P-keto amides

A general method for malting Camps precursors has been developed/ Treatment of an anthranilic acid 15 with an acid anhydride or chloride in the usual way results in the corresponding benzoxazinone (16). Subsequent treatment with the dianion of an N-substituted acetamide furnishes P-keto amide 17. The reactions were run with crude 16, yields typically 50-80% overall. The effect of substituents on the reaction has not been extensively investigated. 

The zinc-mediated reaction tolerates a variety of functionality in the p-keto ester. In fact, the method described above has been applied successfully to p-keto amides and p-keto phosphonates, Unsubstituted p-keto esters, amides and phosphonates have been chain-extended in yields that ranged from 58% to 98% (Table I). The primary limitation to this method is the inefficiency with which a-substituted esters and amides undergo methylene insertion. The zinc carbenoid must be employed in at least a threefold excess h... 

Widenhoefer has developed methods for Pd-catalyzed addition of 1,3-dicarbonyl nucleophiles to alkenes [ 171-173]. Most of these reactions employ stoichiometric copper as the oxidant however, Yang and coworkers recently reported a modified procedure that employs cocatalytic lanthanide Lewis acids to achieve direct dioxygen-coupled turnover (Eq. 39) [174], The Lewis acid is thought to activate the carbon nucleophile, P-keto amide, toward attack on the tethered alkene. 

In order for this strategy to be competitive with the convergent approach, we would have to first improve the synthesis of the triazole fragment and tlien find an alternative to the Masamune chemistry to get access to P-keto amides directly. 

With an improved synthesis of the triazole fragment in hand, which would allow for its introduction much earher in the synthesis, we started searching for a direct preparation of the P-keto amide intermediate from trifluorophenylacetic acid (9). This type of transformation has been accomplished in the past using acyl Mel-drum s acid adducts [16]. This methodology involves reaction of Meldrum s acid with activated carboxyhc acids followed by decarboxylation in the presence of nucleophiles such as alcohols or amines (Scheme 5.13). The abihty of readily avail-... 

If a C—H bond is acidic enough, it couples with diazonium salts in the presence of a base, most often aqueous sodium acetate.153 The reaction is commonly carried out on compounds of the form Z—CH2—Z, where Z and Z are as defined on p. 464, e.g., P-keto esters, p-keto amides, malonic ester. 

Stereoselective reduction of -keto amides.1 a-Methyl-p-keto amides are reduced by this silane in combination with tris(diethylamino)sulfonium difluorotri-methylsilicate (10, 452-453) in DMPU to the anti-alcohol, but are reduced by this silane in TFA to the syn-alcohol. 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

M. Fujita and T. Hiyama 44 ERYTHRO-DIRECTED REDUCTION OF OF A p-KETO AMIDE ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYLPROPANOYL)PIPERIDINE... 

Although Curran s rate data for the reduction of radicals to organosamar-iums allow for an element of predictablity,2 problems can arise when multifunctional substrates are involved. For example, in the attempted intramolecular Barbier reaction of alkyl iodide 13, treatment with Sml2 results in the formation of side product 15 in addition to the expected product cyclohexanol 14 (Scheme 3.7).8 In this case, the p-keto amide motif in 13 is reduced at a rate competitive with alkyl iodide reduction, indicating that there are likely two mechanistic pathways through which the reaction proceeds a thermodynamic pathway initiated by reduction of the R I bond providing the... 

Similar to p-keto esters, P-keto amides may be readily hydrogenolyzed by conditions. Thus, 3-acyloxyindole (10), a P-keto amide, is cleanly hydrogenolyzed to the corresponding 3-alkyl derivative in ethanol over Adams palladium oxide catalyst (eq. 5.37).126... 

Ketones can also be obtained by treatment of the lithium salt of a carboxylic acid with an alkyllithium reagent (16-28). For an indirect way to convert carboxylic esters to ketones, see 16-82. A similar reaction with hindered aryl carboxylic acids has been reported. " Treatment of a p-amido acid with two equivalents of M-butyllithium, followed by reaction with an acid chloride leads to a p-keto amide.Carboxylic acids can be treated with 2-chloro-4,6-dimethoxy[l,3,5]-triazine and the RMgX/Cul to give ketones. " ... 

Metal thiolates or benzenethiols in the presence of triethylamine also react very smoothly with di-ketene to yield S-alkyl (35) or S-aryl acetothioacetates (36). The p-keto thioesters (35) can be used in exceptionally mild preparations of P-keto amides (37), whereas (36) can be cyclized by Lewis acids to form thiocumarins (38). The S-f-butyl thiol ester (35) is also a suitable substrate for C-alkylation in the P-position or, after double deprotonation, in the 8-position (Scheme 3). ... 

Intramolecular addition of allylsilanes performed under chelation-controlled conditions represents an efficient method in which useful levels of stereoselectivity can be achieved. This process has been demonstrated for a variety of a-alkoxy, a,3-dialkoxy and p-dicarbonyl compounds, including 3-keto esters, P-keto amides and P-keto lactones. 

A practical one-pot process for preparation of p-keto amides/enamine has been developed. The use of online IR and subsequent principal component analysis for kinetic studies were critical as tools for profiling the concentration changes of the arfion and free acid forms, as well as the product, throughout the course of the reaction. The mechanistic understanding about the reaction provided an in-depth understanding to design and develop the efficient, one-pot process. 

Toward this end, Caryn Kenny set out to investigate the scope and limitations of the process. Indeed, the reaction turned out to be quite versatile (Eqs. 4 and 5). Both p-keto esters and p-keto amides could be used as substrates. Unactivated alkenes, electron deficient alkenes, and alkynes all served as suitable ketyl acceptors under Sm(II)-promoted conditions. As anticipated, high diastereoselectivity over three stereocenters could be achieved. However, although five-membered rings could be formed with exceptional ease, in these systems virtually all attempts at forming six-membered rings met with disappointment. 

KCN, 21, 263, 264 P-keto amides, 140 P-keto esters, 140 ketyl-olefin coupling, 141 ketyl-olefin cyclization, 139, 153 kinetic resolution, 162, 163, 167 KMn04, 214... 

Oxidation. P-Enamino carboxamides derived from cyclic p-keto amides are oxidized by Mn(OAc)j-Cu(OAc)2 to give enones, dienamines, or aniline derivatives, depending on the ring size. 

---