Alkylation of p-ketoester

Keto esters represent interesting substrates that permit ready and various opportunities for further stmctural manipulation, but until 2002 only limited asymmetric a-alkylation procedures were developed [85]. In 2002, Dehmlow et al. [86] demonstrated the use of cinchonidinium bromide Ic in asymmetric a-alkylation of p-ketoester 24 when the corresponding benzylated product 29 (Scheme 8.11, entry 1) was obtained in excellent yield (97%), satisfying 46% ee. Better results in terms of enantioselectivity (up to 97% ee) were reported by Kim and co-workers [87], who showed the effectiveness of bulky cinchonine-derived catalysts IL in asymmetric a-alkylation of P-ketoesters(Scheme 8.11, entry 2). An asymmetric a-alkylation procedure with broad generahty in terms of the stmcture of P-ketoesters 25 and alkyl hahdes under PTC with C2-symmetric PTC L was developed by Maruoka and co-workers [88] (Scheme 8.11, entry 3). Further optimization led to the development of a reliable route for the asymmetric synthesis of not only a,a-dialkyl-P-hydroxy and p-amino esters, but also functionalized aza-cyclic a-amino esters [89], a-alkylated ketolactones [90], and functionalized a-benzoyloxy-P-ketoesters [91]. Shghtly changed catalyst XXV (Scheme 8.12) was also successfully used for the constmction of enantiomerically enriched various a-alkyl-a-fluoro-P-keto esters... 

In a systematic study, the highly enantioselective alkylation of P-ketoesters was achieved using boxmi-copper(II) catalysts. In particular, benzyhc and allylic... 

As illustrated in Scheme 72, Langer et al. were also able to generate 2-alkylidene tetrahydrofuran substrates from the alkylation of p-ketoesters with epibromo-hydrins (Scheme 72) [78], Hydrogenation gave 2,5-c/s-tetrahydrofuran 270 with relatively high diastereocontrol. 

Scheme 5-7. Double decarboxylative asymmetric alkylation of P-ketoesters. ...

The reaction is generally performed between 0 and 100 °C with the majority of the reactions being mn at reflux. Polar protic solvents such as methanol, ethanol, isopropanol, and water are commonly used as solvents. Addition of acid or use of acetic acid as solvent generally helps push sluggish reactions. The use of P-ketoesters as the dicarbonyl partner occasionally requires added base for cyclization to occur to form the pyrazolone. When using alkyl hydrazine salts, base may be required to deprotonate the hydrazine for the reaction to take place. 

The alternate use of the dianion of P-ketoester 22 did not improve the alkylation yield because subsequent saponification of alkylation product 23 epimerized C-2... 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

The base-catalyzed reaction of P-ketoesters such as ethyl acetoacetate (acetoacetic ester) (3.2) with the alkyl halide gives monosubstituted P-ketoesters. In a similar manner, on treatment with a base and alkyl halide, a disubstituted ethyl acetoacetate is formed. 

Asymmetric alkylation of P-keto carbonyl derivatives under phase-transfer conditions is a very convenient and useful way to construct a chiral quaternary carbon center. In 2002, Dehmlow and coworkers reported the asymmetric benzylation of the cyclic (3-ketoester, 2-(tert-butoxycarbonyl)cyclopentanone (70) in the presence of the cinchoninium PTC 72 in excellent chemical yield with 46% ee (Scheme 6.21) [46]. 

Several routes to this class of compounds have been reported, such as (a) crossed Claisen condensation reactions (50-53) (b) acylation of the anion derived from ethyl fluoroacetate (54) or self-condensation of the anion derived from ethyl bromofluoroacetate (55) (c) electrophilic fluorination of the anion of p-ketoesters (56,57) (d) acylation-hydrolysis of fluoroolefins (58) and (e) acylation of fluorine-containing ketene silyl acetals (Easdon, J.C., University of Iowa, unpublished data). The limitations associated with these methods and the success achieved in the alkylation-hydrolysis of a-fluoro phosphorus ylides prompted us to examine acylation-hydrolysis of these a-fluoro ylides as a general route to 2-fluoro-3-oxoesters. 

The asymmetric Michael addition of nonstabilised ketone enolates has proved difficult, with most success achieved using 1,3-dicarbonyls as donors. However, Shibasaki and coworkers have achieved high ees in the addition of a-hydroxyketones with both aromatic Michael acceptors such as (11.32) and also cyclic enones and alkyl vinyl ketones, using bifiinctional zinc catalysts prepared from linked BINOL (11.33). These catalysts are also effective in the asymmetric aldol reaction (see Section 7.1) and incorporate two zinc atoms, one of which activates the acceptor carbonyl group and the other forms a zinc enolate with the donor. In addition, catalysts of this type have been used to good effect in the addition of P-ketoesters to cyclic enones. 

