Preparation of P-Keto Amides

9) The mechanism involving acyl Meldrum s acids in solution was never clarified. Several proposed reaction pathways are often found in the same publication. 

Second-Ceneration Chiral Auxiliary Route. The PGA Enamine-amide Route 

With the improved route to prepare the triazole fragment 3 and the one-pot method to access keto amide 25 demonstrated, we set out to explore the chiral auxiliary strategy that had been demonstrated previously from keto ester 10. 

Purification of this crude stream, which contains a stoichiometric amount of 2-phenylacetamide, was achieved by crystallizahon of the amine 1 as its l -larirate salt with 90% recovery and upgrade in purity to 99.9% ee. The 2-phenylacetamide was completely rejected during this crystallizahon. 

The tartrate salt was then converted to the phosphate salt, the desired salt form of sitagliptin by free-basing first with KOH in aqueous THF, solvent-switching the organic phase to ethanol and adding phosphoric acid to crystallize the phosphate salt in 93% yield with high enantiomeric and chemical purities. 

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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). ... 

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. 

Nu = alcohol, amine Scheme 5.13 Preparation of P-keto esters and amides from acyl Meldrum s acids... 

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-... 

A useful preparation of A-acylureas initiated by the addition of A-halo amides to isocyanides was described (equation 35)53. / -Keto-a-(phenylthio)alkyl p-tolyl sulfones in... 

Phosphoranes and phosphonate derived carbanions are also known to react with carbonyl compounds other than aldehydes and ketones, in reactions often referred to as non-classical Wittig reactions.35 Wittig olefination products can be obtained from the reaction of esters, anhydrides and some amides and imides with a range of stabilized and reactive phosphoranes. The reaction of stabilized and semi-stabilized phosphoranes with esters gives alkenes (Scheme 7). However, non-stabilized phosphoranes, such as methylenetriphenylphosphorane, tend to give P-keto phosphoranes on reaction with esters (Scheme 7)—the careful choice of the reaction conditions can also permit the preparation of the alkene in these reactions. 

The most important method for the preparation of aryl ketones is known as Friedel-Crafts acylation. The reaction is of wide scope. Reagents other than acyl halides can be used," including carboxylic acids," anhydrides, and ketenes. Oxalyl chloride has been used to give diaryl 1,2-diketones." Carboxylic esters usually give alkylation as the predominant product (see 11-11)." A-Carbamoyl p-lactams reacted with naphthalene in the presence of trifluoromethanesulfonic acid to give the keto-amide." ... 

Some synthetic approaches to pyrazines relied on metal-assisted reactions. A synthesis of 6-substituted 5H-pyrrolol2,3-bJpyrazines via Pd-catalyzed heteroannulation from W-(3-chloropyrazin-2-yl)methanesulfonamide and alkynes was developed <04TL8087>, and 3- and 5-substituted 2(l//)-pyrazinones were prepared by Suzuki and Heck reactions using 3,5-dichloro-2(l//)-pyrazinones <04TL1885>. An improved synthesis of 6-substituted-5//-pyrrolo 2,3-iiJ-pyrazines via microwave-assisted Pd-catalyzed heteroannulation was developed <04TL8631>, and the reaction of a-diazo-P-keto esters with Boc amino acid amides in the presence of a Rh catalyst gave, after air oxidation, pyrazin-6-ones 111, which were then converted into tetrasubstituted pyrazines 112 <04OL4627>. 

Ketone syntheses. Acyl derivatives that favor the arrestment of Grignard reactions beyond the first round include A-acylpyrazoles, acyl hemiacetals, and acyl tributylphosphonium chlorides (generated in situ from RCOCl and Bu,P). The protocol involving Al-methoxy-Al-methyl carboxamides has been extended to the preparation of a-chloro ketones, a-keto amides, and a-diketones (the last two from the oxalyl diamides). Symmetrical diketones are obtained by the Grignard reaction of bis(benzimidazole) methiodides. Note that an analogous reaction of 1,3-disubstituted benzimidazolium salts furnishes aldehydes. ... 

As a final set of examples, enantioselective allylic substitution of unstabilized eno-lates to form a new stereocenter at the enolate carbon have been developed through the decarboxylative reactions of allyl enol carbonates. - - These reactions are enantioselective versions of reactions closely related to those in Equation 20.18 and Scheme 20.4, and two examples are shown in Equations 20.60 and 20.61. In these cases, a new stereocenter is formed at the a-carbon of the enolate nucleophile. Most of these reactions have been conducted with allyl enol carbonates that generate cyclic ketone enolates, but enantioselective reactions of acyclic allyl enol carbonates have also been reported. Although allyl enol carbonates undergo decarboxylation faster than the 3-keto ester isomers, the 0-allyl p-keto esters are more difficult to prepare, and enantioselective allylations starting with p-ketoesters have been reported. - Decarboxylative reactions of amines and a-amino acids have been conducted to form allylic and homoallylic amines (Equation 20.62), respectively, and enantioselective decarboxylative allylations of amides have been reportedIridium-catalyzed enantioselective decarboxylative allylation of amides starting with 0-allyl imides has also been reported. ... 

Although the selfcondensation of amide chlorides proceeds well to give amide chlorides derived from P-keto acids (56 equation 35) this reaction has only been used to synthesize P-keto acid amides, which result after hydrolysis of the condensation products (56), and not to prepare the salts (56) in the pure state. The condensation reaction of aromatic aldehydes with the lV.iV-dimethylacetamide-TkDCl3 adduct... 

Amides can also be obtained by AICI3 catalyzed ester amine exchange which proceeds primarily without racemization of chiral centers (eq 24). The reaction of phenols with p-keto esters is known as the Pechmann condensation (eq 25). Aryl amines are used in the Riehm quinoline synthesis (eq 26). Aromatic systems may be coupled via the Scholl reaction (eq 27) and indole derivatives are prepared in the Stolle synthesis (eq 28). In the Zincke-Suhl reaction, phenols are converted to dienones (eq 29). ... 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

One of the standard methods for preparing enantiomerically pure compounds is the enantioselective hydrogenation of olefins, a,/3-unsaturated amino acids (esters, amides), a,/3-unsaturated carboxylic acid esters, enol esters, enamides, /3- and y-keto esters etc. catalyzed by chiral cationic rhodium, ruthenium and iridium complexes ". In isotope chemistry, it has only been exploited for the synthesis of e.p. natural and nonnatural H-, C-, C-, and F-labeled a-amino acids and small peptides from TV-protected a-(acylamino)acrylates or cinnamates and unsaturated peptides, respectively (Figure 11.9). This methodology has seen only hmited use, perhaps because of perceived radiation safety issues with the use of hydrogenation procedures on radioactive substrates. Also, versatile alternatives are available, including enantioselective metal hydride/tritide reductions, chiral auxiliary-controlled and biochemical procedures (see this chapter. Sections 11.2.2 and 11.3 and Chapter 12). 

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