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Article

Selective Synthesis of N-[1,3,5]Triazinyl-α-Ketoamides and N-[1,3,5]Triazinyl-Amides from the Reactions of 2-Amine-[1,3,5]Triazines with Ketones

by
Yue Li
1,†,
Pengzhen Zhong
1,†,
Junna Zhao
1,
Zexi Pan
1,
Chen Zhang
2,* and
Dongmei Cui
1,*
1
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
2
School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(11), 4338; https://doi.org/10.3390/molecules28114338
Submission received: 22 April 2023 / Revised: 11 May 2023 / Accepted: 19 May 2023 / Published: 25 May 2023
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Abstract

:
In this study, we report a selective approach for synthesizing N-([1,3,5]triazine-2-yl) α-ketoamides and N-([1,3,5]triazine-2-yl) amides from ketones with 2-amino[1,3,5]triazines through oxidation and oxidative C−C bond cleavage reaction, respectively. The transformation proceeds under mild conditions, provides good functional group tolerance and chemoselectivity, and will serve as a valuable tool for the synthesis of bioactive products.

1. Introduction

The 1,3,5-triazines are ubiquitous structural motifs in pharmaceutically active molecules and have a wide array of biological activities, including antibacterial, anti-HSV-1, anticancer, and anti-HIV biological activities [1,2,3]. Therefore, the development of novel and practical methods for the construction of functionalized 1,3,5-triazines is highly desirable. The α-ketoamides and amides are important intermediates in organic synthesis and are also building blocks in many natural products and pharmaceuticals [4,5,6,7,8,9,10,11,12]. Due to their wide utilities, the synthesis of these compounds has attracted considerable interest in recent years. Traditionally, α-ketoamides and amides have been synthesized mainly by the amidation of carboxylic acid derivatives, such as acids and acyl halides. However, this conventional method requires harsh reaction conditions, harmful reagents, and the generation of waste, limiting their practical applicability. Recently, the direct synthesis of α-ketoamides and amides from ketones via oxidation or oxidative C−C bond cleavage has been reported; however, the utility of these methods is restricted owing to the limited availability of the starting materials and other reasons [13,14,15,16,17,18,19,20,21,22,23,24]. Very recently, we developed a new protocol for the synthesis of imidazo [1,2-a][1,3,5]triazines by using the reaction of 2-amino[1,3,5]triazines and ketones (Scheme 1) [25]. As part of our continued research on 2-amino[1,3,5]triazines, herein we report an efficient method for the selective construction of N-([1,3,5]triazine-2-yl) α-ketoamide and N-([1,3,5]triazine-2-yl) amide derivatives from 2-amino[1,3,5]triazines and ketones [26,27,28].

