Cobalt(II)-Catalyzed C−H Deuteriomethoxylation of Benzamides with CD₃OD

Abstract

Herein, we report a practical example of salicylaldehyde-based cobalt-catalyzed C−H deuteriomethoxylation of benzamides using deuterated methanol, facilitated by 8-aminoquinoline as a directing group. The salicylaldehyde-based cobalt catalyst is user-friendly, and the reaction exhibits broad functional group tolerance, accommodating benzene, heterocycles, and naphthalene rings. The synthetic utility of this methodology was demonstrated through a gram-scale reaction and the subsequent removal of the 8-aminoquinoline directing group to yield deuteriomethoxylated benzoic acid. Preliminary mechanistic studies suggest that C−H activation is not the rate-determining step of the reaction.

1. Introduction

Deuterium is one of the most important building blocks in synthetic and medicinal chemistry due to its higher efficiency and safety compared to its non-deuterated counterparts, which has drawn extensive research interest [1,2,3,4]. In 2017, Austedo (deutetrabenazine) became the first FDA-approved deuterated drug for the treatment of Huntington’s disease [5]. Because the −OCD₃ motif exhibits greater stability against biological oxidation, the deuterated methoxyl group is of extraordinary significance, being one of the most common fragments in numerous biologically active molecules. Examples include AVP-786 and SD-254 (Scheme 1a) [6,7,8].

In recent years, the strategy of using CD₃OD to introduce the −OCD₃ group has attracted significant attention. Most of these reactions employ pre-functionalized groups with strong bases or transition metals alongside aryl halides or aromatic hydrocarbons to achieve the introduction of the −OCD₃ group (Scheme 1b) [9,10,11,12,13]. In 2020, Shen’s group reported the C−H d3-alkoxylation of quinoxalinones using deuterated alcohols with iodobenzene as the catalyst (Scheme 1c) [14]. Subsequently, Shi’s group developed a Salox-Co(II) catalytic system that enabled C−H alkoxylation and d3-alkoxylation at the ortho-position of phosphoramides [15]. These successful results inspired us to extend this approach to the ortho−OCD₃ benzamide derivatives using CD₃OD. In this work, we used moderate amounts of CD₃OD to achieve a broader substrate scope and high yields with salicylaldehyde-Co(II) as the catalyst. Moreover, this method could be extended to heteroaromatic compounds (Scheme 1d) [16,17,18,19].

2. Results and Discussion

Initially, the reaction was carried out with benzamide assisted by 8-aminoquinoline 1a and CD₃OD 2 in the presence of 20 mol% of a Co-catalyst, and Ag₂O as the oxidant, at 100 °C under air in EtOAc (

Table 1. Optimization of reaction conditions ^a.

Entry	[Co]	Yield of 3a (%)
1	Co-1	58
2	Co-2	<5
3	Co-3	57
4	Co-4	30
5	Co-5	30
6	Co-6	18
7	Co-7	15
8	Co-8	11
9	Co-9	86
10	Co(OAc)2	20
11	CoCl2	<5
12	Co(acac)2	14
13	CoCO3	<5
14	Co(NO3)2·6H2O	<5

^a Reaction conditions: 1a (0.1 mmol), 2 (20 equiv), [Co] (20 mol%), Ag₂O (2 eq.), in 1 mL of EtOAc at 100 °C under air, 12 h. Yields determined by ¹H NMR using CH₂Br₂ as the internal standard.

). To our delight, a 58% yield of the desired product 3a was observed in the presence of the Co-1 catalyst (Table 1, entry 1). Encouraged by this result, a series of cobalt catalysts with different substituted salicylaldehydes were extensively screened (entries 1–9). Although most of the substituted salicylaldehydes could promote the reaction, the salicylaldehyde with a 6-Cl substituent gave the best results, probably due to its favorable electronic properties matching with the Co metal center (Table 1, entry 9). Other substituted salicylaldehydes, such as -OMe (entry 3, 6), -F (entry 4), and -NO₂ (entry 7), exhibited lower activity for this transformation. Some readily available Co-catalysts, such as Co(OAc)₂, CoCl₂, Co(acac)₂, CoCO₃, and Co(NO₃)₂·6H₂O, which are widely used in C−H activation, were also tested but showed low catalytic activity (entries 10–14). These results indicate that this transformation is a unique salicylaldehyde-promoted C−H deuteriomethoxylation of benzamides.

