Heteroatomic nucleophiles oxidation additions

A. 1.1. Covalently Functionalized Dendrimers Applied in a CFMR The palladium-catalyzed allylic substitution reaction has been investigated extensively in the preceding decades and provides an important tool for the formation of carbon—carbon and carbon—heteroatom bonds 14). The product is formed after attack of a nucleophile to an (f/ -allyl)Pd(II) species, formed by oxidative addition of the unsaturated substrate to palladium(0) (Scheme 1). To date several nucleophiles have been used, mostly resulting in the formation of carbon—carbon and... 

Following the oxidative addition, in the transmetalation step the anionic form of the heteroatom containing coupling partner (amide, alkoxide) is transferred onto the palladium, which is usually achieved by the combined use of the neutral form of the nucleophile and a suitable base. The choice of the proper base might be crucial for the success of the coupling. The transmetalation, as depicted in Figure 2-3, usually follows a coordination-... 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

In 1,3-benzazoIes (benzoxazoles, benzothiazoies, benzoselenazoles) the heteroatom that is not nitrogen shows very low nucleophilicity and does not serve as a reaction center in electrophilic addition and oxidation-addition reactions. By contrast the tellurium atom in benzotellurazoles is quite susceptible to attack by electrophiles and oxidants. 

The general catalytic cycle for this carbonylation coupling reaction is analogous to direct carbon-heteroatom coupling [scheme (39)] except that carbon monoxide insertion takes place after the oxidative addition step and prior to the nucleophilic attack of the amine [scheme (40)] ... 

Alkylidenes have been prepared by reduction of alkyli-dynes, by C H oxidative addition from alkyls, and by treatment of unsaturated metal clusters with diazoalkanes. In most instances, the alkylidene adopts a /r2-h coordination mode. However, alkylidenes with heteroatom substituents may also be found in terminal coordination modes. The latter are typically prepared by the Fischer-type carbene route (see Fischer-type Carbene Complexes) (sequential addition of nucleophilic and electrophilic alkylating agents to carbonyl or isocyanide ligands), by condensation of metal fragments with mono- or dimetallic carbene complexes, or by C-H activation of alkylamines. These heteroatom substituted carbenes may also bind in a p3-ri mode, as in (12). 

Heteroatomic nucleophiles which also have been shown to undergo addition across the 3,4-double bond of quinazolines 5 and with which the addition products 6 were isolated include the methoxide anionand sodium hydrogen sulfite.(For addition of sodium hydrogen sulfite and hydrazine at the 4-position of quinazoline 3-oxides with concomitant deoxygenation of the A(-oxide group, cf p 105.) Equilibrium and rate constants have been determined at 25 °C for the covalent addition of water, the bisulfite ion, hydroxylamine, urea, 2-sulfanylethanol, and hydrogen sulfide to the 3,4-bond of the quinazoline cation. ... 

The propensity for C-N vs. N-H activation correlates well with substituent Hammet parameters groups that increase the basicity of aniline increase the relative rate of N-H activation, suggesting that nucleophilic attack by the amine at an empty d /dy orbital of Ta(silox)3 preceeds oxidative addition. On the other hand, electron-withdrawing substituents decrease the rate of N-H activation and increase the rate of C-N activation, similarly to the effects observed on electrophilic aromatic substitution. Nucleophilic attack by the filled d a orbital of Ta(silox)3 is expected to occur at the arylamine ipso carbon preceding C-N oxidative addition. The carbon-heteroatom cleavages can be accomodated by mechanisms using both electrophilic and nucleophilic sites on the metal center. 

The Wacker-type addition is the anti-addition of (most commonly) a heteroatom and a Pd(II) species across a C-C double bond. The Wacker-type oxidations are Pd(II)-catalyzed transformations involving heteroatom nucleophiles and alkenes or alkynes as electrophiles.27 In most of these reactions, the Pd(II) catalyst is converted to an inactive Pd(0) species in the final step of the process, and use of stoichiometric oxidants is required to effect catalytic turnover. For example, the synthesis of furan 33 from a-allyl-p-diketone 32 is achieved via treatment of the substrates with a catalytic amount of Pd(OAc)2 in the presence of a stoichiometric amount of CuCh-28 This transformation proceeds via Pd(II) activation of the alkene to afford 34, which undergoes nucleophilic attack of the enol oxygen onto the alkene double bond to provide alkylpalladium complex 35. p-Hydride elimination of 35 gives 36, which undergoes... 

Once it is recognized that cyclohexadienyl anionic complexes of chromium (41) can be generated by addition of sufficiently reactive nucleophiles and that simple oxidizing techniques convert the anionic intermediates to free substituted arenes, a general substitution process becomes available which does not depend on a specific leaving group on the arene [2]. The process is general for carban-ions derived from carbon acids with pK >22 or so only one example of a heteroatom nucleophile is reported [102]. 

