Carbene equivalents

The carbene synthon might be difficult, but since the olefin is conjugated with a carbonyl group we could try a sulphur ylid as a nucleopliilic carbene equivalent (as in frame 283). Synthesis The diene could be made by this route ... 

First the normal Wittig reaction, and then a second mol of Wittig reagent must be behaving as a carbene equivalent, just as we hoped the sulphur yhd would. 

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. 

Diazoester aziridinations may be carried out in ionic liquids [39]. Other carbene equivalents have been investigated in aziridination reactions, though not to the same extent as diazocarbonyl compounds. Dibromo(tert-butyldimethylsilyl)me-thyllithium, for example, aziridinates N-arylimines to give l-bromo-2-aryl-3-silyla-ziridines these compounds function as useful synthetic intermediates, reacting... 

The alternative disconnection (25a) requires the Michael addition to a nucleophilic carbene equivalent to an enone. 

Murai and Chatani speculated that the two acetylene carbons should be converted into two carbene equivalents to give XVIII during the reaction." To trap this intermediate, the reaction of 6,11-dien-l-yne 69c, which has an olefin moiety in a tether, is carried out in the presence of [RuCl2(CO)3]2 in toluene at 80 °C for 4 h to give tetracyclic compound 71 in 84% yield. It is interesting to note that other transition metal complexes, such as PtCl2, [Rh(OOCCF3)2]2, [IrCl(CO)3] , arid ReCl(CO)s also show catalytic activity for this very complex transformation (Scheme 27). 

The germacyclobutane will behave like the silacyclopropane in eliminating a carbene equivalent. The germylene so formed then reinserts into the germacyclobutane, giving the 1,2-digermacyclopentane (60 Scheme 88) (70DOK(194)1096). 

Dialkyl sulphides are converted into trialkylsulphonium salts by treatment with an alkyl halide (the bromide or iodide is usually the reactant of choice). An important example of this group is trimethylsulphonium iodide, which is used as a methylene transfer reagent by virtue of its being converted in the presence of base into a sulphur ylide, which is a nucleophilic carbene equivalent. 

Characterization of lower Group 14 carbene equivalents ER2 (E = Si, Ge, Sn, Pb) has been reviewed.98 Matrix IR spectroscopy and quantum chemistry methods were considered and trends in changes in the spectral characteristics, structures, and stability... 

The Shapiro reaction has been used as a method for the initiation of anionic cyclisations, as described in section 7.2. Hydrazones derived from 23 are particularly valuable in this area, not only as the source of vinyllithiums but also as carbene equivalents. Nucleophilic addition to 26 promotes the collapse of the product lithioamine to give the organolithium 27. 

Reaction of Electrondeficient Olefins with Donor-Carbene-Equivalents One interesting application of Fischer-type carbene complexes in organic synthesis is their addition to acceptor olefins affording methoxy substituted cyclopropanes 65 (Eq. 20). 

Finally, the a,/ -unsaturated carbene complex may be generated in situ by alkyne insertion into a chromium-carbene bond of a saturated chromium carbene leading to a chromium vinyl carbene (equivalent to intermediate (f )-D in the mechanism of the benzannulation reaction, see Section 8.2.1, Scheme 3), which may undergo subsequent benzannulation with a second equivalent of the alkyne [43a]. This strategy was subsequently applied to the synthesis of (Z)-enediynes and related compounds [43b], and to that of substituted benzofurans (see also Section 8.5) [43c, 43d]. 

Because of these and other useful molecules containing three-membered rings, methods to make them are important as well as interesting. Most chemical syntheses of compounds containing cyclopropyl groups make use of the addition of a carbene, or carbene equivalent, to an aikene. What do we mean by carbene equivalent Usually, this is a molecule that has the potential to form a carbene, though it may not actually react via a carbene intermediate. One such example is a zinc carbenoid formed when diiodomethane is reacted with zinc metal it reacts with alkenes just as a carbene would—it undergoes addition to the 7t bond and produces a cyclopropane. 

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. 

