A Simple Route to Unsymmetrically Substituted 1,2,4,5-Tetrazines

Fields, Stephen C.; Parker, Marshall H.; Erickson, W. Randal

doi:10.1021/jo00105a059

Cited by 20 publications

(13 citation statements)

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“…[12] Unsymmetrical 3thiomethyltetrazines were synthesized in low yield through the condensation of S-methylisothiocarbonohydrazidium iodide (2)w ith either trimethylorthoacetate or trimethylorthoformate. [20] Recently, our group described ap rocedure for the conversion of trimethylorthoacetateinto a3-methyl-6-thioalkyltetrazine that can in turn be used for the installation of minimal tetrazines through the silver-mediated Liebeskind-Srogl coupling with arylboronic acids. [21] This method was limited to trimethylorthoacetate and triethylorthobenzoate,and we hoped to develop ag eneral approach for directly converting ester precursors into tetrazines.H owever,t rimethyl-and triethylorthoesters cannot be prepared directly from esters but instead require nitrile precursors and harshly acidic conditions.…”

Section: Introductionmentioning

confidence: 99%

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6‐Disubstituted Tetrazines from Carboxylic Ester Precursors

et al. 2020

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Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3‐monosubstituted tetrazines. Described here is a general, one‐pot method for converting (3‐methyloxetan‐3‐yl)methyl carboxylic esters into 3‐thiomethyltetrazines. These versatile intermediates were applied to the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied to the labeling of endogenous MAGL in live cells.

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Section: Introductionmentioning

confidence: 99%

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6‐Disubstituted Tetrazines from Carboxylic Ester Precursors

et al. 2020

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“…[19][20][21] Unsymmetrical 3-thiomethyltetrazines were synthesized in low yield through the condensation of Smethylisothiocarbonohydrazidium iodide (2) with either trimethylorthoacetate or trimethylorthoformate. [20] Recently, our group described a procedure for the conversion of trimethylorthoacetate to a 3-methyl-6-thioalkyltetrazine that can in turn be used for the installation of minimal tetrazines through the silver-mediated Liebeskind-Srogl coupling with arylboronic acids. [21] This method was limited to orthoacetate, and we hoped to develop a general approach for directly converting ester precursors into tetazines.…”

Section: Divergent Synthesis Of Monosubstituted and Unsymmetrical 36-disubstituted Tetrazines From Carboxylic Ester Precursorsmentioning

confidence: 99%

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6- Disubstituted Tetrazines from Carboxylic Ester Precursors

Xie¹,

Fang²,

Huang³

et al. 2020

Preprint

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As tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3-monosubstituted tetrazines. Described here is a general, one-pot method for converting (3methyloxetan-3-yl)methyl carboxylic esters into 3thiomethyltetrazines. These versatile intermediates were applied as a platform for the synthesis of unsymmetrical tetrazines via Pdcatalyzed cross-coupling and in the first example of catalytic thioether reduction to access monosubstituted tetrazines. The method enables the development of new tetrazines possessing a favorable combination of kinetics, small size and hydrophilicity. The chemistry was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied in labeling of endogenous MAGL in live cells<br>

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“…The tetrazine 4 (2.70 g, 10 mmol) was added in a single portion (slight exotherm observed) to a stirred solution of ethylenediamine (0.30 g, 5 mmol) in dry toluene (50 cm 3 ). The slurry was stirred for 18 h at room temp., and the orange-red solid was filtered off, washed sequentially with dry toluene (30 cm 3 ) and diethyl ether (2 × 30 cm 3 ), sucked dry, and recrystallised from acetic acid-propan-2-ol (1 : 1) to give pure 12a (1.98 (10).…”

Section: Nnј-bis[6-(35-dimethylpyrazol-1-yl)-1245-tetrazin-3-yl]ethan...mentioning

confidence: 99%

“…those required for efficient coupling) is generally a more difficult challenge. 10 We now report the results of our initial investigations in this area.…”

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confidence: 93%

The ‘inverse electron-demand' Diels–Alder reaction in polymer synthesis. Part 4.1 The preparation and crystal structures of some bis(1,2,4,5-tetrazines)

Glidewell¹,

Lightfoot²,

Royles³

et al. 1997

J. Chem. Soc., Perkin Trans. 2

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Reaction of 3,6-bis(3,5-dimethylpyrazolyl)-1,2,4,5-tetrazine with mono-and di-amines gives rise to nucleophilic substitution of one or both of the pyrazolyl substituents, and reaction with diamines under appropriate conditions can lead to bis(3-amino-1,2,4,5-tetrazines), e.g. 12a, 12b and 13. The crystal structures of two of these (12a and 13) show electronic interaction between the tetrazine rings and the amino groups, but none between the tetrazine and pyrazole rings. In 12a there is an extensive network of N᎐H ؒ ؒ ؒ N hydrogen bonds.

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A Simple Route to Unsymmetrically Substituted 1,2,4,5-Tetrazines

Cited by 20 publications

References 0 publications

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6‐Disubstituted Tetrazines from Carboxylic Ester Precursors

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6‐Disubstituted Tetrazines from Carboxylic Ester Precursors

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6- Disubstituted Tetrazines from Carboxylic Ester Precursors

The ‘inverse electron-demand' Diels–Alder reaction in polymer synthesis. Part 4.1 The preparation and crystal structures of some bis(1,2,4,5-tetrazines)

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