Allylic C-H Insertion

In the case of the cyclic substrate 51, the intervention of a C-H insertion pathway reveals itself in terms of the diastereoselectivity, not regioselectivity. Thus, exposure of enyne 51 to the standard Ru catalyst at ambient temperature produced the transfused bicyclo[5.4.0]undecene 52 (Equation 1.60, path a) [55]. If a metallacycle mechanism was operative, coordination of the metal with both the alkene and alkyne must occur to form the cis-fused product. On the other hand, coordination of the Ru with the Lewis basic bridgehead substituent directs it to abstract an allylic C-H on the same face as the substituent, which then leads to the trans-fused product as observed. On the other hand, cycloisomerization using a Pd(0) precatalyst does indeed lead to the Z-fused bicycle (Equation 1.60, path b). 

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Alkyl diazoacetates undergo little or no allylic C/H insertion when decomposed catalytically in the presence of appropriate olefins 6,13,I4). In contrast, such insertions occur with diazomalonates or ot-diazoketones. From the available facts, the conclusion can be drawn that different pathways may lead to what finally looks like the direct or rearranged allylic insertion product, but convincing evidence for one or the other mechanism is available only in a few cases. As Scheme 22 shows, the C/H insertion products 98-100 may arise from one of three major sources ... 

Whereas this mechanistic proposal seems reasonable and no reason can be seen why it should not be cited to explain the allylic C/H insertion product from cyclohexene, other cases exist where cyclohexene is not the best substrate to distinguish between this and one of the other alternatives of Scheme 22. 

Allylic C/H insertion accompanied by an allylic rearrangement has been observed for carbenoid reactions of ethyl diazoacetate with allylamines (Scheme 23)1S1). Apparently, metal-catalyzed isomerization 117 118 proceeds the C/H insertion process. Although mechanistic details have not yet been unraveled, T)3-allyl complexes... 

Contrary to the allyldimethylamines, the less nucleophilic l-morpholino-2-butene 117 and 3-morpholino-l-butene 118 do not yield products derived from an intermediary N-ylide rather, allylic C/H insertion products were isolated (see Sect. 2.3.3)151). 

The reaction of aryldiazoacetates with cyclohexene is a good example of the influence of steric effects on the chemistry of the donor/acceptor-substituted rhodium carbenoids. The Rh2(reaction with cyclohexene resulted in the formation of a mixture of the cyclopropane and the G-H insertion products. The enantios-electivity of the C-H insertion was high but the diastereoselectivity was very low (Equation (31)). 0 In contrast, the introduction of a silyl group on the cyclohexene, as in 15, totally blocked the cyclopropanation, and, furthermore, added sufficient size differentiation between the two substituents at the methylene site to make the reaction to form 16 proceed with high diastereoselectivity (Equation (32)).90 The allylic C-H insertion is applicable to a wide array of cyclic and acyclic substrates, and even systems capable of achieving high levels of kinetic resolution are known.90... 

Cyclopropanation.2 This metal carbonyl cluster is an effective catalyst for cyclo-propanation of alkenes with ethyl diazoacetate. Minor by-products are diethyl maleate and fumarate, but products of allylic C -H insertion are not formed. The yield of the cyclopropane can be increased if the ethyl diazoacetate is added slowly over a period of 6 hours to the olefin and catalyst. Under these conditions yields of eyclopropanes are 85 -90%. 

Examples are known where intermolecular carbenoid transformations between diazomalonates or certain diazoketones and appropriate olefins result in competition between formation of cyclopropane and products derived from allylic C—H insertion2-4. For example, catalytic decomposition of ethyl diazopyruvate in the presence of cyclohexene gave the 7-ejco-substituted norcarane 93 together with a small amount of the allylic C—H insertion product 94 (equation 95)142 143. In some cases, e.g. rhodium(II) decomposition of a-diazo-j8-ketoester 95, the major pathway afforded C—H insertion products 96 and 97 with only a small amount of the cyclopropane derivative 98. In contrast, however, when a copper catalyst was employed for this carbenoid transformation, cyclopropane 98 was the dominant product (equation 96)144. The choice of the rhodium(II) catalyst s ligand can also markedly influence the chemoselectivity between cyclopropanation and C—H... 