2. Results

In a recent paper, we reported the annulation of 2-amino-[1,3,5]triazines and ketones to construct imidazo [1,2-a][1,3,5]triazines. However, trace unexpected α-ketoamides 3 and amides 4 were found as byproducts. Interestingly, α-ketoamides 3a became the favored product using CuCl (20 mol%) along with iodine (2 eq.) in DMSO at 120 °C for 1.5 h under a nitrogen atmosphere (90%) (Table 1, entry 1). Solvent screening studies revealed that PhCl, 1,2-dichlorobenzene (1,2-DCB), toluene, DMF, and dioxane furnished only a trace amount of the product 3a (Table 1, entries 2–6). Increasing and reducing the temperature or time lowered the yields (Table 1, entries 7–10). Only a trace of the product 3a was observed for long time (13 h), and the reaction became complex. Different copper salts were examined, but the yield did not improve (Table 1, entries 11–14). We also observed that the yield of the product was lower when CuCl, I2 or 2a was reduced (Table 1, entries 15–17). Notably, 3a was afforded in 75% or 48% yield when running the reaction under air or O2 (Table 1, entries 18–19).
Having established the optimal conditions, the substrate scope was examined (Scheme 2). Various electron-donating substituents on the aryl unit of ketones were investigated and furnished the respective products in 67–93% yields (3b–f). In addition, aryl ketones with electron-withdrawing substituents also work well in the reaction. For example, aryl ketones substituted with halogens at either the meta or para positions successfully underwent amidation to give α-ketoamides 3g–j in good yields. In addition, thiophone was found to be suitable reaction partner and afforded the desired product 3k with a 59% yield. Next, we surveyed the scope of 2-amino[1,3,5]triazine derivatives with different substituents on the C4-position. The derivatives with N,N-diethylamino, morpholino, pyrrolidino, and piperidino substituents were also competent starting materials for this strategy and performed the corresponding products 3l–o in 75–99% yields. 2-Amine-[1,3,5]triazines with phenylamino substituent at the C4-position were also tolerated under the standard reaction conditions, giving the desired product 3p with an 82% yield. Additionally, the structure of 3a was unambiguously confirmed using the single crystal X-ray analysis (CCDC 2180473).
After demonstrating the reaction scope for the synthesis of N-([1,3,5]triazine-2-yl) α-ketoamides, we decided to pursue an oxidative C−C bond cleavage approach with N-([1,3,5]triazine-2-yl) amides formation. Using the above reaction conditions, we failed to obtain the desired product 4a (Table 2, entry 1). The use of other copper salts such as CuI, CuBr, and Cu(OAc)2 was also found ineffective for the reaction (Table 2, entries 2–5). Employing CuCl2 along with 1,2-DCB or Diethylene glycol dimethyl ether (diglyme) solvent afforded the desired product 4a with 27% and 11% yields, respectively (Table 2, entries 6–7). However, the other solvent (1,2,4-trichlorobenzene (1,2,4-TCB), DMF, NMP, and toluene) proved to be unproductive for the reaction (Table 2, entries 8–11). Increasing the amount of CuCl2 to 40 mol% and the temperature to 140 °C in the mixture of 1,2-DCB and diglyme afforded product 4a with a 63% yield (Table 2, entry 13). The amount of I2 was screened, and the results showed that 1.5 equiv of I2 was optimal for this reaction (Table 2, entry 15). Stirring the reaction for a longer time and a shorter time gave product 4a in lower yields (Table 2, entries 18–19). The reaction did not proceed either in the absence of copper salts and I2, and control experiments showed that oxygen was needed to perform the reaction (Table 2, entries 20–23).
With a set of optimized conditions for the construction of N-([1,3,5]triazine-2-yl) amides in hand, the generality and scope of this protocol were explored (Scheme 3). Methyl and methoxy substituted aryl ketones reacted smoothly under the standard reaction conditions to deliver the desired products 4b–d. Likewise, aryl ketones with electron-withdrawing groups such as F, Cl, and Br illustrated similar reactivity and afforded the corresponding amides 4e–j with 53–63% yields. Regarding the scope of 2-amine-[1,3,5]triazines, the reaction proceeded well for substrates with morpholino, pyrrolidino, and piperidino groups.
To probe the reaction mechanistic path, a series of control experiments were further conducted (Scheme 4). For α-ketoamidation reaction, treatment of 2a in the absence of 1a under the standard condition gave phenyl glyoxal (5) (63%), and then 5 treated with 1a to isolate the desired product 3a with a 97% yield, indicating that 5 should be an intermediate for the formation of 3a (Equations (1) and (2)). For the amidation reaction, first, when the reaction of 1a with 2a was carried out under the standard conditions, the trace of benzoic acid could be detected using 1H NMR (Equation (3)). However, no desired product 4a was obtained from benzoic acid with 1a, indicating that it is a byproduct for the formation of amides (Equation (4)). Next, the reaction of 5 that is potentially generated with 1a did not give the amide 4a, indicated that this compound was not the intermediate (Equation (5)). Furthermore, the reaction failed to furnish desired amide 4a using TEMPO as a radical scavenger, suggesting that a radical pathway might be involved in this C–C single cleavage reaction (Equation (6)).
On the basis of our study and related reports, a plausible mechanism is depicted (Scheme 5) [14,17,20,23,29,30]. Initially, acetophenone 2 with I2 produced intermediate A, followed by the oxidation to produce intermediate B. The latter then reacted with 2-amino[1,3,5]triazine 1 to furnish intermediate C or C′, followed by further rapid oxidation to give 3 under the reaction conditions. On the other hand, ketone 2 was oxidized in the presence of copper, I2, and oxygen to generate superoxide intermediate D′ via intermediate D. Then, the nucleophilic attack of 2-amine-[1,3,5]triazines to intermediate D′ occurred to produce intermediate E. Subsequently, the cleavage of the C–C bond occurred during the rearrangement of intermediate E, leading to amide 4 and the aldehyde byproduct.

3. Materials and Methods

3.1. General Experiment

Under otherwise noted, materials were obtained from commercial suppliers and used without further purification. Thin layer chromatography (TLC) was performed using silica gel 60 F254 and visualized using UV light. Column chromatography was performed with silica gel (mesh 300–400). 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 500 MHz spectrometer in CDCl3 with Me4Si as an internal standard. Data were reported as follows: chemical shift in parts per million (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, and m = multiplet), coupling constant in Hertz (Hz) and integration. IR spectra were recorded on an FT-IR spectrometer, and only major peaks are reported in cm−1. HRMS and mass data were recorded via ESI on a TOF mass spectrometer.

