Metathesis nucleophile

In addition to ring-closing metathesis, nucleophilic aromatic substitution and Heck coupling reactions can also be used to efficiently form cyclic peptides using microwave irradiation. 

Cassidy JH, Marsden SP, Stemp G. Stereoselective synthesis of 2,3,5-trisubstituted tetrahydrofurans by an allyl silane metathesis-nucleophilic addition sequence. Synlett 1997 1411-1413. 

AT-heterocyclic carbenes show a pure donor nature. Comparing them to other monodentate ligands such as phosphines and amines on several metal-carbonyl complexes showed the significantly increased donor capacity relative to phosphines, even to trialkylphosphines, while the 7r-acceptor capability of the NHCs is in the order of those of nitriles and pyridine [29]. This was used to synthesize the metathesis catalysts discussed in the next section. Experimental evidence comes from the fact that it has been shown for several metals that an exchange of phosphines versus NHCs proceeds rapidly and without the need of an excess quantity of the NHC. X-ray structures of the NHC complexes show exceptionally long metal-carbon bonds indicating a different type of bond compared to the Schrock-type carbene double bond. As a result, the reactivity of these NHC complexes is also unique. They are relatively resistant towards an attack by nucleophiles and electrophiles at the divalent carbon atom. 

The homoallylation product 16a presumably stems from oxidative cycloaddition of a Ni(0) species across the diene and aldehyde moieties of 15, leading to an oxanickellacycle intermediate 17 (path A, Scheme 5), which undergoes 0-bond metathesis with triethylsilane giving rise to a o-allylnickel 19. On the other hand, formation of 16b may start with addition of a Ni - H species upon the diene followed by intramolecular nucleophilic allylation as described in Eqs. 4-6 (path B). Alternatively, allylic transposition of the NiH group providing 20 from 19 may be related to the formation of 16b. The different reactivity between cyclohexadiene and many other acyclic dienes is also observed for the reaction undertaken under typical homoallylation conditions (see Scheme 14). 

Osborn and Green s elegant results are instructive, but their relevance to metathesis must be qualified. Until actual catalytic activity with the respective complexes is demonstrated, it remains uncertain whether this chemistry indeed relates to olefin metathesis. With this qualification in mind, their work in concert is pioneering as it provides the initial experimental backing for a basic reaction wherein an olefin and a metal exclusively may produce the initiating carbene-metal complex by a simple sequence of 7r-complexation followed by a hydride shift, thus forming a 77-allyl-metal hydride entity which then rearranges into a metallocyclobutane via a nucleophilic attack of the hydride on the central atom of the 7r-allyl species ... 

Pampus and co-workers (65) established the relative reactivity of a series of olefins to be 1-butene > 2-butene > isobutylene. This order of reactivity has been confirmed by others, and exactly parallels the reported order of stability of transition metal (Rh) complexes with these olefins (66), thus clearly implicating precomplexation of the olefin with the transition metal prior to metathesis. On a limited scale, Schrock observed a similar order of reactivity for olefins in reactions with (175-C5H5 )TaCl2[=CH(CH3 )3 ], which is known to possess a nucleophilic car-bene carbon (64). This complex also provides the requisite empty coordination site needed for precomplexation. In that study, cyclopropanes or metathesis olefins were not observed as products. 

Additional evidence for the contention that metathesis carbenes are nucleophilic was offered by Gassman in an interesting series of trapping experiments utilizing Michael acceptors as carbene traps (15, 17). Thus, an ethylidene carbene generated from 2-butene was trapped by ethyl acrylate to yield the expected ethylcyclopropyl ester, although yields were quite low. 

This correlation, between metathesis selectivity and the nucleophilicity of the alkyl-substituted alkene, was explained by considering the possible intermediate metallacyclobutanes 9-12 formed in the reaction (see Scheme 2). 

Crowe proposed that benzylidene 6 would be stabilised, relative to alkylidene 8, by conjugation of the a-aryl substituent with the electron-rich metal-carbon bond. Formation of metallacyclobutane 10, rather than 9, should then be favoured by the smaller size and greater nucleophilicity of an incoming alkyl-substituted alkene. Electron-deficient alkyl-substituents would stabilise the competing alkylidene 8, leading to increased production of the self-metathesis product. The high trans selectivity observed was attributed to the greater stability of a fra s- ,p-disubstituted metallacyclobutane intermediate. 

