Generation of Carbenes

Carbenes from Diazo Compounds. Decomposition of diazo compounds to form carbenes is a quite general reaction that is applicable to diazomethane and other diazoalkanes, diazoalkenes, and diazo compounds with aryl and acyl substituents. The main restrictions on this method are the limitations on synthesis and limited stability of the diazo compounds. The smaller diazoalkanes are toxic and potentially explosive, and they are usually prepared immediately before use. The most general synthetic routes involve base-catalyzed decomposition of V-nitroso derivatives of amides, ureas, or sulfonamides, as illustrated by several reactions used for the preparation of diazomethane. 

Salts of sulfonylhydrazones [R2C = NNS02Ar]- Photolysis or thermolysis diazoalkanes are intermediates R2C + N2 + ArS02 b 

Alkyl halides R2CH-X Strong base, including metalation R2C + X- + B-H d 

Reactions Involving Carbocations, Carbenes, and Radicals as Reactive Intermediates 0=N O O N=0  

The details of the base-catalyzed decompositions vary somewhat but the mechanisms involve two essential steps.128 The initial reactants undergo a base-catalyzed addition-elimination to form an alkyl diazoate. This is followed by a deprotonation of the a-carbon and elimination of hydroxide. 

Carbenes may be synthesized by a variety of pathways that result in the elimination of two bonds from a tetravalent carbon atom. Among the more prominent of these reactions are the following  

Thermolysis or photolysis of diazoalkanes (equation 3.6) and dialkyl-diazirines (equation 3.7) 

For example, N-nitrosoureas react with base to generate diazoalkanes, which can then eliminate nitrogen.  

A carbene produced by elimination of N2 or Cl is a singlet initially, but electronic relaxation to a lower energy triplet ground state can occur if reaction does not occur first. It is possible to produce a triplet carbene directly through a process known as sensitization, in which a triplet electronic excited state of a sensitizer (S) transfers energy to a carbene precursor and returns to its singlet groimd electronic state (equation 5.35). Conservation of electron spin requires that the carbene be produced in its triplet state. 

Generation of carbenoids. The Simmons-Smith reaction produces a carbene equivalent that is stabilized by association with a metal and that reacts as a singlet carbene.  

REACTIONS INVOLVING CARBOCATIONS, CARBENES, AND Diazoalkanes R2C=]Cn- Photolysis, thermolysis, or metal-ion catalysis R2C +N2 a 

There are several ways of generating carbene intermediates. Some of the most general routes are summarized in Table 10.3 and will be discussed in the succeeding paragraphs. 

Decomposition of diazo compounds to carbenes is a quite general reaction. Examples include the simplest diazo compound, diazomethane, as well as diaryl-diazomethanes and diazo compounds in which one or both of the substituents is an acyl group. The inability to synthesize the required diazo compound is sometimes a limitation on the method. The low-molecular-weight diazoalkanes are toxic and unstable, and are usually prepared and used in situ rather than isolated. The simple aliphatic diazo compounds are synthesized from derivatives of the corresponding amine. All the common precursors of diazomethane, for example, are derivatives of methylamine. The details of the base-catalyzed decompositions vary somewhat 

When an a-diazoketone is needed, the usual synthesis starts with an acid halide. Reaction with a diazoalkane gives the diazoketone as a result of nucleophilic attack, with displacement of the chloride ion  

Under the usual conditions one equivalent of the diazoalkane is consumed by the liberated acid but this can be avoided by use of an added base such as triethylamine/ Cyclic a-diazoketones, which are not available from acid chloride, can be prepared by reaction of a nucleophilic derivative such as the a-hydroxymethylene enolate with arylsulfonyl azides. Several combinations of carbon nucleophile and sulfonyl 

Addition of certain copper salts to solutions of diazo compounds also leads to evolution of nitrogen and formation of products of the same general types as those formed in thermal and photochemical decompositions of diazoalkanes. The weight of the evidence, however, indicates that free carbene intermediates are not involved in such reactions. Instead, complexes of the carbene unit with the metallic catalyst 

For a review of available synthetic methods, see E. Schmitz, Dreiringe mit Zwei Heteroatomen, Springer Verlag, Berlin (1967), pp. 114-121. 

Decomposition of diazo compounds to carbenes is a quite general reaction. Examples of compounds that can be used include diazomethane and other diazoalkanes, diazoalkenes, and diazo compounds with aryl and acyl substituents. The 

Diazo compounds can also be obtained b oxidation of the corresponding hydrazone. This route is employed most frequently when one of the substitutents is an aromatic ring. 

