Darzens-type reaction

The synthesis of vinylaziridines through reactions between allylic carbenoid reagents and imines (i.e., Darzen-type reactions) was first reported by Mauze in 1980 [13]. Treatment of aldimines or ketimines 16 with gem-chloro(methyl)allyllithium (17) afforded N-substituted vinylaziridines 18 (Scheme 2.6). Similarly, 2,3-trans-N-diphenylphosphinyl-2-vinylaziridines 21 were prepared with good stereoselectivities (trans cis= 10 1 Scheme 2.7) by treatment of a-bromoallyllithium (20) with N-diphenylphosphinyl aldimines 19 in the presence of zinc chloride [14]. 

Scheme 2.6 Aza-Darzen-type reaction with chloro(methyl) allyllithium (17).

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

Some related reactions are worth mentioning in this context. Addition of allylnickel bromide to styrene oxide to give an alcohol has been reported (example 7, Table IV). Tsutsumi has described the Darzens-type reaction of two molecules of a-bromoketones to give dimethylfurans (example 8, Table IV). This reaction consists of the addition of the ketomethylenic group to the carbonyl group of another molecule, followed by epoxide formation and bromide elimination. A subsequent rearrangement leads to a dialkylfuran. 

There are many routes available for the synthesis of aziridine 2-carboxylic acids, however there are few reactions which yield enantiomerically pure products. These compounds (especially those with cis-stereochemistry) are especially useful for the synthesis of bioactive molecules556. There is thus significant effort in this area of synthesis557,558, but most methods are lengthy multistep procedures. Recently, a simple, one-pot procedure, utilizing imines, has been developed for the asymmetric synthesis of c/s-N-substituted aziridine-2-carboxylic acids via a Darzens-type reaction (equation 154)559. 

The topic of nucleophilic attack at an sp2 carbon would be too wide a field to review in one chapter, if one were to discuss all facets and outcomes, some of which are shown in Figure 1. If the nucleophile is anionic an anion is formed, but if the nucleophile is neutral a zwitterion is produced. If X is oxygen or nitrogen, then the outcome can be carbonyl addition, substitution or a Darzens-type reaction. If the X is another carbon then addition leads to conjugate additions or polymerization. Alternatively the nucleophile could be expelled after rotation about the C—C bond to give overall isomerization. Both substitution and cyclization are also observed. 

An intriguing route to ethylamino epoxides through a Darzens-type reaction has been reported <07CC2500>. Rather than the typical a-halo ester, this method uses an a-ammonium azetidinium salt 12 as the leaving group. This method provides the aminoethyl substituted epoxide 13 in excellent yield. 

A related approach uses a Darzens-type reaction to prepare aziridines <2001M849, 2002M1071>. Chloromethyl sulfones and sulfonamides were deprotonated with powdered KOH in DMSO. Addition of this carbanion to the more electrophilic C=N bond followed by aziridine ring formation provides aziridine 135 (Equation 32). No information was provided on the relative stereochemistry of the aziridine. 

In a related report, a Darzens-type reaction performed in the presence of BINOL-derived phase-transfer catalyst allowed for epoxide formation with high enantioselectivity and moderate diastereoselectivity <1996TL1845>. 

When chloromethyl phenyl sulfone (130 Ar = phenyl) was subjected to the Darzens-type reaction with an aldehyde, a thermodynamically stable trans isomer (133) was produced exclusively (equation 32). This is in sharp contrast with the corresponding reaction of chloromethyl phenyl sulfoxide. Tavares proposed that the initial nucleophilic attack of the a-sulfonyl carbanion upon a carbonyl compound is rapidly reversible due to its stability, and that the product-determining step is the ring closure. Thermodynamic equilibrium between the two diastereomers of (132) allows predominant formation of the thermodynamically stable isomer (133) from the preferred transition state. ... 

During the enantioselective total synthesis of (-)-coriolin, I. Kuwajima and co-workers used a Darzens-type reaction to construct the spiro epoxide moiety on the triquinane skeleton. Interestingly, the usual Darzens condensation where the a-bromoketone was condensed with paraformaldehyde yielded a bromohydrin in which the hydroxymethyl group was introduced from the concave face of the molecule. This bromohydrin upon treatment with DBU gave the undesired stereochemistry at C3 (found in 3-ep/-coriolin). To obtain the correct stereochemistry at C3, the substituents were introduced in a reverse manner. It was also necessary to enhance the reactivity of the enolate with potassium pinacolate by generating a labile potassium enolate in the presence of NIS. The in situ formed iodohydrin, then cyclized to the spiro epoxide having the desired stereochemistry at C3. 

Hirashita, T., Kinoshita, K., Yamamura, H., Kawai, M., Araki, S. Afacile preparation of indium enolates and their Reformatskii- and Darzens-type reactions. Perkin 1 2000, 825-828. 

Kim, D.Y., Suh, K.H., Choi, J.S., Mang, J.Y, and Chang, S.K., Asymmetric synthesis of aziridinyl phosphonates using Darzens-type reaction of chloromethyl phosphonate to chiral sulfinimines, Synth. Commun., 30, 87, 2000. 

Darzens-type reactionThe Darzens reaction2 of a-halocarbonyl compounds with an aldehyde requires a base, which can promote side reactions. Darzens reactions can proceed under neutral conditions when effected with this neutral reagent (I cquiv.). Presumably, the reaction proceeds via an organotin(lV) enolate. When the reaction is conducted in THF, the rron.v-epoxidc is generally favored, but addition of HMPA can favor cis-sclectivity. ci.v-Selectivity is also favored in reactions of aliphatic aldehydes. The Darzens-type reaction can also be extended to or-halo esters, particularly in the presence of Bu4NF or LiBr. 

In a similar vein, Davis and co-workers have found the p-toluenesulf nyl group to be useful for such purposes. Aziridine-2-carboxylic acid derivatives 138 are prepared in high diastereomeric purity by a Darzens-type reaction of the lithium enolate of methyl bromoacetate (137) with enantiopure sulfrnimines (e.g., 136) [94JOC3243]. These compounds have been employed as intermediates in the asymmetric synthesis of the antibiotic (+)-thiamphenicol (139) [94TL7525]. 

Three- and Four-membered Rings.- A convenient synthesis of substituted aziridines (157) has been described which utilizes a Darzens-type reaction between diarylimines (155) and isopropyl dichloroacetate (156). The reaction is limited to aromatic... 

SCHEME 2.28 Synthesis of resolved steroidal epoxides through an aqueous Darzens-type reaction [36],... 

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