Ester amides, reduction

A substituted benzoic acid serves as precursor for the nontricyclic antidepressant bipena-mol (175). Selective. saponification of ester 171 afford.s the half-acid 172. Reaction of the acid chloride derived from this intermediate (173) with ammonia gives the amide 174. Reduction of the last by means of lithium aluminum hydride gives bipenamol (175) [44]. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

The stereochemistry of reduction by homogeneous catalysts is often controlled by functional groups in the reactant. Delivery of hydrogen occurs cis to a polar functional group. This behavior has been found to be particularly characteristic of an iridium-based catalyst that contains cyclooctadiene, pyridine, and tricyclohexylphosphine as ligands, known as the Crabtree catalyst 6 Homogeneous iridium catalysts have been found to be influenced not only by hydroxy groups, but also by amide, ester, and ether substituents.17... 

Modifications at the carboxyl group include reduction (with dibor-ane260 or borohydride, after activation with soluble carbodiimide261,262), esterification (with diazomethane,101,223,283,264 or acyl or aryl chlorides224,264), and formation of amide esters.263,265... 

Not a great deal of work has been done on the acid or ester reduction mechanisms. There is no fundamental reason why a carboxylic acid should not be reduced electrolytically just as easily as the ester or amide. However, one... 

Many functional groups can co-ordinate to the metal of a hydrogenation catalyst, thereby playing an important part in the directing of diastereoselective reductions of proximal double bonds61. Particularly effective groups in this respect are alcohols, amides, ester and carboxylic acids. Many of these processes have been studied in great detail. 

Simple modifications of the ester group of 3-carboxyalkyl /3-sultams can be achieved and aminolysis furnishes the corresponding amides while reduction leads to the corresponding alcohol (Scheme 35) <2004HCA90>. 

Alternatively, the electron-withdrawing properties of the a-heteroatom and its ability to coordinate Sml2 may facilitate reduction of the ester carbonyl group and formation of ketyl radicals 37 (Scheme 4.22). Once the activating heteroatom group has been removed, no further ester reduction is possible. A similar mechanism is possible for the reduction of a-heteroatom-substituted amides. 

In the amide reduction scheme on p. 618, the step framed in green gives an iminium ion. Stopping the reaction here would therefore provide a way of making aldehydes from amides. Because these tetrahedral intermediates are rather more stable than those from ester reduction, this can often be achieved simply by carrying out the amide reduction, and quenching, at 0°C (-70 °C is usually needed to stop esters overreducing to alcohols). 

Eukuyama reduction is a mild method for the conversion of thioesters to aldehydes in the presence of other susceptible functional groups, including amides, esters, lactones, and acetonides. Review Eukuyama, T. Tokuyama, H. Aldrichimica Acta 2004, 37. 87-96. 

The reaction of N-arylsulfonylsuinmides with a range of trivalent phosphorus compounds gave near quantitative yields of the phosphinimides and the sulfide. I Addition of protic solvents led to reduction products, which contain, besides the original sulfides, an alkyl-exchanged sulfide in which the alkyl group derived from the alcohol. 126.127 other derivatives, (acid anhydride, amide, ester or thioester) were formed in the presence of carboxylic acid derivatives. 128,129 xhese reactions were favoured by the dipolar nature of the intermediately formed sulfurane. 127... 

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