Next Article in Journal
Development and Validation of a Simple and Cost-Effective LC-MS/MS Method for the Quantitation of the Gut-Derived Metabolite Trimethylamine N-Oxide in Human Plasma of Healthy and Hyperlipidemic Volunteers
Previous Article in Journal
Morphology-Engineered NiMo Alloy on Nickel Foam for Enhanced Hydrogen Evolution Reaction Performance
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 30
Issue 11
10.3390/molecules30112397
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Iodide/Nickel Co-Catalyzed Manganese-Mediated Denitrogenative Cross-Electrophile Coupling of Benzotriazinones with Alkyl Sulfonates

by
Yingying Hong
,
Xuanxuan Zhang
and
Gang Zou
*
School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, China
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(11), 2397; https://doi.org/10.3390/molecules30112397
Submission received: 4 May 2025 / Revised: 26 May 2025 / Accepted: 27 May 2025 / Published: 30 May 2025
(This article belongs to the Special Issue Design and Preparation of New Metal Catalysts for Functional Organic Compounds Synthesis)
Browse Figures
Versions Notes

Abstract

:
An efficient Ni-catalyzed, Mn-mediated denitrogenative cross-electrophile coupling of N-alkyl-1,2,3-benzotriazinones with alkyl tosylates and mesylates for access to o-alkyl secondary benzamides is reported. The method uses inexpensive non-anhydrous dimethyl acetamide (DMA) in combination with tetrabutyl ammonium iodide (TBAI) as a co-catalyst to convert sulfonates into iodides in situ. Scope and limitations of the protocol have been demonstrated by >30 examples with yields up to 91%, showing a large electronic effect from the N-substituent in benzotriazinones. An unexpected steric acceleration has been observed from the core of benzotriazinones, not only promising a highly efficient access to 2-alkyl-2,3-disubstituted benzamides but also shedding light on the rate-limiting steps in the catalytic cycle.

Graphical Abstract

1. Introduction

Construction of a carboncarbon bond via transition-metal catalyzed cross-electrophile coupling (XEC) has become increasingly prevalent [1,2,3,4,5,6,7,8,9,10,11,12] since the breakthrough by Weix and Gong etc. just a decade ago [13,14,15,16]; although, the seminal work was reported by Durandetti et al. as early as 1996 [17,18]. Alkyl halides, in fact bromides, have proven to be the most useful alkyl source in XEC. Given that alcohol moieties are widely found in natural and synthetic chemicals, it is attractive to utilize alcohols or their non-halide derivatives. Although progress has recently been made in the direct use of alcohols as coupling partners in XEC by electrochemistry [19], co-catalysis [9,12,20,21,22,23,24], or in situ derivatization [9,12,25,26,27,28,29], the hydroxy group or its protic byproducts from in situ derivatization make alcohols incompatible to acidic proton sensitive processes. Alternatively, XEC using alcohol derivatives such as triflates [27,30], sulfonates [31,32,33], acetates [34,35], pivalates [36,37], and oxalates [38,39,40], etc., has been reported but is still relatively undeveloped, in particular, in coupling with counterparts derived from anilines [12,41]. We have recently reported Ni-catalyzed Mn-mediated denitrogenative XEC of benzotriazinones, an easily accessible anthranilic acid derivative [42], with alkyl halides to afford ortho-alkylated secondary benzamides both in air- and moisture-free solution [43] and under air-tolerant liquid-assisted grinding (LAG) conditions [44,45]. However, the air-tolerant LAG conditions were less effective for the corresponding alkyl tosylates, due to the protodenitrogenation of benzotriazinones as well as the slow radical formation vs. the fast hydrolysis of tosylates. Although preliminary experiments indicated that modest yields could possibly be obtained from solution reaction in DMA under rigorous air- and moisture-free conditions, unfortunately, the requirement of an expensive anhydrous strong polar solvent would hamper the potential applications of the XEC protocol using alkyl tosylates, the most economical and easy-to-handle alcohol derivative. It has been reported that the reactivities of benzotriazinones could be tuned by their N-substituents [42,46,47]. We envisioned that the protodenitrogenation of benzotriazinones could possibly be suppressed by tuning their N-substituents; meanwhile, the slow radical formation from alkyl tosylates could be circumvented by in situ conversion into the more reactive halides. Herein, we report an efficient Ni-catalyzed, Mn-mediated denitrogenative XEC of N-alkyl-1,2,3 benzotriazinones with alkyl tosylates and mesylates in inexpensive non-anhydrous DMA by using TBAI as co-catalyst.

