Activated carboxylic acid derivatives

The cinnamyl ester can be prepared from an activated carboxylic acid derivative and cinnamyl alcohol it is cleaved under nearly neutral conditions [Hg(OAc)2, MeOH, 23°, 2-4 h KSCN, H2O, 23°, 12-16 h, 90% yield]. 

The cinnamyl ester can be prepared from an activated carboxylic acid derivative and cinnamyl alcohol or by transesterification with cinnamyl alcohol in the presence of the H-Beta Zeolite (toluene, reflux, 8 h, 59-96% yield). It is cleaved under nearly neutral conditions [Hg(OAc)2, MeOH, 23°, 2-A h KSCN, H2O, 23°, 12-16 h, 90% yield]or by treatment with Sulfated-Sn02, toluene, anisole, reflux. The latter conditions also cleave crotyl and prenyl esters. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

As noted in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.5 dealt with two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There is also the acid-catalyzed reaction of carboxylic acids with alcohols, which is called the Fischer esterification. 

The best yields are obtained when the ketene has an electronegative substituent, such as halogen. Simple ketenes are not very stable and must usually be generated in situ. The most common method for generating ketenes for synthesis is by dehydrohalo-genation of acyl chlorides. This is usually done with an amine such as triethylamine.167 Other activated carboxylic acid derivatives, such as acyloxypyridinium ions, have also been used as ketene precursors.168 Ketene itself and certain alkyl derivatives can be generated by pyrolysis of carboxylic anhydrides.169... 

The next step is an unusual approach to making an ester via an Sn2 reaction. We usually make esters by the reaction of alcohols with activated carboxylic acid derivatives like acyl chlorides, or anhydrides as we have just seen. We do not particularly want to have to convert the carboxylic acid (X) into a more reactive... 

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

Accordingly, if one wants to react a nucleophile and carboxylic acid derivative to produce a carbonyl compound in a chemoselective fashion via the mechanism of Figure 6.2, then one should use acid chlorides or comparably strongly activated carboxylic acid derivatives. In addition, the reaction must be carried out with the weakest possible nucleophile because only... 

Accordingly, if one wants to react a nucleophile and carboxylic acid derivative to produce a carbonyl compound in a chemoselective fashion according to the mechanism of Figure 6.2, then one best employs carboxylic acid chlorides or comparably strongly activated carboxylic acid derivatives. In addition, the respective reaction must be carried out with the weakest possible nucleophile because only such a nucleophile reacts considerably faster with the activated carboxylic add derivative than with the product carbonyl compound (see above). The nucleophile must react considerably faster with the carboxylic acid derivative because at 95% conversion there is almost twenty times more carbonyl compound present than carboxylic acid derivative, but even at this stage the carboxylic acid derivative must be the preferred reaction partner of the nucleophile. 

Azole approach. The isoxazole ring can be regarded as analogous to the phenyl ring in the synthesis of quinazolines. One method is to react a vicinal aminocarboxamide with an activated carboxylic acid derivative to form the fused pyrimidine the isoxazole (50) is reacted in this manner (67T687). Sometimes it is advantageous to carry out this type of reaction in two steps, such as in the reaction via the 5-ethoxymethyleneamino intermediate (51) (64JOC2116). 

This procedure offers a convenient method for the esterification of carboxylic acids with alcohols2 and thiols2 under mild conditions. Its success depends on the high efficiency of 4-dialkylaminopyridines as nucleophilic catalysts 1n group transfer reactions. The esterification proceeds without the need of a preformed, activated carboxylic acid derivative, at room temperature, under nonacidic, mildly basic conditions. In addition to dichloromethane other aprotic solvents of comparable polarity such as diethyl ether, tetrahydrofuran, and acetonitrile can be used. The reaction can be applied to a wide variety of acids and alcohols, including polyols,2 6 a-hydroxycarboxylic acid esters,7 and even very acid labile... 

It is a novel finding that in special cases the alcohols and their derivatives, obtained by reduction of the corresponding active carboxylic acid derivatives,also possess antihyperlipaemic activity. These qualities were found with all the compounds listed in Table 6. Compounds 59 and 60 deserve particular mention as their activities are by far superior to clofibrate and equal those of the corresponding acid HCG-004 5. There exists some indication that this is an intrinsic effect of the compounds and not the effect of the acid 5 produced by biotransformation. This finding is sufficiently important to deserve more detailed investigation. 

