The kinetics and mechanism of the electrophilic substitution of heteroaromatic compounds. Part XXVIII. The preparation and kinetic nitration of 2-, 3-, and 4-dimethylaminopyridines and their 1-oxides in sulphuric acid

Burton, A. G.; Frampton, Roger; Johnson, C. D.; Katritzky, Alan R.

doi:10.1039/p29720001940

Cited by 19 publications

(9 citation statements)

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“…So far imidazo[2,1-a]pyridine systems are only known in the fully aromatic series, [5][6][7] as compounds with saturated imidazole and pyridine ring [8,9] as systems with a C-C double bond in the imidazole ring, [10] or with a fully aromatic pyridinium ring. [11] Such known compounds were synthesized from 2-aminopyridines as N-C-N building block and a suitable C-C bielectrophile (Scheme 1). It has to be mentioned that a higher homologue of condensed dihydroimidazo[2,1-a]pyridines is found in the naturally occurring Evodiamine.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids

2005

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Reaction of isoquinolines 1 with N-arylsulfonylamino acid fluorides 2 provides a highly stereoselective access to new dihydroimidazo[2,1-a]isoquinolin-3-ones 5 via intermediate N-acylisoquinolinium salts 3. Addition reactions to the enamine double bond, such as hydrogenation or epoxidation with dimethyldioxirane, leads to tetrahydroimidazo[2,1-a]isoquinoline-3-ones 6, 7 and oxiranes 8, respectively. Opening of the oxirane ring of the 8 with nucleophiles allows the synthesis of hydroxytetrahydroimidazo[2,1-a]isoquinolin-3-ones

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Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids

2005

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“…Under the mild reaction conditions applied, only the ring-nitrogen atom was oxidized to give the 4-(N,N-dimethylamino)pyridine oxide (18) in 70% yield. 14 Although aromatic rings react with HOF◊CH 3 CN producing various phenols epoxides and quinones, 15 the nitrogen atom proved once again more reactive. This is demonstrated by isoquinoline (19) which produced isoquinoline N-oxide (20) in good yield without affecting the aromaticity.…”

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confidence: 99%

Tertiary Amine Oxidation using HOF ⋅ CH3CN: A Novel Synthesis of N-Oxides

Dayan¹

1999

Synthesis

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HOF◊CH 3 CN, probably the best oxygen transfer agent organic chemistry has to offer, is easily made by bubbling diluted fluorine (10-15%) through aqueous acetonitrile solution. Used as formed without any isolation or purification, it reacts with various tertiary amines such as pyridine derivatives, polyaromatic nitrogen containing compounds and aliphatic and alicyclic ones to form the corresponding N-oxides. When two nitrogen atoms are present it is possible to make both the N-monoxides and the N,N-dioxides. The reaction times are short (a few minutes), conditions are very mild (0-25°C) and the yields range from good to excellent (70-95%).Tertiary amine N-oxides are a class of compounds which assumes increasing importance. They are used in a variety of processes as well as final products such as fiber preparation, 1 hair tonics, 2 topical pharmaceuticals, 3 and cellulose solvents. 4 The increased attention these compounds are receiving encouraged us to examine their preparation by using one of the best oxygen transfer agents organic chemistry has to offer, the HOF◊CH 3 CN complex.The preparation of this reagent, first introduced by us some years ago, 5 is quite simple. Its solution is formed in good yields by passing nitrogen-diluted fluorine through aqueous acetonitrile. The HOF◊CH 3 CN complex is used as obtained and does not require any isolation or purification. It is able to transfer an oxygen atom under mild conditions even to very weak nucleophiles. In the past we have demonstrated its ability to epoxidize normal 6 and very electron deficient alkenes, 7 oxidize amines, 8 ethers, 9 a variety of sulfides, 10 and much more. 11 We report here yet another of its fast and efficient reactions, this time with tertiary amines forming the corresponding N-oxides. It should be noted that although some of the N-oxides had been previously prepared, the combination of the very mild conditions and short reaction times gave in most cases better results than those reported in the literature. 12Pyridines react quickly at temperatures ranging from 0 to 25°C to produce the N-oxide compounds in good yields. Pyridine (1) itself was transformed into its N-oxide derivative 2 in 85% yield within less than five minutes. Similarly 3-and 4-methylpyridines 3 and 4 were converted to the corresponding N-oxides 5 and 6 in high yields. Rings substituted with strong electron-donating groups such as 2-methoxypyridine 13 (7) or with electron-withdrawing ones such as 2-cyano-(8), 3-acetyl-(9) and 2-chloropyridine (10) also proved to be excellent substrates producing the respective N-oxides 11-14 in good yields. Although we had already demonstrated that double bonds react with HOF◊CH 3 CN to form epoxides 11 the nitrogen atom of the pyridine is activated first. Thus 4-vinylpyridine (15) was converted in 70% yield to the corresponding N-oxide 16 without affecting the alkene. Another interesting example is 4-(N,N-dimethylamino)pyridine (17) with its two tertiary nitrogen atoms. Under the mild reaction conditions applied, only the ring-nitrogen at...

