Darzens aziridine synthesis

An asymmetric aziridine synthesis was reported through an aza-Darzens reaction of T-diphenylphosphinylimines with a chiral a-bromo enolate of 582 (R = GOGH2Br) <2006T3694>. Asymmetric /7-halomethoxylation catalyzed by silver(l) <2006TA210>, yy -dihydroxylation <2000TA1027>, and epoxidation with different oxidants <2004T6657> of unsaturated sultams 582 (R = GOGR =GR R ) were performed. 

Davis, F. A., Liu, H., Zhou, P., Fang, T., Reddy, G. V., Zhang, Y. Aza-Darzens asymmetric synthesis of N-(p-toluenesulfinyl)aziridine 2-carboxylate esters from sulfinimines (N-sulfinyl imines). J. Org. Chem. 1999, 64, 7559-7567. 

McLaren, A. B., Sweeney, J. B. Inverted Diastereoselectivity in Asymmetric Aziridine Synthesis via Aza-Darzens Reaction of (2S)-N-Bromoacyl Camphorsultam. Org. Lett. 1999,1,1339-1341. 

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

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 formation of bonds c and b can take a couple of forms, either a Darzens-type approach (i.e., addition of a nucleophile bearing a leaving group) or addition of a carbene. Both of these routes have been used in the synthesis of fused-ring aziridines as well as monocyclic aziridines. The addition of a carbene or nucleophile such as an ylide to an imine can provide a nice route to fused-ring aziridines. The necessary cyclic imines are sometimes more readily obtained and used than the acyclic imines. These methods have largely been used on pyridine and quinoline derivatives. 

A procedure has been developed which extends the Darzens synthesis to the preparation of aziridine esters and amides (equation 29). Reaction of benzalaniline (80) and ethyl chloroacetate (in BuKDK/DME) results in the formation of the trans-aziridine (82a) in 29% yield analysis of the crude reaction mixture showed no more than 10% of the isomeric cis adduct (83a). Similarly, condensation of 2-chloro-N,N-diethylacetamide and (80) affords aziridines (82b) and (83b) in 65% yield. However, in this case the cis isomer predominates ( 90 10, cis trans). The formation of (83a R = OEt) as the major product is consistent with the overlap control model suggested by Zimmerman. Apparently, the decreased stability of the amide (81b) enolate relative to the ester (81a) enolate causes ki (cyclization) to become greater than k (addition Scheme 19) it follows that the stereochemical outcome is determined in the initial aldol step, and steric arguments are advanced to explain this outcome. 

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]. 

At the same time, Antilla et al. developed a vaulted biphenanthrol (VAPOL)-based magnesium phosphate 20b mediated asymmetric aza-Darzens reaction for the synthesis of chiral aziridine derivatives. The catalyst was prepared in an identical procedure to the previously described process with VAPOL-derived phosphate and magnesium fert-butoxide, and applied in the enantioselective aza-Darzens reaction of N-benzoyl imines 23 and ot-chloro-1,3-diketone 24. The process formed a series of substituted aziridines 25 bearing various substituents at the aromatic ring, with good... 

In addition to alkenes, imines are tremendously popular aziridine precursors via an aza-Darzens approach. For example, a stereoselective synthesis of C-sulfonylated aziridines was reported via an aza-Darzens approach employing bromomethyl phenyl sulfbne, NaHMDS, and a series of N-tert-butanesulfinyl imines (14MI969). Likewise as shown below, chiral tert-butane- and mesitylsulfinimines were subjected to an aza-Darzens reaction with substituted 2-bromoesters to provide a host of aziridines in good yield with excellent stereocontrol (14OL6920). In turn, these aziridines could be subsequently converted to chiral A/-H aziridines in a total of three steps starting with a wide range of commercially available aldehydes. 

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... 

Stereoselective synthesis of 2,3-di- and 2,2, 3-tri-substituted aziridines in good yields and excellent diastereo-selectivities (>98% de) is achieved through aza-Darzens... 

Other uses of phosphonate anions prepared from deprotonation with LHMDS include the acylation reaction for the synthesis of (diphenylphosphono)acetic acid esters (eq 55) as well as the aza-Darzens reaction leading to aziridine 2-phosphonates (eq 56). In both cases, LHMDS proved to be equal or superior to other lithium bases. 

Scheme 37.17 Synthesis of aziridines through the aza-Darzens reaction (PMP = pora-methoxyphenyl).

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