Heteroatom-containing ene analogues react with imine or carbene equivalents to give heterocycles in reactions similar to [2-1-1] carbene/alkene cyclopropanation. Alkylidenoaminoboranes R2N=B=CR 2 react slowly with various azides with loss of N2 to form azaboriridines 36 in poor yield. An example appears in Equation (21) (R = PhCH2 or Ph) <1985AGE416, 1989CB595>. 

The lithium dienolate 23, generated by treatment of ethyl (Z)-2-bromo-2-butenoate (22) with lithium diisopropylamide, undergoes smooth addition to enones and provides vinylcyclopropane derivatives in good yield15. The simple diastereoselectivity of this formal [2 I 1] cycloaddition is usually mildly moderate, as demonstrated by the addition of 23 to cyclopentenone which affords bicyclo[3.1.0]hexan-2-one 24 as a 57 43 mixture of endolexo-isomers. On the other hand, the diastereofacial selectivity of the carbene equivalent 23 is very high. Thus, the cy-clopentene derivative 25 is attacked only anti with respect to the dioxolane moiety giving the adduct 26 as enrfo/ew-isomers. 

This same disconnection of a carbon atom is also helpful for epoxides (11) without carbonyl substituents. The reagent should be a nucleophilic carbene equivalent and a sulphur ylid (12) is the answer.These can be made from the sulphide (13) by a similar process to phosphorus ylid synthesis (Chapter 15), though the reactions of the two ylids with carbonyl compounds are significantly different (there is a third type of reaction with the ylid CH2N2 in Chapter 31). 

All disconnections are the same on cyclopropane, requiring a carbene equivalent which will add to an unactivated double bond. Diazomethane will do this, but one of the best carbene sources is CH2I2 with a zinc-copper couple (the Simmons-Smith reaction ). This works particularly well on allylic alcohols (31), no doubt because of hydrogen bonding between the OH group and the reagent. The reaction is then totally stereoselective. 

Carbenes constitute a further class of neutral reactive species that provide a route to alkylation of the prosthetic heme group. The oxidation of sydnones by cytochrome P-450, which yields an alkyl diazonium product, results in inactivation of the enzyme (Ortiz de Montellano and Grab, 1986 Grab et al., 1988). This loss of activity is associated with the formation of (V-alkyl heme adducts best rationalized by addition of a catalytically generated carbene or carbene equivalent to the heme group (Fig. 32). Model studies have shown that diazo compounds do react with reduced iron porphyrins to give N-alkylated products (Komives et al., 1988). The details of the enzymic N-alkylation reactions remain to be defined, but evidence exists for two distinct reaction pathways. The first is... 

Cyclopropanation. The reagent is an electrophilic carbene equivalent. Thus it behaves differently from dimethyloxosulfonium methylide toward 2-benzenesul-fonyl-1,3-butadiene. 

It has been shown that these carbenes can insert into Fe-Npor bonds to form vinylidine (A(-alkyl-iron porphyrin metallacycle (N-C-C-Fe)) complexes, " which can then go on to form c/s-bridged vinylidines of the porphyrin, with loss of iron. Carbene equivalents of iodosylbenzene can also react with iron porphyrins to give five-membered Fe-O-C-C-N metallocycles. Iron porphyrin carbenes can also react with amines to produce the isocyanide complexes (equation 58) ... 

Acyl carbene equivalents The moderately stabilized RCOCH=BPhj ylides are generated from the tetrafluoroborate salts. These ylides react with aldehydes to give a,p-epoxy ketones, in contrast to the stibonium, arsonium, and phosphonium ylides, which afford enones. The weaker Bi-0 bond disfavors decomposition of the adducts into enones and the bismuthine oxides. 

By stereoselective additions of carbenes or carbene equivalents to alkenes optically pure cyclopropanes are obtained. " In concerted [2+1] cycloadditions the stereochemistry of the alkene is conserved in the products. (Z)-configurated alkenes lead stereospecifically to cis-cyclopropanes. So far, compared to [2+1] cycloadditions involving alkenes bearing the chiral auxiliary, asymmetric reactions involving chiral carbene precursors proved to be less efficient. 

---