Imines bond formation, aziridine

Aziridines are commonly prepared from imine precursors. Carbene addition to the C=N bond is illustrated by the formation of aziridine 127 from imine 126. ° Difluorocarbene, generated from HFPO (1), also adds to imines such as 128 to give the highly fluorinated aziridine 129. In the presence of Lewis acids, diazo compounds react with imines to produce aziridines. Ethyl diazoacetate and imine 130 gave aziridine 131 in 93% yield, with a cis/trans ratio of 95 5. Chiral diazo compound 132 reacted with the aldimine precursor 133 to afford aziridine 134 in 81 % yield.The reaction displayed both high cis selectivity (>95 5) and excellent diasteroselectivity (94% de). Reductive removal of the chiral auxiliary gave the optically active hydroxymethylaziridine 135. 

The ambivalent role of metal chlorides, which may act as Lewis acids or electron donors, in ring-opening reactions of 2//-aziridines by imines, enaminones, and enam-inoesters to form imidazoles, pyrroles, and pyrrohnones has been discussed. Experimental and theoretical mechanistic studies of the Davis-Beirut reaction, whereby 2//-indazolenes are obtained from o-nitrosobenzaldehydes and primary amines, implicate o-nitrosobenzylidine imine as a pivotal intermediate in the Nfl-bond formation. 

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. 

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. 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

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. 

Simple carbon-carbon double bonds react slowly with azides and frequently take more than a week to react at 25 C. Increasing the reaction temperature is restricted by the thermal lability of most triazolines. In fact, some classes of triazolines decompose spontaneously at room temperature with the extrusion of nitrogen.189 The principal decomposition modes involve the formation of aziridines and imines and are outlined in Scheme 55. Usually, just a few of these modes operate in any particular system.190... 

Alternatively, one can add a carbene source to some form of a C=N bond. This will generate bonds c and b . This model is limited by the availability of cyclic imine or imine-like structures. Several methods are available to prepare aziridines through the functionalization of a C=N bond, although formation of the fused rings will require an intramolecular addition to a pendent imido-bond. The Darzens process and ylide addition to C=N bond are generally not applicable in most cases owing to the structural requirements of the cyclic system. This requirement renders this process less useful overall than the addition to a C=C bond. 

The formation of type II aziridines can also be carried out via the formation of two bonds simultaneously. One of the most common is the formation of two C-N bonds (bonds c and e ) to generate the aziridine ring. This quite often takes the form of a nitrene or nitrene equivalent adding to an alkene. Another highly common route that forms two bonds simultaneously is the reaction of a monocyclic azirine with a difunctional molecule such as a diene or dipole to form bonds d and e . A significantly less common route is the formation of bonds c and b through the addition of carbene or carbene equivalent to a cyclic imine. 

An interesting use of the bond e disconnection for the synthesis of perfluoro aziridines was reported <1999CC47>. Treatment of perfluoro imine 65 with an excess of PhLi provides the aziridine 67 in good yield (Equation 20). This reaction is believed to go through intermediate 66 after an initial addition of 2 equiv of PhLi. A subsequent nucleophilic attach of the nitrogen anion to displace a fluorine results in aziridine ring formation. The ease with which this strained system forms is attributed to relief of the 1,3-diaxial interactions found in intermediate 66. In addition, an X-ray structure of aziridine 67 was obtained. 

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. 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Salicyl A-thiophosphinyl imines (39) undergo novel domino annulations with certain sulfur ylides (40, R = C02R/C0R/CH=CHC02H, R typically = H) to give highly substituted fra 5-2,3-dihydrobenzofurans (41) in high yield and rfe. After formation 0 of the N-C bond, an otherwise likely kinetic preference for aziridine formation is suppressed by steric hindrance. 

---