Claisen-type esters

Second, methyl ester 61 is subjected to crossed ester condensation with methyl formate and triphenyl methyl sodium 64 as base.5,6 Ester 61 is deprotonated and the resulting anion 65 adds to methyl formate. The anion formed is stabilized by loss of methanolate yielding the desired product as its conjugated base. As a Claisen type ester condensation, all steps but the last are reversible since the resulting aldehydo ester 67 is more acidic than methanol therefore the last deprotonation step occurs irreversibly. The use of LDA19 as a base is also possible for this transformation. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Claisen-type rearrangements of ester enolates, ketene acetals, and silyl ketene acetals... 

To participate in this sort of reaction, the carboxylic acid derivative acting as nucleophile must have a-hydrogens in order to generate an enolate anion. In practice, esters are most commonly employed in Claisen-type reactions. 

Stereoselective Claisen-type [3,3] sigmatropic rearrangements of propynyl vinyl ethers, which are intermediates in the reaction of propynyl alcohols with aldehydes or ortho esters leading to a-allenic aldehydes or esters, have been reported15,16. 

There are two main methods for the synthesis of monothio-/i-diketones, both affording yields in excess of 50%. The first method involves the passage of H,S through a dilute solution of the /5-diketone in ethanol, followed by the rapid passage of HC1 at — 70 °C the conditions are critical.184,183 The second method involves the Claisen-type condensation of ketones with thionic esters, RC(S)OMe, or dithionic esters, RC(S)SMe, in ether in the presence of sodamide.186-188 This method has the advantage that both isomers (46) and (47) can be prepared, whereas the first method yields only isomer (46) when R has a greater electron-withdrawing power than R. 

The most common group G is an ester function (aldiougli many odier groups have been employed as well). The starting /f-ketoester, which can be prepared easily by a Claisen-type reaction of an ester enolate and an acid chloride, has a... 

If both ester groups are in the same molecule and are connected by a chain, then a Claisen-type reaction between the a position of one ester and the carbonyl... 

Trilithiated acetoacetanilides can undergo a Claisen-type condensation with benzoate esters to form initially pyran-4-ones, which can then undergo complex acid promoted rearangements to afford 277-pyran-2-ones (Scheme 157) <2004CJC659>. 

The Claisen rearrangement has been instrumental in the synthesis of a number of natural products.279-289 Many useful derivatives have been prepared using the Claisen-type rearrangement including enol ethers,290 amides,291-293 esters and orthoesters,294-296 acids,297-298 oxazolines,299 ketene acetals,300-301 and thioesters.302 Many of these variants use a cyclic primer to control relative and absolute stereochemistry. The Claisen and oxy Cope provide the best candidates for scale up as a result of the irreversible nature of these reactions. 

Enzymes called polyketide synthases catalyze a series of Claisen-type reactions to generate many useful natural products, such as the antibiotic erythromycin (page 1025). These enzymes use thioesters instead of the oxygen esters. 

Note Reactions of the mixed-Claisen type afford a convenient route from pyrazinecarboxylic esters to some pyrazine ketones. 

In the presence of a strong base, e.g., lactam anions, the imide groups containing at least one ct-hydrogen undergo a Claisen type condensation analogous to the condensation of esters or ketones [121, 125], viz. 

A feature distinguishing Reformatsky enolates from base-generated enolates is that zinc enolates add to highly hindered as well as to easily enolizable ketones, such as cyclopentanones, thus avoiding formation of condensation products. Moreover, there is no danger of a Claisen-type self-condensation since zinc-enolates do not react with esters but react readily with aldehydes and ketones to furnish aldol-type products. 

Transition metal catalysis of the Michael reaction of 1,3-dicarbonyl compounds with acceptor activated alkenes has been known since the early 1980 s 2>3 It is a valuable alternative to the classic base catalysis of the reaction. Because of the mild and neutral conditions, the chemoselectivity of these reactions is superior to that provided by base catalysis, since the latter suffers from various unwanted side or subsequent reactions, such as aldol cyclizations, ester solvolyses or retro-Claisen type decompositions. A number of transition metal and lanthanide compounds have been reported to catalyze the Michael reaction, but FeCb 6 H20 is one of the most efficient systems to date. A number of 3-diketones or p-oxo esters and MVK are cleanly converted to the corresponding Michael reaction products within a few hours at room... 

A final example in this category involves the enamines produced by addition of an a-amino acid ester to dimethyl acetylenedicarboxylate leading to 3-hydroxypyrroles by Claisen-type ring closure. ... 

The intermolecular variant of the O-H insertion reaction gets stuck at the stage of the initial adduct 8. We envisioned that if R1 = allyl, coordination of the double bond to the metal would initiate a Claisen-type process to form the jr-allylruthenium complex 9, whose reductive elimination would form the allyl ketone starting from terminal alkynes and allyl alcohols (Equation 1.10). Gratifyingly, this prediction was fully realized as shown in Equation 1.11 [13]. A tertiary ester does not undergo elimination under these reaction conditions (Equation 1.12). Dihydroxylationofthe double bond and subsequent acidification effect cyclodehydration to form furans in two overall steps. Subsequent elimination of the elements of acetic acid completes a synthesis of rosefuran 10, one of the most prized fragrances [14]. 

Once deprotonated by a strong base, the carbanion will react with electrophilic carbon in an alkyl halide or sulfonate ester to elongate the side-chain alkyl group, or with carbonyl carbon in an aldol or Claisen type reaction. The aldol readily loses water to form an alkenyl derivative, where the double bond is conjugated with the pyrimidine ring. Selective reactivity is demonstrated by the reaction of 2,5-dimethylpyrimidine with benzaldehyde, where only the electrophilic 2-methyl group reacts, to yield the 2-styryl derivative (389) (Scheme 64). Several examples are known . 

Enzyme-catalyzed Claisen-type condensations are formally similar to enzyme-catalyzed aldol condensations, with the exception that the nucleophilic substrate is an ester or thioester [Eq. (35)] ... 

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