Keto esters and related compounds

-keto esters and related compounds. The phenomenon of conjugate chelation has already been described in some detail in the case of diketones (Chapter 9), and essentially similar effects are observed with esters of comparable structure. Rasmussen and Brattain [6] have studied a number of esters in which this effect is 

With compounds such as methyl-lO-hydroxy-9-phenanthrene carboxylate [30], the increased degree of fixation of the ring double bonds results in stronger chelation, so that the frequency shift is increased to about 75 cm . As in the case of the corresponding ketones, the frequency shifts of chelated esters have been used to measure double-bond character in the indane series [55]. 

Chelation also occurs in cyclic 3-keto esters, such as derivatives of enolisable keto esters of cyc/ohexanone and cyc/opentanone. Leonard et al. [31] and Bellamy and Beecher [56] have examined a number of such cases. Non-enolisable keto esters of cyc/ohexanone show absorptions near 1735 cm and 1718 cm corresponding to the ester and ketonic carbonyl groups. However, compounds such as ethyl-cyc/ohexanone-2-carboxylate show these bands and two others at 1656 cm and 1618 cm which must arise from the chelate structure of the enol form. Leonard et al. [31] associate the first of these new bands with the chelated carbonyl absorption and the second with the double-bond absorption. A similar effect is observed 

Chelation is also to be expected in jS-amino-a/S-unsaturated esters [6] by analogy with the ketones. This has been found experimentally in the case of methyl-iV-methylanthranilate, which absorbs at 1685 cm, indicating a chelation of about the same strength as occurs with the salicylate. Removal of the chelating hydrogen atom results in reversion of the ester carbonyl frequency to 1730 cm-i. 

---

Interest in the uses of HMPT has also been maintained, but a warning has been issued (by the E. I. du Pont de Nemours Company and the U.S. National Institute for Occupational Safety and Health) about its potential acute toxicity. HMPT has been used in the synthesis of 2,4-bis(dimethylamino)qui nolines,9 8 as a solvent for reactions between carbonyl compounds and sulphur," for the conversion of iV-benzylcarbox-amides into 3-phenylpropionitriles,100 in reactions between metals or organometallic compounds with a variety of organic substrates,101 and as a solvent for alkylation reactions of /J-keto-esters and related compounds in which the alkylation reaction is accompanied by de(alkoxycarbonylation) (Scheme 7).102... 

The self-condensation of /3-keto esters and related compounds occurs under the influence of either acidic or basic catalysts and constitutes one of the earliest syntheses of pyran-2-ones (l883LA(222)l). It exemplifies a synthesis of type (ii) (Scheme 85). Ethyl acetoacetate, for instance, gives a mixture of 4,6-dimethyl-2-oxopyran-5-carboxylic acid and its ethyl ester other esters behave similarly (59RTC364). Decarboxylation of the pyrancarboxylic acid occurs at 160 °C in sulfuric acid. The formation of the pyranone proceeds through a 5-keto ester which is considered to result from attack of the enolic form of the ester on protonated ethyl acetoacetate (51JA3531). A detailed synthesis of the pyran-5-carboxylic acid is available <630SC(4)549). 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

Synthetic Applications of Dealkoxycarbonylation of Malonate Esters, p-Keto Esters, a-Cyano Esters and Related Compounds in Dipolar Aprotic Solvents. Krapcho, A. Synthesis, 1962, 805, 893,... 

Krapcho, A. P. Synthetic applications of dealkoxycarbonylations of malonate esters, 3-keto esters, a-cyano esters and related compounds in dipolar aprotic media. Part II. Synthesis 1982, 893-914. 

Cox, M. T., Howarth, T. T., Jackson, A. H., Kenner, G. W. (1974a). Pyrroles and related compounds. Part XXVUI. (3-Keto-esters in the porphyrin series, J. Chem. Soc., Perkin Trans.l, p. 512. 