With the optimized reaction conditions, the generality of ortho-C−H deuteriomethoxylation of benzamides was examined (Scheme 2). To our delight, the reaction showed high efficiency and successfully provided the deuterated methoxylated benzamides. Substituted benzamides at the ortho-, meta-, or para-positions with diverse common groups such as F (1b, 1f, 1n), Me (1c, 1d, 1i), CO₂Me (1e), Cl (1g, 1m), Br (1h), MeO (1j), ^tBu (1k), I (1o), and Ph (1p) could react with CD₃OD (2) smoothly, generating the corresponding products in moderate to high yields (3b–3p, 55–84%). Notably, bisubstituted benzamides were also effective for this reaction, affording the desired deuterated methoxylated products in moderate to high yields (3q–3r, 62–81%). Moreover, naphthyl (1s), thienyl (1t), and indolyl (1u) benzamides exhibited good activity and delivered the desired products in yields of 54–86%.

To demonstrate the applicability of this protocol, the reaction with substrate 1a was performed at a gram scale, affording the deuteriomethoxylation product 3a in an 81% yield (1.14 g) (Scheme 3a). Additionally, removal of the 8-aminoquinoline directing group could be achieved according to the previous method (Scheme 3b) [20].

To gain insight into this transformation, a series of control experiments were performed. First, an intermolecular competition experiment was conducted to examine the electron-rich substrate 1j and its electron-deficient counterpart 1l. There was no difference between the yields of 3j and 3l, which proved that the electron effect had little influence on the deuteriomethoxylation reaction (Scheme 4a). Moreover, a one-pot competitive reaction between 1a and 1a-D₅ demonstrated a significant kinetic isotope effect, which indicated that the C(sp2)−H bond cleavage may not be the rate-limiting step (Scheme 4b). Finally, the H/D exchange experiment was carried out; 0% of the ortho-C−H bond was deuterated, and this result showed that the cleavage of the C−H bond was not a reversible process (Scheme 4c).

Based on these experimental results and the previous literature [15,21,22], a plausible mechanism is proposed (Scheme 5). First, the catalyst Co-9^(II) coordinates with substrate 1a. Next, intermediate A undergoes C−H activation to generate the trivalent five-membered cyclocobalt intermediate B, which then undergoes deuteroalkoxy transfer in the presence of Ag₂O and 2, forming tetravalent intermediate C. Finally, the reductive elimination of intermediate C and protodemetallation deliver the product 3a, completing the catalytic cycle.

3. Experimental Section

3.1. General Information

Unless otherwise noted, all chemicals were purchased from commercial suppliers and used without further purification. All solvents were treated prior to use according to the standard methods. All reactions were carried out in a flame-dried, screw-capped sealed tube under an atmosphere of air. Analytical thin-layer chromatography (TLC) was performed on silica gel plates with an F-254 indicator and compounds were visualized by irradiation with UV light. Column chromatography was carried out using silica gel (200–300 mesh) at increased pressure. The ¹H, ¹³C, and ¹⁹F spectroscopic data were recorded on Bruker Mercury Plus 400 MHz (Bruker Corporation, Billerica, Germany) or Bruker AVANCE NEO 500 MHz NMR spectrometers (Bruker Corporation, Billerica, Germany). Chemical shifts were reported in parts per million (ppm) relative to internal TMS for ¹H NMR data, and the deuterated solvent for ¹³C NMR data. ¹H NMR coupling constants were reported in Hz, and multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); dd (doublet of doublets); and td (triplet of doublets). High-resolution mass spectra (HRMS) were recorded on the Thermo Scientific Exactive Plus (orbitrap) equipped with an ESI ionization source.

