Abstract
Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1H)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1H)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.
Introduction
Quinoxalin-2(1H)-ones are commonly found N-containing heterocycles in a wide range of natural products and biologically active compounds.1 Particularly, 3-functionalized quinoxalinones usually exhibit important biological and pharmaceutical properties as shown in Figure 1.2 Numerous protocols for synthesizing diverse 3-functionalized quinoxalinones through C-3-selectivity C–H functionalization of quinoxalinones have been well established,3 which include alkylation, alkoxylation, acylation, arylation, amination, esterification, hydroxylation, phosphonation, sulfenylation, silylation, and trifluoromethylation reactions (Scheme 1a). Among the structurally diverse functionalized quinoxalinones, 3-carbamoylquinoxalinone exhibits a diversity of biological properties, such as the c-Met kinase inhibitors,4 HCV inhibitors,5 PDE4 inhibitors,6 ORL-1 receptor agonist,7 cannabinoid CB2 receptor agonist,8 and anticancer properties9 (Figure 1). The synthesis of carbamoylated quinoxalin-2(1H)-ones has been reported by the direct C–H amidation.10 In Ma’s work, hydrazinecarboxamide was used for the direct carbamoylation of quinoxalin-2(1H)-ones by Cu catalysis. Yuan and co-workers developed transition-metal-free direct C–H functionalization of quinoxalin-2(1H)-ones with oxamic acids, where primary/secondary/tertiary amides can be formed. Very recently, Li’s group reported the carbamoylation of quinoxalin-2(1H)-ones with isocyanates under mild conditions; in this protocol, Selectfluor was used as the oxidant. Despite the fact that these protocols are efficient and regioselective, from an environmental viewpoint, these processes still suffer from some limitations, such as the employment of transition metal, an excess amount of peroxide oxidant, and a high reaction temperature. To the best of our knowledge, a mild C-3 acylation of quinoxalin-2(1H)-ones employing air as an oxidant under metal- and strong oxidant-free conditions has never been reported.
Figure 1.
Representative samples of 3-carbamoylquinoxalin-2(1H)-one derivatives.
Scheme 1. C–H Functionalization at the C-3 Position of Quinoxalin-2(1H)-ones.
Traditionally, the use of volatile organic solvents (VOSs) is the main contributor to environmental pollution, which is a major drive toward sustainable synthesis and catalysis to replace the VOCs by some alternative green solvent mediums,11 such as water, supercritical fluids, ionic liquids, and fluorous solvents.12 Among these alternative solvents, water is the most preferred nonclassical medium and has received increasing popularity.13
As a synthon with similar properties to carbene intermediate, isocyanide is often stable and has also been widely used in organic synthesis as an important source of C1 due to its unique, versatile, and useful properties.14 As a continuation of our interest in the synthesis of N-contain compound by isocyanide chemistry, and, moreover, in view of the importance of 3-carbamoylquinoxalinone, we reported herein an acid-promoted efficient carbamoylation of quinoxalin-2(1H)-ones with isocyanide in water for the synthesis of 3-carbamoylquinoxalinone.
Results and Discussion
Our investigation began with testing the carbamoylation conditions for the direct C–H functionalization of quinoxalinone 1a with tert-butyl isocyanide 2a in water in the presence of acid. The results of reaction optimization are summarized in Table 1. As we screened various conditions, poor yield was obtained when 1.0 equiv of 2a was used with hydrochloric acid in water at room temperature (entries 1–3). To our delight, as the temperature increased, the desired compound 3a was presented in a relatively higher yield (entries 4–5). However, the starting material 1a still could be detected by liquid chromatography–mass spectrometry (LC/MS). To improve the synthetic efficiency, the amount of 2a was screened (entries 5–7). When 1.5 equiv of 2a was used, there was a significant improvement in the yield. Other acids, including inorganic and organic acid, were tested, and the results are shown in Table 1 (entries 8–12). The inorganic acid perchlorate gave an outstanding yield of 81%. For the organic acid, the use of P-toluene sulfonic acid (PTSA) can also afford compound 3a with good yield. The Lewis acid was also tested, but the desired compound was not detected under the conditions. Overall, the optimal conditions of the carbamoylation reaction were quinoxalin-2(1H)-one (1.0 equiv), isocyanide (1.5 equiv), and perchlorate as the catalyst in water (0.2 M) at 90 °C for 3 h.