2. Results and Discussion

N-Substituted benzotriazinones were prepared by following the previously reported procedures [43,48] (see Supplementary Materials for details) (Scheme 1).
Initially, a reaction of N-methyl benzotriazinone (1a) with methyl tosylate (2a) was selected as the model to develop an efficient denitrogenative XEC of benzotriazinones with alkyl sulfonates tolerant to non-anhydrous solvent based on the following considerations. (1) Benzotriazinones bearing an electron-neutral alkyl substituent at N(3) have shown a good balance between their stability and reactivity in XEC with alkyl/aryl halides [43,44,45,48]. (2) Selective and efficient installation of a methyl group at specific positions of an organic molecule is very important in medicinal chemistry, because of the so-called magic methyl effect [49,50,51]. (3) Methyl tosylate is more user-friendly than methyl halides (X = Cl, Br, I) under the most current conditions for XEC because of the toxicity and low boiling points of the latter compounds [52]. To minimize the deleterious effects of water residue, commercial non-anhydrous DMA was dried over a 4 Å molecular sieve (MS) overnight prior to use. Unfortunately, serious protodenitrogenation still took place in the MS-dried non-anhydrous DMA to give N-methylbenzamide in 26–29% yields using our previously developed 2,2′-bipyridine (bpy) supported nickel catalyst system [43], with 10 mol% NiCl2(bpy)/KI in the presence of 25 mol% trimethylsilyl chloride (TMSCl) as an activator for Mn powders at 80–100 °C (Scheme 2).
In addition, the 1H NMR spectrum showed that the XEC product 3aa isolated by chromatography was still contaminated by the dimethylation side product, N, N, 2-trimethyl benzamide (4aa, 8–12%), which was confirmed by 1H NMR spectroscopy and GC-MS analyses of the crude products (See Supplementary Materials). The chromatographically inseparable side product 4aa makes the reaction with MeOTs 2a inconvenient as the model since the recrystallization after chromatography had to be used to obtain a spectroscopically pure product 3aa. Fortunately, when ethyl tosylate 2b was used in place of methyl 2a under the otherwise identical conditions, the N-alkylation side-reaction was not observed. Therefore, ethyl tosylate (2b) was used in the following condition optimization.
A control experiment indicated both bromide and iodide salts could serve as the co-catalyst, although a significantly smaller promotion was observed from 10 mol% KBr than KI (Table 1, entries 1–4). We have reported that some quaternary ammonium halides could promote denitrogenative Sonogashira coupling of N-tosyl aryltriazenes [53], a sort of closely related noncyclic triazenes; therefore, we tested the effectiveness of quaternary ammonium co-catalyst, e.g., tetrabutyl ammonium bromide (TBAB) and iodide (TBAI). Although TBAB performed much less efficiently, to our delight, the yield of 3ab increased to 86% with 10 mol% TBAI as the co-catalyst. The reaction could still proceed smoothly even with 3 mol% TBAI at a lower temperature, i.e., 60–80 °C (Table 1, entries 5–11). The loading of nickel catalyst NiCl2(bpy) could also be reduced to 5 mol% without decreasing 3ab yield, although the reaction became slower to some extent (Table 1, entries 10 and 12). Direct combination of NiCl2 with bpy worked as effectively as NiCl2(bpy), making the catalyst system convenient to use. In fact, a combination of 5 mol% NiCl2(DME) with 5 mol% bpy gave the highest yield (89%) among the tested nickel precursors, e.g., NiCl2 (85%), Ni(OAc)2 (70%), and Ni(acac)2 (68%). 2,2-Bipyridine (bpy, 85% at 3 mol% catalyst loading) has proven to be the choice of supporting ligand for nickel catalyst since 1,10-phenanthroline (phen, 71%) and 4,4′-bis(tert-butyl)-2,2′-bipyridine (dtbbpy, 26%) performed less efficiently (Table 1, entries 19–21). The model reaction could also proceed in DMF, giving 3ab in 74% yield while no reaction was observed in the other common solvents, e.g., DMSO, THF, DME, dioxane, and toluene, etc. The doses of TMSCl could be reduced to 5–10 mol%, while the reaction took place rather slowly in the absence of the activator (Table 1, entries 25–27). In sharp contrast, the use of 50 mol% TMSCl led to a lower yield (65%), possibly due to the formation of the less reactive ethyl chloride from tosylate 2b via OTs/Cl exchange (vide infra). The yield of 3ab could not be increased further with 2.0 equiv. tosylate 2b while 1.0 equiv. led to a lower yield (72%) (Table 1, entries 28 and 29). Based on these experiments, the optimal conditions for the Ni-catalyzed, Mn-mediated denitrogenative XEC of benzotriazinones with alkyl tosylates were set as 1.5 equiv. tosylate, 2.0 equiv. Mn powders as the reductant, with 10 mol% TMSCl as activator, and 5 mol% NiCl2(DME)/bpy as the catalyst in the presence of 3 mol% TBAI co-catalyst at 60 °C under N2 in non-anhydrous DMA dried over 4 Å MS overnight prior to use.
Tolerance of the model reaction to H2O content in the DMA solvent was investigated under the optimal conditions (Table 1, entries 30–32). With direct use of commercial non-anhydrous DMA (up to 500 ppm H2O), the model reaction could still proceed smoothly to give the XEC product 3ab in 86% yield. In fact, when the water content in the DMA was deliberately increased to 1000 ppm, the 3ab yield just slightly decreased to 81% while no reaction could take place in DMA containing 5000 ppm water.
Scope and limitations of the iodide/nickel co-catalyzed, Mn-mediated denitrogenative XEC of benzotriazinones with alkyl sulfonates were explored briefly (Figure 1). Besides the undesired N-methylation, methyl tosylate 2a appeared to be less effective than its homologues. In fact, spectroscopically pure (NMR) 3aa, as determined by 1H NMR spectroscopy, was obtained in only 29% yield by recrystallization in CH2Cl2/petroleum ether after column chromatography to remove the N-methylation side-product N, N, 2-trimethylbenzamide (4aa). Mesylates MeOMs (2a’) and EtOMs (2b’), albeit less reactive than tosylates, could still react effectively at a slightly higher temperature (80 °C), giving the methylation (3aa) and ethylation (3ab) products in 42% and 90% yields, respectively. The better result from the reaction of MeOMs (2a’) than MeOTs (2a) could possibly be attributed to its relatively lower reactivity in the undesired N-methylation. In fact, formation of 4aa decreased to <3% (1H NMR) in the reaction with MeOMs from about 10% with MeOTs.
A high chemoselectivity of Csp3-OTs vs. Csp3-Cl could be achieved since the reaction of 3-chloropropyl tosylate 3d with 1a gave 3ad in 84% yield while the Csp3-Br (2e) competed strongly. In addition, 1H NMR and GC-MS (see Supplementary Materials) showed Cl/Br/I scramble in the oily XEC product (3ae) from the reaction of 2e due to halo-exchange. The denitrogenative XEC-based benzylation of 1a gave 3ag and 3ah in very low yields (14–15%), although benzyl tosylates disappeared completely in about 2 h due to their serious dimerization. Allyl tosylate (2i) performed poorly under the optimal conditions since only trace XEC product could be detected in GC-MS analysis (see Supplementary Materials). Steric hindrance from alkyl tosylates could be overcome by slightly increasing the reaction temperature to 80 °C. For example, 2-ethylhexyl tosylate 2j reacted to afford 3aj in 33% (12 h) and 76% (8 h) yields at 60 °C and 80 °C, respectively. Similarly, secondary alkyl tosylates, e.g., isopropyl (2k) and sec-butyl (2l), also required 80 °C to react effectively.
Electronic and steric influences from the benzotriazinone counterpart were then investigated. The steric effects from the N-alkyl substituents appeared to be negligible since N-propyl (1b, 90%), N-isopropyl (1c, 89%), N-cyclichexyl (1d, 90%), N-2-methoxyethyl (1e, 87%), and N-benzyl (1f, 91%) benzotriazinones reacted as smoothly as the N-methyl one (1a). However, an electron-deficient alkyl group at N(3) in benzotriazinones, e.g., 2,2,2-trifluoroethyl (1i) and 2-ethoxy-2-oxoethyl (1j), led to serious proto-denitrogenation, thus resulting in low yields for the desired XEC product 3ib (22%) and 3jb (41%). In fact, N-(4-cyanobenzyl) benzotriazinone (1h, 72%, 4 h) gave a relatively lower yield than the corresponding benzyl one (1f, 91%, 4 h). The reaction of N-(4-formylbenzyl)benzotriazinone (1g, 24%, 10h) became sluggish, implying incompatibility of the CHO group with the catalyst system beside the electronic effects. Proto-denitrogenation became dominate for N-phenyl benzotriazinone 1k most likely because, similar to an electron-deficient alkyl group at the N(3) atom, the N/aryl conjugation could also decrease the stability of the key azanickelacycle intermediates in the catalytic cycle (vide infra). A mild electron-withdrawing group, e.g., 7-CO2Me (1l, 61%, 10 h), 6-F (1m, 88%, 10 h), and 6-Cl (1n, 80%, 10 h), or electron-donating one, e.g., 6-Me (1p, 76%, 12 h) and 6-OMe (1q, 76%, 12 h), on the core of benzotriazinones could be tolerated to a large extent. The CAr-Br bond competed seriously with the CAr-N in the triazene moiety, giving a rather complicated mixture. Surprisingly, a steric acceleration was observed from benzotriazinones in the reaction with 2b. For example, o-substituted 1r (8-OMe) and 1t (8-Me) reacted faster and afforded higher yields for 3rb (91%, 6 h) and 3tb (86%, 4 h) than their para-isomers 1p (6-Me, 76%, 12 h) and 1q (6-OMe, 76%, 12 h). Even 8-phenyl benzotriazinone (1s) could react smoothly to give the sterically demanding product 3sa in 84% yield (6 h). To the best of our knowledge, this steric acceleration has not been previously reported in transition-metal catalyzed transformations of benzotriazinones and would promise highly efficient access to 2-alkyl-2,3-disubstited benzamides.
The practical utility of iodide/nickel co-catalyzed Mn-mediated denitrogenative XEC was demonstrated by the gram-scale synthesis of 2-ethyl-N,3-dimethylbenzamide (3tb) under the optimal conditions (Scheme 3). The reaction of 3,8-dimethylbenzotriazinone (1t) with ethyl tosylate 2b (1.5 equiv.) at 10 mmol scale proceeded smoothly to afford 3tb in 84% yield in 8 h.
To unmistakably confirm the unique steric acceleration from benzotriazinones, a competing experiment using a 1:1 mixture of 6-OMe (1q) and 8-OMe (1r) isomers was carried out (Scheme 4). GC-MS analysis (see Supplementary Materials) of the reaction mixture at 4 h showed that almost all of the more steric isomer 1r was converted into XEC product 3rb (1r/3rb < 1/99) without detectable proto-denitrogenation while about one-third (33% GC area) of the less steric one 1q remained in the solution, producing 3qb in only 55% along with about 12% 3-methoxy-N-methylbenzamide from proto-denitrogenation. These results have not only confirmed the steric acceleration effect from the core of the benzotriazinone counterpart but also provide a clue to the rate-limiting steps in catalytic cycle (vide infra).
A radical clock experiment using cyclopropylmethyl tosylate gave the XEC products as a mixture of 1-(but-3-enyl)-N-methylbenzamide (51%) and its internal isomers (in total 12%, GC) as major products along with ~10% (1H NMR and GC) normal coupling one 1-(cyclopropylmethyl)-N-methylbenzamide (see Supplementary Materials), consistent with a caged radical process although a combination of a free radical process with a minor non-radical one could not be excluded (Scheme 5).
Based on the experimental results and the literature on Ni-catalyzed cross-coupling [6,12,14,43,54,55], a plausible mechanism is proposed for the iodide/nickel co-catalyzed, manganese-assisted denitrogenative cross-coupling of benzotriazinones with alkyl sulfonates (Scheme 6). Given the low catalytic efficiency in the absence of iodide co-catalyst, it is reasonable to propose that alkyl sulfonates should be converted into iodides at first and then follow the Ni(0-II-III-I-II) catalytic cycle for Ni-catalyzed denitrogenative XEC of benzotriazinones with alkyl halides. Denitrogenative oxidative addition of Ni(0) to CAr-N in benzotriazinones initiates the nickel catalysis to produce Ni(II) azanickelacycle; a subsequent single electron oxidation by alkyl radical generated from in situ-formed alkyl iodides leads to alkyl Ni(III) azanickelacycle. An aryl group or electron-deficient alkyl substituent at the N(3) atom of benzotriazinones decreases the stability of the subsequently formed Ni(II/III) azanickelacycle intermediates in the catalytic cycle, increasing the proto-denitrogenation by water residue in the system. Reductive elimination from the alkyl Ni(III) azanickelacycle could be sterically accelerated by 8-substitent in benzotriazinones because of the crowded environment around the Ni center [56,57,58], which should also improve the compatibility of the corresponding Ni(II/III) azanickelacycles to the protic source since the proto-denitrogenation was only observed from 6-OMe (1q) isomer in the competing reaction (vide supra). The observed steric acceleration from the 8-substituent at the core of benzotriazinones implies that there are sterically switchable rate-determining steps in the catalytic cycle.

