Catalysts Robinson annulation

Besides a polymerization of the Michael acceptor, a double alkylation of the starting ketone, by reaction with a second Michael acceptor molecule, may take place as a side reaction, and thus further reduce the yield. The polymerization of the enone 2 as well as the double alkylation of the starting ketone can be avoided by application of a modern procedure for the Robinson annulation that uses an organotin triflate as catalyst." ... 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

A procedure using a phase-transfer catalyst is employed to prevent the rapid polymerisation of crotonaldehyde dining the Robinson annulation reaction. 

Inspired by the proline-catalyzed Robinson annulation pioneered by Wiechert, Hajos, Parrish and coworkers [39], they were able to construct cyclohexanones of type 2-107 with up to four stereogenic centers with excellent enantio- and di-astereoselectivity from unsaturated ketones 2-104 and acyclic (l-ketoesters 2-105 in the presence of 10 mol% phenylalanine-derived imidazohdine catalyst 2-106. The final products can easily be converted into useful cyclohexanediols, as well as y- and e-lactones. 

Why does this pathway occur instead of the Robinson annulation when the seemingly trivial change of increasing the concentration of NaOH is made Good question. It is not clear. It seems likely that the Robinson annulation does occur first (because quick quenching helps to increase the quantity of Robinson product), but the Elcb elimination at the end of the annulation mechanism is reversible in the presence of NaOH as base. It seems likely, then, that if NaOEt were used as base instead, only the Robinson product would be observed regardless of the quantity of catalyst. 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

The Robinson annulation of ethyl acetoacetate and tra i -chalcone was investigated with pulverized NaOH in [BMIMjPFg as the base catalyst at 100°C 110). The mixture was neutralized before extraction with toluene. The product, 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone, was obtained by purification in a silica gel chromatography column. A yield of 48% was obtained (Scheme 7). The ionic liquid could be recycled and reused with no diminution of product yield. The C2 position in imidazolium cations is an acidic proton donor and may have reacted... 

Asymmetric Robinson Annulation. 2-Propyl-1-indanone undergoes Robinson annulation with the catalyst and methyl vinyl ketone (eq 6). Higher ee values were achieved using 1,3-dichloro-2-butene (Wichterle Reagent) as an MVK surrogate for the Michael addition and overall Robinson annulation (eq 9)... 

Using (2) as catalyst provided the (R) enantiomer in 99% yield, 78% ee. The key introduction of asynunetry during the synthesis of (+)-podocarp-8(14)-en-13-one was the phase-transfer-catalyzed Robinson annulation of 6-methoxy-l-methyl-2-tetralone with ethyl vinyl ketone. The authors carried out a comparative study of the A/-(4-trifluoromethyl)benzyl derivatives of cinchonine, cinchonidine, dihydrocinchonine, and dihydrocinchonidine and found that (5) produced the highest ee of the desired (S) enantiomer at —45 °C using toluene and 60% aq KOH (eq 10). ... 

Dibutyltin bis(triflate), Bu2Sn(OTf)2, is a mild Lewis acid which catalyzes clean Michael addition of enol silyl ethers [148]. The new catalyst enables use of various labile acceptors such as methyl vinyl ketone and 2-cyclopentenone which do not undergo smooth reaction with conventional Lewis acids. A variety of enol silyl ethers are also employable and thus 2-(trimethylsiloxy)propene, the simplest of this class of compounds, can be used. The adducts of enol silyl ethers of cycloalkanones with vinyl ketones are readily cyclized to give the desired annulated enones free of isomers. Consequently, a practical version of the Robinson annulation has been realized. 

The next breakthrough was made by Pracejus in 1960 who also used alkaloids as catalysts, namely 0-acetlyquinine in the addition of methanol to phenylmethylke-tene in an impressive ee of 74 % [20]. Then in 1973 the (5)-proUne (27) catalysed Robinson annulation was discovered by Hajos and Parrish and independently by Wiechert and co-workers [21, 22]. High levels of enantioselectivity of up to 93 % were observed using 3 mol% of catalyst in the transformation which later became known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction (Scheme 4.9). 

Although asymmetric organocatalysis is now considered as a powerful tool for the synthesis of chiral compounds this research held experimented its own revolution. It was restricted after the seventies only to the nse of simple a-amino acids as catalyst for the Robinson annulations and above all with the application of proline to the enantioselective intermolecular aldol reaction. 

There are different approaches for stereocontrol for the Robinson annulation the control can either arise fi-om the inherent nature of the starting ketone and/or the vinyl ketones substituents in combination with the reaction conditions, or by the use of a chiral catalyst. In the first case, an example is the stereoselective aldol cyclization to give the ketol intermediate 50. In this case the cyclization is kinetically controlled under protic basic conditions of sodium ethoxide and ethanol as it gives the cw-fused adduct rather than the more stable trans-fased ketol, which is not detected at any time during the reaction. 

A more efficient approach to control the stereochemical outcome for the Robinson annulation can be through the use of chiral catalysts such as in the case of the enantioselective Hajos-Wiechert variation introduced earlier. There are other chiral agents other than the popular (S)-proline-mediated annulation reaction that are used for these transformations—for example the use of (Bronsted acid such as trifluoroacetic (TFA). This new catalyst for the Robinson annulation was reported in 2007 by Endo et. al., where the Bronsted acid, contrary to Hajos-Wiechert reaction, gives the (i )-isomer of the Wieland-Miescher ketone 44 in a moderate yield of 47% and 75% ee. 

In 2009 Miro et al. reported the use of phosphoric acids as a chiral catalyst for enantioselective transformation of the Robinson annulation. Chrial phosphoric acids 61 and 62 are used in sequence first for the Michael reaction step and are then followed by the cyclization step. Synthesis of the aimulation adduct 64 is shown as an example in the group s report. The cyclized adduct is formed from the reaction of the P-keto ester 63 in the presence of the phosphoric acid 61 at 40 °C for 24 h and is followed by... 

The Hajos and Wiechert research groups looked at a number of other potential proline based catalysts for their intramolecular Robinson annulation. (. -(-)-Hygrinic acid, Af-methylproline 13, was examined, but only the racemic intermediate ketol product 2 was obtained. In a similar manner, the proline methyl ester 14 also produced the racemic ketol intermediate. No reaction was observed with the piperidine analog 15. The homo-proline analog 16 gave the enantiomeric product. An explanation for this change in selectivity has not been provided yet. Please note that the use of (i )-proline provides the enantiomeric product. 

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