Synthesis applications with carbenes

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

In contrast to considerations of 50 years ago, today carbene and nitrene chemistries are integral to synthetic design and applications. Always a unique methodology for the synthesis of cyclopropane and cyclopropene compounds, applications of carbene chemistry have been extended with notable success to insertion reactions, aromatic cycloaddition and substitution, and ylide generation and reactions. And metathesis is in the lexicon of everyone planning the synthesis of an organic compound. Intramolecular reactions now extend to ring sizes well beyond 20, and insertion reactions can be effectively and selectively implemented even for intermolecular processes. 

MetaIIa-l,3,5-trienes M = C—C=C—C=C play a pivotal role in many applications of carbene complexes to organic synthesis. These compounds are readily available from methylcarbene complexes (by condensation, e.g. with a,/3-unsaturated aldehydes), from 1-metalladienes (by insertion of an... 

The first carbene compound to be well characterized was prepared in 1966 and was one of many Fischer-Type Carbene Complexes to be reported (see equation 7). Fischer carbenes are characterized by heteroatom substituents at the carbene carbon, stabilization by a low-valent metal center, and a partial positive charge at the carbene carbon. In contrast, Schrock-Type Carbene Complexes, or alkylidenes," that have alkyl substituents, are found on metal centers in higher oxidation states, and are nucleophihc at carbon. Many Fischer carbenes are known for chromium, whereas chromium alkylidenes are much less common. Monohalocarbenes of chromium, for example, (OC)5Cr=C(F)NEt2, have also been extensively investigated." Two carbene reactions of note for their application to organic synthesis are the cycloaddition of alkenes with carbene complexes and the reaction of aromatic carbenes with aUcynes to yield complexed naphthols (the Dotz reaction ). ... 

The volume continues with a contribution by A. F. Khlebnikov, M. S. Novikov, and R. R. Kostikov (all of St. Petersburg State University, Russia) on the role of carbenes and carbenoids in the synthesis of heterocycles. The application of carbenes to heterocyclic chemistry was covered in Volume 3 of our series in 1964 by C. W. Rees and C. Smithen, and subsequently in Volume 28 in 1981 by C. Wentrup. The present review covers the literature between 1979 and early 1995. 

The most common application of carbenes in synthesis is in the formation of three-membered rings by addition to multiple bonds. This is a typical reaction of all carbenes that do not undergo intramolecular insertion. Generation of the carbene in the presence of an alkene gives a cyclopropane product. Addition of halocarbenes to alkenes is a stereospecific cis reaction, but this is not necessarily the case with all carbenes. Hence Z-2-butene 109 gives the cyclopropane 110, in which the two methyl groups remain cis to one another (4.86). The stereospecificity... 

Despite the fact that transition metal complexes have found wide application in the synthesis of carbo- and heterocycles, [3+3] cyclisation reactions mediated or assisted by transition metals remain almost unexplored [3, 86]. However, a few examples involving Fischer carbene complexes have been reported. In all cases, this complex is a,/J-unsaturated in order to act as a C3-synthon and it reacts with different types of substrates acting as C3-synthons as well. 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

Although olefin metathesis had soon after its discovery attracted considerable interest in industrial chemistry, polymer chemistry and, due to the fact that transition metal carbene species are involved, organometallic chemistry, the reaction was hardly used in organic synthesis for many years. This situation changed when the first structurally defined and stable carbene complexes with high activity in olefin metathesis reactions were described in the late 1980s and early 1990s. A selection of precatalysts discovered in this period and representative applications are summarized in Table 1. 

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. 

The synthetic utility of the ring expansion reaction was demonstrated by its application to the synthesis of thermolabile thiepins. When the diazo compound (66) obtained from benzo[c]thiopyrylium salt 65 was treated with palladium catalyst under the same conditions as in the case of 63, the product isolated was ethyl 2-naphthoate (68)48). The plausible reaction pathway is one comprising i) decomposition of 66 to the corresponding carbene intermediate, ii) ring expansion to the... 

The importance of transition metal carbene complexes (compounds with formal M=C bonds) and of transition metal carbyne complexes (compounds with formal M=C bonds) is now well appreciated. Carbene complexes are involved in olefin metathesis (7) and have many applications in organic synthesis (2), while carbyne complexes have similar relevance to... 

Reports on the coordination chemistry of A-heterocyclic carbene-containing metal complexes started to appear as long ago as 1968,50,51 while metal-free carbenes have only been isolated very recently.52 In view of the fact that the general chemistry and applications of organic carbenes and related metal complexes in chemical synthesis have been reviewed several times recently,53-57 examples limited only to those carbene complexes with silver(i) have been discussed. Nevertheless, it is worth mentioning that the developments in silver(i) A-heterocyclic carbenes have also been reviewed recently by Lin.5... 

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. 

An alternative to the synthesis of epoxides is the reaction of sulfur ylide with aldehydes and ketones.107 This is a carbon-carbon bond formation reaction and may offer a method complementary to the oxidative processes described thus far. The formation of sulfur ylide involves a chiral sulfide and a carbene or carbenoid, and the general reaction procedure for epoxidation of aldehydes may involve the application of a sulfide, an aldehyde, or a carbene precursor as well as a copper salt. This reaction may also be considered as a thiol acetal-mediated carbene addition to carbonyl groups in the aldehyde. 

---