Carboxylate O-alkylation

The hydroxy group of ethyl 9-hydroxy-4-oxo-4//-pyrido[l,2-u]pyrimi-dine-3-carboxylate was O-alkylated with 2-chloromethyl-4-isopropyl-l,... 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

Carboxylic esters 1, having an O-alkyl group with a /3-hydrogen, can be cleaved thermally into the corresponding carboxylic acid 2 and an alkene 3. This reaction often is carried out in the gas phase generally the use of a solvent is not necessary. 

Scheme 7.102 Polymer-supported O-alkylation of carboxylic acids.

The group of Lindau has demonstrated the effective O-alkylation of carboxylic acids using a polymer-supported O-methylisourea reagent [123], Under conventional conditions, complete esterifications were observed only after refluxing for several hours in tetrahydrofuran, and the acidic work-up required limited the scope of applicable substituents. In contrast, employing microwave heating led to complete esterifications within 15-20 min, with only 2 equivalents of the polymer-bound... 

N, O-Diacylated or O-alkylated N-hydroxysulfonamides release nitroxyl (HNO) upon hydrolysis or metabolic dealkylation, as determined by gas chromatographic identification of nitrous oxide in the reaction headspace [27-29, 38]. Scheme 7.5 depicts the decomposition of a representative compound (7) to a C-acyl nitroso species that hydrolyzes to yield HNO. Either hydrolysis or metabolism removes the O-acyl or O-alkyl group to give an N-hydroxy species that rapidly decomposes to give a sulfinic acid and an acyl nitroso species. This C-acyl nitroso species (8) hydrolyzes to the carboxylic acid and HNO (Scheme 7.5). These compounds demonstrate the ability to relax smooth muscle preparations in vitro and also inhibit aldehyde dehydrogenase, similar to other HNO donors [27, 29]. 

The ability of quaternary ammonium halides to form weakly H-bonded complex ion-pairs with acids is well established, as illustrated by the stability of quaternary ammonium hydrogen difluoride and dihydrogen trifluorides [e.g. 60] and the extractability of halogen acids [61]. It has also been shown that weaker acids, such as hypochlorous acid, carboxylic acids, phenols, alcohols and hydrogen peroxide [61-64] also form complex ion-pairs. Such ion-pairs can often be beneficial in phase-transfer reactions, but the lipophilic nature of H-bonded complex ion-pairs with oxy acids, e.g. [Q+X HOAr] or [Q+X HO.CO.R], inhibits O-alkylation reactions necessitating the maintenance of the aqueous phase at pH > 7.0 with sodium or potassium carbonate to ensure effective formation of ethers or esterification [49,64]. 

A broad range of compounds can be O-alkylated with carbene complexes, including primary, secondary, and tertiary alcohols, phenols, enols, hemiaminals, hydroxylamines, carboxylic acids, dialkyl phosphates, etc. When either strongly acidic substrates [1214] and/or sensitive carbene precursors are used (e.g. aliphatic diazoalkanes [1215] or diazoketones) etherification can occur spontaneously without the need for any catalyst, or upon catalysis by Lewis acids [1216]. 

Treatment of aldehydes or ketones with acceptor-substituted carbene complexes leads to formation of enol ethers [1271-1274], oxiranes [1048], or 1,3-dioxolanes [989,1275] by O-alkylation of the carbonyl compound. Carboxylic acid derivatives... 

SYNTHESIS and CHARACTERIZATION of O-ALKYLATED EXTRACTS. Alkylation occurs when tetrabutylanunonium hydroxide is used to promote the reaction of the alkyl iodide with the coal in tetrahydrofuran.(14) The alkylation reaction occurs primarily on acidic oxygen functionalities such as phenolic hydroxyl and carboxylic acid groups, as shown below. 

For each alkylated extract, there was an absorption at 1700 cm which was absent in the untreated extract. This absorption may be attributed to esters that form from alkylation of carboxylic acids. This interpretation is consistent with the NMR analysis described below. For each O-alkylated extract, there was an increase in the intensity of the C-H absorption bands at 2800-3000 cm consistent with the introduction of aliphatic carbon. 

The 1-hydroxymethyl group of l-hydroxymethyl-7-oxo-l//,7//-pyrido [3,2,l-y]cinnoline-8-carboxylate (81) was O-alkylated by treatment with diethylaminosulfur trichloride and an alcohol in THE. The 4-hydroxy group of 4-hydroxy-7-oxo-l//,7//-pyrido[3,2,l-t7]cinnoline-8-carboxylate... 

In a communication by Tanimoto and coworkers, ketene O-alkyl O -trunethylsilyl acetals 49 provide either a-nitroso esters 50 or their oximes 51 on reaction with nitric oxide or isoamyl nitrite in the presence of titanium(IV) chloride (Scheme 29). These reactions seem to provide a relatively direct way to introduce a nitrogen substituent at the a-carbon atom of carboxylic esters. 

In 2003, Banerjee et al. designed an efficient photoremovable protecting group for the release of carboxylic acids based on similar p-elimination from photoenols (Scheme 14). They showed that o-alkyl acetophenone derivatives with various ester groups in the p-position release their ester moiety in high chemical yields. The authors proposed that the photorelease took place as shown in Scheme 14 but did not support the mechanism with transient spectroscopy. Formation of 21, which is expected to be the major product in the reaction, was not confirmed, and thus, the authors speculated that 21 undergoes polymerization to yield oligomers. 

Polymeric phosphonium salt-bound carboxylate, benzenesulphinate and phenoxide anions have been used in nucleophilic substitution reactions for the synthesis of carboxylic acid esters, sulphones and C/O alkylation of phenols from alkyl halides. The polymeric reagent seems to increase the nucleophilicity of the anions376 and the yields are higher than those for corresponding polymer phase-transfer catalysis (reaction 273). 

Three different strategies are generally used for the attachment of carboxylic acids to resins as benzyl esters (a) acylation of resin-bound benzyl alcohols [38-40], (b) O-alkylation of carboxylates by resin-bound benzylic halides [4143], or (c) O-alkylation of carboxylic acids under Mitsunobu conditions [44,45] (Figure 3.3). These reactions are treated in detail in Section 13.4. 

Entries 6 and 7 in Table 3.3 are additional linkers based on intramolecular nucleophilic cleavage. In Entry 6, it is an imidazole that efficiently catalyzes the saponification of the ester linkage, whereas in Entry 7 a hydroquinone is O-alkylated intramole-cularly, with the carboxylate acting as a leaving group. Esters of resin-bound (2-hydro-xyethyl)silanes have also been used as linkers, which can be cleaved by treatment with either TFA or fluoride ions (TBAF in THF [76]). 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Esters, which have no possible site of attachment, cannot be directly linked to supports, but may be generated upon cleavage from a support. This cleavage can be mediated by electrophiles, nucleophiles, or oxidants. Only a few examples have been reported of the preparation of esters by O-alkylation of carboxylates by resin-bound alkylating agents, such as sulfonic esters [369-372] or diazonium salts [373] (see also Section 3.13). 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

Hydroxylamines and hydrazines can be acylated on insoluble supports using the same type of acylating agent as is used for the acylation of amines [146-149]. Because of their higher nucleophilicity, hydroxylamines or hydrazines can be acylated more readily than amines, and unreactive acylating agents such as carboxylic esters can sometimes be successfully employed (Table 13.10). Polystyrene-bound O-alkyl hydroxamic acids can be N-alkylated by treatment with reactive alkyl halides and bases such as DBU (Entry 5, Table 13.10). 

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