3.2. General Procedure for the Synthesis of N-([1,3,5]Triazine-2-yl) α-Ketoamides 3

A mixture of 1,3,5-triazine (0.5 mmol), ketone (1.1 mmol), CuCl (0.10 mmol) and I2 (1.00 mmol) was added in DMSO (4 mL). The resulting mixture was then stirred at 120 °C under N2. After the completion of the reaction, the reaction mixture was cooled to room temperature, 10% Na2S2O3 was added and the mixture was extracted with ethyl acetate (4 × 20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using flash chromatography with petroleum ether and ethyl acetate as the eluent to give the pure product.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxo-2-phenylacetamide (3a), White solid; mp 222–223 °C; 1H NMR (500 MHz, CDCl3) δ 11.66 (br, 1H), 8.51 (s, 1H), 8.10–7.94 (m, 2H), 7.67–7.60 (m, 1H), 7.51 (t, J = 7.4 Hz, 2H), 3.08 (s, 3H), 2.52 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 187.5, 165.9, 163.6, 161.4, 134.3, 133.1, 129.8, 128.8, 36.7, 36.0; IR (KBr, cm−1): 3413, 2873, 1682, 1609, 1545, 1413, 1357, 1215, 1176, 993, 725, 597. HRMS (ESI) m/z [M + H]+ calcd for C13H14N5O2 272.1147, found 272.1148
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxo-2-(p-tolyl)acetamide (3b), White solid; mp 219–221 °C; 1H NMR (500 MHz, CDCl3) δ 11.55 (br, 1H), 8.51 (s, 1H), 7.99–7.84 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.08 (s, 3H), 2.57 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 187.2, 165.9, 163.7, 161.4, 145.4, 130.7, 129.9, 129.5, 36.7, 36.1, 21.9; IR (KBr, cm−1): 3443, 1689, 1608, 1549, 1409, 1358, 1220, 1177, 996, 762. HRMS (ESI) m/z [M + H]+ calcd for C14H16N5O2 286.1304, found 286.1281.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxo-2-(m-tolyl)acetamide (3c), White solid; mp 241–242 °C; 1H NMR (400 MHz, CDCl3) δ 11.59 (br, 1H), 8.53 (s, 1H), 7.93–7.73 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 3.10 (s, 3H), 2.57 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.7, 165.9, 163.6, 161.4, 138.7, 135.1, 133.1, 130.3, 128.7, 127.0, 36.7, 36.0, 21.3; IR (KBr, cm−1): 3463, 2888, 1693, 1602, 1551, 1410, 1356, 1210, 1180, 996, 774. HRMS (ESI) m/z [M + H]+ calcd for C14H16N5O2 286.1304, found 286.1312.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxo-2-(o-tolyl)acetamide (3d), White solid; mp 236–237 °C; 1H NMR (500 MHz, CDCl3) δ 11.28 (br, 1H), 8.50 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.49–7.43 (m, 1H), 7.34–7.27 (m, 2H), 3.08 (s, 3H), 2.69 (s, 3H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.2, 165.9, 163.7, 161.4, 141.5, 133.3, 133.1, 132.3, 131.2, 126.0, 36.6, 35.6, 21.7; IR (KBr, cm−1): 3486, 1688, 1604, 1548, 1 412, 1343, 729, 600. HRMS (ESI) m/z [M + H]+ calcd for C14H16N5O2 286.1304, found 286.1318
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-(4-methoxyphenyl)-2-oxoacetamide (3e), White solid; mp 208–209 °C; 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 8.08–7.95 (m, 2H), 6.97 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H), 3.10 (s, 3H), 2.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 186.3, 166.0, 164.5, 163.8, 161.5, 132.4, 126.1, 114.1, 55.6, 36.6, 36.1; IR (KBr, cm−1): 2848, 1684, 1610, 1551, 1415, 1359, 1265, 1170, 996, 777. HRMS (ESI) m/z [M + H]+ calcd for C14H16N5O3 302.1253, found 302.1259
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-(3-methoxyphenyl)-2-oxoacetamide (3f), White solid; mp 191–192 °C; 1H NMR (400 MHz, CDCl3) δ 11.44 (br, 1H), 8.51 (s, 1H), 7.66–7.54 (m, 2H), 7.42 (t, J = 7.9 Hz, 1H), 7.19 (dd, J = 7.9, 2.1 Hz, 1H), 3.11 (s, 3H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.1, 165.9, 163.7, 161.4, 159.9, 134.4, 129.9, 122.9, 121.0, 113.3, 55.6, 36.7, 36.0; IR (KBr, cm−1): 3461, 2843, 1698, 1675, 1603, 1549, 1426, 1345, 1261, 1000, 810, 763. HRMS (ESI) m/z [M + H]+ calcd for C14H16N5O3 302.1253, found 302.1232.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-(4-fluorophenyl)-2-oxoacetamide (3g), White solid; mp 214–215 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, H), 8.16–8.00 (m, 2H), 7.28–6.94 (m, 2H), 3.12 (s, 3H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.6, 166.4 (d, J = 257.7 Hz), 166.0, 163.8, 161.4, 132.7 (d, J = 15.1 Hz), 129.6 (d, J = 2.8 Hz), 116.2 (d, J = 22.2 Hz), 36.7, 36.1; IR (KBr, cm−1): 3850, 1558, 1539, 1127, 1109, 1076, 1062, 1029, 477, 438. HRMS (ESI) m/z [M + H]+ calcd for C13H13FN5O2 290.1053, found 290.1070
2-(4-chlorophenyl)-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxoacetamide (3h), White solid; mp 233–234 °C; 1H NMR (400 MHz, CDCl3) δ 11.36 (br, 1H), 8.50 (s, 1H), 8.10–7.89 (m, 2H), 7.51 (d, J = 8.7 Hz, 2H), 3.13 (s, 3H), 2.61 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 186.6, 169.6, 166.7, 163.6, 162.3, 139.6, 132.1, 131.4, 129.8, 36.6, 35.7. IR (KBr, cm−1): 3484, 1693, 1614, 1552, 1410, 1359, 1213, 1175, 996, 769. HRMS (ESI) m/z [M + H]+ calcd for C13H13ClN5O2 306.0758, found 306.0752