3.2. General Procedure for Co-Catalyzed C−H Deuteriomethoxylation

In a 25 mL sealed tube, 1 mL of EtOAc and CD₃OD (2, 20 equiv.) was added to a mixture of 1 (0.1 mmol, 1 equiv.), Co-9 (7.5 mg, 20 mol%), and Ag₂O (46.3 mg, 2 equiv.), under air. The tube was sealed with a Teflon-lined cap and the reaction mixture was stirred at 100 °C by heating a metal mantle for 12 h. After cooling to room temperature, the mixture was filtered over celite, and concentrated under vacuum, and the residue was purified by preparative chromatography with a gradient eluent of petroleum ether, ethyl acetate, and dichloromethane to give the corresponding products, 3.

2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3a): 24 mg (yield: 84%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.34 (s,1H), 9.04 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 8.85–8.83 (m, 1H), 8.36 (dd, J = 7.6 Hz, 6.0 Hz, 1H), 8.15–8.12 (m, 1H), 7.59–7.55 (m, 1H), 7.51–7.47 (m, 2H), 7.45–7.40 (m, 1H), 7.15–7.11 (m, 1H), 7.06–7.03 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 163.7, 157.7, 157.2, 148.3, 139.3, 136.3, 135.8, 133.2, 132.4, 128.1, 127.6, 122.4, 121.5, 121.3, 117.4, 111.6, 77.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₂D₃N₂O₂⁺): 282.1316 found: 282.1317.

6-fluoro-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3b): 17 mg (yield: 56%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 9.00 (d, J = 6.4 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.63–7.55 (m, 2H), 7.46-7.43 (m, 1H), 7.35–7.31 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 163.6, 157.7, 148.4, 138.6, 136.5, 134.6, 132.4, 131.0, 128.1, 127.6, 126.8, 122.1, 122.0, 121.8, 117.2, 109.8, 77.4. ¹⁹F NMR (376 MHz, CDCl₃) δ −113.7 (dd, J = 12.0 Hz, 8.0 Hz). HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁D₃FN₂O₂⁺): 300.1222 found: 300.1220.

2-(methoxy-d3)-6-methyl-N-(quinolin-8-yl)benzamide (3c): 18 mg (yield: 61%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 9.01 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 8.75 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.17 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.62–7.53 (m, 2H), 7.45–7.42 (m, 1H), 7.32–7.28 (m, 1H), 6.90–6.83 (m, 2H), 2.45 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.7, 156.6, 148.3, 138.7, 137.6, 136.4, 134.9, 130.5, 128.1, 127.6, 127.1, 123.0, 121.8, 121.7, 116.9, 108.7, 77.4, 19.7. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₈H₁₄D₃N₂O₂⁺): 296.1473 found: 296.1472.

2-(methoxy-d3)-5-methyl-N-(quinolin-8-yl)benzamide (3d): 19 mg (yield: 63%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.36 (s, 1H), 9.04 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 8.87 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.20–8.11 (m, 2H), 7.60–7.43 (m, 3H), 7.29 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.0, 155.9, 148.4, 139.4, 136.4, 136.0, 133.7, 132.7, 130.7, 128.2, 127.7, 122.0, 121.5, 117.5, 111.8, 77.4, 20.6. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₈H₁₄D₃N₂O₂⁺): 296.1473 found: 296.1474.

4-(methoxy-d3)-3-(quinolin-8-ylcarbamoyl)phenyl acetate (3e): 27 mg (yield: 79%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.19 (s, 1H), 9.04–8.99 (m, 2H), 8.83 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.17–8.14 (m, 2H), 7.60–7.53 (m, 2H), 7.51–7.48 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.4, 162.6, 161.0, 148.4, 139.3, 136.4, 135.6, 134.7, 134.4, 128.2, 127.7, 123.5, 122.4, 121.8, 121.6, 117.5, 111.5, 77.4, 52.2. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₉H₁₄D₃N₂O₄⁺): 340.1371 found: 340.1382.

