Aldehydes Claisen rearrangement

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

CLAISEN - IRELAND Rearrangment Rearrangement ol allyl phenyl ethers to o (or p-)allylphenols or of allyl vinyl ethers to y.S-unsaturated aldehydes or ketones (Claisen) Rearrangement ol allyl esters as enolale anions to y.S-unsaturated acids (Ireland)... 

A salient structural feature of intermediate 18 (Scheme 2b), the retrosynthetic precursor of aldehyde 13, is its y,r5-unsaturated ester moiety. As it turns out, the Johnson ortho ester variant of the Clai-sen rearrangement is an excellent method for the synthesis of y,<5-unsaturated esters.11 In fact, the Claisen rearrangement, its many variants included, is particularly valuable in organic synthesis as a method for the stereocontrolled construction of trans di- and tri-substituted carbon-carbon double bonds.12,13 Thus, it is conceivable that intermediate 18 could be fashioned in one step from allylic alcohol 20 through a Johnson ortho ester Claisen rearrangement. In... 

The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has also been demonstrated on a number of other substrates. These studies showed that this methodology has potential applications in organic synthesis. In Eq. 12.72, the unprotected vinyl ether in a 2.5 1 water-methanol solvent with an equivalent of sodium hydroxide underwent rearrangement to give the aldehyde in 85% yield.157... 

Nordmann and Buchwald have reported a diastereoselective Claisen rearrangement of an allyl vinyl ether to an aldehyde (Scheme 6.81) [170]. Using N,N-dimeth-ylformamide as solvent, an 80% yield with a diastereomeric ratio of 91 9 was obtained by microwave heating at 250 °C for 5 min. Conventional heating at 120 °C for 24 h provided somewhat higher yields and selectivities (90% yield, dr = 94 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. 

The procedure given above is an excellent example of the utilization of the Claisen rearrangement to generate an angularly functionalized steroid. The vinyl ether and aldehyde were originally prepared by Burgstahler and Nordin.2 This procedure combines variations employed by Ireland and co-workers and, in addition, introduces the use of silica gel for the purification of the vinyl ether, thereby improving the reproducibility of the procedure. 

The Claisen rearrangement goes through a transition state in the chair conformation. This is the supported by the fact that trans, trans-crotyl propenyl ether gave more than 97% of the threo aldehyde showing a preference for the chair form while reaction in the boat gave mainly erythro aldehyde. 

The silylative conversion of a ketone or aldehyde to silylenol ether developed by Marshall, Ireland and Danishevsky produces a reactive diene which can participate in Diel-Alder or Claisen rearrangements. 

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. 

An elegant ring expansion methodology has been developed by Paquette [699] (Figure 3.41). This synthetic sequence is based on the double methylenation of an a-(acyloxy)aldehyde to give an allyl vinyl ether, which undergoes (reductive) Claisen rearrangement when treated with trialkylalanes. 

The reaction was achieved through transfer vinylation of 67 with 68 by action of the [IrCl(cod)]2 complex to afford allyl homoallyl ethers 69, followed by a Claisen rearrangement of the ether 70. The Claisen rearrangement of allyl homoallyl ethers to y,5-unsaturated aldehydes has been reported previously [6]. 

The procedure described illustrates a new general synthetic method for the preparation of (E)-3-allyloxyacryl ic acids and their conversion to a-unsubstituted y,5-unsaturated aldehydes by subsequent Claisen rearrangement-decarboxyl at ion. Such aldehydes are traditionally prepared by Claisen rearrangements of allyl vinyl ethers. Allyl vinyl ethers are typically prepared by either mercury-catalyzed vinyl ether exchange with allylic alcohols or acid-catalyzed vinylation of allylic alcohols with acetals. The basic conditions required for alkoxide addition to the betaine to produce carboxyvinyl allyl ethers, as described in this report, nicely complements these two methods. In addition, this Claisen rearrangement is an... 

The full paper on the synthesis of onikulactone and mitsugashiwalactone (Vol. 7, p. 24) has been published.Whitesell reports two further useful sequences (cf. Vol. 7, p. 26) from accessible bicyclo[3,3,0]octanes which may lead to iridoids (123 X=H2, Y = H) may be converted into (124) via (123 X = H2, Y = C02Me), the product of ester enolate Claisen rearrangement of the derived allylic alcohol and oxidative decarboxylation/ whereas (123 X = 0, Y = H) readily leads to (125), a known derivative of antirride (126) via an alkylation-dehydration-epoxi-dation-rearrangement sequence. Aucubigenin (121 X = OH, R = H), which is stable at —20°C and readily obtained by enzymic hydrolysis of aucubin (121 X = OH, R = j8-Glu), is converted by mild acid into (127) ° with no dialdehyde detected sodium borohydride reduction of aucubigenin yields the non-naturally occurring isoeucommiol (128 X=H,OH) probably via the aldehyde (128 X = O). ... 

The hydrogenation of Claisen rearrangement products (R)-(E)- and (S)-(Z)-3,7-dimethyl-4-octenal [obtained highly selectively from (7 )-( )-6-methyl-4-vinyloxy-2-heptene, see p421] to give (S)- and (7 )-3,7-dimethyloctanal, respectively. Authentic samples of these aldehydes were obtained from (5)- and (7 )-citronellal 14°. 

Conversion of the Claisen rearrangement product (3S)-3-phenyl-l-trimethylsilyl-4-penten-1-one (see p 402) to the known aldehyde 9 by desilylation74. 

Organomagnesium compounds react with imines, prepared from 3-methoxy-2-naphth-aldehydes by a 1.4-addition mechanism. This reaction can be performed with high diastere-oselectivity. The method was applied for the synthesis of optically pure S-tetralones . Vinyhnagnesium bromide reacts as an acceptor with a ketone dimethyl hydrazone zincate 207, yielding a 1,1-bimetallic species, which can be reacted sequentially with two different electrophiles (equations 131 and 132) . The reaction proceeds via a metalla-aza-Claisen rearrangement, where the dimethylhydrazone anion behaves as an aza-allylic system . 

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