Boekelheide

Boekelheide rearrangement, 3, 303 Lumazine, 6,7,8-trimethyl-hydrogen exchange, 3, 303 Lumazine, 1,3,6-trimethyl-7-hydroxy-bromination, 3, 302 Lumazinecarboxylic acid occurence, 3, 324 Lumazine-6-carboxylic acid methylation, 3, 297... 

Picoline-V-oxide (4-methylpyridine-l-oxide) [1003-67-4] M 109.1, m 182-184 , 185-186 , 186-188 , pK 1.29. Recryst from EtOH-EtOAc, Mc2C0-Et20 or C6H6. [Bullitt and Maynard 7 Am Chem Soc 76 1370 1954 Boekelheide and Linn J Am Chem Soc 76 1286 1954]. 

Submitted by J. F. Bunnett and R. M. Conner. Checked by Virgil Boekelheide and James S. Todd. 

Submitted by Charles R. Hauser and W. R. Dunnavant. Checked by Virgil Boekelheide and P. Warrick. 

Submitted by Tod W. Campbell and Richard N. McDonald. Checked by Virgil Boekelheide and Richard E. Partch. 

Submitted by Melvin S. Newman and Walter R. Reichle. Checked by Virgil Boekelheide and Graham Solomons. 

In 1959, Crawford and Little reported superior yields of 3 in reactions of aromatic aldehydes by using isolated, crystalline 2-phenyloxazol-5-one (2, Ri = Ph) compared to direct reaction with hippuric acid (1, Ri = Ph). An early report by Boekelheide and Schramm on the use of ketones in the Erlenmeyer azlactone synthesis includes treatment... 

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. 

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... 

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. 

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