Nucleophilic substitution oxazoles

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

Pyridino-oxazoles 198 were obtained in an analogous way starting from o-bromoaminopyridine 196, which was first acylated and then cyclized imder microwave irradiation at 165 °C in DMA via an aromatic nucleophilic substitution (Scheme 71) [126]. 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

Rearrangements of oxazoles 392 and 393 (Scheme 62). which assume nucleophilic attack of the side-chain at the C(5) position and consequent fission of the ring O—C(5) bond, have been considered [76JCS(PI)315]. Nevertheless, the phenylhydrazide 394 does not rearrange into the expected 395 and remains unchanged under various conditions. In this context, unsuccessful attempts are reported for some structurally related 4-substituted oxazoles, whereas specific examples concerning oxazolium substrates 393 are not mentioned [76JCS(P1)3I5]. 

Ferrini and Marxer65 have recently shown that vinylene carbonate reacts with primary amides, in the presence of polyphosphoric acid, to yield 2-substituted oxazole derivatives. Yields are low (2-34%), and phenoxy- and phenyl-acetamide, p-methylbenzamide, and salicylamide do not give oxazole derivatives. Although the reaction has been interpreted according to Scheme 3, the nucleophilic attack of a nitrile molecule (from the amide dehydration), with a nitrilium salt as intermediate (Scheme 4), cannot be excluded.06... 

Nucleophilic substitution in the azine ring is a normal reaction. The fused oxazole ring, however, is susceptible to nucleophilic ring opening reactions, especially in oxazolium salts and dihydro derivatives. When fused to pyrimidine, substituents in the pyrimidine ring may promote a Dimroth rearrangement of the latter. 

Fused oxazoles are susceptible to ring opening reactions. In appropriately substituted systems, however, nucleophilic substitutions in the azine ring are possible. Thus, in the 7-pyrimidinone (190) chlorination is effected in the usual manner by means of phosphorus oxychloride. The chlorine can be substituted by amino or sulfur nucleophiles (71JHC503). 

The reaction of substituted oxazoles 631 with nitrosoarenes in acetonitrile at room temperature gives 2,5-dihydro-1,2,4-oxadiazoles 632, a reaction that is believed to proceed via a nucleophilic attack of the nitrosoarene by the 2-position of the oxazole to give the intermediate 633, which undergoes ring opening followed by cyclization to afford the isolated 2,5-dihydro-l,2,4-oxadiazoles 632 (Scheme 278) <1998BCJ1231, CHEC-III(5.04.10.2)297>. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Bicyclo[4.1.0]heptane-7,7-diyl)dimorpholine reacted with oxazol-5(47/)-one derivatives in a nucleophilic substitution reaction. - A 1 2 ratio of the reagents was necessary since morpholine as leaving group consumes one mole of oxazol-5(4//)-one to give a carboxamide. 

In the most common syntheses in this group, an iV-(y-substituted-propyl)barbituric acid or uracil, bearing a nucleophilic y-substituent, undergoes ring closure via intramolecular (7-alkylation, condensation or a nucleophilic substitution onto C-2 of the pyrimidine ring. In the ring closure of the uracils (269), the cyclic ethers (214) are formed under kinetic control (Scheme 16) <89JCS(P2)1209>. For the bifunctional (271), both the pyrimido-oxazine and the pyrimido-oxazole derivatives were... 

As a consequence of the low r-electron density on C-2, nucleophilic substitution reactions of 2-halo-oxazoles proceed rapidly, e.g. ... 

TABLE 1.49 2-ARYL-5-SUBSTITUTED 4-(TRIFLUOROMETHYL)OXAZOLES FROM NUCLEOPHILIC SUBSTITUTION OF 2-ARYL-5-FLUORO-4-(TRIFLUOROMETHYL) OXAZOLES, 142... 

Nucleophilic substitution reactions can be carried out on poly(methyl methacrylate) with heterocyclic organolithium reagents. " The reactions are conducted in homogeneous solutions in tetrahydrofuran or in benzene combined with hexamethylphosphoramide. Copolymers will form with tautomeric keto-j5-heterocyclic structures. The following heterocyclic reagents are useful 2-picolinyllithium, [(4,4-dimethyl-2-oxazole-2-yl)methyl]lithium, quinaldinyllithium, and [2-thiazole-2-yl-methyl]lithium. 

