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Article

Synthesis of 2-Oxazolines from Ring Opening Isomerization of 3-Amido-2-Phenyl Azetidines

by
Xin Zhou
,
Baiyi Mao
and
Zhanbin Zhang
*
College of Chemistry, Beijing Normal University, Beijing 100875, China
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(4), 857; https://doi.org/10.3390/molecules26040857
Submission received: 17 January 2021 / Revised: 2 February 2021 / Accepted: 3 February 2021 / Published: 6 February 2021
(This article belongs to the Section Organic Chemistry)
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Abstract

:
Chiral 2-oxazolines are valuable building blocks and famous ligands for asymmetric catalysis. The most common synthesis involves the reaction of an amino alcohol with a carboxylic acid. In this paper, an efficient synthesis of 2-oxazolines has been achieved via the stereospecific isomerization of 3-amido-2-phenyl azetidines. The reactions were studied in the presence of both Brønsted and Lewis acids, and Cu(OTf)2 was found to be the most effective.

1. Introduction

2-Oxazolines are very important five-membered heterocycles existing in numerous medicinally active compounds and natural products [1,2,3,4,5,6]. They are also widely applied as synthetic intermediates, protecting, activating and directing groups in organic synthesis. In addition, the optically active 2-oxazolines are valuable chiral building blocks and famous ligands for asymmetric catalysis [7,8,9,10,11]. There are numerous methods that have been developed for the preparation of 2-oxazolines [12,13,14,15]. The most common process for their preparation involves the reaction of an amino alcohol with a carboxylic acid [16,17]. In this way, oxazoline amines can be accessed from commercially available β-amino alcohols and suitably protected α-amino acids [18].
Recently, we reported the synthesis of chiral 4,5-dihydrothiazol-2-amines and 4,5-dihydrooxazol-2-amines through an unexpected ring opening reaction of azetidines [19]. Based on this strategy, we now extend our research work and report herein the asymmetric synthesis of 2-oxazolines via the stereospecific isomerization of 3-amido-2-phenyl azetidines in the presence of acid (Scheme 1).

2. Results

Chiral 3-amino-2-phenyl azetidine 1 was prepared as previously reported by our group [20]. The coupling of 3-amino-2-phenyl azetidine 1 with acids 2 led to the corresponding amides 3, which were obtained in 77% to 95% yields (Scheme 2; see Supplementary Materials).
The isomerization of amide 3a was examined in different conditions (Scheme 3, Table 1). The results (Table 1) showed that the isomerization of 3a did not occur at reflux in 1,2-dichloroethane (Table 1, entry 1) or in toluene (Table 1, entry 2) without additive or in the presence of bases such as DABCO, t-BuOK and NaH (Table 1, entries 3–5). Nevertheless, isomerization of amide 3a to 2-oxazoline 4a occurred in the presence of acids, including Lewis acids and Brønsted acids but excepting acetic acid (Table 1, entries 6–16). In search for a better additive, we explored Brønsted acids such as HClO4, CF3SO3H, CH3COOH and CF3COOH (TFA). It was found that TFA was the suitable additive for this transformation and the yield of 4a could achieve up to 91% in 1,2-dichloroethane for about half an hour (Table 1, entry 10). However, prolonging the reaction time to over 2 h resulted in some degradation (Table 1, entry 11). Moreover, among the Lewis acids, Cu(OTf)2 turned out to be the most efficient for this transformation, allowing the formation of 4a in a 93% yield (Table 1, entry 14).
After optimizing the reaction conditions, we extended the substrate scope and different amides were examined (Scheme 4, Table 2). The amides with aryl, heteroaryl and alkyl groups were successfully isomerized to 2-oxazolines in the presence of Cu(OTf)2 in high yields (Table 2, entries 1–9 and 13–16). However, those substrates with 2-hydroxyl or 2-amino groups could not be isomerized, presumably due to their coordination to Cu(OTf)2. Nevertheless, these substrates could be isomerized to 2-oxazolines in the presence of CF3COOH in good yields (Table 2, entries 10–12).
A proposed mechanism for this transformation is shown below (Scheme 5). The isomerization of amides 3 occurred regiospecifically by presumably an SN2 nucleophilic attack at the more active C2 but not the less-hindered C4 of the azetidine ring, thus the stereochemistry of 2-oxazolines 4 was shown to be cis [21]. This is also supported by comparison of the coupling constant (10 Hz) between H4 and H5 with reported cis-2-oxazolines [22,23]. In addition, all the structures of 2-oxazolines were established by 1H and 13C NMR, high resolution mass spectra (HRMS), IR. Furthermore, the absolute configuration of 4l was further confirmed by X-ray analysis (Figure 1).

