Oxazoles acid chlorides

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

The order of events In this synthesis can be varied - one possibility is to keep the nitrile until after the oxazole has been made. The acid chloride is used for the cyclisation. 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from aryl-substituted tosylmethyl isocyanides and aldehydes . Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>. 

The reaction of acylsilanes with acid chlorides in the presence of A1C13 leads to furans (Table 9.41) [45]. In these reactions an acyl cation initiates the addition with ensuing silyl migration yielding an intermediate vinyl cation. Attack of the carbonyl oxygen followed by proton loss affords the observed products (Scheme 9.16). An analogous reaction with nitrosyl fluoroborate provides a route to oxazoles (Table 9.42) [65]. The nitrosyl cation serves as the electrophile in this application. 

Aromatic acid chlorides and 2-(triphenylphosphoranylidenamino)cinna-mates (127) give rise to l,3-oxazol-5-ones (129), as shown in Scheme 51. After an intermolecular aza-Wittig reaction with 127, the ethoxy O attacks... 

This reaction is a modification of Schollkopf s oxazole synthesis2 from acid chlorides and a-metalated isonilrilcs (equation II). 

Azirines react with carboxylic acid chlorides in benzene to give the Ar-benzoyl-2-chloroaziridines (133) in good yield.23,60 These aziridines are unstable and are converted in polar solvents or by heating into a mixture of the oxazole and dichloroamide (134). 

Sato et al. observed that the reaction of 2-phenyl-1-azirine with acid chlorides and anhydrides in the presence of triethylamine gives the oxazole directly.57 They have reported that azirines also react with carboxylic anhydrides to give oxazoles (136).57 Aziridine (135) is suggested as a likely intermediate in the reaction of acetic anhydride with azirine (42a), since carrying out the reaction at lower temperature and for a shorter reaction time gave a compound to which they assigned structure 135. 

Similar tautomerisation of the enol group gives an actual intermediate 3.13, and disconnection of the amide linkage reveals aminoketone 3.15 and an acylating species 3.14 such as an acid chloride. The forward process, cyclocondensation of amides 3.13 to yield oxazoles 3.10, is known as the Robinson-Gabriel synthesis. 

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 

Thermal dehydration of o- (acylamino)phenols is the method of choice for the preparation of benzoxazoles (equation 96) and other annulated oxazoles. 0,iV-Diacyl derivatives of o-aminophenols cyclize at lower temperatures than do the monoacyl compounds. The synthesis is often carried out by heating the aminophenol with the carboxylic acid or a derivative, such as the acid chloride, anhydride, an ester, amide or nitrile. The Beckmann rearrangement of oximes of o-hydroxybenzophenones leads directly to benzoxazoles (equation 97). 

Oxazoles by a Consecutive SCR of Acid Chlorides, Propargyl Amine, and Acid Chlorides... 

Liu et al. [16] synthesized twenty novel 2,4,5-trisubstituted oxazole derivatives (iv) containing heterocycle moiety and evaluated them for their antiproliferative activity. They showed that the microwave irradiation promoted the rapid 0,N-acylation-cyclodehydration cascade reaction of oximes and acid chlorides. 

Conditions for the efficient use of Fmoc-protected amino acid chlorides in stepwise peptide synthesis have been delineated. The acid chlorides are reasonably stable solids that are readily aminolyzed if a base is added to neutralize the hydrogen chloride liberated in the reaction. They form the corresponding oxazol-5(4//)-ones and undergo stereomutation if left in the presence of tertiary amines, however, amide formation without stereomutation can be obtained under appropriate conditions. The acid chlorides are advantageously applied to acylate weak nucleophiles and sterically hindered amino components, but their application may be limited by the lack of stability of tert-butyl-type side-chain protecting groups toward conditions of acid chloride preparation. 

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

An especially difficult acylation of the resin-bound, stericaUy hindered D-Piz(Z) derivative 3 (Scheme 3) was achieved by using silver cyanide as additive. While Fmoc-Ile-Cl itself led to a yield of only 50%, the efficiency was increased when the reaction was carried out in the presence of silver cyanide. The exact mechanism of silver cyanide catalysis is not clear, but it was shown that silver cyanide effects conversion of the acid chloride to the oxazol-5(4//)-one. Although the hydrogen cyanide formed during this process may catalyze the reaction of the oxazol-5(4//)-one, the results of separate hydrogen cyanide catalyzed coupling of preformed oxazol-5(4//)-one did not match exactly the silver cyanide catalyzed reaction of the acid chloride. ... 

The acid chloride method has been successfully used for the synthesis of depsipeptides by O-acylation of hydroxy acids. Although Fmoc amino acid chlorides were recommended for such reactions, and can be used for the introduction of the first amino acid onto hydroxy resins for SPPS, oxazol-5(4//)-one formation promoted by the presence of the required tertiary amine leads to relatively low yields compared to other activation methods such as those involving UNCA groups. ... 

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