Magnesium-Catalyzed Regioselective Reduction of Unprotected Indoles and Quinoxalines with Ammonia Borane

Magnesium-Catalyzed Regioselective Reduction of Unprotected Indoles and Quinoxalines with Ammonia Borane | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 17 August 2025 V1 Latest version Share on Magnesium-Catalyzed Regioselective Reduction of Unprotected Indoles and Quinoxalines with Ammonia Borane Authors : Nana Wei , Wanzhen Guo , Xing Lu , Zhiqiang Ren , Haojie Ma 0000-0002-5604-7524 , Yuqi Zhang , Jijiang Wang , and Bo Han 0000-0003-1247-7095 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175539798.86964397/v1 198 views 134 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract This study present a transfer hydrogenation method employing ammonia borane (H 3 N·BH 3 ) as the hydrogen source and inexpensive magnesium as the catalyst for the selective reduction of unprotected indoles, quinoxalines, benzofurans, benzothiophenes, quinolines, and their derivatives, resulting the corresponding alicyclic heterocyclic compounds with desirable yields. This catalytic system is applicable to gram-scale syntheses and demonstrates compatibility with various functional groups, including fluorine, chlorine, bromine, trifluoromethyl, and hydroxyl. Deuterium labeling experiments show that the BH 3 counterpart of NH 3 ·BH 3 served as the hydride source, while the NH 3 counterpart of ammonia borane acted as a proton source. It offers a novel approach for the preparation of partially saturated heterocyclic derivatives. Cite this paper: Chin. J. Chem. 2024 , 41 , XXX—XXX. DOI: 10.1002/cjoc.202400XXX Magnesium-Catalyzed Regioselective Reduction of Unprotected Indoles and Quinoxalines with Ammonia Borane Nana Wei, Wanzhen Guo, Xing Lu, Zhiqiang Ren, Haojie Ma, Yuqi Zhang, Jijiang Wang and Bo Han* Laboratory of New Energy & New Function Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering, Yan’an University, Yan’an, Shaanxi,716000, P. R. China Keywords Reduction | Magnesium | Indoles | Quinoxalines | Ammonia borane Comprehensive Summary This study present a transfer hydrogenation method employing ammonia borane (H 3 N·BH 3 ) as the hydrogen source and inexpensive magnesium as the catalyst for the selective reduction of unprotected indoles, quinoxalines, benzofurans, benzothiophenes, quinolines, and their derivatives, resulting the corresponding alicyclic heterocyclic compounds with desirable yields. This catalytic system is applicable to gram-scale syntheses and demonstrates compatibility with various functional groups, including fluorine, chlorine, bromine, trifluoromethyl, and hydroxyl. Deuterium labeling experiments show that the BH 3 counterpart of NH 3 ·BH 3 served as the hydride source, while the NH 3 counterpart of ammonia borane acted as a proton source. It offers a novel approach for the preparation of partially saturated heterocyclic derivatives. Background and Originality Content The conversion of nitrogen-containing heterocycles, including quinoxalines and indoles, into corresponding saturated compound is a transformation of considerable significance in organic synthesis, providing useful intermediates for the production of pharmaceuticals, dyes, agrochemicals, alkaloids, and other bioactive molecules. [1,2] Furthermore, partially saturated heterocyclic compounds have become highly important in the field of liquid organic hydrogen storage carriers (LOHCs) due to their potential in hydrogen storage and transportation. [3] Significant progress has been made in the transition metal-catalyzed reduction of indoles and quinoxalines to their partially saturated heterocycles, utilizing metals such as Ir, Pd, Pt, Ru, Rh, Co and Ni with hydrogen as the reductant. [4] Notably, these reactions involve the use of flammable and explosive hydrogen gas, necessitating specialized equipment and often requiring elevated temperatures and/or high pressures (Scheme 1a). [5] Therefore, transfer hydrogenation reactions that utilize hydrogen equivalents instead of molecular hydrogen provide cost-effective and operationally simpler alternatives, offering enhanced safety