Alkenylations oxazole

Zinc Derivatives Oxazole and 5-substituted oxazoles are lithiated in the 2-position. Subsequent zincation gives the corresponding 2-oxazolylzinc chloride 112 for alkenylation (Scheme 48). Excess of zinc chloride was used in the zincation. Subsequent cross-coupling with a 1-butenyl iodide yields 2-alkenyl derivatives. The Pd-catalyst was pregenerated by reduction with DlBALH.t The alkenylated oxazole 113 was formed in a corresponding coupling reaction with a cyclic vinyl triflate. ... 

Quaternization of the nitrogen atom in a heterocyclic system can activate the ring towards addition reactions. An oxazoline moiety was converted to an aldehyde in 97% overall yield by alkylation of oxazoline with MeOTf, reduction with sodium boro-hydride, and hydrolysis of the resulting aminal (eq 10). Alternatively, treatment of an TV-methylated oxazolium triflate with a Grignard reagent followed by aqueous acid produced a ketone. Reaction of alkenyl oxazoles with MeOTf induced spontaneous intramolecular [4 -i- 2] cycloaddition at room temperature leading to a hydroindole or a hydroisoquinoline after reduction by sodium borohydride (eq 11). ... 

Meanwhile, in 2013, Yamaguchi, Itami, and coworkers reported a C-H alkenylation of 1,3-azoles with enol derivatives (C-H/C-O type alkenylation) or alkenyl esters (decarbonylative C—H alkenylation) as electrophiles and applied this strategy to the formal synthesis of siphonazole B (Scheme 16.29b) [63]. Oxazole 137 was coupled with enol derivative 144 under their nickel catalytic system using the dcype ligand to form alkenyl oxazole 145 in 72% yield by C-H alkenylation at the C2 position of oxazoles. Since oxazole 145 was a known intermediate from the previous synthesis of siphonazole B [64], a convergent formal synthesis of siphonazole B has therefore been achieved. 

Lithiated 2-(chloromethyl)- and 2-(l-chloroethyl)-4,5-dihydro-l,3-oxazoles (366) and (367) behave in a different way. The reaction of (366) with nitrones leads stereoselectively to 2-[(Z)-alkenyl]-4,5-dihydro-l,3-oxazoles (368a) and (368b) (Scheme 2.158), while the 2-(l-chloroethyl)-derivative (367) gives... 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A -pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include ot-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) l-benzopyran-2(77)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

Several polymerizable oxazole- and isoxazole-functional monomers have been reported in the literature (70MI11100). The polymerizabilities of several alkenyl heterocyclic monomers, including oxazoles (83) and 3-isopropenyl-5-methylisoxazole (84) have been thoroughly studied (75MI11102). These heterocyclic monomers were found to be more... 

Table2. Hexahydro-lff-pyrrolo[l,2-e][l,3]oxazin-l-ones and Tetrahydro-1 f/,3/f-pyrrolo[l,2-c]oxazol-3-ones by Halocyclization of 2-(l-Alkenyl)-l-pyrrolidine Carboxylates...

Control in the selection of ring substituents is an important element of oxazole synthesis. This is a feature of a new route that employs 0-trimethylsilyl acyltrimethylsilane cyanohydrins (148), which are obtained from aldehydes or acyl silanes <92JOC333l>. These intermediates, which provide the C-5 substituent and four of the five ring atoms, are reacted sequentially with organolithium reagents (C-4 substituent) and acyl chlorides or anhydrides (C-2 substituent) to furnish, -bis(trimethylsilyl) enamines (149), which cyclize under thermal conditions or upon treatment with trimethylsilyl trilluoromethanesulfonate (Scheme 68). The range of oxazoles accessible by this method includes those with alkyl, alkenyl, phenyl, and functionalized substituents at C-2, alkyl, alkenyl, and phenyl substituents at C-4, and alkyl and phenyl substituents at C-5. The rare 4-(, -dialkylamino)oxazoles (150) may also be prepared. 

In a recent work, Piguel has shown that direct alkenylation of various electron-rich heterocycles by alkenyl bromides is possible under copper catalysis [99], Employing a combination of Cul with tra n v-1,2-A, /V - dim e l It y Ic y c I o It exan e diamine ligand and fBuOLi base, 5-aryloxazoles, benzothiazole, benzoxazole, and unsubstituted oxazole were alkenylated by P-bromostyrenes and isocrotyl bromide in good... 

