1. Introduction
Chemodivergent reactions are interesting and efficient protocols that form the structurally different heterocyclic compounds from the same starting materials through simple change of reaction conditions [1,2,3,4,5,6,7,8,9,10]. Among them, the solvent-dependent or solvent-controlled chemodivergent reactions have been well applied in the synthesis of heterocyclic compounds [11,12,13,14,15,16,17,18,19,20,21]. On the other hand, benzo-fused seven- and six-membered heterocycles containing two heteroatoms of oxygen and nitrogen such as 1,4-benzoxazepin-5(4H)-ones [22], 3,4-dihydro-1,4-benzoxazepin-5(2H)-ones [23,24], 2,3,4,5-tetrahydro-1,4-benzoxazepines [25,26,27,28,29], and 2,3-dihydro-1,3-benzoxazin-4(4H)-ones [30,31,32], are important and interesting heterocyclic compounds due to their wide spectrum of biological activities (Scheme 1). In addition, as the structures shown in Scheme 1, 1,4-benzoxazepin-5(4H)-one is the useful and potential precursor for the synthesis of its derivatives by simple transformation. Therefore, the synthetic approach to 1,4-benzoxazepin-5(4H)-one ring has been well investigated. However, the known procedures for the formation of the seven-membered benzo-fused heterocycle either are multi-step with low atom-utilization or using uneasily available starting materials catalyzed by palladium complexes [33,34,35].
As part of our continued interest in the development of the application of base/DMSO-promoted SNAr reaction for the formation of C–N bond under transition-metal-free conditions [36,37,38], and the chemodivergent transformations of alkynes [39,40,41], as well as the new synthetic methods of heterocyclic compounds [42,43,44], we herein describe an efficient protocol for the formation of 1,4-benzoxazepin-5(4H)-ones and 2-vinyl-1,3-benzoxazin-4(4H)-ones via KOH-promoted solvent-controlled intermolecular cyclization reaction between substituted ortho-fluorobenzamide and 2-propyn-1-ol [45].
2. Results and Discussion
Table 1 concludes the results from the reaction of ortho-fluoro-N-propylbenzamide (1a) with 2-propyn-1-ol. We firstly examined the reaction of 1a with 2-propyn-1-ol (1.2 equivalents) in the presence of KOH (3.0 equivalents) in DMSO at 50 °C for 12 h. Two products could be isolated from the reaction mixture, and their structures were confirmed to be N-propyl-3-methyl-1,4- benzoxazepin-5(4H)-one (2a, 45%) and N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-ones (3a, 12%) (entry 1) [46]. When the same reaction was repeated at 30 °C, the yield of 2a was slightly increased (entry 2), and if the reaction was carried out at 30 °C for 12 h firstly and then 50 °C for 12 h, 2a was isolated in 54% yield (entry 3). In this case, 3a was determined only in a small amount (<5%) in the reaction mixture with the complete conversion of 1a. The use of either 1.0 equivalent or 1.5 equivalents of 2-propyn-1-ol resulted in the decrease of 2a yield (entries 4 and 5). Increase of the reaction temperature to 70 °C for 12 h also led to the lower yield of 2a (entry 6). Decreasing the amount of KOH to 1.0 or 2.0 equivalents affected the formation of 2a (entries 7 and 8). Other inorganic bases, such as NaOH, K2CO3, Cs2CO3, and t-BuOK were not efficient in promoting the cyclocondensation (entries 9–12). Very interestingly, the screening of solvents disclosed that the selective chemodivergent formation of 2a and 3a greatly depended on the use of solvents (entries 13–18). In the cases of THF, DMF and a mixture solvent of DMSO/MeCN used, 3a was the major product, and in MeCN, 3a could be isolated in 83% yield with a small amount of 2a formation. In addition, either increasing the amount of 2-propyn-1-ol or increasing the reaction temperature did not improve the yield of 3a (entries 19 and 20).
