Abstract
The reactions of β-aminoethanethiol with N,N-dimethyl enaminones are performed to selectively provide disulfide-functionalized enaminones and 1,4-thiazines. By performing the reaction in water and catalyst-free conditions, the transamination and oxidative S–S coupling between the two substrates take place to give disulfide-functionalized enaminones. On the other hand, by using identical starting materials, the employment of the CuI catalyst in dimethyl sulfoxide enables the selective generation of 1,4-thiazines via tandem transamination and C(sp2)–H bond thiolation.
Introduction
Enaminones are highly useful building blocks in organic synthesis. Owing to the versatile reactive sites of different functions in enaminones, their application spans widely from diversity-oriented synthesis to target-oriented synthesis.1 Although a number of different reaction models employing enaminones as building blocks have been already disclosed, a significant issue in further expanding the synthetic application of enaminones is preparing enaminones with unprecedented functional substructures. On the other hand, the featured S–S bond in disulfide is well-documented as a useful group with widespread utility in organic synthesis or bioactive molecules.2 Therefore, installing disulfide structure to enaminones can reasonably be useful because disulfide-functionalized enaminones are potentially valuable building blocks in the synthesis of diverse organic products.
1,4-Thiazine is a typical N,S-heterocyclic backbone with enriched pharmacological profiles, such as vasopressin receptor antagonistic activity,3 antimicrobial activity,4 calcium antagonistic activity,5 and so forth. Currently, 1,4-thiazines are known to be synthetically accessible by several different synthetic methods, including the reactions of tertiary diisopropylamines and sulfurothious dichloride,6 the tandem C–S cross-coupling and S-nucleophilic substitution reactions,7 the ring-forming reactions of electron-deficient alkynes and α-hydroxyimino-β-oxodithioesters,8 the microwave-assisted ring-opening reactions of 2-aminobenzothiazoles with terminal alkynes,9 and the base-catalyzed cascade reactions between 1,4-dithiane-2,5-diol and 1,2-diaza-1,3-dienes.10 Despite the rich availability on the synthetic methods toward 1,4-thiazines, some limits such as harsh reaction condition, tedious preparation of substrates, and/or unsatisfactory application scope remain to be improved. In this regard, developing new methods on 1,4-thiazine synthesis to complement those known works is still highly desirable.
Recently, our and other groups have disclosed that the direct C(sp2)–H bond thiolation of enaminones is a highly useful transformation in designing the synthesis of various sulfur-containing products such as sulfenylated enaminones,11 sufur-bridged bisenaminones,12 sulfenylated chromones,13 and sulfonylated chromones.14 Inspired by these results and our sustaining efforts in developing new reactions based on the enaminone building block, we report herein the reactions of enaminones and β-aminoethanethiol for the tunable synthesis of disulfide-functionalized enaminones and 1,4-thiazines via tandem transformation of transamination,15 S–S bond formation, or the selective C(sp2)–H bond thiolation.
Results and Discussion
Initially, the reaction of enaminone 1a and β-aminoethanethiol 2 was carried out in the presence of molecular iodine in ethyl lactate (EL), and heating at 90 °C led to the formation of enamino disulfide 3a with a moderate yield (entry 1, Table 1). Subsequently, reaction conditions were briefly optimized on the same reaction. It was found that equally good result could be obtained without using any catalyst (entry 2, Table 1). Moreover, the variation on the reaction medium indicated that water was the best medium for this reaction. Furthermore, the entries conducted at different temperatures proved that 70 °C was the most favorable temperature (entries 6–8, Table 1).
Table 1. Different Conditions for the Formation of Disulfide-Functionalized Enaminonea.
| entry | catalyst | solvent | T (°C) | yield (%)b |
|---|---|---|---|---|
| 1 | I2 | EL | 90 | 69 |
| 2 | no | EL | 90 | 72 |
| 3 | no | DMF | 90 | 47 |
| 4 | no | DMSO | 90 | 18 |
| 5 | no | toluene | 90 | 15 |
| 6 | no | H2O | 90 | 90 |
| 7 | no | H2O | 70 | 92 |
| 8 | no | H2O | 50 | 56 |
General conditions: 1a (0.4 mmol), 2 (0.4 mmol), catalyst (0.12 mmol or no catalyst), and 2 mL of solvent stirred for 12 h at rt under air atmosphere.