Table 1. Optimization of the Reaction Conditionsa.
| entry | 2a (equiv) | acid (1.0 equiv) | temp. (°C) | time (h) | yield of 3a (%)b |
|---|---|---|---|---|---|
| 1 | 1.0 | HCl | 30 | 3 | 0 |
| 2 | 1.0 | HCl | 30 | 6 | trace |
| 3 | 1.0 | HCl | 30 | 12 | trace |
| 4 | 1.0 | HCl | 60 | 3 | 35 |
| 5 | 1.0 | HCl | 90 | 3 | 50 |
| 6 | 1.5 | HCl | 90 | 3 | 76 |
| 7 | 2.0 | HCl | 90 | 3 | 72 |
| 8 | 1.5 | HClO4 | 90 | 3 | 81 |
| 9 | 1.5 | AcOH | 90 | 3 | trace |
| 10 | 1.5 | PTSA | 90 | 3 | 78 |
| 11 | 1.5 | TfOH | 90 | 3 | 45 |
| 12 | 1.5 | PPA | 90 | 3 | trace |
| 13 | 1.5 | ZnCl2 | 90 | 3 | 0 |
| 14 | 1.5 | AlCl3 | 90 | 3 | 0 |
| 15c | 1.5 | HClO4 | 90 | 3 | 85 |
| 16d | 1.5 | HClO4 | 90 | 3 | 70 |
Reaction conditions: 1a (0.3 mmol), acid (1.0 equiv), and 2a (relative equiv) in water (1.0 mL).
Isolated yields.
In 1.5 mL of water.
In 3 mL of water.
With the optimized reaction condition in hand, the scope was investigated as shown in Scheme 2. First, we tested the effect of different isocyanides on the reaction. The result showed that different substituents on the isocyanides were well tolerated and either aliphatic isocyanides or aryl isocyanides exhibited good performance, affording good to excellent yields (3a–o, 78–92%). The aliphatic isocyanides bearing ester group also provided the 3-carbamoylquinoxalinone 3f and 3g with 78 and 81% yields. For the aryl isocyanides, different substituted groups on the benzene ring showed satisfactory efficiency and over 90% yield for compounds 3l–3o. Then, we investigated the substrates of different N-substituent quinoxalin-2(1H)-ones. Various N-substituent quinoxalin-2(1H)-ones were explored in the present protocol, and in all cases, the reactions took place smoothly to afford the desired amidation products 3p–3ab in 62–90% yield, which indicated that the reaction showed good functional-group tolerance. Also, different substituents on the benzene ring of quinoxalinone were investigated (3ac–3af), and these substrates were tolerated and led to the desired compounds in moderate yield (72–81%). It is worth mentioning that the reaction took place smoothly when the quinoxalin-2(1H)-one with no substituent on the nitrogen atoms (3ag–3ai).
Scheme 2. Scope of 3-Carbamoylquinoxalin-2(1H)-ones.
Reaction conditions: quinoxalin-2(1H)-ones (0.5 mmol), isocyanides (0.75 mmol), 2.5 mL of aqueous perchloric acid (0.2 M), isolated yield.
The potential application value of the reaction was further evaluated. First, a gram-scale reaction was performed under similar conditions, as is shown in Scheme 3. When the reaction was conducted using 6 mmol of quinoxalin-2(1H)-one and 9 mmol of benzyl isocyanide as substrates, 1.36 g of the desired compound 3ag was obtained. The yield of the gram-scale reaction was not decreased significantly compared with that of milligram-scale reaction (Scheme 3a). Then, the protocol was applied to the synthesis of cannabinoid CB2 receptor agonist 4. The cannabinoid CB2 receptor agonist was synthesized from two different routes through the electrophilic substitution reaction with similar overall yield (Scheme 3b).
Scheme 3. Synthetic Application.
