2- -4-oxazole triflate

Barrett and Kohrt" ° and Kelly and Lang" independently reported the first examples of oxazole triflates (Scheme 6.17). In both cases, the requisite 2-aryl-4(5/7)-oxazolone, 56 or 59, was treated with trifluoromethanesulfonic anhydride (Tf20) to afford 60a or 60b, respectively, which were then coupled successfully with a variety of organostannanes. Kelly and Lang" attempted to extend this methodology to prepare the key oxazole triflates 63 in their approach to sulfomycin I. However, they were unexpectedly thwarted when 61 could not be cyclized to the requisite 4(57/)-oxazolone precursors 62. Schaus and Panek described an unproved procedure to prepare 56 in 90% yield very recently. 

Smith and co-workers adapted Sheehan and Izzo s original synthesis of 2-aryl-4(57/)-oxazolones and developed a general synthesis of 2-aIkylA(57/)-oxazo-lones. Teatment of an acid halide with AgNCO followed by diazomethane produced 344 that were immediately converted to the 2-alkylA-oxazole triflates 345. The authors noted that ethanol-free diazomethane was required to prepare 344. The oxazole triflates 345 were, in turn, key intermediates leading to a variety of 2,4-disubstituted oxazoles required for natural products (Scheme 6.73). 

Oxazole triflate 79 was treated with alkynamide 80 under the Sonogashira coupling conditions to give the corresponding side chain precursor 81 [6],... 

Kelly and reported the first examples of oxazole triflates as... 

Schaus and Panek also employed oxazole triflates as coupling partners in their palladium-catalyzed synthesis of vinyloxazoles for application to the C(26)-C(31) subunit of phorboxazole. They reported an improved procedure of preparing 2-phenyl-4-oxazole triflate 984 from 2-phenyl-4(57/)oxazolone 983 (Scheme 1.263). With 984 in hand, they developed a one-pot Cp2ZrCl2 catalyzed carboalumination of a terminal alkyne to produce an intermediate vinyl alane (not shown), which was then coupled with 984 to generate a 4-( )-alkenyl-2-phenyloxazole, e.g., 985 or 987, respectively. 

In addition, the authors also prepared 986 via a Stille coupling of 984 with (E)-alkenylstannanes. After considerable experimentation, they also prepared 987, a structural analog of the C(26)-C(31) phorboxazole subunit. These examples further broaden the scope of transition metal catalyzed couplings of oxazole triflates. Examples of 4-(E)-alkenyl-2-phenyloxazoles 985 and 986 are shown in Table 1.71. 

TABLE 1.71. 4-( 0-ALKENYL-2-PHENYLOXAZOLES FROM PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF 2-PHENYL-4-OXAZOLE TRIFLATE"... 

A facile assembly of 2,4-orthogonally-functionalised oxazoles as useful bidirectional linchpins was achieved by treatment with diazomethane of acyl isocyanates, generated in situ from acyl halides 132 oxazolones 133 were converted to the oxazole triflates 134, useful intermediates for further synthetic elaborations as highlighted by the synthesis of 135 via Wittig and Stille reactions <01SL1739>. This linchpin tactic was used in the stereocontrol led total synthesis of the potent cytostatic agent (+)-phorboxazole A <01JA10942>. 

Larhed et al. investigated enantioselective Heck reactions with 2,3-dihydrofuran as alkene [86]. In the coupling with phenyl triflate, conditions previously reported by Pfaltz [87] were attempted under microwave irradiation. Interestingly, the catalytic system Pd2(dba)3/(4S)-4-t-butyl-2-[2-(diphenylphosphanyl)phenyl]-4,5-dihydro-l,3-oxazole, identified by the Swiss team, was found suitable for high-temperature microwave-assisted enantioselective Heck reactions (Scheme 76). Using a proton sponge as a base and benzene as a solvent gave the best conversions (Scheme 76). At tempera-... 

Jacobi reports using a variant of method A to access the A,B,E-ring system of wortmannin.14 The sequential addition of methyl lithium and acetylenic Grignard reagent followed by triflation proceeds from 7 to the corresponding triflate 8 in 74% yield (Fig. 4.13). Subsequent carbonylation of the alkyne and the phenol produces the acyl oxazole 9, which is smoothly converted into the furanolactone 10 over three more steps. 