3. Materials and Methods

3.1. General Information

All reactants and reagents were commercially available and were used without further purification. 1H and 13C NMR spectra were recorded on a Bruker Advance III 400 MHz spectrometer (Billerica, MA, USA). Chemical shifts are reported in δ values (ppm) relative to an internal reference (0.03% v/v) of tetramethylsilane (TMS) for 1H NMR or the solvent signal, chloroform (CDCl3), for 13C NMR. IR data was obtained with an IRAffinity-1 spectrometer (Shimadzu, Kyoto, Japan). High resolution mass spectrometry (HRMS) was conducted with a high-resolution LCT Premier XE mass spectrometer in positive ESI mode (Waters, MA, USA). Melting points were measured on a digital melting point apparatus and are uncorrected.

3.2. General Procedure for the Isomeization of Amide 3

A mixture of amide 3 (1 mmol), Cu(OTf)2 (0.5 mmol) in 1,2-dichloroethane (10 mL) was refluxed for 4 h. The mixture was washed with water (10 mL), saturated NaHCO3 (10 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by gradient column chromatography on silica gel with PE/EA (5:1–2:1) as eluent to give oxazoline 4.
(S)-N-(((4S,5R)-2,5-diphenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4a)
Yellow oil, 96% yield, [α]D20 = −322.0 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 8.02 (d, J = 7.4 Hz, 2H), 7.59–7.00 (m, 13H), 5.79 (d, J = 9.9 Hz, 1H), 4.68 (q, J = 7.2 Hz, 1H), 3.46 (q, J = 6.4 Hz, 1H), 2.43–2.14 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.72, 49.35, 58.29, 69.67, 83.13, 126.36, 126.49, 126.89, 127.53, 128.21, 128.35, 128.38, 128.42, 128.44, 131.60, 136.41, 144.86, 163.76; IR (KBr) ν 3061, 3028, 2963, 2924, 1651, 1603, 1580, 1495, 1450, 1368, 1333, 1277, 1246, 1209, 1175, 1128, 1082, 1065, 1024, 964, 781, 760, 696, 540 cm−1; HRMS m/z [M + H]+ calcd. for [C24H25N2O]+ 357.1961, found 357.1962.
(S)-N-(((4S,5R)-2-(4-methoxyphenyl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4b)
Yellow solid, 94% yield, mp:71~74 °C, [α]D20 = −273.8 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.96 (d, J = 8.8 Hz, 2H), 7.37–7.07 (m, 10H), 6.92 (d, J = 8.9 Hz, 2H), 5.73 (d, J = 9.9 Hz, 1H), 4.61 (dt, J = 9.8, 7.0 Hz, 1H), 3.81 (s, 3H), 3.41 (q, J = 6.5 Hz, 1H), 2.28 (d, J = 7.0 Hz, 2H), 1.69 (br s, 1H), 1.12 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.99, 49.55, 55.38, 58.23, 69.85, 83.10, 113.80, 120.08, 126.42, 126.46, 126.74, 128.12, 128.31, 128.33, 130.16, 136.69, 145.50, 162.28, 163.51; IR (KBr) ν 3061, 3026, 2961, 2930, 2837, 1647, 1609, 1512, 1495, 1452, 1420, 1368, 1335, 1310, 1256, 1167, 1076, 1030, 966, 841, 741, 700, 685 cm−1; HRMS m/z [M + H]+ calcd. for [C25H27N2O2]+ 387.2067, found 387.2067.
(S)-N-(((4S,5R)-2-(2-methoxyphenyl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4c)
