Phase Darzens-reaction

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

Of course, the most practical and synthetically elegant approach to the asymmetric Darzens reaction would be to use a sub-stoichiometric amount of a chiral catalyst. The most notable approach has been the use of chiral phase-transfer catalysts. By rendering the intermediate etiolate 86 (Scheme 1.24) soluble in the reaction solvent, the phase-transfer catalyst can effectively provide the enolate with a chiral environment in which to react with carbonyl compounds. 

Early work on the use of chiral phase-transfer catalysis in asymmetric Darzens reactions was conducted independently by the groups of Wynberg [38] and Co-lonna [39], but the observed asymmetric induction was low. More recently Toke s group has used catalytic chiral aza crown ethers in Darzens reactions [40-42], but again only low to moderate enantioselectivities resulted. 

Table 1.12 Cinchona alkaloid-derived phase-transfer catalysts for asymmetric Darzens reactions.

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

The Darzens reaction can also proceed in the presence of a chiral catalyst. When chloroacetophenone and benzaldehyde are subjected to asymmetric Darzens reaction, product 89 with 64% ee is obtained if chiral crown ether 88 is used as a phase transfer catalyst (Scheme 8-30).69... 

S. Arai, Y. Shirai, T. Ishida, T. Shioiri, Phase-Transfer-Catalyzed Asymmetric Darzens Reactions , Tetrahedron... 

The Darzens reaction between aldehydes and ketones with activated halomethyl compounds is an effective route to oxiranes under phase-transfer catalytic conditions and the catalyst has a profound stereochemical control of the substituents (see Chapter 12). The reaction has been conducted in high yield under liquidtliquid and solidrliquid two-phase conditions with a range of halomethyl compounds [e.g. 25-30], Ketones tend to be much slower in their reaction and benzylic ketones undergo alkylation with chloroacetonitrile in preference to the Darzens reaction [25]. 

Although the effect of quaternary ammonium salts on the stereochemistry of the two-phase condensation reaction of a-chloroacetonitrile with acrylonitriles to form cyclopropanes [4, 7] is not as pronounced as with the Darzens reaction, it can be rationalized in an analogous manner (Scheme 12.2). In the absence of the catalyst, the more highly stabilized anion (4a) is favoured leading to the preferential production of the cis isomer (5). As with the Darzens reaction, addition of the catalyst causes diffusion of the anions (4a) and (4b), as ion-pairs, into the bulk of the organic phase where their relative stabilities are similar and a more equal ratio of the two isomeric cyclopropanes (5) and (6) results (Table 12.2). 

The use of quininium salts can add to the high stereoselectivity (65-80% ee) that can be achieved under phase-transfer catalytic conditions in the synthesis of oxiranes by the Darzens reaction (Section 12.1) from chloromethylsulphones and aromatic aldehydes [6],... 

Some organic reactions can be accomplished by using two-layer systems in which phase-transfer catalysts play an important role (34). The phase-transfer reaction proceeds via ion pairs, and asymmetric induction is expected to emerge when chiral quaternary ammonium salts are used. The ion-pair interaction, however, is usually not strong enough to control the absolute stereochemistry of the reaction (35). Numerous trials have resulted in low or only moderate stereoselectivity, probably because of the loose orientation of the ion-paired intermediates or transition states. These reactions include, but are not limited to, carbene addition to alkenes, reaction of sulfur ylides and aldehydes, nucleophilic substitution of secondary alkyl halides, Darzens reaction, chlorination... 

A somewhat more successful approach to asymmetric Darzens reactions has been observed in the reaction of a-halosulfones with aldehydes under phase-transfer conditions <07T8099>. The reaction of an a-chlorosulfone with benzaldehyde in the presence of quinine derived phase-transfer catalyst 11, provides the epoxide in excellent yield with very good enantioselectivity. The use of RbOH as the base was crucial to both yield and enantioselectivity. 

The Darzens reaction has been performed enantioselectively, by coupling optically active a-bromo-p-hydroxy esters with aldehydes.Chiral phase-transfer agents have been used to give epoxy ketones with modest enantioselectivity. Chiral additives have proven to be effective. 

Aral, S., Shirai, Y., Ishida, T., Shioiri, T. Phase-transfer-catalyzed asymmetric Darzens reaction. Tetrahedron 1999, 55, 6375-6386. 

Aral, S., Shioiri, T. Asymmetric Darzens reaction utilizing chloromethyl phenyl sulfone under phase-transfer catalyzed conditions. Tetrahedron 2002, 58,1407-1413. 

The Darzens reaction (tandem aldol-intramolecular cyclization sequence reaction) is a powerful complementary approach to epoxidation (see Chapter 5) that can be used for the synthesis of a,P-epoxy carbonyl and a,p-epoxysulfonyl compounds (Scheme 8.32). Currently, all catalytic asymmetric variants of the Darzens reactions are based on chiral phase-transfer catalysis using quaternary ammonium salts as catalysts. 

