Carboxamide enolates

A method relying on the reduction of bicyclic thioglycolate lactams by lithium di-f-butylbiphenylide (LiDBB) has also been proposed (Scheme 48)196. This route has the advantage of affording carboxamide enolates with E/Z ratios that depend directly on the stereochemistry of the starting bicyclic lactam and do not rely on the steric difference between the two substituents. 

S. Ito et al. utilized the aza-Claisen rearrangement of carboxamide enolates for the enantioselective total synthesis of (-)-isoiridomyrmecin, which is a constituent of Actinidia polygama and exhibits unique bioactivity. The rearrangement of the (S,S) stereoisomer was conducted under standard conditions, and the product was isolated as a single [R,R) stereoisomer in 77% yield. 

More recently Scheldt [42] tried to condense psendo-ephedrine carboxamide enolates onto acylsilanes, but unfortunately no adduct was formed. 

Chiral carboxyamides derived from acid chlorides and A-chiral cA-aminoindanol can be protonated and Li Cu transmetallated to generate copper enolates which react with A-lithium derivative of A-Boc-O-tosylhydroxylamine (LiBTOC) 31 to give a-A-Boc amino carboxamides in high yields and enantiomeric excess (Scheme 38) . The chiral auxiliary can be removed by acidic hydrolysis to obtain the a-aminocarboxylic acid. 

The chiral enolate-imine addition methodology was examined in detail (Thiruvengadam et al., 1999). Enolate formation proceeds to completion within an hour at temperatures from — 30 to 0°C with either 1 equiv. TiCl4 or TiClaO-iPr (preformed or prepared in the presence of substrate by addition of TiCl4 and followed by a third of an equivalent Ti(0-iPr)4 and two equivalents of a tertiary amine base). Unlike the aldol process with the same titanium enolate, the nature of the tertiary amine base had no effect on the diaster-eoselectivity. The diastereoselectivity is maximized by careful control of the internal temperature to below — 20°C during the imine addition (2 equiv.) as well as during the acetic acid quench. The purity of the crude 2-amino carboxamide derivatives (17a or... 

The dehydration of carboxamide is believed to proceed through its enol form (ref.11). On a Lewis acid catalyst the reaction is likely to follow the following mechanism. 

The name tetracycline derives from the naph-thacene nucleus that it possesses. The rings are lettered A through D from right to left and the numbers start at the bottom of ring A. The enolized form as illustrated on next page has been selected arbitrarily and is used most exclusively in the literature. It is further defined as hydrochloride of 4 3-di-methylamino-l,4,4a,5,5a,6,ll,12a-octahydro-3,6 10,12, 12aB-pentahydroxy-6-methyl-1,11-dioxonaphtnacene-2-carboxamide. 

Bromopyridine undergoes photoassisted SrnI reaction with a variety of stabilized carbanions <1997JOC6152>. The reaction is carried out in the presence of potassium amide in liquid ammonia at —33 °C under photoirradiation at 350 nm and proceeds in moderate to good yield with anions derived from 2-benzyl-4,4-dimethyloxazoline, 2,4-dialkylthiazoles, and dimethyl methylphosphonate and also with carboxamide and ester enolates. 

The Merck group s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[l,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound. 

The influence of the structure of the base on the stereoselectivity has been studied. In 1980, the stereoselectivity of the deprotonation by LDA, LiHMDS and LiTMP of a set of ketones, esters and carboxamides at low temperature was measured after quenching with TMSC176. The authors found that the proportion of the Z(O) enolate tends to increase according to the series LiTMP < LDA < LiHMDS and to the bulkiness of the R group borne by the ketone (Scheme 13). This important finding avoided the use of toxic HMPA to prepare Z(O) enolates. 

The enantioselective a-benzylation of the lithium enolate of acyclic carboxamides, such as propionamides and butyramides, generated with CLA derived from original pen-tamines bearing several asymmetric centers has been reported495. Complementary, cyclic carboxamides such as perhydropyrimidinones lithium enolates, obtained from more classic Simpkins-type CLAs, were methylated or benzylated in toluene at —78 °C in the... 

