Elsevier

Tetrahedron

Volume 62, Issue 41, 9 October 2006, Pages 9507-9522
Tetrahedron

Tetrahedron report number 770
Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis

https://doi.org/10.1016/j.tet.2006.07.039Get rights and content

Graphical abstract

A new recently published application of 2,4,6-trichloro-1,3,5-triazine (CC) and its derivatives in organic synthesis are reviewed

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Introduction

1,3,5-Triazine derivatives have been known for a long period of time. They have found widespread applications in the pharmaceutical, textile, plastic, and rubber industries, and are used as pesticides, dyestuffs, optical bleaches, explosives, and surface active agents. The chemistry of this group of compounds has been studied intensively and has been the subject of many reviews.1, 2, 3, 4, 5, 6

Development of valuable methods for the preparation of many substances is still a challenge. The main issues in modern synthetic organic chemistry are selectivity, mildness, improvement of efficiency, and the avoidance of toxic reagents and by-products. From this point of view, considerable attention has been devoted to the development of new 1,3,5-triazine derivatives as reagents in organic synthesis.

Because common, nonsystematic nomenclature is prevalent in the chemical literature of triazine, it is important to briefly review the systematic and common names of some important derivatives, which are shown in Figure 1.

All of the s-triazine derivatives that have wide practical applications are 2,4,6-mono, di- or tri-substituted, symmetrical and nonsymmetrical compounds bearing different substituents. The most important reagent for obtaining these compounds is cyanuric chloride (CC), because of the reactivity of its chlorine atoms toward nucleophiles. It is also important to stress that CC is commercially available and a very inexpensive reagent, which makes its applications even more attractive. In this review, the synthesis of new 2,4,6-derivatives of 1,3,5-triazine together with novel applications of cyanuric chloride and its derivatives, in a variety of synthetic transformations, will be presented. Because of the large volume of work in this area, only the most relevant recently published applications will be presented.

Section snippets

2,4,6-Trichloro-1,3,5-triazine (CC)

The ease of displacement of chlorine atoms in cyanuric chloride by various nucleophiles, in the presence of a hydrochloride acceptor (usually sodium carbonate, bicarbonate, hydroxide or tertiary amines), makes this reagent useful for the preparation of mono-, di- and tri-substituted 1,3,5-triazines.2 The substitution of chlorine can be controlled by temperature to run in a stepwise manner. An empirical rule, based upon observation, is that mono-substitution of chlorine occurs below or at 0 °C,

Applications of CC in synthesis of substituted s-triazines

Falorni et al.13 synthesized tri-functionalized orthogonally protected templates 1 (Fig. 2) in a one-pot procedure, which was used in a liquid-phase parallel synthesis.

By reacting CC with 3 equiv of p-hydroxybenzaldehyde, Tahmassebi and Sasaki14 obtained, a triangular- ‘tripod’ in a single step 2 (Fig. 2). It was used for the imprinting of a silica surface14 or for linking to N-terminus peptides by reductive amination to assemble three-helix bundle proteins.15 A linear template- ‘dipod’ 3 was

CC in dendrimers synthesis and supramolecular complexes

Controlling the reaction temperature of CC with different diamines allowed Simanek's group34, 35, 36, 37, 38, 39, 40 and Lai et al.41 to synthesize dendrimers, e.g., 17 (Fig. 5), even without employing protection and deprotection processes. They have potential applications in medicine as vehicles for drug delivery, and in the area of electro- and optomaterials.

Triazine derivatives, such as cyanuric or isocyanuric acids and melamines (obtained from CC), can act as both hydrogen bond donors and

Cyanuric chloride in functional group transformation

In spite of the enormous number of publications devoted to functional group transformation,58 there is still a need for mild methods that exhibit selectivity among functional groups, especially in the case of polyfunctional derivatives. In the older literature, one can find examples of applications of 2,4,6-trichloro-1,3,5-triazine in synthesis.59, 60, 61, 62, 63, 64, 65, 66 Recently there has been a considerable growth of interest in the use of cyanuric chloride and its derivatives in organic

Cyanuric chloride in solid-phase synthesis

Solid-phase synthesis, since it's discovery by Merifield,85 is now routinely used in automated synthesizers.86 Cyanuric chloride also found applications in solid-supported strategy.

Masala and Tadei69 loaded CC on different types of amino functionalized resins. These new reagents were used for activation of carboxylic acids to give amides and dipeptides (Scheme 16). A series of aliphatic and aromatic carboxylic acids, and primary and secondary amines, gave amides with good yields.

A new resin

2-Chloro-4,6-dimethoxy-1,3,5-triazine in functional group transformation

2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was recently found to have wide applications as a condensing reagent in peptide chemistry.73 It is commercially available, but can also be easily synthesized.7, 89 Activation of carboxylic acids by means of CDMT is a multi-step process, and was elegantly and thoroughly examined by Kaminski.73,90,91 It depends upon the specific reaction conditions, such as the order of addition of reagents.92 The reaction requires the presence of a tertiary amine,

Applications of other derivatives of s-triazine in organic synthesis

Markowicz and Dembinski developed a fluorous 2-chloro-4,6-bis-[(heptadecafluorononyl)oxy]-1,3,5-triazine (FCDMT), an analog of CDMT, as a new coupling reagent in peptide synthesis.107 It was prepared from CC and heptadecafluorononan-1-ol (Scheme 21), and fully characterized. It is believed that the mechanism of activation of a carboxylic acid by FCDMT is similar to that of CDMT (Scheme 19). The advantage of this method lies in nonaqueous and nonacidic isolation protocol. The fluorous by-product

Conclusion

This paper has reviewed recently published applications of 2,4,6-trichloro-1,3,5-triazine, and its related derivatives in organic synthesis. Increased interest in CC lies in the different reactivities of chlorine atoms, which are easily controlled by temperature. It allows sequential introduction of various substituents into a s-triazine ring using a one-pot procedure. These reagents also found applications in solid-phase synthesis by a combinatorial approach, as a template for peptides, for

Acknowledgements

Support from the Department of Chemistry and Biochemistry, University of Maryland Baltimore County is gratefully acknowledged. I thank Dr. R. M. Pollack for carefully reading the manuscript, for his critical comments, and valuable suggestions. I also thank Ms. N. Eaton for technical help.

Grzegorz Blotny was born in Bydgoszcz (Poland). He studied chemistry at Gdansk Technical University (Gdansk, Poland) and completed his PhD in the field of peptide chemistry in 1966 with Emil Taschner and Zygmunt Ledochowski. As faculty at Gdansk Technical University, he completed his habilitation in 1983. During the period of 1983–1984, he was a visiting scientist at N.I.H. (USA). In 1985 he moved to the University of Maryland Baltimore County (Baltimore, USA), where he is a Research Associate

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    Grzegorz Blotny was born in Bydgoszcz (Poland). He studied chemistry at Gdansk Technical University (Gdansk, Poland) and completed his PhD in the field of peptide chemistry in 1966 with Emil Taschner and Zygmunt Ledochowski. As faculty at Gdansk Technical University, he completed his habilitation in 1983. During the period of 1983–1984, he was a visiting scientist at N.I.H. (USA). In 1985 he moved to the University of Maryland Baltimore County (Baltimore, USA), where he is a Research Associate Professor. His research interests focus on peptide chemistry and the development of new methodologies in organic synthesis.

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