Oxazole syntheses, additional

Additionally, this oxazole synthesis can also be used when the group at C4 is not likely to stabilize a negative charge, which lends further support to the elimination-addition sequence via intermediate 26 and its resonance structure 27. 

Schollkopf and Gerhart " pioneered the use of metallated isocyanides in organic synthesis. This section discusses the versatility of such intermediates for preparing monosubstituted and disubstituted oxazoles as well as the parent 1, itself. In addition, continuing advances in solid-phase synthesis have enhanced the use of tosylmethyl isocyanide (TosMIC) for oxazole synthesis several examples are presented. 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

According to route II, FGA d (addition of H2O at C-4) gives rise to hydroxyoxazoHne 26, which by disconnection e leads to the iminoester 28 and FGI f to the (a-acyloxy)carbonyl compound 29 and two sets of components, namely 31/33 (via disconnection h) and 34/carboxylate (via disconnection i). Alternatively, 28 can be disconnected according to g leading to components (a-halogeno)carbonyl compound 32/carboxamide. Thus, retrosynthesis proposes systems 27-29 to be suitable educts for approaches to oxazole synthesis [262]. 

In analogy to the van Leusen oxazole. synthesis (cf. p. 173), the anion of TosMIC adds to the imine function and the addition product 46 cyclizes to the imidazoline 47, which undergoes base-induced elimination of sulfinic acid producing the imidazole 45. 

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. ... 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

More recently, Williams has described the one pot synthesis of 2-substituted oxazoles 11 by the thermolysis of triazole amides 9 the reaction does not proceed photo-chemically.<92TL1033> Although the reaction does not involve addition to a nitrile, it is an interesting application of a diazo compound since the proposed zwitterionic intermediate 10 is a resonance form of a diazo imine, so formally the reaction may be thought of as a thermal decomposition of a diazo imine (Scheme 6). 

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. " ... 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

The formation of methyl-oxazole compounds was also described by Wang et al. [34] utilizing an analog of the keto-enol intermediate (22) described in Sect. 2.1.1, Scheme 2. Scheme 11 shows the synthesis of compound 57 which exhibits anti-tubulin activity of 7.7. iM [34], In addition, a range of oxazole COX-2 inhibitors has been reported by Hashimoto et al. [55] employing similar chemistry. 

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

Diketo oxime 43 (Scheme 27) find extensive use in organic synthesis. These compounds are useful building blocks in five-membered heterocyclic chemistry. These oximes can be used for the synthesis of pyrroles , thiazoles , oxazoles and pyrazoles . The diketo oxime 43 was synthesized in high yield by addition of an aqueous solution of sodium nitrite to a 0°C solution of 1-benzoylacetone 42 in AcOH . ... 

Synthesis of imidazoles, oxazoles and thiazoles by C-C bond formation or 1,3-dipolar addition 570... 

Huisgen s group488 have described a new synthesis of pyrroles (26) from oxazol-5-ones (azlactones) (25) with DMAD and MP. The pyrrole derivatives formed in situ from 2,4-dimethyl- and 4-benzyl-2-methyloxazolone with DMAD underwent nucleophilic addition to a second mole of the acetylenic ester to give the Michael adducts 27 and 28... 

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