To get a deep insight into the mechanism of the amidation process, control experiments were conducted. First, when the reaction was conducted in 18O-water, the 18O-labeled product was obtained in 79% yield (see the Supporting Information for details). To prove the oxidant coming from air, the nitrogen-protected experiment was conducted. The desired compound 3ag was detected in trace, instead, the hydrogenated product 6 was observed in 88% yield (see the Supporting Information for details). The result indicated that the 3-carbamoylquinoxalinone was formed through the oxidation of tetrahydroquinoxaline intermediates by oxygen in the air (Scheme 4).
Scheme 4. Control Experiments.
On the basis of the above experiment results, we proposed a possible mechanism for the reaction, as shown in Scheme 5. First, quinoxalin-2(1H)-ones were protonated in the presence of acid to generate electrophilic intermediate A. Then, the isocyanide undergoes a nucleophilic attack to the C-3 carbon of the protonated quinoxalin-2(1H)-one A, resulting in the formation of intermediate B. Subsequently, H2O acts as a nucleophile to attack the carbocation to yield the oxonium ion C, which deprotonates to form the hydroxyimine D. Following by the intramolecular rearrangement of the double bond, the amide E was generated, which is a more stable formation than hydroxyimine D. Intermediate E is easily oxidized by the air under heating to afford compound 3.
Scheme 5. Proposed Reaction Mechanism.
Conclusions
In conclusion, an eco-friendly carbamoylation of quinoxalin-2(1H)-ones with isocyanide in water and ambient air as the oxidant was established. This protocol is metal-free, strong oxidant-free, and mild, featuring good functional-group tolerance and high yield. And more importantly, the protocol can be scaled up and applied to synthesize cannabinoid CB2 receptor agonist. Given the ready availability of starting materials, the clean reaction conditions, high scalability, and operational simplicity, the developed method is highly attractive for organic synthesis and pharmaceutical chemistry.
Experimental Section
General Procedure for the Synthesis of Compound 3
To a solution of quinoxalin-2(1H)-ones 1 (0.5 mmol) and 2.5 mL of aqueous perchloric acid (0.2 M) in a vial, isocyanides 2 (0.75 mmol) was added to the vial and sealed. The reaction mixture was stirred at 90 °C for 3 h (extreme caution should be exercised when heating this solution because of the potential explosiveness by heating of a concentrated HClO4 solution and the use of a shield in a fume hood is recommended). After completion of the reaction, the reaction mixture was diluted with EtOAc (15 mL) and washed with saturated sodium bicarbonate and brine successively. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate/hexane (0–60%) or methanol/methylene chloride (0–10%) to afford the relative 3-carbamoylquinoxalinone compound 3.
N-(tert-Butyl)-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3a
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 116 mg, 85% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.48–7.39 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.52 (s, 9H), 1.43 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 154.9, 145.4, 133.0, 132.8, 132.7, 132.6, 124.6, 113.6, 51.6, 38.0, 28.6, 12.4. High-resolution mass spectrometry (HRMS) (ESI) m/z calcd for C15H20N3O2+ (M + H)+ 274.1550, found 274.1535.
4-Ethyl-3-oxo-N-(2,4,4-trimethylpentan-2-yl)-3,4-dihydroquinoxaline-2-carboxamide 3b
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 140 mg, 85% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.39 (dd, J = 17.9, 8.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 1.90 (s, 2H), 1.53 (s, 6H), 1.39 (t, J = 7.2 Hz, 3H), 1.00 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 154.8, 145.2, 133.0, 132.7, 132.6, 124.4, 113.5, 55.4, 51.1, 38.0, 31.7, 31.4, 29.0, 12.4. HRMS (ESI) m/z calcd for C19H28N3O2+ (M + H)+ 330.2176, found 330.2165.
N-Cyclohexyl-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3c
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 124 mg, 83% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.50–7.38 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.18–4.05 (m, 1H), 2.10–1.99 (m, 2H), 1.81–1.55 (m, 4H), 1.50–1.37 (m, 7H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5, 154.8, 144.9, 133.1, 133.0, 132.8, 132.6, 124.6, 113.6, 48.5, 38.0, 32.7, 25.7, 24.6, 12.4. HRMS (ESI) m/z calcd for C17H22N3O2+ (M + H)+ 300.1707, found 300.1699.
