¹H−¹⁵N HMBC NMR as a tool for rapid identification of isomeric azaindoles: The case of 5F‐MDMB‐P7AICA

Abstract

The high frequency of the synthetic cannabinoid receptor agonists (SCRAs) emergence renders this group of new psychoactive compounds particularly demanding in terms of detection, identification, and responding. Without the available reference material, one of the specific problems is differentiation and structure elucidation of constitutional isomers. Herein, we report a simple and efficient flow chart diagram applicable for a rapid nuclear magnetic resonance (NMR) identification and differentiation between azaindoles, 4‐, 5‐, 6‐, and 7‐azaindole, which is a common structural motif of synthetic cannabinoids. The flow chart diagram is based on 1H NMR and 1H–15N NMR spectra, and to prove the concept, it has been tested on 5F‐MDMB‐P7AICA (1). Spectral and analytical data including standard 1D and 2D NMR spectra, gas chromatography−mass spectrometry (GC−MS), Fourier transform infrared−attenuated total reflectant (FTIR−ATR), Raman, melting point, and combustion analysis are provided for compound 1.

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

“…To this end, 1 H‐ 15 N heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) spectroscopy has recently been utilized to provide an analytical method for the differentiation of unsubstituted 4‐, 5‐, 6‐, and 7‐azaindole constitutional isomers. Using the latter approach has permitted Martek et al to unambiguously assign the structure of 7‐azaindole 5F‐MDMB‐P7AICA ( 25 ) . The latter work highlights the importance of spectroscopic methods in the continued struggle to monitor a rapidly evolving class of NPS.…”

“…However, from an impurity profiling perspective, it is noteworthy that the dehalogenation of 1‐bromoadamantane, when in the presence of silver carbonate, resulted in the inadvertent structural incorporation of the given reaction solvent (dimethylsulfoxide or acetonitrile) in the final reaction step to 28 , affording by‐products 39 and 40 , respectively (Figure ) . Additionally, Košmrlj and co‐workers have recently reported the detection of methyl 2‐acetamido‐3,3‐dimethylbutanoate ( 41 ) in test purchase recreational samples of 5F‐MDMB‐P7AICA ( 25 ) . Amide impurity 41 has been proposed to form via amidation of ethyl acetate (a potential solvent used in the manufacture of 5F‐MDMB‐P7AICA [ 25 ]).…”

“…Longworth et al have noted the formation of side products 39 and 40 during attempted syntheses of azaindole SCRA carboxylate esters 28 . similarly, acetamide 41 has been identified as an impurity in illicit samples of 5F‐MDMB‐P7AICA ( 25 )…”

“Walking the nitrogen around the ring”: Chemical synthesis and spectroscopic characterization of novel 4‐, 5‐, 6‐, and 7‐azaindazole analogs of the synthetic cannabinoid receptor agonist MDMB‐PINACA

“…20 Subsequently, Martek et al have provided an elegant protocol for the identification and differentiation between 4-, 5-, 6-, and 7-azaindole isomers of SCRA 27 using 1 H- 15 N HMBC NMR spectroscopy. 21 Considering the analytical challenges associated with the accurate identification and unambiguous structural elucidation of newly emerging NPS containing multiple nitrogen core atoms, we sought to highlight the chemical synthesis and describe the spectroscopic characterization and differentiation of a set of four novel isomeric 4-, 5-, 6-, and 7-azaindazole analogs (28)(29)(30)(31), employing the known potent indazole SCRA, MDMB-PINACA 32 as the exemplar (Figure 4). 22 Notably, MDMB-PINACA (32) shares close structural similarity with its 5-fluoro congener, 5F-MDMB-PINACA, an SCRA that has been implicated in several cases of fatal toxicity.…”

“…18 Similarly, following the test purchase of a sample marketed online as 4‐azaindole 26 (5F‐MDMB‐P4AICA) in 2017, further confirmation of structure using 1‐ and 2‐D nuclear magnetic resonance (NMR) experiments, including 1 H‐ 13 C heteronuclear multiple bond correlation (HMBC), revealed that it was in fact the 7‐azaindole isomer 27 20 . Subsequently, Martek et al have provided an elegant protocol for the identification and differentiation between 4‐, 5‐, 6‐, and 7‐azaindole isomers of SCRA 27 using 1 H‐ 15 N HMBC NMR spectroscopy 21 …”