Yellow oil, 93% yield, [α]D20 = −204.5 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.80 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.39–7.06 (m, 10H), 6.98 (d, J = 7.9 Hz, 2H), 5.76 (d, J = 9.9 Hz, 1H), 4.80–4.74 (m, 1H), 3.90 (s, 4H), 3.52–3.45 (m, 1H), 2.39–2.27 (m, 2H), 1.21 (d, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.31, 49.09, 55.99, 58.38, 69.43, 82.44, 111.71, 116.89, 120.35, 126.45, 126.64, 127.10, 128.13, 128.32, 128.41, 131.40, 132.58, 136.43, 143.87, 158.61, 162.87; IR (KBr) ν 3061, 3028, 2961, 2924, 2837, 1653, 1636, 1578, 1560, 1491, 1458, 1437, 1331, 1283, 1258, 1123, 1043, 1024, 968, 754, 700, 592 cm−1; HRMS m/z [M + H]+ calcd. for [C25H27N2O2]+ 387.2067, found 387.2064.
(S)-N-(((4S,5R)-2-(4-nitrophenyl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4d)
White solid, 94% yield, mp: 68~71 °C, [α]D20 = −145.8 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 8.29 (d, J = 8.9 Hz, 2H), 8.19 (d, J = 8.9 Hz, 2H), 7.42–7.30 (m, 3H), 7.28–7.11 (m, 7H), 5.85 (d, J = 10.1 Hz, 1H), 4.72 (dt, J = 10.0, 7.1 Hz, 1H), 3.45 (q, J = 6.5 Hz, 1H), 2.38–2.21 (m, 2H), 2.02 (br s, 1H), 1.16 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.72, 49.16, 58.25, 70.20, 83.83, 123.62, 126.28, 126.41, 126.91, 128.38, 128.44, 128.46, 129.42, 133.31, 135.79, 144.99, 149.64, 161.93; IR (KBr) ν 3082, 3061, 3030, 2959, 2924, 2873, 1653, 1647, 1599, 1524, 1493, 1452, 1410, 1348, 1277, 1107, 1076, 1014, 961, 866, 851, 762, 702 cm−1; HRMS m/z [M + H]+ calcd. for [C24H24N3O3]+ 402.1812, found 402.1812.
(S)-N-(((4S,5R)-2-(2-nitrophenyl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4e)
White solid, 91% yield, mp: 44~47 °C, [α]D20 = −314.7 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.90–7.79 (m, 2H), 7.68–7.53 (m, 2H), 7.39–7.06 (m, 10H), 5.80 (d, J = 10.0 Hz, 1H), 4.66 (dt, J = 9.8, 7.0 Hz, 1H), 3.44 (q, J = 6.5 Hz, 1H), 2.44–2.12 (m, 2H), 1.47 (br s, 1H), 1.12 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 24.00, 49.00, 58.11, 69.98, 84.57, 123.14, 123.96, 126.34, 126.42, 126.74, 128.28, 128.32, 128.40, 131.12, 131.61, 132.49, 135.43, 145.30, 149.13, 161.28; IR (KBr) ν 3327, 3063, 3028, 2963, 2926, 2833, 1661, 1607, 1576, 1537, 1493, 1450, 1368, 1352, 1279, 1244, 1209, 1107, 1059, 1032, 957, 852, 762, 736, 700, 681, 650 cm−1; HRMS m/z [M + H]+ calcd. for [C24H24N3O3]+ 402.1812, found 402.1812.
(S)-N-(((4S,5R)-2-(4-chlorophenyl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4f)
Yellow oil, 79% yield, [α]D20 = −171.0 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.36–7.08 (m, 10H), 5.76 (d, J = 10.0 Hz, 1H), 4.64 (dt, J = 9.9, 7.0 Hz, 1H), 3.42 (q, J = 6.5 Hz, 1H), 2.28 (d, J = 7.0 Hz, 2H), 1.57 (br s, 1H), 1.12 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.95, 49.39, 58.22, 70.06, 83.44, 126.12, 126.37, 126.43, 126.78, 128.26, 128.35, 128.75, 129.77, 136.33, 137.77, 145.45, 162.82; IR (KBr) ν 3318, 3061, 3028, 2965, 2924, 1651, 1599, 1491, 1452, 1402, 1368, 1333, 1277, 1244, 1170, 1128, 1092, 1074, 1015, 964, 841, 760, 731, 700, 677, 550, 534 cm−1; HRMS m/z [M + H]+ calcd. for [C24H24ClN2O]+ 391.1572, found 391.1572.