and improved selectivity. [6] Over the past two decades, a variety of hydrogen donors—including alcohols, [7] HCOOH/HCOONa, [8] Hantzsch esters, [9] silanes, [10] and pinacolborane (HBpin) [2b,11] have been employed for the catalytic transfer hydrogenation of indoles (Scheme 1b). Ammonia borane (NH 3 ·BH 3 , AB), a crystalline hydrogen storage material, has attracted significant research interest because of its exceptional physicochemical properties. [12] This compound features a high gravimetric hydrogen capacity (19.6 wt%) while exhibiting non-flammability and stability at room temperature under standard conditions. [13] These properties make AB an attractive candidate for catalytic processes, particularly transfer hydrogenation (TH), where its efficiency has been confirmed in recent investigations. AB has been broadly applied as a hydrogen donor for the reduction of a wide range of unsaturated substrates, including alkenes, [14] alkynes, [15] nitriles, [16] ketones, [17] carboxylic acids, [18] imines, [19] pyridines, [20] azoarenes, [21] and nitroarenes. [22] Nevertheless, the catalytic reduction of indoles and quinoxalines using AB has rarely been explored. [23] In 2020, Han’s group reported the synthesis of saturated heterocycles via palladium(II) complex-catalyzed reduction of indoles with NH 3 ·BH 3 and provided three indole substrates. [24] In 2021, Wu reported the zirconium-catalyzed transfer hydrogenation of indoles with AB as a proton and hydride source. [25] Recently, Kishore Natte’s group developed a method to selectively reduce quinoxalines and indoles derivatives to the corresponding saturated heterocyclic compounds using commercially available RuCl 3 ·xH 2 O as a precatalyst and ammonia borane as a hydrogen source. [26] Scheme 1 Reduction of unprotected indole. The use of earth-abundant alkaline earth metals as alternatives to transition metals for chemical bond transformations in organic synthesis, consistent with the goals of sustainable chemistry, has attracted growing interest in recent years. [27,28] Among these metals, magnesium stands out as the earliest adopted and most widely employed in organic synthesis. [29] In this context, magnesium catalysis has been limited to the hydrogen functionalization of substrates containing polarized and nonpolarized unsaturated bonds. [30-32] However, there are few reports on the use of magnesium in the reduction of aldehydes and ketones. In 2019, the Rueping’s group reported the magnesium(II)-catalyzed asymmetric hydroboration of ketones, and a series of chiral secondary alcohols were constructed with high yields. [33] In addition, the research group have developed the MgBu 2 /HBpin system for the chemoselective reduction of α,β -unsaturated ketones to form a wide range of ketones. [34] In 2023, we developed the method for synthesizing alcohols through the reduction of aldehydes, ketones, and α,β -unsaturated aldehydes/ketones, employing low-cost and commercially available MgCl 2 as an effective catalyst. [35] A method for preparing partially saturated heterocyclic compounds via the low catalyst loading of magnesium-catalyzed chemoselective reduction of indoles and quinoxalines using ammonia borane as the hydrogen source has not been reported. Herein, a novel magnesium(0)- catalyzed reduction method for a variety of indoles and quinoxalines is presented, affording partially saturated aromatic heterocyclic compounds using ammonia borane as a H 2 equivalent (Scheme 1c). Results and Discussion Table 1 Optimization of the Mg-catalyzed hydrogenation of 1a. a entry Catalyst (mol%) AB (eq.) Solvent Temp./ o C 2a /% 1 MgCl 2 (10) 2.0 Toluene 80 49 2 MgSO 4 (10) 2.0 Toluene 80 52 3 Mg(OTf) 2 (10) 2.0 Toluene 80 40 4 MgI 2 (10) 2.0 Toluene 80 37 5 Mg(50) 2.0 Toluene 80 75 6 Zn(50) 2.0 Toluene 80 50 7 Al(50) 2.0 Toluene 80 40 8 Mn(50) 2.0 Toluene 80 45 9 Mg(50) 2.0 Et 2 O 80 24 10 Mg(50) 2.0 THF 80 nd b 11 Mg(50) 2.0 CH 2 Cl 2 80 43 12 Mg(50) 2.0 CH 3 CN 80 trace 13 Mg(50) 2.0 Toluene 100 77 14 Mg(50) 2.0 Toluene 120 78 15 Mg(50) 3.0 Toluene 80 85 16 Mg(50) 4.0 Toluene 80 83 17 c Mg(50) 3.0 Toluene 80 71 18 