The cyclocondensation of other substrates 1b–k, bearing different substituents on nitrogen or benzene ring with 2-propyn-1-ol, was then studied under the conditions of entry 3 in Table 1. As can be seen from Scheme 2, N-alkyl-2-fluorobenzamides (alkyl = Me (1b), isopropyl (1c), t-butyl (1d), t-amyl (1e), cyclopentyl (1f), cyclohexyl (1g)) showed similar reactivity to 1a affording the corresponding N-alkyl-3-methyl-1,4-benzoxazepin-5(4H)-ones (2b–2g) in good yields. It was also noted that N-phenyl-2-fluorobenzamide showed unexpectedly sluggish reactivity, and almost all starting materials could be recovered after the reaction under the same conditions. In addition, the results from the reactions of 2-fluoro-3-methyl-N-propylbenzamide (1h), 2-fluoro-4-methoxy-N- propylbenzamide (1i), and 4-chloro-2-fluoro-N-propylbenzamide (1j) with 2-propyn-1-ol apparently indicated that the electron-withdrawing group in 1j was unfavorable in the formation of 1,4-benzoxazepin-5(4H)-one ring. Moreover, the reaction of 2-fluorobenzamide (1k), bearing an unprotected NH2 group, afforded the corresponding product (2k) in only 31% yield. It should be noted that the reaction of ortho-fluorobenzamides bearing a strong electron-withdrawing group, such as 2-fluoro-5-nitro-N-propylbenzamide (1l) and 2-fluoro-N-propyl-5-trifluoromethyl- benzamide (1m), resulted in a complex mixture.
We also examined the substrate scope under the reaction conditions indicated in entry 17 of Table 1 access to 1,3-benzoxazin-4(4H)-ones (3) by reacting 2-propyn-1-ol with different ortho-fluorobenzamides in MeCN. As summarized in Scheme 3, the reactions of 1b–d and 1g–j afforded the corresponding 2-vinyl-1,3-benzoxazin-4(4H)-one derivatives 3b–d and 3g–j in good to high yields. It should be noted that, compared to KOH/DMSO system, ortho-fluorobenzamides having electron-withdrawing group displayed a higher reactivity than ones with an electron-donating group (1j vs. 1i) in KOH/MeCN in undergoing the cyclization reaction to give the expected cyclic products in good yield (3j vs. 2j and 3i vs. 2i) (vide infra). In addition, both 1l and 1m also showed good reactivity, giving the corresponding products of 3l and 3m (vide supra). Note that in KOH/MeCN, all the reactions occurred with excellent chemoselectivity, and only a trace amount of the corresponding product 2 formed in the reaction mixtures.
However, when substituted propargyl alcohols, such as 1-methyl-2-propyn-1-ol, 1-phenyl- 2-propyn-1-ol, 3-methyl-2-propyn-1-ol, and 3-phenyl-2-propyn-1-ol, were subjected to the similar reaction conditions, although the formation of the corresponding cyclic compounds 2 and 3 could be determined by GC-MS, the reactions unfortunately occurred not only with low chemoselectivity in both DMSO and MeCN solvents, but also with low total yields of 2 and 3.
In order to understand the chemodivergent formation of 2 and 3 switched by solvents, the observation of real-time reactions of 1a with 2-propyn-1-ol in NMR tube using DMSO-d6 or CD3CN were introduced. As shown in Scheme 4, in KOH/DMSO-d6, the cyclization reaction occurred fast, and a 1 h reaction at 30 °C resulted in the formation of 2a and 3a in 58% and 10% NMR yields, respectively. In this case, no considerable amount of intermediates could be observed in 1H-NMR. An additional 1 h reaction led to the yield increase of 2a to 74%, whereas the NMR yield of 3a was decreased to 6%. A subsequent 2 h reaction at 50 °C afforded 2a in 82% NMR yield, and 3a was determined in a small amount (<5%). In addition, we also examined the conversion of 3a in KOH/DMSO at 50 °C for 2 h, and found that 3a completely disappeared due possibly to its polymerization, as the formation of 2a could not be observed at all in the reaction mixture. Therefore, it can be concluded that in the KOH/DMSO system, the excellent regioselectivity for the formation of 2a resulted from the easy formation of 2a and the side-reaction of 3a.
On the other hand, in KOH/CD3CN, the reaction of 1a with 2-propyn-1-ol in NMR tube without stirring occurred very slowly, and only small amount of intermediate 4a could be determined from the SNAr reaction. 1a was almost remained, and neither 2a nor 3a formed at all at 30 °C for 12 h. Even a prolonged reaction time (at 30 °C for 36 h) did not result in the formation of considerable amount of 3a, and in this case, 4a was the major product. With the subsequent reaction at 50 °C for 12 h, 3a formed in 31% NMR yield, and in the sequent reaction for 36 h, the yield of 3a was increased to 54%.
