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2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks, Takemoto thiourea catalyst analogs, and olfactory mapping of a sweet-smelling triazine

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Abstract

The chemistry of 4,6-dialkyl-2-amino-1,3,5-triazines with bulky alkyl substituents was investigated and their use as building blocks for preparing chiral thiourea organocatalysts explored. Reaction of ammonia with 4,6-di-tert-butyl-2-chloro-1,3,5-triazine gave 4,6-di-tert-butyl-1,3,5-triazin-2-amine which formed extended hydrogen-bond networks in the solid state according to X-ray crystallography. Selected heterocyclic amines were converted to isothiocyanates, and the latter reacted with (S,S)-2-(dimethylamino)cyclohexylamine to give enantiopure 1-hetaryl-3-[2-(dimethylamino)cyclohexyl]thioureas, with hetaryl representing either 4,6-dimethyl-1,3-diazin-2-yl, 4,6-diisopropyl-1,3,5-triazin-2-yl, or 4,6-di-tert-butyl-1,3,5-triazin-2-yl groups. These compounds are structural analogs of Takemotos’s chiral thiourea organocatalysts (1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(dimethylamino)cyclohexyl]thiourea) with an aza-aryl instead of the 3,5-bis(trifluoromethyl)phenyl group. They feature a strong intramolecular N–H to N-1 hydrogen bond, as shown by X-ray crystallography of 1-(4,6-di-tert-butyl-1,3,5-triazin-2-yl)-3-[2-(dimethylamino)cyclohexyl]thiourea in the solid state and by 1H NMR spectroscopy of all derivatives in CDCl3 solution, which prevents them from acting as bifunctional organocatalyst. In the reaction of 4,6-di-tert-butyl-2-chloro-1,3,5-triazine with ammonia, 4,6-di-tert-butyl-2-ethoxy-1,3,5-triazine was identified as side-product displaying a mildly sweet, floral odor that is unusual for a 1,3,5-triazine. Analogs (>35) of 4,6-di-tert-butyl-2-ethoxy-1,3,5-triazine were prepared to define the important structural factors of the olfactophore.

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Notes

  1. The pK a value for NH2-ionization of 4 was derived from that of aniline by taking into account incremental substitution effects of the CF3-group [40], or by applying a relationship given in Ref. [41].

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Acknowledgments

This project received funding from the Deutsche Forschungsgemeinschaft (SPP 1179). We thank Dr. Marco Schmitz (RWTH Aachen, 2009) for performing catalysis tests.

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Authors and Affiliations

  1. Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85748, Garching bei München, Germany

    Li Xiao, Alexander Pöthig & Lukas Hintermann

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  1. Li Xiao
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  2. Alexander Pöthig
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  3. Lukas Hintermann
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Correspondence to Lukas Hintermann.

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Dedicated to Prof. Dr. Walter Weissensteiner on the occasion of his retirement.

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Xiao, L., Pöthig, A. & Hintermann, L. 2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks, Takemoto thiourea catalyst analogs, and olfactory mapping of a sweet-smelling triazine. Monatsh Chem 146, 1529–1539 (2015). https://doi.org/10.1007/s00706-015-1515-7

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