Mg(40) 3.0 Toluene 80 80 19 Mg(30) 3.0 Toluene 80 77 20 no 3.0 Toluene 80 14 a Unless otherwise noted, all reactions were performed with 1a (0.2 mmol), AB=ammonia borane, solvent (2.5 mL), 24 h. Isolated yield are given. b Not detected. c The time was 12 h. In our preliminary study, 0.2 mmol of indole ( 1a ) was employed as the model substrate, with 2 equivalents of ammonia borane as the hydrogen source and 10 mol% MgCl 2 as the catalyst. The transfer hydrogenation reaction was conducted in 2.5 mL of toluene at 80 o C for 24 h, affording indoline ( 2a ) in 49% yield (Table 1, entry 1), while a large quantity of starting material remained. Different Mg(II) salts or zero-valent magnesium were subsequently investigated in the presence of 2 equivalents of ammonia borane at 80 o C (Table 1, entries 2-5). The results show that the effect of zero-valent magnesium as a catalyst is better than that of MgSO 4 , Mg(OTf) 2 , MgI 2 and MgCl 2 , and the isolated yield of the hydrogenation product indoline reaches 75%. Encouraged by the above experimental results, we selected several well-known metal reducing agents, such as zinc (Zn), aluminum (Al) and manganese (Mn), as catalysts instead of magnesium, but they did not effectively promote the hydrogenation reaction (Table 1, entries 6-8). Next, a few solvents, such as Et 2 O, THF, CH 2 Cl 2 and CH 3 CN, were examined and found to be ineffective (Table 1, entries 9-12). When the reaction was carried out at 100 o C or 120 o C, yields of 2a were 77% and 78%, respectively (Table 1, entries 13 and 14). While raising the temperature to 100 o C or 120 o C resulted in a modest increase in yield, the improvement was not pronounced. The effect of ammonia borane loading was then assessed by adjusting its amount from 3 to 4 equivalents (Table 1, entries 15-16). The findings suggest that increasing the equivalents of ammonia borane facilitates the transfer hydrogenation reaction; however, using 4 equivalents did not lead to a notable enhancement in yield. Therefore, three equivalents of ammonia borane were identified as optimal. Although lowering the catalyst loading slightly affected the hydrogenation outcome, it also made the experimental procedure more difficult to handle (Table 1, entries 18-19). Without Mg(0) as the catalyst, the isolated yield of the hydrogenation product was limited to 14% (Table 1, entry 20). Table 2 Substrate Scope for Magnesium(0)-Catalyzed Hydrogenation of Indoles. a All reactions were performed with 1 (0.2 mmol), Mg (0.1 mmol, 50 mol%), ammonia borane (3.0 equiv.), Toluene (2.5 mL), at 80 °C under N 2 atmosphere for 24 h. Isolated yields were given based on 1 . After determining the optimal reaction conditions, we conducted a substrate universality study. First, the scope of indole substrates was studied. It was observed that indole derivatives containing electron-donating groups (such as Me, Et, or OMe) as well as electron-withdrawing groups (such as F, Cl, or Br) at various positions on the indole aromatic ring underwent the reaction successfully. The corresponding indolines (Table 2, 2b – 2q ) were produced in moderate to good yields ranging from 55% to 95%. Notably, for the halogen-substituted indole derivatives, no dehalogenation byproducts were observed among the hydrogenation products; the lower yields obtained for these substrates were attributed to the substantial amount of unreacted starting material (Table 2, 2i – 2o ). The presence of electron-withdrawing groups in multiply halogenated indole derivatives did not adversely affect the reaction, with 1p and 1q being converted to the corresponding indolines in 78% and 75% yields, respectively. Introduction of a hydroxyl group at the 7-position of indole was also well tolerated, affording indoline in 64% yield (Table 2, 2r ). In addition, the introduction of aryl or substituted aryl groups at other positions of the indole aromatic ring was well tolerated, affording a series of indoline derivatives in 71–96% yields (Table 2, 2s – 2ab ). Next, the effects of the substituents on the indole heterocyclic skeleton on the reaction were investigated. When