SNAr strategy

A short and practical synthesis of glucokinase activator 1 was developed utilizing a convergent strategy involving an SNAr coupling of the activated aryl fluoride 11 with hydroxypyridine 9. 

SNAr reactions also provide an important strategy for the preparation of various kinds of diaryl ethers. p-Dinitrobenzene reacts with even sterically hindered phenols to give the corre-... 

Double intramolecular SNAr reaction leads to a model bicyclic C-O-D-O-E ring, as shown in Eq. 9.9.12 Synthesis of a model 22-membered AB-C-O-D ring of vancomycin using similar strategy has been reported.13 Total synthesis of vancomycin has been accomplished by Nicolaou and coworkers.14... 

Kraus has reported the synthesis of a tricyclic indole related to the pyrroloiminoquinone marine natural products (Scheme 10.9), in which an intramolecular SNAr and the reductive cyclization of a nitro aldehyde are involved as key steps.94 Related target compounds have been prepared by Joule and coworkers via a similar strategy.95... 

Although 1,2-diazinamines are not very nucleophilic by themselves the nucleophilicity can be increased via initial deprotonation with strong base. This strategy has been followed by Heinisch and co-workers when studying intramolecular SNAr reactions (Equations 22 and 23) <1997H(45)673, 1997AP29>. 

A brief exploration of annulations with nitro-free fluoro arene 37—readily prepared from ( )-methyl 3-methoxyacrylate (36) by a Michael addition elimination strategy with 2-(2-fluorophenyl)acetonitrile (35)—again revealed that direct SNAr cyclization was impeded under all conditions. Extended conjugation may have contributed however, the necessity for the conjugated sp2-hybridized aryl-propene anion to couple intramolecularly with another sp2-hybridized carbon atom imposed a highly strained reaction trajectory (Scheme 9). 

This strategy is used mostly for the synthesis of annelated pyrazoles in which the second reactant has two electrophilic sites in a 1,3-juxtaposition. Under control conditions, the first synthesis of a 3-aminopyrrolo[2,3-d]pyrazole (129) was realized from ethyl(3-cyano-4,5-diphenyl-pyrrolylthio)acetate (128) (Scheme 18) <91T8243>. The synthesis of the benzothieno[3,2-c]pyrazole (131) occurred as a two-step process with initial SNAr addition of hydrazine to the chloro-benzothiophene 5,5-dioxide (130) (Equation (42)) <74LA1248>. 

Several attributes of these early oxacalixarene syntheses are notable. First, many of the formed products had very low solubility, which hindered purification and characterization. Second, oxacalix[4] arenes were selectively produced over higher cyclic oligomers or linear oligomers, and in certain cases in exceptionally high yield. Finally, all of the early syntheses of oxacalixarenes relied on SNAr reactions of a nucleophilic diphenol and an electrophilic dihalobenzene, and this simple and effective synthetic strategy still pervades to current day. 

A recent and important new development in the application of [Fe(arene)Gp] chemistry is that iron-assisted SnAr reactions have, for the first time, been performed in the solid phase. A library of 36 unsymetrically substituted phenylpiperazines and phenyl-1,4-diazepanes was synthesized using this novel strategy. Scheme 29 shows some of the iron complexes 114a-d that were prepared. Decomplexation of resin-bound iron complexes was achieved with 1,10-phenanthroline under irradiation. ... 

PEG has also been applied for the synthesis of benzimidazole-pyrrolo[l,2-a]-quinoxaline using Pictet-Spengler reaction under microwave (MW) conditions [42]. The synthetic strategy followed a linear sequence of SNAr, nitro reduction, and Pictet-Spengler cyclization (Scheme 22). 

Bailey, K.L. and Molinski, T.F, (2002) Synthesis of bastadin analogs through an SNAr coupling strategy. Tetrahedron Lett., 43,9657-9661. 

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