(S)-N-(((4S,5R)-2-(2-chlorophenyl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4g)
Yellow oil, 84.8% yield, [α]D20 = −259.2 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.80 (dd, J = 7.7, 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 0.8 Hz, 1H), 7.39–7.06 (m, 12H), 5.79 (d, J = 10.1 Hz, 1H), 4.69 (dt, J = 10.0, 6.9 Hz, 1H), 3.43 (q, J = 6.6 Hz, 1H), 2.39–2.20 (m, 2H), 1.54 (br s, 1H), 1.13 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 24.05, 49.39, 58.18, 70.12, 83.55, 126.43, 126.44, 126.63, 126.72, 127.45, 128.17, 128.30, 128.32, 130.77, 131.45, 131.74, 133.53, 136.05, 145.37, 162.47; IR (KBr) ν 3323, 3061, 3028, 2961, 1651, 1593, 1493, 1477, 1452, 1435, 1368, 1331, 1279, 1240, 1132, 1096, 1036, 961, 914, 762, 735, 700, 654 cm−1; HRMS m/z [M + H]+ calcd. for [C24H24ClN2O]+ 391.1572, found 391.1575.
(S)-1-phenyl-N-(((4S,5R)-5-phenyl-2-(pyridin-4-yl)-4,5-dihydrooxazol-4-yl)methyl)ethanamine (4h)
Yellow oil, 82% yield, [α]D20 = −302.7 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 8.74 (d, J = 5.9 Hz, 2H), 7.85 (d, J = 5.9 Hz, 2H), 7.40–7.09 (m, 10H), 5.82 (d, J = 10.1 Hz, 1H), 4.70 (dt, J = 10.0, 7.1 Hz, 1H), 3.44 (q, J = 6.5 Hz, 1H), 2.39–2.20 (m, 2H), 1.97 (br s, 1H), 1.15 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.78, 49.16, 58.22, 70.09, 83.63, 122.05, 126.30, 126.41, 126.88, 128.37, 128.42, 134.88, 135.83, 145.06, 150.38, 162.03; IR (KBr) ν 3061, 3030, 2963, 2924, 1655, 1599, 1558, 1493, 1452, 1410, 1368, 1339, 1277, 1210, 1128, 1094, 1080, 1063, 991, 961, 837, 760, 745, 700, 681 cm−1; HRMS m/z [M + H]+ calcd. for [C23H24N3O]+ 358.1914, found 358.1914.
(S)-1-phenyl-N-(((4S,5R)-5-phenyl-2-(pyridin-2-yl)-4,5-dihydrooxazol-4-yl)methyl)ethanamine (4i)
Yellow oil, 87% yield, [α]D20 = −261.0 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 8.74 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.79 (td, J = 7.8, 1.6 Hz, 1H), 7.48–7.35 (m, 1H), 7.35–7.01 (m, 10H), 5.85 (d, J = 10.1 Hz, 1H), 4.89–4.67 (m, 1H), 3.52 (q, J = 6.5 Hz, 1H), 3.25 (s, 1H), 2.43–2.12 (m, 2H), 1.19 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.31, 49.11, 58.32, 69.63, 83.76, 124.09, 125.81, 126.36, 126.59, 127.01, 128.30, 128.34, 128.36, 135.87, 136.79, 144.34, 146.37, 150.03, 162.96; IR (KBr) ν 3314, 3059, 3028, 2961, 2924, 1653, 1647, 1582, 1570, 1493, 1468, 1452, 1439, 1368, 1341, 1246, 1117, 1098, 1043, 993, 962, 799, 745, 700, 621 cm−1; HRMS m/z [M + H]+ calcd. for [C23H24N3O]+ 358.1914, found 358.1913.
