Electrophilicity of 5-Benzylidene-1,3-dimethylbarbituric and -thiobarbituric Acids

Seeliger, Florian; Berger, Stefan; Remennikov, Grygoriy Y.; Polborn, Kurt; Mayr, Herbert

doi:10.1021/jo071273g

Cited by 77 publications

(65 citation statements)

References 72 publications

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“…[9][10][11][12] Benzylidenebarbiturates are employed in several well known reactions in the literature 10,[13][14][15][16][17] and have even been used as methionine aminopeptidase inhibitors. 18 The preparation of the 5-chloro-5-benzolbarbiturates was Vol.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and in vivo evaluation of 5-chloro-5-benzobarbiturates as new central nervous system depressants

Vieira¹,

Gomes²,

Matheus³

et al. 2011

J. Braz. Chem. Soc.

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Uma nova família de barbituratos, ácidos 5-cloro-5-benzilbarbitúricos, foi preparada usando um método simples e eficiente a partir de aldeídos aromáticos e ácido barbitúrico, seguido de redução e cloração usando ácido tricloroisocianúrico, com rendimento global de 53 a 70%. Por avaliação in vivo com camundongos, os produtos apresentaram atividade tranqüilizante.A new family of barbiturates, 5-chloro-5-benzylbarbituric acids, was prepared using a simple efficient synthetic method from aromatic aldehydes and barbituric acid, followed by reduction and chlorination with trichloro-isocyanuric acid, affording overall yields of 53 to 70%. The in vivo evaluation with mice showed that these compounds present tranquilizing activity.Keywords: 5-chloro-5-benzylbarbituric acids, tranquilizers, benzylidenebarbiturates, trichloroisocyanuric acid, rota-rod tests IntroductionBarbiturates are very well known drugs with activity at the central nervous system (CNS), with specific activity as anticonvulsants, anxiolytics, tranquilizers and sedatives-hypnotics. 1 The mechanism of action of barbiturates at the CNS is not well known, but it has been shown that they are able to interfere with acetylcholine, norepinephrine and glutamate activity and also that they can inhibit the calcium uptake of nerve terminals, thus allowing their use as analgesics. 2,3 In fact, today barbiturates are commonly used to induce anesthesia in surgery procedures. They are also known as GABA-mimetics, thus functioning as agonists of GABA receptors. 3,4 For many years the barbiturates were the main drugs used to cause effects on the CNS. However, after the discovery of the very effective benzodiazepines, their use became less common simply because benzodiazepines have less potential for lethal overdoses. 5,6 The main cause of death by overdoses of barbiturates is respiratory failure, because they are very potent respiratory depressants. Today, the main uses of barbiturates are the induction of anesthesia and for the treatment of refractory status epilepticus. 7 Regarding the significant historical and actual use of barbiturates as neurological drugs, and the importance of this type of disease in the actual condition of mankind, we developed a very simple new family of barbiturates with CNS activity. Interestingly, 5-chlorobarbituric acid and their derivatives have been rarely investigated. The only similar compounds that have been reported as anticonvulsants are the 5-chloro-5-phenyl barbiturates. 8 Surprisingly, 5-benzyl-5-chlorobarbituric acids have not been reported in the literature. We developed a very simple and efficient method for the preparation of this new family of barbiturates as potential tranquilizers. Results and DiscussionOur strategy for the preparation of 5-benzyl-5-chlorobabiturates was based on the use of benzylidenebarbiturates as intermediates, which are very easy to prepare. [9][10][11][12] Benzylidenebarbiturates are employed in several well known reactions in the literature 10,13-17 and have even been used as methionine aminopeptidas...

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Section: Resultsmentioning

confidence: 99%

Synthesis and in vivo evaluation of 5-chloro-5-benzobarbiturates as new central nervous system depressants

Vieira¹,

Gomes²,

Matheus³

et al. 2011

J. Braz. Chem. Soc.

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“…However, the established reaction systems based on the use of homogeneous catalysts are often plagued by many intrinsic problems including corrosion, difficulty of catalyst recycling and the generation of waste. [17][18][19][20][21][22][23] Thus, the discovery of new synthetic methodologies that facilitate the preparation of organic compounds is of great interest. One approach to address the abovementioned challenges involves the development of new environmentally friendly catalysts for the condensation reaction.…”

Section: Introductionmentioning

confidence: 99%

Clean Synthesis of Pyrano[2,3- D]Pyrimidines Using ZnO Nano-Powders

et al. 2016

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“…17 The draw of this last method is the need for relatively long reaction times at high temperatures, for example 1.5 hours at 260 °C, affording oxadeazaflavines in medium to low yields (50% or lower). On the other hand, because benzylidene barbiturates are easy to prepare by reaction of benzaldehydes with barbituric acid [17][18][19][20] and have been used as starting materials for different reactions, [21][22][23][24][25][26][27][28] the optimization of the second reaction method is important.…”

