Iron(III)-Mediated Rapid Radical-Type Three-Component Deuteration of Quinoxalinones With Olefins and NaBD4

Iron(III)-promoted rapid three-component deuteration of quinoxalinones with olefins and NaBD4 is reported for the first time, which provides a novel, economic, and efficient method for the rapid synthesis of deuterated quinoxalinones. In this transformation, a radical pathway is involved according to the results of control experiments.


INTRODUCTION
In recent years, deuterium-labeled compounds have received much attention because they play an important role in studying chemical and biological processes (Mutlib, 2008;Gómez-Gallego and Sierra, 2011;Konermann et al., 2011;Simmons and Hartwig, 2012;Atzrodt et al., 2018;Pirali et al., 2019). The incorporation of deuterium is a very efficient strategy not only to measure the kinetic isotope effect and track the reaction path in synthetic chemistry but also to change the absorption, distribution, metabolism, and excretion (ADME) properties of drug candidates in pharmaceutical chemistry (Atzrodt et al., 2007;Meanwell, 2011;Guengerich, 2012;Katsnelson, 2013;Gant, 2014). Since the first deuterated drug, deutetrabenazine, for the treatment of chorea associated with Huntington's disease was approved by the Food and Drug Administration in 2017 (Schmidt, 2017), which clearly proved a route for the development of deuterated drugs in clinical medicine (Scheme 1A) (Junk and Catallo, 1997;Gowrisankar et al., 2012;Tolnai et al., 2014;Ray et al., 2018), considerable interests have been devoted to developing novel and efficient methods for the synthesis of such compounds (Yu et al., 2016;Kerr et al., 2017;Liang et al., 2017;Li et al., 2017;Liu et al., 2018;Yang et al., 2018;Han et al., 2019;Shen et al., 2019;Xu et al., 2019;Zhao et al., 2019;Chang et al., 2020;Dong et al., 2020). For instances, in 2016, Chirik and coworkers reported an iron-catalyzed transformation for the deuteration and tritiation of pharmaceuticals (Yu et al., 2016). Kerr's group developed an iridium-catalyzed hydrogen isotope exchange method for the site-selective deuteration of N-heterocycles (Kerr et al., 2017). In 2012, Fe(III)/NaBH 4 -mediated free radical hydrofluorination of unactivated alkenes was reported by Boger's group (Barker and Boger, 2012) (Scheme 1B). Subsequently, Liu and coworkers reported a similar method with Fe(III)-promoted free-radical hydroheteroarylation of alkenes (Liang et al., 2017) (Scheme 1B). Dai and Yan, respectively developed novel methods for the synthesis of deuterated arenes by a palladium-catalyzed, pyridine-directed remote meta-C-H bond deuteration of arenes  or ruthenium catalysis . In 2019, Wasa and coworkers demonstrated a B(C 6 F 5 ) 3catalyzed α-deuteration of carbonyl compounds with D 2 O, providing an efficient protocol for the synthesis of deuterium labeling carbonyl-based pharmaceuticals (Chang et al., 2020). Despite their utilities, there is still a substantial interest in developing novel and efficient methods for the synthesis of such organic compounds.
Multicomponent reactions have become a hot field in modern organic chemistry in recent years because multicomponent reaction can form multiple chemical bonds in one step in comparison with the traditional synthesis method, thus realizing the simple, efficient, and atomic economic synthesis of structural diversity compounds. Quinoxalines and their derivatives are one of the important organic compounds because they have been widely applied in organic synthesis, material chemistry, agrochemical industries, and pharmaceutical chemistry (TenBrink et al., 1994;Monge et al., 1995;Badran et al., 2003;Refaat et al., 2004;Hoogewijs et al., 2013;Nakane et al., 2015;Renault et al., 2017). Although a plenty of twocomponent reactions for the synthesis of quinoxalinones were achieved (Hong et al., 2019;Jin et al., 2019;Ke et al., 2019;Liu et al., 2019;Wang et al., 2019Wang et al., , 2020Wei et al., 2019;Xie et al., 2019;Xue et al., 2019;Yan et al., 2019;Zhang H. et al., 2019;Bao et al., 2020).
We also achieved a useful method for the rapid synthesis of quinoxalinone-containing organoazides using three-component cascade reaction of quinoxalinones with olefins and TMSN 3 (Shen et al., 2020). Keeping on our interests in developing simple and efficient methods for the synthesis of quinoxalinones Zhang H. et al., 2019;Shen et al., 2020), herein, we demonstrated a radical-type three-component deuteration of quinoxalinones with olefins and NaBD 4 mediated by Fe(NO 3 ) 3 •9H 2 O for the first time (Scheme 1C).
With the optimized reaction conditions in hand, the substrate scope of the three-component deuteration was subsequently explored by using various quinoxalinones (1) with styrene (2a) and NaBD 4 (3) ( Table 2). To our delight, a wide range of Nprotecting groups including N-methyl, N-ethyl, N-butyl, Ncyclopropylmethyl, and N-esteryl groups could work well under standard conditions, affording the target products (4a−4e) in 70-77% yields. Quinoxalinones with various N-benzyl groups or the methoxyl, chloro, bromo, and methyl groups on the benzene ring were also tolerated in this reaction, as demonstrated with products 4f−4q, or 4r−4u in good yields. It was noteworthy that the N-free protecting quinoxalinone was also suitable for the transformation; the product (4v) was obtained in 66% yield. Unfortunately, other N-heterocycles, such as theophylline and 4-hydroxyquinazoline, could not undergo the reaction (see SI).
Based on the above experimental results and previous reports (Yi et al., 2017;Yan et al., 2019;Shen et al., 2020), a probable radical mechanism for the three-component reaction was proposed (Scheme 4). First, deuterium radical (A) was generated from NaBD 4 in the presence of Fe(III). Second, the generated deuterium radical (A) attacked olefin 2a to afford alkyl radical (B). Third, alkyl radical (B) then attacked quinoxalinone 1a to give nitrogen radical (C), which underwent a 1,2-hydrogen shift process to produce carbon radical (D). After the generation of carbon cation (E) from carbon radical (D) by the oxidation of Fe(III), the final product 4a was obtained through a deprotonation process.

