Highly efficient [3+3] cycloaddition reactions of in situ generated aza-oxyallyl cation with nitrones
-
Rongxing Chen
,
Shaofa Sun
and
Yalan Xing
Abstract
An efficient protocol was developed for the synthesis of 1,2,4-oxadiazinan-5-one derivatives via [3+3] cycloaddition of in situ generated aza-oxyallyl cations with nitrones. This method provides high yields of the heterocyclic products, excellent regioselectivity and broad substrate scope.
A number of medicinally important heterocycles have been prepared by [3+1], [3+2], [3+3], and [3+4] cycloadditions [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12] of aza-oxyallylic cations with various synthons including alkynes, dienes and aldehydes. However, the [3+3] cycloadditions of aza-oxyallylic cations with nitrones have not received much attention until recently [6]. To the best of our knowledge, reference [6] is the only report of this type of synthesis of 1,2,4-oxadiazinan-5-ones. Nitrones are particularly useful for the construction of a variety of nitrogen- and oxygen-containing five and six-membered heterocycles [13], [14], [15], [16], [17], [18], [19].
As part of our effort to develop efficient synthetic methodologies for the synthesis of heterocyclic molecules [19], [20], we wish to report the synthesis of 1,2,4-oxadiazinan-5-ones via [3+3] cycloaddition of in situ generated an aza-oxyallyl cation with nitrones. The aza-oxyallyl cation is easily generated from N-(benzyloxy)-2-bromo-2-methylpropanamide (1 in Scheme 1). Compared to Wang’s report [6], our method utilizes simple and readily available inorganic base Na2CO3 instead of 4-dimethylaminopyridine (DMAP) used in Wang’s reaction. Acetonitrile was employed as a solvent in our method in contrast to the more expensive hexafluoro-2-propanol used in Wang’s reaction.
The reaction of 1 and nitrone 2a was investigated as a model [3+3] cycloaddition (Scheme 1). The desired 1,2,4-oxadiazinan-5-one 3a was obtained in a 98% yield using Na2CO3 as the base and acetonitrile as the solvent at 50°C. The use of other bases including K2CO3, NaOAc, NaOH, pyridine, DBU and TEA resulted in a greatly diminished yield of 3a. Also, only a trace amount of the product was isolated for the reaction conducted in MeOH, CF3CH2OH, DMF, THF or DCM. It is worth mentioning that the use of Wang’s solvent gave only a moderate yield of 3a of 65%. Under the optimized conditions, the use of other substrates 2b and 2d–m gave good to excellent yields of products 3 ranging from 77% to 98%. The only exception was a failed synthesis of 3c which, apparently, is due to the steric hindrance in the starting nitrone 2c.
Experimental
1H nuclear magnetic resonance (NMR) and 13 C NMR spectra were taken in CDCl3 at 400 MHz and 100 MHz, respectively. Mass spectra were obtained using the electrospray ionization (ESI) mode. Nitrones 2a–m were prepared as previously reported [6]. All products 3a–m are colorless oils.
General procedure for synthesis of substrate 1
The following modification of the previously reported procedure was used [6]. A mixture of O-benzylhydroxylamine hydrochloride (1 g, 6.3 mmol) and triethylamine (0.88 mL, 6.3 mmol) in dichloromethane (30 mL) was cooled to 0°C and treated dropwise with 2-bromo-2-methylpropanoyl bromide (0.75 mL, 6.3 mmol). The mixture was stirred for 4 h at 0°C, then quenched with water and washed with brine (×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexanes to give haloamide 1 as a white solid; yield 1.3 g (80%).
Synthesis of 3a,b and 3d–m
A mixture of nitrone 2 (1.1 mmol), haloamide 1 (1.0 mmol) and sodium carbonate (2 mmol) in acetonitrile (20 mL) was stirred at 50°C, and the reaction progress was monitored by silica gel TLC eluting with hexanes/ethyl acetate, 5:1. The mixture was filtered through the short pad of celite, and the filtrate was concentrated under reduced pressure. The residue of 3 was purified by silica gel chromatography eluting with hexanes/ethyl acetate, 10:1.
4-(Benzyloxy)-3,6,6-trimethyl-2-phenyl-1,2,4-oxadiazinan-5-one (3a)
Yield 96%; 1H NMR: δ 7.47–7.38 (m, 5H), 7.32–7.28 (m, 3H), 7.13–7.11 (m, 2H), 5.00 (d, 1H, J=10 Hz), 4.89 (s, 1H), 4.40 (d, 1H, J=10 Hz), 2.35 (s, 3H), 1.71 (s, 3H), 1.51 (s, 3H); 13C NMR: δ 170.6, 134.7, 133.9, 129.9, 129.8, 129.1, 128.8, 128.6, 128.4, 81.8, 77.1, 41.3, 24.1, 23.9. HR-MS. Calcd for C19H22N2O3Na, [M+Na]+: m/z 349.1528. Found: m/z 349.1525.
