Iodine as a novel and efficient reagent for the synthesis of α-aminonitriles by a three-component condensation of carbonyl compounds, amines, and trimethylsilyl cyanide

doi:10.1016/j.tetlet.2005.05.005

Tetrahedron Letters

Volume 46, Issue 27, 4 July 2005, Pages 4595-4597

https://doi.org/10.1016/j.tetlet.2005.05.005 Get rights and content

Abstract

A straightforward and general method has been developed for the synthesis of α-aminonitriles by simply combining aldehydes or ketones, amines, and trimethylsilyl cyanides in the presence of a catalytic amount of molecular iodine at room temperature.

Graphical abstract

Introduction

α-Aminonitriles are important intermediates in the preparation of many amino acids¹ and various nitrogen containing heterocycles such as imidazoles and thiadiazoles.2, 3 They are usually synthesized by the nucleophilic addition of a cyanide anion to imines. Numerous methods describing the preparation of α-aminonitriles have been reported4, 5, 6, 7, 8, 9, 10, 11, 12 in the literature. However, most of these methods involve the use of expensive reagents, lengthy reaction times, and tedious work-up procedure. Furthermore, many of these protocols are limited to aldehydes only and are not applicable to acyclic ketones. Most recently, we reported BiCl₃ as a catalyst¹³ for the Strecker amino acid synthesis reaction, but this procedure did not work with ketones. Therefore, there is a need of an efficient and inexpensive catalyst for the synthesis of α-aminonitriles.

In continuation of our work to develop new organic transformations,¹⁴ we report herein that iodine, which acts as a mild Lewis acid, might be a useful and inexpensive catalyst for the synthesis of α-aminonitriles. Although, iodine has been extensively used as a mild catalyst for a plethora of organic transformations,¹⁵ there are no examples of the use of molecular iodine as catalyst for the synthesis of α-aminonitriles.

Section snippets

Results and discussion

The treatment of benzaldehyde and benzyl amine with TMSCN in the presence of a catalytic amount of iodine afforded 2-(N-benzylamino)-1-phenylacetonitrile in 94% yield. In the same manner, a variety of aldehydes were coupled with a wide range of amines and trimethylsilyl cyanide in a one-pot operation in the presence of a catalytic amount of iodine at room temperature to give the corresponding α-aminonitriles in good to excellent yields (Scheme 1). Both aromatic and aliphatic aldehydes afforded

Conclusion

We have demonstrated a very simple, efficient, and practical method for the synthesis of α-aminonitriles through a one-pot three component coupling of carbonyl compounds, amines, and trimethylsilyl cyanide using a catalytic amount of molecular iodine. High diastereoselection can be obtained in the synthesis of α-aminonitriles using R or Sα-methylbenzylamine. The major advantage of this method is that it is truly a one-pot procedure that does not require a separate step to prepare an imine for

A typical procedure

A mixture of benzaldehyde (212 mg, 2 mmol), aniline (186 mg, 2 mmol), and trimethylsilyl cyanide (300 mg, 3 mmol) in dry acetonitrile (2 mL) was stirred at room temperature in the presence of iodine (51 mg, 0.2 mmol). After completion of reaction (TLC), the reaction mixture was extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with water (20 mL), and brine (20 mL) dried (MgSO₄), and concentrated. The residue was chromatographed over silica gel, eluted 20% ethyl acetate in hexane to

Acknowledgments

We thank the reviewers for their valuable suggestions and comments.

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Iodine as a novel and efficient reagent for the synthesis of α-aminonitriles by a three-component condensation of carbonyl compounds, amines, and trimethylsilyl cyanide

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

A typical procedure

Acknowledgments

Chem. Rev.

J. Am. Chem. Soc.

Tetrahedron

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Chem. Lett.

J. Org. Chem.

Nouv. J. Chem.

J. Am. Chem. Soc.

Tetrahedron Lett.

Tetrahedron

Synthesis

Org. Lett.

Angew. Chem., Int. Ed.

Russ. Chem. Rev.