Site-selectivity in the cyanation of 3-substituted pyridine 1-oxides with trimethylsilanecarbonitrile.

Sakamoto, Takao; Kaneda, Sohichi; Nishimura, Syusaku; Yamanaka, Hiroshi

doi:10.1248/cpb.33.565

Cited by 49 publications

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“…A literature survey revealed that although the synthesis of 1 had previously been reported, [1] it was only recovered as a minor Our initial route to prepare 1 was relatively straightforward, involving the displacement of fluoride from 5-bromo-2-fluoropyridine (2) with NaCN or KCN in DMF at 150 C (Sch. 1).…”

Section: An Efficient Synthesis Of 5-bromopyridine-2-carbonitrilementioning

confidence: 99%

“…Indeed, treatment of compound 5 with t-butyl isocyanate at À78 C in toluene cleanly and quantitatively furnished 5-bromopyridine-2-carboxylic acid tert-butylamide (6), which was converted smoothly to 1 following a modified literature procedure [5] that involved the dehydration of the amide in POCl 3 and toluene at 110 C. The structural identity of 1 was confirmed by comparing our analytical data with that reported previously for the compound. [1] In summary, the title compound 1 was efficiently prepared from commercially available 2,5-dibromopyridine in a two-step yield of 75%. One attractive feature of the sequence is that it introduces the cyano functionality without the use of toxic metal cyanides.…”

Section: Marcel Dekker Inc • 270 Madison Avenue • New York Ny 10016mentioning

confidence: 99%

“…The layers were separated and the toluene layer was dried over Na 2 SO 4 , filtered, and concentrated to dryness to furnish 1.4 g (99%) of crude 6, which was judged to be 90-95% pure by 1 (1). Crude 6 (1.4 g) was dissolved in a mixture of toluene (5 mL) and POCl 3 (5 mL).…”

Section: -Bromopyridine-2-carbonitrile 3287mentioning

confidence: 99%

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An Efficient Synthesis of 5-Bromopyridine-2-carbonitrile

2003

Synthetic Comm.

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Section: An Efficient Synthesis Of 5-bromopyridine-2-carbonitrilementioning

confidence: 99%

Section: Marcel Dekker Inc • 270 Madison Avenue • New York Ny 10016mentioning

confidence: 99%

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An Efficient Synthesis of 5-Bromopyridine-2-carbonitrile

2003

Synthetic Comm.

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“…Therefore, it is apparent that these particular methodologies need not only high cost but have environmental issues. However, the greatest and most obvious drawback in most of these cases is the lack of regioselectivity…”

Section: Introductionmentioning

confidence: 99%

Regioselective Cyanation of Six‐Membered N‐Heteroaromatic Compounds Under Metal‐, Activator‐, Base‐ and Solvent‐Free Conditions

et al. 2019

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A regioselective cyanation of heteroaromatic N-oxides with trimethylsilyl cyanide has been developed to obtain 2-substituted N-heteroaromatic nitrile without the requirement of any external activator-, metal-, base-, and solvent. The present protocol is a straightforward, one-pot heteroaromatic CÀ H cyanation process, and proceeds smoothly in conventional heating but also under microwave irradiation with shorter reaction times. This approach now allows access to a broad class of quinoline N-oxides and other heteroarene N-oxides with high to good yields and can also be scaled up to obtain gram quantities. Further application of this process was observed and utilized in late-stage cyanation of the anti-malarial drug quinine as well as transformation of the 2-cyanoazines to a series of biologically important molecules. Based on the experimental observations, a plausible mechanism has also been proposed highlighting the dual role of trimethylsilyl cyanide as a nitrile source and as an activating agent.

