Intramolecular electrophilic induced nucleophilic reaction

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

The ease of adduct formation depends largely on the electron density on the N atom of the imine and the electrophilicity of the center carbon atom of the isocyanate. Most reactive are persubstituted guanidines and amidines on one side and aryl isocyanates with electron withdrawing substituents on the other side. The initial attack occurs on the more nucleophilic center. Delocalization of the developing charges favors intermolecular [2-I-2-I-2] cycloaddition over intramolecular [2-1-2] cycloaddition or the exchange reaction. When a hydrogen shift can occur, the intramolecular isocyanate induced enurea reaction is faster than the intermolecular [2-I-2-I-2] cycloaddition reaction. Thermodynamically controlled equilibria are established above 100 °C and the thermodynamically more stable reaction product is isolated. 

Intramolecular Induced Nucleophilic Reaction In an intermolecular nucleophilic reaction, if the reactant with an electrophilic center is activated by the intramolecular reaction, then such a reaction may be called intramolecular induced nucleophilic reaction. For instance, A-benzyloxy-carbonyl derivatives of a-aminophosphonochloridates (7, 8, and 9) react nearly 10 to 10" times faster than C1CH2P(0)(0CH3)C1 (10) with isopropanol (PrOH) to give substitution products as shown in Equation 2.25 and Equation 2.26. Significantly high reactivity of 7, 8, and 9 compared to 10 is attributed to the occurrence of reaction... 

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

Here, either X = (I T2C(0)-R j and ox = Jones reagent or X — CN and ox = CeIv. It has been emphasized that the addition of nucleophiles to (arene)Mn(CO)3+ complexes does not occur through an initial ET from the nucleophile to the metal center [2]. This represents an additional advantage since such redox reactions frequently lead to the decomposition of the metal complex, a typical example being the reductive deligation of bis(arene)Fe2+ complexes [48]. On the other hand, intramolecular charge transfer from the arene to the metal not only induces an electron deficiency in the arene ring (which is critical for effective attack of the nucleophile), but it also results in an attenuation of the electrophilicity of the metal center so as to avoid undesired ET reactions of the metal with the nucleophile. 

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