Determination of substitution sites in monosubstituted five‐membered aromatic heterocycles

Abstract

Similar magnitudes of proton-proton couplings across three, four, and five bonds and proton-carbon couplings across two and three bonds combined with difficult to predict substituent effects make the results of an indiscriminate use of routine (COSY, HSQC, HMBC, etc.) techniques for substitution site determination in C-monosubstituted five-membered heteroaromatics suspect. As demonstrated on two examples of natural products, the use of 1,1-ADEQUATE leads to unambiguous substitution site determination lending thus further support to suggested inclusion of 1,1-ADEQUATE data into computer-assisted structure elucidation (CASE) protocols.

Allium Discoloration: The Precursor and Formation of the Red Pigment in Giant Onion (Allium giganteum Regel) and Some Other Subgenus Melanocrommyum Species

“…The 1,1-ADEQUATE NMR spectrum of 2 provided fool-proof evidence that the pyrrole moiety is substituted at position 3 (see Supporting Information). Furthermore, the signals corresponding to the three pyrrolyl −CH= hydrogens appeared as one triplet (H-2′) and two doublets of doublets (H-4′ and H-5′), which is fully in agreement with literature data reported for 3-sulfinyl pyrrole derivatives. , …”

“…Foolproof evidence that the pyrrolyl moiety is indeed substituted at position 2 was obtained by a 1,1-ADEQUATE NMR experiment (see Supporting Information). 17 CD and 1 H NMR spectroscopy together with polarimetry were used to determine the absolute configuration around the two chiral centers of 1 (around the sulfur and the R-carbon). The CD spectrum of the amino acid showed a positive maximum at 251 nm (see Supporting Information).…”

Using HMBC and ADEQUATE NMR Data To Define and Differentiate Long-Range Coupling Pathways: Is the Crews Rule Obsolete?

“…It should also be noted that from these data it was necessary to interchange the assignments of the C-7a and C-4c resonances previously reported by Meksurien and Cordell, 19 which may have been incorrectly assigned due to the difficulty of differentiating 2 J CH from 3 J CH HMBC correlations in fivemembered heterocycles such as the γ-lactam moiety. 20 Such difficulties may have led to the numerous incorrect reported structures that have served as the basis for several reviews on the value of synthesis for structure verification. 21,22 It is also worth noting that several 1 J CC correlations were not observed in the conventional 1,1-ADEQUATE spectrum, specifically C-1− C-13a, C-2−C-3, C-8−C-7a, and C-9−C-10.…”

Application of 1,1-ADEQUATE, HMBC, and Density Functional Theory To Determine Regioselectivity in the Halogenation of Pyridine N-Oxides

“…The specific two-bond proton to carbon correlation from 1,1-ADEQUATE can speed up the determination of the correct structure using the computer-assisted structure elucidation (CASE) algorithm . Other examples using 1,1-ADEQUATE for unambiguous structure elucidation include (1) determination of the substitution site on the pyrrole moiety of natural products (Figure a,b), where the 3-pyrrolyl derivative was elucidated as the 2-pyrrolyl derivative previously, and (2) structural revision of coniothyrione with respect to the Cl position attached to C4 instead of C3 (Figure c). , Additional structural elucidation examples using the ADEQUATE family of experiments have recently been reviewed …”