2-(4-bromophenyl)-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxoacetamide (3i), White solid; mp 221–222 °C; 1H NMR (400 MHz, CDCl3) δ 11.48 (br, 1H), 8.51 (s, 1H), 8.00–7.80 (m, 2H), 7.68 (d, J = 8.5 Hz, 2H), 3.13 (s, 3H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.2, 166.0, 163.7, 161.4, 132.2, 131.9, 131.4, 129.7, 36.7, 36.1. IR (KBr, cm−1): 3480, 1680, 1607, 1553, 1409, 1354, 1245, 1155, 993, 810. HRMS (ESI) m/z [M + H]+ calcd for C13H13BrN5O2 350.0253, found 350.0259.
2-(3-bromophenyl)-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxoacetamide (3j), White solid; mp 176–177 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.22–8.11 (m, 1H), 8.03–7.88 (m, 1H), 7.81–7.72 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 3.13 (s, 3H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.8, 165.8, 163.6, 161.3, 137.1, 134.9, 132.5, 130.4, 128.4, 123.0, 36.8, 36.1; IR (KBr, cm−1): 3446, 1683, 1609, 1548, 1407, 1356, 1200, 1179, 997, 782. HRMS (ESI) m/z [M + H]+ calcd for C13H13BrN5O2 350.0253, found 350.0250.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-oxo-2-(thiophen-2-yl)acetamide (3k), Yellow solid; mp 193–194 °C; 1H NMR (400 MHz, CDCl3) δ 9.61 (br, 1H), 8.54 (s, 1H), 8.41 (d, J = 4.2 Hz, 1H), 7.89 (d, J = 4.4 Hz, 1H), 7.24 (dd, J = 4.4, 4.2 Hz, 1H), 3.22 (s, 3H), 3.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.4, 166.6, 164.5, 161.8, 139.1, 138.9, 138.6, 128.6, 36.5, 36.3; IR (KBr, cm−1): 3461, 2358, 1645, 1614, 1547, 1408, 1360, 1238, 1155, 1054, 996, 722. HRMS (ESI) m/z [M + H]+ calcd for C11H12N5O2S 278.0712, found 278.0708.
N-(4-(diethylamino)-1,3,5-triazin-2-yl)-2-oxo-2-phenylacetamide (3l), Pale yellow solid; mp 165–166 °C; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.10–7.98 (m, 2H), 7.68–7.61 (m, 1H), 7.54 (t, J = 7.4 Hz, 2H), 3.55–3.47 (m, 2H), 3.08–2.88 (m, 2H), 1.11 (t, J = 6.8 Hz, 3H), 0.75–0.54 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 187.3, 166.0, 162.7, 161.5, 134.3, 133.0, 130.0, 128.8, 41.9, 41.4, 12.7, 12.1; IR (KBr, cm−1): 3457, 1682, 1607, 1544, 1424, 1353, 1213, 1167, 994, 726. HRMS (ESI) m/z [M + H]+ calcd for C15H18N5O2 300.1460, found 300.1465
2-oxo-2-phenyl-N-(4-(piperidin-1-yl)-1,3,5-triazin-2-yl)acetamide (3m), White solid; mp 222–223 °C; 1H NMR (500 MHz, CDCl3) δ 11.40 (br, 1H), 8.37 (s, 1H), 7.97–7.90 (m, 2H), 7.68–7.61 (m, 1H), 7.53 (t, J = 7.4 Hz, 2H), 3.77–3.65 (m, 2H), 3.64–3.53 (m, 2H), 3.33–3.19 (m, 2H), 3.11–2.96 (m, 2H), 2.85–2.72 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 187.4, 166.5, 162.8, 162.1, 134.2, 132.9, 129.4, 128.8, 66.2, 65.9, 43.9, 43.1, 39.9; IR (KBr, cm−1): 3466, 1681, 1601, 1548, 1422, 1351, 1218, 1110, 992, 728. HRMS (ESI) m/z [M + H]+ calcd for C16H18N5O2 312.1460, found 312.1434.
N-(4-morpholino-1,3,5-triazin-2-yl)-2-oxo-2-phenylacetamide (3n), White solid; mp 213–214 °C; 1H NMR (500 MHz, CDCl3) δ 11.46 (br, 1H), 8.51 (s, 1H), 8.08–7.94 (m, 2H), 7.68–7.58 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 3.82–3.71 (m, 2H), 3.67–3.56 (m, 2H), 3.38–3.32 (m, 2H), 3.15–2.95 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 187.3, 166.4, 163.0, 161.8, 134.5, 132.9, 129.8, 128.9, 66.4, 66.1, 44.0, 43.4; IR (KBr, cm−1): 3448, 2860, 1686, 1611, 1543, 1407, 1357, 1201, 1179, 997, 751. HRMS (ESI) m/z [M + H]+ calcd for C15H16N5O3 314.1253, found 314.1263.
2-oxo-2-phenyl-N-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)acetamide (3o), White solid; mp 232–233 °C; 1H NMR (500 MHz, CDCl3) δ 11.70 (br, 1H), 8.51 (s, 1H), 8.07–7.94 (m, 2H), 7.66–7.59 (m, 1H), 7.51 (t, J = 7.7 Hz, 2H), 3.53–3.42 (m, 2H), 2.99–2.55 (m, 2H), 1.90–1.78 (m, 2H), 1.78–1.66 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 187.5, 165.8, 161.2, 134.1, 133.2, 129.8, 128.7, 46.6, 45.8, 25.0, 24.7; IR (KBr, cm−1): 3466, 1694, 1603, 1539, 1417, 1351, 1327, 1208, 997, 725. HRMS (ESI) m/z [M + H]+ calcd for C15H16N5O2 298.1304, found 298.1293.
2-oxo-2-phenyl-N-(4-(phenylamino)-1,3,5-triazin-2-yl)acetamide (3p), Yellow solid; mp 209–210 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.84 (br, 1H), 10.29 (s, 1H), 8.29 (s, 1H), 7.90–7.75 (m, 2H), 7.70–7.43 (m, 6H), 7.33–7.20 (m, 1H), 7.11–7.04 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 188.0, 166.6, 163.8, 162.8, 138.5, 137.6, 134.6, 133.4, 129.5, 129.0, 126.1, 121.0; IR (KBr, cm−1): 3423, 1681, 1587, 1538, 1453, 1417, 1352, 1215, 1177, 1002, 813, 725. HRMS (ESI) m/z [M + H]+ calcd for C17H14N5O2 320.1147, found 320.1128.

