Synthesis of aziridines

Dedicated, with respect, to Professor Sir Charles Rees, FRS Joseph B. Sweeney 

In 1999, Bob Atkinson wrote [1] that aziridination reactions were qs epoxida-tion s poor relation qe , and this was undoubtedly true at that time the scope of the synthetic methods available for preparation of aziridines was rather narrow when compared to the diversity of the procedures used for the preparation of the analogous oxygenated heterocycles. The preparation of aziridines has formed the basis of several reviews [2] and the reader is directed towards those works for a comprehensive analysis of the area this chapter presents a concise overview of classical methods and focuses on modern advances in the area of aziridine synthesis, with particular attention to stereoselective reactions between nitrenes and al-kenes on the one hand, and carbenes and imines on the other. 

Aziridines and Epoxides in Organic Synthesis. Andrei K. Yudin Copyright 2006 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-31213-7 

The carbene-imine route to aziridines has attracted increasing attention of late, though there have also been notable recent advances in addition processes involving alkenes and nitrene equivalents. 

In more recent years, a number of discoveries involving the use of nitre-noid or carbenoid intermediates have been made [35-37]. In 1993, Evans [139] and Jacobsen [140] independently described the asymmetric aziridination of olefins with Phi = NTs mediated by Cu(I) catalysts [141]. The chiral ligands included bisoxazoline 173 (Equation 29) [139] and diimine 176 (Equation 30) [140]. The methods displayed complementary substrate 

Komatsu synthesized the chiral salen complex 185 and demonstrated that aziridinations of various styrene derivatives proceeded enantioselectively in the presence of pyridine N-oxide (Equation 31) [145], Thus, treatment of 

6 lodolactonizations and Other Olefin Cyclizations Induced by Electrophiles 

The fact that olefins are susceptible to electrophilic attack has led to the development of a wide range of methods in which electrophilic activation of the olefin is followed by intramolecular nucleophilic attack. In particular, halolactonizations and -etherifications have enjoyed widespread popularity in stereoselective synthesis. A range of other asymmetric electrophilic olefin cyclizations are also discussed in this section [38, 39]. 

In contrast, a preference for the 1,2-syn diastereomers is observed under conditions favoring kinetic control. In the presence of NaHC03, 204 and 207 were thus obtained as the major products (dr=l 3 and 1 4, respectively) [158]. The modest observed diastereoselectivity is the result of the 

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One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

Iodine isocyanate was used to synthesize the first steroidal aziridine, 2, 3 -iminocholestane (95). from 5a-cholest-2-ene (91). This reaction sequence which is believed to proceed through a three-membered ring iodonium ion (92) illustrates the limitation of pseudohalogen additions for the synthesis of -aziridines. The iodonium complex forms from the least hindered side (usually alpha) and is opened tmK5-diaxially to give a -oriented nitrogen function. The 3a-iodo-2 -isocyanate (93) is converted by treatment with... 

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. 

Synthesis and chemistry of substituted l-azabicyclo[1.1.0]butanes 97SL1029. Synthesis of aziridines via stereoselective reactions with imines 99PAC1033. 

Davis has also employed a similar procedure for the synthesis of aziridine-2-phosphonoates, involving the addition of N-(2,4,6-trimethylphenylsulfinyl)imine to anions of diethyl a-halomethyl phosphonates (Scheme 1.29) [53, 54], Aziridines... 

Synthesis of aziridines by treatment of carbenes with imines was reported by Jacobsen [56]. A metallocarbene 104 derived from ethyl diazoacetate and copper fluorophosphate was treated with N-arylaldimines to form aziridines with reasonable diastereoselectivities (>10 1 in favor of cis) but with low enantioselectivities (about 44% ee). This was shown to result from a competitive achiral reaction path-... 

Table 1.15 Chiral guanidylium ylides for asymmetric synthesis of aziridines.

Methodology for the cyclization of a-hydroxy-P-amino phosphonates has also been developed and employed in synthesis of aziridine-2-phosphonates [79, 80]. Mesyla-tion of a-hydroxy-P-amino phosphonates 89 (Scheme 3.29), for example, gave a-mesyloxy-P-amino phosphonates 90. Treatment of 90 with K2CO3 afforded azir-idine-2-phosphonates 91 in 93-95% yield [79]. 

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],... 