2-((4S,5R)-5-phenyl-4-((((S)-1-phenylethyl)amino)methyl)-4,5-dihydrooxazol-2-yl)phenol (4j)
White solid, 87% yield, mp:76~79 °C, [α]D20 = −256.6 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 11.96 (s, 1H), 7.74 (dd, J = 7.8, 1.5 Hz, 1H), 7.43–7.14 (m, 9H), 7.11 (d, J = 7.0 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 5.75 (d, J = 9.9 Hz, 1H), 4.68 (dt, J = 9.8, 6.9 Hz, 1H), 3.39 (q, J = 6.6 Hz, 1H), 2.34–2.22 (m, 2H), 1.11 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.89, 49.25, 58.14, 68.82, 82.51, 110.43, 116.85, 118.84, 126.36, 126.49, 126.93, 128.31, 128.46, 128.53, 133.70, 135.59, 145.18, 160.00, 165.44; IR (KBr) ν 3061, 3028, 2961, 2924, 2849, 1643, 1616, 1491, 1454, 1368, 1352, 1312, 1258, 1231, 1155, 1130, 1070, 1032, 961, 756, 700, 571, 540 cm−1; HRMS m/z [M + H]+ calcd. for [C24H25N2O2]+ 373.1911, found 373.1909.
2-((4S,5R)-5-phenyl-4-((((S)-1-phenylethyl)amino)methyl)-4,5-dihydrooxazol-2-yl)aniline (4k)
Yellow oil, 82% yield, [α]D20 = −285.7 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 7.1 Hz, 1H), 7.35–7.11 (m, 11H), 6.66 (dd, J = 13.6, 7.6 Hz, 2H), 6.04 (s, 2H), 5.65 (d, J = 9.9 Hz, 1H), 4.68 (dt, J = 9.7, 7.1 Hz, 1H), 3.41 (q, J = 6.5 Hz, 1H), 2.36–2.13 (m, 2H), 1.44 (br s, 1H), 1.11 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.91, 49.76, 58.21, 70.06, 81.32, 108.70, 115.75, 116.14, 126.46, 126.49, 126.85, 128.35, 128.41, 129.91, 132.37, 136.66, 145.54, 148.80, 164.07; IR (KBr) ν 3466, 3296, 3061, 3028, 2961, 2924, 1636, 1609, 1595, 1560, 1490, 1454, 1368, 1348, 1319, 1263, 1161, 1078, 1053, 970, 914, 750, 700, 569, 538 cm−1; HRMS m/z [M + H]+ calcd. for [C24H26N3O]+ 372.2070, found 372.2070.
2-((4S,5R)-5-phenyl-4-((((S)-1-phenylethyl)amino)methyl)-4,5-dihydrooxazol-2-yl)naphthalen-1-ol (4l)
Dark green solid, 88% yield, mp: 79~81 °C, [α]D20 = +166.9 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 13.11 (br s, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.57 (td, J = 7.0, 1.4 Hz, 1H), 7.51 (td, J = 6.9, 1.3 Hz, 1H), 7.40–7.05 (m, 11H), 5.81 (d, J = 9.8 Hz, 1H), 4.74 (dt, J = 9.8, 6.9 Hz, 1H), 3.43 (q, J = 6.6 Hz, 1H), 2.37–2.28 (m, 2H), 1.13 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.87, 49.32, 58.13, 68.52, 82.68, 103.37, 118.20, 123.47, 123.70, 124.75, 125.54, 126.37, 126.51, 126.90, 127.54, 128.44, 128.50, 128.52, 135.62, 136.28, 145.18, 158.85, 166.38; IR (KBr) ν 3061, 3030, 2959, 2924, 2851, 1628, 1599, 1578, 1466, 1450, 1408, 1391, 1304, 1260, 1140, 1078, 964, 810, 756, 700 cm−1; HRMS m/z [M + H]+ calcd. for [C28H27N2O2]+ 423.2067, found 423.2064.
(S)-1-phenyl-N-(((4S,5R)-5-phenyl-2-(thiophen-2-yl)-4,5-dihydrooxazol-4-yl)methyl)ethanamine (4m)