4-(Benzyloxy)-2-(2-chlorophenyl)-3,6,6-trimethyl-1,2,4-oxadiazinan-5-one (3b)
Yield 80%; 1H NMR: δ 7.45 (s, 1H), 7.44–7.42 (m, 1H), 7.35–7.30 (m, 6H), 7.28–7.23 (s, 2H), 5.02 (d, 1H, J=10 Hz), 4.89 (s, 1H), 4.65 (d, 1H, J=10 Hz), 2.42 (s, 3H), 1.62 (s, 3H), 1.53 (s, 3H); 13C NMR: δ 170.4, 134.9, 134.5, 130.6, 130.5, 129.7, 128.8, 128.4, 127.2, 82.0, 70.0, 40.7, 24.0. HR-MS. Calcd for C19H21ClN2O3Na, [M+Na]+: m/z 383.1138). Found: m/z 383.1136.
4-(Benzyloxy)-2-(3-chlorophenyl)-3,6,6-trimethyl-1,2,4-oxadiazinan-5-one (3d)
Yield 89%; 1H NMR: δ 7.43–7.15 (m, 9H), 4.99 (d, 1H, J=10 Hz), 4.80 (s, 1H), 4.48 (d, 1H, J=10 Hz), 2.33 (s, 3H), 1.68 (s, 3H), 1.51 (s, 3H); 13C NMR: δ 170.4, 136.0, 134.7, 134.5, 130.0, 129.9, 129.0, 128.5, 127.3, 82.0, 77.2, 41.4, 24.0, 23.9. HR-MS. Calcd for C19H21ClN2O3Na, [M+Na]+ : m/z 383.1138. Found: m/z 383.1136.
4-(Benzyloxy)-2-(4-methoxyphenyl)-3,6,6-trimethyl-1,2,4-oxadiazinan-5-one (3e)
Yield 96%; 1H NMR: δ 7.32-7.28 (m, 5H), 7.16–7.14 (m, 2H), 6.94 (d, 2H, J=9 Hz), 4.98 (d, 1H, J=10 Hz), 4.83 (s, 1H), 4.42 (d, 1H, J=10 Hz), 3.86 (s, 3H), 2.33 (s, 3H), 1.69 (s, 3H), 1.50 (s, 3H); 13C NMR: δ 170.4, 160.7, 134.9, 130.3, 129.8, 128.8, 128.4, 126.0, 113.9, 81.8, 77.1, 55.4, 41.3, 24.1, 24.0. HR-MS. Calcd for C20H24N2O4Na, [M+Na]+: m/z 379.1634. Found: m/z 379.1635.
4-(Benzyloxy)-3,6,6-trimethyl-2-(4-nitrophenyl)-1,2,4-oxadiazinan-5-one (3f)
Yield 81%; 1H NMR: δ 8.23 (d, 2H, J=9 Hz), 7.45 (d, 2H, J=9 Hz), 7.36–7.28 (m, 3H), 7.17–7.14 (m, 2H), 4.97 (d, 1H, J=10 Hz), 4.89 (s, 1H), 4.57 (d, 1H, J=10 Hz), 2.29 (s, 3H), 1.66 (s, 3H), 1.52 (s, 3H); 13C NMR: δ 170.4, 148.7, 140.8, 134.7, 130.0, 129.8, 129.1, 128.5, 123.7, 82.3, 77.1, 41.2, 23.9. HR-MS. Calcd for C19H21N3O5Na, [M+Na]+: m/z 394.1379. Found: m/z 394.1378.
4-(Benzyloxy)-3,6,6-trimethyl-2-(naphthalen-2-yl)-1,2,4-oxadiazinan-5-one (3g)
Yield 89%; 1H NMR: δ 7.93–7.88 (m, 3H), 7.75–7.56 (m, 4H), 7.31–7.24 (m, 3H), 7.07 (d, 2H, J=7 Hz), 5.04 (d, 1H, J=10 Hz), 5.01 (s, 1H), 4.44 (d, 1H, J=10 Hz), 2.38 (s, 3H), 1.78 (s, 3H), 1.57 (s, 3H); 13C NMR: δ 170.5, 134.8, 134.1, 132.9, 131.4, 129.9, 128.9, 128.6, 128.4, 128.2, 127.9, 126.0, 125.6, 82.0, 77.2, 41.5, 24.1, 24.0. HR-MS. Calcd for C23H24N2O3Na, [M+Na]+: m/z 399.1690. Found: m/z 399.1685.