N-Cyclopentyl-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3d
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 115 mg, 81% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.44 (dd, J = 19.4, 8.1 Hz, 2H), 4.49 (dd, J = 12.5, 6.2 Hz, 1H), 4.39 (dd, J = 14.2, 7.0 Hz, 2H), 2.09 (dd, J = 11.3, 6.8 Hz, 2H), 1.77 (d, J = 5.6 Hz, 2H), 1.70–1.59 (m, 4H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.0, 154.8, 144.8, 133.0, 133.0, 132.8, 124.6, 113.6, 51.7, 38.1, 33.1, 23.9, 12.4. HRMS (ESI) m/z calcd for C16H20N3O2+ (M + H)+ 286.1550, found 286.1541.
N-Butyl-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3e
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 108 mg, 79% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.44 (dd, J = 16.7, 8.3 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.55 (dd, J = 12.9, 6.7 Hz, 2H), 1.71–1.62 (m, 2H), 1.47–1.39 (m, 5H), 0.97 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.6, 154.8, 144.8, 133.0, 132.7, 132.6 124.6, 113.6, 39.8, 38.0, 31.4, 20.3, 13.8, 12.4. HRMS (ESI) m/z calcd for C15H20N3O2+ (M + H)+ 274.1550, found 274.1548.
Ethyl (4-Ethyl-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)glycinate 3f
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 118 mg, 78% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.45 (dd, J = 15.8, 8.1 Hz, 2H), 4.42 (dd, J = 14.2, 7.0 Hz, 2H), 4.33 (d, J = 5.2 Hz, 2H), 4.27 (dd, J = 14.2, 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.5, 161.8, 154.7, 144.0, 133.4, 132.9, 132.8, 124.7, 113.7, 61.6, 42.1, 38.1, 14.2, 12.4. HRMS (ESI) m/z calcd for C15H18N3O4+ (M + H)+ 304.1292, found 304.1282.
Methyl (4-Ethyl-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)glycinate 3g
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 117 mg, 81% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.45 (dd, J = 15.3, 8.1 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.36 (d, J = 5.3 Hz, 2H), 3.81 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.9, 161.8, 154.7, 144.0, 133.4, 132.9, 132.7, 124.6, 113.8, 52.4, 41.9, 38.1, 12.4. HRMS (ESI) m/z calcd for C14H16N3O4+ (M + H)+ 290.1135, found 290.1133.
Methyl (4-Ethyl-3-oxo-3,4-dihydroquinoxaline-2-carbonyl)glycinate 3h
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 143 mg, 89% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.49–7.39 (m, 2H), 7.34–7.20 (m, 5H), 4.38 (q, J = 7.1 Hz, 2H), 3.79 (dd, J = 13.5, 6.8 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.8, 154.7, 144.5, 139.0, 133.2, 132.7, 128.9, 128.6, 126.4, 124.6, 113.7, 41.5, 38.1, 35.5, 12.4. HRMS (ESI) m/z calcd for C19H20N3O2+ (M + H)+ 322.1550, found 322.1545.
N-Benzyl-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3i
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 137 mg, 89% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.47 – 7.37 (m, 4H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 4.74 (d, J = 5.7 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.6, 154.7, 144.6, 138.0, 133.2, 133.0, 132.7, 128.7, 128.0, 127.4, 124.6, 113.7, 44.0, 38.1, 12.4. HRMS (ESI) m/z calcd for C18H18N3O2+ (M + H)+ 308.1394, found 308.1396.
4-Ethyl-N-(4-methoxybenzyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3j
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 138 mg, 82% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.20 (d, J = 6.5 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 7.9 Hz, 2H), 4.65 (d, J = 4.8 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.7, 159.0, 154.7, 144.4, 133.3, 132.9, 132.6, 130.0, 129.3, 124.6, 114.1, 113.8, 55.3, 43.5, 38.1, 12.4. HRMS (ESI) m/z calcd for C19H20N3O3+ (M + H)+ 338.1499, found 338.1506.
Methyl 4-((4-Ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate 3k
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 146 mg, 80% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.50–7.40 (m, 4H), 4.79 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.9, 161.8, 154.8, 144.4, 143.3, 133.3, 133.1, 132.8, 130.0, 129.3, 127.8, 124.7, 113.7, 52.1, 43.6, 38.1, 12.4. HRMS (ESI) m/z calcd for C20H20N3O4+ (M + H)+ 366.1448, found 366.1446.
