The SN mechanism in aromatic compounds. XXXVI. Reactivity of monochlorodiazabenzenes

Abstract

An investigation has been made of the reactions of p-nitrophenoxide ion in methanol with equimolar quantities (0.01-0.02M) of the six monochlorodiaza-benzenes, viz. 3- and 4-chloropyridazine (1,2- diazabenzene); 2-, 4-, and 5-chloro-pyrimidines (1,3-diazabenzene); and 2-chloropyrazine (1,4-diazabenzene) in the presence of a tenfold excess (0.1-0.2M) of p-nitrophenol. Results have been compared with earlier results from the pyridine series, and reactivity shown to be in reasonable agreement with that predicted from kinetic data for the pyridine series assuming independent activation by each nitrogen. There is evidence for mild acid catalysis by the p-nitrophenol added to prevent concurrent methanolysis. It is estimated that this leads to an increase in Hammett substituent constant (σ-) values of only 0.2 units or less. The reactivity order is 2- > 4-chloro-N-methylpyridinium > 2- > 4- chloro-pyrimidine > 4-chloropyridazine≈3-chloropyridazine≈2- chloropyrazine>3-chloro-N-methylpyridinium≈5-chloropyrimidine, and this corresponds with the theoretical order as modified by mild acid catalysis, more effective in the order ortho-> meta- > para- to the point of substitution, and including the inverted order, 2- > 4- chloropyrimidine, whereas the usual reactivity order with anionic reagents is 4- > 2-chloropyrimidine.

Amination of Heteroaryl Chlorides: Palladium Catalysis or SNAr in Green Solvents?

“…As expected, reactions with the more reactive 2-chloropyrimidine generally produced higher yields (2-chloropyrimidine is ≈100 times more reactive than chloropyrazine)[9] and reacted in moderate to excellent yield with primary and secondary amines (Table 2, entries 1–11). In the case of α-methylbenzylamine (entry 5), HPLC demonstrated that there was no loss of enantiomeric excess in the final product ( ee >98).…”

“…[19] With the useful KF-in-water conditions now established, chloropyrazine and 2-chloropyrimidine were screened against a wide range of primary and secondary amines as well as anilines and NH heteroaromatic compounds; they were selected because they contain a range of functional groups that are relevant to contemporary medicinal chemistry and yielded the corresponding N-arylamines 1-23 (Table 2 and Figure 2). As expected, reactions with the more reactive 2-chloropyrimidine generally produced higher yields (2-chloropyrimidine is % 100 times more reactive than chloropyrazine) [9] and reacted in moderate to excellent yield with primary and secondary amines ( Table 2, entries 1-11). In the case of a-methylbenzylamine (entry 5), HPLC demonstrated that there was no loss of enantiomeric excess in the final product (ee > 98).…”

“…[8] However, precious metals are expensive and dwindling resources, and although the success of palladium-catalysed reactions has revolutionised N-arylation chemistry, there is a risk that they are used without due consideration of alternatives. For instance, 2-chloropyrimidine is 10 14 -10 16 times more reactive than chlorobenzene in terms of its ability to undergo S N Ar reactions; [9,10] however, an examination of the recent literature reveals that even such reactive substrates are subjected to palladium-catalysed amination reactions. Some recent examples of the palladium-catalysed amination of 2-chloropyrimidine and chloropyrazine are shown in Scheme 1, [11][12][13][14][15][16] and although these reactions, some of which are performed under fairly forcing conditions with non-trivial ligands, proceed in good yield, it does beg the question as to whether palladium is really needed for such highly activated substrates.…”

Oxidative Addition of Haloheteroarenes to Palladium(0): Concerted versus SNAr‐Type Mechanism

“…Both chlorodiazines ubstrates 4 and 5 reacted significantly faster than 1a at comparable concentrations, which reflects their more electrophilic nature.T he decrease in activation energy for 2-chloropyrazine (4), relative to 1a,w as 11.1 kJ mol À1 ,w hile av alue of 7.7 kJ mol À1 was determined for 3-chloropyridazine (5). [17] The influence of benzoannelationo f (di)azines ubstrates was also investigated. 2-Chloroquinoline (7;T able 5, entry 5; Figures S43 and 44 in the Supporting Information) as well as 2-chloroquinoxaline( 9 ;T able 5, entry 7; FigureS47 in the Supporting Information) gave al ower activation energy of 15.0 and 14.5 kJ mol À1 ,r espectively,i nc omparison with 1a and 2-chloropyrazine (4;T able 5, compare entries 1a nd 5, 2a nd 7).…”

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

“…Interestingly, 2-chloro-pyrimidines, which are reported to exhibit SNAr reactivity (26), had no significant effect on the p53 melting temperature. Overall, these findings clearly show the potential for fine-tuning the reactivity of the 2-sulfonylpyrimidine core scaffold through appropriate substitutions.…”