3. Materials and Methods

3.1. General Information

All reactions were carried out under an N2 atmosphere unless otherwise stated. Chemicals obtained from commercial sources were used as received. The reaction progress was monitored by TLC. Column chromatography was performed on 300–400 mesh silica gel. 1H and 13C NMR spectra were recorded in CDCl3 at ambient temperature on a Bruker Avance Ⅲ (400 MHz) instrument (Bruker BioSpin GmbH, Rheinstetten, Germany). Coupling constants J are reported in Hz. Proton coupling patterns were described as singlet (s), doublet (d), triplet (t), quartet (q), and multiple (m). All new compounds were further characterized by high-resolution mass spectra (HRMS) using an Agilent mass spectrometer (HR-TOF-ESI). Melting points were determined on a digital melting point apparatus, and temperatures were uncorrected. All the known products were characterized by comparing their NMR with those reported in the literature, and the new compounds were further characterized by HRMS.

3.2. General Procedure for the Iodide/Nickel Co-Catalyzed Manganese-Mediated Denitrogenative Cross-Electrophile Coupling of Benzotriazinones with Alkyl Sulfonates

To a 25 mL dry flask, benzotriazinone (1.0 mmol, 1.0 equiv.), alkyl sulfonate (1.5 mmol, 1.5 equiv.), NiCl2(DME) (0.011 g, 0.05 mmol, 5 mol%), bpy (0.008 g, 0.05 mmol, 5 mol%), TBAI (0.011 g, 0.03 mmol, 3 mol%), and Mn powder (0.110 g, 2.0 mmol, 2.0 equiv.) were added. After replacement of the air in the flask with N2 using a standard Schlenk line, TMSCl (13 μL, 0.1 mmol, 10 mol%) and non-anhydrous DMA (dried over 4 Å MS, 3 mL) were added by syringe. The mixture was stirred at room temperature for 20 min and then heated at 60 °C (oil bath). The reaction progress was monitored by TLC until the consumption of 1 or for 12 h. Then, the reaction was quenched with 10% HCl (2 mL) and diluted and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over Na2SO4, filtered, and evaporated by rotavapor to give the crude product, which was purified by column chromatography on silica gel with petroleum ether/ethyl acetate eluent to afford product 3.
N,2-Dimethylbenzamide (3aa) [59] White solid (43.5 mg, 29%; 62.7 mg, 42% from MeOMs at 80 °C); m.p. = 75–77 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.31–7.26 (m, 2H), 7.20–7.14 (m, 2H), 5.99 (s, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.9, 136.5, 135.9, 130.9, 129.7, 126.7, 125.6, 26.5, 19.7.
2-Ethyl-N-methylbenzamide (3ab) [60] White solid (144.2 mg, 88%; 105.9 mg, 65% from EtOMs at 60 °C; 146.3 mg, 90% from EtOMs at 80 °C); m.p. = 92–93 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34–7.23 (m, 3H), 7.18–7.15 (t, J = 7.2 Hz, 1H), 5.96 (s, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.77 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.1, 142.1, 136.3, 129.7, 129.2, 126.7, 125.6, 26.4, 26.3, 15.7.
N-Methyl-2-(3-phenylpropyl)benzamide (3ac) [43] White solid (204.6 mg, 81%); m.p. = 80–82 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.32–7.24 (m, 4H), 7.21–7.14 (m, 5H), 5.80 (s, 1H), 2.89 (d, J = 5.2 Hz, 3H), 2.79 (t, J = 8.0 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.97–1.89 (m, 2H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.9, 142.2, 140.3, 136.5, 130.0, 129.7, 128.4, 128.3, 126.9, 125.8, 125.7, 35.7, 33.0, 32.8, 26.5.
2-(4-Chlorobutyl)-N-methylbenzamide (3ad) White solid (190.7 mg, 84%); m.p. = 36–38 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34–7.27 (m, 2H), 7.24–7.16 (m, 2H), 5.94 (s, 1H), 3.53 (t, J = 6.0 Hz, 2H), 2.95 (d, J = 5.2 Hz, 3H), 2.78 (t, J = 7.6 Hz, 2H), 1.82–1.71 (m, 4H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.9, 140.2, 136.4, 130.0, 129.9, 126.8, 126.0, 44.9, 32.3, 32.3, 28.7, 26.6. HRMS (ESI) m/z: [M + Na]+ calcd for C12H16ClNONa 248.0818; found 248.0820.
2-(6-Bromohexyl)-N-methylbenzamide (3ae) Yellow oil (118.0 mg (3ae with inseparable halo-exchange products) ~40%). 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34–7.29 (m, 2H), 7.23–7.16 (m, 2H), 5.82 (s, 1H), 3.39 (t, J = 6.8 Hz, 2H), 2.98 (d, J = 5.2 Hz, 2H), 2.76 (t, J = 8.0 Hz, 2H), 1.88–1.81 (m, 2H), 1.66–1.58 (m, 2H), 1.49–1.34 (m, 4H).
Ethyl 6-(2-(methylcarbamoyl)phenyl)hexanoate (3af) Yellow oil (216.0 mg, 78%). 1H NMR (400 MHz, CDCl3) δ(ppm): 7.33–7.28 (m, 2H), 7.22–7.15 (m, 2H), 5.95 (s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 2.96 (d, J = 4.8 Hz, 3H), 2.76 (t, J = 7.6 Hz, 2H), 2.27 (t, J = 7.6 Hz, 2H), 1.67–1.58 (m, 4H), 1.39–1.32 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 173.9, 171.0, 140.5, 136.4, 129.9, 129.6, 126.8, 125.7, 60.2, 34.2, 32.9, 31.0, 28.8, 26.5, 24.7, 14.2. HRMS (ESI) m/z: [M + Na]+ calcd for C16H23NO3Na 300.1576; found 300.1577.
2-Benzyl-N-methylbenzamide (3ag) [45] White solid (34.3 mg, 15%); m.p. = 108–110 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.33–7.30 (m, 2H), 7.26–7.20 (m, 4H), 7.18–7.14 (m, 3H), 5.69 (s, 1H), 4.15 (s, 2H), 2.81 (d, J = 4.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.8, 140.9, 138.9, 136.8, 130.9, 129.9, 129.0, 128.4, 127.1, 126.3, 126.1, 38.9, 26.5.
Methyl 2-(4-(methylcarbamoyl)benzyl)benzoate (3ah) [45] White solid (40.1 mg, 14%); m.p. = 139–141 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.91 (d, J = 8.4 Hz, 2H), 7.35–7.32 (m, 2H), 7.24–7.19 (m, 4H), 5.69 (s, 1H), 4.22 (s, 2H), 3.87 (s, 3H), 2.84 (d, J = 4.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.6, 167.2, 146.5, 138.4, 136.7, 131.1, 130.2, 129.8, 129.1, 128.1, 127.1, 126.7, 52.1, 39.0, 26.7.
2-(2-Ethylhexyl)-N-methylbenzamide (3aj) [43] Colorless oil (81.3 mg, 33%; 189.0 mg, 76% at 80 °C). 1H NMR (400 MHz, CDCl3) δ(ppm): 7.32–7.27 (m, 2H), 7.20–7.15 (m, 2H), 5.81 (s, 1H), 2.95 (d, J = 4.8 Hz, 3H), 2.76–2.67 (m, 2H), 1.57–1.51 (m, 1H), 1.29–1.19 (m, 8H), 0.88–0.81 (m, 6H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.2, 139.9, 137.1, 130.8, 129.3, 126.8, 125.6, 40.9, 37.2, 32.5, 28.8, 26.5, 25.5, 23.0, 14.1, 10.7.
2-(sec-Butyl)-N-methylbenzamide (3ak) [43] White solid (59.7 mg, 31%; 126.0 mg, 66% at 80 °C); m.p. = 77–79 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.37–7.33 (m, 1H), 7.30–7.23 (m, 2H), 7.17–7.13 (m, 1H), 5.88 (s, 1H), 3.06–2.97 (m, 1H), 2.94 (d, J = 4.8 Hz, 3H), 1.67–1.54 (m, 2H), 1.22 (d, J = 6.8 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.3, 145.5, 137.0, 129.8, 126.5, 126.3, 125.5, 37.0, 31.0, 26.6, 22.2, 12.3.
2-iso-Propyl-N-methylbenzamide (3al) [61] White solid (62.1 mg, 35%; 130.8 mg, 74% at 80 °C); m.p. = 91–93 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.38–7.33 (m, 2H), 7.27–7.23 (m, 1H), 7.18–7.14 (m, 1H), 5.88 (s, 1H), 3.34–3.27(m, 1H), 2.95 (d, J = 4.8 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.3, 146.5, 136.2, 129.8, 126.5, 125.9, 125.5, 29.9, 26.5, 24.1.
2-Ethyl-N-propylbenzamide (3bb) [62] Colorless oil (171.5 mg, 90%). 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34–7.28 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.19–7.15 (m, 1H), 5.91 (s, 1H), 3.39–3.34 (m, 2H), 2.78 (q, J = 7.6 Hz, 2H), 1.66–1.56 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.4, 142.0, 136.6, 129.7, 129.2, 126.6, 125.6, 41.5, 26.2, 22.8, 15.8, 11.4.
2-Ethyl-N-isopropylbenzamide (3cb) [63] White solid (170.3 mg, 89%); m.p. = 74–75 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34–7.28 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 5.63 (s, 1H), 4.31–4.22 (m, 1H), 2.79 (q, J = 7.6 Hz, 2H), 1.25–1.21 (m, 9H). 13C NMR (100 MHz, CDCl3) δ(ppm): 169.5, 142.0, 136.7, 129.7, 129.3, 126.6, 125.6, 41.7, 26.3, 22.7, 15.8.
