Alkylation at nitrogen

Azolone anions are readily alkylated at nitrogen, e.g. 2-triazolone with methyl iodide gives the 1-methyl derivative. 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

Alkylation at nitrogen has been achieved by treating indole or pyrrole with alkyl halides in ionic solutions of potassium carbonate in l- -butyl-3-methylimidazolium tetrafluoroborate [bmim][BFJ <06TL2435>. Bis-protection of 3,3 -diiodo-2,2 -biindoles with Me, Boc, C02Et, or S02Ph has been described by Roy and Gribble <06SC3487>. 

Methods have been developed for selective alkylation at nitrogen in (459) and (460) (77JOC2551). Compound (460) also underwent a base-induced ring contraction analogous to the (448) to (453) conversion discussed earlier. 

Epoxidation also proceeds (Eq. 141) under mild conditions and with high stereoselectivity (95 5 erythro threo) despite the deactivating effect of the fluorine atom [361]. At a higher oxidation level, the Lausanne group described chemistry of a metallated azomethine derived from a,/Lunsaturated-a-fluoroaldehydes [362]. Highly flexible chemistry allowed alkylation at nitrogen, or at the (fluori-nated) -position, or at the -position (Fig. 8). 

Chiral alkoxy allenes derived from 1,3-alkylidene-L-erythritol and -D-threitol have been used in cycloaddition reactions to provide the 4-substituted /3-lactams 418 (R = Me, Ph). Intramolecular alkylation at nitrogen was achieved by the action of potassium carbonate and tetrabutylammonium bromide in dry acetonitrile. The absolute stereochemistry of the product 419 (R = Me, Ph) was assigned on the basis of the CD helicity rule (see Section 2.04.3.5) and NMR spectroscopy. The [2+2] cycloaddition of CSI to threitol vinyl ethers was found to have low stereoselectivity in contrast to the findings with erythritol derivatives <2004CH414, 2005EJ0429>. 

ATMM complex 121 reacts analogously, protonating and alkylating at nitrogen to form /3-aminoallyl complexes 122 and 123, respectively <1994ICA1 >. The aminoallyl complex 122 can be deprotonated, regenerating the ATMM complex (Equation 39). 

Now the quinolone synthesis can be executed with the same reagents we used before and all that remains is ester hydrolysis and alkylation at nitrogen. Notice that the quinolone cyclization could in theory have occurred in two ways as the two positions ortho to the amino group are different. In practice cyclization occurs away from the pyridine ring as the alternative quinolone would be impossibly crowded. 

Similarly, the regio- and diastereoselective formation of azetidines can be accomplished through olefin insertion into the Zr-C bond of zirconaaziridines (Eq. 14). Cleavage of the Zr-C bond with I2 introduces an alkyl iodide functionality, which alkylates at nitrogen to result in intramolecular cyclization and the diastereoselective formation of azetidines, the products of the formal zirconium-mediated [2+2] reaction of an imine and an olefin. Hindered cyclic alkenes can also insert into the Zr-C bonds of zirconaaziridines to yield bi-cyclic products [55], albeit with low diastereoselectivity (2 1 for norbornene). 

Oximes may be alkylated at nitrogen or oxygen both types are electrolytically reducible [1,94,95] in their protonated form. The nitrones are generally also reducible in alkaline solution, whereas the O-methyl ethers of oximes are not reducible in ordinary media containing alkali metal ions. In solutions containing quaternary ammonium /j-toluenesul-fonates, some 0-alkylated oximes give a polarographic wave,... 

The most general method of preparing allyl ethers is to react the alcohol with allyl bromide or iodide in the presence of sodium hydride. The reaction is best carried out in a polar solvent, usually DMF [72]. Alcohols may also be alkylated after conversion to their barium salts. This technique is employed in the case of A-acyl derivatives of aminosugars to avoid any risk of alkylation at nitrogen which would accompany the use of sodium hydride as the base [73,74]. Conversion of alcohols to allyl carbonates, followed by palladium-catalyzed extrusion of CO2, constitutes a milder alternative to the classical Williamson-type pro-... 

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