Synthesis of (−)-PNU-286607 by Asymmetric Cyclization of Alkylidene Barbiturates

Ruble, J. Craig; Hurd, Alexander R.; Johnson, Timothy A.; Sherry, Debra A; Barbachyn, Michael R.; Toogood, Peter L.; Bundy, Gordon L.; Graber, David R.; Kamilar, Gregg M.

doi:10.1021/ja808014h

Cited by 158 publications

(97 citation statements)

References 18 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the conversion of nitrile 3a did not occur through irreversible parallel cyclization reactions, but rather by a reversible process. This hypothesis is in complete accord with the literature data [2]. On the basis of our kinetic results and literature data [2], we propose that two products were formed, namely, a kinetic control product 5 and a thermodynamic control product 4a.…”

supporting

confidence: 92%

“…This hypothesis is in complete accord with the literature data [2]. On the basis of our kinetic results and literature data [2], we propose that two products were formed, namely, a kinetic control product 5 and a thermodynamic control product 4a. The interconversion of these two isomers occurred under the reaction conditions through dipolar intermediate 6, obtained as a result of a [1,5] hydride shift.…”

supporting

confidence: 92%

“…

We studied the reaction of 2-dialkylaminobenzaldehydes 1a-i with benzoylacetonitrile (2), leading to N,N-dialkyl-o-vinylanilines 3a-i, which, in turn, cyclized to the condensed 1,2,3,4-tetrahydroquinolino-5-carbonitriles 4a-i.

…”

mentioning

confidence: 99%

See 2 more Smart Citations

Synthesis and Kinetics of the Cyclization of 3-(Dialkylaminophenyl)-2-(phenylcarbonyl)-prop-2-enenitriles

Platonova

Глухарева

Zimovets

et al. 2013

Chem Heterocycl Comp

View full text Add to dashboard Cite

The considerable interest in tetrahydroquinolines and their derivatives is primarily due to the biological activity of tetrahydroquinolines themselves [1,2], as well as their remarkable reactivity and the variety of chemical transformations, which make these compounds convenient building blocks in the synthesis of other structures with high biological activity [3]. One method for the synthesis of tetrahydroquinoline systems is the cyclization of N,N-dialkyl-o-vinylanilines proceeding through a tert-amino effect mechanism [4][5][6][7].We studied the reaction of 2-dialkylaminobenzaldehydes 1a-i with benzoylacetonitrile (2), leading to N,N-dialkyl-o-vinylanilines 3a-i, which, in turn, cyclized to the condensed 1,2,3,4-tetrahydroquinolino-5-carbonitriles 4a-i. Examination of the literature showed that an analogous reaction has been carried out only using o-piperidinobenzaldehyde as the starting reagent [8].Knoevenagel condensation products 3a-e,h,i could not be isolated in the condensation of 2-piperidinobenzaldehydes 1a-e,h,i, since the cyclization to give 1,2,3,4-tetrahydroquinolino-5-carbonitriles 4a-e,h,i dominated under these reaction conditions [9]. Knoevenagel condensation products 3f,g, that did not undergo cyclization in toluene, were isolated only in the case of benzaldehydes 1f,g. This finding may be attributed to the lower basicity of the morpholine and piperazine dialkylamino groups. 1,2,3,4-Tetrahydroquinolino-5-carbonitriles 4f,g were obtained by the cyclization of N,N-dialkyl-o-vinylanilines 3f,g upon heating in 1-butanol at reflux. 1,2,3,4-Tetrahydroquinolino-5-carbonitriles 4a-i contain from two to four asymmetric sites.

show abstract

supporting

confidence: 92%

supporting

confidence: 92%

“…

…”

mentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Kinetics of the Cyclization of 3-(Dialkylaminophenyl)-2-(phenylcarbonyl)-prop-2-enenitriles

Platonova

Глухарева

Zimovets

et al. 2013

Chem Heterocycl Comp

View full text Add to dashboard Cite

show abstract

“…[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.

View full text Add to dashboard Cite

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...

show abstract

“…Several examples of the arylidene derivatives of barbituric acid possessing significant implementation in the pharmaceutical field such as antitumor [1], immunomodulating, matrix metalloproteinase (MMP) inhibitor [2], antioxidant [3], antibacterial agent [4], anticonvulsant potentials [5], and mutant SOD1-dependent protein aggregation [6] were investigated. Additionally, these compounds were shown to haveseveral targets in dye manufacturing [7], supramolecular chemistry [8], and in nonlinear optical study [9].…”

Section: Introductionmentioning

confidence: 99%

Molecular Structure, Spectroscopic and DFT Computational Studies of Arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

et al. 2016

View full text Add to dashboard Cite

Reaction of barbituric acid derivatives and di-substituted benzaldehyde in water afforded arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives (1 and 2). The one step reaction proceeded efficiently, smoothly, and in excellent yield. The arylidene compounds were characterized by spectrophotometric tools plus X-ray single crystal diffraction technique. Quantum chemical calculations were performed using the DFT/B3LYP method to optimize the structure of the two isomers (1 and 2) in the gas phase. The optimized structures were found to agree well with the experimental X-ray structure data. The highest occupied (HOMO) and lowest unoccupied (LUMO) frontier molecular orbitals analyses were performed and the atomic charges were calculated using natural populationanalysis.

show abstract

Synthesis of (−)-PNU-286607 by Asymmetric Cyclization of Alkylidene Barbiturates

Cited by 158 publications

References 18 publications

Synthesis and Kinetics of the Cyclization of 3-(Dialkylaminophenyl)-2-(phenylcarbonyl)-prop-2-enenitriles

Synthesis and Kinetics of the Cyclization of 3-(Dialkylaminophenyl)-2-(phenylcarbonyl)-prop-2-enenitriles

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

Molecular Structure, Spectroscopic and DFT Computational Studies of Arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

Contact Info

Product

Resources

About