A more versatile method than most of those previously available for the synthesis of triaryloxazolopyridine is based on the cyclization of 4-benzylidene-oxazol-S-one with N-phenacylpyridinium bromide [3152]. Hot phosphorus oxychloride promotes C—C lx>nd formation between a lactam carbonyl and a ring-carbon and the pyrimidinone ring is chlorinated [3093]. Malononitrile in a basic medium converts an alkenyl-lactam into a fused 3-cyanopyridine ring. Yields in this reaction are low and heating for 16 h is necessary [3427]. 

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"... 

TABLE 1.73. 2-ALKENYL(ARYL)OXAZOLES OR 2-ALKENYL(ARYL)-5-SUBSTITUTED OXAZOLES FROM PALLADIUM-CATALYZED CROSS-COUPLING OF OXAZOL-2YLZINC CHLORIDES"... 

The authors found that branched alkyl phosphines were not useful at all, whereas aryl phosphines afforded 1145 in acceptable yield but modest trans/cis selectivity (Scheme 1.298). However, both triethylphosphine and tri- -butylphosphine produced 1145 in nearly quantitative yield with 100 0 trans/cis selectivity. Operationally, the phosphonium salts were generated in situ, triethylphosphine was the reagent of choice. Similarly, the tranr-2-alkenyl bis- and ttis-oxazoles 1147—1150 were readily prepared. A further application of this methodology for the synthesis of ulapuahde A is discussed in Section 1.5.6. 

Wenkert and co-workers prepared a series of 5-alkenyl-substituted oxazolium salts and investigated their intramolecular Diels-Alder reactions as a means to construct alkaloids (Scheme 1.427). The starting oxazoles 1662a-c, 1663, and 1664 were prepared from an acyclic methyl ester and lithiomethyl isocyanide. Methylation of 1662a-c, 1663, and 1664 with methyl trillate then afforded the corresponding iV-methyloxazolium salt quantitatively. The oxazolium salts 1665, 1666, and 1667 were stable for up to 3 h at 90°C. 

A variety of substituents—including alkyl, alkenyl, cyano, acetyl, and alkoxy— is tolerated at the 2 and 5 positions of the oxazole ring for these cycloadditions. Acetylenic dienophiles with alkyl, trialkylsilyl, phenyl, ester, ketone, and acetal substituents, as well as terminal alkynes, are precedented. Ab initio calculations predict a slightly higher activation energy for the cycloaddition of oxazole with acetylene compared to the oxazole-ethylene reaction. ... 

To functionalize the C5 position, Williams and Fu developed a 2-phenylsulfonyl substituted oxazole. The C5 position of this oxazole can be cleanly deprotonated with LDA and trapped with either NIS or NBS to form the 5-iodo- or 5-bromo-2-phenylsulfonyloxazole in good yield. The same report details that the 2-phenylsulfonyl group can subsequently be displaced with alkyl, alkenyl, or aryl lithium reagents to form 2,5-disubstituted oxazoles efficiently. A triflate at the C5 position can be prepared from the corresponding oxazolone however, the oxazolone decomposes at room temperature, and Kelly reported that attempted Stille coupling with C5 triflates failed due to decomposition of the triflate. ... 

The authors succeeded in conducting the C5-selective alkenylation of various thia- and oxazoles using Pd(OAc)2/AgOAc (Scheme 18.60) [58]. 

C4-Alkenylation of 2,5 -substituted oxazoles was reported by Antilla and coworkers [59] (Scheme 18.61). The alkenylated products can be converted to functionalized amino alcohol and amino acid derivatives. 

Daugulis and Piguel s groups also developed the Cu-catalyzed versions. Thus, perfluoroarenes [70] and 5-substituted oxazoles [71] undergo alkenylation in the... 

An alternative to the use of benzyl hahdes in direct C-H benzylations was disclosed by Ackermaim and coworkers. These authors optimized conditions for the C-H arylation and alkenylation of (benz)oxazoles with phosphate and sulfamate electrophiles and extended their results to the C-2 benzylation of (benz)oxazoles with benzyl phosphate (Scheme 19.21) [35]. More recently, the same group reported the use of a palladium catalyst containing an air- and moisture-stable secondary phosphine oxide ligand for this reaction [36]. 

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