Yield of the isolated product.
To examine the application scope of this catalyst-free protocol, a broad array of N,N-dimethyl enaminones 1 were individually subjected with β-aminoethanethiol 2 in water. As outlined in Table 2, the enaminone substrate exhibited broad tolerance to this transformation, and the products with various functional groups such as alkyl, alkoxyl, halogen, perfluoroalkyl, naphthyl, thiophenyl, and so forth in enaminone 1 participated in the reaction smoothly. Most of these products were acquired with excellent yields under the standard reaction conditions. No notable effect of the substituent in the substrate 1 to the yield of the products was observed. However, because of the limited availability of a similar aminothiol substrate, the synthesis using different aminothiols was not conducted.
Table 2. Catalyst-Free Synthesis of Different Disulfide-Functionalized Enaminonesa.
| entry | Ar | product | yieldb (%) |
|---|---|---|---|
| 1 | Ph | 3a | 92 |
| 2 | 4-CH3C6H4 | 3b | 94 |
| 3 | 3-CH3OC6H4 | 3c | 96 |
| 4 | 2-CH3C6H4 | 3d | 78 |
| 5 | 3,4-(OCH2O)C6H3 | 3e | 88 |
| 6 | 4-ClC6H4 | 3f | 90 |
| 7 | 4-BrC6H4 | 3g | 91 |
| 8 | 4-CF3C6H4 | 3h | 86 |
| 9 | 4-NCC6H4 | 3i | 84 |
| 10 | 3-ClC6H4 | 3j | 89 |
| 11 | 3,4-Cl2C6H3 | 3k | 86 |
| 12 | naphth-2-yl | 3l | 93 |
| 13 | thiophen-3-yl | 3m | 85 |
General conditions: 1 (0.4 mmol), 2 (0.4 mmol) in 2 mL of H2O stirred at 70 °C for 12 h under air atmosphere.
Yield of the isolated product.
To develop the synthetic application of the enaminone and aminothiol substrates in the tunable synthesis of more diverse compounds, we assumed to accomplish the synthesis of 1,4-thiazines via the domino transamination and enaminone C–H thiolation. To our delight, after screening the catalytic conditions, the selective synthesis of 1,4-thiazine 4a was realized by employing a copper catalyst. As shown in Table 3, CuI displayed the best catalytic effect among the tested copper salts (entries 1–4, Table 3). The dimethyl sulfoxide (DMSO), on the other hand, was found to be much better medium than MeCN, toluene, dioxane, 1,1-dichloroethane (DCE), water, and EL for the selective formation of 4a (entries 5–11, Table 3). The variation on the reaction temperature suggested that neither heightening nor lowering the temperature was effective to improve the result (entries 12–13, Table 3). What is more, reducing the loading of CuI to 0.1 equiv led to a sharp decrease on the yield of 4a (entry 14, Table 3). In addition, the reaction conducted in the presence of NiCl2 gave 4a with a low yield, and no expected product was observed when FeCl3 was used as a catalyst (entries 15–16, Table 3).
Table 3. Optimization Data for the Synthesis of 1,4-Thiazinesa.
| entry | catalyst | solvent | T (°C) | yieldb (%) |
|---|---|---|---|---|
| 1 | Cu(OAc)2 | CH3CN | 70 | 45 |
| 2 | CuCl | CH3CN | 70 | 55 |
| 3 | CuBr | CH3CN | 70 | 51 |
| 4 | CuI | CH3CN | 70 | 58 |
| 5 | CuI | toluene | 70 | trace |
| 6 | CuI | dioxane | 70 | 53 |
| 7 | CuI | DMF | 70 | 70 |
| 8 | CuI | DMSO | 70 | 73 |
| 9 | CuI | DCE | 70 | nr |
| 10 | CuI | H2O | 70 | trace |
| 11 | CuI | EL | 70 | 40 |
| 12 | CuI | DMSO | 80 | 68 |
| 13 | CuI | DMSO | 60 | 65 |
| 14c | CuI | DMSO | 70 | 41 |
| 15 | NiCl2 | DMSO | 70 | 35 |
| 16d | FeCl3 | DMSO | 70 |
General conditions: 1a (0.2 mmol), 2 (0.2 mmol), and copper catalyst (0.3 equiv) in 2 mL of solvent stirred for 12 h.