N-Cyclohexyl-2-ethylbenzamide (3db) [62] White solid (208.2 mg, 90%); m.p. = 134–136 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.34–7.28 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 5.67 (d, J = 6.0 Hz, 1H), 4.01–3.92 (m, 1H), 2.79 (q, J = 7.6 Hz, 2H), 2.05–2.01 (m, 2H), 1.76–1.71 (m, 2H), 1.67–1.63 (m, 1H), 1.48–1.37 (m, 2H), 1.25–1.16 (m, 6H). 13C NMR (100 MHz, CDCl3) δ(ppm): 169.4, 142.0, 136.8, 129.7, 129.3, 126.6, 125.6, 48.5, 33.1, 26.3, 25.5, 24.9, 15.8.
2-Ethyl-N-(2-methoxyethyl)benzamide (3eb) Yellow oil (181.0 mg, 87%). 1H NMR (400 MHz, CDCl3) δ(ppm): 7.35–7.32 (m, 2H), 7.27–7.24 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.22 (s, 1H), 3.63–3.59 (m, 2H), 3.56–3.53 (m, 2H), 3.36 (s, 3H), 2.80 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.3, 142.0, 136.2, 129.8, 129.3, 126.7, 125.6, 71.0, 58.6, 39.4, 26.2, 15.8. HRMS (ESI) m/z: [M + H]+ calcd for C12H18NO2 208.1338; found 208.1337.
N-Benzyl-2-ethylbenzamide (3fb) [60] White solid (218.0 mg, 91%); m.p. = 94–96 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.35–7.24 (m, 8H), 7.17 (t, J = 7.6 Hz, 1H), 6.12 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.1, 142.4, 138.3, 136.0, 130.0, 129.4, 128.7, 127.8, 127.5, 126.7, 125.7, 43.8, 26.3, 15.9.
2-Ethyl-N-(4-formylbenzyl)benzamide (3gb) White solid (63.2 mg, 24%); m.p. = 109–111 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 9.96 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.37–7.32 (m, 2H), 7.27–7.25 (m, 1H), 7.18 (t, J = 7.2 Hz, 1H), 6.45 (s, 1H), 4.65 (d, J = 6.0 Hz, 2H), 2.78 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 191.9, 170.4, 145.6, 142.3, 135.6, 135.4, 130.1, 130.0, 129.4, 128.0, 126.7, 125.6, 43.3, 26.2, 15.8. HRMS (ESI) m/z: [M + Na]+ calcd for C17H17NO2Na 290.1157; found 290.1156.
N-(4-Cyanobenzyl)-2-ethylbenzamide (3hb) White solid (189.9 mg, 72%); m.p. = 110–111 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.61 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.38–7.32 (m, 2H), 7.27–7.25 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.41 (s, 1H), 4.63 (d, J = 6.0 Hz, 2H), 2.78 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.4, 144.1, 142.5, 135.4, 132.4, 130.3, 129.6, 128.2, 126.7, 125.8, 118.8, 111.1, 43.2, 26.3, 15.9. HRMS (ESI) m/z: [M + Na]+ calcd for C17H16N2ONa 287.1160; found 287.1161.
2-Ethyl-N-(2,2,2-trifluoroethyl)benzamide (3ib) White solid (50.9 mg, 22%); m.p. = 68–69 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.39–7.35 (m, 1H), 7.32–7.26 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 6.22 (s, 1H), 4.09–4.01 (m, 2H), 2.76 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.3, 142.8, 134.9, 130.7, 129.8, 126.8, 125.9, 124.2 (q, J = 277.0 Hz), 40.9 (q, J = 34.0 Hz), 26.4, 15.9. 19F NMR (400 MHz, CDCl3) δ(ppm): −72.41 (t, J = 9.6 Hz). HRMS (ESI) m/z: [M + Na]+ calcd for C11H12NOF3Na 254.0769; found 254.0767.
Ethyl (2-ethylbenzoyl)glycinate (3jb) White solid (97.6 mg, 41%); m.p. = 49–51 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.40–7.34 (m 2H), 7.28–7.26 (m, 1H), 7.21 (t, J = 7.2 Hz, 1H), 6.34 (s, 1H), 4.24 (q, J = 7.2 Hz, 2H), 4.20 (d, J = 5.2 Hz, 2H), 2.82 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.4, 169.9, 142.6, 135.4, 130.3, 129.5, 127.0, 125.8, 61.6, 41.7, 26.3, 15.9, 14.2. HRMS (ESI) m/z: [M + Na]+ calcd for C13H17NO3Na 258.1106; found 258.1108.
2-Ethyl-N-phenylbenzamide (3kb) [62] White solid (24.8 mg, 11%); m.p. = 141–142 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.63–7.58 (m, 3H), 7.42–7.32(m, 4H), 7.30–7.28 (m, 1H), 7.24–7.20 (m, 1H), 7.13 (t, J = 7.2 Hz, 1H), 2.83 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ(ppm): 168.4, 142.6, 138.1, 136.3, 130.4, 129.7, 129.1, 126.7, 125.9, 124.6, 120.0, 26.4, 15.9.
Methyl 3-ethyl-4-(methylcarbamoyl)benzoate (3lb) White solid (135.1 mg, 61%); m.p. = 119–121 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.90 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 6.07 (s, 1H), 3.91 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H), 2.79 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.2, 166.7, 142.4, 140.5, 131.1, 130.3, 126.9, 126.8, 52.2, 26.6, 26.2, 15.5. HRMS (ESI) m/z: [M + Na]+ calcd for C12H15NO3Na 244.0950; found 244.0952.
2-Ethyl-5-fluoro-N-methylbenzamide (3mb) White solid (159.4 mg, 88%); m.p. = 92–93 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.21–7.17 (m, 1H), 7.04–6.96 (m, 2H), 6.05 (s, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 169.8, 160.5 (d, J = 244.0 Hz), 137.8 (d, J = 3.0 Hz), 137.6 (d, J = 6.0 Hz), 130.9 (d, J = 8.0 Hz), 116.5 (d, J = 21.0 Hz), 113.7(d, J = 23.0 Hz), 26.6, 25.6, 15.8. 19F NMR (400 MHz, CDCl3) δ(ppm): −117.14 (m). HRMS (ESI) m/z: [M + H]+ calcd for C10H13NOF 182.0981; found 182.0982.
5-Chloro-2-ethyl-N-methylbenzamide (3nb) White solid (158.3 mg, 80%); m.p. = 120–121 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.30–7.25 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.03 (s, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.72 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 169.6, 140.7, 137.7, 131.2, 130.8, 129.8, 126.8, 26.6, 25.8, 15.6. HRMS (ESI) m/z: [M + H]+ calcd for C10H13NOCl 198.0686; found 198.0689.
2-Ethyl-N,5-dimethylbenzamide (3pb) White solid (134.8 mg, 76%; 151.2 mg, 85% using 5 mol% NiCl2(DME)/10 mol% bpy); m.p. = 120–122 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.13–7.11 (m, 3H), 5.88 (s, 1H), 2.95 (d, J = 4.4 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.30 (s, 3H), 1.19 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.2, 139.1, 136.2, 135.1, 130.5, 129.2, 127.4, 26.5, 25.9, 20.8, 15.9. HRMS (ESI) m/z: [M + H]+ calcd for C11H16NO 178.1232; found 178.1233.
2-Ethyl-5-methoxy-N-methylbenzamide (3qb) White solid (147.3 mg, 76%; 169.6 mg, 88% using 5 mol% NiCl2(DME)/10 mol% bpy); m.p. = 108–110 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.14 (d, J = 8.4 Hz, 1H), 6.88–6.83 (m, 2H), 5.92 (s, 1H), 3.77 (s, 3H), 2.95 (d, J = 4.8 Hz, 3H), 2.69 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.8, 157.4, 137.1, 134.0, 130.4, 115.5, 112.2, 55.4, 26.6, 25.5, 16.0. HRMS (ESI) m/z: [M + H]+ calcd for C11H16NO2 194.1181; found 194.1182.
2-Ethyl-3-methoxy-N-methylbenzamide (3rb) White solid (176.2 mg, 91%); m.p. = 109–112 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.14 (t, J = 8.0 Hz, 1H), 6.89–6.87 (m, 2H), 5.86 (s, 1H), 3.83(s, 3H), 2.94 (d, J = 4.8 Hz, 3H), 2.71 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.0, 157.7, 137.9, 130.6, 126.6, 118.8, 111.5, 55.5, 26.4, 20.5, 14.8. HRMS (ESI) m/z: [M + H]+ calcd for C11H16NO2 194.1181; found 194.1182.
2-Ethyl-N-methyl-[1,1′-biphenyl]-3-carboxamide (3sb) White solid (201.2 mg, 84%); m.p. = 134–136 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.41–7.35 (m, 3H), 7.29–7.26 (m, 3H), 7.21–7.20 (m, 2H), 5.96 (s, 1H), 2.98 (d, J = 4.8 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 0.96 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.6, 143.1, 141.6, 139.6, 137.4, 131.6, 129.1, 128.1, 127.0, 126.2, 125.4, 26.6, 23.2, 15.9. HRMS (ESI) m/z: [M + H]+ calcd for C16H18NO 240.1388; found 240.1387.
2-Ethyl-N,3-dimethylbenzamide (3tb) White solid (153.1 mg, 86%); m.p. = 72–74 °C. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.18–7.16 (m, 1H), 7.11–7.04 (m, 2H), 5.87 (s, 1H), 2.95 (d, J = 4.8 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.34 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ(ppm): 171.7, 140.0, 137.1, 136.8, 131.5, 125.4, 124.5, 26.4, 23.3, 19.2, 14.8. HRMS (ESI) m/z: [M + H]+ calcd for C11H16NO 178.1232; found 178.1234.

