Carbonucleophile

In 1985, Tsuji s group carried out a Pd-catalyzed reaction of propargyl carbonate with methyl acetoacetate as a soft carbonucleophile under neutral conditions to afford 4,5-dihydrofuran 109 [89-91]. The resulting unstable 109 readily isomerized to furan 110 under acidic conditions. In addition, they also reported formation of disubstituted furan 112 via a Pd-catalyzed heteroannulation of hydroxy propargylic carbonate 111 [92], Presumably, an allenylpalladium complex (c/. 114) was the key intermediate. 

N-l-cinnamyluracil isolated in 80 % yield (Scheme 6.20). Similar changes in regioselectivity were also observed in reactions of various carbonucleophiles with aUyhc acetates or carbonates [48]. 

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

Asymmetric C-C bond formation is the most important and most challenging problem in synthetic organic chemistry. In Nature, such reactions are facilitated by lyases, which catalyze the addition of carbonucleophiles to C=0 double bonds in a manner that is classified mechanistically as an aldol addition [1]. Most enzymes that have been investigated lately for synthetic applications include aldolases from carbohydrate, amino acid, or sialic acid metabolism [1, 2]. Because enzymes are active on unprotected substrates under very mild conditions and with high chemo-, regio-, and stereoselectivity, aldolases and related enzymes hold particularly high potential for the synthesis of polyfunctionalized products that are otherwise difficult to prepare and to handle by conventional chemical methods. 

Ma and co-workers have reported the selective synthesis of pyrrolidine derivatives through a three-component reaction based on a conceptually related strategy (Scheme 8.29) [72], Beginning with the catalytic intermolecular carbopalladation of y-allenic malonate 57 in the presence of a base, they succeeded in intercepting the internal carbonucleophile 58 with an imine such as the N-benzylidene p-toluenesulfonamide 59. The attack of the newly formed heteronucleophile on the 7r-allyl palladium intermediate affords the functionalized pyrrolidine 60 with high... 

De Meijere and co-workers have extended the scope of this process by applying this palladium-mediated multicomponent reaction to the bicyclopropylidene 72 as the alkene partner (Scheme 8.33). In this case, the intermolecular trapping of 7r-allyl palladium intermediate 73 with a soft carbonucleophile or with primary or secondary amines affords only products 74 having a methylenecyclopropane end group [78],... 

Synthesis 2003, 2115-2134 (b) For reactions involving carbonucleophiles, Balme, G. Monteiro, N. Bouyssi,... 

The formation of carbon-carbon bonds by conjugate addition of carbonucleophiles to a,/3-unsaturated systems has been studied intensively and reviewed over the past few years . Interestingly, applications with simple, unstabilized lithium enolates are relatively rare. Most reported examples are limited to the addition of stabilized enolates, such as those derived from malonates or acetoacetates. Nevertheless, some diastereo- and enantioselective versions of the conjugate addition, even with unstabilized lithium enolates, are well known. In 2004, Tomioka and coworkers studied the influence of a chiral diether (191) on the 1,4-addition of lithium ester enolates (189) to a,-unsaturated ketones (equation 51) . Their investigations showed that good enantioselectivities were obtained with cyclic enones, like 2-cyclopentenone (190) addition to a mixture of 189 and 191 gave the desired 1,4-adduct (R)-192 with 74% ee, but only 47% yield. Unfortunately, also the Peterson product 193 was formed in a yield of 22% by initial 1,2-addition of the enolate to the Michael acceptor. 

The addition of carbonucleophiles to alkynes promoted by ruthenium complexes is not documented. However, several examples of C-H bond addition to alkynes with C-C bond formation have been performed. These involve the ruthenium activation of a C-H bond of aromatic ketones [117, 118] such as 2-methylacetophenone, tetra-lone [119[ (Scheme 8.42), and enones [120, 121]. 

Many methods of ruthenium-promoted C-C bond formation implicating alkynes have been discovered. Most of these have involved oxidative coupling at a ruthe-nium(O) or (II) site, rather than addition of carbonucleophiles to electrophilically activated alkynes. These methods have been reported in several reviews [3,122]. 

The Michael-type addition reaction of a carbonucleophile with an activated olefin constitutes one of the most versatile methodologies for carbon-carbon bond formation [1]. Because of the usefulness of the reaction as well as the product, many approaches to the asymmetric Michael-type addition reactions have been reported, especially using chirally modified olefins [2-8]. However, the approach directed towards the enantioselective Michael-type addition reaction is a developing area. In this Chapter, the recent progress of the enantioselective Michael-type addition reaction of active methylene compounds and also organometallic reagents with achiral activated olefins under the control of an external chiral ligand or chiral catalysts will be summarized [9]. 

Catalytic conversion of esters through the C-0 bond cleavage has been developed. Pd-catalyzed carbonucleophilic substitution of naphthylmethyl and 1-naphthylethyl esters has been achieved as shown in Eq. 25 [65]. The ease of the naphthylalkyl-0 bond cleavage may be partly due to the stability of the naphthylmethyl entity that can form an r 3-allylic-palladium bond. 

In 1985, Tsuji s group carried out a Pd-catalyzed reaction of propargyl carbonate with methyl acetoacetate as a soft carbonucleophile under neutral conditions to afford... 

The allylation reaction was extended to various carbonucleophiles [7, 10-12], It was observed that the selectivity in the formation of mono- and diallylated compounds was very sensitive to the nature of carbonucleophile and its p Ka. The acyclic carbonucleophiles such as ethyl acetoacetate, acetylacetone, dimethyl malo-nate, dicyanomethane, and bis(phenylsulfone)methane, gave predominantly the monoallylated product (Eq. 2), although the cyclic carbonucleophiles such as te-tronic acid, dimedone, and barbituric acid gave predominantly the diallylated product (Eq. 3). 

The synthesis of chiral fluorous bisoxazolines is very easy to reproduce. This ligand in association with palladium is an efficient catalyst for the asymmetric catalytic alkylation of l,3-diphenylprop-2-enyl acetate with various carbonucleophiles. Table 3.2 gives some examples of such allylic alkylation. 

The N-aryl substitution in the starting imines exerts a profoimd effect on enantioselectivities. Particularly in the case of addition to the imines bearing substituted N-4-methoxyphenyl or M-naphthyl groups 77, excellent enantioselectivities (up to 97% ee) were obtained (Scheme 23) [71].Reaction of heterocy-cle-involving imine and heterocyclic carbonucleophiles in the presence of a chiral ligand has been also reported [72,73]. 

Other carbonucleophiles such as nitromethane [27] and indoles [28] have been used under similar oxidative conditions to produce sp -sp and sp -sp carbon-carbon bonds, respectively. 

Competing reaction channels can be prevented if an organometallic compound serves as the carbonucleophile and is irreversibly generated under aprotic conditions, i.e., generally in an ethereal medium. In this way, fluorocyclooctatetraene (99), a highlight in early dynamic nmr studies, was prepared from bromocyclooctatetraene through the lithium species, albeit in a yield of not more than 10% (Scheme 1-68). ... 

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