Rearrangements Claisen-type

Claisen-type rearrangements of ester enolates, ketene acetals, and silyl ketene acetals... 

In a related example, reaction of N-hydroxy-N-methylthiophene-2-carboximidamide 56 with DMAD gave a double Michael addition product 57, which when heated at reflux in xylenes, afforded hydroxypyrimidinone 60 in 57% overall yield (Scheme 6.21) [9f]. The mechanism invoked was opening of the oxa-diazole 57 to 58, followed by a [3,3]-Claisen-type rearrangement to 59, which, after tautomerization and cyclization, afforded 60. 

A mixture of metals was utilized to promote a type Ilae synthesis of penta-substituted pyrroles <06OL2151>. Treatment of enyne 37 with a Ag(I) catalyst followed by BnNH2 and a Au(I) catalyst gave pyrrole 38 via a Claisen-type rearrangement and cyclocondensation. 

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). 

The retrosynthetic concept of the Nicolaou group is shown in Scheme 22. The target molecule 36 is disconnected via an IMDA cyclization of the diene quinone precursor 138, which would be generated from the tetraline derivative 139 using Wittig chemistry followed by aromatic oxidation. A Claisen-type rearrangement would provide access to 139 whereby the side chain required for the rearrangement of 140 would be introduced by 0-acylation. The core of 141 would be formed via an intermolecular Diels-Alder reaction between diene 142 andp-benzoquinone 130 [42]. 

Recently, Gagosz et al. extended the methodology to other substrates for the synthesis of functionalized furans via Claisen-type rearrangement. The future asymmetric version of the process could be a very useful tool for the synthesis of natural products [101]. 

Allylimidates underwent a clean Claisen-type rearrangement in the presence of 5 mol % palladium chloride (equation 28),40 as did allyl carbamates39 and S-allylthioimidates (equation 29).41 This S to N rearrangement has found application particularly in the synthesis of pyrimidines, systems for which thermal S to N allylic rearrangements were generally ineffective (equation 30).42 Finally, 0-allyI S-methyl dithiocarbonates cleanly underwent palladium(ll)-catalyzed O to S allylic transposition (equation 31 ).43... 

The reactivities of 9-W-phenylaminoalkyl)phenanthrenes 421 and 424 depend on the length of methylene chain. In the case of n = 1, photo-Claisen-type rearranged products 422 are mainly produced [467] (Scheme 126). 9-Methylene-9,10-dihydrophenanthrene 423 is exclusively obtained in a 60% isolated yield... 

Table 24 Claisen-type rearrangement of tetrazoles (Equation 22) <2004SOS(13)861 >...

The N,N-dimclhylkclcniminium cation (46) is not formed directly from DMAc, but via its enol form (52), see Scheme 19. The formation of the enol form (imine form) is strongly facilitated by the presence of lithium ions, which coordinate to the amide oxygen. Also the intermediacy of enol precursor 52 was proven by means of trapping reactions in the presence of allyl alcohol as the trap, the enol 52 formed an allyl enol ether, which at the prevailing elevated temperatures immediately underwent a Claisen-type rearrangement to produce 4-pentenoic acid N,N-dimethylamidc (53) (Scheme 20). This... 

Behr et al. [114] investigated the selective formation of octadienyl phenol ethers in a liquid-liquid biphasic loop reactor. Although the Pd/TPPTS system showed good activity and selectivity (86% conversion with 74% selectivity towards the telomer after 5 h) in a lab-scale batch reactor, telomer yields in the loop reactor were insufficient for efficient phase separation. Telomerization with phenol was therefore deemed unsuitable for this type of reactor. The authors also noted that the C-allylated octadienyl phenol product rather than the telomerization product became the main product after 6 h of reaction, attributing this to a metal-catalyzed Claisen-type rearrangement. 

The Claisen rearrangement has been instrumental in the synthesis of a number of natural products.279-289 Many useful derivatives have been prepared using the Claisen-type rearrangement including enol ethers,290 amides,291-293 esters and orthoesters,294-296 acids,297-298 oxazolines,299 ketene acetals,300-301 and thioesters.302 Many of these variants use a cyclic primer to control relative and absolute stereochemistry. The Claisen and oxy Cope provide the best candidates for scale up as a result of the irreversible nature of these reactions. 

