Amines, acylation with esters

The most typical type of hydrolase-catalyzed stereoselective reactions under continuous-flow conditions is KR. Continuous-flow KRs were performed on racemic acids by direct esterification with alcohols [100-102, 108, 109] or on racemic amines by acylation with esters (Figure 9.7 and Table 9.5) [110-114]. However, the most frequent so far is the continuous-flow KR of racemic primary... 

The reaction of ammonia and amines with esters follows the same general mech anistic course as other nucleophilic acyl substitution reactions (Figure 20 6) A tetrahe dral intermediate is formed m the first stage of the process and dissociates m the second stage... 

Acylation. Aromatic amines react with acids, acid chlorides, anhydrides, and esters to form amides. In general, acid chlorides give the best yield of the pure product. The reaction with acetic, propionic, butanoic, or benzoic acid can be catalyzed with phosphoms oxychloride or trichloride. 

Unprotected racemic amines can be resolved by enantioselective acylations with activated esters (110,111). This approach is based on the discovery that enantioselectivity of some enzymes strongly depends on the nature of the reaction medium. For example, the enantioselectivity factor (defined as the ratio of the initial rates for (3)- and (R)-isomers) of subtiHsin in the acylation of CX-methyl-ben zyl amine with tritiuoroethyl butyrate varies from 0.95 in toluene to 7.7 in 3-methyl-3-pentanol (110). The latter solvent has been used for enantioselective resolutions of a number of racemic amines (110). 

This sequence is equally applicable to keto esters. Thus, condensation of guanidine with ethyl acetoacetate gives the pyrimidone, 134. Elaboration as above gives the pyrimidine, IJ5 acylation with the sulfonyl chloride (88) followed by hydrolysis yields sulfamerazine (107). Reaction of guanidine with beta dicarbonyl compounds gives the pyrimidine directly. Condensation of the base with acetonyl acetone affords the starting amine for sulfadimidine (108). ... 

Preparation of the key tropine is achieved by any one of several variations on the method first developed by Robinson, which involves reaction of a primary amine with dihydroxyacetone and glyoxal. Reduction of the carbonyl group in the product (86) followed by acylation affords the aminoester (88). Transesterification with ester aldehyde 89... 

A-Acylation can be preformed with esters of A-hydroxysuccinimide A-succinimidyl 4-nitrophenylacetate (95) was used to derivatize the primary and secondary amines conferring bad odor to water253. Derivatization of amines with the ester of A-hydroxysuccinimide with A-(quinolin-6-yl)carbamic acid (96) gives excellent yields of... 

Another important part of Organic 11 is carbonyl chemistry. We look at the basics of the carbonyls in Chapter 9. It s like a family reunion where 1 (John, one of your authors) grew up in North Carolina — everybody is related. You meet aldehydes, ketones, carboxylic acids, acyl chlorides, esters, cimides, and on and on. It s a quick peek, because later we go back and examine many of these in detail. For example, in Chapter 10 you study aldehydes and ketones, along with some of the amines, while in Chapter 11 we introduce you to other carbonyl compounds, enols and enolates, along with nitroalkanes and nitriles. 

The classes of compounds which are conveniently considered together as derivatives of carboxylic acids include the carboxylic acid anhydrides, acyl chlorides, esters, and amides. In the case of simple aliphatic and aromatic acids, synthetic transformations among these derivatives are usually a straightforward matter involving such fundamental reactions as ester saponification, formation of acyl chlorides, and the reactions of amines with acid anhydrides or acyl chlorides ... 

In continuation of our investigations on asymmetric nucleophilic acylations with lithiated a-aminonitriles [40], we envisaged the asymmetric synthesis of 3-substituted 5-amino-4-oxo esters A, bearing both a-amino ketone and 5-amino ester functionalities (Scheme 1.1.14) [41]. Since a-amino ketones are precursors of chiral p-amino alcohols [42, 43] and chiral amines [43], their asymmetric synthesis has the potential to provide valuable intermediates for the synthesis of biologically active compounds, including peptidomimetics [44]. The retrosynthetic analysis of A leads to the a-aminoacyl carbanion B and p-ester carbocation... 

If an amine P-NH2 is used in the aqueous solution, one obtains RCONHP instead of RCOOH. Rates of cleavage of three acyl nitrophenyl esters were followed by the appearance of p-nitrophenolate ion as reflected by increased absorbances at 400 nm. The reaction was carried out at pH 9.0, in 0.02 M tris(hydroxymethyl)aminomethane buffer, at 25°C. Rate constants were determined from measurements under pseudo-first-order conditions, with the residue molarity of primary amine present in approximately tenfold excess. First-order rate graphs were linear for at least 80% of the reaction. With nitrophenyl acetate and nitrophenyl caproate, the initial ester concentration was 6.66xlO 5M. With nitrophenyl laur-ate at this concentration, aminolysis by polymer was too fast to follow and, therefore, both substrate and amine were diluted tenfold for rate measurements. 

With nonacylated polyethylenimines (Table II) the rate constant is increased by a factor of about 4 over that of propylamine. This small enhancement may be due merely to the fact that a greater fraction of primary amine groups in the polymer are in the basic, NH2 state. With these polyethylenimines, as with propylamine, k drops with increasing length of the hydrocarbon chain of the acyl nitrophenyl ester. 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

Other Carboxylic Esters. Selective 2-0-acylation of sucrose has been achieved by way of the 2-oxyanion compound. Treatment of sucrose in DMF with 3-lauryl-, 3-stearyl-, 3-hydrocinnamoyl-, and 3-(4-phenylbutyryl)-thiazolidine-2-thione derivatives and sodium hydride produced the corresponding 2-0-acyl derivatives in good yield (69). Syntheses of 6-O-acylsucroses were also achieved by acylation with 3-acylthiazolidine-2-thione and 3-acyl-5-methyl-1,3,4-thiadiazole-2(3ff)-thione derivatives in the presence of sodium hydride in DMF, followed by acyl migration using l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or aqueous triethyl amine. 6-0-Acylsucroses were obtained directly when onlyDBU was used (70). 

Friedel-Crafts acylation with nitriles and HC1 is called the Hoesch or the Houben-Hoesch reaction,354 In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds, e.g., pyrrole, but it can be extended to aromatic amines by the use of BCly.355 Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones354 but are attacked at the oxygen to produce imino esters. 

BrOP). These active esters react smoothly with amines at room temperature (reaction 9).42 Similarly, supported oximino esters 2743 and hydroxamic esters 2844 undergo facile acyl transfer reactions with amines at room temperature (reaction 10). The spent activating agent can be regenerated many times (by acylation with the appropriate acid chloride) without appreciable loss in activity. 

Alkylation or acylation of ketones, sulfides, and amines. This reagent generally reacts with alcohols or carboxylic acids to form 2,2,2-trifluoroethyl ethers or esters in satisfactory yields, except in the case of alcohols prone to dehydration. The reaction of these ethers provides a simple synthesis of unsymmctrical sulfides (equation I). A similar reaction can be used for preparation of secondary amines or amides (equation II). Enolatc anions (generated from silyl cnol ethers with KF) can be alkylated or acylated with a or b (equation III). Use of Grignard reagents in this type of coupling results in mediocre yields. 

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