Reactions of Alicyclic Aminonitrile

Sudo, Rokuro; Ichihara, Shigehiro

doi:10.1246/bcsj.36.34

Cited by 12 publications

(4 citation statements)

References 3 publications

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“…Sterically hindered SNRs of the piperazine series ( 115, 116, 118 , and 120) were obtained for the first time to study the effect of substituents on hyperfine coupling constant A N in the EPR spectra of stable radicals [ 126 ]. For instance, under reduced pressure, heating the aminonitrile of cyclohexanone 111 gives bis(1-cyanocyclohexyl)amine 112 , followed by a one-pot step, including acid-catalyzed hydrolysis and intramolecular cyclization, leading to the starting compound of SNR synthesis—cyclic piperazinedione 113 [ 127 ]. Carboxylation of the latter with chloroethyl formate and oxidation of amine 114 with m -CPBA give nitroxide 115 in a 63% yield.…”

Section: Piperazine- and Morpholine-type Snrsmentioning

confidence: 99%

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Zaytseva

Mazhukin

2021

Molecules

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Spirocyclic nitroxyl radicals (SNRs) are stable paramagnetics bearing spiro-junction at α-, β-, or γ-carbon atom of the nitroxide fragment, which is part of the heterocyclic system. Despite the fact that the first representatives of SNRs were obtained about 50 years ago, the methodology of their synthesis and their usage in chemistry and biochemical applications have begun to develop rapidly only in the last two decades. Due to the presence of spiro-function in the SNRs molecules, the latter have increased stability to various reducing agents (including biogenic ones), while the structures of the biradicals (SNBRs) comprises a rigid spiro-fused core that fixes mutual position and orientation of nitroxide moieties that favors their use in dynamic nuclear polarization (DNP) experiments. This first review on SNRs will give a glance at various strategies for the synthesis of spiro-substituted, mono-, and bis-nitroxides on the base of six-membered (piperidine, 1,2,3,4-tetrahydroquinoline, 9,9′(10H,10H′)-spirobiacridine, piperazine, and morpholine) or five-membered (2,5-dihydro-1H-pyrrole, pyrrolidine, 2,5-dihydro-1H-imidazole, 4,5-dihydro-1H-imidazole, imidazolidine, and oxazolidine) heterocyclic cores.

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Section: Piperazine- and Morpholine-type Snrsmentioning

confidence: 99%

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Zaytseva

Mazhukin

2021

Molecules

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“…These piperazines and bicyclo-derived analogues 21, 18 22, 19 23, 20 24, 21 25, 22 26, 22 27, 23 and 28 24 were prepared to fully explore the structure-activity relationship (SAR) of the urea substituent. Piperazine 32 (1-isopropyl-cis-2,6-dimethylpiperazine) was synthesized by straightforward chemistry as shown in Scheme 4.…”

Section: Chemistrymentioning

confidence: 99%

“…Hydrogenation using Pearlman's catalyst provided a 97% yield of the desired quinoxaline, which was isolated in its enol form 19 due to the A number of noncommercial piperazines (Figure 2) were synthesized according to literature precedent, with minor protecting group manipulation, if necessary. These piperazines and bicyclo-derived analogues 21, 18 22, 19 23, 20 24, 21 25, 22 26, 22 27, 23 and 28 24 were prepared to fully explore the structure-activity relationship (SAR) of the urea substituent. Piperazine 32 (1-isopropyl-cis-2,6-dimethylpiperazine) was synthesized by straightforward chemistry as shown in Scheme 4.…”

Section: Chemistrymentioning

confidence: 99%

Piperazine Imidazo[1,5-a]quinoxaline Ureas as High-Affinity GABA_A Ligands of Dual Functionality