4-Ethyl-N-(4-methoxyphenyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3l
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 140 mg, 87% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.82–7.68 (m, 3H), 7.47 (dd, J = 18.2, 8.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.7, 156.7, 155.1, 144.4, 133.3, 132.8, 132.6, 131.3, 124.8, 121.9, 114.2, 113.8, 55.5, 38.3, 12.4. HRMS (ESI) m/z calcd for C18H18N3O3+ (M + H)+ 324.1343, found 324.1338.
N-(2,6-Dimethylphenyl)-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3m
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 146 mg, 91% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.23 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 13.7, 8.0 Hz, 2H), 7.13 (s, 3H), 4.47 (q, J = 7.2 Hz, 2H), 2.35 (s, 6H), 1.48 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.4, 155.2, 144.9, 134.8, 134.0, 133.3, 132.9, 132.8, 128.2, 127.1, 124.7, 113.7, 38.2, 18.9, 12.5. HRMS (ESI) m/z calcd for C19H20N3O2+ (M + H)+ 322.1550, found 322.1552.
4-Ethyl-N-(naphthalen-2-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3n
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 158 mg, 92% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.16 (s, 1H), 8.53 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.85–7.67 (m, 5H), 7.44 (ddd, J = 24.5, 14.3, 7.9 Hz, 4H), 4.42 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.2, 155.1, 144.1, 135.4, 133.9, 133.4, 132.8, 132.6, 131.0, 128.8, 128.0, 127.6, 126.4, 125.2, 124.9, 120.4, 117.6, 113.8, 38.3, 12.4. HRMS (ESI) m/z calcd for C21H18N3O2+ (M + H)+ 344.1394, found 344.1388.
N-(2-Chloro-6-methylphenyl)-4-ethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3o
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 154 mg, 90% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.49 (s, 1H), 8.23 (dd, J = 8.1, 1.2 Hz, 1H), 7.76–7.68 (m, 1H), 7.49–7.41 (m, 2H), 7.29 (dd, J = 7.7, 1.5 Hz, 1H), 7.20–7.09 (m, 2H), 4.44 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 155.1, 144.3, 137.6, 133.4, 133.1, 132.9, 130.9, 129.2, 127.7, 127.0, 124.7, 113.8, 38.2, 19.4, 12.4. HRMS (ESI) m/z calcd for C18H17ClN3O2+ (M + H)+ 342.1004, found 342.1014.
N-(tert-Butyl)-4-methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3p
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 111 mg, 86% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 3.78 (s, 3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 155.4, 145.4, 133.6, 132.9, 132.8, 132.5, 124.7, 113.8, 51.6, 29.5, 28.6. HRMS (ESI) m/z calcd for C14H18N3O2+ (M + H)+ 260.1394, found 260.1387.
4-Allyl-N-(tert-butyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3q
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 125 mg, 88% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 5.97 (ddd, J = 22.0, 10.1, 4.9 Hz, 1H), 5.32 (d, J = 17.3 Hz, 1H), 5.14 (d, J = 17.3 Hz, 1H), 4.98 (d, J = 4.8 Hz, 2H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.1, 154.9, 145.5, 132.9, 132.8, 132.5, 129.8, 124.7, 118.5, 114.3, 51.7, 44.9, 28.6. HRMS (ESI) m/z calcd for C16H20N3O2+ (M + H)+ 286.1550, found 286.1551.
N-(tert-Butyl)-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydroquinoxaline-2-carboxamide 3r
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 127 mg, 90% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.56–7.44 (m, 2H), 5.12 (s, 2H), 2.36 (s, 1H), 1.51 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 154.4, 145.4, 133.0, 132.9, 132.5, 132.2, 125.1, 114.2, 76.0, 73.9, 51.7, 32.0, 28.6. HRMS (ESI) m/z calcd for C16H18N3O2+ (M + H)+ 284.1394, found 284.1396.
