Synthesis of Macrocycles Derived from Substituted Triazines

Abstract

A triazine ring derivatized with morpholine, an N‐alkyl‐N′‐BOC‐hydrazine (alkyl=isopropyl or benzyl) and the diethylacetal of glycinylpropionaldehyde undergoes spontaneous dimerization in good yields upon acid‐catalyzed deprotection. The resulting 24‐member macrocycles can be characterized by NMR spectroscopy, mass spectrometry, and single crystal X‐ray diffraction. In the solid state, both homodimers adopt a taco‐like conformation. Although each shows π–π stacking between the triazine rings, different patterns of hydrogen bonds emerge. The crystal structure of the isopropyl dimer shows that it includes two molecules of trifluoracetic acid per macrocycle. The trifluoroacetate anion charge balances the protonated triazines, which engage in bifurcated hydrogen bonds with the carbonyl acceptor of the distant glycine. This carbonyl also forms a hydrogen bond with the NH of the proximate glycine. The crystal structure of the benzyl derivative does not include trifluoracetic acid. Instead, two hydrogen bonds form, each between a glycine NH and the lone pair of the C=N nitrogen of the hydrazine group. In the solid state, both molecules present the alkyl side chains and morpholine groups in close proximity. A heterodimer is accessible in approximately statistical yields—along with both homodimers—by mixing the two protected monomers prior to subjecting them to deprotection.

Computational and Experimental Evidence for Templated Macrocyclization: The Role of a Hydrogen Bond Network in the Quantitative Dimerization of 24-Atom Macrocycles

“…However, even before the adoption of the current method, the yields for cyclization were high. In the initial report, macrocycles were subjected to purification by centrifugation and chromatography [ 20 ]. Yields averaged 90%.…”

Efficient syntheses of macrocycles ranging from 22–28 atoms through spontaneous dimerization to yield bis-hydrazones

“…7 Recently, we showed that macrocycles containing 24 atoms could be obtained through the spontaneous dimerization of protected monomers upon treatment with acid. 8 Each monomer presents a BOC-protected hydrazine, a morpholine group, and a tethered acetal. By varying the choice of amino acidusing either glycine or b-alanine-as well as the length of the amino acetal, the tether length is readily manipulated to generate rings of varying sizes.…”

A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

“…To obtain crystals suitable for X-ray diffraction, dimethylamine was replaced with morpholine (leading to a shift in nomenclature from G-G to G′-G′ , etc.) because these derivatives are more amenable to crystallization − and behave like the dimethylamine analogues in solution. That is, all adopt an ( E )-hydrazone and show identical protonation sites, common NMR features, the same rotamer states, and folded structures.…”

“…29 Initial efforts produced macrocycles ranging from 22 to 28 atoms�each a different Murcko framework�displaying different molecular shapes ranging from ones that were compact and folded to those that were extended and flat. 27,28 During the course of these studies, however, two isomeric 24atom macrocycles were prepared�one with glycine and a three carbon acetal (−NHCH 2 CONHCH 2 CH 2 C�N−) and the other with β-alanine and a two-carbon acetal (−NHCH 2 CH 2 CONHCH 2 C�N−). 27 Both showed markedly similar, folded structures in the solid state.…”

“…Our longstanding interest in triazine chemistry and recent studies of hydrazine-substituted triazines , led us to explore macrocycles incorporating triazinyl hydrazones as molecular frameworks. , The ease of synthesis and the numerous sites available to explore functional variation make triazine-based macrocycles a versatile platform for pursuing structure–property relationships. Zerkowski and coworkers showed earlier that static, covalent chemistry could yield similar triazine targets …”