Yield of the isolated product.
The loading of CuI was 0.1 equiv.
No expected product was observed.
To illustrate the scope on the selective synthesis of heterocyclic products 4, a class of different enaminones 1 were subjected to react with β-aminoethanethiol 2 in the presence of CuI. As outlined in Scheme 1, the examination on the synthesis of different 1,4-thiazines 4 containing various substitutions, including alkyl, alkoxyl, halogen, nitro, heteroaryl, and so forth, was smoothly furnished by using corresponding enaminone substrates (4a–4i, Scheme 1), suggesting the fine tolerance of the present catalytic reaction in the synthesis of diverse 1,4-thiazines. The products were generally afforded with moderate to good yield. The generally lower yield in the synthesis of 4 than disulfides 3 was afforded because of related enaminone disulfides was found as the minor byproducts in these entries.
Scheme 1. Scope on the Selective Synthesis of 1,4-Thiazines.
To explore the possible reaction mechanisms for the generation of products 4, several control experiments were conducted. At first, the model reaction of enaminone 1a and 2 could give 4a with good yield even in the presence of 5 equiv TEMPO, indicating that the ring formation reaction took place via the ionic pathway (eq 1). On the other hand, directly subjecting disulfide 3a to the standard condition enabled the production of 4a with excellent yield (eq 2). This result implied that disulfide 3a might be an intermediate in the formation of the heterocyclic products.
 |
1 |
 |
2 |
Under the inspiration of the control experiment results, the plausible mechanism for the reactions providing product 4 is proposed. As shown in Scheme 2, the transamination between the dimethyl amino group in 1 and primary amine as well as the aerobic oxidative S–S coupling of thiols is well-documented in the literature in which disulfide 3 is generated. Subsequently, the decomposition of 3 via the S–S bond cleavage affords Cu(I) species 5 and the iodothioite intermediate 6. The simultaneously generated iodine anion may get oxidized to molecular iodine under aerobic atmosphere. On the other hand, as the isomeric version of 5, intermediate 8 can readily be iodinated to provide 9 which undergoes intramolecular nucleophilic substitution to provide cyclic intermediate 10. The target product 4 is finally produced via the tautomerization of 10 (path a). However, considering the low yield in forming disulfide 3a in the entry using DMSO and starting materials 1a and 2 (entry 4, Table 1), it is also possible that the reaction proceeds directly via the thiolated NH enaminone intermediate 7, which can also react with CuI to provide intermediate 5. In addition, the subsequent transformations as in path a then led to the product 4 (path b).
Scheme 2. Proposed Mechanism for the Reactions Providing 1,4-Thiazines.
Conclusions
In summary, we have developed the tunable reactions between N,N-dimethyl enaminones and β-aminoethanethiol for the synthesis of enaminones containing the disulfide structure and 3,4-dihydro-1,4-thiazines. The former ones are produced by means of tandem transamination and oxidative S–S coupling by simply heating in water without any catalyst, and the latter compounds, on the other hand, were selectively afforded via transamination and C(sp2)–H bond thiolation by using CuI as the catalyst. The results disclose new applications of enaminones in the synthesis of diverse and useful organic products.
Experimental Section
General
All reactions were performed in an open air atmosphere under magnetic stirring. N,N-Dimethyl enaminones 1 were synthesized by following the literature procedure,16 and all other chemicals and solvents were obtained from commercial sources, which were used directly without further treatment. The 1H and 13C NMR spectra were recorded in a 400 MHz apparatus. The frequencies for 1H NMR and 13C NMR test are 400 and 100 MHz, respectively. The chemical shifts were reported in ppm with tetramethylsilane as an internal standard. Melting points were tested in a X-4A instrument without correcting the temperature, and the high-resolution mass spectrometry (HRMS) data for all new products were obtained under the ESI model.
