Adjacent to a heteroatom

Many additional examples of pyridazine ring construction via the reaction of the terminal nitrogen of hydrazones and a properly positioned cyano or ester group appeared since 1995 and some selected references are mentioned here 1996T5819, 2001T1813, 2001T6787, 2006H(67)815 . 

Intramolecular cyclization of A, /V-disubstituted 2-(2-fluorophenyl)acetohydrazides 237 gave 1,1-disubstituted l,4-dihydrocinnolin-l-mm-3-olates 238 (Equation 55) 1997J(P1)2229 . 

An aza analog of phthalazine 240 (pyrido[3,4-r/]pyridazine skeleton) was obtained via intramolecular addition-elimination reaction in azaphthalohydrazide 239 with the loss of hydrazine (Equation 56) 1997T8225 . In a similar approach also the 5,6-dihydro[l,2,3]triazolo[4,5-r/]pyridazin-4,7-dione skeleton was constructed 2002JHC889 . 

Intramolecular Heck-type reaction of 2-bromo-A -(I//-indol-l-yl)-A -methylnicotinamide 241 yielded tetracyclic 6-methylpyrido[3, 2 4,5]-pyridazino[I,6- ]indol-5(6//)-one 242 in 92% yield (Equation 57) 1995TI94I . 

Intramolecular nucleophilic aromatic substitution on 243 allowed l,4-dihydropyridazin-3(2//)-one ring construction (Equation 58) I995TIII25 . Similarly, a tetrahydropyridazine unit could be constructed starting from 244 (Equation 59) I995JOC3928 . 

This type of cyclization was reviewed in CHEC-I 84CHEC-I(3B)1 , particularly with reference to the formation of pyridazines by formation of a bond between the terminal nitrogen of hydrazones and an appropriately positioned cyano group or Michael aeceptor. Developments of this approach have been published, including application to the synthesis of phthalazines and cinnolines. 

When heated in toluene certain arylazomethylenetriphenylphosphoranes (prepared from isatoic acids) undergo an intramolecular Wittig reaction to give 3,4,6-trisubstituted cinnolines (Equation 

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Alkylation of sp3 C-H bonds adjacent to a heteroatom such as nitrogen and oxygen is possible. The early works using tungsten or iridium complexes involved the reaction of dimethylamine with 1-pentene (Equation (29)) and the alkylation of a C-H bond adjacent to oxygen with / r/-butylethylene.34,34a,34b... 

The alkylation of the sp3 C-H bonds adjacent to a heteroatom becomes more practical when the chelation assistance exists in the reaction system. The ruthenium-catalyzed alkylation of the sp3, C-H bond occurs in the reaction of benzyl(3-methylpyridin-2-yl)amine with 1-hexene (Equation (30)).35 The coordination of the pyridine nitrogen to the ruthenium complex assists the C-H bond cleavage. The ruthenium-catalyzed alkylation is much improved by use of 2-propanol as a solvent 36 The reaction of 2-(2-pyrrolidyl)pyridine with ethene affords the double alkylation product (Equation (31)). 

It has been known for many years that hydrogens adjacent to a heteroatom are more acidic when the heteroatom is sulfur than when oxygen359. A striking example of this phenomenon is the behavior of dithiane, A, compared to its oxygen analog,... 

Nucleophilic attack on ring atoms adjacent to a heteroatom or conjugated with a... 

Fig. 4. Free valence plotted against radical superdelocalizability for a group of benzo derivatives of thiophene (Model B2). Designation (class) A (0), o (1), (2). Positions adjacent to a heteroatom are designated by solid symbols.

There are a number of reactions related to the photo-Fries process, in which cleavage of a bond adjacent to a heteroatom ring substituent leads by way of radical intermediates to a ring-substituted product. As an illustration, N-phenylcaprolactam, which can be regarded as... 

Carbonyl groups not adjacent to a heteroatom are less stabilized by resonance and react with the relatively weakly nucleophilic ketonic reagents. If carbonyl groups of both types are present, as in... 

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