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“…The orienting effect of these substituents on the cyanation has been explained by assuming a cyclic mechanism due to the interaction between the substituents and TMSCN. 4) Our interest was next focussed on the comparison of these two different orienting effects in the same ring system. The present paper deals with the reaction of 4,5-disubstituted pyrimidine 1-oxides with TMSCN, because such pyrimidine 1-oxides are considered to be easily available substrates having favorable structures for the comparison of these effects in a single molecule.…”

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Studies on pyrimidine derivatives. XXXIX. Site-selectivity in the reaction of 5-substituted and 4,5-disubstituted pyrimidine N-oxides with trimethylsilyl cyanide.

Yamanaka

Sakamoto

Nishimura

et al. 1987

CHEMICAL & PHARMACEUTICAL BULLETIN

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The site-selectivity in the modified Reissert-Henze reaction of 5-substituted, and 4,5-disubstituted pyrimidine 1-oxides with trimethylsilyl cyanide was examined. The reaction of 5-substituted 4-methoxypyrimidine 1-oxides with trimethylsilyl cyanide gave exclusively 2-pyrimidinecarbonitriles in good yields without exception. On the other hand, the other 5-substituted and 4,5-disubstituted pyrimidine 1-oxides gave mainly 6-pyrimidinecarbonitriles.Keywords site-selectivity; pyrimidine N-oxide; trimethylsilyl cyanide; Reissert-Henze reaction; pyrimidinecarbonitrile As reported previously, when pyrimidine 1-oxides substituted with an electron-donating group at position 4 were treated with trimethylsilyl cyanide (TMSCN),2) significant siteselectivity due to substituent effects was observed, and 2-pyrimidinecarbonitriles were formed predominantly.3) For example, the reaction of 4-methylpyrimidine 1-oxide with TMSCN gave 4-methyl-2-pyrimidinecarbonitrile as a sole product, while the reaction of pyrimidine 1-oxide itself under the same conditions gave a 2 : 3 mixture of 4-pyrimidinecarbonitrile and 2-pyrimidinecarbonitrile.On the other hand, the reaction of 3-halopyridine 1-oxides with TMSCN was reported to give 3-halo-2-pyridinecarbonitriles selectively.4) Similar results were observed in the reaction of 3-methoxy-and 3-dimethylaminopyridine 1-oxides with the same reagent. The orienting effect of these substituents on the cyanation has been explained by assuming a cyclic mechanism due to the interaction between the substituents and TMSCN.4) Our interest was next focussed on the comparison of these two different orienting effects in the same ring system. The present paper deals with the reaction of 4,5-disubstituted pyrimidine 1-oxides with TMSCN, because such pyrimidine 1-oxides are considered to be easily available substrates having favorable structures for the comparison of these effects in a single molecule.In advance of the main investigation, the reaction of 5-substituted pyrimidine 1-oxides with TMSCN was carried out. When 5-phenyl-(1a), 5-methyl-(1b), 5-methoxy-(1c), 5-chloro-(1d), and 5-bromopyrimidine 1-oxide (1e) were treated with TMSCN under the reported conditions,3m the corresponding 5-substituted 4-pyrimidinecarbonitriles (5'a-e) were formed predominantly. The formation ratio of the isomers determined by gaschromatographic analysis are listed in Table I. Based on the results described above, it is concluded that the reaction of 5-substituted pyrimidine 1-oxides tends to give 4-pyrimidinecarbonitriles, although the orienting effect due to the interaction between 5-substituents and TMSCN is not sharply observed as in the case of 3-substituted pyridine 1-oxides.

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Site-selectivity in the cyanation of 3-substituted pyridine 1-oxides with trimethylsilanecarbonitrile.

Cited by 49 publications

References 0 publications

An Efficient Synthesis of 5-Bromopyridine-2-carbonitrile

An Efficient Synthesis of 5-Bromopyridine-2-carbonitrile

Regioselective Cyanation of Six‐Membered N‐Heteroaromatic Compounds Under Metal‐, Activator‐, Base‐ and Solvent‐Free Conditions

Studies on pyrimidine derivatives. XXXIX. Site-selectivity in the reaction of 5-substituted and 4,5-disubstituted pyrimidine N-oxides with trimethylsilyl cyanide.

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