Reaction of 2-thienyl propargyl sulfide (98) in HMPA led to 2i/-thieno[2,3-Z ]thiopyran (99) (Equation (21)). Claisen type rearrangements are involved in the reaction, which proceeded in excellent yields. The reaction is also a useful method for the preparation of 57/-thieno[3,2-6]thio-pyran and methyl derivatives of these compounds <69RTC732,72RTC785). 

The Fischer indole synthesis. The Fischer acid-catalyzed conversion of an 7V-arylhydrazone 42 into an indole is one of the most powerful and versatile methods for the preparation of indoles . The mechanism involves a [3,3] sigmatropic Claisen-type rearrangement of a protonated enehydrazine tautomer 43 to give intermediate 44, which spontaneously cyclizes by loss of ammonia, probably via indoline 45, to an indole 46 (Scheme 27). For unsymmetrical ketones, two isomeric indoles are possible and the general result is that the indole derived from the more stable (usually the more highly substituted) enehydrazine is formed. 

On successive treatment with trimethyloxonium tetrafluoroborate, triethylamine and aqueous acid, oxime acetate 83 prepared from cyclohexanone oxime and Ac20 yields a-acetoxy ketone 87 (Scheme 7). A similar result is obtained with other symmetric ketones including 4-heptanone, deoxybenzoin and dibenzyl ketone. 87 can also be formed by the reaction of cyclohexanone and O-acetyl-Af-methylhydroxylamine hydrochloride upon hydrolysis. If the reaction time is prolonged prior to hydrolysis, ketoamide 89 is isolated as the main product. The key step of the reaction is the [l,3]-acetoxy shift of 7V-acetoxyenamine 85 to the a-acetoxyimine 86. The formation of 89 provides support for the intermediacy of acetoxyimine 86 in the reaction sequence. The evidence available suggests that the [l,3]-acetoxy migration proceeds via a Claisen-type rearrangement (Scheme 7)78. 

The cycloaddition of sulfenic acids to unsaturated system is often a crucial step in thio-Claisen type rearrangements. 

Stereoselective Cyclizations. Sultams have been demonstrated to be superior sources of chirality in selected cases of iodolactonizations, oxidative 1,5-diene cyclizations, and Claisen-type rearrangements of p-acetoxyl substrates. ... 

Asymmetric Pericyclic Reactions. Several reports illustrate the utility of fra/is-2,5-dimethylpyirolidine as a chiral auxiliary in asymmetric Claisen-type rearrangements, [4 + 2], and [2 + 2] cycloaddition reactions. The enantioselective Claisen-type rearrangement of N,0-ketene acetals derived from tram-2,5-dimethylpyrrolidine has been studied. For example, the rearrangement of the iV.O-ketene acetal, formed in situ by the reaction of A-propionyl-fra/w-(25,55)-dimethylpyrrolidine with ( )-crotyl alcohol, affords the [3,3]-rearrangement product in 50% yield and 10 1 diastereoselectivity (eq 9). 

Claisen-Type Rearrangement of a Mixed Ketal Intermediate... 

A third alternative may also be conceived, if for a moment one disregards all the nonparticipant atoms in compound IV. What is left is just an allyl-vinyl amine, a molecular combination reminiscent of what is necessary to perform a Claisen-type rearrangement (see Problem 19). Application of this rationale to intermediate IV would lead to cis structure III in a smooth, concerted fashion. This transformation is known in the literature as the amino-Claisen rearrange-... 

Three main reaction types are considered below, bond fissions, reverse ene reactions, and non-aromatic Claisen-type rearrangements. 

In the non-aromatic Claisen-type rearrangements, a sigma bond breaks, a sigma bond is formed, and two t-bonds migrate concertedly. The basic reaction is illustrated below... 

The empirical equation (1) used in estimating activation energies for the reverse ene reactions shows some promise in yielding reasonable activation energy estimates for Cope and Claisen type rearrangements as well (Table 131). However, additional data are needed before the usefulness of equation (1) can be assessed. 

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