A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used l-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1-(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>. 

In the model studies toward the total synthesis of dimethyl sulfomycinamate, Kelly et al. successfully carried out the Stille couplings of oxazolyl triflate 18 with an array of organostannanes [19, 20]. Thus, 2-aryl-4-oxalone 17 was transformed into the corresponding triflate 18, which was then coupled with 2-trimethylstannylpyridine under the agency of Pd(Ph3P)4 and LiCl to provide adduct 19. The couplings of triflate 18 with phenyl-, vinyl- and phenylethynyl trimethyltin all proceeded in excellent yields. Unfortunately, application to the more delicate system in the natural product failed and the oxazole moiety was installed from acyclic precursors. 

Analogously, Barrett and Kohrt transformed 2-phenyl-4-oxalone into triflate 20, which was then converted to the corresponding stannane 21 using Pd-catalyzed coupling with hexamethyldistannane. Subsequent coupling with 2-iodooxazole 4 elaborated bis-oxazole 22 [2],... 

A series of a,a-dimethoxysilyl enol ethers has been prepared and shown to undergo diastereoselective [4+3]-cycloaddition with furan and cyclopentadiene in the presence of catalytic amounts of trimethylsilyl triflate <99SL213>. Furo[3,4-d]oxazoles and furo[3,4-d]thiazo-les react with 13-dimethyloxyallyl to give [4+3]-cycloadducts. The ring opening reaction of these compounds with H2S04Mt20 yields armulated hydroxytropones <99H(51)1225>. 

The treatment of acetophenones with DAIB/triflic acid in nitrile solvents leads to the oxazoles 42 (Scheme 12) (98JHC1533). Such reactions presumably involve the intermediate formation of ketol triflates 41 (89TL667) and do not occur with HTIB. 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

The total synthesis of the peptide derived macrocycle dendroamide A 163 has been accomplished in 19% overall yield from appropriately protected heterocyclic amino acids. The oxazole amino acid 162 resulted from cyclodehydration of P-ketodipeptide 161 with bis(triphenyl)oxodiphosphonium triflate, with notable chemo- and stereoselectivity <03JOC9506>. 

Finally, in order to directly incorporate the nitrogen and sulphur functionalities in a single step with total stereoselectivity, the chiral allylic trichloroacetimidate 16 was treated with methyl sulfenyl triflate to give the corresponding A -sulfenyl imidate 17 in good yield. Further reaction of 17 with methyl sulfenyl triflate gave the 4,5-dihydro-l,3-oxazole 18, together with a minor amount of the trichloroacetamide 19, formed by hydrolysis of 18246. 

The oxazolium salt (160), formed from the oxazole (159) by reaction with methyl triflate in acetonitrile, may be reductively ring opened by treatment with phenylsilane in the presence of cesium fluoride to give the azomethine ylide (161) (presumably this species is in tautomeric equilibrium with the corresponding oxazoline). The azomethine ylide can be trapped as an adduct with a suitable dipolarophile, such as dimethyl acetylenedicarboxylate (DMAD). In the case of this reagent the adduct (162) can be ox-... 

The enantioselective cyclopropanation of styrene with diazoacetic esters has been tested to evaluate a variety of other chiral copper catalysts, but the enantiomeric excesses were never as high as in the aforementioned cases. With a chiral 1,6-bis(4,5-dihydro-l, 3-oxazol-2-yl) ligand, the ee-values dropped to 28% trans) and 0% (c/s). Similar low values were observed when chiral derivatives of 2,2 -bipyridyl and related chelating compounds were used as ligands.Only moderate ee-values also resulted when copper(Il) tartrate, or the catalyst derived from copper(I) triflate and borate 3, was applied. 

Smith 111 et al. reported an effective synthesis of a variety of 2,4-orthogonally functionalized oxazoles with shorter reaction times and modest to excellent overall yields (48-90%). 2-Chloromethyl-4-vinyloxazole (36) was obtained in 78% yield via the Stille coupling of 2-chloromethyl-4-triflate with vinyltributyltin [40]. 

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