In addition to the several examples mentioned above, the syntheses of the following natural products and related compounds via Pd-catalyzed allylation have been reported, and they are summarized in Sect, in.2.18 ( )-neomanoalide, vineomycinone B2 methyl ester, cephalosporin analogs,hennoxazole stypoldione, 6-keto-prostanoids, constanolactones A and lurlene, lurlenic acid, and lurlennlJ " ... 

A range of tetrahydro-9f/-xanthen-9-ones arise from photo-induced C-O bond formation of 2-methoxyaryl 2-chlorocyclohex-l-enyl ketones and related compounds (14CC5254). Some examples of tetrahydro-9ff-xanthen-9-ones were obtained as diastereomeric mixtures of cis- and traws-isomers through a 4-DMAP-mediated tandem addition reaction of l-(2-hydroxyaryl)alkynones bearing an aldehyde function (Scheme 76) (140L1642). A Robinson annulation of a P-keto ester and methyl vinyl ketone mediated by tin(lV) chloride afforded a tetrahydro-9H-xanthen-9-one-l-carboxylic acid-type compound (14JOC10689). 

The Simonis chromone synthesis is the reaction of a phenol la-c with a P-keto ester 2 using an appropriate acid promoter to generate a chromone or benzo-y-pyrone 3 (also called a benzo-l,4-pyrone). While compound 3 is actually a chromenone, for this article, whether the double bond is present or not, the system will be characterized as a chromone. The condensation is related to the Pechmann-Duisberg reaction, which yields coumarins from the condensation of a phenol with a P-keto ester and like its relative, the reaction conditions require the loss of water from the ketone moiety and alcohol from the ester moiety. 

In biosynthesis, pyruvic acid, a representative 1,2-dicarbonyl compound, is used as a key C2 and C3 donor unit. The use of related 1,2-dicarbonyl compounds, such as a-keto esters and ct-keto anilides, as nucleophiles in catalytic asymmetric synthesis, however, is rather limited due to their high reactivity as electrophiles. Chemoselective activation of 1,2-dicarbonyl compounds as nucleophiles is required to avoid undesired self-condensation reactions of 1,2-dicarbonyl compounds. Applications of 1,2-dicarbonyl compounds as donors in asymmetric Michael reactions remained unsolved until a recent report by Sodeoka et oL Indeed, these authors have described the first example of a diastereo- and... 

Transition metal-catalysed methods for carbenoid insertion into C-H bonds remain well documented. The asymmetric intramolecular Cu(II)-catalysed C-H insertion reactions of (i) a-diazo-/ -keto esters and phosphonates and (ii) a-diazo sulfones have been described. One can note that the optimal reaction conditions have been found to be quite similar regardless of the nature of the carbenoid precursor the best conditions featured CUCI2 as Cu(II)-source, bis(oxazoline) (68) as chiral ligand and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (i.e., NaBARF) as additive. Under the so-optimized reaction conditions, each of these carbenoid sources have been eonverted into five-membered cyclopentanone-based derivatives (69), whereas a-sulfonyl diazo esters (70) have led to six-membered cyclic compounds (71), thus featuring a distinct but well-known selectivity. In a related work, the asymmetric C-H insertion cyclization of (70) to (71) has also been achieved under Rh(II)-catalysis, using a combination of Rh2(5-pttl)4 (72) as chiral catalyst and menthyl ester as chiral auxiliary. As already mentioned in the previous section, allene-containing substrates (49) have been shown to undergo an intramolecular C-H insertion process under Rh(II)-catalysis. ... 

PhCOCl very often gives a mixture of the O- and C-acylated products. To prepare the enol ester (kinetic conditions) a more reactive acylating agent such as Acetyl Chloride is generally used. Moreover, carboxylic acid anhydrides are generally preferred to acyl halides. Accordingly, PhCOCl is preferred to prepare 1,3-dicarbonyl compounds. Ketones (eq 10), esters (eq 11), and more commonly p-keto esters or related CH acidic compounds... 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

---