Carbene Addition to Imines

A similar reaction sequence accounts for the formation of 1,l-dichloro-2,2,3,3-tetramethylcyclopropane in 15% yield from the reaction of pinacol with dichloro-carbene. Likewise, reaction of m 5o-dihydrobenzoin with dichlorocarbene gave a 15% yield of cw-stilbene [10] (Eq. 3.7). 

The facile addition of dichlorocarbenes to olefins under phase transfer conditions has also been observed with imines. The carbon-nitrogen double bond reacts with dichlorocarbene under conditions similar to those required for isolated alkenes. Thus, dichlorocarbene addition to C,N-diaryl substituted Schiff s bases afford good yields of l,3-diaryl-2,2-dichloroaziridines (Eq. 3.8). Hydrolysis of the C,N-diarylaziridines (IV) to the corresponding aryl-o -chloroacetanilides (V) is also reported (Eq. 3.9) and examples of both processes are recorded in Table 3.3. 

---

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>... 

CO)sCr=CHNBzli- (cf. 11, 400-401). This carbene, like typical Fischer carbenes, undergoes a photolytic addition to imines to give mixtures of cis- and trans-3-dibenzylamino-p-lactams in fair to good yield. The products are convertible into 3-amino-2-azetidinones.1 2 4 5... 

The synthesis of y-lactams has been achieved under similar reaction conditions (Table 18) [124]. Initially, Bode and co-workers screened a variety of acyl imines in order to find suitable electrophiles. Control experiments provided evidence for carbene addition to the acyl imine, yielding a stable complex with complete inhibition of the desired reactivity. Reversibility of this addition was key to the success of the reaction. A -4-Methoxybenzenesulfonyl imines 212 proved to be the most efficient partners for lactamization with cinnamaldehydes 228 to provide y-lactams 229 in moderate yields and good diastereoselectivities. Notably, no benzoin or S tetter products or their corresponding derivatives were observed during this reaction. 

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. 

Aziridines can be formed by nitrene (-like) additions to double bonds, or by carbene (-like) additions to imines. Both processes especially the latter one can also occur by a stepwise addition-elimination process [172]. Similar to cyclopropa-nations, aziridinations of imines can foUow two protocols alkylation-deprotonation-substitution and sulfide reactions with metallocarbenes. 

Other potential synthetic routes to these unsaturated aziridine derivatives which involve the addition of nitrenes to allenes <75JOC224), carbenes to imines with subsequent hydrolysis <67JA362), and of carbenoid species to ketenimines <76TL1317,79TL559) have been investigated but are collectively of little or no preparative value. 

Those reactions that have found general use for the preparation of aziridines can be grouped into two broad classes addition and cyclization processes, and each of these categories can be further divided. Addition processes can be classified as being C2+N1 reactions (addition of nitrenes, or nitrene equivalents [ nitrenoids ], to alkenes Scheme 4.1) or (J N1+C1 reactions (addition of carbenes or carbenoids to imines Scheme 4.2). 

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. 

Addition of A-mesityl benzimidazolyl carbene 720 to an a,/3-unsaturated aldehyde generates a homoenolate intermediate that undergoes an addition/acylation sequence with azomethine imine 719 to afford (3R, 5S, 6S )-177-pyrazolo[l,2- ]pyridazine-l,8(5//)-diones 721 with excellent diastereoselectivity. Compound 721 (Ar = R = Ph) treated with sodium hydoxide in methanol or benzylamine provided nearly quantitatively, ring-opened products 722a and 722b, respectively (Scheme 116) <2007JA5334>. 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

In addition to copper and rhodium catalysts commonly used in the generation of metal carbene complexes, other transition metals have also been explored in the diazo decomposition and subsequent ylide generation.Che and co-workers have recently studied ruthenium porphyrin-catalyzed diazo decomposition and demonstrated a three-component coupling reaction of a-diazo ester with a series of iV-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities (Scheme 20). ... 

A review has appeared on the synthesis of enantiomerically enriched aziridines by the addition of nitrenes to alkenes and of carbenes to imines.45 A study of the metal-catalysed aziridination of imines by ethyl diazoacetate found that mam group complexes, early and late transition metal complexes, and rare-earth metal complexes can catalyse the reaction.46 The proposed mechanism did not involve carbene intermediates, the role of the metal being as a Lewis acid to complex the imine lone pah. Ruthenium porphyrins were found to be efficient catalysts for the cyclopropana-tion of styrenes 47 High diastereoselectivities in favour of the //-product were seen but the use of chiral porphyrins gave only low ees. 

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. 

The addition of carbenes and carbenoids to imines and nitriles continues to be a popular approach to aziridines and 2//-azirines. These processes have been well reviewed by Deyrup (B-83MI101-01). Dichlorocarbene and other dihalocarbenes have been added to a wide variety of imines to provide dihaloaziridines. A recent example is shown in Equation (64), illustrating the use of phase-transfer conditions <93H(36)69i). The treatment of azides with excess dichlorocarbene results in the formation of the 2,2,3,3-tetrachloroaziridines (92TL2339). Presumably, the azide is converted by dichlorocarbene to the imidoyl dihalide RN=CC12 which reacts further with dichlorocarbene. Transition metal-promoted reaction of a-diazoesters with imines provides 2-(alkoxycarbonyl)aziridines [Pg.46]

---