Pivalic anhydride, acylation

Bismuth(III) triflate is also a powerful acylation catalyst that catalyzes reactions with acetic anhydride and other less reactive anhydrides such as benzoic and pivalic anhydrides.113 Good results are achieved with tertiary and hindered secondary alcohols, as well as with alcohols containing acid- and base-sensitive functional groups. 

Steric effects were evaluated by a study of the DMAP-catalysed acylation of 1 y, 2y and 3y alcohols by acetic, propionic, isobutyric, isovaleric, and pivalic anhydrides in CH2C12 at 20 °C. In all cases the reaction kinetics could be described by rate laws containing a DMAP-catalysed term and an uncatalysed (background) term. Steric effects were evident in both reactions, but were generally greater for the DMAP-catalysed reaction. For example, the uncatalysed reactions between cyclohexanol and acetic and pivalic anhydrides differed about 500-fold, but for the corresponding DMAP-catalysed reactions the factor was 8000-fold. The implications of these findings for the kinetic resolution of alcohols were discussed.32... 

Hollander and co-workers [303—305] dealt with the problem in detail and developed a method for the isolation of hormones from blood, using Bio-Rad AG 50W-X2 (100—120 mesh) ion-exchange resin. Acylation with pivalic anhydride—methanol—triethylamine (20 1 1) was performed at 70°C for 10 min. The derivatives were purified with the aid of Amberlite IR-45 resin and benzene as a solvent. The dry residue was dissolved in 100 jul of benzene and 5 /il were injected directly on to a 60 cm X 4 mm I.D. column packed with 5% OV-1 on Chromosorb W HP after an isothermal period at 220°C for 12 min, the temperature was increased at 3°C/min up to 300°C. Calibration standards were injected immediately after the sample. Almost identical results were obtained for T3 by GC and radioimmunoassay [304], Other workers [306] applied the same procedure to the seeds and analysed pivalyl methyl esters of T3 and T4 on an 81 cm column packed with 3% of Dexsil on Chromosorb W HP at 305°C. 

To prevent interference by ChiroCLEC, the acyl carrier intended for phosphine activation (the mixed mesitoate anhydride 212) was placed on an insoluble solid support where it can be accessed by the soluble phosphine, but not by the insoluble ChiroCLEC. Under three phase conditions, interference was prevented because the phosphine does not activate vinyl pivalate, the acyl donor intended for activation by ChiroCLEC in the form of an activated ester 214 nor does the activated acylphosphonium species 213 come into contact with the ChiroCLEC. Potential destruction of the lipase catalyst is thereby avoided, and the enantio-complementary activated intermediates convert the racemic alcohol R,S)-7 into the solid phase-bound ester 215 and the soluble pivalate 216 with excellent enantioselectivity. This is a proof-of-concept experiment that demonstrates the most difficult application, the case where two similar catalytic reactions are conducted in parallel. Furthermore, the experiment demonstrates PKR with the incorporation of achiral subunits to achieve enantiodivergence, and achieves product separation by simple filtration. 

Aryl- and alkyl-carboxylic dihalophosphoric anhydrides acylate activated arenes without the need for a conventional Friedel-Crafts catalyst. The anhydrides are prepared in situ, and the low temperatures required (20 C) allow reasonable yields of ketones to be obtained from mixed anhydrides of low stability, for example those derived from acetic and pivalic acids [equation (8)]. 

Obtained by electrochemical acylation of 2-methoxy-naphihalene with pivalic anhydride in methylene chloride in the presence of LiClO at 35° (22%) [7841]. 

The reaction proceeds via the formation of a first chiral zwitterionic intermediate from pivalic anhydride and the amidine-based catalyst. A mixed anhydride is then generated in the presence of the racemic carboxylic acid and activated by the chiral acyl-transfer catalyst to form the second zwitterionic intermediate. The latter species selectively reacts with a nucleophilic alcohol to afford the desired enantioenriched carboxylic ester (Scheme 41.10). 

A potential liability associated with such reductive hydroacylations resides in the fact that only one acyl residue of the symmetric anhydride is incorporated into the coupling product. For more precious carboxylic acids, selective acyl transfer from mixed anhydrides is possible. Mixed anhydrides derived from pivalic acid are especially convenient, as they may be isolated chromato-graphically in most cases. In practice, mixed anhydrides of this type enable completely branch-selective hydroacylation with selective delivery of the aromatic and a,()-unsalurated acyl donors (Scheme 19). 

Scheme 19 Selective acyl transfer in reductive hydroacylations involving mixed carboxylic anhydrides derived from pivalic acid...

The Z-protected derivative, again prepared by standard methods using benzyl chloroformate,t208 may serve in the case of racemic pipecolic acid for resolution into the pure enantiomers by fractional crystallization with L-tyrosine hydrazide/208 Acylation with N-protected pipecolic acid or of pipecolyl peptides is performed by standard procedures via the active ester methods, e.g. A-hydroxysuccinimide ester/121 by the mixed anhydride method, e.g. with isobutyl chloro-formate 95-114 or pivalic acid chloride/121 as well as by DCC/HOBt/118 In the synthesis on solid support, longer coupling times are required when compared to N-protected proline.1[235 ... 

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

The DBU salt of 7-amino-3-(5-methyl-l,3,4-thiadiazol-2-yl-thiomethyl)-3-cephen-4-carboxylic acid (316) in dichloromethane was acylated with the mixed anhydride of tetrazolylacetic acid and pivalic acid or with tetrazolylace-tic anhydride to afford 317 (82EUP53077 82MIP497076). 

An improvement resulting in a decreased amount of the second acylation product is the introduction of mixed anhydrides with a-branched carboxylic acids like isovaleric and pivalic acid, due to deactivating electronic and steric effects. 

In the example below, one enantiomer of compound is acylated by a lipase and the other by a phosphine-catalysed process.10,33 We want the lipase to catalyse the reaction between vinyl pivalate 58 and the R-alcohol, and the phosphine to catalyse the acylation of the S-alcohol using the polymer-bound anhydride 60. But, the lipase must not use the polymer-bound anhydride or the wrong enantiomer of alcohol will end up polymer-bound. Similarly, the phosphine must not react with the vinyl pivalate. Fortunately, the phosphine does not react with the vinyl pivalate and the lipase, which is insoluble, cannot interact with the polymer bound material. Also, the lipase will be kept away from the potentially damaging F-acyIphosphon iurn intermediates. The conditions are described as a Three-Phase System . The three phases are the solution phase and the two separate insoluble phases of the polymer bound anhydride and the cross-linked lipase. 

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