Like styrene, acrylonitrile is a non-nucleophilic alkene which can stabilise the electron-rich molybdenum-carbon bond and therefore the cross-/self-metathe-sis selectivity was similarly dependent on the nucleophilicity of the second alkene [metallacycle 10 versus 12, see Scheme 2 (replace Ar with CN)]. A notable difference between the styrene and acrylonitrile cross-metathesis reactions is the reversal in stereochemistry observed, with the cis isomer dominating (3 1— 9 1) in the nitrile products. In general, the greater the steric bulk of the alkyl-substituted alkene, the higher the trans cis ratio in the product (Eq. 11). 

Attacking the problem of cross-metathesis selectivity from a different angle, Crowe and co-workers explored the reactivity of a more nucleophilic partner for the Ji-substituted alkenes. They chose to use allyltrimethylsilane since they proposed that the CH2SiMe3 substituent should have a negligible effect on alkyli-dene stability, but enhance the nucleophilicity of the alkene via the silicon P-ef-fect (Fig. 1). 

The ratio of cross-/self-metathesis products, with respect to the alkyl-substituted alkene, was generally poorer (typically 3 1) than the analogous reactions with styrene or acrylonitrile, probably due to the absence of a good alkylidene stabilising substituent on either alkene and the closer nucleophilicities of the two substrates. 

It is noticeable that cross-metathesis with the unfunctionalised alkenes occurred in significantly higher yields over shorter reaction times and required a smaller excess of the soluble alkene. This was possibly due to the unfunctionalised alkenes, which are more nucleophilic than their ester containing counterparts, complementing the less nucleophilic/more carbon-metal bond stabilising allylglycinol 18. Comparable results were obtained from cross-metathesis reactions of the polymer-bound isomeric N-Boc C-allylglycinol with the same four alkenes. 

Whereas Hegedus [335] and Danishefsky [336] were the first to discover a tandem Heck reaction from o-allyl-A -acryloylanilines leading to tricyclic pyrrolo[l,2-a]indoles or pyridino[l,2-a]indoles [336], it has been the fantastic work of Grigg to unleash the enormous potential of this chemistry. Grigg and his co-workers parlayed their Pd-catalyzed tandem polycyclization-anion capture sequence into a treasure trove of syntheses starting with IV-allyl-o-haloanilines [337-345], Diels-Alder and olefin metathesis reactions can be interwoven into the sequence or can serve as the culmination step, as can a wide variety of nucleophiles. An example of the transformation of 289 to 290 is shown below in which indole is the terminating nucleophile [340],... 

The reactivity of organoxenonium salts [RXe]Y towards anions X is determined by the nucleophilicity of the latter and nature of solvent. When X is a weakly nucleophilic anion, anion exchange (metathesis) occurs in polar solvents forming the corresponding [RXe]X salts in high yields (eqs 11,12). 

In situation (a) a strong carbon-metal bond results. To this group belong the typical Schrock-type carbenes [e.g. Np3Ta=CH(7Bu)], many of which are nucleophilic at carbon. Situation (b) should also lead to nucleophilic carbene complexes, albeit with a weaker carbon-metal bond. Typical reactions of nucleophilic carbene complexes include carbonyl olefination (Section 3.2.4) and olefin metathesis (Section 3.2.5). 

Several other observations suggest that nucleophilic carbene complexes, similarly to, e.g., sulfur ylides, can cyclopropanate acceptor-substituted olefins by an addition-elimination mechanism. If, e.g., acceptor-substituted olefins are added to a mixture of a simple alkene and the metathesis catalyst PhWCl3/AlCl3, the metathesis reaction is quenched and small amounts of acceptor-substituted cyclopropanes can be isolated [34]. 

Closely related to the ring-closing metathesis of enynes (Section 3.2.5.6), catalyzed by non-heteroatom-substituted carbene complexes, is the reaction of stoichiometric amounts of Fischer-type carbene complexes with enynes [266,308 -315] (for catalytic reactions, see [316]). In this reaction [2 + 2] cycloaddition of the carbene complex and the alkyne followed by [2 -t- 2] cycloreversion leads to the intermediate formation of a non-heteroatom-substituted, electrophilic carbene complex. This intermediate, unlike the corresponding nucleophilic carbene... 

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