluminium hydride yield amines. 

During studies on the total synthesis of Aspidosperma type alkaloids, unexpected difficulty was encountered in attempts to reduce the amide carbonyl group of the intermediate 1. Thus, many attempts to reduce 1 with lithium aluminium hydride resulted in reduction of both the amide carbonyl group and the C=C double bond. In an effort to circumvent this problem 1 was reacted with hot phosphorus oxychloride and the intermediate thus obtained treated with sodium borohydride in anhydrous methanol. The product which was isolated, however, was the pentacyclic compound 2, which was obtained in 50% yield. 

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). 

Acylation of the C3 position can also be accomplished with acid chlorides, as illustrated in the synthesis of indole 7.34, a drug for the treatment of depression. Reaction of indole 7.31 with oxalyl chloride affords C3-substituted product 7.32 even though the benzene ring is very electron-rich. Conversion to amide 7.33 is followed by reduction with lithium aluminium hydride which removes both carbonyl groups, affording the target indole 7.34. 

Protopine has been isolated from Bocconia frutescens,110 Fumaria judaica,111 F. schleicheri,112 and Papaver bracteatum,146 cryptopine from F. schleicheri,112 and allocryptopine from B. frutescens110 and Zanthoxylum nitidum.141 The protopine ring-system has been prepared from tetrahydrobenzindenoazepines (75) by photo-oxidation to the amides (76) followed by reduction with lithium aluminium hydride and re-oxidation with manganese dioxide.148-150 The tetrahydrobenzindenoazepines have been prepared from A-chloroacetyl-/ -phenylethylamines (73) by cyclization to the lactam (74) followed by reaction with a benzyl bromide and phosphorus oxychloride. -Protopine (77 R R2 — CH2)148 and fagarine II (77 R1 = R2 = Me)149 have been synthesized in this way. 

The Leukart reaction has also been used in the conversion of dehydroepiandro-sterone into 17/3-formylamino-3/3-formyloxyandrost-5-ene, which on reduction with lithium aluminium hydride afforded 3/3-hydroxy-17/3-me thylaminoandrost-5-ene. Acylation with isocaproyl chloride then furnished the N-methyl-N-isocaproyl steroid (197), after selective ester hydrolysis of the initially formed ON-diacyl derivative. The amide (197) was further converted into its 3,5-cyclo-6-ketone via the 3,5-cyclo-6/3-alcohol and thence by reaction with hydrogen bromide into the corresponding 3/3-bromo-5a-6-ketone which upon dehydrobromination furnished a A2-5a-6-ketone and ultimately the 2-monoacetate of the 2/3,3/3-diol (198) after reaction with silver acetate and iodine. Hydrolysis to the 2/3,3/3-diol (198) gave a separable mixture of the 2/3,3/8-dihydroxy-5a- and -5/3-ketones.88... 

The reduction of a number of nitrogen derivatives such as amides, oximes, alkyl cyanides or nitro compounds, particularly with lithium aluminium hydride, provides useful ways of making amines. The value of these methods lies in the fact that these derivatives allow the nitrogen to be introduced into a compound at different oxidation levels (Scheme 2.30a). 

The reduction of amides to amines may be achieved with lithium aluminium hydride and with borane (Scheme 3.73). 

The trihalogenomethyltin compounds can be prepared by acidolysis of a tin amide R3SnNEt2 (R = Me, Bu, or Ph) with the haloform HCX3 (X = Cl, Br, or I), and the CX3 group can then be reduced to CHX2 and CH2X with lithium aluminium hydride.14... 

The total synthesis of (+ )-dehydroheliotridine (4), a toxic metabolite of the pyrrolizidine alkaloids (e.g. lasiocarpine and heliotrine), has also been described.2 The pyrrole ring was obtained by reaction of l,6-dihydroxy-2,5-dicyanohexa-l,3,5-triene-l,6-dicarboxylic ester (5) with j3-alanine, which afforded the N-substituted pyrrole ester (6), together with the appropriate amide of oxalic acid. Careful hydrolysis of (6) with dilute alkali afforded the related tricarboxylic acid, which was converted, by Dieckmann cyclization, hydrolysis and decarboxylation, into the keto-acid (7). Esterification of (7) with diazomethane, followed by reduction with lithium aluminium hydride, finally afforded ( )-dehydroheliotridine (4), identical, except in optical rotation, with dehydroheliotridine obtained earlier by Culvenor et al.3... 

We reasoned that the /-butyl group is still too small for an efficient chiral induction therefore, the optically pure 0-TBDPS lactaldehyde was chosen for the formation of the N,O-acetal. But only amides 39 and 41 are now non-racemic 39 exhibits a satisfactory chiral induction on allylation, because the enolate carbon is shielded by the adjacent axial bulky substituent. In 41, both sidechains at C-2 and C-4 are equatorial and the stereocontrol drops significantly.The use of a chiral aldehyde for acetal formation even allows the use of the achiral O-aminobenzylalcohol (43) as a template. Acetals 44 and 45 are formed and separated due to the allylic 1,3-strain of the amide moiety both derivatives have axial sidechains (as detectable in the crystal structure of alkylation product 46d) (Fig. 2) and the chiral induction is similarly high in both cases. The chiral auxiliary is removed with lithium aluminium hydride without any racemization of the newly created stereocenter (6). 