Nonalkylated 3,4-dehydroprolines 914 were obtained in 76-81% yields by diastereoselective protonation of an enolate resulting from Birch reduction of the A -BOC-pyrrole-2-carboxamide 913 (Equation 223) <1999T12309>. The reaction was quenched by addition of solid ammonium chloride after a reaction time of 1 h. The results using lithium and sodium are similar but the reaction with potassium failed. Remarkably, asymmetric protonation is more selective (de 88-90%) than methylation (de 50%). The selectivity decreases with increasing temperature (de 82% at —30°C). The diastereoselectivity of the reaction was detected by HPLC. 

Quite a number of other electron withdrawing groups containing multiple heteroatomic bonds, such as the ester carbonyl, nitrile, carboxamide, etc., can likewise stabilize carbanions. The lithium salt of tert-butyl acetate 32 is an example of an enolate anion sufficiently stable as a salt to be used as a shelf reagent. Substituents containing easily polarizable atoms, such as sulfur or selenium, are also capable of stabilizing an adjacent anionic center. 

These results are consistent with the chelated transition states depicted in Scheme 18. Steric interactions between the substituent and the carboxamide favor (AC) for ( )-allylic ethers. The R -substi-tuent of a (Z)-allylic ether, though less affected by this interaction, still experiences a certain degree of steric strain in the anti transition state (AB) thus diminishing anti selectivity. Enantioselectivity is controlled by the substituents R and R on the pyrrolidine ring. As pictured in Scheme 18, bonding occurs preferentially on the face of the enolate anti to R. For the diastereomeric secondary allylic ethers (Table 21, entries 8) transition state (AB) represents the matched arrangement for R = H and R = alkyl, whereas (AC) is matched for R = alkyl and R = H. The former arrangement would lead to an ( )-pro-duct and the latter to a (Z)-product. 

Obach RS, Kalgutkar AS, Ryder TF, Walker GS. In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam Insights into the hepatotoxicity of sudoxicam. Chem Res Toxicol. 2008 21(9) 1890-1899. 

The carbonyl group is one of the most prevalent of the functional groups and is involved in many synthetically important reactions. Reactions involving carbonyl groups are also particularly important in biological processes. Most of the reactions of aldehydes, ketones, esters, carboxamides, and the other carboxylic acid derivatives directly involve the carbonyl group. We discussed properties of enols and enolates derived from carbonyl compounds in Chapter 6. In the present chapter, the primary topic is the mechanisms of addition, condensation and substitution reactions at carbonyl centers. We deal with the use of carbonyl compounds to form carbon-carbon bonds in synthesis in Chapters 1 and 2 of Part B. 

Addition to aromatic ketones An extensive study of the reaction of CSI with aromatic ketones (1) presents evidence that the first step is formation of a 3-keto carboxamide (2), which can react with another molecule of CSI to form a malonamide (3). Generally, however, (2) reacts with CSI to form, after reductive hydrolysis with sodium sulfite, either an oxathiazine 2,2-dioxide (4) and/or an oxazinedione (5). The ratio of (4) to (5) depends on the keto-enol equilibrium of the intermediate (2) and on the reaction conditions. 

Within the series of 4-hydroxy-1,2-benzothiazine carboxamides represented by the general structure shown below, optimum activity was observed when Ri was a methyl substituent. The carboxamide substituent, R, generally is an aryl or heteroaryl substituent, because alkyl substituents are less active. Oxicams are acidic compounds, with pKa values in the range of four to six. N-heterocyclic carboxamides generally are more acidic than the corresponding N-aryl carboxamides, and this enhanced acidity was attributed (69) to stabilization of the enolate anion by the pyridine nitrogen atom, as illustrated in tautomer A and additional stabilization by tautomer B ... 

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