3.3. General Procedure for the Synthesis of N-([1,3,5]Triazine-2-yl) Amides 4

A mixture of 1,3,5-triazine (0.5 mmol), ketone (1.1 mmol), CuCl2 (0.20 mmol), and I2 (0.75 mmol) was added in 1,2-dichlorobenzene (2 mL) and bis(2-methoxy ethyl)ether (1 mL). The resulting mixture was then sealed and stirred at 140 °C under O2. After completion of the reaction, the reaction mixture was cooled to room temperature, 10% Na2S2O3 was added and the mixture was extracted with ethyl acetate (4 × 20 mL). The organic phase was dried over anhydrous Na2SO4. The crude residue was obtained after the evaporation of the solvent in vacuum, and the residue was purified using flash chromatography with petroleum ether/ethyl acetate as the eluent to give the pure product.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)benzamide (4a), White solid; mp 186–188 °C ([lit]27: 187–189 °C); 1H NMR (500 MHz, CDCl3) δ 8.85 (br, 1H), 8.32 (s, 1H), 7.88 (dt, J = 7.5, 1.0 Hz, 2H), 7.57 (tt, J = 7.5, 1.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 3.20 (s, 3H), 3.17 (s, 3H).
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-4-methylbenzamide (4b), White solid; mp 186–188 °C ([lit]27: 182–184 °C); 1H NMR (400 MHz, CDCl3) δ 8.59 (br, 1H), 8.38 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 3.21 (s, 3H), 3.20 (s, 3H), 2.42 (s, 3H).
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-3-methylbenzamide (4c), White solid; mp 119–121 °C; 1H NMR (400 MHz, CDCl3) δ 8.79 (br, 1H), 8.34–8.30 (m, 1H), 7.72–7.62 (m, 2H), 7.39–7.34 (m, 2H), 3.19 (s, 6H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 165.9, 164.8, 162.8, 138.8, 134.4, 133.4, 128.7, 128.4, 124.7, 36.5, 36.3, 21.4; IR (KBr, cm−1): 3177, 2933, 1712, 1616, 1543, 1402, 1276, 1217, 1182, 1032, 813, 753. HRMS (ESI) m/z [M + H]+ calcd for C13H16N5O 258.1355, found 258.1356.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-3-methoxybenzamide (4d), White solid; mp 116–119 °C; 1H NMR (400 MHz, CDCl3) δ 8.74 (br, 1H), 8.35 (s, 1H), 7.45–7.41 (m, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.12–7.09 (m, 1H), 3.86 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 165.4, 164.8, 162.8, 160.1, 135.8, 129.9, 119.5, 118.9, 113.0, 55.6, 36.5, 36.4; IR (KBr, cm−1): 3174, 2945, 1711, 1615, 1539, 1402, 1275, 1181, 1114, 983, 813, 755. HRMS (ESI) m/z [M + H]+ calcd for C13H16N5O2 274.1304, found 274.1293.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-4-fluorobenzamide (4e), White solid; mp 175–177 °C ([lit]27: 173–178 °C); 1H NMR (400 MHz, CDCl3) δ 8.80 (br, 1H), 8.35 (s, 1H), 7.96–7.87 (m, 2H), 7.21–7.12 (m, 2H), 3.20 (s, 3H), 3.17 (s, 3H).
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-2-fluorobenzamide (4f), White solid; mp 178–180 °C; 1H NMR (400 MHz, CDCl3) δ 9.01 (br, 1H), 8.45 (s, 1H), 8.10–8.05 (m, 1H), 7.57–7.51 (m, 1H), 7.33–7.27 (m, 1H), 7.20–7.15 (m, 1H), 3.21 (s, 3H), 3.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 164.8, 162.6, 161.9, 160.5 (d, J = 247.3 Hz), 134.2 (d, J = 9.2 Hz), 132.2 (d, J = 2.1 Hz), 125.3 (d, J = 3.3 Hz), 121.9 (d, J = 12.0 Hz), 116.3 (d, J = 24.1 Hz), 36.5, 36.3; IR (KBr, cm−1): 3100, 2930, 1683, 1604, 1551, 1493, 1413, 1341, 1219, 1136, 992, 751, 625. HRMS (ESI) m/z [M + H]+ calcd for C12H13FN5O 262.1104, found 262.1068.
