Amides and Lactames

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

All that remains before the final destination is reached is the introduction of the C-l3 oxygen and attachment of the side chain. A simple oxidation of compound 4 with pyridinium chlorochro-mate (PCC) provides the desired A-ring enone in 75 % yield via a regioselective allylic oxidation. Sodium borohydride reduction of the latter compound then leads to the desired 13a-hydroxy compound 2 (83% yield). Sequential treatment of 2 with sodium bis(trimethylsilyl)amide and /(-lactam 3 according to the Ojima-Holton method36 provides taxol bis(triethylsilyl ether) (86 % yield, based on 89% conversion) from which taxol (1) can be liberated, in 80 % yield, by exposure to HF pyridine in THF at room temperature. Thus the total synthesis of (-)-taxol (1) was accomplished. 

Smith M. B. N-Dienyl Amides and Lactams. Preparation and Diels-Alder Reactivity Org. Prep. Proced. Int. 1990 22 315-397... 

Saponification of Esters or Lactones and Reaction of Persilylated Amides and Lactams with Alkali I 71... 

Various oxidations of amides or carbamates can also generate acyliminium ions. An electrochemical oxidation forms a-alkoxy amides and lactams, which then generate... 

TV-Substituted amides and lactams possess potentially reactive C—H bonds on carbon atoms alpha to the nitrogen and carbonyl group. These hydrogen atoms are easily abstracted by excited carbonyl compounds (e.g., acetone or benzophenone) to produce radicals which undergo olefin addition <9a,98 97) ... 

Warshel, Levitt, and Lifson derived a partially optimised consistent force field for amides and lactams (25). It is composed of an alkane part and an amide-part. The former was taken over from analogous earlier calculations for saturated hydrocarbons (17). The potential constants of the amide-part were optimised with the help of a large number of experimental frequencies (taken from TV-methylform amide, acetamide, iV-methylacetamide, and several deuterated species) as well as experimental geometry data for 7V-methylacet-amide. The resulting force field was used for the calculation of vibrational and conformational properties of 2-pyrrolidone, 2-piperidone and e-caprolactam. 

N-Substituted amides and lactams can be rapidly N-alkylated under solid-liquid PTC conditions by use of microwave irradiation. The reactions were performed simply by mixing an amide with 50% excess of an alkyl halide and a catalytic amount of TBAB. These mixtures were absorbed on a mixture of potassium carbonate and potassium hydroxide [41] and then irradiated in an open vessel in a domestic micro-wave oven for 55-150 s (Eq. 28). 

N-Tosyl amides and lactams.2 DCC in combination with 4-pyrrolidinopyri-dine (4-PPy) effects condensation of carboxylic acids with secondary sulfonamides to provide N-tosyl amides in 75-90% yield. The intramolecular version of this reaction provides 4-, 5-, and 6-membered N-tosyl lactams in 60-90% yield. 

C-NH-CH Substituted ureas, amides, and lactams that have a hydrogen atom on a carbon atom attached to nitrogen... 

An explanation for the smaller-than-expected effect of strain energy upon the rate of hydrolysis of /3-lactam rings can be found upon examination of the mechanism of cleavage of the C-N bond amides and lactams are hydro-... 

Reduction of Amides and Lactams Containing Double Bonds and Reducible Functional Groups... 

Various oxidations of amines can also generate acyliminium ions. The methods most used in synthetic procedures involve electrochemical oxidation to form z-alkoxy amides and lactams, which then generate acyliminium ions.108 Acyliminium ions are sufficiently electrophilic to react with enolate equivalents such as silyl enol ethers109 and enol esters.110... 

E. Reactions of Magnesium Amide and Lactam Enoiates with Electrophiles. 499... 

These structural peculiarities make some properties of quinuclidin-2-ones closer to those of aminoketones than of amides. The nitrogen of quinuclidin-2-one is easily protonated (common amides and lactams are O-protonated) and can be methylated. They are very basic (pK 5.33-5.6)44 compared with other amides (e.g., A-acetyl-piperidine, pK 0.4). 

Aryl nitriles with (Me3Si)2S in the presence of MeONa/l,3-dimethyl-2-imidazolidinone results in the conversion to primary thioamides, while amides and lactams yields the thio derivative using (Me3Si)2S and an oxophilic promoter such as POCI3, triphosgene or oxalyl chloride. Thus the intermediate [CIRC=NR R"]+C1 reacts with the silthiane to give the thioamide (equation 24)44. 

Reductive amination amides and lactams.1 The a-nitro ketone 1, prepared as shown, on reduction with NaBH4 in the presence of ammonia gas is converted into the amide 2 in 30% yield. 

Substitution of chloride in a variety of heterocyclic chlorides by esters, lactones, amides and lactams has been shown to occur in toluene in the presence of hexam-ethyldisilazide (NaHMDS) acting as a base.52 An example using a chlorothiadiazole derivative is shown in Scheme 6. There has been a report53 of a mild and convenient method for the introduction of tetrafluoroethyl substituents into nitrogen heterocycles using the reaction of hexafluoropropane with azine and azole A-oxidcs. 

The amide and lactam groups in 136 and 137 are inactive when boiled with concentrated HC1 on reaction with Grignard reagents they yield trialkylgermyl derivatives (equation 35). According to the IR spectra, there is no intramolecular O — Ge interaction in compounds of type 141480. 

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