Excellent heat and mass transfer characteristics of the SDR have been confirmed by the study of a phase-transfer-catalyzed Darzens reaction for preparing a drug intermediate. The SDR allowed for a 99.9% reduction in reaction time, 99% reduction of inventory and 93% reduction in the level of impurities [106]. Other possible applications of the SDR include polymerizations and polycondensations (in both cases considerable time savings and more uniform product) as well as precipitation/crystallization (smaller crystals with much narrower size distribution). Two large chemical companies have patented processes based on spinning-disc technology. SmithKline Beecham has claimed a method to epoxidize substituted... 

Aldehydes can also be converted to enantioenriched chiral epoxides through the Darzens reaction. Thus, haloimides (e.g., 47) react with benzaldehyde in the presence of a novel phase transfer catalyst 45 derived from BINOL to give 1,2-disubstituted epoxides in good yields with... 

Normally, the Darzens reaction of simple a-halo esters is carried out under anhydrous conditions, since in aqueous media or under phase-transfer catalysis conditions the esters are prone to hydrolysis. Saponification can be largely prevented by using r-butyl esters, but this strategy also poses potential problems, as hydrolysis of the resulting glycidic ester is often the next stage of a synthetic process. Recently, a procedure has been developed in which a-chloro esters are deprotonated by treatment with potassium... 

Until recently, little success had been achieved in developing a highly enantioselective version of the Darzens reaction. Several investigations of chiral phase-transfer catalysts for this condensation, in which low or modest asymmetric induction is obtained, have been reported. These include the use of N-alky -N-methylephedrinium halides, the quinine-derived salt (120), and polyamino acids. A related study has examined the use of achiral phase-transfer catalysts in the condensations of carbonyl compounds and the asymmetric chloromethylsulfonate ester (121). The same group of researchers subsequently reported similar studies employing the sulfonamides (122)-(124). ... 

The asymmetric Darzens reaction of a-chlorocycloalkanones using quatemized cinchona alkaloids as phase-transfer catalyst and LiOH as base in BU2O at room temperature is usually high yielding. However, the moderate ee is disappointing. 

A Darzens-type condensation has been employed in the synthesis of (46) by the reaction of 9-chlorofluorene anion (45) with PhCHO.A two-phase system was used to prepare (f)-(47 R = H, Cl, or NO2) almost exclusively, via a Darzens reaction of the substituted benzaldehyde with PhCOCH2Br in the presence of a quaternary ammonium salt as catalyst. ... 

Numerous other reactions of carbanions are efficiently executed in two-phase systems using concentrated aqueous NaOH and PT catalysts for deprotonation of the carbanion precursors. These conditions are particularly suitable for synthesis of oxiranes via condensation of aldehydes and ketones with carbanions of, e.g., ot-chloronitriles, sulfones, and esters of a-chlorocarboxylic acids, known as the Darzens reaction, or with sulfonium... 

Optically active a, -epoxy stdfones. - The Darzens reaction of ethyl methyl ketone with chloromethyl / -tolyl sulfone in a two-phase system in the presence of chiral ammonium salts such as N-ethylephedrinium bromide results in a,/3-epoxy sulfones with 0-2.57o optical yields. However, if the supported catalyst (1) is used, optical yields of up to 23% can be obtained as in the example formulated in equation (I). On the other hand, the reaction is slower when the catalyst is supported. The presence of a hydroxy group jS to the nitrogen atom of the catalyst is essential for asymmetric induction. 

Phase transfer reactions have featured in several sections of this book, including epoxidation (Section 4.5), Darzens condensation (Section 7.5) and Wadsworth-Emmons reactions (Section 12.5). Another important aspect of phase-transfer catalysed reactions has been with alkylation reactions. The asymmetric alkylation of glycinate Schiff base (12.45) using N-benzylcinchoninium halides as catalysts is particularly noteworthy, since the products are readily converted into amino acids. Corey and coworkers have developed the original work. 

Scheme 16.34 Asymmetric phase-transfer catalytic Darzen reaction of a-halo ketones.

Scheme 16.35 Aqmmetric phase-transfer catal)d ic Darzens reactions of a-halo sulfones.

A phase-transfer-catalysed asymmetric Darzens reaction of cyclic a-chloro ketones has been reported. ... 

Akabari, S., Ohtomi, N., and Yatabe, S., Two-phase Darzene condensation reaction with octopus compounds as catalysts. Bull. Soc. Chem. Japan, 53, 1463, 1980. Dehmlow, E. W, and Lissel, H., Alkyne synthesis using tert-BuOH-18C6 crown ether-petroleum ether as catalytic system, Liebigs Ann., 1980, 1. 

Anhydrous sodium or potassium carbonates have been shown to act as efficient strong bases in solid-organic liquid two-phase systems in the presence of crown ethers this by-passes the requirement for concentrated aqueous hydroxide solutions in the equivalent liquid-liquid techniques. Among the reactions possible with this new method are the alkylation of active methylene compounds, the Williamson ether synthesis, and the Darzens reaction. 

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