A common intermediate in the synthesis of benzo[c]phenanthridines is the 2-aryl-l-tetralone, which provides rings A, B, and D of the alkaloid nucleus. In 1973, two independent research groups reported the synthesis of nitidine via the 3,4-dihydro-2-(3,4-dimethoxyphenyl)-6,7-methylenedioxy-(2/7)-naphthalone 29 (Scheme 2). The synthesis of this intermediate was arrived at by two different routes. Kametani ei al. (73JHC31) reduced 3-(3,4-methylenedioxyphenyl)proprionate 21 to the corresponding alcohol 22 with lithium aluminium hydride, which was then converted to the chloride 23 with thionyl chloride. After production of the nitrile 24 by reaction with sodium cyanide and subsequent hydrolysis to the carboxylic acid 25, Friedel-Crafts cyclization of the acid chloride 26 afforded the tetralone intermediate 27. Reaction with l-bromo-3,4-dimethoxybenzene 28 in the presence of sodium amide yielded the tetralone intermediate 29 in an overall yield of 4%. 

Reduction with lithium aluminium hydride-aluminium chloride (3 1) provides a good route from a,(3-unsaturated carbonyl compounds to unsaturated alcohols (or amines), which are difficult to prepare with lithium aluminivun hydride alone because of competing reduction of the carbon-carbon double bond. For example, a,p-unsaturated esters are reduced to allylic alcohols, although diisobutyla-luminium hydride (DIBAL-H) is normally the reagent of choice for this transformation. Reduction of carboxylic amides can sometimes be preferable using AIH3 (7.78). 

The iminium ion is, of course, more electrophilic than the starting amides (amide carbonyl groups are about the least electrophilic of any ), so it gets reduced to the secondary amine. This reaction can be used to make secondary amines from primary amines and acyl chlorides. A similar reduction with lithium aluminium hydride gives a primary amine from a nitrile. 

A-Acylimidazoles are even more easily hydrolysed than A-acylpyrroles, moist air is sufficient. The ready susceptibility to nucleophilic attack at carbonyl carbon has been capitalised upon commercially available I,r-carbonyldiimida-zole (CDI), prepared from imidazole and phosgene, can be used as a safe phosgene-equivalent, i.e. a synthon for 0=C, and also in the activation of acids for formation of amides and esters via the A-acylimidazole. In another application, A-acylimidazoles react with lithium aluminium hydride at O C to give aldehydes, providing a route from the acid oxidation level. 

Treatment of 4-aminophenol (77) with 2-(3,4-dimethoxyphenyl)acetyl chloride (78) gave amide 79, converted to amine 80 by a reduction with lithium aluminium hydride. By treatment of 80 with ethyl 3-chloro-3-oxopropanoate, ethyl 3-((4-hydroxyphenethyl)(4-hydroxyphenyl)amino )-3-oxopropanoate (81) was obtained in 50% yield. 

In the selection of the drying agent, care must always be taken that it does not attack the solvent itself. For example, in dehydrations with lithium aluminium hydride, it is not only water which reacts with the drying agent the hydride also reduces aldehydes, ketones and esters to alcohols, and nitriles, amides and aldimides to amines. It is naturally not suitable, therefore, for the dehydration of solvents having such chemical composition. 

The amides and hydrazides of pyridine-carboxylic acids arc of some importance, though their chemistry is not marked by unusual properties. Nicotinamide is, of course, an important compound, and isonicotinic acid hydrazide (isoniazid) is an antitubercular drug. Substituted derivatives are used as antidepressants. In general, however, these compounds show normal chemical behaviour. The amides undergo hydrolysis, dehydration and Hofmann bromination without difficulty. Their reduction has been much studied as a route to pyridine aldehydes. The Sonn-Muller reduction is not very satisfactory in this series, but the McFadyen-Stevens reaction is useful . Nicotinic acid diethylamide gives only poor yields of the aldehyde upon reduction with lithium aluminium hydride, but yields from the methyl-phenylamide are high. Most satisfactory is the reduction of nicotinic acid dimethylamide with lithium diethoxyaluminium hydride . 

Cyclization of the Weinreb amide 356 under reductive conditions using lithium aluminium hydride (LAH) led to formation of the carbinolamine 357 which underwent elimination on treatment with methanesulfonic acid to give 358 in 72% yield as shown in Scheme 27 <2005TL249>. 

This method is very useful for the construction of 1-substituted 3,4-dihydroisoquinolines, which if necessary can be oxidized to isoquinolines. A P-phenylethylamine (l-amino-2-phenylethane) is the starting material, and this is usually preformed by reacting an aromatic aldehyde with nitromethane in the presence of sodium methoxide, and allowing the adduct to eliminate methanol and give a P-nitrostyrene (l-nitro-2-phenylethene) (Scheme 3.17). This product is then reduced to the p-phenylethylamine, commonly by the action of lithium aluminium hydride. Once prepared, the p-phenylethylamine is reacted with an acyl chloride and a base to give the corresponding amide (R = H) and then this is cyclized to a 3,4-dihydro-isoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride (Scheme 3.18). Finally, aromatization is accomplished by heating the 3,4-dihydroisoquinoline over palladium on charcoal. 

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