4-chloro-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)benzamide (4g), White solid; mp 183–185 °C ([lit]27: 176–177 °C); 1H NMR (400 MHz, CDCl3) δ 8.78 (br, 1H), 8.37 (s, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 3.21 (s, 3H), 3.16 (s, 3H).
3-chloro-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)benzamide (4h), White solid; mp 149–151 °C ([lit]27: 163–165 °C); 1H NMR (400 MHz, CDCl3) δ 9.13 (br, 1H), 8.40 (s, 1H), 7.95–7.90 (m, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.58–7.52 (m, 1H), 7.47–7.40 (m, 1H), 3.22 (s, 3H), 3.19 (s, 3H).
4-bromo-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)benzamide (4i), White solid; mp 191–192 °C; 1H NMR (400 MHz, CDCl3) δ 9.04 (br, 1H), 8.34 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 3.20 (s, 3H), 3.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 165.3, 164.7, 162.7, 133.4, 132.1, 129.4, 127.4, 36.5, 36.3; IR (KBr, cm−1): 3101, 2874, 1668, 1611, 1542,1427, 1339, 1124, 994, 758, 707, 647. HRMS (ESI) m/z [M + H]+ calcd for C12H13BrN5O 322.0303, found 322.0275.
3-bromo-N-(4-(dimethylamino)-1,3,5-triazin-2-yl)benzamide (4j), White solid; mp 152–153 °C; 1H NMR (400 MHz, CDCl3) δ 8.82 (br, 1H), 8.39 (s, 1H), 8.08–8.01 (m, 1H), 7.82–7.80 (m, 1H), 7.71–7.68 (m, 1H), 7.37 (t, J = 7.9 Hz, 1H), 3.21 (s, 3H), 3.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 165.0, 164.6, 162.6, 136.5, 135.4, 131.0, 130.3, 126.4, 122.9, 36.5, 36.3; IR (KBr, cm−1): 3211, 3060, 2923, 1731, 1636, 1543, 1411, 1310, 1256, 1183, 993, 807, 747. HRMS (ESI) m/z [M + H]+ calcd for C12H13BrN5O 322.0303, found 322.0274.
N-(4-(dimethylamino)-1,3,5-triazin-2-yl)-4-nitrobenzamide (4k), Light yellow solid (87.0 mg, 61%), mp 237–240 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (br, 1H), 8.43 (s, 1H), 8.31 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 3.11 (s, 3H), 2.98 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 166.4, 165.5, 164.2, 163.2, 149.2, 140.5, 129.6, 123.4, 35.8, 35.4; IR (KBr, cm−1): 3106, 2881, 1676, 1611, 1540,1521, 1417, 1328, 1314, 1124, 993, 863, 751, 645. HRMS (ESI) m/z [M + H]+ calcd for C12H13N6O3 289.1049, found 289.1081
N-(4-(piperidin-1-yl)-1,3,5-triazin-2-yl)benzamide (4l), White solid; mp 166–168 °C ([lit]27: 164–166 °C); 1H NMR (400 MHz, CDCl3) δ 8.85 (br, 1H), 8.49–8.18 (m, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 3.93–3.63 (m, 4H), 1.70–1.60 (m, 6H).
N-(4-morpholino-1,3,5-triazin-2-yl)benzamide (4m), White solid; mp 178–179 °C; 1H NMR (400 MHz, CDCl3) δ 8.76 (br, 1H), 8.36–8.34 (m, 1H), 7.90–7.87 (m, 2H), 7.60–7.55 (m, 1H), 7.53–7.45 (m, 2H), 3.93–3.80 (m, 4H), 3.78–3.70 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 166.8, 165.7, 164.1, 163.0, 134.3, 132.6, 128.8, 127.7, 66.6, 43.8, 43.6; IR (KBr, cm−1): 3172, 2910, 2853, 1717, 1610, 1534, 1424, 1268, 1209, 1114, 980, 810, 697. HRMS (ESI) m/z [M + H]+ calcd for C14H16N5O2 286.1304, found 286.1304.
4-fluoro-N-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)benzamide (4n), White solid; mp 197–199 °C; 1H NMR (400 MHz, CDCl3) δ 8.85 (br, 1H), 8.34 (s, 1H), 7.93–7.88 (m, 2H), 7.26–7.11 (m, 2H), 3.60–3.52 (m, 4H), 2.00–1.94 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 166.3, 165.4 (d, J = 254.8 Hz), 164.9, 162.7, 162.5, 130.6 (d, J = 3.2 Hz), 130.4 (d, J = 9.1 Hz), 116.0 (d, J = 21.9 Hz), 46.6, 46.5, 25.3, 25.2; IR (KBr, cm−1): 3109, 2974, 2882, 1670, 1603, 1537, 1422, 1326, 1230, 1157, 994, 846, 760. HRMS (ESI) m/z [M + H]+ calcd for C14H15FN5O 288.1261, found 288.1248.