Depending on the mode of generation, a carbene may be initially formed in either the singlet or triplet state, irrespective of its stability. Common methods used for the generation of carbenes include photolytic, thermal, or metal catalyzed decomposition of diazocompounds, elimination of halogenfrom gem-dihalides, elimination of Hx from CHX3, decomposition of ketenes, thermolysis of a-halo-mercury compounds and cycloelimination of shelf stable substrates such as cyclopropanes, epoxides, aziridines and diazirines. 

The thermal decomposition of monoanions of tosylhydrazone (Ar = p-tolyl) in a protic solvent like diglyme at 130°C or higher temperature generates dialkyl carbenes. Dialkyl carbenes can also be generated photochemically from salts of tosylhydrazones, but it is difficult to perform the reaction on a large scale. 

Ketenes can be decomposed thermally or photolytically to generate carbenes. 

Thermal or photolytic decomposition of ylides generates carbenes. 

Besides the decomposition of diazo compounds, thermal cycloeliminations from carbocy-cles and heterocycles with odd numbers of ring atoms have been found to be suitable for dialkoxycarbenes , which are very difficult to obtain in any other way. 

Most commonly, photolytic, thermal, or transition metal catalyzed decomposition of diazoalkanes is used to create carbene molecules. A variation on catalyzed decomposition of diazoalkanes is the Bamford-Stevens reaction, which gives carbenes in aprotic solvents and carbenium ions in protic solvents. Another method is induced elimination of halogen from gem-dihalides or HX from a CHXj moiety, employing organoHthium reagents (or another strong base). It is not certain that in these reactions actual free carbenes are formed. In some cases there is evidence that completely free carbene is never present instead, it is likely that a metal-carbene complex forms. Nevertheless, these metallocarbenes (or carbenoids) give the expected products. 

5 R2CH-X halides strong base or organometallic compounds R2C + BH + X- 

CHAPTER 8 REACTIONS INVOLVING ELECTRON-DEFICIENT INTERMEDIATES 

RADICALS AS REACTIVE Salts of sulfonylhydrazones Photolysis or thermolysis RjC+Ni + ArSOj- b 

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Photolytically generated carbene, as mentioned above, undergoes a variety of undiscriminated addition and insertion reactions and is therefore of limited synthetic utility. The discovery (3) of the generation of carbenes by the zinc-copper couple, however, makes carbene addition to double bonds synthetically useful. The iodo-methylzinc iodide complex is believed to function by electrophilic addition to the double bond in a three-center transition state giving essentially cis addition. Use of the... 

In contrast to carbenes of the AX2 type, which contain three atoms, generation of carbenes with a more complex structure under photolysis or vacuum pyrolysis conditions may be accompanied by intramolecular rearrangements. Thus, the matrix isolation study of the vacuum pyrolysis... 

Nevertheless, a more traditional approach to the stabilization of carbenes and the investigation of their spectral properties deals with the direct generation of carbenes in low-temperature matrices, e.g. by the photolysis of diazo-compounds or ketenes. The method allows stabilization of carbenes in their ground electronic state, prevents intramolecular isomerization and also facilitates direct spectroscopic monitoring of their chemical transformations in low-temperature matrices. 

Different methods have been developed for the generation of carbene and diradical negative ions. One of the most commonly used approaches involves the reaction of an organic substrate with atomic oxygen ion, O , to form water by H2 abstraction (Eq. 5.7). "... 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

Photolytic generation of carbene 19 from a precursor diazirine afforded cyclobutenes 27 (68%) and 28 (14%) via CH2 and CMe2 migrations, respectively cf. Eq. 15.45... 

When, however, carbenes are directly generated from diazoalkanes, RIES becomes significant.56 Photolytic generation of carbene 45 from diazoalkane precursors in the presence of >1.5 M pyridine gave values for the derived pyridinium ylides. 

Our approach to the synthesis of model compounds, suited for the generation of carbenes, which are bound to the bridgehead of a strained bicyclic system, used the facile synthesis of [n.l.ljpropellanes, which we developed some years ago. Starting from substituted allyl chlorides 35, dibromocarbene addi-... 