5-fluoro-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3f): 18 mg (yield: 58%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 9.01 (d, J = 7.2 Hz, 1H), 8.87 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00 (dd, J = 9.6 Hz, 2.8 Hz, 1H), 7.60–7.52 (m, 2H), 7.48–7.45 (m, 1H), 7.22–7.17 (m, 1H), 7.02 (dd, J = 8.8 Hz, 4.0 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 162.4, 158.5, 155.1 (d, J = 215.1 Hz), 148.5, 139.4, 136.4, 135.6, 128.2, 127.7, 123.9 (d, J = 7.1 Hz), 121.9, 121.6, 119.6 (d, J = 24.2 Hz), 118.7 (d, J = 25.3 Hz), 117.6, 113.1 (d, J = 7.1 Hz), 77.4. ¹⁹F NMR (376 MHz, CDCl₃) δ −122.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁FD₃N₂O₂⁺): 300.1222 found: 300.1230.

5-chloro-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3g): 22 mg (yield: 68%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.30 (s, 1H), 9.00 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 8.88 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.33 (d, J = 2.8, 1H), 8.19 (dd, J = 8.0 Hz, 1.6Hz, 1H), 7.60–7.56 (m, 1H), 7.54 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.50–7.44 (m, 2H), 7.02 (d, J = 8.8, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 162.3, 156.4, 148.5, 139.3, 136.4, 135.6, 132.8, 132.2, 128.2, 127.7, 126.8, 123.9, 121.9, 121.6, 117.6, 113.2, 77.4. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁D₃ClN₂O₂⁺): 316.0927 found: 316.0926.

5-bromo-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3h): 24 mg (yield: 68%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.29 (s, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.63–7.52 (m, 2H), 7.47–7.42 (m, 2H), 6.99 (dd, J = 8.8 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 162.2, 156.9, 148.5, 139.3, 136.4, 135.7, 135.5, 135.1, 128.2, 127.7, 124.2, 121.9, 121.6, 117.6, 114.0, 113.6, 77.4. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁D₃BrN₂O₂⁺): 360.0421 found: 360.0417.

2-(methoxy-d3)-4-methyl-N-(quinolin-8-yl)benzamide (3i): 20 mg (yield: 68%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.33 (s, 1H), 9.04 (d, J = 7.2 Hz, 1H), 8.85 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.59–7.43 (m, 3H), 6.94 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 2.42 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.9, 157.8, 148.3, 144.2, 139.4, 136.3, 136.0, 132.4, 128.2, 127.1, 122.2, 121.5, 121.4, 119.7, 117.4, 112.4, 77.4, 21.9. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₈H₁₄D₃N₂O₂⁺): 296.1473 found: 296.1474.

4-methoxy-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3j): 23 mg (yield: 73%), purification of the residue by preparative chromatography (PE/DCM/EA = 3/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.26 (s, 1H), 9.03 (d, J = 6.8 Hz, 1H), 8.87 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.16 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.60–7.56 (m, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.47–7.43 (m, 1H), 6.67 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.9, 163.7, 159.3, 148.3, 139.4, 136.4, 136.1, 134.2, 128.3, 127.8, 121.5, 121.3, 117.3, 115.5, 105.6, 98.8, 77.4, 55.7. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₈H₁₄D₃N₂O₃⁺): 312.1422 found: 312.1421.

4-(tert-butyl)-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3k): 24 mg (yield: 71%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.34 (s, 1H), 9.04 (d, J = 7.6 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.60–7.56 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46–7.43 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 1.38 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 163.9, 157.7, 157.4, 148.3, 139.4, 136.3, 136.0, 132.2, 128.2, 127.7, 121.5, 121.4, 119.8, 118.6, 117.4, 108.9, 77.4, 35.4, 31.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₂₁H₂₀D₃N₂O₂⁺): 338.1942 found: 338.1940.