3.4. Synthesis of 2-oxo-2-phenylacetaldehyde (5)

A mixture of acetophenone (1.0 mmol, 121.3 mg), CuCl (0.2 mmol, 20.1 mg) and I2 (2.0 mmol, 508.6 mg) was added in DMSO (4 mL). The resulting mixture was then stirred at 120 °C for 1.5 h under N2. After completion of the reaction, the reaction mixture was cooled to room temperature, 10% Na2S2O3 was added and the mixture was extracted with ethyl acetate (4 × 20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using flash chromatography with petroleum ether/ethyl acetate as the eluent to give 5 [31] (85.3 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.21–8.19 (m, 2H), 7.70–7.65 (m, 3H).

4. Conclusions

In summary, we found that oxidative α-ketoamidation and oxidative C−C bond cleavage amidation of ketones with 2-amino[1,3,5]triazines to form N-([1,3,5]triazine-2-yl) α-ketoamide and N-([1,3,5]triazine-2-yl) amide derivatives are available by using a suitable reaction condition. The new method tolerates a variety of functional groups of the substrate and furnished moderate to good yields of the corresponding products under mild conditions. Work is currently ongoing to investigate the use of afforded products in the fields of medicinal chemistry.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114338/s1, crystal data, copies of NMR spectra, IR spectra, and HRMS spectra.

Author Contributions

Conceptualization and methodology D.C.; conceptualization, supervision, writing—reviewing and editing, C.Z.; data curation and writing—original draft preparation, Y.L. and P.Z.; visualization and investigation, J.Z. and Z.P. 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

The data presented in this study are available in the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3a–p and 4a–n are available from the authors.