Ethyl 2-(3-(tert-Butylcarbamoyl)-2-oxoquinoxalin-1(2H)-yl)acetate 3s
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 109 mg, 66% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 5.08 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.51 (s, 9H), 1.30 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.5, 159.9, 154.9, 145.5, 133.0, 132.8, 132.8, 132.7, 125.0, 113.2, 62.4, 51.7, 43.9, 28.6, 14.1. HRMS (ESI) m/z calcd for C17H22N3O4+ (M + H)+ 332.1605, found 332.1602.
Benzyl 2-(3-(tert-Butylcarbamoyl)-2-oxoquinoxalin-1(2H)-yl)acetate 3t
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 122 mg, 62% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.37–7.33 (m, 3H), 7.29 (d, J = 2.9 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 5.12 (s, 2H), 1.51 (s, 10H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.4, 159.8, 154.9, 145.5, 134.6, 133.1, 132.7, 128.7, 128.4, 125.0, 113.2, 68.0, 51.7, 43.9, 28.6. HRMS (ESI) m/z calcd for C22H24N3O4+ (M + H)+ 394.1758, found 394.1758.
N-(tert-Butyl)-4-(2-(4-chlorophenyl)-2-oxoethyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3u
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 161 mg, 81% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 16.0, 8.1 Hz, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.76 (s, 2H), 1.49 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 189.2, 159.9, 155.0, 145.4, 141.3, 133.0, 132.6, 129.6, 129.6, 124.9, 113.5, 51.7, 48.7, 28.6. HRMS (ESI) m/z calcd for C21H21ClN3O3+ (M + H)+ 398.1266, found 398.1284.
N-(tert-Butyl)-4-(2-(4-nitrophenyl)-2-oxoethyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3v
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 149 mg, 73% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.42 (d, J = 8.3 Hz, 2H), 8.28 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.82 (s, 2H), 1.49 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 189.4, 159.9, 154.8, 151.1, 145.4, 138.6, 133.1, 132.9, 132.8, 132.7, 129.4, 125.1, 124.4, 113.4, 51.8, 49.1, 28.6. HRMS (ESI) m/z calcd for C21H21N4O5+ (M + H)+ 409.1506, found 409.1512.
4-Benzyl-N-(tert-butyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3w
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 139 mg, 83% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.37–7.26 (m, 4H), 7.20 (d, J = 7.4 Hz, 2H), 5.57 (s, 2H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 155.4, 145.6, 134.4, 133.1, 133.0, 132.5, 129.1, 128.0, 126.6, 124.8, 114.6, 51.7, 46.3, 28.6. HRMS (ESI) m/z calcd for C20H22N3O2+ (M + H)+ 336.1707, found 336.1691.
4-(4-Bromobenzyl)-N-(tert-butyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3x
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 178 mg, 86% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.44 (dd, J = 16.3, 8.0 Hz, 3H), 7.28 (s, 1H), 7.10 (d, J = 8.3 Hz, 2H), 5.51 (s, 2H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 155.2, 145.6, 133.4, 133.0, 132.6, 132.3, 128.4, 124.9, 122.0, 114.3, 51.7, 45.8, 28.6. HRMS (ESI) m/z calcd for C20H21BrN3O2+ (M + H)+ 414.0812, found 414.0826.
N-(tert-Butyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3y
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 139 mg, 76% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.44–7.33 (m, 2H), 7.16 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 5.50 (s, 2H), 3.77 (s, 3H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 159.3, 155.4, 145.6, 133.1, 133.0, 132.8, 132.5, 128.1, 126.4, 124.7, 114.5, 55.3, 51.7, 45.8, 28.6. HRMS (ESI) m/z calcd for C21H24N3O3+ (M + H)+ 366.1812, found 366.1810.
N-(tert-Butyl)-4-(4-chlorobenzyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3z
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 152 mg, 82% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.21 (dd, J = 15.9, 8.1 Hz, 3H), 7.08 (d, J = 8.1 Hz, 2H), 5.45 (s, 2H), 1.45 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.0, 154.2, 144.6, 132.9, 131.9, 131.6, 128.3, 127.1, 123.9, 113.3, 50.7, 44.7, 27.6. HRMS (ESI) m/z calcd for C20H21ClN3O2+ (M + H)+ 370.1317, found 370.1326.