Taking into consideration of the results shown in Scheme 2, Scheme 3 and Scheme 4, it might be concluded that the chemodivergent formation of either 2 or 3 switched by using DMSO or MeCN as solvents resulted from the base strength of the reaction mixture. KOH/DMSO was well-applied as the superbase medium to promote the diverse organic transformation due to the high solubility of KOH in DMSO [47], whereas KOH/MeCN is a medium alkaline condition owing to the low solubility of KOH in MeCN. In fact, the present reaction mixtures in DMSO were homogeneous to afford 2, but the reaction mixtures in MeCN were heterogeneous to give 3. Thus, it is also easy to understand why in NMR tube, without stirring, a very low rate of reaction in CD3CN was observed (Scheme 4 vs. Scheme 3).
On the basis of the obtained results and above discussion, a proposed mechanism for the formation of either 2 in DMSO or 3 in MeCN is depicted in Scheme 5. It involves the SNAr reaction of 1 with 2-propyn-1-ol, giving the intermediate of ortho-[(2-propynyl)oxy]benzamide 4. In the KOH/DMSO system, a superbase medium [47], the formation of 4 and the subsequent formation of a nitrogen anion 5 are very fast and favorable, leading to the quickly intramolecular nucleophilic addition to alkyne concurrently to construct the seven-membered ring via a 7-exo-dig cyclization, and the final protonation step afforded 2. On the other hand, in the KOH/MeCN system, a relatively weak base medium compared to KOH/DMSO, not only is the formation of 4 slow, but also the isomerization of 4 into allenyl intermediate 6 is possible [48], which undergoes the base-promoted intramolecular Michael addition of N–H to allene giving 3 [49].
We also examined the conversion of the isolated intermediate 4a under the similar reaction conditions as shown in Scheme 2 and Scheme 3. As expected, 2a and 3a could be isolated in 65% and 41% yields, respectively (Scheme 6).
3. Materials and Methods 3.1. General Methods
All commercial reagents and metal salts are analytically pure and used directly without further purification. 1k is commercially available and other ortho-fluoro-N-alkylbenzamides are known compounds and were prepared by a modified procedure via the reactions of ortho-fluorobenzoyl chlorides with primary amines (the procedure, yields in both weight and percentage, and 1H-NMR charts are reported in the Supplementary Information) [50]. KOH (99.99%) was obtained from Sigma-Aldrich (St. Louis, MO, USA). Nuclear magnetic resonance (NMR) spectra were recorded on an ECA-400 spectrometer (JEOL, Tokyo, Japan) using CDCl3 as solvent at 298 K. 1H NMR (400 MHz) chemical shifts (δ) were referenced to internal standard TMS (for 1H, δ = 0.00). 13C NMR (100 MHz) chemical shifts were referenced to internal solvent CDCl3 (for 13C, δ = 77.16). The high-resolution mass spectra (HRMS) with electron spray ionization (ESI) were obtained with a micrOTOF-Q spectrometer (Agilent, Santa Clara, CA, USA). The melting points were uncorrected. Single crystals of 2g and 3g were obtained by slow evaporation of their solution in a mixture solvent of acetone and n-hexane.
3.2. Typical Experimental Procedure for the Synthesis of N-Propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2a)
A mixture of 2-fluoro-N-propylbenzamide (1a, 90.5 mg, 0.5 mmol), 2-propyl-1-ol (ca. 34.0 mg, 0.6 mmol), KOH (84.0 mg, 1.5 mmol), and DMSO (4.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at 30 °C for 12 h, and then at 50 °C for 12 h. After the reaction mixture was cooled to room temperature, water (10 mL) was added with stirring, and the mixture was extracted with ethyl acetate three times (3 × 10 mL). The combined organic phases were dried over anhydrous MgSO4. The filtered solution was then concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate (gradient mixture ratio from 20:1 to 4:1 in volume) to afford 2a as a pale yellow oil in 54% yield (58.5 mg).
When MeCN was used as solvent to replace DMSO, the similar operation afforded N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-ones (3a) as a pale yellow oil in 83% yield (90.5 mg).
3.3. Characterization Data of Products:
N-Propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2a): Pale yellow oil (58.5 mg, 54%). 1H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.18 (apparent t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 5.43 (s, 1H), 3.57 (t, J = 7.4 Hz, 2H), 1.93 (s, 3H), 1.64–1.73 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.6, 160.5, 148.5, 133.1, 132.2, 127.3, 124.8, 120.1, 115.0, 49.8, 21.4, 17.7, 11.2. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1174.