Yellow oil, 90% yield, [α]D20 = −256.6 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 4.5 Hz, 1H), 7.41–7.03 (m, 11H), 5.77 (d, J = 9.8 Hz, 1H), 4.62 (q, J = 7.1 Hz, 1H), 3.51–3.27 (m, 1H), 2.34–2.24 (m, 2H), 1.53 (br s, 1H), 1.11 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 24.01, 49.28, 58.21, 70.05, 83.67, 126.43, 126.74, 127.71, 128.26, 128.33, 130.19, 130.21, 130.66, 136.18, 145.38, 159.54; IR (KBr) ν 3323, 3082, 3061, 3026, 2963, 2924, 1649, 1522, 1493, 1452, 1433, 1369, 1329, 1277, 1217, 1128, 1082, 1059, 1018, 959, 851, 760, 716, 700, 650 cm−1; HRMS m/z [M + H]+ calcd. for [C22H23N2OS]+ 363.1526, found 363.1526.
(S)-N-(((4S,5R)-2-(furan-2-yl)-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4n)
White solid, 84% yield, mp: 45~48 °C; [α]D20 = −279.1 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.57 (s, 1H), 7.42–7.09 (m, 10H), 7.02 (d, J = 3.1 Hz, 1H), 6.51 (s, 1H), 5.74 (d, J = 9.9 Hz, 1H), 4.69–4.69 (m, 1H), 3.45 (q, J = 6.4 Hz, 1H), 2.29 (d, J = 6.9 Hz, 2H), 2.00 (br s, 1H), 1.13 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.70, 49.24, 58.20, 69.69, 83.35, 111.63, 114.90, 126.38, 126.47, 126.80, 128.30, 128.34, 135.96, 142.71, 145.12, 145.56, 156.15; IR (KBr) ν 3318, 3061, 3028, 2963, 2924, 2855, 1674, 1580, 1560, 1493, 1481, 1452, 1402, 1331, 1229, 1169, 1092, 1011, 962, 885, 754, 700, 631, 596, 552 cm−1; HRMS m/z [M + H]+ calcd. for [C22H23N2O2]+ 347.1754, found 347.1754.
(S)-N-(((4S,5R)-2-methyl-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4o)
Yellow solid, 85% yield, mp: 44~47 °C; [α]D20 = −252.6 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.37–7.04 (m, 10H), 5.57 (d, J = 10.0 Hz, 1H), 4.44–4.37 (m, 1H), 3.39 (q, J = 6.5 Hz, 1H), 2.24–2.10 (m, 2H), 2.07 (d, J = 0.8 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 14.06, 23.82, 49.41, 58.14, 69.48, 83.12, 126.24, 126.40, 126.69, 128.05, 128.25, 136.43, 145.43, 164.76; IR (KBr) ν 3320, 3061, 3026, 2967, 2928, 1680, 1603, 1493, 1452, 1387, 1369, 1310, 1229, 1130, 1078, 1028, 974, 914, 760, 700, 623, 592, 538 cm−1; HRMS m/z [M + H]+ calcd. for [C19H23N2O]+ 295.1805, found 295.1801.
(S)-N-(((4S,5R)-2-benzyl-5-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1-phenylethanamine (4p)
White solid, 83% yield, mp: 103~106 °C, [α]D20 = −248.0 (c 1.0 CH3COOC2H5); 1H NMR (400 MHz, CDCl3) δ = 7.44–7.15 (m, 11H), 7.08–7.02 (m, 4H), 5.56 (d, J = 10.0 Hz, 1H), 4.47–4.40 (m, 1H), 3.69 (q, J = 14.6 Hz, 2H), 3.37 (q, J = 6.5 Hz, 1H), 2.21–2.05 (m, 2H), 1.52 (br s, 1H), 1.10 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 23.99, 35.08, 49.41, 58.17, 69.41, 83.25, 126.20, 126.40, 126.72, 127.10, 128.00, 128.19, 128.30, 128.65, 129.06, 135.07, 136.32, 145.33, 166.20; IR (KBr) ν 3302, 3057, 3028, 2985, 2932, 2857, 1663, 1603, 1558, 1495, 1449, 1267, 1244, 1219, 1167, 1142, 1126, 1076, 1055, 1028, 993, 972, 920, 822, 784, 736, 723, 700, 575, 538 cm−1; HRMS m/z [M + H]+ calcd. for [C25H27N2O]+ 371.2118, found 371.2118.

