Oxoalkyl Acids

5 Oxoalkyl Acids. - P-Ketophosphonates have been synthesised in good yields by treatment of the carbanion of diethyl phosphonoacetic acid with acyl 

Finally, the acid (186) has been isolated as the ( ) and (Z) forms of the methyl carboxylates, characterized crystallographically as their dicyclohcxylammonium salts. The two compounds exhibit markedly different reactivities. Thus, the ( ) form requires prolonged treatment with alkali for its conversion into the tetrasodium salt which at pH 6-7 then yields phosphoric acid the (Z) form reacts rapidly with alkali to give the tetrasodium salt, and this at pH 6-7 yields H2O3P.CN.  

Reagents i, MeNOa, KF, MeaCHOH ii, MeSOaCI, EtaN, CHaCIa  

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Oxoalkyl Acids. Various types of readily available a-hydroxyphosphon-ates have been converted to a-ketophosphonates in high yield by potassium... 

In complete contrast to the (l-oxoalkyl)phosphonic acids, for which essentially only one synthesis is available, based on the Michaelis-Arbuzov or Michaelis-Becker reactions, there are several procedures available for the synthesis of those acids with the 0x0 group at C(2) or at a carbon atom site even further from the phosphoryl centre. Historically, esters of (2-oxoalkyl)phosphonic acids were also obtained through application of the Michaelis-Arbuzov and Michaelis-Becker reactions, but it soon became apparent that complications occur, the major one being the concomitant formation, in many instances, of enol phosphates and, in some cases, this reaction became the main one, indeed, sometimes the only one. Several other procedures are now available for the preparation of oxoalkyl acids which place the 0x0 group accurately and with no side reactions of any importance, and these are therefore considered first in the following survey. 

Analogous open-chain precursors also lead readily to 1,3-dithiolylium salts. S-a-Oxoalkyl thioesters such as (20) on treatment with perchloric acid in glacial acetic acid and HaS undergo ready cyclization to the 1,3-dithiolylium perchlorate (22) (66AH0.7)39). The oxoalkyl dithioesters (21) are probably intermediates in this cyclization as they themselves undergo cyclization with warm 70% perchloric acid or sulfuric acid (80AHC(27)15l). 

The cathodic cyclization of several types of A -(5-oxoalkyl)pyridinium salts in 1 M sulfuric acid afforded quinolizine derivatives. For example, compound 256, prepared from 4-methylpyridine, gave a diastereomeric mixture of quinolizines 257 and 258. Differential pulse polarographic studies allowed a mechanism to be proposed, which is outlined in Scheme 53 <2003EJ02919>. 

The acid-catalyzed ot7, o-acylation of /3-oxoalkyl derivatives of 7t-excess aromatic heterocycles known as the Dorofeenko-Dulenko-Krivun reaction affords condensed pyrylium derivatives which are convenient precursors of the corresponding pyridines <2001CHE1310>. By this approach (Scheme 14), carbazole 100 is converted into carba-zolo[3,2-f]pyrylium 101, a new ISrt-electron heteroaromatic system, and 101 is readily transformed into isomer 102 of 6-methylellipticine via an Sn(ANRORC) reaction using ammonia. The yields for these transformations were not reported. 

Alkylalkanoic Acids by Hydrolysis of l-(2-Alkyl-l-oxoalkyl)-2-(methoxymethyl)pyrrolidines General Pro-cedure2,13 ... 

Acid hydrolysis of l-(2-alkyl-l-oxoalkyl)-a,a-dimethyl-2-pyrrolidinemethanols 2 furnishes 2-alkyl-alkanoic acids 4 in 76-99 % ee, along with the protonated chiral auxiliary 9. The latter can be recycled by acylation to yield l-acyl-a,a-dimethyl-2-pyrrolidinemethanols19-22. Although slightly more drastic conditions are required for hydrolysis of these derivatives compared with the conditions used for l-acyl-2-pyrrolidinemethanols (see Section 1.1.1.3.3.4.1.2.1.), racemiza-tion of the resulting acids does not seem to be a problem. 

A solution of 20 mmol of a .s-3-(2-alkyl-l-oxoalkyl)-l, 5-dimethyl-4-phenyl-2-imidazolidinone 5 in 40 mL of dry THF is slowly added at 0 3C to a stirred suspension of lithium aluminum hydride in 30 mL of THF under argon. The mixture is stirred for 1 h, then the reaction is quenched by the cautious addition of methanol, followed by 2M aq hydrochloric acid. Extraction with ethyl acetate is followed by concentration under vacuum and flash chromatography (cyclohexane/ethyl acetate). For specific examples, see Table 12. 

Formation of the bicyclo[3.2.0]heptane system was visualized as a neopentyl-type rearrangement with the oxoalkyl group acting as the migrating group. However, neopentyl rearrangements occur in acid media via cations. 

PK Chakravarty, WJ Greenleem, WH Parsons, AA Patchett, P Combs, A Roth, RD Busch, TN Mellin. (3-Amino-2-oxoalkyl)phosphponic acids and their analogs as novel inhibitors of D-alanine D-alanine ligase. J Med Chem 32 1886-1890, 1989. 

Azine approach. Pyridazinium salts (216) can be prepared by acid-catalyzed cyclodehydration of 2-/3-oxoalkyl-3(2//)-pyridazinones (77YZ422). The same cyclization of 3,4-dihydro-... 

The cyclization can also be effected in the opposite direction, viz. at the sulfur atom as in (404). For this reaction the sulfur is introduced after the /8-oxoalkyl substituent has been attached to the nuclear nitrogen (78JMC489). The intermediate in this cyclization corresponds to the product from the acid-catalyzed Pummerer reaction of the 2,3-dihydrothiazolo sulfoxide (405) (81H(15)1349). When the (3-oxo group is part of a carboxy group or its derivatives, 3-hydroxythiazolylium derivatives are formed (408) (81H(15)1349>. 

Another method starts with the above-postulated intermediate oxoalkyl dithioesters (224). These dithioesters (224) can be cyclized to the corresponding 1,3-dithiolylium salts (31) in the presence of strong acids by warming either in 70% perchloric acid or concentrated sulfuric acid. The results are sometimes improved by the presence of H2S or of the complex H2S/BF3 (80AHC(27)151). 

Oxoalkyl dithioesters 259 are cyclized by perchloric acid to dithiolylium salts 260 (Scheme 127) <1980AHC(27)151>. Similarly, dithiocarbamate 261 with phosphorus pentasulfide and tetrafluoroboric acid gives the 2-amino-l,3-dithioly-lium tetrafluoroborate 262 (Scheme 128) <1969CPB1924>. 

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