Carbene stereospecificity

The converse situation in which ring closure is initiated by the attack of a carbon-based radical on the heteroatom has been employed only infrequently (Scheme 18c) (66JA4096). The example in Scheme 18d begins with an intramolecular carbene attack on sulfur followed by rearrangement (75BCJ1490). The formation of pyrrolidines by intramolecular attack of an amino radical on a carbon-carbon double bond is exemplified in Scheme 19. In the third example, where cyclization is catalyzed by a metal ion (Ti, Cu, Fe, Co " ), the stereospecificity of the reaction depends upon the choice of metal ion. 

Other non-oxidative procedures have also been used to deaminate aziridines. For example, aziridines react with carbenes to yield ylides which subsequently decompose to the alkene. Dichlorocarbene and ethoxycarbonylcarbene have served as the divalent carbon source. The former gives dichioroisocyanides, e.g. (281), as by-products (72TL3827) and the latter yields imines (72TL4659). This procedure has also been applied to aziridines unsubstituted on the nitrogen atom although the decomposition step, in this case, is not totally stereospecific (72TL3827). 

There is a limitation to the use of stereospecificity of addition as a diagnostic test for singlet or triplet carbenes.When carbenes are generated by photolytic methods, they are often in a highly excited singlet state. When they add to the double bond, the addition is stereospecific but the cyclopropane formed carries excess... 

Photolysis of the sulphinyl-3ff-pyrazole 587 in ether or methylene chloride leads to the formation of a relatively stable carbene 588 that can be identified by physical methods. When the irradiation is performed in ethyl vinyl ether or in furan, the expected cyclopropanes are formed smoothly and stereospecifically (equation 374). 

The stereospecificity of addition suggests a singlet(10) carbene although the ground state of cyclopentadienylidene is known to be a triplet. Attempts to produce a triplet species, which would be expected to react nonstereospecific-ally, in a 4-methyl-cw-2-pentene matrix at 77°K or by dilution of mixtures of the azo compound and olefin with hexafluorobenzene or octafluorocyclo-butane (inert diluents) were unsuccessful. It was concluded that the singlet carbene produced upon photolysis reacts more rapidly with the olefinic... 

A singlet carbene was proposed to account for this stereoselectivity. Attempts to produce triplet carbene by collisional deactivation with octafluorocyclo-butane were unsuccessful and stereospecific addition to olefin still occurred. However, nonstereospecific addition to olefins and larger amounts of olefinic (insertion) products result from irradiation of the phenyldiazomethane in a frozen m-butene matrix at — 196°C ... 

The addition of the methylmercuriacetylcarbene to cis- and //ms-butene was found to be completely stereospecific, suggesting that this carbene has a singlet ground state (with the heavy mercury atom, relaxation to the ground state should be rapid). 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

Dimethyl-4-silacyclohexadienylidene (lv) is of interest as a potential source of silaxylene 24, however, all attempts to convert the carbene into an aromatic compound failed.107 The only isolated product from gas phase reactions is the dimer 25. In solution, carbene lv was found to add stereospecifically to cis-2-butene. With butadiene as trapping reagent both the products of the 1,2- and 1,4-addition 26 and 27, respectively, are observed (Scheme 21).107 In addition, silacyclopentene 28 is formed, which is the trapping product of cyclo-... 

The stereochemistry of the insertion by (phenylthio)carbene to the a C-H bond of trans- and c/s-4-terr-butylcyclohexyloxides 16 was investigated19 to find that the reaction proceeds stereospecifically giving trans and cw-4-rert-butyl-l-methylcyclohexanol 19, respectively, after desulfurization of the primary insertion products 17 (Scheme 9). 

A complicating factor associated with experimental application of the Skell Hypothesis is that triplet carbenes abstract hydrogen atoms from many olefins more rapidly than they add to them. Also, in general, the two cyclopropanes that can be formed are diastereomers, and thus there is no reason to expect that they will be formed from an intermediate with equal efficiency. To allay these problems, stereospecifically deuteriated a-methyl-styrene has been employed as a probe for the multiplicity of the reacting carbene. In this case, one bond formation from the triplet carbene is expected to be rapid since it generates a particularly well-stabilized 1,3-biradical. Also, the two cyclopropane isomers differ only in isotopic substitution and this is anticipated to have only a small effect on the efficiencies of their formation. The expected non-stereospecific reaction of the triplet carbene is shown in (15) and its stereospecific counterpart in (16). 

