Claisen rearrangement substituent effect

We attempted the synthesis of 1,2-dihydropyridines from propargyl vinyl ethers in an independent study (11JOC2145). In our early experiments, we studied propargyl vinyl ethers 79 with additional alkyl substituents at the vinylic position. The propargyl Claisen rearrangement was effected by catalytic amounts of silver(I) hexafluoroantimonate, and the addition of an amine to the aUenylcarbonyl intermediate was expected to provide the 1,2-dihydropyridine product 80. Unfortunately, the major product was, in aU cases, the 2ff-pyran 81, and the desired dihydropyridine 80 was only formed in yields ranging from 10% to 44% when aniline derivatives were employed (Scheme 27).With aliphatic amines, the formation of 1,2-dihydropyridines was not observed. 

Like the Cope rearrangement, the Claisen rearrangement is sensitive to substituents on the reacting system. Cyano groups promote the rearrangement by a factor of 10 at positions 2 and 4 and have smaller effects at the other positions, as shown below. Data are also available for methoxy groups at positions 2, 4, 5, and 6. ... 

The Claisen rearrangement is an electrocyclic reaction which converts an allyl vinyl ether into a y,8-unsaturated aldehyde or ketone, via a (3.3) sigmatropic shift. The rate of this reaction can be largely increased in polar solvents. Several works have addressed the study of the reaction mechanism and the electronic structure of the transition state (TS) by examining substituent and solvent effects on the rate of this reaction. 

A theoretical study of substituent effects in the thio-Claisen rearrangement (91) -> (92) has been carried out. The study has shown that 2,5-disubstimtion leads to tighter transition states and to a substantial lowering of the enthalpy of... 

Recall that in the latter, certain types of substituents adjacent to oxygen in the ring actually prefer axial arrangements. This observation has been codified in what is commonly referred to as the anomeric effect and is responsible in part for the conformations of carbohydrates. Is it possible that conformational preferences seen in substituted tetrahydropyrans will carry over into preferences in transition-state geometries for Claisen rearrangements ... 

An interesting aspect of the allylic C-H insertion is that the products are y,6-unsaturated esters. Traditionally, y,6-unsaturated esters are most commonly prepared by a Claisen rearrangement, especially if stereocontrol is required. Diastereocontrol is also possible in the C-H insertion as long as the reaction occurs at a methylene site where there is good size differentiation between the two substituents [21]. An example is the reaction between 17 and the silylcyclohex-ene 18 which forms the C-H insertion product 19 in 88% de and 97% ee [21]. Other catalysts such as Rh2(.R-BNP)4 and Rh2(S-MEPY)4 have been explored for allylic C-H activation of cyclohexene but none were was as effective as Rh2(S-DOSP)4 [22]. 

Alkenyl(phenyl)iodine(III) compounds can also serve as starting materials in rearrangements. Allenyl(aryl)iodine(III) compounds of type 86 can be synthesized from (diacetoxyiodo) derivatives 85 and propargylsilanes [145]. It depends on the leaving group ability of the aromatic substituent on iodine in 86 as to whether the reaction proceeds via nucleophilic substitution to compounds of type 87 or by an iodonio-Claisen rearrangement to compounds 88, Scheme 37 [146,147]. The easy access to propynyl compounds 87 has been shown [148] and solvent effects in these reactions have been investigated as well [149,150]. 

It can be seen from the examples displayed above that the Claisen rearrangement of allyl vinyl ethers with an amino substituent at C(n and C(2) proceeds much faster than that of allyl vinyl ether itself. Several models98- 00 have been proposed in order to interpret the substituent effect on the rate of Claisen rearrangement. Both the acceleration of the rearrangements of / -allyloxyenamine and 0-allylketene TV, 0-acetals and deceleration of the reaction of enamine 120 are in agreement with the prediction of the models. 

The experimentally observed effects of donor and withdrawing substituents on the rates of Claisen rearrangements are summarised in 6.288 and 6.289. Predictions based on the simple theory above, whether allowing for the effect of the oxygen lone pair or not, match most of the substituent effects, and more elaborate treatments and calculations account for the anomalous accelerating effect of a donor substituent at C-6. 

For this reaction, the rate was found to vary by a factor of 34 in going from the least polar ( -tetradecane) to the most polar solvent (phenol), and by a factor of 102 in going from the gas phase to the most polar solvent [153]. The small solvent and substituent effects observed suggest that a slightly dipolar activated complex must be formed during the Claisen rearrangement of this allyl aryl ether [153]. 

Claisen Rearrangements. A modified BINOL-derived aluminum reagent is an effective chiral catalyst for asymmetric Claisen rearrangement of allylic vinyl ethers (eq 29). The use of vinyl ethers with sterically demanding C-3 substituents is necessary for the high level of asymmetric induction. 

A C(6) donor substituent exerts a similar enhancing efiect on the rate of the Claisen rearrangement, though somehow less pronounced than the rate-accelerating effect of the 2-silyloxy substituent (approx. 1.4 kcal mol" ). As Curran and coworkers reported, " this vinylogous anomeric effect of the C(6) donor substituent is especially effective in glycal systems. The energy of the TS is decreased by assist-... 

Figure 3 Qualitive effect of C-6-caibon and C 6-oxygen substituents on the transition sute energy of the ester enolate Claisen rearrangement...

The ability of charged substituents to accelerate the 3,3-sigmatropic reiarrangement of allyl vinyl ethers (the Claisen rearrangement) has also been documented. The effect of oxyanion substituents on the rate and course of aliphatic Claisen rearrangements has been the subject of particular attention. " In 1972, Ireland and Mueller reported that the lithium enolate derivatives of allyl esters undergo rapid and effi-... 

The only examples of asymmetric Claisen rearrangements catalyzed by a chiral aluminum catalyst are those published by Yamamoto and coworkers [24-27]. The Claisen rearrangement of allyl vinyl ethers of type 91 (Sch. 13) can proceed via either of the two enantiomeric chair transition states 92 or 94. If a chiral Lewis acid is used to activate the process, the transition states become diastereomeric and preferential formation of one enantiomer of the product is possible. This is complicated because coordination of a chiral Lewis acid to the ether oxygen of allyl vinyl ether produces a new chiral center as indicated in 96 and asymmetric induction might occur from a substituent on aluminum to the oxygen and then from the oxygen to the C-3 carbon in the product. In their initial report, Maruoka, Banno, and Yamamoto found that a catalyst prepared from the 3,3 -disilyl-substituted BINOL 97 and trimethylaluminum was effective in this transformation [24]. The catalyst 98 was shown to be monomeric by measurement of freezing point depression. 

The effect of substituents upon the or/An-Claisen rearrangement as given in... 

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