the α and β positions of the indole heterocycle are substituted with groups such as methyl groups, the reaction proceeds smoothly, affording the target compounds in yields of 83% and 75%, respectively (Table 2, 2ac - 2ad ). Additionally, other heterocyclic compounds, such as benzoxazole and benzothiazole derivatives, did not cause catalyst poisoning and successfully underwent the reaction (65–97%, 2ae – 2af ). Table 3 Scope for the Mg(0)-catalyzed reduction of quinoxalines. a All reactions were performed with 3 (0.2 mmol), Mg (0.1 mmol, 50 mol%), ammonia borane (3.0 equiv.), Toluene (2.5 mL), at 80 °C under N 2 atmosphere for 24 h. Isolated yields were given based on 3 . b 1.0 equiv. ammonia borane was used. Tetrahydroquinoxalines are important structural components that are widely present in natural products and in biological or pharmaceutically active molecules; thus, their synthesis has received widespread attention and has been significantly improved. [36] Therefore, we used a magnesium/ammonia borane catalytic system for the selective hydrogenation of quinoxalines. Notably, quinoxaline derivatives substituted with either electron-donating groups (e.g., methyl) or electron-withdrawing groups (e.g., Cl, Br) at different positions underwent efficient conversion, affording the corresponding tetrahydroquinoxaline derivatives in high yields (78%–95%) (Table 3, entries 4b – 4d ). Notably, when the ortho -position of quinoxaline contains two phenyl groups in the large conjugated quinoxaline derivative, the reaction proceeds smoothly, and the isolated yield can reach 84% (Table 3, 4e ). Other representative aromatic heterocyclic compounds, such as acridine, 1,8-naphthyridine, and quinoline, were tested. When acridine was used as the substrate, 9,10-dihydroacridine was obtained in an isolated yield of 85% (Table 3, 4f ). For 1,8-naphthyridine, the product is only one C=N bond reduced under standard conditions, accompanied by a small amount of an unknown compound (Table 3, 4g ). Quinoline has been used many times in this catalytic system, but the yield of the detected tetrahydroquinoline derivative products is low, and follow-up research is still in progress (Table 3, 4h ). To evaluate the scalability of the Mg/NH 3 ·BH 3 system, 1a (1.17 g, 10 mmol) was subjected to the optimized conditions with an longer reaction time of 60 h at 80 °C, affording the target compound 2a in 72% isolated yield (0.85 g). Scheme 2 Gram-scale reduction of 1a . The kinetic profile of the Mg-catalyzed reduction of 1a was also investigated to understand the reaction mechanism. The reaction curve for the magnesium(0)-catalyzed reduction of indole indicates that the hydrogenation proceeds slowly, with no detectable product formation during the first hour, during which only starting material is present. After 2.5 h of reaction, the conversion rate was close to 50%, and the yield of product 2a was 45%. After reaction time 12 h, the yield of the target compound was 71% (Figure 1a). Figure 1 Kinetic analysis of the Mg(0)-catalyzed reduction of 1a : (a) Concentration-time profile; (b) Initial rate versus 1a concen tration; (c) Initial rate versus Mg concentration; (d) Initial rate versus NH 3 ·BH 3 concentration. We observed the kinetic profile of 1a hydrogenation at various concentrations of 1a , Mg(0), or NH 3 ·BH 3 . The order of the reactions with respect to the substrate and catalyst were 1.42 and 1.22, respectively, indicating that the rate of hydrogenation enhances with alleviating initial concentration of Mg/indole (Figure 1b and 1c). The findings suggest that the indole substrate and the Mg(0) catalyst are likely involved in the initial phase of the reduction process. The initial reaction rate (Δ[ 2a ]/Δt) displayed a first-order dependence on the content of NH 3 ·BH 3 , as its initial concentration was varied from 0.08 M to 0.4 M. This observation implies that NH 3 ·BH 3 may participate in the rate-determining step or at least influence the early stage of the hydrogenation reaction (Figure 1d). To further investigate the mechanism of magnesium-catalyzed reduction of indole to indoline, a