Section: Introductionmentioning

confidence: 99%

“…2102 for relatively long reaction times at high temperatures, for example 1.5 hours at 260 °C, affording oxadeazaflavines in medium to low yields (50% or lower). On the other hand, because benzylidene barbiturates are easy to prepare by reaction of benzaldehydes with barbituric acid [17][18][19][20] and have been used as starting materials for different reactions, [21][22][23][24][25][26][27][28] the optimization of the second reaction method is important.One important procedure to improve reactions and decrease their environmental impact is the exclusion of solvents in combination with the use of microwave irradiation. [29][30][31][32][33][34][35] The use of microwaves has an important effect to improve yields and reduce reaction times.…”

mentioning

confidence: 99%

Synthesis and mechanism of formation of oxadeazaflavines by microwave thermal cyclization of ortho-halobenzylidene barbiturates

Figueroa‐Villar¹,

Oliveira²

2011

J. Braz. Chem. Soc.

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A reação de ciclização térmica de o-halobenzilideno barbituratos foi desenvolvida como um simples e eficiente método para a preparação de oxadeazaflavinas. A utilização de condições de reação em estado sólido com irradiação de microondas forneceu os produtos em 5 min e com rendimentos entre 47 e 98%. Os resultados experimentais das sínteses e a análise termogravimétrica das reações concordam com os resultados da simulação do mecanismo por modelagem molecular, indicando que a reação ocorre através de uma ciclização hetero-Diels-Alder intra-molecular, seguida por um processo rápido de re-aromatização.The thermal cyclization reaction of o-halobenzylidene barbiturates was developed as an efficient and simple method for the preparation of oxadeazaflavines. The use of solid state reaction conditions with microwave irradiation afforded the products in 5 min with 47 to 98% yield. Experimental synthetic results and thermogravimetric reaction analyses agree with the molecular modeling mechanism simulation, indicating that this reaction occurs through an intramolecular hetero-Diels-Alder cyclization followed by fast re-aromatization. Keywords: oxadeazaflavines, o-halobenzylidene barbiturates, microwave irradiation, intramolecular hetero-Diels-AlderIntroduction pyrimidine-2,4-(3H)-diones or 10-oxa-5-deazaflavines) are interesting compounds with great potential as intermediates for the synthesis of new heterocyclic systems [1][2][3][4][5][6][7][8] and as selective organic oxidants under mild conditions.3 Also, derivatives and analogues of oxadeazaflavines display important bioactivity, being potential drugs.9-12 For many years, several chemists tried without success to prepare the simplest oxadeazaflavine by the direct reaction of barbituric acid with salicylaldehyde, [13][14][15] thus making necessary the use of more complex synthetic procedures to obtain the desired products. [1][2][3] In the beginning of the 1990 decade there were reported two new simple and complementary methods for the preparation of oxadeazaflavines from barbituric acid. 16,17 The first method uses the condensation reaction of salicylaldehyde and analogues with barbituric acid at room temperature to yield an orange oxonium salt that affords oxadeazaflavines under dehydrating conditions, 16 as shown in Scheme 1. Unfortunately, this method only functions well with salicylaldehydes without effective electron-withdrawing groups at the aromatic ring.The second method, which is based on the thermal cyclization of o-halobenzylidene barbiturates, can be applied with success to starting materials containing electron-withdrawing and electron-donating groups at the aromatic ring. 17 The draw of this last method is the need Scheme 1. Synthesis of oxadeazaflavines from salicylaldehyde and barbituric acid. 16Synthesis and Mechanism of Formation of Oxadeazaflavines J. Braz. Chem. Soc. 2102 for relatively long reaction times at high temperatures, for example 1.5 hours at 260 °C, affording oxadeazaflavines in medium to low yields (50% or lower). On the other hand, ...

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Electrophilicity of 5-Benzylidene-1,3-dimethylbarbituric and -thiobarbituric Acids

Cited by 77 publications

References 72 publications

Synthesis and in vivo evaluation of 5-chloro-5-benzobarbiturates as new central nervous system depressants

Synthesis and in vivo evaluation of 5-chloro-5-benzobarbiturates as new central nervous system depressants

Clean Synthesis of Pyrano[2,3- D]Pyrimidines Using ZnO Nano-Powders

Synthesis and mechanism of formation of oxadeazaflavines by microwave thermal cyclization of ortho-halobenzylidene barbiturates

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