Carboxamides basicity

Acrylamide, C H NO, is an interesting difiinctional monomer containing a reactive electron-deficient double bond and an amide group, and it undergoes reactions typical of those two functionalities. It exhibits both weak acidic and basic properties. The electron withdrawing carboxamide group activates the double bond, which consequendy reacts readily with nucleophilic reagents, eg, by addition. 

Compared to other classes of vanilloid antagonists, the 4-hetero-arylpiperazine-1-carboxamides are characterized by the presence of a mildly basic nitrogenous polar head. Based on the published studies [79, 82], the structure-activity relationships of this class of vanilloid antagonists can be summarized as follows ... 

Another domino Michael addition/SN sequence has been elaborated by the group of de Meijere. It was discovered that upon basic treatment of 2-chloro-2-cyclopropyl-idenacetates 2-168 with carboxamides 2-169 in MeCN, 4-spirocyclopropane-anne-lated oxazoline-5-carboxylates 2-172 are formed (Scheme 2.40) [91]. As intermediates, the carbanion 2-170 and 2-171 can be proposed. 

The acidities of sulphonamides are considerably greater than those of the carboxamides and, as a consequence, their A. A -dialkylation proceeds extremely easily [3]. Generally, use is made of a basic solid.liquid two-phase system and yields are usually greater than 80%, except when secondary bromoalkanes are used (Table... 

It took more than 20 years for manufacturers to devise production and distribution networks for delivering consistently high-quality gels to customers. The problems that the companies faced stem from the limited shelf life of polyacrylamide gels. Because polyacrylamide gels hydrolyze over time as shown in Figure 8.2, they are inherently unstable. At basic pH, the pendant, neutral carboxamide groups (-CO-NH of the acrylamide monomers hydrolyze to ionized carboxyl... 

Hydration of nitriles providing carboxamides is usually carried out m strongly basic or acidic aqueous media - these reactions require rather bars conditions and suffer from incomplete selectivity to the desired amide product. A few papers in the literature deal with the possibihty of transition metal catalysis of this reaction [28-30]. According to a recent report [30], acetonitrile can be hydrated into acetamide with water-soluble rhodium(I) complexes (such as the one obtained from [ RhCl(COD) 2] and TPPTS) under reasonably mild conditions with unprecedently high rate... 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

A number of studies have also been made of the hydrolysis of nitriles in the coordination sphere of cobalt(III). Pinnell et al.3 4 found that benzonitrile and 3- and 4-cyanophenol coordinated to pentaamminecobalt(III) are hydrolyzed in basic solution to the corresponding N-bonded carboxamide (equation 22). The reaction is first order in hydroxide ion and first order in the complex with koH= 18.8M 1s 1 at 25.6 °C for the benzonitrile derivative. As fc0H for the base hydrolysis of benzonitrile is 8.2 x 10-6 M-1 s at 25.6 °C, the rate acceleration is ca. 2.3 x 106-fold. The product of hydrolysis is converted to [(NH3)5CoNH2COPh]3+ in acidic solution and the pJC of the protonated complex is 1.65 at 25 °C. Similar effects have been observed with aliphatic nitriles.315 Thus, base hydrolysis of acetonitrile to acetamide is promoted by a factor of 2 x 106 on coordination to [Co(NH3)5]3+. 

Dirhodium(II) compounds are reported to be the most suitable catalysts for insertion. Selectivity is higher and yields are greater with dirhodium(II) carboxylates or carboxamidates than with copper catalysts, whereas Ru catalysts are not known to facilitate C-H insertion. As expected by a process that is basically electrophilic, electron-donating substituents that are adjacent to the site of insertion activate that center for C-H insertion ril4]. In addition to electronic influences, however, conformational effects that are basically steric in origin can also control reaction selectivity [115]. 

Treatments of malonoamide 121 with unsaturated ketones are carried out using a basic catalyst (sodium methoxide and ethoxide). At room temperature these reactions lead to 2-oxo-l,2,3,4-tetrahydro-3-pyridinecarboxamide like 122 (Scheme 3.38). Heating of the reaction mixture is followed by further addition of the carboxamide group to the carbon-carbon double bond, resulting in the formation of 2,7-diazabicycle [2.2.2]octan-3,8-dione 123 [130]. 

Reaction via unstable acidic or basic intermediates can be promoted by proton transfer to a base or from an acid, respectively, thus giving rise to base or acid catalysis. The concept is illustrated for nucleophilic attack on carboxamide derivatives (Scheme 11.6). With base catalysis, deprotonation of the first-formed intermediate promotes the forward reaction, as does protonation of the first-formed intermediate with acid catalysis. 

The Ugi-4CR between (E)-cinnamaldehyde, amines, cyclohexyl isocyanide, and chloroacetic acid afforded N-substituted 2-amino-4-phenylbutenoic amides 55 which were cyclized in basic medium to N-substituted 2-(phenylethenyl)-4-oxoazetidine-2-carboxamides 57 via the highly delocalized intermediate anion 56 [47]. When R was an electron-poor aryl group, the f-lactam ring underwent a rearrangement to give succinimides 58 (Scheme 2.22) [48]. 

The Ugi-4CR between cinnamaldehyde, benzoylformic acid, amines, and cyclohexyl isocyanide afforded the condensation products 103, which, under basic conditions, cyclized to the l,6-dihydro-6-oxopyridine-2-carboxamides 104 in high yields (Scheme 2.37) [68],... 

The /V-(benzyloxy)carboxamide (522) upon oxidation cyclizes to furnish an intermediate 2-benzyloxy derivative (523) which under basic conditions eliminates benzaldehyde to give the N-unsubstituted derivative (524) (Scheme 65) <85S86l>. 

---