3.3. Procedure for Gram-Scale Synthesis of 2-Ethyl-N,3-Dimethylbenzamide (3tb)

To a 100 mL dry flask, 3,8-dimethylbenzotriazinone (1t, 1.752 g, 10.0 mmol, 1.0 equiv.), NiCl2(DME) (0.110 g, 0.5 mmol, 5 mol%), bpy (0.078 g, 0.5 mmol, 5 mol%), TBAI (0.110 g, 0.3 mmol, 3 mol%), and Mn powder (1.100 g, 20.0 mmol, 2.0 equiv.) were added. After replacement of the air in the flask with N2 using a standard Schlenk line, non-anhydrous DMA (dried over 4 Å MS, 30 mL), ethyl tosylate (2b, 3.000 g, 15.0 mmol, 1.5 equiv.), and TMSCl (130 μL, 1.0 mmol, 10 mol%) were added by syringe. The mixture was stirred at room temperature for 30 min and then heated at 60 °C (oil bath) for 8 h. After being cooled to room temperature, 5% HCl (20 mL) was added to quench the reaction. The mixture was filtered to remove insoluble solids. The filtrate was diluted and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over Na2SO4, filtered, and evaporated by rotavapor to give the crude product, which was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (3:1) eluent to afford product 3tb 1.478 g (84%).

4. Conclusions

In summary, an efficient denitrogenative XEC of N-alkyl-1,2,3-benzotriazinones with alkyl tosylates and mesylates has been effected in inexpensive non-anhydrous DMA by using 5 mol% NiCl2(DME)/bpy catalyst in the presence of 3 mol% TBAI co-catalyst to convert sulfonates into iodides in situ. The stabilizing effect of the electron-neutral/-rich N-alkyl groups in benzotriazinones and the in situ conversion of alkyl sulfonates into iodides have been proposed to be the key for the compatibility to water residue in non-anhydrous DMA solvent. An optimal condition has been established, under which the scope and limitations of the protocol have been briefly explored, showing a large electronic effect from the N-substituents in benzotriazinones while their steric hindrance could be well tolerated. In fact, an unexpected steric acceleration has been observed from the core of benzotriazinones, not only promising highly efficient access to 2-alkyl-2,3-disubstituted benzamides from readily accessible substrates but also implying sterically switchable rate-determining steps in the catalytic cycle. Mesylates appeared to be as usable as tosylates in the iodide/nickel co-catalyzed XEC with benzotriazinones and even better in the case of methylation. In addition, good tolerance to up to 1000 ppm water content in DMA solvent makes the protocol more practical and economical, in particular if conducted at scale.

Supplementary Materials

The following Supplementary Materials can be downloaded at https://www.mdpi.com/article/10.3390/molecules30112397/s1: Copies of 1H & 13C NMR spectra of products; HRMS for all new compounds and GC-MS data mentioned in the text.

Author Contributions

Conceptualization, G.Z.; methodology, Y.H. and X.Z.; investigation, Y.H. and X.Z.; writing—original draft preparation, Y.H.; writing—review and editing, G.Z.; supervision, G.Z.; project administration, G.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are reported in this paper and the Supplementary Materials.