2-(methoxy-d3)-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide (3l): 23 mg (yield: 66%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 M Hz, CDCl₃) δ 12.30 (s, 1H), 9.01 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 8.87 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.18 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.62–7.54 (m, 2H), 7.49–7.46 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 162.4, 157.7, 148.5, 139.3, 136.5, 135.4, 134.7 (d, J = 33.3 Hz), 133.8, 128.2, 127.7, 125.6, 125.0, 122.1, 121.7, 118.1 (d, J = 4.0 Hz), 117.7, 108.7 (d, J = 4.0 Hz), 77.4. ¹⁹F NMR (376 MHz, CDCl₃) δ 62.9. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₈H₁₁D₃F₃N₂O₂⁺): 350.1190 found: 350.1200.

4-chloro-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3m): 17 mg (yield: 55%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.23 (s, 1H), 9.00 (d, J = 6.8 Hz, 1H), 8.86 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H) 8.17 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.60–7.42 (m, 3H), 7.12 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), ¹³C NMR (101 MHz, CDCl₃) δ 162.8, 158.2, 148.4, 139.3, 138.9, 136.4, 135.6, 133.7, 128.2, 127.7, 121.8, 121.7, 121.6, 121.1, 117.5, 112.4, 77.4. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁D₃ClN₂O₂⁺): 316.0927 found: 316.0934.

4-fluoro-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3n): 19 mg (yield: 64%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.21 (s, 1H), 9.00 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 8.84 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.35 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 8.16 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.58–7.53 (m, 3H), 6.86–6.81 (m, 1H), 6.75 (dd, J = 10.4 Hz, 0.8 Hz, 1H), ¹³C NMR (101 MHz, CDCl₃) δ 162.6, 158.1, 148.3, 139.2, 138.8, 136.3, 135.5, 133.6, 128.1, 127.6, 121.6 (d, J = 5.0 Hz), 121.5, 121.0, 117.4, 112.2, 77.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁D₃FN₂O₂⁺): 300.1222 found: 300.1228.

4-iodo-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3o): 25 mg (yield: 62%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.23 (s, 1H), 9.00 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 8.84 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.17 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 8.03 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.54–7.44 (m, 3H), 7.40–7.39 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 162.9, 157.7, 148.3, 139.3, 136.3, 135.5, 133.7, 130.8, 128.1, 127.6, 122.2, 121.8, 121.5, 121.1, 117.5, 99.4, 77.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₇H₁₁D₃IN₂O₂⁺): 408.0283 found: 408.0291.

3-(methoxy-d3)-N-(quinolin-8-yl)-[1,1′-biphenyl]-4-carboxamide (3p): 27 mg (yield: 77%), purification of the residue by preparative chromatography (PE/DCM/EA = 3/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.40 (s, 1H), 9.06 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 8.89 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.18 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.68–7.65 (m, 2H), 7.60–7.57 (m, 1H), 7.54–7.42 (m, 5H), 7.37 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.25 (s, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 163.5, 158.0, 148.3, 146.3, 140.2, 139.3, 136.3, 135.8, 132.9, 129.0, 128.2, 127.7, 127.3, 121.5, 121.1, 120.1, 117.4, 110.4, 77.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₂₃H₁₆D₃N₂O₂⁺): 358.1629 found: 358.1629.