General Information
All reagents and deuterated solvents were commercially available and used without further purification. All products were separated by silica gel (200-300 mesh) column chromatography with petroleum ether (PE) (60-90 • C) and ethyl acetate (EA). 1 H, 13 C, and 19 F NMR spectra were recorded on a  Bruker Advance 500 spectrometer at ambient temperature with CDCl 3 as solvent and tetramethylsilane (TMS) as the internal standard. Melting points were determined on an X-5 Data microscopic melting point apparatus. Analytical thin layer chromatography (TLC) was performed on Merk precoated TLC (silica gel 60 F254) plates. Compounds for highresolution mass spectrometry (HRMS) were analyzed by positive mode electrospray ionization (ESI) using Agilent 6530 QTOF mass spectrometer.
Typical Reaction Procedure for the Cascade Reaction of Quinoxalinones With Unactivated Alkenes and NaBD 4 A mixture of quinoxalinones (1) (0.2 mmol), olefins (2) (2.0 equiv), Fe(NO 3 ) 3 •9H 2 O (4.0 equiv), and MeCN/EtOH (4.0 ml, v/v = 1:1) in a 15-ml tube was stirred at room temperature for 5 min to make all the components dissolved. Then, NaBD 4 (2.0 equiv) was slowly added. The resulting mixture was stirred for another 5 min. After the completion (as indicated by TLC), the reaction mixture was quenched with aqueous NH 3 •H 2 O (2 ml) and extracted with EtOAc (5 ml × 3). The collected organic layer was washed with brine and dried with MgSO 4 . Finally, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 3:1).

CONCLUSION
In conclusion, a rapid three-component deuteration of quinoxalinones with olefins and NaBD 4 was reported for the first time. Quinoxalinones or olefins bearing SCHEME 4 | Plausible mechanism.
various functional groups could undergo the reaction smoothly, producing the target products in moderate to good yields. This transformation gave a novel and efficient method for the synthesis of previously unknown deuterated quinoxalinones.

DATA AVAILABILITY STATEMENT
All datasets presented in this study are included in the article/Supplementary Material.