Boekelheide reaction

In addition to the formation of the pyridine framework by de novo approaches (see section 8.1) or by the cycloaddition/cycloreversion sequence (see section 8.2), one can employ reactions that proceed through a rearrangement pathway. The Boekelheide reaction (see section 8.3.1) involves the rearrangement of an existing pyridine skeleton to a more functionalized scaffold, while the Ciamician-Dennstedt reaction (section 8.3.2) generates the pyridine nucleus by rearrangement of an alternative heterocycle. 

The Boekelheide reaction and related reactions involves treating pyridine N Oxides 1 with acylating agents to afford rearranged products 2. Traditionally, the rearrangement occurs at the a-position but variations andyor side-products of this reaction afford y-position modification. 

Katada, working in the labs of Ochiai, first described the reaction of N-oxide 3 with acetic anhydride. The resultant rearrangement produced a-pyridone 4. Shortly 

Several groups have contributed pieces to the puzzle of how this reaction proceeds and understanding of the events that transpire has evolved with time. While on the surface, this reaction looks analogous to the Polonovsky reaction (5 — 6) or the Pummerer 

The Boekelheide reaction has found utility in a number of synthetic applications. A notable example of its application to natural product synthesis was described by 

Treatment of 2-methylpyridine A -oxide with trifluoroacetic anhydride gives rise to 2-hydroxymethylpyridine. 

Katritzky, A. R. Lagowski, J. M. Chemistry of the Heterocylic -Oxides Academic Press, NY, 1971. (Review). 

Galatsis, P. Boekelheide Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 340-349. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 26, Springer-Verlag Berlin Heidelberg 2009 

Pyridine synthesis via hetero-Diels-Alder reaetion of 1,2,4-triazines and dieno-philes (e.g., enamine) followed by extrusion of N2. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 30, Springer International Publishing Switzerland 2014 

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Nicolaou in his model system for an approach to the thiopeptide antibiotic thiostrepton, in particular, the elaboration of the quinaldic acid moiety. The tetrahydroquinoline 21 was converted to the A-oxide by /n-CPBA oxidation. Subsequent treatment with TFAA, to carry out the Boekelheide reaction, was followed by hydrolysis of the resultant ester to produce 22 as a mixture of alcohols. 

Building blocks, useful for supramolecular or material science, have also been prepared using the Boekelheide reaction. Thus bipyridyl derivative 23 was subjected to the standard sequence of reactions (oxidation, rearrangement, and hydrolysis) to afford the diol 24. 

The Boekelheide reaction has been applied to the synthesis of non-natural products with the preparation of quaterpyridines serving as an example. The sequence began with the 2,4-linked bipyridyl-N-oxide 25. Execution under the typical reaction conditions produced the expected bis-pyridone 26. Treatment with POCI3 afforded the corresponding dichloride that was submitted to a palladium-catalyzed coupling with 2-stannyl pyridine to produce the desired quaterpyridine 27. 

The Boekelheide reaction has found utility in other synthetic methodology. An approach to 2,3-pyridynes made use of this chemistry in the preparation of the key intermediate 30. Treatment of 28 with acetic anhydride produced the desired pyridone 29. Lithiation was followed by trapping with trimethylsilyl chloride and exposure to triflic anhydride gave the pyridyne precursor 30. Fluoride initiated the cascade of reactions that resulted in the formation of 2,3-pyridyne 31 that could be trapped with appropriate dienes in Diels-Alder reactions. 

An approach to the construction of Fe(II)-binding agent pyrimine 40, isolated from Pseudomonas species, employed the bis-homophenylalanine 38. Initiation of the Boekelheide reaction with TFAA and hydrolysis gave the advanced intermediate 39 that provided access to the natural product. 

The formation of a library of 2-substituted quinolines employed a variation on the Boekelheide reaction. Treatment of A-oxide 41 with isobutylchloroformate did not result in the typical rearrangement. However, subsequent exposure to Grignard reagents resulted in loss of the carbonate with concomitant formation of the 2-substitute derivatives 42. 

Pyridylmethyl chloride 11 was obtained by direct chlorination of alcohol 10 using thionyl chloride The hydroxymethyl-pyndine 10, in turn, was synthesized from 3,5-dimethylpyndine in 6 steps utilizing a Boekelheide reaction that transformed the 2-methylpyridine-A -oxide to the corresponding hydroxymethyl-pyridine 10. 

Certain substituted pyridines can be obtained via rearrangement of pyridine iV-oxides (Boekelheide reaction) or via rearrangement of an alternative heterocycle system, i.e., pyrrole (Ciamician—Dennstedt reaction). 

The Boekelheide reaction was applied by the Nicolaou groups in the synthesis of a model system of the thiopeptide antibiotic thiostrepton (302). The tetrahydroquinoline 303 was converted into the A -oxide by /w-CPBA oxidation followed by treatment with TFAA and then hydrolysis to afford key intermediate alcohol 304 as a diastereomeric mixture. 

Ticolubant (310) is a leukotriene receptor antagonist that exhibits anti-inflammatory activities. The Wittig reaction with 3-hydroxy-6-methylpicolinaldehyde followed by a Mitsunobu reaction with 2-phenylethanol gave phenyl ether 308. Oxidation with wCPBA converted the pyridine ring into the corresponding A-oxide, which then underwent the Boekelheide reaction with TFAA to afford the methyl alcohol 309. Reaction with thionyl chloride and then 2,5-dichlorothiophenol followed by saponification gave 310. ° ... 

In contrast, N-oxides of 2- and 4-alkylpyridines are functionalized in the side-chain (Boekelheide reaction) by acylation reagents (acid anhydrides [104] leading to acy-loxylation, sulfonyl chlorides, or POCI3 [105] leading to chlorination). For instance, 2-picoline-N-oxide on reaction with AC2O yields a mixture of acetoxy compounds (97-99), in which the methyl-acetoxylated product 97 dominates [106] ... 

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