Acknowledgments

Support from ECUST are gratefully acknowledged.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Knappke, C.E.I.; Grupe, S.; Gartner, D.; Corpet, M.; Gosmini, C.; Jacobi von Wangelin, A. Reductive cross-coupling reactions between two electrophiles. Chem. Eur. J. 2014, 20, 6828–6842. [Google Scholar] [CrossRef] [PubMed]
  2. Moragas, T.; Correa, A.; Martin, R. Metal-catalyzed reductive coupling reactions of organic halides with carbonyl-type compounds. Chem. Eur. J. 2014, 20, 8242–8258. [Google Scholar] [CrossRef] [PubMed]
  3. Weix, D.J. Methods and mechanisms for cross-electrophile coupling of Csp2 halides with alkyl electrophiles. Acc. Chem. Res. 2015, 48, 1767–1775. [Google Scholar] [CrossRef]
  4. Richmond, E.; Moran, J. Recent advances in nickel catalysis enabled by stoichiometric metallic reducing agents. Synthesis 2018, 50, 499–513. [Google Scholar] [CrossRef]
  5. Pang, X.; Peng, X.; Shu, X.-Z. Reductive cross-coupling of vinyl electrophiles. Synthesis 2020, 52, 3751–3763. [Google Scholar] [CrossRef]
  6. Diccianni, J.; Lin, Q.; Diao, T. Mechanisms of nickel-catalyzed coupling reactions and applications in alkene functionalization. Acc. Chem. Res. 2020, 53, 906–919. [Google Scholar] [CrossRef]
  7. Liu, J.; Ye, Y.; Sessler, J.L.; Gong, H. Cross-electrophile couplings of activated and sterically hindered halides and alcohol derivatives. Acc. Chem. Res. 2020, 53, 1833–1845. [Google Scholar] [CrossRef]
  8. Pang, X.; Su, P.-F.; Shu, X.-Z. Reductive cross-coupling of unreactive electrophiles. Acc. Chem. Res. 2022, 55, 2491–2509. [Google Scholar] [CrossRef] [PubMed]
  9. Pang, X.; Shu, X.-Z. Reductive deoxygenative functionalization of alcohols by first-row transition metal catalysis. Chin. J. Chem. 2023, 41, 1637–1652. [Google Scholar] [CrossRef]
  10. Gong, Y.; Hu, J.; Qiu, C.; Gong, H. Insights into recent nickel-catalyzed reductive and redox C-C coupling of electrophiles, C(sp3)-H bonds and alkenes. Acc. Chem. Res. 2024, 57, 1149–1162. [Google Scholar] [CrossRef]
  11. Lei, J.; Yu, S.; Xu, Z.-G. Cross-electrophile couplings (XECs) between similar electrophile reagents. Chin. J. Chem. 2024, 42, 3518–3532. [Google Scholar] [CrossRef]
  12. Ehehalt, L.E.; Beleh, O.M.; Priest, I.C.; Mouat, J.M.; Olszewski, A.K.; Ahern, B.N.; Cruz, A.R.; Chi, B.K.; Castro, A.J.; Kang, K.; et al. Cross-electrophile coupling: Principles, methods, and applications in synthesis. Chem. Rev. 2024, 124, 13397–13569. [Google Scholar] [CrossRef]
  13. Everson, D.A.; Shrestha, R.; Weix, D.J. Nickel-catalyzed reductive cross-coupling of aryl halides with alkyl halides. J. Am. Chem. Soc. 2010, 132, 920–921. [Google Scholar] [CrossRef] [PubMed]
  14. Everson, D.A.; Jones, B.A.; Weix, D.J. Replacing conventional carbon nucleophiles with electrophiles: Nickel-catalyzed reductive alkylation of aryl bromides and chlorides. J. Am. Chem. Soc. 2012, 134, 6146–6159. [Google Scholar] [CrossRef]
  15. Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Nickel-catalyzed reductive cross-coupling of unactivated alkyl halides. Org. Lett. 2011, 13, 2138–2141. [Google Scholar] [CrossRef] [PubMed]
  16. Wang, S.; Qian, Q.; Gong, H. Nickel-catalyzed reductive coupling of aryl halides with secondary alkyl bromides and allylic acetate. Org. Lett. 2012, 14, 3352–3355. [Google Scholar] [CrossRef]
  17. Durandetti, M.; Nédélec, J.-Y.; Périchon, J. Nickel-catalyzed direct electrochemical cross-coupling between aryl halides and activated alkyl halides. J. Org. Chem. 1996, 61, 1748–1755. [Google Scholar] [CrossRef]
  18. Durandetti, M.; Gosmini, C.; Périchon, J. Ni-catalyzed activation of α-chloroesters: A simple method for the synthesis of α-arylesters and β-hydroxyesters. Tetrahedron 2007, 63, 1146–1153. [Google Scholar] [CrossRef]
  19. Li, Z.; Sun, W.; Wang, X.; Li, L.; Zhang, Y.; Li, C. Electrochemically enabled, nickel-catalyzed dehydroxylative cross-coupling of alcohols with aryl halides. J. Am. Chem. Soc. 2021, 143, 3536–3543. [Google Scholar] [CrossRef]
  20. Xie, H.; Guo, J.; Wang, Y.-Q.; Wang, K.; Guo, P.; Su, P.-F.; Wang, X.; Shu, X.-Z. Radical dehydroxylative alkylation of tertiary alcohols by Ti catalysis. J. Am. Chem. Soc. 2020, 142, 16787–16794. [Google Scholar] [CrossRef]
  21. Dong, Z.; MacMillan, D.W.C. Metallaphotoredox-enabled deoxygenative arylation of alcohols. Nature 2021, 598, 451–456. [Google Scholar] [CrossRef] [PubMed]
  22. Xie, H.; Wang, S.; Wang, Y.; Guo, P.; Shu, X.-Z. Ti-catalyzed reductive dehydroxylative vinylation of tertiary alcohols. ACS Catal. 2022, 12, 1018–1023. [Google Scholar] [CrossRef]
  23. Intermaggio, N.E.; Millet, A.; Davis, D.L.; MacMillan, D.W.C. Deoxytrifluoromethylation of alcohols. J. Am. Chem. Soc. 2022, 144, 11961–11968. [Google Scholar] [CrossRef] [PubMed]
  24. Xiong, W.; Kang, T.; Li, F.; Liao, H.; Yan, Y.; Dong, J.; Li, G.; Xue, D. Ni-catalyzed deoxygenative cross-coupling of alcohols with aryl chlorides via an organic photoredox process. ACS Catal. 2024, 14, 14089–14097. [Google Scholar] [CrossRef]
  25. Lin, Q.; Ma, G.; Gong, H. Ni-catalyzed formal cross-electrophile coupling of alcohols with aryl halides. ACS Catal. 2021, 11, 14102–14109. [Google Scholar] [CrossRef]
  26. Guo, P.; Wang, K.; Jin, W.-J.; Xie, H.; Qi, L.; Liu, X.-Y.; Shu, X.-Z. Dynamic kinetic cross-electrophile arylation of benzyl alcohols by nickel catalysis. J. Am. Chem. Soc. 2021, 143, 513–523. [Google Scholar] [CrossRef]
  27. Ma, W.-Y.; Han, G.-Y.; Kang, S.; Pang, X.; Liu, X.-Y.; Shu, X.-Z. Cobalt-catalyzed enantiospecific dynamic kinetic cross-electrophile vinylation of allylic alcohols with vinyl triflates. J. Am. Chem. Soc. 2021, 143, 15930–15935. [Google Scholar] [CrossRef]
  28. Chi, B.K.; Widness, J.K.; Gilbert, M.M.; Salgueiro, D.C.; Garcia, K.J.; Weix, D.J. In-situ bromination enables formal cross-electrophile coupling of alcohols with aryl and alkenyl halides. ACS Catal. 2022, 12, 580–586. [Google Scholar] [CrossRef]
  29. Ahern, B.N.; Weix, D.J. One-pot chlorination and cross-electrophile coupling of alcohols with aryl chlorides. Org. Lett. 2025, 27, 1164–1169. [Google Scholar] [CrossRef]
  30. Duan, J.; Du, Y.-F.; Pang, X.; Shu, X.-Z. Ni-catalyzed cross-electrophile coupling between vinyl/aryl and alkyl sulfonates: Synthesis of cycloalkenes and modification of peptides. Chem. Sci. 2019, 10, 8706–8712. [Google Scholar] [CrossRef]