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“…As shown in Figure 1.24, the conjugate acid of 2,5-dimethylthiazole has a pKa value of 3.91 136 whereas the conjugate acid of 1-methyl-1,2,3-triazole has a significantly lower pKa value of 1.25. 137 This means that the basicity of the nitrogen atom in 1,2,3-triazole is lower than the nitrogen atom in thiazole and therefore 1,2,3-triazole is not an easily protonable functional group when compared to thiazole.…”

Section: Analogue Designmentioning

confidence: 99%

“…The substitution of the thiazole for the triazole may affect its binding ability to the target protein, and this modification could be the major cause of the significant loss in the activity. dimethylthiazole 136 and 1-methyltriazole. 137 To provide evidence for this hypothesis, it is necessary to reintroduce the thiazole ring into the analogue scaffold, and therefore, thiazole analogue 183 would be the first target (Figure 1.25) in this project.…”

Section: Analogue Designmentioning

confidence: 99%

“…Compared to the potent simplified analogue DMDA PatA (136), the other major change in the structure of triazole analogue 182 is the absence of the methyl groups at the C12, C15, C22 and C24 positions (PatA numbering). As the so-called 'magic' methyl effects have been proven to be very important in molecular recognition by bioreceptors in medicinal chemistry, 138,139 we propose that the absence of methyl groups may also contribute to the reduction in the activity.…”

Section: Analogue Designmentioning

confidence: 99%

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Towards Synthesis of Simplified Analogues of Pateamine A

Xu¹

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<p>Pateamine A (22) is a natural product that was isolated from a marine sponge inhabiting the coast of New Zealand. It exhibits potent inhibition of protein synthesis and nonsense-mediated mRNA decay through binding with eIF4A isoforms. Due to the scarcity of pateamine A (22) in the natural source and the low yield of total synthesis of pateamine A, it is necessary to prepare structurally simplified analogues which would allow further research on structure-activity relationships (SAR) of pateamine A (22). Based on the structure-activity relationship studies reported by Romo and co-workers, a simplified triazole analogue 182 lacking methyl groups was synthesized by Hemi Cumming, a previous Ph.D. student who studied at Victoria University of Wellington. The antiproliferative activity of this analogue was found to be significantly lower than that of pateamine A, suggesting that the thiazole embedded within the molecule or the excised methyl groups are crucial for its potency. Therefore, to further explore the necessary features for its selective activity for eIF4A isoforms, new thiazole analogues 183 – 186 and triazole analogues (10S)-and (10R)-analogue 187 were targeted in this project. The preparation of the thiazole-containing macrocyclic core of analogues 183 and 184 was achieved. It features: (1) gold-catalysed thiazole formation through coupling between an alkyne fragment and a thioamide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of a δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. The synthesis of the triazole-containing macrocyclic core of (10S)-analogue 187 was completed. It features: (1) a copper-catalysed triazole formation through 1,3-dipolar cycloaddition between an alkyne fragment and an azide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. Studies on the preparation of a side-chain fragment with suitable functionalities to allow coupling with the various macrocycles through olefination reactions were also conducted. The attachment of the side-chain fragment onto the macrocyclic cores for the synthesis of the targeted analogues 183 and 184 and (10S)-analogue 187 will be investigated in future work. These experimental results will inform the synthesis of new generation analogues to further study the key structures required for effective binding to the protein target eIF4A and selectivity between isoforms.</p>

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The kinetics and mechanism of the electrophilic substitution of heteroaromatic compounds. Part XXVIII. The preparation and kinetic nitration of 2-, 3-, and 4-dimethylaminopyridines and their 1-oxides in sulphuric acid

Cited by 19 publications

References 0 publications

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids

Asymmetric Synthesis of Isoquinoline Derivatives from Amino Acids

Tertiary Amine Oxidation using HOF ⋅ CH3CN: A Novel Synthesis of N-Oxides

Towards Synthesis of Simplified Analogues of Pateamine A

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