General Procedure for the Synthesis of Disulfide Enaminones
To a 25 mL round-bottom flask were added enaminone 1 (0.4 mmol), β-aminoethanethiol 2 (0.4 mmol), and H2O (2 mL). Then, the mixture was heated up to 70 °C and stirred at the same temperature for 12 h under air atmosphere [thin-layer chromatography (TLC)]. After cooling down to room temperature (rt), the resulting mixture was extracted with ethyl acetate. The organic phases were collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid was filtered and the solvent was removed under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography to provide pure products with the elution of mixed petroleum ether/ethyl acetate (v/v = 1:1).
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-phenylprop-2-en-1-one) (3a)
Yield 92%, 76 mg; yellow solid; mp 124–125 °C; 1H NMR (400 MHz, CDCl3): δ 10.42 (s, 2H), 7.86 (d, J = 6.8 Hz, 4H), 7.47–7.38 (m, 6H), 6.96 (dd, J = 12.5, 7.5 Hz, 2H), 5.72 (d, J = 7.5 Hz, 2H), 3.59 (q, J = 6.5 Hz, 4H), 2.87 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 190.3, 154.0, 139.6, 131.0, 128.3, 127.1, 91.0, 47.8, 39.4; ESI-HRMS calcd for C22H24N2NaO2S2 [M + Na]+ 435.1171; found, 435.1163.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(p-tolyl)prop-2-en-1-one) (3b)
Yield 94%, 83 mg; yellow solid; mp 121–123 °C; 1H NMR (400 MHz, CDCl3): δ 10.37 (s, 2H), 7.76 (d, J = 8.1 Hz, 4H), 7.20 (d, 8.0 Hz, 4H), 6.93 (dd, J = 12.5, 7.5 Hz, 2H), 5.69 (d, J = 7.5 Hz, 2H), 3.57 (q, J = 6.5 Hz, 4H), 2.86 (t, J = 6.6 Hz, 4H), 2.38 (s, 6H); 13C NMR (100 MHz, CDCl3): 190.1, 153.8, 141.4, 136.9, 129.0, 127.2, 90.8, 47.8, 39.4, 21.5; ESI-HRMS calcd for C24H28N2NaO2S2 [M + Na]+ 463.1484; found, 463.1485.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(3-methoxyphenyl)prop-2-en-1-one) (3c)
Yield 96%, 91 mg; yellow oil; 1H NMR (400 MHz, CDCl3): δ 10.41 (s, 2H), 7.42 (d, J = 7.9 Hz, 4H), 7.32–7.27 (m, 2H), 7.01–6.93 (m, 4H), 5.70 (d, J = 7.5 Hz, 2H), 3.84 (s, 6H), 3.59 (q, J = 6.4 Hz, 4H), 2.85 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 189.9, 159.7, 154.1, 141.1, 129.2, 119.6, 117.4, 111.8, 91.0, 55.4, 47.8, 39.3; ESI-HRMS calcd for C24H28N2NaO4S2 [M + Na]+ 495.1383; found, 495.1379.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(o-tolyl)prop-2-en-1-one) (3d)
Yield 78%, 69 mg; yellow oil; 1H NMR (400 MHz, CDCl3): δ 10.28 (s, 2H), 7.41 (d, J = 7.1 Hz, 2H), 7.27–7.16 (m, 6H), 6.89 (dd, J = 12.6, 7.5 Hz, 2H), 5.35 (d, J = 7.4 Hz, 2H), 3.59 (q, J = 6.6 Hz, 4H), 2.88 (t, J = 6.5 Hz, 4H), 2.46 (s, 6 H); 13C NMR (100 MHz, CDCl3): 195.3, 153.5, 141.4, 135.8, 131.0, 129.3, 127.5, 125.4, 95.0, 47.9, 39.3, 20.4; ESI-HRMS calcd for C24H28N2NaO2S2 [M + Na]+ 463.1484; found, 463.1495.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one) (3e)