(E)-4-(Benzyloxy)-3,6,6-trimethyl-2-styryl-1,2,4-oxadiazinan-5-one (3h)
Yield 82%; 1H NMR: δ 7.43–7.28 (m, 10H), 6.58 (d, 1H, J=15 Hz), 5.04 (d, 1H, J=10 Hz), 4.86 (d, 1H, J=10 Hz), 4.53 (d, 1H, J=10 Hz), 2.53 (s, 3H), 1.52 (s, 3H), 1.50 (s, 3H); 13C NMR: δ 170.1, 138.0, 135.4, 134.9, 130.0, 128.8, 128.4, 127.0, 122.0, 82.0, 77.4, 41.3, 24.0, 23.8. HR-MS. Calcd for C21H24N2O3Na, [M+Na]+: m/z 375.1685. Found: m/z 375.1683.
4-(Benzyloxy)-2-(2,4-dichlorophenyl)-3,6,6-trimethyl-1,2,4-oxadiazinan-5-one (3i)
Yield 85%; 1H NMR: δ 7.36–7.28 (m, 5H), 7.44–7.43 (m, 2H), 7.34–7.24 (m, 6H), 5.73 (s, 1H), 5.00 (d, 1H, J=10 Hz), 4.70 (d, 1H, J=10 Hz), 2.40 (s, 3H), 1.63 (s, 3H), 1.52 (s, 3H); 13C NMR: δ 170.7, 135.9, 135.5, 134.4, 131.3, 129.7, 129.4, 129.0, 128.5, 127.7, 82.2, 77.0, 40.6, 23.9, 23.8. HR-MS. Calcd for C19H20Cl2N2O3Na, [M+Na]+: m/z 417.0749. Found: m/z 417.0750.
4-(Benzyloxy)-3,6,6-trimethyl-2-(thiophen-2-yl)-1,2,4-oxadiazinan-5-one (3j)
Yield 98%; 1H NMR: δ 7.46–7.06 (m, 8H), 5.31 (s, 1H), 5.04 (d, 1H, J=10.1Hz), 4.45 (d, 1H, J=10Hz), 2.43 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H); 13C NMR: δ 169.8, 134.8, 129.7, 128.8, 128.5, 128.4, 128.2, 126.2, 82.3, 77.6, 41.0, 24.0, 23.5. HR-MS. Calcd for C17H20N2O3SNa, [M+Na]+: m/z 355.1092. Found: m/z 355.1090.
4-(Benzyloxy)-3,6,6-trimethyl-2-propyl-1,2,4-oxadiazinan-5-one (3k)
Yield 77%; 1H NMR: δ 7.47–7.39 (m, 5H), 4.97 (s, 2H), 4.00 (t, 1H, J=3.7 Hz), 2.57 (s, 3H), 1.93–1.75 (m, 2H), 1.56–1.40 (m, 8H), 0.90 (t, 3H, J=7 Hz); 13C NMR: δ 170.3, 135.0, 129.9, 129.0, 128.6, 83.2, 81.5, 76.5, 41,3, 30.6, 24.1, 23.5, 14.2. HR-MS. Calcd for C16H24N2O3Na, [M+Na]+: m/z 315.1685. Found: m/z 315.1681.
2-Benzyl-4-(benzyloxy)-6,6-dimethyl-3-(p-tolyl)-1,2,4-oxadiazinan-5-one (3l)
Yield 92%; 1H NMR: δ 7.40–7.17 (m, 14H), 5.09 (s, 1H), 5.03 (d, 1H, J=10Hz), 4.45 (d, 1H, J=10 Hz), 3.63 (d, 1H, J=10 Hz), 3.45 (d, 1H, J=10 Hz), 2.44 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H); 13C NMR: δ 170.5, 139.8, 136.4, 134.9, 131.1, 130.3, 129.8, 129.4, 129.3, 129.1, 128.8, 128.6, 128.4, 128.0, 127.4, 81.8, 77.1, 57.2, 24.0, 23.8, 21.4. HR-MS. Calcd for C26H28N2O3Na, [M+Na]+: m/z 439.1998. Found: m/z 439.1995.
2-Benzyl-4-(benzyloxy)-6,6-dimethyl-3-(thiophen-2-yl)-1,2,4-oxadiazinan-5-one (3m)
Yield 98%; 1H NMR: δ 7.51–7.09 (m, 13H), 5.41 (s, 1H), 5.03 (d, 1H, J=10 Hz), 4.44 (d, 1H, J=10 Hz), 3.80 (d, 1H, J=10 Hz), 3.52 (d, 1H, J=10 Hz), 1.50 (s, 3H), 1.48 (s, 3H); 13C NMR: δ 170.0, 134.6, 130.0, 129.7, 129.4, 128.9, 128.5, 128.4, 128.3, 127.8, 126.2, 82.5, 77.7, 57.3, 23.9, 23.3. HR-MS. Calcd for C23H24N2O4SNa, [M+Na]+: m/z 431.1405. Found: m/z 431.1400.
Acknowledgment
This work was supported by grants of the Hubei Provincial Department of Education (T201419), National Natural Science Foundation (21602053) and Center for Research, College of Science and Health, William Paterson University of New Jersey.
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