Aldehydes Darzens reaction

Of interest is a recent report of a rapid synthesis of efaroxin (51), a potent, selective O2 adrenoceptor antagonist, using Darzens Reaction. Accordingly, a-bromoester 48 was condensed with aldehyde 47. The glycidic ester (49) was then hydrogenated to reduce the more labile epoxide bond to give alcohol 50. Subsequent standard transformations subsequently lead to a completed 4-step synthesis of efaroxin. o... 

The aza-Darzens reaction is analogous to the Darzens synthesis of epoxides (see Section 1.2.3.2) but employs imines in the place of aldehydes (Scheme 1.27). 

Vinylsilanes (Chapter 3) can be readily converted into a/3-epoxysilanes, normally by treatment with mcpba (/). Alternatively, a-chloro-a-lithio-a-trimethylsilanes react efficiently with aldehydes and ketones in a manner reminiscent of the Darzens reaction (2). 

The direct product is an enol that tautomerizes to the aldehyde. This is the usual last step in the Darzens reaction (16-45). 

An unexpected, one-step synthesis of a-chloro-P-lactones in 40-83% yield resulted when phenyl esters of a-chlorocarboxylic acids were treated under the conditions of the Darzens reaction with strong base in the presence of ketones or aldehydes <95AG(E)2028>. Previously, phenyl esters do not appear to have been used in this reaction. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

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]. 

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],... 

A number of glycidates are important intermediates in the synthesis of fragrance materials. A few glycidates are fragrance materials in themselves. They are prepared either by epoxidation of the corresponding acrylates or by condensation of aldehydes or ketones with a-chloro substituted fatty acid esters (Darzens reaction). 

Glycidic esters can easily be converted to aldehydes (2-40). The reaction has been extended to the formation of analogous aziridines by treatment of an imine with an a-halo ester or an a-halo N,N-disubstituted amide and f-BuOK in the solvent 1,2-dimethoxy-ethane.636 However, yields were not high. Acid-catalyzed Darzens reactions have also been reported.637 See also 6-61. 

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... 

The Darzens reaction is the base-promoted generation of epoxides XIII from aldehydes (or ketones) XI and alkyl halides XII, the latter carrying an electron withdrawing group, for example the carbonyl, nitrile, or sulfonyl, in the a-position (Scheme 6.83) [188, 189]. It is, formally, addition of a carbene to the C=0 double bond (Scheme 6.83, path B) and thus complements oxygen atom transfer to olefins... 

A complementary approach to similar products involved the asymmetric Darzens reaction of a-chloro ketones such as 29 with aldehydes. The cinchoninium salt 2f allowed the epoxide 30 to be prepared with reasonably high enantiomeric excess (Scheme 11) [19]. 

A typical Darzens reaction involves the base-catalysed formation of an epoxide from an a-haloketone and an aldehyde. Suggest a mechanism for the Darzens reaction consistent with the results shown below. 

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. 

Darzens reaction. Under the usual condiiions (sodium alkoxides as base and the corresponding alcohol as solvent), the condensation of aliphatic aldehydes with a-halo... 

Enantiomerically enriched epoxides have also been generated using (1) in the Darzens reaction of a-chloro ketones with aldehydes, as well as through ring closure of racemic halohydrins. The extent of enantioselectivity for both reactions is similar (optical purity 6-8% 1), suggesting a moderate degree of kinetic resolution occurring in each case. 

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. 

By the Darzens reaction. -ionone afforded a C14 aldehyde which as the diethyl acetal underwent addition to ethyl vinyl ether in the presence of boron trifluoride etherate to yield a Cl6 acetal. After hydrolysis, loss of ethanol and formation of the diethyl acetal as before, reaction under acidic condiions with ethyl propenyl ether gave the unsaturated Cl9 aldehyde after hydrolysis and removal of ethanol. Reaction of two moles with ethyne dimagnesiuro bromide produced the C40 chain and dehydration of the diol, selective catalytic hydrogenation followed by isomerisation completed a remarkable technical synthesis of i-carotene. Further variations have involved the use of two moles of the C14 aldehyde and a Cl2 divinyl ether. An independent approach (ref.29) has utilised vitamin A (32) converted to a phosphonium salt, thence to the corresponding phosphoran, autoxidation of which afforded s-carotene ( scheme 16). 

Alternatively, epoxy esters may be prepared via the Darzens reaction, which involves base-mediated condensation of a-chloro esters with aldehydes or ketones. ... 

Aral, S., Suzuki, Y., Tokumaru, K., Shioiri, T. Diastereoselective Darzens reactions of a-chloro esters, amides and nitriles with aromatic aldehydes under phase-transfer catalyzed conditions. Tetrahedron Lett. 2002, 43, 833-836. 

Deschamps, B., Seyden-Penne, J. Solvent effects on the stereochemistry of the Darzens reaction. III. Condensation of chloroacetonitrile and aromatic aldehydes in a basic medium. Tetrahedron 1971, 27, 3959-3964. 

Later, Arai, and coworkers applied their PTC-mediated Darzens reaction conditions to the synthesis of optically active oc, 3-epoxysulfones [43], The reaction of the chloromethyl phenyl sulfone 102 with aromatic aldehydes under PTC conditions (101 (10mol%), KOH-toluene) at room temperature afforded the desired trans-epoxysulfones 103 in good yields and with moderate to good ee values (33-81%) (Scheme 8.35). On the other hand, aliphatic aldehydes gave the Darzens product as the racemates. The use of a Lewis acid additive (Sn(OTf)2) improved the selectivity, but only slightly (up to 32% ee). Under PTC conditions, chloromethylsulfone is transformed into the corresponding carbanion, which then reacts with the... 

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