Imines Darzens’ reactions

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). 

Darzens reactions between the chiral imine 52 and a-halo enolates 53 for the preparation of nonracemic aziridine-2-carboxylic esters 54 (Scheme 3.17) were studied by Fujisawa and co-workers [61], It is interesting to note that the lithium enolate afforded (2K,3S)-aziridirie (2i ,3S)-54 as the sole product, whereas the zinc enolate give rise to the isomer (2S,3i )-54. The a-halogen did not seem to affect the stereoselectivity. 

The classical aza-Darzens reaction (between bromoenolates and imines) has been investigated by several groups in recent years, especially with respect to the design and execution of asymmetric variants. Both stoichiometric and catalytic methods have been studied thus, the reactions between N-Dpp imines and chiral ot-bromoenolates [49] (derived from Oppolzer s sultams Scheme 4.35) and between S-chiral sulfmylimines and achiral bromoenolates [50] (Scheme 4.36) have been reported. 

Diazoesters 22 have an electronically unique a-carbon atom. (Scheme 9) They are commonly used for the formation of aziridines 23 from imines 24. The intermediate (25) resulting from the addition of a-diazoesters 22 to the latter (24) can undergo elimination of the proton at the a-position prior to extrusion of molecular nitrogen. This interrupted aza-Darzens reaction allows for the direct alkylation of diazoesters 22 via cleavage of a carbon-hydrogen bond. 

Exploiting the Lewis basic phosphoryl oxygen of Im, Terada reported the direct alkylation of a-diazoesters with N-acyl imines to afford P-amino-a-diazoesters in high yields and ee s (Scheme 5.12) [23]. Earlier, Johnston had observed that catalytic TfOH promoted aziridine formation (Aza-Darzens reaction) between diazoacetates and N-benzyl imines [24]. The authors propose that aziridine formation is circumvented through C—H bond cleavage by the phosphoryl oxygen of 1 (Intermediate A). However, as noted by the authors, the low nucleophilicity of N-acyl imines might also be considered as the cause of this selective transformation. 

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. 

Diazoacetates are commonly used for the formation of aziridines from imines under Lewis or Bronsted acidic conditions - a process known as the aza-Darzens reaction. A useful twist on the reaction is achieved if the 1,2-addition intermediate undergoes deprotonation of the a proton prior to intramolecular aziridine formation with N2 extrusion. Such an interrupted aza-Darzens reaction accomplishes a... 

Imines can readily serve as aziridine precursors via an aza-Darzens or Darzens-like approach. Vinyl aziridines were synthesized in 57 to 77% yield by reacting ylides generated from substituted allyltetrahydrothiphenium salts with V-(dimethylsulfamoyl)phenyl imine <07SL2879>. Aziridines carrying two or three heteroaryl groups were synthesized on the basis of the Darzens reaction between imines and a-chloroalkyl heterocycles <07EJO5926>. 

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. 

Addition of sulfur ylides to imines results in formation of aziridines—a process similar to the Darzens reaction (eqs. 75 and 76). 

Bianthryl derivatives. The utility of a chiral magnesium phosphate salt (386) in the synthesis of aziridines (385) via the enantioselective aza-Darzens reaction of 3-chloro-pentane-2,4-dione (384) and imines (383), has been investigated by Antilla et al. (Scheme 101). ... 

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]. 

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],... 

Attempts at deprotonation of epoxyketone 190 with EDA or n-BuLi at —95°C result only in reduction or addition to the carbonyl moiety. By contrast, deprotonation of the epoxy imine 191 leads to the aziridine 192 through a stereoselective dimerization/aza-Darzens//3-deprotonation process (Scheme 84). No example of reaction of this lithiooxirane with other electrophiles is reported. 

Three groups of polar processes to form aziridines are shown in Scheme 16. In every case, each of the two reactants must be capable of acting formally as either a bis-nucleophile or a bis-electrophile, or they must each have both nucleophilic and electrophilic character. In the aza-Darzens route (B-83MI 101-01, 84CHEC-(7)47), the imine acts as an electrophile at carbon and later as a nucleophile at nitrogen, while the a-haloenolate acts initially as a nucleophile at carbon and later as an electrophile at the same carbon. The roles of the two components are reversed for the polar aziridination route, which is related to the epoxidation reaction. In the last route, the 1,2-dihalide or a-haloenone acts formally as a bis-electrophile while the amine acts as a bis-nucleophile. 

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. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

The addition of halomethyl metal reagents provides another Darzens-like route to aziridines <06JOC9373>. Reaction of ICHjCl with MeLi generates a chloromethyllithium reagent, which then adds to the imine 74. A subsequent intramolecular A -alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene. 

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