Yield 88%, 88 mg; yellow solid; mp 123–124 °C; 1H NMR (400 MHz, CDCl3): δ 10.29 (s, 2H), 7.44 (d, J = 6.8 Hz, 2H), 7.38 (s, 2H), 6.91 (dd, J = 12.5, 7.6 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.00 (s, 4H), 5.62 (d, J = 7.6 Hz, 2H), 3.57 (q, J = 6.5 Hz, 4H), 2.86 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 188.9, 153.7, 150.1, 147.8, 134.3, 122.3, 107.8, 107.5, 101.5, 90.5, 47.8, 39.5; ESI-HRMS calcd for C24H24N2NaO6S2 [M + Na]+ 523.0968; found, 523.0978.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(4-chlorophenyl)prop-2-en-1-one) (3f)
Yield 90%, 86 mg; yellow solid; mp 134–135 °C; 1H NMR (400 MHz, CDCl3): δ 10.42 (s, 2H), 7.79 (d, J = 8.5 Hz, 4H), 7.37 (d, J = 8.5 Hz, 4H), 6.96 (dd, J = 12.6, 7.5 Hz, 2H), 5.65 (d, J = 7.5 Hz, 2H), 3.60 (q, J = 6.4 Hz, 4H), 2.86 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 188.8, 154.4, 137.9, 137.2, 128.5, 100.0, 90.6, 47.8, 39.3; ESI-HRMS calcd for C22H22Cl2N2NaO2S2 [M + Na]+ 503.0392; found, 503.0409.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(4-bromophenyl)prop-2-en-1-one) (3g)
Yield 91%, 103 mg; yellow solid; mp 138–139 °C; 1H NMR (400 MHz, CDCl3): δ 10.43 (s, 2H), 7.72 (d, J = 8.4 Hz, 4H), 7.53 (d, J = 8.3 Hz, 4H), 6.97 (dd, J = 12.6, 7.5 Hz, 2H), 5.65 (d, J = 7.5 Hz, 2H), 3.60 (q, J = 6.4 Hz, 4H), 2.87 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 188.9, 154.4, 138.3, 131.5, 128.7, 125.7, 90.6, 47.8, 39.4; ESI-HRMS calcd for C22H22Br2N2NaO2S2 [M + Na]+ 590.9382; found, 590.9361.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one) (3h)
Yield 86%, 94 mg; white solid; mp 136–137 °C; 1H NMR (400 MHz, CDCl3): δ 10.54 (s, 2H), 7.94 (d, J = 8.1 Hz, 4H), 7.66 (d, J = 8.2 Hz, 4H), 7.02 (dd, J = 12.7, 7.4 Hz, 2H), 5.70 (d, J = 7.4 Hz, 2H), 3.63 (q, J = 6.4 Hz, 4H), 2.88 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 188.6, 154.8, 142.6, 132.6–132.3 (d, J = 32.5 Hz), 127.4, 125.3–125.2 (q, J = 3.6 Hz), 122.6, 90.9, 47.8, 39.2; ESI-HRMS calcd for C24H22F6N2NaO2S2 [M + Na]+ 571.0919; found, 571.0940.
4,4′-((2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(acryloyl))dibenzonitrile (3i)
Yield 84%, 78 mg; yellow solid; mp 142–143 °C; 1H NMR (400 MHz, CDCl3): δ 10.57 (s, 2H), 7.93 (d, J = 8.3 Hz, 4H), 7.70 (d, J = 8.3 Hz, 4H), 7.04 (dd, J = 12.7, 7.4 Hz, 2H), 5.70 (d, J = 7.4 Hz, 2H), 3.65 (q, J = 6.4 Hz, 4H), 2.90 (t, J = 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3): 187.8, 155.1, 143.2, 132.2, 127.6, 118.5, 114.3, 90.9, 47.9, 39.2; ESI-HRMS calcd for C24H22N4NaO2S2 [M + Na]+ 485.1076; found, 485.1086.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(3-chlorophenyl)prop-2-en-1-one) (3j)
Yield 89%, 85 mg; yellow solid; mp 73–74 °C; 1H NMR (400 MHz, CDCl3): δ 10.44 (s, 2H), 7.84 (s, 2H), 7.72 (d, J = 7.7 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 6.98 (dd, J = 12.6, 7.4 Hz, 2H), 5.66 (d, J = 7.4 Hz, 2H), 3.60 (q, J = 6.2 Hz, 4H), 2.86 (t, J = 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3): 188.4, 154.6, 141.3, 134.4, 130.9, 129.6, 127.3, 125.2, 90.7, 47.8, 39.3; ESI-HRMS calcd for C22H22Cl2N2NaO2S2 [M + Na]+ 503.0392; found, 503.0382.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(3,4-dichlorophenyl)prop-2-en-1-one) (3k)
