Benzyl alcohol, Claisen rearrangement

Another powerful approach to prepare a-amino acids bearing an aromatic or unsaturated side chain in /I (but also many other compounds) is based on the reactivity of 5-fluoro-4-trifluoromethyloxazole, a starting material easily accessible from hexafluoroacetone. The fluorine atom in the 5 position is easily displaced by an allylic or benzylic alcohol. Then, the obtained ethers spontaneously undergo a Claisen rearrangement to afford, after acidic hydrolysis, an a-trifluoromethyl amino acid... 

Use of benzyl alcohol resulted in formation of the benzyl ether corresponding to allyl ethers 52, but attempted Claisen rearrangement resulted in an 82 % yield of the product of a 1,3-benzyl shift (see Section 5.1.3.).20 To demonstrate the utility of the methodology outlined in Table 14, x-oxoester 53a was converted into the corresponding x-amino acid by hydrolysis and reductive animation.20... 

When the double bond of the allyl fragment is part of a benzene ring, i.e. when benzyl alcohols are used, a 1,3-benzyl shift takes place instead of the Claisen rearrangement (see Section 5.I.3.).28... 

A wide variety of a-trifluoromethyl-substituted amino acids are now available from the reaction of 5-fluoro-4-trifluoromethyl-l,3-oxazoles with allylic alcohols and benzyl alcohols. The reaction sequence involves a low-temperature Claisen rearrangement or a radical 1,3-benzyl shift from oxygen to carbon, respectively [88AG(E)848 89S850] (Scheme 86). 

The C27-C38 segment 208 was prepared from D-galactal 227 (O Scheme 26). The silyl ether, prepared from 227, was selectively benzylated, and the resulting C3-alcohol was desilylated and propanoylated to afford 228. After the Ireland-Claisen rearrangement of 228, carboxylic acid 229 was subjected to iodolactonization followed by reductive removal of iodine to give y-lactone 230. This was converted to the C27-C38 segment 208. 

Wick, A. E., Felix, D., Steen, K., Eschenmoser, A. Claisen rearrangement of allyl and benzyl alcohols by N,N-dimethylacetamide acetals. Helv. Chim. Acta 1964, 47, 2425-2429. 

Reaction of allyl and benzyl alcohols with 1-dimethylamino-1-methoxy-ethene 2 leading to acetamidation-rearrangement, proceeding via ether exchange followed by Claisen rearrangement (enamine SN2 displacement). 

Claisen rearrangement. On contrary, thioethers 226 and 227 synthesized by the reaction of the corresponding furan or thiophene with allyl mercaptane are thermally stable and no evidence of thio-Claisen rearrangement of these compounds was found. ° The fluorine atom of 2-fluoro-3-trifluoromethylfurans and thiophenes can be replaced upon nucleophilic substitution with benzyl alcohols. Compounds 228 are susceptible to [1,3]- and [l,5]-benzyl group migration. " ... 

The allylic alcohol was subjected to an Eschenmoser-Claisen rearrangement with dimethylacetamide dimethylacetal to introduce the C14 substituent in a stereoselective manner. Reduction of the amide to the corresponding aldehyde with phenyl silane in the presence of Ti(0/Pr)4 was followed by an acid-promoted closure of the C-ring of codeine. In order to prevent N-oxidation, the amine was converted to the corresponding tosylamide, via debenzylation and treatment with tosyl chloride, before the allylic alcohol was introduced by the reaction of the alkene with selenium dioxide (65). The stereochemistry of the C6 hydroxy functionality was corrected by applying the well-known oxidation/reduction protocol [46, 60] before the benzylic double bond was reductively removed under Birch conditions. Codeine (2) was obtained in 17 steps with an overall yield of approximately 0.6%. 

Since its original discovery, the Meerwein-Eschenmoser-Claisen rearrangement has proven to be a reUable reaction with considerable scope. Apart from the aUylic and benzylic systems [4-6] shown below, propargylic alcohols [7,8] and aUenyl... 

Both Parsons [49] and Mulzer [50, 51] used related Eschenmoser-Claisen rearrangements to set a benzylic quaternary stereocenter in their approach to morphine alkaloids (Scheme 7.25) [5, 52, 53]. Reduction of cyclohexenone 65 followed by Eschenmoser-Claisen rearrangement gave unsaturated amide 66, which was subsequently converted into a known precursor of morphine (Scheme 7.24, Eq. 1). Treatment of the acid sensitive phenanthrenol 67 with dimethylacetamide dimethyl acetal (4) afforded amide 68 comprising the entire carbon skeleton of the morphine (Eq. 2). The amide was subsequently reduced to a primary alcohol (69) using lithium triethylborohydride (Super-Hydride), the most suited reagent to perform this task. Previous total syntheses of the alkaloid were intercepted at the stage of dehydrocodeinone. 

Danishefsky et al. took recourse to an Eschenmoser-Claisen rearrangement in a total synthesis ofgelsemine (Scheme 7.26) [54]. Although the implementation of the reaction required the subsequent removal of one carbon, it proved to be the only viable way to install the spirocycHc stereocenter. A variety of alternative [2,3]-and [3,3]-sigmatropic rearrangements were found to be unsuccessful. Treatment of allylic alcohol 70 with DMADMA furnished amide 71, which underwent condensation with the nearby benzyl carbamate to yield lactam 73 upon purification on silica gel in 45% overall yield. The unusual byproduct 72 could be recycled to 70 by treatment with aqueous acid. 

Reaction of 2-fluoro-3-trifluoromethylfurans 235 with allyl alcohols followed by Claisen rearrangement directly produced butenolides 237 [145, 146]. Oppositely, allyl mercaptane formed stable substitution product 236 [146], A similar transformation was reported for benzyl alcohols. While benzhydryl and (2-thienyl)methyl groups migrated at room temperature directly furnishing butenolides 239, in the case of benzyloxy derivatives, heating at 120 °C was required to reach the transformation. On the other hand, stable up to 140 °C products 238 were formed in the reaction of benzylamine, benzyl mercaptane, and 2-(hydroxymethyl)pyridine [147]. 

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