Convenient ketone synthesis n-acylaziridines

Wattanasin, Sompong; Kathawala, F. G.

doi:10.1016/s0040-4039(01)80033-2

Cited by 32 publications

(5 citation statements)

References 11 publications

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“…The N-benzoyl-2-methylaziridines 2 were condensed with the lithium anion of methylpyridine 3 to afford the corresponding ketones 4. 30,32) In this reaction, the selective lithiation at methyl proton was occurred and no product from lithium anion of pyridine core was observed. Ketones 4 were brominated to give a-bromoketones 5.…”

Section: Chemistrymentioning

confidence: 91%

“…The N-benzoyl-2-methylaziridines 2 were condensed with the lithium anion of methylpyridine 3 to afford the corresponding ketones 4. 30,32) In this reaction, the selective lithiation at methyl proton was occurred and no product from Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.; 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Received March 4, 2008; accepted May 20, 2008; published online May 22, 2008 To investigate the potency of an adenosine A 3 receptor (A 3 AR) antagonist as an anti-asthmatic drug, a novel series of 4-phenyl-5-pyridyl-1,3-thiazole derivatives was synthesized and evaluated in human adenosine A 1 , A 2A and A 3 receptor and rat adenosine A 3 receptor binding assays.…”

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confidence: 99%

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Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Miwatashi

Arikawa

Matsumoto

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Adenosine, an endogenous purine nucleoside, modulates a variety of physiological functions in various organs and tissues, and interacts with four specific G-protein-coupled receptor subtypes (GPCRs), classified as A 1 , A 2A , A 2B , and A 3 .1,2) All four receptors are coupled via G proteins to the adenylate cyclase-cAMP signal transduction pathway. Activation of A 1 and A 3 receptors inhibits adenylate cyclase through G i coupling, while activation of A 2A and A 2B receptors stimulates adenylate cyclase through G s coupling.3) In particular, the adenosine A 3 receptor (A 3 AR) is distributed in different organs (lung, liver, kidney, heart and brain), 4) and the potential therapeutic applications of antagonizing this receptor are proposed to be useful for the treatment of inflammation, 5) myocardial and brain ischemia, [6][7][8] and cancer. 27,28) have been reported as new hA 3 AR antagonists. Although these antagonists showed strong hA 3 AR antagonistic activity and good selectivity against other adenosine receptor subtypes, they were found to be weak or ineffective against rat A 3 AR (rA 3 AR), 1,11,12,15,28,29) and could therefore not be evaluated in rat in vivo models. The homology of A 3 AR among several species was reported and the only 72% homology between human and rat A 3 AR was one reason for species differences.28) As selective hA 3 AR antagonists that showed moderate affinity to rA 3 AR, only MRS 1191 14) and MRS 1523 15) (K i ϭ1.42, 0.113 mM, respectively) have been reported, but these activities seemed to be insufficient for evaluation in rat models. Thus, A 3 AR antagonists which show equipotent affinity and selectivity in different species have been desired for pharmacological probes on animal models, and the evaluation and selection of new drugs in preclinical phase candidates is likely to be easier.Our focus on an anti-asthmatic research program prompted us to evaluate the potential of A 3 AR antagonist as a therapeutic target. From high throughput screening, 4-phenyl-5-pyridyl-1,3-thiazole derivative 7a was identified as the preferable lead compound. We have already reported 1,3-thiazole derivatives as p38 MAP kinase inhibitors. 30,31) These compounds were bound at the ATP binding site of the kinase, and ATP is an adenosine-related compound. We therefore focused our attention on compound 7a and investigated further. In the in vitro binding assay, compound 7a showed strong hA 3 AR antagonistic activity (K i ϭ0.16 nM) and good hA 3 AR selectivity, as shown in Fig. 1. Moreover, the rA 3 AR antagonistic activity of this compound was moderate (K i ϭ23 nM). To evaluate the efficacy of the rat asthma model, improvement of the rA 3 AR antagonistic activity of 7a was critical. In the present paper, we report the discovery of a series of 2-acylamino-4-phenyl-5-pyridyl-1,3-thiazole derivatives as novel and potent antagonists against human and rat A 3 AR through structural modification based on screening hit 7a. ChemistryThe general approach for the several 4,5-disubstituted 2-acylamino-1,3-thiazoles 7 ...

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“…The N-benzoyl-2-methylaziridines 2 were condensed with the lithium anion of methylpyridine 3 to afford the corresponding ketones 4. 30,32) In this reaction, the selective lithiation at methyl proton was occurred and no product from lithium anion of pyridine core was observed. Ketones 4 were brominated to give a-bromoketones 5.…”

Section: Chemistrymentioning

confidence: 91%

“…The N-benzoyl-2-methylaziridines 2 were condensed with the lithium anion of methylpyridine 3 to afford the corresponding ketones 4. 30,32) In this reaction, the selective lithiation at methyl proton was occurred and no product from Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.; 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Received March 4, 2008; accepted May 20, 2008; published online May 22, 2008 To investigate the potency of an adenosine A 3 receptor (A 3 AR) antagonist as an anti-asthmatic drug, a novel series of 4-phenyl-5-pyridyl-1,3-thiazole derivatives was synthesized and evaluated in human adenosine A 1 , A 2A and A 3 receptor and rat adenosine A 3 receptor binding assays.…”

mentioning

confidence: 99%

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Miwatashi

Arikawa

Matsumoto

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…[18] Based on x-ray crystal structural analysis, Evans et al reported stabilization of one such intermediate by a remarkable anomeric effect. [18a] Other stable tetrahedral intermediates have been generated by the reactions of "distorted" amides such as N-acylaziridine [19] or Nacylazetidine [20] ( Figure 1B [4]).…”

Section: Introductionmentioning

confidence: 99%

Chemoselective Ketone Synthesis by the Strontium‐mediated Alkylation or Arylation of N,N‐Dimethylamides or Urea

et al. 2020

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Ketone synthesis via the addition of organometallic reagents to amides has long been investigated. In many cases, it is necessary to control the solvent, reaction temperature, and adhere to strict nucleophile stoichiometry for each combination of amide and organometallic reagent. Strontium, with an electronegativity comparable to lithium but a larger ionic radius, may display high reactivity with the characteristics of monoalkylation. Here, we show that the monoalkylation of various N,N-dimethylamide derivatives with alkyl iodides to afford the ketones proceeds smoothly under generally mild temperature conditions. By this method, not only aromatic amides but also α-proton-bearing aliphatic amides were suitable substrates for ketone synthesis. In addition, we found that tetramethylurea, typically a poor electrophile, also reacted to afford benzophenone in good yield with excellent selectivity.

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“…N, N-Dimethylacetamides, 8 N-acylaziridines, 9 and ethyl trifluoroacetate 10 reacted cleanly with both organolithiums and Grignard reagents to form the ketones upon acidic workup of the tetrahedral intermediates, where no significant amounts of overaddition products were not detected. The reaction of benzimidazole methiodide 11 and benzoyl cyanides 12 with Grignard reagents also afforded the methyl ketones and diaryl ketones, respectively.…”

mentioning

confidence: 99%

A Novel Synthesis of Ketones Using 4,6-Pyrimidyl Diesters

Lee

2007

Bulletin of the Korean Chemical Society

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Convenient ketone synthesis n-acylaziridines

Cited by 32 publications

References 11 publications

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

Chemoselective Ketone Synthesis by the Strontium‐mediated Alkylation or Arylation of N,N‐Dimethylamides or Urea

A Novel Synthesis of Ketones Using 4,6-Pyrimidyl Diesters

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