Ganem and co-workers have developed the use of a Zn(OTf)2/TMSCl system to promote a variety of Passerini-type processes. The combination is active even for a,P-unsaturated aldehydes and usually problematic ketones. The promoter system was developed around a strategy of tethering nucleophilic functional groups to the isonitrile component to intercept the transient nitrilium species internally. Depending on the attached functionality either the a-hydroxy amide or a substituted oxazole could be obtained in high yield. For 1-isocyano-(2-morphilino)ethane (28), the reaction with... 

As a consequence of the relatively low it-electron density at C-2 (cf p. 167), 2-halogeno oxazoles undergo nucleophilic substitution reactions (following an addition/elimination mechanism) ... 

The 5-fluoro-4-(trifluoromethyl)oxazoles are able to participate in nucleophilic substitution of fluorine by a wide range of various nucleophiles. CF3 group being electron-withdrawing substituent facilitates nucleophilic substitution in position 5... 

Like thiazole, oxazole is a jt-electron-excessive heterocycle. The electronegativity of the N-atom attracts electrons so that C(2) is partially electropositive and therefore susceptible to nucleophilic attack. However, electrophilic substitution of oxazoles takes place at the electron-rich position C(5) preferentially. More relevant to palladium chemistry, 2-halooxazoles or 2-halobenzoxazoles are prone to oxidative addition to Pd(0). Even 2-chlorooxazole and 2-chlorobenzoxazole are viable substrates for Pd-catalyzed reactions. 

As shown in previous sections, NHCs promote acyl transfer in transesterification reactions. In a similar manner, O C acyl transfer can be achieved with substrates such as 351 in the presence of 0.9 mol% of triazolium pre-catalyst 353 and KHMDS (Scheme 53). Moderate yields are obtained by varying substitution of the oxazole from R = Me, Ph, t-Bu, and t-Pr [171], Deprotonation of the triazolium salt followed by nucleophilic addition to the carbonate moiety of the oxazole results in enolate intermediate LXXXIII and activated carboxylate LXXXIV. Enolate addition and regeneration of the active catalyst provides quaternary stereocenters 352. 

Dihydroimidazo[2,l-b]oxazoles were prepared fi om an intramolecular nucleophilic ipso-substitution of 2-alkylsulfonylimidazoles <99S1613>. The synthesis of hitherto unknown 2-(2,4,6-triarylphenyl)substituted 4,5-dihydro-1/f-imidazolium perchlorates from 2-methyl imidazolium perchlorates and 2,4,6-triarylpyrylium perchlorate salts was published <99JC813>. Substituted aromatic heterocycles from reactions of 2,3-dihydrospiro[l/f-4-and... 

Substituted binaphthyl compounds can be synthesized in high optical yields using nucleophilic aromatic substitution reactions in which the chiral leaving groups are alkoxy moieties derived from naturally occurring alcohols28-29. For example, the condensation of 2-(l-alkoxynaphth-2-yl)-4.5-dihydro-4,4-dimethyl-l,3-oxazole with 1-naphthyllithium or 2-methoxy-l-naphthyl 2-magnesium bromide leads to (ft)- or (.S)-(l,T-binaphthyl-2-yl)-4,5-dihydro-4,4-dimethyl-l,3-oxazole derivatives. 

Nucleophilic aromatic substitutions 1,3-azoles are more reactive than pyrrole, furan or thiaphene towards nucleophilic attack. Some examples of nucleophilic aromatic substitutions of oxazole, imidazole and thiazoles and their derivatives are given below. In the reaction with imidazole, the presence of a nitro-group in the reactant can activate the reaction because the nitro-group can act as an electron acceptor. 

Nucleophilic aromatic substitution of oxazoles, imidazoles, and thiazoles... 

The ease of replacement of halogen atoms attached to the oxazole ring by nucleophiles follows the order Hal-2 Hal-4 > Hal-5. Halogen-metal exchange of 4- or 5-bromooxazoles with butyllithium, followed by quenching with D20, affords the corresponding deuterated oxazoles, but other replacement reactions are difficult. The 4-bromooxazole (139) gives a low yield of mandelic acid on alkaline hydrolysis (equation 6). The substitution of all three chlorine atoms in (140) by piperidine has been observed. 

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