N-Methyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2b): Pale yellow oil (54.1 mg, 57%). 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 (apparent td, J = 7.8, 1.8 Hz, 1H), 7.19 (apparent td, J = 7.8, 1.8 Hz, 1H), 6.97 (dd, J = 7.8, 1.8 Hz, 1H), 5.46 (s, 1H), 3.19 (s, 3H), 1.93 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.8, 160.4, 147.9, 133.1, 132.1, 126.9, 124.8, 120.1, 115.8, 35.9, 17.5. HRMS (ESI) m/z: [M + H]+ calcd for C11H12NO2, 190.0863; found, 190.0862.
N-Isopropyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2c): Pale yellow oil (64.7 mg, 60%). 1H NMR (400 MHz, CDCl3): δ 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.39 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.18 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.49 (s, 1H), 5.04 (hept, J = 6.8 Hz, 1H), 1.95 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 166.2, 160.5, 149.8, 132.9, 132.4, 127.3, 124.7, 112.0, 109.9, 45.7, 20.3, 17.7. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1173.
N-t-Butyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2d): Pale yellow oil (68.2 mg, 59%). 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 7.37 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.17 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.59 (q, J = 0.8 Hz, 1H), 1.90 (d, J = 0.8 Hz, 3H), 1.54 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 166.7, 161.2, 150.0, 132.5, 128.2, 124.5, 119.7, 113.7, 58.9, 28.7, 17.2. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1332.
N-t-Amyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2e): Pale yellow oil (62.1 mg, 51%). 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.36 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.16 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.56 (s, 1H), 2.02 (q, J = 7.5 Hz, 2H), 1.89 (s, 3H), 1.48 (s, 6H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.8, 161.3, 150.2, 132.5, 128.3, 124.6, 119.7, 114.3, 62.0, 32.4, 27.0, 17.2, 8.6. HRMS (ESI) m/z: [M + H]+ calcd for C15H20NO2, 246.1489; found, 246.1487.
N-Cyclopentyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2f): Pale yellow oil (78.1 mg, 64%). 1H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.37 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.16 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.94 (dd, J = 7.8, 1.6 Hz, 1H), 5.44 (s, 1H), 5.10 (pent, J = 8.2 Hz, 1H), 2.00–1.95 (m, 2H), 1.93 (s, 3H), 1.74–1.53 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 166.7, 160.5, 149.8, 132.9, 132.5, 127.3, 124.7, 112.0, 110.8, 55.6, 29.6, 24.6, 17.8. HRMS (ESI) m/z: [M + H]+ calcd for C15H18NO2, 244.1332; found, 244.1331.
N-Cyclohexyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2g): Pale yellow solid (89.4 mg, 70%). mp 63–65 °C. 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.19 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 5.51 (q, J = 0.9 Hz, 1H), 4.67–4.55 (m, 1H), 1.94 (d, J = 0.9 Hz, 3H), 1.91–1.78 (m, 4H), 1.73–1.62 (m, 2H), 1.50–1.40 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 166.2, 160.5, 149.3, 132.8, 132.4, 127.4, 124.7, 119.9, 110.9, 53.9, 30.7, 25.8, 25.6, 17.7. HRMS (ESI) m/z: [M + H]+ calcd for C16H20NO2, 258.1489; found, 258.1488.
N-Propyl-3,9-dimethyl-1,4-benzoxazepin-5(4H)-one (2h): Pale yellow oil (52.3 mg, 45%). 1H NMR (400 MHz, CDCl3): δ 7.67 (dd, J = 7.8, 1.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.07 (apparent t, J = 7.8 Hz, 1H), 5.45 (s, 1H), 3.57 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.97 (s, 3H), 1.76–1.65 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 167.0, 159.3, 148.7, 134.3, 129.9, 129.0, 127.4, 124.3, 115.5, 49.9, 21.5, 18.3, 16.1, 11.3. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1331.
8-Methoxyl-N-propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2i): Pale yellow oil (84.1 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.7 Hz, 1H), 6.73 (dd, J = 8.7, 2.8 Hz 1H), 6.48 (d, J = 2.8 Hz, 1H), 5.43 (s, 1H), 3.83 (s, 3H), 3.55 (t, J = 7.4 Hz, 2H), 1.94 (s, 3H), 1.75–1.62 (m, 2H), 0.96 (td, J = 7.4, 3.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.2, 163.7, 161.6, 147.7, 133.5, 119.5, 115.1, 111.0, 105.1, 55.7, 49.8, 21.5, 17.8, 11.3. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO3, 248.1281; found, 248.1279.