Access to a 1,4-dicarbonyl substrate has been realised in several ways alkylation of imines with 2-alkoxy-allyl halides (equivalents of 2-haloketones), addition of P-ketoester anions to nitroalkenes, followed by Nef reaction, and rhodium-catalysed carbonylation of 2-substituted acrolein acetals are just three routes by which such precursors can be obtained. The dialdehyde (as a mono-acetal) necessary for a synthesis of diethyl furan-3,4-dicarboxylate was obtained by two successive Claisen condensations between diethyl succinate and ethyl formate. 

One variation of the 1,4-dihydropyridine synthesis uses acetylene derivatives in place of P-ketoesters. Chennant and Eisner reported on the reaction between 2 equiv of methyl propionate 182 with aromatic aldehydes such as 183 and ammonium acetate in acetic acid to produce a series of dihydropyridine derivatives 184 in good yield. Unfortunately, differentially substituted acetylene derivatives and alkyl or nitrosubstituted aromatic aldehydes gave little to no yield of the desired 1,4-diydropyridine derivatives under the reported conditions. However, this method remains the best way to prepare of 2,6-unsubsitituted 1,4-dihydropyridines. 

Base-catalyzed alkylation or arylation of p-ketoesters. Subsequent mild hydrolysis and decarboxylation yield substituted acetones. Alternately, treatment with concentrated base produces substituted esters ... 

In the reaction of P-ketoesters with a-haloketones, the possible competition between C-alkylation (followed by reaction of the Paal-Knorr type) and aldol addition (followed by reaction of the Feist-Benary type) can result in mixtures of isomeric furans. Regioselec-tivity can, however, sometimes be controlled by the reaction conditions, as, for instance, in the interaction of chloroacetone with acetoacetate, leading to the furan-3-carboxylates 66/67 ... 

Langer and coworkers have synthesized a number of substituted tetrahydrofurans from alkylidene tetrahydrofurans which in turn were generated from an alkylation/cyclization sequence of p-ketoesters [76]. For example, alkylation of the dianion of p-ketoester 264 with l-bromo-2-chloroethane resulted in the synthesis of 2-alkylidene tetrahydrofuran 265 (Scheme 69). 

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

One of the most powerful strategies for asymmetric ring construction is to desymmelrize a preformed ring. Yasamusa Hamada of Chiba University in Japan has reported (J. Am. Chem. Soc. 2004, /26, 3690) that the inexpensive diaminophosphine oxide 2 nicely catalyzes the asymmetric alkylation of the cyclohexanone carboxylate 1 to give 3. Although no examples were given, this asymmetric alkylation would probably work as well with heterocyclic P-ketoesters. 

As described previously [63], P-ketoester 111 [Fig. (31)] was subjected to Baker s yeast reduction to afford the optically active P-hydroxyester 112 (60-80% yield). Dianion alkylation of 112 with (E)-3-methyl-4-(0-tert-butyldimehtylsilyl)-2-butene afforded the desired a-alkyl product 113 in 58-70% isolated yield. 

Asymmetric induction in intramolecular C-H insertion reactions was first reported by McKervey and co-workers [53], who used chiral Rh(II) prolinate 17a (Eq. 5.24). Although enantiocontrol was low, this report established the feasibility of the methodology and left open advances that were subsequently made by Ikegami and Hashimoto, who were able to convert a-diazo-p-ketoester 47 into cyclopentanone 48 with 18a (Eq. 5.25) with 32-76% ee, dependent on the substituent Z and the size of the ester alkyl group [54,116],... 

With BINAPO as ligand, the alkylation of dibenzoate 92 with p-ketoester 101 provides the mono-alkylated product 102 in modest ee (Scheme 8E.13) [65], Subsequently, a simultaneous allylation-Heck annulation reaction provided the pentacycle 103, which was further function-... 

Isopropyl anisole (171) was converted to bromide (172) by metalation, formylation and bromination. Alkylation with cyclopropyl ketoester produced (173) whose transformation to alcohol (174) was achieved by saponification, decarboxylation and reduction.. Its conversion to homoallylic bromide (175) was accomplished by the method of Julia et al. [56]. Alkylation of ethyl acetoacetate with bromide (175) furnished p-ketoester (176). It was subjected to cyclization with stannic chloride in dichloromethane. The resulting tricyclic alcohol provided the olefinic ester (177) by treatment with mesylchloride and triethylamine. Epoxidation followed by elimination led to the previously reported intermediate (146) whose conversion to triptolide (149) has already been described. 

---