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Molecules 28 04338 sch001 550
Scheme 1. The reaction of 2-amino[1,3,5]triazines and ketones.
Scheme 1. The reaction of 2-amino[1,3,5]triazines and ketones.
Molecules 28 04338 sch001
Molecules 28 04338 sch002 550
Scheme 2. Substrate scope for synthesis of α-ketoamides 3. Reaction Conditions: All reactions were performed with 1 (0.5 mmol), 2 (1.1 mmol), I2 (2.0 eq.), and CuCl (20 mol%) in DMSO (4 mL) for 1.5 h at 120 °C under N2; isolated yields.
Scheme 2. Substrate scope for synthesis of α-ketoamides 3. Reaction Conditions: All reactions were performed with 1 (0.5 mmol), 2 (1.1 mmol), I2 (2.0 eq.), and CuCl (20 mol%) in DMSO (4 mL) for 1.5 h at 120 °C under N2; isolated yields.
Molecules 28 04338 sch002
Molecules 28 04338 sch003 550
Scheme 3. Substrate scope for synthesis of amides 4. Reaction Conditions: All reactions were performed with 1 (0.5 mmol), 2 (1.1 mmol), I2 (0.75 eq.), and CuCl2 (40 mol%) in 1,2-DCB (2 mL) and diglyme (1 mL) at 140 °C oil bath under O2; isolated yields.
Scheme 3. Substrate scope for synthesis of amides 4. Reaction Conditions: All reactions were performed with 1 (0.5 mmol), 2 (1.1 mmol), I2 (0.75 eq.), and CuCl2 (40 mol%) in 1,2-DCB (2 mL) and diglyme (1 mL) at 140 °C oil bath under O2; isolated yields.
Molecules 28 04338 sch003
Molecules 28 04338 sch004 550
Scheme 4. Control experiments.
Scheme 4. Control experiments.
Molecules 28 04338 sch004
Molecules 28 04338 sch005 550
Scheme 5. Proposed mechanism.
Scheme 5. Proposed mechanism.
Molecules 28 04338 sch005
Table
Table 1. Optimization of the reaction conditions for the formation of 3a a.
Table 1. Optimization of the reaction conditions for the formation of 3a a.
Molecules 28 04338 i001
Entry[Cu] (mol%)I2 (Eq.)SolventTime (h)Yield of 3a (%)
1CuCl (20)2.0DMSO1.590
2CuCl (20)2.0PhCl1.5trace
3CuCl (20)2.01,2-DCB1.5trace
4CuCl (20)2.0Toluene1.5trace
5CuCl (20)2.0DMF1.5trace
6CuCl (20)2.0Dioxane1.5trace
7CuCl (20)2.0DMSO363
8CuCl (20)2.0DMSO1.088
9CuCl (20)2.0DMSO1.079 b
10CuCl (20)2.0DMSO1.569 c
11CuBr (20)2.0DMSO1.582
12CuI (20)2.0DMSO1.577
13Cu(OAc)2 (20)2.0DMSO1.569
14CuCl2 (20)2.0DMSO1.580
15CuCl (10)2.0DMSO1.564
16CuCl (20)2.0DMSO1.569 d
17CuCl (20)1.0DMSO1.553
18CuCl (20)2.0DMSO1.575 e
19CuCl (20)2.0DMSO1.548 f
a Reaction Conditions: 1a (0.5 mmol), 2a (1.1 mmol), [Cu] (10–20 mol%), I2 (1.0–2.0 eq.), solvent (4 mL) under N2; isolated yields. b 130 °C. c 100 °C. d 2a (0.7 mmol). e Air. f O2.
Table
Table 2. Optimization of the reaction conditions for the formation of 4a a.
Table 2. Optimization of the reaction conditions for the formation of 4a a.
Molecules 28 04338 i002
EntryCat. (Mol%)I2 (Eq.)SolventTemp. (°C)Time (h)Yield (%)
1CuCl (20)1DMSO12013trace
2CuCl (20)11,2-DCB12013trace
3CuI (20)11,2-DCB12013trace
4CuBr (20)11,2-DCB12013trace
5Cu2(OAc)4 (20)11,2-DCB12013trace
6CuCl2 (20)11,2-DCB1201327
7CuCl2 (20)1Diglyme1201311
8CuCl2 (20)11,2,4-TCB12013trace
9CuCl2 (20)1DMF12013trace
10CuCl2 (20)1NMP12013trace
11CuCl2 (20)1Toluene12013trace
12CuCl2 (20)11,2-DCB/diglyme = 2:11201343
13CuCl2 (40)11,2-DCB/diglyme = 2:11401363
14CuCl2 (40)11,2-DCB/diglyme = 2:11501327
15CuCl2 (40)0.751,2-DCB/diglyme = 2:11401367
16CuCl2 (40)0.51,2-DCB/diglyme = 2:11401340
17CuCl2 (50)0.751,2-DCB/diglyme = 2:11401361
18CuCl2 (40)0.751,2-DCB/diglyme = 2:11401813
19CuCl2 (40)0.751,2-DCB/diglyme = 2:1140834
20CuCl2 (40)-1,2-DCB/diglyme = 2:1140130
21-0.751,2-DCB/diglyme = 2:1140130
22CuCl2 (40)0.751,2-DCB/diglyme = 2:114013trace b
23CuCl2 (40)0.751,2-DCB/diglyme = 2:114013trace c
a Reaction Conditions: a mixture of 1a (0.5 mmol), 2a (1.1 mmol), I2 and Cu salts in solvent (3 mL) was stirred under O2 (1 atm); isolated yields are shown. b N2. c Air.
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Li, Y.; Zhong, P.; Zhao, J.; Pan, Z.; Zhang, C.; Cui, D. Selective Synthesis of N-[1,3,5]Triazinyl-α-Ketoamides and N-[1,3,5]Triazinyl-Amides from the Reactions of 2-Amine-[1,3,5]Triazines with Ketones. Molecules 2023, 28, 4338. https://doi.org/10.3390/molecules28114338

AMA Style

Li Y, Zhong P, Zhao J, Pan Z, Zhang C, Cui D. Selective Synthesis of N-[1,3,5]Triazinyl-α-Ketoamides and N-[1,3,5]Triazinyl-Amides from the Reactions of 2-Amine-[1,3,5]Triazines with Ketones. Molecules. 2023; 28(11):4338. https://doi.org/10.3390/molecules28114338

Chicago/Turabian Style

Li, Yue, Pengzhen Zhong, Junna Zhao, Zexi Pan, Chen Zhang, and Dongmei Cui. 2023. "Selective Synthesis of N-[1,3,5]Triazinyl-α-Ketoamides and N-[1,3,5]Triazinyl-Amides from the Reactions of 2-Amine-[1,3,5]Triazines with Ketones" Molecules 28, no. 11: 4338. https://doi.org/10.3390/molecules28114338

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