Jacobsen¹,

Stelzer²,

Tenbrink³

et al. 1999

J. Med. Chem.

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A series of imidazo[1,5-a]quinoxaline piperazine ureas appended with a tert-butyl ester side chain at the 3-position was developed. Analogues within this series have high affinity for the gamma-aminobutyric acid A (GABAA)/benzodiazepine receptor complex with efficacies ranging from inverse agonists to full agonists. Many analogues were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Uniquely, a number of these analogues were found to have a bell-shaped dose-response profile in the alpha1 beta2 gamma2 subtype as determined by whole cell patch-clamp technique, where in vitro efficacy was found to decrease with increasing drug concentration. Many of the compounds from this series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant and possibly anxiolytic activity. Additionally, several analogues were also effective in lowering cGMP levels (to control values) after applied stress, also consistent with anxiolytic-like properties. The most effective compounds in these screens were also active in animal models of anxiety such as the Vogel and Geller assays. The use of the piperazine substituent allowed for excellent drug levels and a long duration of action in the central nervous system for many of the quinoxalines, as determined by ex vivo assay. Pharmacokinetic analysis of several compounds indicated excellent oral bioavailability and a reasonable half-life in rats. From this series emerged two partial agonists (55, 91) which had good activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.

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“…Although the hydrolysis of symmetrical secondary iminodinitriles (10 with RЈ = R and RЈЈ = H) in sulfuric acid yields the corresponding imino diacids, [15] our investigation on acidic hydrolysis/decomposition of iminodinitriles 10 [11a] did not provide good results because of the competing decomposition reaction. Hydrolysis of iminodinitriles 10a-d (either -R or -S) at 110°C in 6  HCl afforded the expected Scheme 4. amino acids 2a-d with good optical purity (ee ≈ 98 %) but with poor yields, especially for the -R series (entries 1-8 in Table 1), together with important degradation of the cyanodihydrocarvone moiety (Scheme 4).…”

mentioning

confidence: 93%

Regioselective Hydration and Deprotection of Chiral, Dissymmetric Iminodinitriles in the Scope of an Asymmetric Strecker Strategy

Rossi¹,

Marull²,

Boiteau³

et al. 2007

Eur J Org Chem

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The controlled, selective decomposition of dissymmetric iminodinitriles (DIDN) of formula RCH(CN)-NH-C(CN)RЈRЈЈ (considered as N-protected alpha-aminonitriles), is a critical issue for an original asymmetric Strecker strategy previously outlined by us for the enantioselective synthesis of amino acids. This strategy, derived from Harada's work, involves a double sequence of (i) stereoselective Strecker condensation of a chiral ketone RЈRЈЈCO with NH 3 and HCN, followed by (ii) stereoselective Strecker condensation with an aldehyde RCHO and HCN, then (iii) regioselective retro-Strecker decomposition of the DIDN intermediate to release the target alpha-aminonitrile. In addition to the use of quite simple, cheap cyclic ketones (e.g. carvone derivatives) as chiral auxiliaries, another great advantage of this strategy is that step (iii) enables the recovery of the chiral ketone and hence its reuse. While our previous investigations on step (iii) under various conditions, either preceded or followed by the hy-

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Reactions of Alicyclic Aminonitrile

Cited by 12 publications

References 3 publications

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Piperazine Imidazo[1,5-a]quinoxaline Ureas as High-Affinity GABA_A Ligands of Dual Functionality

Regioselective Hydration and Deprotection of Chiral, Dissymmetric Iminodinitriles in the Scope of an Asymmetric Strecker Strategy

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Reactions of Alicyclic Aminonitrile

Cited by 12 publications

References 3 publications

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Spirocyclic Nitroxides as Versatile Tools in Modern Natural Sciences: From Synthesis to Applications. Part I. Old and New Synthetic Approaches to Spirocyclic Nitroxyl Radicals

Piperazine Imidazo[1,5-a]quinoxaline Ureas as High-Affinity GABAA Ligands of Dual Functionality

Regioselective Hydration and Deprotection of Chiral, Dissymmetric Iminodinitriles in the Scope of an Asymmetric Strecker Strategy

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Piperazine Imidazo[1,5-a]quinoxaline Ureas as High-Affinity GABA_A Ligands of Dual Functionality