Claisen isomerization

Scheme 4 also represents the classical route to isoxazoles, first studied in 1888 by Claisen and his coworkers (1888CB1149). Reaction of a 1,3-diketone with hydroxylamine gives, via the isolable monoxime (108) and the 4-hydroxyisoxazole (109), the isoxazole (110). Unsym-metrical 1,3-diketones result in both possible isomers (110) and (111), but the ratio of the isomeric products can be controlled by the right combination of the 1,3-dicarbonyl component and the reaction conditions used. These important considerations are described in Chapter 4.16, along with the variations possible in the 1,3-dicarbonyl component designed to yield diverse substituents in the resultant isoxazole. 

Like the Diels-Alder reaction discussed in Sections 14.4 and 14.5, the Claisen rearrangement reaction takes place through a pericyclic mechanism in which a concerted reorganization of bonding electrons occurs through a six-membered, cyclic transition state. The 6-allyl-2,4-cyclohexadienone intermediate then isomerizes to o-allylpbenol (Figure 18.1). 

Isomerization of vinylaziridines is widely used in organic synthesis. Six types of isomerization of vinylaziridines are shown in Scheme 2.40. Outlined in this section are i) azepine formation by aza-[3,3]-Claisen rearrangement of 1,2-divinyl- or 2,3-divinylaziridines 153 (Section 2.4.1), ii) pyrroline formation from 155 (Section 2.4.2), Hi) aza-[2,3]-Wittig rearrangement of anionic species 157 (Section 2.4.3),... 

Formation of azepine derivatives by aza-[3,3]-Claisen rearrangements was first reported by Stogryn and Brois, an isomeric mixture of 2,3-divinylaziridines 166, generated by treatment of sulfonate 165 with NaOH, being converted into azepine 167 by steam distillation (Scheme 2.41) [61]. In this case, unchanged trans-azir-... 

Similar to the well-known thio-Claisen rearrangement of allyl aryl sulfides211 and sulfonium salts212, the thio-Claisen rearrangement of allyl aryl sulfoxides has also been reported213. For example, heating of allyl 2-naphthyl sulfoxide (147) at 120 °C for 2h in dimethylformamide resulted in quantitative isomerization to the dihydronaphthothio-... 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

Allenes add nitrile oxides either to one or two double bonds. For mono- and 1,1-disubstituted allenes, relative activity of the two bonds depends on the nature of substituents. The reaction (Scheme 1.18) of N-propadienylanilines 54 with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide proceeds site- and regioselectively to give 5-substituted 4-methylene-4,5-dihydroisoxazoles 55, which add a second molecule of nitrile oxide to afford 4,5/-spirobi-(4,5-dihydroisoxazoles) 56. Dihy-droisoxazoles 55 isomerize to 4-(2-aminobenzyl)isoxazoles 57 via a Claisen-type rearrangement (224). 

Claisen rearrangementThe allyl ether 1 when heated rearranges and cyclizes slowly and in low yield to the dihydrobenzofuran 2. However, the dianion (NaH) of 1 rearranges in refluxing DMF mainly to the isomeric dihydrobenzofuran 3, a precursor to the antibiotic ( )-atrovenetin (4). 

Some allyl phenyl ethers with an alkyl substituent on the end carbon of the allyl group rearrange to give the normal ortho-Claisen product together with another isomeric O-allyl phenol. The latter, formed by the rearrangement of the normal product, has been established. This is called abnormal Claisen rearrangement, is illustrated by the following example. 

Alkoxyallenes turned out to be excellent starting materials also for the synthesis of highly functionalized 1,3-dienes, two examples being depicted in Schemes 8.61 and 8.62. As described by Kantlehner et al., 1,3-dienes such as 238 were obtained from methoxyallene derivative 50 by condensation with CH-acidic compounds 237 [135]. Hoppe and co-workers explored the stereochemical course of the allene Claisen rearrangement under Johnson s conditions, e.g. the reaction of 239 with trimethyl orthoacetate, which furnished intermediate 240 followed by rearrangement to the isomeric dienes 241a,b [136],... 

TV-Acetyl indolin-3-one 123 was converted to 3-cyanomethyl-3-(l,l-dimethylallyl) indol-2-one, 127, by a successive isomerization-Claisen rearrangement sequence (equation 63)91.7V-Acetylindolin-3-one 123 was converted in two steps to a mixture of E- and Z-isomers of 124. Isomerization of both isomers of 124 to 125 was accomplished with DBU. Claisen rearrangement of 125 afforded a 13% yield of 126, which was subsequently deprotected to give 3-cyanomethyl-3-(l,l-dimethylallyl)indol-2-one, 127, in 47% yield. 

An irreversible consecutive reaction as a driving force to shift an unfavorable Cope rearrangement equilibria in the needed direction can be illustrated by the Cope-Claisen tandem process used for the synthesis of chiral natural compounds243. It was found that thermolysis of fraws-isomeric allyl ethers 484 or 485 at 255 °C leads to an equilibrium mixture of the two isomers in a 55 45 ratio without conversion into any other products (equation 184). Under the same conditions the isomer 487 rearranges to give the Cope-Claisen aldehyde 491 (equation 185). Presumably, the interconversion 484 485 proceeds via intermediate 486 whose structure is not favorable for Claisen rearrangement. In contrast, one of the two cyclodiene intermediates of process 487 488 (viz. 490 rather than 489) has a conformation appropriate for irreversible Claisen rearrangement243. 

C nitriles 269 were formed in 25 to 60% yield. This outcome was explained by an initial extrusion of Ph3P=0 to generate ynamines 273. The consecutive isomerization delivered iminoketenes 268, which underwent the usual iminoketene Claisen rearrangement to produce the nitriles 269. Detailed information is given in Table 18 (Scheme 51). 

Thus, the (R)-glycidol (R)-897 was transformed to ethyl (S)-6-benzyloxy-3-methyl-4(E)-hexenoate (S)-899 via addition of acetylide followed by spontaneous isomerization, stereoselective reduction, and Claisen-Johnson rearrangement. The chiral ester (S)-899 was converted to (R)-4-methyl-6-phenylthiohexanol (R)-902. The primary alcohol (R)-902 was then transformed to the terminal acetylene (R)-904, a common intermediate for the synthesis of carbazoquinocins A (272) and D (275). Chain elongation of (R)-904 by two carbon atoms led to (R)-905, the chiral precursor for carbazoquinocin D (275) (639) (Scheme 5.116). 

Higher homologs having a nonterminal fluorine atom were synthesized305 by Claisen condensation of ethyl fluoroacetate with methyl 2,3-O-isopropylidene-DL-glycerate, giving a mixture of the isomeric 2-deoxy-2-fluoro-4,5-0-isopropylidene-DL-3-pentulosonates (540). On... 

If the allylic system is substituted, several isomeric products can be formed. Assuming a chair-like transition state, the stereochemical outcome of a metallo-Claisen rearrangement is controlled by the geometries of the vinyl and allyl moieties, so that, if the vinyl part 68 is stereochemically pure, three different products, syn/anti-73 or 74, can be formed, depending on the exact nature of the active allylic part 72 (Scheme 6)38. 

In the furoquinoline series, Tarbell s technique may also be used 4-acetoxy-l-methyl-3-(l,2-dimethyl-2-propenyl)-2-quinolone (183), obtained by an abnormal Claisen reaction440 and treated with HBr + AcOH at 20° for 26 hours, gives a mixture of the isomeric furoquinolines 184 and 185. 

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