Yield 86%, 94 mg; yellow solid; mp 96–97 °C; 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 2H), 7.94 (s, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 6.99 (dd, J = 12.7, 7.4 Hz, 2H), 5.63 (d, J = 7.4 Hz, 2H), 3.61 (q, J = 6.4 Hz, 4H), 2.87 (t, J = 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3): 187.2, 154.7, 139.3, 135.1, 132.7, 130.3, 129.2, 126.3, 90.4, 47.8, 39.3; ESI-HRMS calcd for C22H20Cl4N2NaO2S2 [M + Na]+ 570.9613; found, 570.9616.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(naphthalen-2-yl)prop-2-en-1-one) (3l)
Yield 93%, 95 mg; yellow solid; mp 140–141 °C; 1H NMR (400 MHz, CDCl3): δ 10.50 (s, 2H), 8.35 (s, 2H), 7.96–7.83 (m, 8H), 7.54–7.47 (m, 4H), 7.00 (dd, J = 12.5, 7.5 Hz, 2H), 5.85 (d, J = 7.5 Hz, 2H), 3.61 (q, J = 6.4 Hz, 4H), 2.88 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 190.1, 154.1, 136.9, 134.8, 132.8, 129.3, 128.0, 127.7, 127.3, 126.3, 124.1, 91.2, 47.8, 39.5; ESI-HRMS calcd for C30H28N2NaO2S2 [M + Na]+ 535.1484; found, 535.1494.
(2Z,2′Z)-3,3′-((Disulfanediylbis(ethane-2,1-diyl))bis(azanediyl))bis(1-(thiophen-3-yl)prop-2-en-1-one) (3m)
Yield 85%, 72 mg; yellow solid; mp 94–95 °C; 1H NMR (400 MHz, CDCl3): δ 10.24 (s, 2H), 7.87 (d, J = 2.9 Hz, 2H), 7.48 (d, J = 5.0 Hz, 2H), 7.28–7.27 (m, 2H), 6.91 (dd, J = 12.6, 7.5 Hz, 2H), 5.55 (d, J = 7.5 Hz, 2H), 3.57 (q, J = 6.5 Hz, 4H), 2.85 (t, J = 6.5 Hz, 4H); 13C NMR (100 MHz, CDCl3): 185.0, 153.8, 144.0, 128.2, 126.7, 125.7, 91.9, 47.8, 39.4; ESI-HRMS calcd for C18H20N2NaO2S4 [M + Na]+ 447.0300; found, 447.0295.
General Procedure for the Synthesis of 1,4-Thiazines
To a 25 mL round-bottom flask were added enaminones 1 (0.2 mmol), β-aminoethanethiol 2 (0.2 mmol), CuI (0.06 mmol), and DMSO (2 mL). Then, the mixture was heated up to 70 °C and stirred at the same temperature for 12 h under air atmosphere (TLC). After cooling down to rt, 5 mL of water was added, and the resulting mixture was extracted with ethyl acetate. The organic phases were collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid was filtered and the solvent was removed under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography to provide pure products with the elution of mixed petroleum ether/ethyl acetate (v/v = 1:1).
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(phenyl)methanone (4a)
Yield 73%, 30 mg; yellow solid; mp 171–172 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 1H), 7.45–7.36 (m, 5H), 7.26 (d, J = 7.2 Hz, 1H), 3.51–3.48 (m, 2H), 2.84 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 189.3, 146.7, 140.4, 129.9, 128.5, 128.2, 100.5, 42.4, 23.0; ESI-HRMS calcd for C11H11NNaOS [M + Na]+ 228.0454; found, 228.0450.
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(p-tolyl)methanone (4b)
Yield 75%, 33 mg; yellow solid; mp 258–260 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.45 (s, 1H), 7.29–7.21 (m, 5H), 3.50–3.47 (m, 2H), 2.83 (t, J = 4.8 Hz, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, DMSO-d6): 189.2, 146.3, 139.6, 137.5, 129.0, 128.4, 100.5, 42.3, 23.0, 21.4; ESI-HRMS calcd for C12H13NNaOS [M + Na]+ 242.0610; found, 242.0600.