N-(tert-Butyl)-4-(4-cyanobenzyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3aa
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 140 mg, 78% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 20.4, 8.2 Hz, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.3 Hz, 1H), 5.61 (s, 2H), 1.52 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.9, 155.1, 145.6, 139.8, 133.2, 132.9, 132.7, 127.4, 125.2, 118.2, 114.0, 112.1, 51.8, 46.0, 28.6. HRMS (ESI) m/z calcd for C21H21N4O2+ (M + H)+ 361.1659, found 361.1673.
N-(tert-Butyl)-4-(4-methoxyphenyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ab
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 151 mg, 86% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.22–8.16 (m, 1H), 7.51–7.46 (m, 1H), 7.41 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 1.48 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5, 160.1, 155.7, 145.9, 134.8, 132.8, 132.0, 128.9, 127.5, 124.9, 115.8, 115.7, 55.8, 51.8, 28.6. HRMS (ESI) m/z calcd for C20H22N3O3+ (M + H)+ 352.1656, found 352.1637.
N-(tert-Butyl)-4-(3-fluorobenzyl)-6,7-dimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ac
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 154 mg, 81% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.93 (s, 1H), 7.31 (d, J = 6.7 Hz, 1H), 7.03–6.96 (m, 3H), 6.89 (d, J = 9.5 Hz, 1H), 5.52 (s, 2H), 2.34 (s, 6H), 1.51 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.4, 161.9, 160.4, 155.3, 149.0, 143.9, 137.1, 134.3, 132.4, 131.4, 130.8, 122.2, 115.1, 114.9, 114.6, 113.7, 51.6, 45.7, 28.6, 21.0, 19.3. 19F NMR (377 MHz, CDCl3) δ −111.7. HRMS (ESI) m/z calcd for C22H25FN3O2+ (M + H)+ 382.1925, found 382.1921.
N-(tert-Butyl)-6,7-dichloro-4-(3-fluorobenzyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ad
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 162 mg, 77% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.24 (s, 1H), 7.36 (d, J = 3.5 Hz, 1H), 7.05–6.97 (m, 3H), 6.94–6.87 (m, 2H), 5.48 (s, 2H), 1.51 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ164.9, 159.4, 154.7, 146.9, 137.5, 136.0, 132.9, 132.0, 129.2, 122.2, 116.6, 116.1, 113.8, 52.0, 46.1, 28.5. 19F NMR (377 MHz, CDCl3) δ −111.0. HRMS (ESI) m/z calcd for C20H19Cl2FN3O2+ (M + H)+ 422.0833, found 422.0849.
6,7-Dibromo-N-(tert-butyl)-4-methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ae
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 163 mg, 78% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.38 (s, 1H), 7.67 (s, 1H), 3.72 (s, 3H), 1.50 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.6, 154.7, 146.8, 135.9, 133.3, 132.2, 129.9, 120.3, 118.6, 51.9, 29.8, 28.5. HRMS (ESI) m/z calcd for C14H16Br2N3O2+ (M + H)+ 415.9604, found 415.9607.
N-(tert-Butyl)-4-(3-fluorobenzyl)-3-oxo-3,4-dihydrobenzo[g]quinoxaline-2-carboxamide 3af
Purified by flash chromatography using a gradient of ethyl acetate/hexane (0–60%), 145 mg, 72% yield, yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.73 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.61–7.49 (m, 3H), 7.34–7.28 (m, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.01–6.95 (m, 2H), 5.60 (s, 2H), 1.54 (s, 10H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.5, 162.0, 160.0, 155.2, 146.1, 137.1, 134.9, 132.9, 131.8, 130.7, 130.3, 129.2, 127.4, 126.0, 122.2, 115.0, 113.9, 111.0, 51.8, 45.8, 28.6. 19F NMR (377 MHz, CDCl3) δ −111.6. HRMS (ESI) m/z calcd for C24H23FN3O2+ (M + H)+ 404.1769, found 404.1764.
N-Benzyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ag
Purified by flash chromatography using a gradient of methanol/methylene chloride (0–10%), 114 mg, 82% yield, yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 9.46 (t, J = 5.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.43–7.32 (m, 6H), 7.28 (t, J = 6.8 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 163.7, 154.4, 139.22, 133.0, 132.3, 131.7, 129.7, 128.8, 128.5, 127.8, 127.4, 127.0, 124.4, 116.1 42.7. HRMS (ESI) m/z calcd for C16H14N3O2+ (M + H)+ 280.1081, found 280.1079.