The metal-bound carbonyl ligand is readily subjected to the attack of not only carbanions but heteroatom nucleophiles such as alcohols and amines to form ligands useful for formation of compounds containing ester and amide functionalities. The ease with which the nucleophilic attack takes place at metal-coordinated alkenes and alkynes provides a basis for oxidation of these molecules in the presence of a transition metal complex catalyst [3,4a], as exemplified by the Wacker type alkene oxidation by the use of a Pd catalyst. Metal catalyzed addition of alcohols or amines to alkenes and alkynes also involve the analogous nucleophilic attack [4b-e]. The attack of carbanions and heteroatom nucleophiles... 

A cascade Heck reaction with termination by nucleophiles is considered to start with an oxidative addition of a heteroatom-carbon bond (starter) onto a palladium(O) species (startup reaction), followed by carbopalladation of a nonaromatic carbon-carbon double or triple bond without subsequent dehydropalladation (relay), a second and possibly further carbopalladation of a carbon-carbon double or triple bond (second etc. relay). The terminating step is a displacement of the palladium residue by an appropriate nucleophile. It is crucial for a successful cascade carbopalladation that no premature dehydropalladation takes place, and that can be prevented by using alkynes and 1,1-disubstituted alkenes (or certain cycloalkenes) as relay stations since they give kinetically stable alkenyl- or neopentylpalladium intermediates, respectively. In addition, reaction of haloalkenes with alkenes in certain cases may form rr-allyl complexes, which are then trapped by various nucleophiles. 

Enantiosdective allyic substitution processes have been developed over the course of 30 years. Initial observations of the reactions of nucleophiles with paUadium-allyl complexes led to the observation of catalytic substitutions of aUylic ethers and esters, and then catalytic enantioselective aUylic substitutions. The use of catalysts based on ottier metals has led to reactions that occur with complementary regiochemistry. Moreover, flie scope of the reactions has expanded to include heteroatom and unstabilized carbon nucleophiles. Suitable electrophiles for these reactions indude allyhc esters of various types, allyhc ethers, aUylic alcohols, and aUylic halides. Enantioselective reactions can be conducted with monoesters or by selection for deavage of one of two equivalent esters. The mechanism of these reactions occurs by initial oxidative addition to form a metal-aUyl complex. The second step involves nudeophilic attadc on ttie aUyl ligand for reaction of "soft" nudeophiles or inner-sphere reductive eUmination for reactions of "hard" nudeophiles. The external nudeophilic attack typicaUy occurs by reaction of the nudeophile with a cationic aUyl complex at the face opposite to that to which Uie metal is bound. Exceptions indude reactions of certain molybdenum-aUyl complexes. Dissociation of product then regenerates the starting catalyst. Because of the diversity of the classes of these reactions, aUylic substitution—in particular asymmetric aUylic substitution—has been used to prepare a wide variety of natural products. 

Cross-coupling of Ar(or vinyl)-X with organometaDic species, terminal alkynes, and olefins, as well as carbonylation in the presence of nucleophiles, represent well-known synthetic routes for C—C bond formation. As far as C-heteroatom bond formation is concerned, powerful synthetic procedures have been developed for selective formation of the C-P (P = R2P, R2P(0), R(R 0)P(0), (R0)2P(0)), C-SR, C SeR, C—NR2, and so on, bonds. All of these catalytic methods are based on substitution reactions. The catalytic cycle of a typical substitution reaction includes the following stages (i) oxidative addition, (ii) transmetaUation, and (iii) C-heter-oatom reductive elimination. 

A number of intramolecular Pd-catalyzed 1,4-oxidations of conjugated dienes were developed.f In these reactions, two nucleophiles are added across the diene, one of which adds intramolecularly. So far, only heteroatom nucleophiles have been employed. In order to extend these intramolecular 1,4-oxidations to carbon nucleophiles, it was found that a vinylpalladium species can be obtained in situ from an alkyne via a chloropalladation. The approach is particularly attractive since it involves a Pd(II) chloride salt and could be compatible with the rest of the catalytic cycle. Reaction of dienyne with LiCl, and benzoquinone in the presence of palladium acetate as the catalyst, afforded the carbocyclization products. The reaction resulted in an overall stereoselective fltiri-addition of carbon and chlorine across the diene t B (Scheme 23). 

Another tandem possibility is to use oxidative addition to generate the palladium(II) species that initiates cyclization (Scheme 6.44). The result is formation of both a C-C bond and a bond between an alkene carbon and a heteroatom. The C-C bond is formed by reductive elimination that generates a palladium(O) species. This is then returned to the palladium(II) state by oxidative addition, hence no added oxidant is required. The reaction has often been used in an intramolecular fashion to ensure regioselectivity. If the nucleophilic attack is slow, a by-product may occur, which is the Heck product arising from alkene insertion. Alkynes may also be used as substrates. 

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