7-Chloro-N-propyl-3-methyl-1,4-benzoxazepin-5(4H)-one (2j): Pale yellow oil (22.3 mg, 18%). 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 2.8 Hz, 1H), 7.34 (dd, J = 8.0, 2.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.43 (s, 1H), 3.56 (t, J = 7.4 Hz, 2H), 1.93 (s, 3H), 1.70–1.62 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 165.3, 159.0, 148.8, 132.9, 131.9, 130.2, 128.6, 121.6, 115.0, 50.0, 21.4, 17.7, 11.3. HRMS (ESI) m/z: [M + H]+ calcd for C13H15ClNO2, 252.0786; found, 252.0786.
3-Methyl-1,4-benzoxazepin-5(4H)-one (2k) [23]: Pale yellow oil (26.9 mg, 31%). 1H NMR (400 MHz, CDCl3): δ 11.18 (s, 1H), 7.71 (dd, J = 7.8, 1.6 Hz, 1H), 7.24 (ddd, J = 8.3, 7.8, 1.6 Hz, 1H), 6.97 (dd, J = 7.8, 1.6 Hz, 1H), 6.88 (ddd, J = 8.3, 7.8, 1.6 Hz, 1H), 6.75 (q, J = 1.2 Hz, 1H), 2.33 (d, J = 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 160.6, 157.1, 147.9, 131.9, 125.7, 122.1, 119.4, 117.2, 111.5, 11.0.
N-Propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3a): Pale yellow oil (90.5 mg, 83%). 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 7.8, 1.8 Hz, 1H), 7.41 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.07 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.91 (dd, J = 7.8, 1.8 Hz, 1H), 5.97 (ddd, J = 16.8, 10.2, 5.8 Hz, 1H), 5.64 (d, J = 5.8 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.36 (d, J = 10.2 Hz, 1H), 3.93 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H), 2.97 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H), 1.77–1.62 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 161.4, 155.4, 134.1, 132.6, 128.0, 122.4, 120.9, 118.7, 116.8, 87.7, 45.8, 21.7, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1175.
N-Methyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3b) [45]: Pale yellow oil (73.7 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 (apparent td, J = 7.8, 1.7 Hz, 1H), 7.07 (apparent td, J = 7.8, 1.7 Hz, 1H), 6.92 (dd, J = 7.8, 1.7 Hz, 1H), 5.97 (ddd, J = 16.8, 10.2, 6.0 Hz, 1H), 5.61 (d, J = 6.0 Hz, 1H), 5.45–5.34 (m, 2H), 3.07 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.8, 155.5, 134.2, 131.9, 128.0, 122.4, 121.1, 118.3, 116.8, 89.2, 31.1. HRMS (ESI) m/z: [M + H]+ calcd for C11H12NO2, 190.0863; found, 190.0861.
N-Isopropyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3c): Pale yellow oil (89.0 mg, 81%). 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.05 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.88 (dd, J = 7.8, 1.6 Hz, 1H), 5.97 (ddd, J = 16.8, 10.0, 6.0 Hz, 1H), 5.78 (d, J = 6.0 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.29 (d, J = 10.0 Hz, 1H), 4.85 (hept, J = 6.8 Hz, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 160.7, 154.9, 134.6, 133.9, 128.0, 122.2, 120.5, 119.5, 116.7, 82.9, 45.0, 20.9, 20.7. HRMS (ESI) m/z: [M + H]+ calcd for C13H16NO2, 218.1176; found, 218.1175.
N-t-Butyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3d): Pale yellow oil (89.9 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.38 (apparent td, J = 7.8, 1.6 Hz, 1H), 7.03 (apparent td, J = 7.8, 1.6 Hz, 1H), 6.86 (dd, J = 7.8, 1.6 Hz, 1H), 6.05–5.92 (m, 2H), 5.41 (d, J = 16.8 Hz, 1H), 5.29 (d, J = 10.0 Hz, 1H), 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 162.1, 154.7, 134.9, 133.8, 127.9, 122.1, 120.5, 120.4, 116.4, 84.6, 57.4, 28.8. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1331.