N-(tert-Butyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ah
Purified by flash chromatography using a gradient of methanol/methylene chloride (0–10%), 88 mg, 72% yield, yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.74 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 1.38 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8, 154.4, 152.5, 132.8, 131.9, 131.7, 129.6, 124.3, 116.0, 79.6, 51.2, 28.9. HRMS (ESI) m/z calcd for C13H16N3O2+ (M + H)+ 246.1237, found 246.1237.
N-(2,6-Dimethylphenyl)-3-oxo-3,4-dihydroquinoxaline-2-carboxamide 3ai
Purified by flash chromatography using a gradient of methanol/methylene chloride (0–10%), 117 mg, 80% yield, yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.32 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 8.1 Hz, 2H), 7.13 (s, 3H), 2.27 (s, 6H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.3, 154.3, 153.2, 135.6, 134.5, 133.0, 132.2, 131.7, 129.7, 128.2, 127.2, 124.4, 116.2, 18.7. HRMS (ESI) m/z calcd for C17H16N3O2+ (M + H)+ 294.1237, found 294.1242.
Gram-Scale Synthesis of Compound 3ag
A flask was charged with quinoxalin-2(1H)-one (6 mmol, 0.88 g, 1.0 equiv) and 30 mL of aqueous perchloric acid (0.2 M). Benzyl isocyanide (9 mmol, 1.5 g, 1.5 equiv) was added to the flask. The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (150 mL) and washed with saturated sodium bicarbonate and brine, successively. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of methanol/methylene chloride (0–10%) to afford 3ag as a yellow solid (1.36 g, 81% yield).
Synthesis of Cannabinoid CB2 Receptor Agonist
Route A: To a solution of 3ag (0.2 mmol, 1.0 equiv) and K2CO3 (2.5 equiv) in DMF (2 mL) in a 5 mL vial, 4-(2-chloroethyl)morpholine hydrochloride (1.5 equiv) was added and stirred at 90 °C for 6 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl methanol/methylene chloride (0–10%) to afford compound 4 as a yellow solid, 83% yield from 3ag. 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.49–7.39 (m, 4H), 7.35 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.0 Hz, 1H), 4.75 (d, J = 5.6 Hz, 2H), 4.52–4.42 (m, 2H), 3.74–3.64 (m, 5H), 2.70 (t, J = 7.2 Hz, 2H), 2.58 (s, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.6, 155.0, 144.5, 138.0, 133.2, 133.0, 128.7, 128.0, 127.5, 124.8, 113.8, 66.8, 55.1, 53.9, 44.1, 40.3. HRMS (ESI) m/z calcd for C22H25N4O3+ (M + H)+ 393.1921, found 393.1919.
Route B: To a solution of quinoxalin-2(1H)-one (3 mmol, 1.0 equiv) and K2CO3 (2.5 equiv) in DMF (30 mL), 4-(2-chloroethyl)morpholine hydrochloride (1.5 equiv) was added and stirred at 90 °C for 6 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl methanol/methylene chloride (0–10%) to afford compound 5 as dark yellow sticky oil, 90% yield.
To a solution of compound 5 (0.5 mmol) and 2.5 mL of aqueous perchloric acid (0.2 M) in a vial, benzyl isocyanide (0.75 mmol) was added and sealed. The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (15 mL) and washed with saturated sodium bicarbonate and brine successively. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of methanol/methylene chloride (0–10%) to afford compound 4 as a yellow solid, 88% yield.
Acknowledgments
The authors thank the Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN202001338 and KJQN202101340), the Natural Science Foundation of Chongqing Science and Technology Bureau (CSTB2022NSCQ-MSX0868, cstc2020jcyj-msxmX0733, and cstc2018jszx-cyzdX0023), and the Scientific Research Foundation of the Chongqing University of Arts and Sciences (P2019XY01). They also thank H.Z. Liu and J. Xu for obtaining the LC/MS, HRMS, and NMR data.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06946.
Copies of the 1H NMR and 13C {1H} NMR spectra of all compounds (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
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