Synthesis of new cyano‐substituted analogues of Tröger's bases from bromo‐derivatives. A stereochemical dependence of long‐range (ⁿJ_HH, n = 4, 5, and 6) proton–proton and proton–carbon (ⁿJ_CH, n = 1, 2, 3, 4, and 5) coupling constants of these compounds

Abstract

A free‐catalyst microwave‐assisted cyanation of brominated Tröger's base derivatives (2a‐f) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds (3a‐e, I) in very good yields. Complete assignment of 1H and 13C chemical shifts of 2a‐f, I and 3a‐d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure‐shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD‐TOCSY) with adiabatic pulses. Determination of the long‐range proton–proton coupling constants nJHH (n = 4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the 1H NMR spectrum and comparing it to the experimental spectrum. The excitation‐sculptured indirect‐detection experiment (EXSIDE) and 1H‐15N CIGARAD‐HMBC (constant time inverse‐detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long‐range carbon–proton coupling constants nJCH (n = 2, 3, and 4) and for assignment of 15N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6‐31G(d,p), 6‐311G(d,p), and 6–311 + G(d,p) basis sets. For calculation of 1H and 13C chemical shifts, nJHH (n = 2, 3, 4, 5, and 6), and nJCH (n = 1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6‐31G(d,p), B3LYP/6‐31+G(d,p), B3LYP/6‐311+G(d,p), B3LYP/6‐311++G(2d,2p), B3LYP/cc‐pVTZ), and B3LYP/aug‐cc‐pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long‐range nJHH (n = 4, 5, and 6) and nJCH (n = 1, 2, 3, 4, and 5) have been found in bromo‐substituted analogues of Tröger's bases.

Uncovering the Mechanism Leading to the Synthesis of Symmetric and Asymmetric Tröger′s Bases

“…Theoretical and practical implications of this type of competitive reactions have been extensively discussed in relation to the combination of free radicals in homogeneous and heterogeneous media, see for example Chesta et al Hence, a‐TB reaction yields reported in Scheme (products 6z , 8z and 9z ) must be analyzed within the framework of the concepts discussed above. Symmetrical TB 5z was obtained in ~96 % yield, which agrees well with previous reports . Compound 6z was obtained by ca.…”

“…Tröger′s bases (TB) were prepared from anilines in trifluoroacetic acid (TFA) and characterized as described before . The yields for the five model syntheses are summarized in Scheme .…”

“…The main goal of these syntheses is to understand the underlying mechanism. However, their synthetic potential is interesting per se since the bromide atom could be replaced for a great number of functionalities to prepare more complex molecules . In the case of the synthesis of 5z , 6z and 8z starting anilines react quantitatively after 24 h. In contrast, significant yields of TB 7z and 9z are only observed after a week.…”

“…However, the synthesis of arbitrarily complex symmetric and, still more problematic, asymmetric Tröger′s base – bridged dyads seems to be a challenging issue. There are descriptions of numerous available synthetic routes for different symmetric species , . Some intermediates have been isolated and some mechanistic proposals have appeared to explain part of the whole process , , , .…”

“…There are descriptions of numerous available synthetic routes for different symmetric species , . Some intermediates have been isolated and some mechanistic proposals have appeared to explain part of the whole process , , , . However, a detailed step by step description of each elementary process leading to the synthesis of these compounds starting from substituted anilines is still uncovered, at least to the best of our knowledge.…”