An interesting aspect of the allylic C-H insertion is that the products are y,6-unsaturated esters. Traditionally, y,6-unsaturated esters are most commonly prepared by a Claisen rearrangement, especially if stereocontrol is required. Diastereocontrol is also possible in the C-H insertion as long as the reaction occurs at a methylene site where there is good size differentiation between the two substituents [21]. An example is the reaction between 17 and the silylcyclohex-ene 18 which forms the C-H insertion product 19 in 88% de and 97% ee [21]. Other catalysts such as Rh2(.R-BNP)4 and Rh2(S-MEPY)4 have been explored for allylic C-H activation of cyclohexene but none were was as effective as Rh2(S-DOSP)4 [22]. 

A related allylic C-H insertion that has considerable promise for strategic organic synthesis is the reaction with enol silyl ethers [23]. The resulting silyl-protected 1,5-dicarbonyls would otherwise typically be formed by means of a Michael addition. Even though with ethyl diazoacetates vinyl ethers are readily cyclopropanated [l],such reactions are generally disfavored in trisubstituted vinyl ethers with the sterically crowded donor/acceptor carbenoids [23]. Instead, C-H insertion predominates. Again, if sufficient size differentiation exists at the C-H activation site, highly diastereoselective and enantioselective reactions can be achieved as illustrated in the reaction of 20 with 17 to form 21 [23]. 

In the presence of alkenes, photolysis of alkyl (silyl)diazoacetates leads mainly to the formation of cyclopropanes as diastereomeric mixtures4,111,112. With (Z)- and ( )-but-2-ene, the cyclopropanation is not completely stereospecific with respect to the double bond configuration, but gives a small amount of the wrong isomer these results point to the participation of a triplet carbene in the cyclopropanation reaction. Allylic C,H insertion products are also formed their yield increases in the series 1,1-, 1,2-, tri- and tetrasubstituted C=C bond. With 2,3-dimethyl-but-2-ene, the allylic C,H insertion product is formed at the complete expense of the cyclopropane. 

Cyclopentammes.2 2-Carboalkoxycyclopentanones can be obtained by cycliza-tion of a-diazo-/0-keto esters catalyzed by Rh2(OAc)4. Allylic C—H insertion can be favored over cyclopropanation. 

Allylic C-H insertions have been used in key steps of the enantioselective synthesis of the pharmaceuticals (+)-ceitedil (26) [21] and (+)-indatraline (27) [22] (Scheme 11). The allylic C-H insertion reaction is an exciting alternative to the Claisen rearrangement as a rapid method for the synthesis of y,c>-unsaturated ester [23 ]. Similarly, the allylic C-H insertion with vinyl silyl ethers generates protected 1,5-dicarbonyl compounds, a complimentary reaction to the Michael addition [24]. Both types of C-H insertion can be achieved with high diastereoselectiv-ity and enantioselectivity [23, 24]. 

Attempted allylic C-H insertion by vinyldiazoacetates results in an even more complicated transformation, a combined C-H activation/Cope rearrangement [27]. These reactions tend to proceed with very high enantioselectivity as illustrated in a short enantioselective synthesis of the antidepressant (+)-sertraline (33) [27a]. Recent studies have shown that this reaction is both highly diastereose-lective and enantioselective [27b],... 

As anticipated, catalytic cyclopropanation of cyclohexene occurs with a much higher preference for the sterically less hindered diastereomer (anh-20) than in the case of the monosubstituted alkenes (Scheme 7). However, the reaction succeeds only with [Ru2(CO)4(OAc)2] as catalyst, whereas decomposition of 10a-SiMc3 wi CuOTf leads to the carbene dimers 11, and decomposition with Rh2(pfb)4 yields the apparent product of allylic C-H insertion (19) besides some ketazine. 

