The Ireland-Claisen Rearrangement

By employing optically active enol borinates instead of silylketene acetals, the Ireland-Claisen rearrangement has been further developed to an enantioselective... 

Entries 10 to 15 involve use of the Ireland-Claisen rearrangement in multistep syntheses. An interesting feature of Entry 11 is the presence of an unprotected ketone. The reaction was done by adding LDA to the ester, which was premixed with TMS-C1 and Et3N. The reaction generates the T-silyl ketene acetal, which rearranges through a chair TS. 

The synthesis in Scheme 13.44 is also based on a carbohydrate-derived starting material. It controlled the stereochemistry at C(2) by means of the stereoselectivity of the Ireland-Claisen rearrangement in Step A (see Section 6.4.2.3). The ester enolate was formed under conditions in which the T -enolate is expected to predominate. Heating the resulting silyl enol ether gave a 9 1 preference for the expected stereoisomer. The... 

Further variations of the Claisen rearrangement protocol were also utilized for the synthesis of allenic amino acid derivatives. Whereas the Ireland-Claisen rearrangement led to unsatisfactory results [133b], a number of variously substituted a-allenic a-amino acids were prepared by Kazmaier [135] by chelate-controlled Claisen rearrangement of ester enolates (Scheme 18.47). For example, deprotonation of the propargylic ester 147 with 2 equiv. of lithium diisopropylamide and transmetallation with zinc chloride furnished the chelate complex 148, which underwent a highly syn-stereoselective rearrangement to the amino acid derivative 149. 

Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield Y,5-unsaturated carboxylic a-cids. The Ireland-Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions. 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

Interestingly, the Ireland-Claisen rearrangement of acetate 3a or propionate 3b docs not give the desired acids 4.40... 

The Ireland-Claisen rearrangement of a 2-fluoroallylic ester of 3-methylcrotonic acid followed by a tandem Cope rearrangement to prepare a 6-fluoroocta-2.6-dienoic acid,7 is given in Section 5.1.5.1. (see compound 11). 

Table 22. Synthesis of 2-(Trifluoromcthyl)alk-4-enoic Acids 18 by the Ireland-Claisen Rearrangement of Allylic 3,3.3-Trifluoropropionates I760...

This conclusion has been applied in the Ireland-Claisen rearrangement 5.56 —> 5.58, which is one of the most frequently used [3,3] sigmatropic rearrangements, because it sets up two usefully substituted stereogenic centres with high levels of predictability, stemming from the chair-like transition structure 5.57. 

The immediate product of the rearrangement, a carboxylic acid silyl ester, cannot be isolated and is hydrolyzed during workup. The Ireland-Claisen Rearrangement thus offers ready access to chain-extended carboxylic acids. 

As shown earlier (Figure 13.22), silyl ketene acetals can be prepared at -78 °C by the reaction of ester enolates with chlorosilanes. O-Allyl-O-silyl ketene acetals (A in Figure 14.48) are formed in this reaction if one employs allyl esters. Silyl ketene acetals of type A undergo [3,3]-rearrangements rapidly upon warming to room temperature. This variation of the Claisen rearrangement is referred to as the Ireland-Claisen rearrangement. 

Ireland-Claisen rearrangements are extraordinarily interesting from a synthetic point of view for several reasons. First, the Ireland-Claisen rearrangement is an important C=C bondforming reaction. Second, Ireland-Claisen rearrangements afford y,<5-unsaturated carboxylic acids, which are valuable bifunctional compounds. Both of the functional groups of these acids can then be manipulated in a variety of ways. 

Structure B corresponds to the most stable transition state of the Ireland-Claisen rearrangement of Figure 14.49. In this transition state, the substituent at the allylic stereocenter is in a pseudo-equatorial orientation with respect to the chair-shaped skeleton. This is the same preferred geometry as in the case of the most stable transition state B of the Claisen rearrangement of Figure 14.48. The reason for this preference is as before that is, an allylic substituent that is oriented in this way experiences the smallest possible interaction with the chair skeleton. The obvious similarity of the preferred transition state structures of the Ireland-Claisen rearrangements of Figures 14.49 and 14.48 causes the same trans-selectivity. 

H.-J. Altenbach, Ester Enolate Claisen Rearrangements , in Organic Synthesis Highlights (J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. ReiBig, Eds.), VCH, Weinheim, New York, 1991, 116-118. S. Pereira, M. Srebnik, The Ireland-Claisen Rearrangement, AldrichimicaActa 1993, 26, 17-29. 

SCHEME 5.20 Use of the Ireland-Claisen rearrangement in C-sialylation. BOM, benzy-loxymethyl LiHMDS, lithium bis(trimethylsilyl)amide TMS, trimethylsilyl. 

S. Pereira and M. Srebnik, The Ireland-Claisen rearrangement, Aldrichimica Acta 1993,26,17-29. 

This reaction is known as the Ireland-Claisen rearrangement as it was a variation of the Claisen rearrangement invented by R.E. Ireland in the 1970s and widely used since. If the substituents are suitably arranged, it shows the same E selectivity as the simple Claisen rearrangement and for the same reason. 

The Ireland-Claisen rearrangement via enolate trapping with TBDMS-Cl gave a substantial amount of C-silylated product, thus presenting a technical difficulty in isolating the desired product and causing a low overall yield,... 

Scheme 3 Synthesis of intermediate for the Ireland-Claisen rearrangement...

Since introduction of the Ireland-Claisen rearrangement in 1972, the Ireland variant has become increasingly popular in organic synthesis [66]. Although excess Ic with appropriate base is often employed as selective silylating agent, the role of residual trialkylsilyl triflate and base has not been detailed. Illustrated here are some examples of silyl triflate-mediated rearrangement which can be conducted under milder conditions. 

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