Intermolecular reactions nitrogen nucleophiles

In the dihapto mode the pyridine ring can be protonated intermolecularly at nitrogen, or even intramolecularly deprotonated at carbon. The first evidence for metal C—N insertion is the reaction of the metallaaziridine complex (111) with homogeneity LiHBEt3 in THF at low temperature that yields (112) (Scheme 49).251-254 Experiments with carbon nucleophiles (RMgCl, MeLi) in place of LiHBEt3 have provided valuable information to allow discrimination between... 

In this sense Organ and coworkers [80] have developed intriguing syntheses of polysubstituted olefins based upon consecutive intermolecular reactions such as allylic and allylic-vinylic halide coupling sequences. Therefore, l-acetoxy-4-chloro but-2-ene can be readily submitted as a template for Pd-catalyzed allylic substitutions with two different carbon or nitrogen nucleophiles, leading to unsymmetrically substituted butene derivatives 66-70 in good yields (Scheme 22). Mechanistically, the chloro substituent is replaced... 

The intermolecular addition of nitrogen nucleophiles has been shown to lead to interesting products, with remarkable control based on the reaction conditions (Scheme 10). Carbonylation of the organo-Pd intermediate can also be efficient, leading to /3-amino esters. Unfortunately, these processes require stoichiometric Pd no reoxidation scheme has been developed. 

Hydroamination of olefins is also possible with gold catalysts. In this reaction, the attack comes Ifom a nitrogen nucleophile as a carbamate,a urea, an amide, or a sulfonamide. In the latter case, the reaction can be carried out intermolecularly. While the carbamates, ureas, and amides give only products of intramolecular anunations, the sulfonamides can perform the intermolecular addition. Only the addition of ureas (equation 146) takes place at room temperature, and in the rest of the additions heating is required. The catalysts of choice in all these reactions are cationic gold(I)-species stabilized by phosphines or NHC ligands. The reaction times have been reduced by the use of microwave irradiation. The mechanism of the hydroamination reaction has been studied in detail theoretically. ... 

In these reactions, the nitrogen nucleophile is typically an amide, carbamate, or sulfonamide. Because of the low nucleophilicity of such nitrogen functions, no intermolecular 1,4-addition involving C—N bond formation is known. In all cases reported, the carbon-nitrogen coupling takes place in an intramolecular aminopalladation. 

An intermolecular reaction, again with overall syn Sn substitution, was successfully applied in a synthesis of the carbocyclic nucleoside analog aristeromycin to introduce the nitrogen base stereoselectively (equation 21), although with heteronucleophiles, unlike the case of carbon nucleophiles, a lower propensity for attack distal to oxygen to give the 1,4-product with vinyloxiranes exists. 

Intramolecular reactions are faster and cleaner than intermolecular reactions. When we want to make a C-N bond in a ring, therefore, we no longer have to take any special precautions and we can use a nitrogen nucleophile and any carbon electrophile. Two useful disconnections are ... 

Scheme 192. Reaction of Alkenyl Epoxides and Aziridines Producing Heterocycles via Carbon-Heteroatom Bond Formation by (a) Intramolecular Allylation of Oxygen and Nitrogen Nucleophiles and (b) Intermolecular [3 + 2]-Cycloaddition with Heterocumulenes...

C.ii.b. Intramolecular Attack by Nitrogen Nucleophiles. The nitrogen nncleophiles, which are compatible with the reaction conditions (HOAc and 1,4-benzoquinone), consist of electron-deficient ones such as amides, carbamates, ureas, and sulfonamides. Because of the low nucleophilicity of these, no intermolecular 1,4-additions involving C—bond formation is known. However, if the nitrogen is tethered to the diene, a cyclization takes place in good yields. 

Carbanions are some of the most common nucleophiles through which a new C—C bond can be formed. C—C instead of C—O or C—N bond formation can be achieved with oxygen and nitrogen bidentate nucleophiles in intermolecular reactions. However, in the intramolecular processes, C—O and C—N bonds could be formed. Nucleophiles derived from other heteroatoms react to form a new C-hetCToatom bond. 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

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