Amides and lactams

All amides show a carbonyl absorption band known as the amide I band. Its position depends on the degree of hydrogen bonding and, thus, on the physical state of the compound. 

FIGURE 3.26. Benzoyl chloride. A. Aromatic C—H stretch, 3065 cm-1. B. The C=0 stretch, 1774 cm-1 (see Table 3.3). (Acid chloride C=0 stretch position shows very small dependence on conjugation aroyl chlorides identified by band such as at C.) C. Fermi resonance band (of C=0 stretch and overtone of 8/2 cm1 band), 1730 cm-1. 

Primary amides and secondary amides, and a few lactams, display a band or bands in the region of 1650-1515 cm-1 caused primarily by NH2 or NH bending the amide II band. This absorption involves coupling be- 

Out-of-plane NH wagging is responsible for a broad band of medium intensity in the 800-666 cm-1 region. 

FIGURE 3.28. 2-methylpropanamide. A. The N—H stretch, coupled, primary amide, hydrogen bonded asymmetric, 3352 cm-1 symmetric, 3170 cm1. B. Aliphatic C—H stretch, 2960 cm-1. C. Overlap C=0 stretch, amide I band, 1640 cm-1 see Table 3.3. 

N—H and O—H stretching frequencies so that an unequivocal differentiation in structure is sometimes impossible. 

Review Comprehensive Organic Synthesis, Eds. B. M. Trost and I. Fleming, Pergamon, Oxford (1991), Vol 2, Part 1.11, p 341 

Ti(0-/-Pr)4 RCHO, cat Cp2ZrH2) cat NiCl2 AiCHO, NaOH 

LDA/H2CO/MsC1, Et3N LDA/H2CO/TsC1, py/DBU LDA/H2CO/Msa, Et3N/DBU 

MeOC02MgOMe / H2CO, Et2NH or PhNHMe, NaOAc, HOAc 

See page 1317, Section 8 and page 1513, Section 13 (directed aldol). 

Shift with respect to C-(C-CH3) =-6 ppm Shift with respect to C-(NH) w-1 to -2 ppm 

Frequently broad to very broad splitting due to H-N-C-H coupling often only recognizable in the CH signal 

Position and shape depend on extent of association, often different bands for H-bonded and 6 00 NH, always at least two bands for NH2 

Strong, range given for amides as well as for 8- and larger lactams, higher wavenumbers for P- and y-lactams 

Often strong, missing for tertiary amides and lactams 

The N-alkylation of acetanilide under the action of microwave irradiation in the presence of a phase-transfer catalyst has also been reported (Eq. 27) [40]. 

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). 

The starting reagents in Gabriel amine synthesis, N-alkylphthalimides, were obtained under the action of microwave irradiation in a solid-liquid PTC system. The reactions were conducted with high yield (50-90%) simply by mixing phthalimide 

The same reaction (R-X = n-OctBr) was studied using TBAB and several basic supports. Na2S04 and CaC03 (yields 93 and 95%, respectively, within 3 min of MW irradiation) were shown to be more efficient than K2C03 (71%) [43], 

Molecnlar ion Aliphatic amides moderate, tendency to protonate Aromatic amides strong 

Fragments Amides cleavage on both sides of the carbonyl gronp followed by loss of CO large nnmber of fragments of even mass Lactams loss of a-snbstitnent, loss of CO 

---

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-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. 

---