4. Conclusions

In conclusion, we have developed a new isomerization of amides 3 that leads to 2-oxzaolines 4 in a completely highly regio- and stereoselective isomerization manner. Further application of these 2-oxzaolines in catalytic asymmetric reaction is currently underway in our laboratory.

Supplementary Materials

The supplementary materials in the text are available online. CCDC 2059257 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (accessed on 6 February 2021), or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033.

Author Contributions

Z.Z. and X.Z. designed the chemical synthesis, analyzed the results, and wrote the manuscript. X.Z. and B.M. performed the chemical synthesis experiments and analyzed the results. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

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Molecules 26 00857 sch001 550
Scheme 1. Isomerization of 3-amido-2-phenyl azetidines to 2-oxazolines.
Scheme 1. Isomerization of 3-amido-2-phenyl azetidines to 2-oxazolines.
Molecules 26 00857 sch001
Molecules 26 00857 sch002 550
Scheme 2. Synthesis of 3-amido-2-phenyl azetidines
Scheme 2. Synthesis of 3-amido-2-phenyl azetidines
Molecules 26 00857 sch002
Molecules 26 00857 sch003 550
Scheme 3. Isomerization of amide 3a in different conditions.
Scheme 3. Isomerization of amide 3a in different conditions.
Molecules 26 00857 sch003
Molecules 26 00857 sch004 550
Scheme 4. Substrate scope of the isomerization of amides 3.
Scheme 4. Substrate scope of the isomerization of amides 3.
Molecules 26 00857 sch004
Molecules 26 00857 sch005 550
Scheme 5. Proposed mechanism.
Scheme 5. Proposed mechanism.
Molecules 26 00857 sch005
Molecules 26 00857 g001 550
Figure 1. Structure of 4l.
Figure 1. Structure of 4l.
Molecules 26 00857 g001
Table
Table 1. Isomerization of amide 3a 1.
Table 1. Isomerization of amide 3a 1.
EntryAdditive (Equiv.)SolventTime (h)Yield (%) 2
1-ClCH2CH2Cl6n.r.
2-Toluene6n.r.
3DABCO (1)ClCH2CH2Cl6n.r.
4t-BuOK (1)THF6n.r.
5NaH (1)THF6n.r.
6HClO4 (1)ClCH2CH2Cl0.587
7CF3SO3H (1)ClCH2CH2Cl0.565
8CH3COOH (1)CH2Cl212n.r.
9CF3COOH (1)CH2Cl21237
10CF3COOH (1)ClCH2CH2Cl0.591
11CF3COOH (1)ClCH2CH2Cl286
12CF3COOH (0.75)ClCH2CH2Cl0.571
13TMSOTf (1)ClCH2CH2Cl472
14Cu(OTf)2 (1)ClCH2CH2Cl493
15Cu(OTf)2 (0.5)ClCH2CH2Cl490
16BF3·Et2O (1)ClCH2CH2Cl687
1 The reactions were conducted with amide 3a (1 mmol) in solvent (10 mL) in the presence of additive at reflux. 2 Isolated yields.
Table
Table 2. Isomerizations of various amides in the presence of Cu(OTf)2 1.
Table 2. Isomerizations of various amides in the presence of Cu(OTf)2 1.
EntryRProductYield (%) 2
13a: C6H5-4a96
23b: 4-MeOC6H4-4b94
33c: 2-MeOC6H4-4c93
43d: 4-O2NC6H4-4d94
53e: 2-O2NC6H4-4e91
63f: 4-ClC6H4-4f79
73g: 2-ClC6H4-4g85
83h: 4-pyridyl4h82
93i: 2-pyridyl4i87
10 33j: 2-HOC6H4-4j87
11 33k: 2-H2NC6H4-4k82
12 33l: 1-hydroxynaphthalen-2-yl4l88
133m: thiophen-2-yl4m90
143n: furan-2-yl4n84
153o: Me-4o85
163p: C6H5CH2-4p83
1 Reactions were conducted with amide 3 (1 mmol) at reflux for 4 h in ClCH2CH2Cl (10 mL) in the presence of Cu(OTf)2 (0.5 mmol). 2 Isolated yields. 3 Reactions were conducted in the presence of CF3COOH (1.5 mmol) at reflux for 30 min.
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Zhou, X.; Mao, B.; Zhang, Z. Synthesis of 2-Oxazolines from Ring Opening Isomerization of 3-Amido-2-Phenyl Azetidines. Molecules 2021, 26, 857. https://doi.org/10.3390/molecules26040857

AMA Style

Zhou X, Mao B, Zhang Z. Synthesis of 2-Oxazolines from Ring Opening Isomerization of 3-Amido-2-Phenyl Azetidines. Molecules. 2021; 26(4):857. https://doi.org/10.3390/molecules26040857

Chicago/Turabian Style

Zhou, Xin, Baiyi Mao, and Zhanbin Zhang. 2021. "Synthesis of 2-Oxazolines from Ring Opening Isomerization of 3-Amido-2-Phenyl Azetidines" Molecules 26, no. 4: 857. https://doi.org/10.3390/molecules26040857

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