Ketenes, 3-keto alkylation

Indirect replacement of the a-hydrogen atom of carboxylic esters by the nitroso group is remarkable. This procedure uses ketene 0-alkyl O -silyl acetals (1), generated from carboxylic esters, which are treated with nitric oxide or isopentyl nitrite in the presence of titanium(IV) chloride. In the absence of an a-hydrogen a-nitroso esters (2) are obtained. a-Nitroso esters with an a-hydrogen undergo isomerization to oximes of a-keto esters (3 equation 1). Similarly, silyl enol ethers of aldehydes or ketones can be used instead of the carbonyl compound itself for nitrosation. Thus, treatment of enol ether (4) with nitro-syl chloride gives the a-nitroso aldehyde (5 equation 2), which is quite stable at 0 C, but dimerizes at room temperature. 

Carbonyl transposition.1 Tetrafluoroboric acid is the most effective acid for rearrangement of a-hydroxy ketene dithioketals to a,p-unsaturated thiol esters. This rearrangement is particularly useful for rearrangement of the tertiary allylic alcohols formed by addition of organometallic reagents to a-keto ketene dithioketals, which are readily available by reaction of ketone enolates with carbon disulfide followed by alkylation with methyl iodide. 

On heating with actueou- - HCl, tlte alkylated (or dialkylatedl acetoacetic eater is hydrolyzed to a /ft keto acid and then decarboxytated to yield the ketene product. The decarboKylation occurs in the same way as in the maU onic ester synthesis and involves a ketone enol as initial product. 

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." ... 

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). ... 

Kerosene, purified, 24, 7 Ketene, 21, 13, 64 Ketene diethylacetal, 23, 45 Ketene, diethyl ketal, 23, 45 Ketene dimer, 21, 4, 64 Ketene lamp, 21, 65 Keto acid, 20, 2 -Ketoglutaric acid, 26, 42 Ketone, 2-Fluorenyl methyl, 28,3,63 Ketone, methyl 9-phenanthryl, 28,6 Ketone, methyl 2-thienyl, 28,1 Knoevenagel condensation, 23, 60 24, 92 25, 42, 51 27, 24 28, 24 Kolbc synthesis of an alkyl a,a>-dicar-boxylatc, 21, 48... 

Silyl alkyl ketene acetals, as ester enolate equivalents, are capable of regioselective acylation by acid chlorides. Rathke and Sullivan showed that a variety of acid chlorides reacted with the acetal (3) to give protected -keto esters (Scheme 11). Acid hydrolysis of the silylated products gave the free -keto ester. The reaction was successful with a variety of acyl chlorides, including acetic, butanoic, (2 )-buten-... 

Monoalkylated products of substrates such as malonic esters, j5-diketones and -keto esters are highly useful because of their ready conversion to the corresponding ketenes or esters and they also function as starting materials for the preparation of a, -unsaturated ketones and esters [111]. A frequent difficulty encountered in attempts to monoalkylate such substrates is concurrent formation of a second C-alkylated side product, 0-alkylated systems and, in some instances, condensation products. Among the approaches to overcome these difficulties has been the use of DBU as a base [111]. However, yields are moderate, reaction times are relatively long, and dialkylation of the carbon as well as 0-alkylation occurs. 

The a-pyrone analogues (101) have been synthesized by a [24]cycloaddition reaction between cyclic a-keto-enamines (100) and di(thioethyl)ketene/ 5-Enamino- 8-keto-esters, derived from the corresponding acetylenic keto-esters, undergo smooth alkylation to give /35-diketo-esters, which can be cyclized to 4-hydroxy-a-pyrones with hot polyphosphoric acid/ ... 

The oxidation of terminal acetylenes, like that of monosubstituted olefins, often results in inactivation of the P450 enzyme involved in the oxidation. In some instances, this inactivation involves reaction of the ketene metabolite with nucleophilic residues on the protein [196, 197], but in other instances it involves alkylation of the prosthetic heme group (Fig. 4.31). Again, as found for heme alkylation in the oxidation of olefins, the terminal carbon of the acetylene binds to a pyrrole nitrogen of the heme and a hydroxyl is attached to the internal carbon of the triple bond. Of course, as one of the two m-bonds of the acetylene remains in the adduct, keto-enol equilibration yields a final adduct structure with a carbonyl on the original internal carbon of the triple bond [182, 198]. It is to be noted that the oxidation of terminal triple bonds that produces ketene metabohtes requires addition of the ferryl oxygen to the imsubstituted, terminal carbon, whereas the oxidation that results in heme alkylation requires its addition to the internal carbon. As a rale, the ratios of metabolite formation to heme alkylation are much smaller for terminal acetylenes than for olefins. 

Methylthio-l,2-dithiolium perchlorates may be obtained directly from keten mercaptals, for example (31), by the action of phosphorus pentasulphide and subsequent treatment of the insoluble residue with perchloric acid. Similar treatment of /3-keto-amides (32) yields 3-arylimino-l,2-dithiole perchlorates (27 R = Ar, X = CIO4). The method succeeds with amides (32 R = alkyl) and thus serves as a route to the previously inaccessible 5-alkyl-l,2-dithiol-3-imines. Demethylation of 3-methylthio-5-phenyl-l,2-dithiolium cation, to give 3-phenyl-l,2-dithiole-3-thione, occurs when the iodide is heated in xylene. 

Romo and coworkers were able to expand on their tetrahydrofuran synthesis by finding conditions for a three-component cascade sequence that resulted in 2,5-cis-tetrahydrofurans from keto-aldehydes, ketene acetals, and EtaSiH (Scheme 8) [11]. Optimal conditions required an excess of ZnCh and Et3SiH to give tetrahydrofurans in high diastereoselectivity. The two-step yields, with alkyl ketones, were in the 42-54 % range with the lowest yield of 13 % coming from the use of a benzylic ketone (R = Ph). The authors found it easier to isolate the products after reduction of the crude reaction mixture. 

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