Kinetics of Electrophilic Alkylations of Barbiturate and Thiobarbiturate Anions

Abstract

Second-order rate constants (k) of the reactions of various barbiturate anions such as the parent barbiturate, 1,3-dimethylbarbiturate, 2-thiobarbiturate, and 1,3-diethyl-2-thiobarbiturate with diarylcarbenium ions and Michael acceptors have been determined in dimethyl sulfoxide solution at 20 °C. The reactivity parameters N and s of the barbiturate anions were derived from the linear plots of log k versus the electrophilicity parameters E of these reference electrophiles, according to the linear-free-energy relationship log k (20 °C) = s (E + N). Several reactions of these nucleophiles with benzylidenemalononitriles and quinone methides proceeded with reversible formation of the new C-C-bond followed by rate-determining proton shift. No evidence for initial attack of the electrophiles at the enolate oxygens of these nucleophiles was found by the kinetic measurements, in line with quantum chemical DFT calculations, which showed that in all cases C-attack is kinetically and thermodynamically preferred over O-attack. The nucleophilic reactivities of barbiturate anions were compared with those of structurally related carbanions, e.g., Meldrum's acid and dimedone anions.

Enantioselective Catalytic Transformations of Barbituric Acid Derivatives

“…As shown in Figure 2a, barbituric acid 1 displays a rather low pK a value (pK a = 8.4 in DMSO) [24] lying just above Meldrum's acid 2 well-known for its remarkable acidity (pK a = 7.03 in DMSO) [25,26]. Consequently, barbituric acid 1 and derivatives will In 2017, Spange and co-workers embarked on the insightful evaluation of the kinetics of derivatives of barbiturate acid anions thanks to the reaction with specific electrophiles, such as benzhydrylium cations and Michael acceptors [28]. Then, the so-called nucleophilicity parameter N and the corresponding nucleophile-specific susceptibility parameter s N of barbiturate anions 1' could be determined and compared to related 1,3-dicarbonyl anions 2'-4' (Figure 2b) [27].…”

“…As aforementioned, barbituric acid derivatives are easily deprotonated with regard to their rather low pK a value. Simple reasoning based upon resonance structures obviously shows that the conjugate base of barbituric acid may undergo either a C-alkylation or an O-alkylation reaction (Figure 4a), an issue known to be dependent on the nature of the electrophile and reaction conditions [28]. Several research groups took advantage of these features to develop enantioselective transformations based on three different strategies ( Figure 4b).…”

“…In 2017, Spange and co-workers embarked on the insightful evaluation of the kinetics of 76 derivatives of barbiturate acid anions thanks to the reaction with specific electrophiles, such as 77 benzhydrylium cations and Michael acceptors [28]. Then, the so-called nucleophilicity parameter N 78 and the corresponding nucleophile-specific susceptibility parameter sN of barbiturate anions 1' could 79 be determined and compared to related 1,3-dicarbonyl anions 2'-4' (Figure 2b) [27].…”

Catalytic Asymmetric Synthesis of Quaternary Barbituric Acids

“…Recently, while our work was in progress, Rawal and co-workers reported the enantioselective conjugate addition of symmetrically N , N ′-disubstituted barbituric acids to prochiral nitroalkenes triggered by a bifunctional amine-thiosquaramide organocatalyst . Whereas N , N ′-disubstituted barbituric acids thus seems to be suitable for a mild Brønsted base deprotonation, the asymmetric organocatalytic C(5)-functionalization of prochiral barbiturates of general structure II (R 1 ≠ R 2 , Figure b) has not yet been realized. A major problem concerns the pseudosymmetrical structure of the 1,3-diamide moiety (Figure b) which makes enantioface discrimination complicated, a situation that would be critical during generation of a quaternary stereocenter .…”

“…For example (Scheme ), at the outset of our investigation barbiturates 1 and 2 , as well as their thio-analogues 3 / 4Aa , were treated with vinyl ketone 6a in the presence of 10 mol % catalyst C1 (Figure ) to give, respectively, adducts 7 – 10 as essentially racemic material (<20% ee at best) . Reaction reversibility (retro-Michael process) , as a cause of the low enantiocontrol could be discarded as no crossover products were detected when adducts 7 and 8 were admixed with vinyl ketone 6b in the presence of a base catalyst . We then questioned whether 2-benzylthio-4,6-dioxopyrimidines 5 (Figure ), which as far as we know have never been employed in asymmetric catalysis, could be used to solve this problem, considering: (i) the ready conversion into the target barbituric acids upon standard hydrolytic conditions, (ii) the enhancement of structural dissymmetry as compared to the nearly symmetric diamides 1 – 4 , and (iii) the suitability toward deprotonation (pseudoaromatic enolate would be formed) promoted by a weak base.…”