series of control experiments were performed. Indole 1a was reduced successfully, though with a slightly lower yield, in the presence of 2.0 equivalents of 2,6- di -tert-butyl-4-methylphenol (BHT) and 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), indicating that the reaction does not proceed via a free radical pathway (Schemes 3a and 3b). When Me 3 NBH 3 was employed as a substitute for ammonia borane under the standard conditions, the reaction proceeded poorly, yielding less than 10% of the product, which was consistent with the results obtained using NH 3 BEt 3 (Schemes 3c and 3d). Next, indole was selected as the substrate for deuterium labeling experiments. We found that 82% and 69% of the D atoms were embedded in the 3rd and 2nd positions of the indole when ND 3 ·BH 3 and NH 3 ·BD 3 were used to replace ammonia borane, respectively (Scheme 3e and 3f). Considering the hydrogen atoms that may be introduced by the catalyst and other proton sources in the system, this D-atom embedding ratio is reasonable. Scheme 3 Control experiment. Conclusions In summary, an alkaline earth metal-catalyzed transfer hydrogenation protocol for N -heteroarenes has been developed, using ammonia borane as the hydrogen source. This system enables high yields (up to 96%) in the reduction of unprotected indoles and quinoxalines. Using a low loading of Mg(0) catalyst and ammonia borane, the reaction efficiently produces the reduced products while tolerating various sensitive functional groups, including halogens (F, Cl, Br), trifluoromethyl, and hydroxyl groups. Preliminary mechanistic insights have been gained through deuteration experiments and kinetic studies. Further investigations, including detailed mechanistic studies via DFT calculations and expanded applications of this system, are currently in progress. Experimental General procedure for Mg-catalyzed hydrogenation of Indoles. A mixture of Indoles (0.2 mmol), Mg (0.0024 g, 50 mol%) and NH 3 ·BH 3 (0.0185 g, 3.0 equiv.) were added to an oven dried schlenk tube under atmosphere of nitrogen. Toluene (2.5 mL) were added by syringe. The reaction mixture was stirred at 80 o C for 24 h. After quenching with saturated NH 4 Cl/H 2 O (10 mL), the crude product was extracted with EtOAc (3×10 mL). 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Lett. 2025 , 27 , 4294−4299. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Accepted manuscript online: XXXX, 2024 Version of record online: XXXX, 2024 The Authors After acceptance, please insert a group photo of the authors taken recently. Left to Right: Authors Names Entry for the Table of Contents Magnesium-Catalyzed Regioselective Reduction of Unprotected Indoles and Quinoxalines with Ammonia Borane Nana Wei, Wanzhen Guo, Xing Lu, Zhiqiang Ren, Haojie Ma, Yuqi Zhang, Jijiang Wang and Bo Han* Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.202300XXX A transfer hydrogenation method employing ammonia borane (H 3 N·BH 3 ) as the hydrogen source and inexpensive magnesium as the catalyst for the selective reduction of unprotected indoles, quinoxalines, benzofurans, benzothiophenes, quinolines, and their derivatives is reported. Information & Authors Information Version history V1 Version 1 17 August 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords ammonia borane indoles magnesium quinoxalines reduction Authors Affiliations Nana Wei Yan'an University View all articles by this author Wanzhen Guo Yan'an University View all articles by this author Xing Lu Yan'an University View all articles by this author Zhiqiang Ren Yan'an University View all articles by this author Haojie Ma 0000-0002-5604-7524 Yan'an University View all articles by this author Yuqi Zhang Yan'an University View all articles by this author Jijiang Wang Yan'an University View all articles by this author Bo Han 0000-0003-1247-7095 [email protected] Yan'an University View all articles by this author Metrics & Citations Metrics Article Usage 198 views 134 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Nana Wei, Wanzhen Guo, Xing Lu, et al. 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