N-Cyclohexyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3g): White solid (109.6 mg, 85%). mp 84–86 °C. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.8 Hz, 1H), 7.39 (apparent t, J = 7.8 Hz, 1H), 7.05 (apparent t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.95 (ddd, J = 16.8, 10.6, 5.7 Hz, 1H), 5.80 (d, J = 5.7 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.28 (d, J = 10.6 Hz, 1H), 4.48 (tt, J = 12.2, 3.4 Hz, 1H), 1.98–1.01 (m, 10H). 13C NMR (100 MHz, CDCl3): δ 160.8, 155.0, 134.7, 134.0, 128.1, 122.3, 120.1, 119.7, 116.8, 83.2, 52.9, 31.4, 31.2, 26.0, 25.9, 25.6. HRMS (ESI) m/z: [M + H]+ calcd for C16H20NO2, 258.1489; found, 258.1487.
N-Propyl-2-vinyl-8-methyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3h): Pale yellow oil (65.8 mg, 54%). 1H NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.25 (dd, J = 7.8, 1.5 Hz, 1H), 6.95 (apparent t, J = 7.8 Hz, 1H), 5.95 (ddd, J = 17.0, 10.6, 6.4 Hz, 1H), 5.67 (d, J = 6.4 Hz, 1H), 5.38 (d, J = 17.0 Hz, 1H), 5.32 (d, J = 10.6 Hz, 1H), 3.94 (ddd, J = 14.0, 8.0, 6.4 Hz, 1H), 2.97 (ddd, J = 14.0, 8.0, 6.4 Hz, 1H), 2.21 (s, 3H), 1.78–1.59 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 161.6, 153.5, 135.0, 132.7, 126.0, 125.4, 121.8, 120.4, 118.3, 87.4, 45.7, 21.6, 15.2, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO2, 232.1332; found, 232.1331.
7-Methoxyl-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3i): Pale yellow oil (55.5 mg, 45%). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.8 Hz, 1H), 6.62 (dd, J = 8.8, 2.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 5.98 (ddd, J = 16.8, 10.4, 5.9 Hz, 1H), 5.61 (d, J = 5.9 Hz, 1H), 5.40 (d, J = 16.8 Hz, 1H), 5.35 (d, J = 10.4 Hz, 1H), 3.91 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H), 3.81 (s, 3H), 2.95 (ddd, J = 14.0, 8.0, 6.8 Hz, 1H), 1.72–1.58 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.5, 161.5, 157.1, 132.6, 129.5, 120.8, 111.8, 109.4, 101.1, 88.0, 55.7, 45.6, 21.7, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C14H18NO3, 248.1281; found, 248.1279.
6-Chloro-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3j): Pale yellow oil (76.2 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.94 (ddd, J = 17.0, 10.3, 5.5 Hz, 1H), 5.65 (d, J = 5.5 Hz, 1H), 5.40 (d, J = 17.0 Hz, 1H), 5.38 (d, J = 10.3 Hz, 1H), 3.92 (ddd, J = 14.0, 8.4, 7.2 Hz, 1H), 2.96 (ddd, J = 14.0, 8.4, 7.2 Hz, 1H), 1.72–1.63 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 160.3, 153.9, 133.9, 132.2, 127.8, 127.7, 121.3, 119.9, 118.4, 87.7, 46.0, 21.6, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C13H15ClNO2, 252.0786; found, 252.0785.
6-Nitro-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3l): Pale yellow oil (85.4 mg, 65%). 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 2.8 Hz, 1H), 8.30 (dd, J = 8.9, 2.8 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 5.94 (ddd, J = 17.0, 10.3, 5.4 Hz, 1H), 5.78 (dd, J = 5.4, 0.8 Hz, 1H), 5.44 (dd, J = 17.0, 0.8 Hz, 1H), 5.44 (d, J = 10.3 Hz, 1H), 3.97 (ddd, J = 14.0, 8.2, 6.8 Hz, 1H), 3.01 (ddd, J = 14.0, 8.2, 6.8 Hz, 1H), 1.83–1.67 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 159.9, 159.5, 143.0, 131.6, 129.2, 124.5, 121.9, 118.8, 118.0, 88.2, 46.2, 21.5, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C13H15N2O4, 263.1026; found, 263.1023.