4,5-dimethoxy-2-(methoxy-d3)-N-(quinolin-8-yl)benzamide (3q): 28 mg (yield: 81%), purification of the residue by preparative chromatography (PE/DCM/EA = 2/1/1). ¹H NMR (400 MHz, CDCl₃) δ 12.38 (s, 1H), 9.01 (d, J = 6.8 Hz, 1H), 8.75 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.15 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.88 (s, 1H), 7.59-7.55 (m, 1H), 7.50–7.43 (m, 2H), 6.60 (s, 1H), 3.96 (d, J = 4.8 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 163.5, 153.1, 152.8, 148.2, 143.4, 139.3, 136.3, 136.0, 128.1, 127.6, 121.4, 121.3, 117.1, 113.9, 96.8, 77.3, 56.3, 56.2. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₉H₁₆D₃N₂O₄⁺): 342.1528 found: 342.1525.

6-iodo-2-(methoxy-d3)-3-methyl-N-(quinolin-8-yl)benzamide (3r): 26 mg (yield: 62%), purification of the residue by preparative chromatography (PE/DCM/EA = 3/1/1). ¹H NMR (400 MHz, CDCl₃) δ 10.00 (s, 1H), 8.97 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 8.76 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.18 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.64–7.55 (m, 3H), 7.47–7.43 (m, 1H), 7.00–6.99 (m, 1H), 2.31 (s, 3H), ¹³C NMR (101 MHz, CDCl₃) δ 166.3, 156.1, 148.5, 38.7, 137.7, 136.5, 134.8, 134.5, 133.7, 132.2, 128.2, 127.6, 122.3, 121.8, 117.1, 89.8, 77.3, 15.9. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₈H₁₃D₃IN₂O₂⁺): 422.0439 found: 422.0438.

2-(methoxy-d3)-N-(quinolin-8-yl)-1-naphthamide (3s): 18 mg (yield: 58%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 10.34 (s, 1H), 9.14 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 8.71 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.17 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.67–7.63 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.47–7.35 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 166.1, 154.0, 138.6, 136.3, 135.0, 131.7, 131.6, 128.9, 128.1, 127.7, 127.6, 124.5, 124.2, 121.8, 121.6, 120.9, 116.9, 113.2, 77.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₂₁H₁₄D₃N₂O₂⁺): 332.1473 found: 332.1460.

2-(methoxy-d3)-N-(quinolin-8-yl)thiophene-3-carboxamide (3t): 18 mg (yield: 61%), purification of the residue by preparative chromatography (PE/DCM/EA = 5/1/1). ¹H NMR (400 MHz, CDCl₃) δ 11.40 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.75 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.16 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.58–7.43 (m, 4H), 6.60 (d, J = 6.0 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 166.9, 160.8, 148.2, 140.0, 136.3, 135.5, 128.1, 127.6, 121.5, 121.2, 117.5, 116.9, 110.2, 77.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₁₅H₁₀D₃N₂O₂S⁺): 288.0881 found: 288.0880.

2-(methoxy-d3)-1-methyl-N-(quinolin-8-yl)-1H-indole-3-carboxamide (3u): 29 mg (yield: 86%), purification of the residue by preparative chromatography (PE/DCM/EA = 1/1/1). ¹H NMR (400 MHz, CDCl₃) δ 11.10 (s, 1H), 9.04 (d, J = 7.6 Hz, 1H), 8.88 (d, J = 2.8 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.61–7.57 (m, 1H), 7.49–7.44 (m, 2H), 7.31–7.28 (m, 3H), 3.73 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 162.8, 153.7, 148.2, 139.1, 136.4, 136.0, 132.3, 128.3, 127.8, 125.4, 122.5, 122.2, 121.7, 121.5, 120.6, 116.4, 109.1, 95.7, 77.4, 28.3. HRMS (ESI+) exact mass calculated for [M + H]⁺ (C₂₀H₁₅D₃N₃O₂⁺): 335.1580 found: 355.1558.

4. Conclusions

In summary, we developed a facile and practical salicylaldehyde-Co(II)-catalyzed C−H deuteriomethoxylation of benzamides. The reaction model is also applicable to heterocyclic compounds with good functional group tolerance, making it potentially useful for industrial applications. Furthermore, the transformation of the −OCD₃ bond can be performed easily, which may serve as a significant tool in the design of new deuterated drugs in the future.