The insertion reactions into cyclohexane C-H bonds (Table 1) give some idea of which nitrenes give synthetically useful yields. However, since most other substrates will contain more than one sort of C—H bond, it is important to know the selectivity of nitrenes for different types of C—bond. Several studies of nitrene selectivity towards tertiary, secondary and primary unactivated C—H bonds have been made, although attempts to study allylic C—H insertion reactions are complicated by the competing nitrene addition to the double bond. In cyclohexene it has been estimated Aat the allylic C—H bond is only about three times more reactive than the homoallylic C—H bond towards insertion of ethoxycarbo-nylnitrene. However, the reaction is totally unsatisfactory as a means of allylic functionalization since, as shown in Scheme 3, the yields are so low. 

Side-products of the latter reactions involved allylic C-H insertion products such as 171 and... 

Analogously, the gas-phase thermal decomposition of trifluoro(l,l,2,2-tetrafluoroethyl)silane (at 140-200 C) or trimethyl(l,l,2,2-tetrafluoroethyI)silane (at 300-370°C) generated di-fluoromethyl(fluoro)carbene which underwent addition to alkenes to give 1-difluoromethyl-l-fluorocyclopropane 8. ° (Z)- and ( )-But-2-ene were cyclopropanated stereospecifically, and allylic C-H insertion was not observed. With dimethyl(vinyl)silane or allyl(dimeth-yl)silane, however, the carbene underwent both double bond addition and Si-H insertion. ... 

Catalytic cyclopropanation of alkenes with diazomalonates is sometimes carried out with copper powder, but it appears that copper(I) halide/trialkyl phosphite complexes (for a procedure see Houben-Weyl Vol. E19b, p 1113), bis(acetylacetonato)copper(II), " ° and tet-raacetatodirhodium can be employed more advantageously (Table 13, entries 7-9). For the cyclopropanation of styrene with dicyclohexyl diazomalonate, however, copper(I) triflate was the catalyst of choice, while intramolecular C —H insertion at the cyclohexyl ring took place in the presence of tetraacetatodirhodium. A detailed comparison of copper catalysts for the cyclopropanation of cyclohexene, 1-methyl- and 1,2-dimethylcyclohexene, (Z)- and ( )-hept-2-ene with dimethyl diazomalonate, including competitive reaction pathways such as allylic C-H insertion and carbene dimer formation, is available. The catalyzed interaction between diazomalonic esters and enol ethers leads to cyclopropanes in some cases (e.g. ethoxymethylenecyclohexane to dimethyl 2-ethoxyspiro[2.5]octane-l,l-dicarboxylate ) and to different products in other cases (e.g. 1-methoxycyclohexene, 2-methoxy-3,4-dihydro-2/7-pyran ). This behavior is attributed to the occurence of stabilized dipolar intermediates in these reactions. 

Alkyl diazoacetates undergo little or no allylic C/H insertion when decomposed catalytically in the presence of appropriate olefins jjj contrast, such insertions... 

Despite these significant advances, allylic C H insertion under these conditions remains problematic, with competing olefin aziridination often observed as the dominant reaction pathway (Scheme 12.5) [29]. 

Representative allylic C-H insertions (absolute stereochemistry not reported)... 

Allylic C H insertion proceeds with complete selectivity for the C H bond, and competing aziridination is not observed. In contrast to the Rh2(S nap)4 catalyst system, a preference for trans olefins is observed under these conditions. Thus, trans olefin is converted to oxathiazinane 49 in good yield (60%) and selectivity (89% ee). Conversely, cis olefins are not good substrates for this catalyst. 

An early example that suggested donor/acceptor carbenoids might be ideally suited to allylic C-H insertion was the Rh2(S -DOSP)4-catalyzed reaction of cyclohep-tatriene (86) with either EDA or methyl aryldiazoacetates 87 (Scheme 18) [85], With EDA as the carbenoid precursor, the monocyclopropanated product 85 was formed in 49% yield ( 3 1 exo endo) and 6% ee. The outcome of the reaction changed dramatically with carbenoids derived from aryldiazoacetates. In these cases, less than 5% of the cyclopropane was observed, and 53-64% yield of the C-H insertion product 88 was isolated in 91-95% ee. 

Allylic C-H Insertion as Equivalents to Traditional Organic Reactions... 

Scheme 22 Allylic C-H insertion as an equivalent to the asymmetric Michael reaction...

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