6-Trifluoromethyl-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one (3m): Pale yellow oil (103.8 mg, 73%). 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.6, 2.1 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 5.94 (ddd, J = 16.4, 10.4, 5.5 Hz, 1H), 5.71 (d, J = 5.5 Hz, 1H), 5.40 (d, J = 16.4 Hz, 1H), 5.40 (d, J = 10.4 Hz, 1H), 3.95 (ddd, J = 14.1, 8.0, 6.5 Hz, 1H), 2.98 (ddd, J = 14.1, 8.0, 6.5 Hz, 1H), 1.72–1.62 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 160.2, 157.7, 132.0, 130.84 (q, J = 13.0 Hz), 125.8 (q, J = 13.0 Hz), 124.9 (q, J = 34.0 Hz), 123.9 (q, J = 270.0 Hz), 121.5, 118.7, 117.6, 87.90, 46.02, 21.55, 11.36. HRMS (ESI) m/z: [M + H]+ calcd for C14H15F3NO2, 286.1049; found, 286.1046.
4. Conclusions
In summary, a facile and efficient solvent-controlled chemodivergent synthesis of 1,4-benzoxazepin-5(4H)-ones and 1,3-benzoxazin-4(4H)-ones via the KOH-promoted cyclization of ortho-fluorobenzamides with 2-propyn-1-ol was developed. The cyclization reaction was proposed to involve the SNAr reaction of C–F bond with 2-propyn-1-ol to give ortho-[(2-propynyl)oxy]benzamide intermediates, which underwent the intramolecular either 7-exo-dig cyclization in a superbase medium of KOH/DMSO or a Michael addition of N–H to allenyl intermediate in KOH/MeCN medium to give different benzo-fused cyclic compounds. The present protocol had the significant advantages of high atom-utilization and high selectivity of product output controlled by simple changing the solvents.
Supplementary Materials
The following are available online: Synthesis of known compound 1, copies of 1H NMR spectra of the prepared 1, copies of NMR spectra of 2, copies of NMR spectra of 3, X-ray structural details of 2g and 3g, results from the reactions of 1a with propargyl alcohol in either KOD/D2O/DMSO or KOD/D2O/MeCN.
Author Contributions
Investigation, writing-original draft preparation, Q.C.; investigation, Y.W.; conceptualization, supervision, writing-review and editing, R.H.
Funding
Financial support from the National Natural Science Foundation of China (No. 21473097 and No. 21673124).
Conflicts of Interest
The authors declare no conflict of interest.
References and Notes
Scheme 1.1,4-Benzoxazepin-5(4H)-ones, 1,3-benzoxazin-4(4H)-ones, and their derivatives.
Scheme 1.1,4-Benzoxazepin-5(4H)-ones, 1,3-benzoxazin-4(4H)-ones, and their derivatives.
Scheme 2.Formation of 1,4-benzoxazepin-5(4H)-ones in KOH/DMSO a.
Scheme 2.Formation of 1,4-benzoxazepin-5(4H)-ones in KOH/DMSO a.
Scheme 3.Formation of 1,3-benzoxazin-4(4H)-ones in KOH/MeCN a.
Scheme 3.Formation of 1,3-benzoxazin-4(4H)-ones in KOH/MeCN a.
Scheme 4.Real-time monitoring of 1a with 2-propyn-1-ol reaction a.
Scheme 4.Real-time monitoring of 1a with 2-propyn-1-ol reaction a.
Scheme 5.Proposed mechanism for the chemodivergent formation of 1,4-benzoxazepin-5(4H)-ones and 1,3-benzoxazin-4(4H)-ones.
Scheme 5.Proposed mechanism for the chemodivergent formation of 1,4-benzoxazepin-5(4H)-ones and 1,3-benzoxazin-4(4H)-ones.
Scheme 6.Formation of 2a and 3a from intermediate 4a.
Scheme 6.Formation of 2a and 3a from intermediate 4a.
Table
Table 1.Effects of reaction conditions on the chemodivergent formation of 1,4-benzoxazepin-5(4H)-ones and 1,3-benzoxazin-4(4H)-ones a.
[ Table omitted. See PDF. ]
a Unless otherwise noted, the reactions were carried out using 0.5 mmol of 1a, 0.6 mmol of 2-propyn-1-ol, and 1.5 mmol of base in 4.0 mL of solvent. b Isolated yields. c 0.5 mmol of 2-propyn-1-ol was used. d 0.75 mmol of 2-propyn-1-ol was used. e DMAc: N,N-dimethyl acetamide.
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Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Beijing 100084, China
*Author to whom correspondence should be addressed.
Academic Editor: Alejandro Baeza Carratalá
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