  31. Liang, Z.; Xue, W.; Lin, K.; Gong, H. Nickel-catalyzed reductive methylation of alkyl halides and acid chlorides with methyl p-tosylate. Org. Lett. 2014, 16, 5620–5623. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, J.; Zhao, J.; Gong, H. Nickel-catalyzed methylation of aryl halides/tosylates with methyl tosylate. Chem. Commun. 2017, 53, 10180–10183. [Google Scholar] [CrossRef]
  33. Komeyama, K.; Michiyuki, T.; Osaka, I. Nickel/cobalt-catalyzed C(sp3)-C(sp3) cross-coupling of alkyl halides with alkyl tosylates. ACS Catal. 2019, 9, 9285–9291. [Google Scholar] [CrossRef]
  34. Anka-Lufford, L.L.; Prinsell, M.R.; Weix, D.J. Selective cross-coupling of organic halides with allylic acetates. J. Org. Chem. 2012, 77, 9989–10000. [Google Scholar] [CrossRef]
  35. He, R.-D.; Bai, Y.; Han, G.-Y.; Zhao, Z.-Z.; Pang, X.; Pan, X.; Liu, X.-Y.; Shu, X.-Z. Reductive alkylation of alkenyl acetates with alkyl bromides by nickel catalysis. Angew. Chem. Int. Ed. 2022, 61, e202114556. [Google Scholar] [CrossRef] [PubMed]
  36. Konev, M.O.; Hanna, L.E.; Jarvo, E.R. Intra- and intermolecular nickel-catalyzed reductive cross-electrophile coupling reactions of benzylic esters with aryl halides. Angew. Chem. Int. Ed. 2016, 55, 6730–6733. [Google Scholar] [CrossRef]
  37. Tao, X.; Chen, Y.; Guo, J.; Wang, X.; Gong, H. Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine. Chem. Sci. 2021, 12, 220–226. [Google Scholar] [CrossRef] [PubMed]
  38. Yan, X.-B.; Li, C.-L.; Jin, W.-J.; Guo, P.; Shu, X.-Z. Reductive coupling of benzyl oxalates with highly functionalized alkyl bromides by nickel catalysis. Chem. Sci. 2018, 9, 4529–4534. [Google Scholar] [CrossRef]
  39. Gao, M.; Sun, D.; Gong, H. Ni-catalyzed reductive C-O bond arylation of oxalates derived from α-hydroxy esters with aryl halides. Org. Lett. 2019, 21, 1645–1648. [Google Scholar] [CrossRef]
  40. Ye, Y.; Chen, H.; Sessler, J.L.; Gong, H. Zn-mediated fragmentation of tertiary alkyl oxalates enabling formation of alkylated and arylated quaternary carbon centers. J. Am. Chem. Soc. 2019, 141, 820–824. [Google Scholar] [CrossRef]
  41. He, R.-D.; Li, C.-L.; Pan, Q.-Q.; Guo, P.; Liu, X.-Y.; Shu, X.-Z. Reductive coupling between C–N and C–O electrophiles. J. Am. Chem. Soc. 2019, 141, 12481–12486. [Google Scholar] [CrossRef] [PubMed]
  42. Doraghi, F.; Karimian, S.; Larijani, B.; Mahdavi, M. Recent advances in synthesis and transformations of 1,2,3-benzotriazinones. J. Organomet. Chem. 2024, 1013, 123156. [Google Scholar] [CrossRef]
  43. Wang, F.; Tong, Y.; Zou, G. Nickel-catalyzed, manganese-assisted denitrogenative cross-electrophile-coupling of benzotriazinones with alkyl halides for ortho-alkylated benzamides. Org. Lett. 2022, 24, 5741–5745. [Google Scholar] [CrossRef]
  44. Wang, H.; Ding, W.; Zou, G. Mechanoredox/nickel co-catalyzed cross electrophile coupling of benzotriazinones with alkyl (pseudo)halides. J. Org. Chem. 2023, 88, 12891–12901. [Google Scholar] [CrossRef] [PubMed]
  45. Zhang, X.; Hong, Y.; Zou, G. Liquid-assisted grinding enables efficient Ni-catalyzed, Mn-mediated denitrogenative cross-electrophile coupling of benzotriazinones with benzyl chlorides. Molecules 2025, 30, 1060. [Google Scholar] [CrossRef]
  46. Xü, M.; Xü, K.; Zou, G. Improved palladium catalysis in Suzuki-type coupling of benzotriazinones for o-aryl/alkenyl benzamides. Adv. Synth. Catal. 2024, 366, 2623–2628. [Google Scholar] [CrossRef]
  47. Wang, F.; Hong, Y.; Zhang, X.; Zou, G. A sequential olefin hydroboration/Suzuki coupling for denitrogenative alkylation of benzotriazinones with α-olefins. J. Organomet. Chem. 2024, 1022, 123383. [Google Scholar] [CrossRef]
  48. Lin, T.; Wang, Y.-E.; Cui, N.; Li, M.; Wang, R.; Bai, J.; Fan, Y.; Xiong, D.; Xue, F.; Walsh, P.J.; et al. Nickel-catalyzed cross-electrophile coupling of 1,2,3-Benzotriazin-4(3H)-ones with aryl bromides. J. Org. Chem. 2022, 87, 16567–16577. [Google Scholar] [CrossRef]
  49. Barreiro, E.J.; Kummerle, A.E.; Fraga, C.A. The methylation effect in medicinal chemistry. Chem. Rev. 2011, 111, 5215–5246. [Google Scholar] [CrossRef]
  50. Schönherr, H.; Cernak, T. Profound methyl effects in drug discovery and a call for new C-H methylation reactions. Angew. Chem. Int. Ed. 2013, 52, 12256–12267. [Google Scholar] [CrossRef]
  51. Pinheiro, P.d.S.M.; Franco, L.S.; Fraga, C.A.M. The magic methyl and its tricks in drug discovery and development. Pharmaceuticals 2023, 16, 1157–1179. [Google Scholar] [CrossRef] [PubMed]
  52. Pearson, R.G.; Figdore, P.E. Relative reactivities of methyl iodide and methyl tosylate with transition-metal nucleophiles. J. Am. Chem. Soc. 1980, 102, 1541–1547. [Google Scholar] [CrossRef]
  53. Cao, J.; Ding, W.; Zou, G. Tetrabutylammonium bromide (TBAB)-promoted, Pd/Cu-catalyzed Sonogashira coupling of N-tosyl aryltriazenes. Org. Lett. 2024, 26, 4576–4580. [Google Scholar] [CrossRef]
  54. Dawson, G.A.; Spielvogel, E.H.; Diao, T. Nickel-catalyzed radical mechanisms: Informing cross-coupling for synthesizing non-canonical biomolecules. Acc. Chem. Res. 2023, 56, 3640–3653. [Google Scholar] [CrossRef] [PubMed]
  55. Lin, Q.; Spielvogel, E.H.; Diao, T. Carbon-centered radical capture at nickel(II) complexes: Spectroscopic evidence, rates, and selectivity. Chem 2023, 9, 1295–1308. [Google Scholar] [CrossRef]
  56. Ju, L.; Hu, C.T.; Diao, T. Strategies for promoting reductive elimination of bi- and bis-oxazoline ligated organonickel complexes. Organometallics 2022, 41, 1748–1753. [Google Scholar] [CrossRef]
  57. Wu, K.; Doyle, A.G. Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects. Nat. Chem 2017, 9, 779–784. [Google Scholar] [CrossRef]
  58. Newman-Stonebraker, S.H.; Smith, S.R.; Borowski, J.E.; Peters, E.; Gensch, T.; Johnson, H.C.; Sigman, M.S.; Doyle, A.G. Univariate classification of phosphine ligation state and reactivity in cross-coupling catalysis. Science 2021, 374, 301–308. [Google Scholar] [CrossRef]
  59. Sato, T.; Yoshida, T.; Al Mamari, H.H.; Ilies, L.; Nakamura, E. Manganese-catalyzed directed methylation of C(sp2)-H bonds at 25 °C with high catalytic turnover. Org. Lett. 2017, 19, 5458–5461. [Google Scholar] [CrossRef]
  60. Havlik, S.E.; Simmons, J.M.; Winton, V.J.; Johnson, J.B. Nickel-mediated decarbonylative cross-coupling of phthalimides with in situ generated diorganozinc reagents. J. Org. Chem. 2011, 76, 3588–3593. [Google Scholar] [CrossRef]
