Oxazoles nucleophilic attack

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... 

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. 

Two possible mechanisms are proposed. Primarily the enol radical cation is formed. It either undergoes deprotonation because of its intrinsic acidity, producing an a-carbonyl radical, which is oxidized in a further one-electron oxidation step to an a-carbonyl cation. Cyclization leads to an intermediate cyclo-hexadienyl cation. On the other hand, cyclization of the enol radical cation can be faster than deprotonation, producing a distonic radical cation, which, after proton loss and second one-electron oxidation, leads to the same cyclo-hexadienyl cation intermediate as in the first reaction pathway. After a 1,2-methyl shift and further deprotonation, the benzofuran is obtained. Since the oxidation potentials of the enols are about 0.3-0.5 V higher than those of the corresponding a-carbonyl radicals, the author prefers the first reaction pathway via a-carbonyl cations [112]. Under the same reaction conditions, the oxidation of 2-mesityl-2-phenylethenol 74 does not lead to benzofuran but to oxazole 75 in yields of up to 85 %. The oxazole 75 is generated by nucleophilic attack of acetonitrile on the a-carbonyl cation or the proceeding enol radical cation. 

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]. 

In parallel with the direct abstraction mechanism, a second important mechanism of epimerization can occur via an intermediate that can be produced from any type of activation. This common intermediate is the oxazol-5(4//)-one, produced by nucleophilic attack of the penultimate carbonyl oxygen atom attached to the amino group on the activated carboxy carbon atom (Scheme 4). 

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. 

The authors used silver salts since gold salts catalyzed the reaction with R=H (giving oxazole 34, Scheme 5.16) but not with R=Me. Moreover, only traces of the desired furopyrrolidinone were formed with the use of a cationic gold species activated with silver additives. Therefore, silver traces were thought to be the active reagent. Indeed, on activation of compound 33 mediated by AgN03 in the presence of sodium acetate (Scheme 5.16), the enol moiety V can then accomplish a nucleophilic attack to produce the pyrrolidinone W and after protonolysis give compound X. Pyrrolidinone Y (the enol version of X) can, in turn, be subject to an oxidative cyclization to yield the furopyrrolidinone 35. Two equivalents of silver salts are needed for the activation step and the oxidative cyclization. 

Oxazole, imidazole, and thiazole can be formally derived from furan, pyrrole, and thiophene respectively by replacement of a CH group by a nitrogen atom at the 3 position. The presence of this pyridine-like nitrogen deactivates the 1,3-azoles towards electrophilic attack and increases their susceptibility towards nucleophilic attack (see later). These 1,3-azoles can be viewed as hybrids between furan, pyrrole, or thiophene, and pyridine. 

We have previously discussed the reduced reactivity to electrophiles of oxazole, imidazole, and thiazole, as compared to furan, pyrrole, and thiophene, which results from the presence of the pyridine-like nitrogen atom. This behaviour is paralleled by increased reactivity to nucleophiles. Nucleophilic attack on furan, pyrrole, and thiophene derivatives only occurs when an additional activating group is present, as in the displacement reaction giving thiophene 3.41. 

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... 

In accord with MO calculations (67BCJ1580), benzo[Z>]furans are attacked by a variety of nucleophiles at the 2-position. Hydroxide under drastic conditions affords (59) and (60), which are presumably formed by Cannizzaro reaction of the aldehyde (58 Scheme 31). Methylsulfinyl anion in DMSO at 70 °C followed by aqueous work up affords 2-ethy-nylphenol (66JOC248). With a -M group at the 3-position, nucleophilic attack at the 2-position is facilitated. 3 -Benzoyl-2-ethylbenzo[Z> ]furan with hydroxide affords products which can be rationalized by / - diketonic fission of the intermediate (61), further transformations of which produce (62) and (63) (Scheme 32). With a nitrile at the 3-position a similar degradation takes place but an ester is not sufficiently electron withdrawing and hydrolysis ensues. Ammonia will attack the ketone (64) at the 2-position, producing the unstable / - enaminoketone (65 Scheme 33). Other nucleophiles attack in a similar manner thus hydroxylamine under certain conditions will afford oxazoles (66BSF1587). 

The oxazole ring possesses less aromatic stabilization than a thiazole ring and is readily opened in many of its fused derivatives, especially in oxazolium salts. In the pyridazinium derivative (191) the oxazole ring is opened by oxygen, sulfur or carbon nucleophilic attack at the C-8a ring junction (77YZ422). In the mesoionic pyridine (192) an amine attacks at C-2, which is a pseudocarbonyl carbon atom (70JCS(C)1485). 

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>. 

A novel oxazole to imidazole transformation occurs when the oxazole (168) reacts with the imidoyl chloride (169) in the presence of phosphoryl chloride. The process probably involves an initial quaternization of the oxazole with subsequent ring opening of the oxazolium salt to form a ketimine (170). Intramolecular nucleophilic attack then leads to the imidazole product (Scheme 96). 

Nucleophilic Attack at Hydrogen and Reactions of Metallated Oxazoles... 

Oxazoles have also been used to generate azomethine ylides in intramolecular [3+2] cycloadditions with alkynes <2000JA5401 1 he nucleophilic attack of cyanide ion on the oxazolinium salt 75 led to the formation of azomethine... 

Moreover, aryl-oxazoles, -imidazoles [17], or-thiazoles [18], anhydrides [19], and imides [20] are accessible via intramolecular Heck-type carbonylations. In addition to typical acid derivatives, aldehydes [21], ketones [22], aroyl cyanides, aroyl acetylenes, and their derivatives [23] could be synthesized via nucleophilic attack of the acyl metal complex with the corresponding hydrogen or carbon nucleophiles. Even anionic metal complexes like [Co(CO)4] can act as nucleophiles and lead to aroylcobalt complexes as products [24]. 

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