Heteroatom-based nucleophile

Similar to the epoxides, the most frequently encountered synthetic transformation for aziridines is nucleophilic ring-opening, whereby carbon- and heteroatom-based nucleophiles are comparably important. As an example of the former type, aziridine-2-carboxylates 100 can be ring-opened with higher order cuprates to give the protected amino acid derivatives 101, corresponding to attack at the less-substituted aziridine carbon [95TL151],... 

There is, of course, no paucity of examples using heteroatom-based nucleophiles. For example, aziridine-2-/-butyl carboxylate 102 reacts with primary amines to give the dialkylated diamino-propionic acid derivatives 103, which are interesting precursors for the synthesis of cyclosporin analogs. Again, attack occurs overwhelmingly at the B-carbon [95TL4955]. 

A wide range of heteroatom-based nucleophiles, and cyanide, react with 2-, 3-, and 4-halopyridines in minutes at elevated temperature in polar solvents such as HMPA, DMSO, or A -methylpyrrolidine (NMP) under microwave irradiation (e.g., Scheme 102) <2002T4931>. Aminations of halopyrimidines are likewise greatly accelerated in this way, e.g., <2004TL757>. 

Hydroxymethylaziridine 67 undergoes ring opening in the presence of either carbon- or heteroatom-based nucleophiles upon treatment with 2 equiv of potassium hydride to provide the t)7aminoalcohol derivative 69. The key step of the reaction is considered to be an aza-Payne rearrangement of the deprotonated aziridine methanol to the... 

Carbohydrates are excellent substrates to test nucleophilic displacement reactions with a variety of heteroatom-based nucleophiles. These reactions can be tried on primary and secondary hydroxyl groups at different sites of the sugar ring, and with different steric or stereoelectronic dispositions [1]. 

In principle, the nucleophilic attack at alkene or alkyne ligand can be a reversible process, like the reaction of carbonyl ligand. The reversibility often has been confirmed in the reaction of heteroatom-based nucleophiles, but carbon nucleophiles rarely undergo the reversible ahack at alkenes and alkynes [30]. Occurrence of an equilibrium reaction was observed between the combination of alkene-metal complex with amine on one hand, and zwiher ionic adduct made from the former combination on the other (Eq. 8.6) [31,32]. The isolation of the latter adduct was also realized in some cases as described later. It was demonstrated that this type of reversible adduct formation did not accompany E-Z isomerization of the alkene, meaning stereospecihc nature of the C-N bond formation and its reverse. A closely related stereochemical analysis demonstrated that the ahack of the amine at the coordinated alkene takes place from the side opposite to the metal atom, as will be discussed later in more detail. 

Conjugate Addition. TBDMS triflate has been used to promote the conjugate addition of carbon- and heteroatom-based nucleophiles to a range of a./S-unsaturated carbonyl compounds, in both stoichiometric and catalytic quantities. In some cases, the silyl enol ether is isolated, in other cases, it is implied as an intermediate but hydrolyzed either in situ or by addition of an acid or a reagent known to cleave a carbon-silicon bond e.g., TBAF. Examples of carbon-based nucleophiles are shown in eqs 22-26. 

In the last few years, the use of NHC-Cu complexes in catalysis has grown exponentially, particularly for the transfer of carbon and heteroatom-based nucleophiles to various electrophilic substrates. Copper-catalyzed boron and silicon transfers have recently been reported, thus expanding the scope of NHC-copper-catalyzed reactions. Notably, the design of new chiral NHC ligands has enabled the successful development of efficient C-C and C-H bond forming enantioselective reactions. 

Halide displacement from the carbene ligands of Ru, Os, and Ir halocarbene complexes by N-, O-, and S-based nucleophiles frequently leads to the formation of new heteroatom-substituted carbene complexes. This important class of reactivity will be discussed in more detail in Section V,D, but it is appropriate here to illustrate the scope of this method with several examples ... 

Most of the reactions which will be discussed lead to carbonyl compounds with a stereogenic center in the 3-position. This is illustrated in Scheme 1 a substrate molecule (1 X = heteroatom or heteroatom-based functional group), having an electron-deficient double bond, is attacked by a nucleophilic reagent (possibly in the presence of a coordinating ligand or a catalyst) to form an anionic intermediate (2), which is then converted to the product (3) on hydrolytic work-up. 

The construction of complex intermediates from simple and readily available starting materials has been accomplished using the electrocyclic ring-opening reaction of halocyclopropanes. This is typically achieved through interception of the cationic haloallyl intermediate by solvent, the silver(I) counteranion, or some alternate tethered heteroatom or carbon-based nucleophile. Examples of these processes are described below. 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

Lone Pairs as Bronsted Bases Lone Pairs on Heteroatoms as Nucleophiles Softness, Solvation, Size, Basicity Easily Oxidizable Metals... 

Coordination of a metal to the itt-orbitals of an arene opens pathways for nucleophile addition to the arene. The power of the effect is related to the oxidation state (Cr°, Mn Fe ) and peripheral ligands (Cp or CO). Under suitable conditions, both heteroatom and carbon-based nucleophiles add rapidly under mild conditions. The fate of the cyclohexadienyl intermediate depends on the conditions of the next stage of the batch-wise process. Loss of an electronegative leaving group leads to an analog of... 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

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