  61. Nozawa-Kumada, K.; Ono, K.; Kurosu, S.; Shigeno, M.; Kondo, Y. Copper-catalyzed aerobic benzylic C(sp3)-H lactonization of 2-alkylbenzamides via N-centered radicals. Org. Biomol. Chem. 2022, 20, 5948–5952. [Google Scholar] [CrossRef] [PubMed]
  62. Li, S.; Li, Y.; Zhu, R.; Bai, J.; Shen, Y.; Pan, M.; Li, W. Synthesis of ortho-methylated benzamides via palladium-catalyzed denitrogenative cross-coupling reaction of [1–3]-benzotriazin-4(3H)-ones with DABAL-Me3. Org. Lett. 2023, 25, 5443–5447. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, Q.; Ilies, L.; Yoshikai, N.; Nakamura, E. Cobalt-catalyzed coupling of alkyl Grignard reagent with Benzamide and 2-phenylpyridine derivatives through directed C-H bond activation under air. Org. Lett. 2011, 13, 3232–3234. [Google Scholar] [CrossRef] [PubMed]
Molecules 30 02397 sch001
Scheme 1. Synthesis of benzotriazinones via (a) diazotization/cyclization or (b) N-alkylation.
Scheme 1. Synthesis of benzotriazinones via (a) diazotization/cyclization or (b) N-alkylation.
Molecules 30 02397 sch001
Molecules 30 02397 sch002
Scheme 2. Preliminary results in denitrogenative XEC-based methylation of benzotriazinone 1a with methyl tosylate 2a.
Scheme 2. Preliminary results in denitrogenative XEC-based methylation of benzotriazinone 1a with methyl tosylate 2a.
Molecules 30 02397 sch002
Molecules 30 02397 g001
Figure 1. Scope and limitations. Reaction run at 1 mmol scale with respect to 1 with 1.5 equiv. 2 in 3 mL non-anhydrous DMA (dried over 4 Å MS). b At 80 °C and a small amount (~1.6%) of isomer in GC-MS (see Supplementary Materials). c Contaminated by halo-exchange. d Incomplete conversion of benzotriazinones. e Proto-denitrogenation product N-2,2,2-trifluoroethyl benzamide isolated in 42% yield. f N-phenyl benzamide isolated in 45% yield. g 5 mol% NiCl2(DME)/10 mol% bpy used.
Figure 1. Scope and limitations. Reaction run at 1 mmol scale with respect to 1 with 1.5 equiv. 2 in 3 mL non-anhydrous DMA (dried over 4 Å MS). b At 80 °C and a small amount (~1.6%) of isomer in GC-MS (see Supplementary Materials). c Contaminated by halo-exchange. d Incomplete conversion of benzotriazinones. e Proto-denitrogenation product N-2,2,2-trifluoroethyl benzamide isolated in 42% yield. f N-phenyl benzamide isolated in 45% yield. g 5 mol% NiCl2(DME)/10 mol% bpy used.
Molecules 30 02397 g001
Molecules 30 02397 sch003
Scheme 3. Gram-scale synthesis of 2-ethyl-N,3-dimethylbenzamide (3tb).
Scheme 3. Gram-scale synthesis of 2-ethyl-N,3-dimethylbenzamide (3tb).
Molecules 30 02397 sch003
Molecules 30 02397 sch004
Scheme 4. Competing reaction of the sterically different benzotriazinone isomers.
Scheme 4. Competing reaction of the sterically different benzotriazinone isomers.
Molecules 30 02397 sch004
Molecules 30 02397 sch005
Scheme 5. Product distribution in radical clock experiment.
Scheme 5. Product distribution in radical clock experiment.
Molecules 30 02397 sch005
Molecules 30 02397 sch006
Scheme 6. A plausible catalytic cycle for iodide/nickel co-catalyzed, manganese-mediated denitrogenative XEC of benzotriazinones with alkyl sulfonates.
Scheme 6. A plausible catalytic cycle for iodide/nickel co-catalyzed, manganese-mediated denitrogenative XEC of benzotriazinones with alkyl sulfonates.
Molecules 30 02397 sch006
Table 1. Optimization of conditions for the model reaction a.
Table 1. Optimization of conditions for the model reaction a.
Molecules 30 02397 i001
EntryCat. (mol%)mol% TMSClAdd. (mol%)Sol.T (℃)Time (h)Yield (%) b
1NiCl2(bpy) (10)25KI (10)DMA100276
2NiCl2(bpy) (10)25NaI (10)DMA100274
3NiCl2(bpy) (10)25/DMA100420
4NiCl2(bpy) (10)25KBr (10)DMA100436
5NiCl2(bpy) (10)25TBAB (10)DMA100441
6NiCl2(bpy) (10)25TBAI (10)DMA100186
7NiCl2(bpy) (10)25TBAI (3)DMA100183
8NiCl2(bpy) (10)25TBAI (1)DMA100377
9NiCl2(bpy) (10)25TBAI (3)DMA80285
10NiCl2(bpy) (10)25TBAI (3)DMA60486
11NiCl2(bpy) (10)25TBAI (3)DMA401056 c
12NiCl2(bpy) (5)25TBAI (3)DMA601086
13NiCl2(bpy) (3)25TBAI (3)DMA601474 c
14NiCl2/bpy (5)25TBAI (3)DMA601085
15Ni(OAc)2/bpy (5)25TBAI (3)DMA601270 c
16Ni(acac)2/bpy (5)25TBAI (3)DMA601268 c
17NiCl2(DME)/bpy (5)25TBAI (3)DMA601089
18NiCl2(PPh3)2(5) d25TBAI (3)DMA6014trace
19NiCl2(DME)/bpy (3)25TBAI (3)DMA601485
20NiCl2(DME)/dtbbpy(3)25TBAI (3)DMA601426 c
21NiCl2(DME)/phen (3)25TBAI (3)DMA601471 c
22NiCl2(DME)/bpy (5)25TBAI (3)DMF601274
23NiCl2(DME)/bpy (5)25TBAI (3)Sol.e6012NR
24NiCl2(DME)/bpy (5)50TBAI (3)DMA60865 c
25NiCl2(DME)/bpy (5)10TBAI (3)DMA601088
26NiCl2(DME)/bpy (5)5TBAI (3)DMA601283 c
27NiCl2(DME)/bpy (5)/TBAI (3)DMA601236 c
28NiCl2(DME)/bpy (5)10TBAI (3)DMA601072 c,f
29NiCl2(DME)/bpy (5)10TBAI (3)DMA60889 g
30NiCl2(DME)/bpy (5)10TBAI (3)DMA601086 h
31NiCl2(DME)/bpy (5)10TBAI (3)DMA601081 i
32NiCl2(DME)/bpy (5)10TBAI (3)DMA608NR j
a Reaction run at 1 mmol scale with respect to 1a with 1.5 equiv. 2b, in 3 mL non-anhydrous DMA dried over 4 Å MS. b Isolated yield. c Incomplete conversion of 1a. d Similarly, no reaction observed with NiCl2 or NiCl2(DME) without supporting ligand. e DMSO, THF, DME, dioxane, or toluene as solvent. f With 1.0 equiv. 2b. g With 2.0 equiv. 2b. h Non-anhydrous DMA without drying over MS. i DMA containing 1000 ppm (0.1% w/w) H2O. j DMA containing 5000 ppm (0.5% w/w) H2O.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Hong, Y.; Zhang, X.; Zou, G. Iodide/Nickel Co-Catalyzed Manganese-Mediated Denitrogenative Cross-Electrophile Coupling of Benzotriazinones with Alkyl Sulfonates. Molecules 2025, 30, 2397. https://doi.org/10.3390/molecules30112397

AMA Style

Hong Y, Zhang X, Zou G. Iodide/Nickel Co-Catalyzed Manganese-Mediated Denitrogenative Cross-Electrophile Coupling of Benzotriazinones with Alkyl Sulfonates. Molecules. 2025; 30(11):2397. https://doi.org/10.3390/molecules30112397

Chicago/Turabian Style

Hong, Yingying, Xuanxuan Zhang, and Gang Zou. 2025. "Iodide/Nickel Co-Catalyzed Manganese-Mediated Denitrogenative Cross-Electrophile Coupling of Benzotriazinones with Alkyl Sulfonates" Molecules 30, no. 11: 2397. https://doi.org/10.3390/molecules30112397

APA Style

Hong, Y., Zhang, X., & Zou, G. (2025). Iodide/Nickel Co-Catalyzed Manganese-Mediated Denitrogenative Cross-Electrophile Coupling of Benzotriazinones with Alkyl Sulfonates. Molecules, 30(11), 2397. https://doi.org/10.3390/molecules30112397

Article Metrics

Back to TopTop