More recently, an improved method for the asymmetric synthesis of aziridine-... 

Since the mid-1990s, synthetic attention has been directed more towards the use of metal-stabilized nitrenes as synthetic effectors of alkene aziridination. In 1969 it was reported that Cu(i) salts were capable of mediating alkene aziridination when treated with tosyl azide, but the method was limited in scope and was not adopted as a general method for the synthesis of aziridines [12]. Metaloporphyrins [13] were shown to be catalysts for the aziridination of alkenes in the presence of the nitrene precursor N-tosyliminophenyliodinane [14] in the early 1980s, but the reaction did... 

The synthesis of aziridines through reactions between nitrenes or nitrenoids and alkenes involves the simultaneous (though often asynchronous vide supra) formation of two new C-N bonds. The most obvious other alternative synthetic analysis would be simultaneous formation of one C-N bond and one C-C bond (Scheme 4.26). Thus, reactions between carbenes or carbene equivalents and imines comprise an increasingly useful method for aziridination. In addition to carbenes and carbenoids, ylides have also been used to effect aziridinations of imines in all classes of this reaction type the mechanism frequently involves a stepwise, addition-elimination process, rather than a synchronous bond-forming event. 

Two methods that are particularly convenient for large-scale synthesis of aziridines are discussed below. Both utilize readily available chloramine salts, such as chloramine-T, as sources of nitrogen. The first method involves direct olefin azir-idination catalyzed by phenyltrimethylammonium tribromide (PhNMe3+Br3 PTAB) [42]. In the second method, 1,2-hydroxysulfonamides, conveniently obtained by osmium-catalyzed aminohydroxylation of olefins, are converted into aziridines by one-pot cyclodehydration. 

Aziridines are versatile intermediates in organic synthesis and commonly found in bioactive molecules. The transition metal-catalyzed nitrene transfer to alkenes is an attractive method for the synthesis of aziridines [7]. In 1984, Mansuy and coworkers reported the first example of an iron-catalyzed alkene aziridination in which iron porphyrin [Fe(TTP)Cl] was used as catalyst and PhINTs was used as nitrene source [30]. Subsequently, the same authors demonstrated that [Fe(TDCPP) (CIO4)] is a more efficient and selective catalyst than [Fe(TTP)Cl] (Scheme 20). 

Aziridines are important compounds due to their versatility as synthetic intermediates. In addition, aziridine rings are present in innumerable natural products and biologically active compounds. Nitrene addition to alkenes is one of the most well established methods for the synthesis of aziridines. Photolysis or thermolysis of azides are good ways to generate nitrenes. Nitrenes can also be prepared in situ from iodosobenzene diacetate and sulfonamides or the ethoxycarbonylnitrene from the A-sulfonyloxy precursor. 

Several reviews on the synthesis of aziridines have been published in the previous year. These publications include a review on the silver catalyzed addition of nitrenes (among other intermediates such as carbene) across a double bond <06EJOC4313> a review on sulfur ylide addition to imines to form aziridines <06SL181> a review on nitrogen addition across double bonds <06ACR194> a general review on functionalization of a,p-unsaturated esters with some discussion of aziridination <06TA1465>... 

One of the most well used methods for the synthesis of aziridines involves a two (or sometimes more) step process in which an epoxide is opened by a nitrogen nucleophile. The resulting P-amino alcohol (e.g. 79) is then converted to an aziridine via a number of different processes. This method is generally not broadly applicable when a variety of different groups on the nitrogen of the aziridine are desired. A useful method to convert an epoxide to a number of different /V-sulfonyl aziridines (e.g. 80) has been reported <06S425>. Simple addition of a sulfonamide to an epoxide provides high yields of 79 which is readily closed to form the aziridine. 

A dry-media technique with microwave irradiation for synthesis of aziridines has recently appeared in the literature [45] (Scheme 8.28). 

The present preparation illustrates the general method for the synthesis of aziridines by reduction of ketoximes 4 having an aromatic ring attached to carbon a or /3 to the oximino function and of aldoximes 4 having the aromatic ring attached to the carbon atom j3 to the oximino group. It has also been applied... 

A convenient new synthesis of aziridines (40) from oxirans and phosphazenes has... 

Scheme 3.33 Solid-phase synthesis of aziridines (223) by Filigheddu et al.

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