The simple reaction scheme outlined in Scheme 2 easily accommodates the results obtained in the investigation of XA. The basic scheme is just the same as it is for BA except that the relative energies of the singlet and triplet states of the carbene are reversed. All of the evidence points to a singlet ground state for XA. This includes the absence of an epr signal, the nearly diffusion-controlled formation of ether in direct and sensitized experiments, the stereospecific cyclopropanation, and the absence of a rapid reaction of the carbene with 02. 

The chemical properties of DPM have been probed with each of the procedures identified earlier. This carbene is known to react with alcohols to give ethers (Kirmse, 1963 Bethell et al., 1965), it adds to olefins non-stereospecifically to form cyclopropanes (Skell, 1959 Baron et al., 1973 Gaspar et al., 1980 Tomioka et al., 1984), and it is rapidly converted to a carbonyl oxide with oxygen (Werstiuk et al., 1984 Casal et al., 1984). 

Much of the literature regarding dihalocarbenes is concerned with reactions of CX2 with olefinic substrates to give 1,1-dihalocyclopropane derivatives. These reactions occur with retention of stereospecificity, as expected for singlet carbenes. Dihalocarbenes also exhibit strong electrophilic behavior towards olefins, and will often not react with weakly nucleophilic species if stronger nucleophiles are present. 

The signature application for the G-H insertion in synthesis is probably the total synthesis of (—)-tetrodotoxin 126 by Du Bois and Hinman.233 Two stereospecific G-H activation steps, rhodium-catalyzed carbene G-H insertion and carbamate-based nitrene C-H insertion, have been used to install the two tetrasubstituted centers C6 and C8a (Scheme 12). Diazoketone 122 was treated with 1.5mol% Rh2(HNCOCPh3)4, and cyclic ketone 123 was selectively formed in high yield without purification. The reaction of carbamate 124 with 10mol% Rh2(HNCOCF3)4, PhI(OAc)4, and MgO in C6H6 solvent furnished the insertion product 125 in 77% yield. 

Among methods of preparing optically active cyclopropane compounds, the Simmons-Smith reaction, first reported in 1958, is of significance. This reaction refers to the cyclopropanation of alkene with a reagent prepared in situ from a zinc-copper alloy and diiodomethane. The reaction is stereospecific with respect to the geometry of the alkene and is generally free from side reactions in contrast to reactions involving free carbenes. 

We know that carbenes have either a singlet or triplet structure. The addition of singlet carbene gives a halogenium ion and is therefore stereospecific. 

It is non stereospecific. So the stereochemistry of the product reveals us whether the carbene was singlet a triplet. 

The addition of carbenes is also a stereospecific reaction, each geometrical isomer forms the cis addition product. Thus carbene generated from the photolysis of diazomethane adds in a cis manner to both cis and trans butene-2. 

In this state the addition of methylene occurs in the triplet state and starting from each a mixture of cis and trans products is obtained. This is because in the triplet state, the two electrons have parallel spins and carbene behaves as diradical. To explain non stereospecificity it is assumed that rotation about the single bond occurs more rapidly than spin inversion. The entire mechanism can be written in the following manner ... 

Much also depends on how the carbene is generated. Duncan et al showed that carbene generated by the photolysis of ketone adds to the above substrate in a non-stereospecific manner. 

Carbenes can add to cts- or irans-ole ns to form cyclopropanes in two different ways the original stereochemistry of the olefin may be retained, when the reaction is stereospecific, or the original stereochemistry of the olefin may be lost, in which case the reaction is regarded as nonstereospecific. This fact was recognized at a very early date by Shell who postulated the following rules for [1 + 23-cycloaddition of a carbene to an olefin ... 

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