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(3-methoxyphenyl)methanone (4c)
Yield 74%, 35 mg; yellow solid; mp 185–186 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.51 (s, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.95–6.90 (m, 2H), 3.77 (s, 3H), 3.51–3.48 (m, 2H), 2.83 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 188.9, 159.3, 146.7, 141.8, 129.6, 120.5, 115.7, 113.5, 100.4, 55.6, 42.4, 23.0; ESI-HRMS calcd for C12H13NNaO2S [M + Na]+ 258.0559; found, 258.0569.
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(o-tolyl)methanone (4d)
Yield 64%, 28 mg; yellow solid; mp 205–207 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.45 (s, 1H), 7.30–7.17 (m, 3H), 7.08 (d, J = 7.3 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 3.50–3.35 (m, 2H), 2.82 (t, J = 4.8 Hz, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6): 190.3, 146.3, 140.6, 135.2, 130.6, 128.8, 127.4, 125.5, 101.2, 42.4, 22.8, 19.3; ESI-HRMS calcd for C12H13NNaOS [M + Na]+ 242.0610; found, 242.0600.
(4-Chlorophenyl)(3,4-dihydro-2H-1,4-thiazin-6-yl)methanone (4e)
Yield 69%, 33 mg; yellow solid; mp 220–221 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.60 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 3.51–3.48 (m, 2H), 2.84 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 187.8, 146.9, 139.1, 134.7, 130.2, 128.6, 100.4, 42.4, 22.9; ESI-HRMS calcd for C11H10ClNNaOS [M + Na]+ 262.0064; found, 262.0054.
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(4-nitrophenyl)methanone (4f)
Yield 64%, 32 mg; yellow solid; mp 316–317 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 8.7 Hz, 2H), 7.77 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 7.3 Hz, 1H), 3.53–3.50 (m, 2H), 2.86 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 191.7, 153.0, 152.4, 151.3, 134.3, 128.6, 105.3, 47.2, 27.5; ESI-HRMS calcd for C11H10N2NaO3S [M + Na]+ 273.0304; found, 273.0307.
(3-Chlorophenyl)(3,4-dihydro-2H-1,4-thiazin-6-yl)methanone (4g)
Yield 67%, 32 mg; yellow solid; mp 184–185 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.53–7.33 (m, 4H), 7.28 (d, J = 7.3 Hz, 1H), 3.52–3.49 (m, 2H), 2.84 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 187.3, 147.1, 142.4, 133.3, 130.5, 129.8, 127.9, 126.9, 100.3, 42.4, 22.9; ESI-HRMS calcd for C11H10ClNNaOS [M + Na]+ 262.0064; found, 262.0055.
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(naphthalen-2-yl)methanone (4h)
Yield 73%, 37 mg; yellow solid; mp 262–263 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.03–8.00 (m, 1H), 7.95 (d, J = 9.0 Hz, 3H), 7.58–7.52 (m, 4H), 7.39 (d, J = 7.2 Hz, 1H), 3.54–3.51 (m, 2H), 2.87 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 189.1, 146.9, 137.6, 133.7, 132.5, 129.0, 128.2, 128.0, 127.7, 127.4, 127.0, 126.0, 100.8, 42.4, 23.0; ESI-HRMS calcd for C15H13NNaOS [M + Na]+ 278.0610; found, 278.0600.
(3,4-Dihydro-2H-1,4-thiazin-6-yl)(thiophen-3-yl)methanone (4i)
Yield 71%, 30 mg; yellow solid; mp 212–213 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J = 1.8 Hz, 1H), 7.57–7.54 (m, 3H), 7.19 (d, J = 4.9 Hz, 1H), 3.51–3.48 (m, 2H), 2.82 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): 183.4, 145.7, 141.5, 128.4, 127.5, 126.6, 101.1, 42.4, 23.0; ESI-HRMS calcd for C9H9NNaOS2 [M + Na]+ 234.0018; found, 234.0007.
Acknowledgments
This work is financially supported by the National Natural Science Foundation of China (21562025), Science Fund for Distinguished Young Scholars in Jiangxi Province (20162BCB23023), and an Open Project of the Key Laboratory of Rheumatic Diseases of Traditional Chinese Medicine in Zhejiang Province.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b01422.
1H and 13C NMR spectra for all products (PDF)
Author Contributions
All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
Supplementary Material
References
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