S)-4-(l-Methylethyl)-5,5-diphenyl-2-oxazolidinone (3), whose preparation is described here, has several advantages over Evans original auxiliaries i) Derivatives of 3 are more likely to crystallize. In many cases the separation and purification of diastereoisomers can be achieved by simple recrystallization rather than by expensive and time-consuming chromatography, ii) Acylation of 3 can be carried out at 0°C (instead of-78°C for 4 and 5) by deprotonation with BuLi, followed by treatment with an activated carboxylic acid derivative, iii) Lithium enolates of N-acyl derivatives of 3 can be obtained directly by treatment with BuLi at -78°C, in comparison to 4 and 5 when the more expensive... 

Recent trend in biosensor manufacturing is to use synthetic procedures to incorporate a label indicative of a change in a physicochemical property upon binding to biomolecule. An example is the preparation of a novel, fluorescently active, carboxylic acid derivative of 2-pyridylazo compounds (PAR) [186]. 

An elegant reconstruction of monensin from two chromic acid degradation products serves as an excellent example of the generality of alkynide addition to activated carboxylic acid derivatives. The al-kynide (59) was prepared in eight steps from one degradation product and was then sequentially deprotonated with n-butyllithium and treated with magnesium bromide. The resultant magnesium salt... 

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

Thus for a leaving group of piT = 0, imidazole is more reactive than hydroxide by three powers of 10. This explains why nitrogen nucleophiles are considerably more reactive than hydroxide towards activated carboxylic acid derivatives, such as acid chlorides (Johnson et al., 1966). The leaving group will modify the free energy correlations obtained in Fig. 16. 

Ammonia and amines react with partially or fully activated carboxylic acid derivatives (acylating reagents) like acid anhydrides, acid halides, ammonium salts of monoesters, monoamides with heating, diesters under basic conditions and dinitriles after partial hydrolysis. ... 

In most cases these C,N2 fragments are prepared by reaction of activated carboxylic acid derivatives (C, fragment), such as dithiocarboxylates 2, thioesters 3. nitriles 5, imidates 6, amidines 7, thioamides 8, selenoamides 9, selenoesters 11, orthocarboxylates 14, with hydrazine (N2 fragment) and are transformed to l,4-dihydro-l,2,4,5-tetrazines 17 without isolation. Therefore, these syntheses are treated as a (2 + 1 +2+1) fragment method. 

The ester-amine reaction is slow and requires long reaction times (see Chapter IV). Many active carboxylic acid derivatives such as the azides, p-nitrophenyl esters, and thiazolidine-2-thiones as well as carboxylic acid activators, such as dicyclohexylcarbodimide (DCCI), have been used to improve this reaction (see Chapter IV) (Kimura et al., 1989a, 1989b Krakowiak et al., 1989, 1990a Nagao et al., 1980, 1981 Uoto et al., 1990). These cyclization reactions seldom need high-dilution conditions. Even though ex-... 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

Amidation, the formation of amides. Amino acid and peptide amides are synthesized by reaction of the appropriate esters or activated carboxylic acid derivatives with ammonia. Amidation of bioactive peptides is performed using the bifunctional enzyme peptidylglycine a-amidating monooxygenase (PAM) by N-oxidative cleavage of a glycine-extended precursor [S. T. Prigge et al.. Science 1997, 278, 1300]. 

Direct decarboxylations to alkanes are accomplished on activated carboxylic acid derivatives either thermally or photochemically in the presence of a hydrogen donor. One of the early reagents used for this purpose was lead tetraacetate While primary and secondary carboxylic acids could be readily decarboxylated with moderate success with this reagent, results with tertiary carboxylic acids were unsatisfactory. 

This Learning Group Problem focuses on the chemical synthesis of small proteins, called peptides. The essence of peptide or protein synthesis is formation of the amide functional group by reaction of an activated carboxylic acid derivative with an amine. 

The metallocarbene intermediates are most often formed from thermal, photolytic, or metal-catalyzed deconposition of diazocarbonyl compounds, with concomitant loss of dinitrogen. Under transition metal catalysis, the initially formed species is a metallocarbene rather than a free carbene, and this is usually desirable due to the moderated reactivity (and, hence, fewer undesired side reactions) of the metal-complexed carbene. The two most common methods for introduction of the diazo group are acylation of diazoalkanes with suitably activated carboxylic acid derivatives and diazo transfer reactions in the case of more acidic active methylene substrates fScheme 16.12T... 

The introduction of a diphosphine ligand to the active site serine of a lipase via a phosphonate inhibitor was reported by Reetz et al. However, the linkage was found to be hydrolytically unstable [72]. Kamer and coworkers reported the covalent anchoring of phosphine ligands using another route. They modified the native Cys of photoactive yellow protein (PYP) using 1,1 -carbonyldiiniidazole (CDI)-activated carboxylic acid derivatives of mono- and diphosphanes (19 and 20 in Figure 10.13) [73,74]. Addition of [Pd(allyl)Cl]2 afforded metalloenzymes with allylic amination activity. Several Rh(I)... 

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