In addition to conventional generation of carbenes from nitrodiazo compounds (22) (79), target intermediates C can be prepared by oxidation of functionalized AN CH2XNO2 with phenyliodonium diacetate. The reactions of Rhodium intermediates with certain olefins afford the corresponding cyclopropanes (23). The cycloaddition reaction was performed in the presence of a catalyst. (The successful synthesis of nitrocyclopropanes from trinitromethane derivatives and nitroacetic ester was also documented (81)). 

Ylides from R N2. This reagent is more effective than bis(acetylacetonate)-copper(II) (5, 244) for generation of carbenes from diazo compounds.2 The decomposition proceeds at a lower temperature, even at room temperature. The mild conditions are particularly useful in the preparation of heat-sensitive ylides, such as those of antimony, bismuth, and tellurium. 

For synthetic purposes, crown ethers have been used frequently as phase-transfer catalysts under conditions where the sodium or potassium hydroxide is present as a concentrated aqueous solution. Various anions of C—H acids have been generated this way (Makosza and Ludwikow, 1974). The use of such conditions for the generation of carbenes will be dicussed in a separate section. 

Fig. 2.9. Generation of carbene complexes from vinylidene complexes.

Fig. 3.25. Generation of carbene complexes by addition of electrophiles to carbyne complexes [533,538,540,543],...

Fig. 3.31. Generation of carbene complexes by [2 -i- 2] cycloreversion of four-membered metallacycles [26,27,605,607-609].

As mentioned in Sections 3.1.6 and 4.1.3, cyclopropenes can also be suitable starting materials for the generation of carbene complexes. Cyclopropenone di-methylacetal [678] and 3-alkyl- or 3-aryl-disubstituted cyclopropenes [679] have been shown to react, upon catalysis by Ni(COD)2, with acceptor-substituted olefins to yield the products of formal, non-concerted vinylcarbene [2-1-1] cycloaddition (Table 3.6). It has been proposed that nucleophilic nickel carbene complexes are formed as intermediates. Similarly, bicyclo[1.1.0]butane also reacts with Ni(COD)2 to yield a nucleophilic homoallylcarbene nickel complex [680]. This intermediate is capable of cyclopropanating electron-poor alkenes (Table 3.6). 

Nyce GW, Glauser T, Connor EF, Mock A, Waymouth RM, Hedrick JL (2003) In situ generation of carbenes a general and versatile platform for organocatalytic living polymerization. J Am Chem Soc 125 3046-3056... 

Ahphatic diazo compounds are convenient starting materials for the generation of carbenes by photolytic or thermal methods. Decomposition of diazo compounds can be catalyzed by some metals or metal salts (63,64). Whereas copper salts were first used, rhodium(ll) acetate has recently become recognized as one of the most efficient catalysts and is now used almost exlusively (65). 

Other possible carbene precursors (vicinal dihalides, peresters, ketenes, carbene adducts with stable hydrocarbons, etc.) cannot generally be used for in situ generation of carbenes, because the fragments are likely to recombine. However, they can be used, for example, in experiments involving pyrolysis or other forms of external carbene generation where the fragments get a chance to separate in the gas phase and become trapped in distant matrix sites. AU conceivable halo- and dihalocar-benes were made and smdied in this way (see, e.g., the 1993 review by Sander et al." ) However, such methods can only be applied to carbenes which resist thermal rearrangement to more stable products. 

More recent results support the view that Lewis acids, on the interaction with metal carbonyls, may facilitate dissociation of a ligand to leave a vacant site for alkene coordination.75 Photochemical generation of carbene species [Eq. (12.20)], the crucial step in photoinduced metathesis, is a complicated, multistep process 74,76,77... 

Photochemical reactions, indicated in reaction schemes by the symbol hv, are considered in Chapter 13. For the present, it is sufficient to note that absorption of light transforms a molecule to an excited state, which, in the case of diazo compounds, has sufficient energy for rupture of the C—N bond. Generation of carbenes from diazo compounds is reviewed by W. J. Baron, M. R. DeCamp, M. E. Hendrick, M. Jones, Jr., R. H. Levin, and M. B. Sohn, in Jones and Moss, Eds., Carbenes, Vol. I, p. 1. 

Apart from the significance of diazoalkanes for the generation of carbenes,195 these compounds also play a dominant role in dipolar cycloaddition chemistry.196197 Recent advances in the synthesis of di-... 

With respect to the complications of method B, it is remarkable that generation of carbene 3a according to method C in the presence of c -but-2-ene or various cycloalkenes gave the corresponding (trimethylsilyl)cyclopropanes in yields up to 30%73,74. Similarly,... 

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