10.1002/ejoc.201701266
European Journal of Organic Chemistry
FULL PAPER
acid (61 mg, 0.5 mmol) and bis(oxy)enamine 1a (0.5 mmol). Yield: 108
mg (67%). White solid. Mp = 66-68oC (Et2O-pentane). Rf = 0.72 (AcOEt-
hexane = 1 : 1). 1H NMR (300 MHz, Chloroform-d) δ 7.98 (d, J = 7.2 Hz,
2H, o-C6H5C(O)), 7.59 (t, J = 7.4 Hz, 1H, p-C6H5C(O)), 7.45 (dd, J = 7.4,
7.2 Hz, 2H, m-C6H5C(O)), 7.38-7.26 (m, 3H, m,p-C6H5), 7.22 (d, J = 7.0
Hz, 2H, o-C6H5), 4.74 (d, J = 12.6 Hz, 1H, CH2O), 4.69 (d, J = 12.6 Hz,
1H, CH2O), 3.66 (dd, J = 11.8, 7.9 Hz, 1H, HaxC-4), 2.15 (dd, J = 13.6,
7.9 Hz, 1H, HeqC-5), 2.02 (dd, J = 13.6, 11.8 Hz, 1H, HaxC-5), 1.42 and
1.37 (2 s, 3H and 3 H, 2 CH3). 13C NMR (75 MHz, DEPT135, CDCl3) δ
165.70 (C=O), 154.20 (C-3), 139.32 (i-C6H5), 133.08, 129.63, 129.15,
128.36, 128.23 and 127.53 (o,m,p-C6H5, o,m,p,i-C6H5C(O)), 75.04 (C-6),
64.59 (CH2O), 40.37 (C-5), 38.10 (C-4), 28.39 and 22.72 (2 CH3). Anal.
calcd. for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found C, 74.23; H,
6.65; N, 4.34.
CH3). Anal. calcd. for C18H19NO4: C, 69.00; H, 6.11; N, 4.47. Found C,
69.07; H, 6.19; N, 4.48.
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl
propiolate (3l). Prepared according to general procedure (i) from
propiolic acid (35 mg, 0.5 mmol) and bis(oxy)enamine 1a (0.5 mmol).
Yield: 119 mg (88%). Oil. Rf = 0.61 (AcOEt-hexane = 1 : 1). 1H NMR (300
MHz, Chloroform-d) δ 7.42-7.26 (m, 3H, m,p-C6H5), 7.21 (d, J = 7.6 Hz,
2H, o-C6H5), 4.55 (s, 2H, CH2O), 3.58 (dd, J = 12.1, 7.8 Hz, 1H, HaxC-4),
2.92 (d, J = 1.5 Hz, 1H, ≡CH), 2.13 (dd, J = 13.6, 7.8 Hz, 1H, HeqC-5),
1.95 (dd, J = 13.6, 12.1 Hz, 1H, HaxC-5), 1.40 and 1.34 (2 s, 3H and 3H,
2 CH3). 13C NMR (75 MHz, JMOD, CDCl3) δ 152.95 and 151.77 (C-3 and
C=O), 138.88 (i-C6H5), 129.22, 128.20 and 127.68 (o,m,p-C6H5), 75.57
(≡C-H), 75.29 (C-6), 74.07 (≡C), 65.52 (CH2O), 39.87 (C-5), 37.69 (C-4),
28.32 and 22.72 (2 CH3). HRMS: calcd. for [C16H17NO3Na]+ 294.1101;
found 294.1106 ([M+Na]+).
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl
4-
(nonyloxy)benzoate (3i). Prepared according to general procedure (i)
from 4-(nonyloxy)benzoic acid (132 mg, 0.5 mmol) and bis(oxy)enamine
1a (0.5 mmol). Yield: 168 mg (72%). White solid. Mp = 56-57oC
(pentane). Rf = 0.82 (AcOEt-hexane = 1 : 1). 1H NMR (300 MHz,
Chloroform-d) δ 7.92 (d, J = 8.6 Hz, 2H, 2 HC-3’), 7.37-7.26 (m, 3H, m,p-
C6H5), 7.21 (d, J = 7.5 Hz, 2H, o-C6H5), 6.92 (d, J = 8.6 Hz, 2H, 2 HC-2’),
4.71 (d, J = 12.4 Hz, 1H, CH2OC(O)), 4.65 (d, J = 12.4 Hz, 1H,
CH2OC(O)), 4.03 (t, J = 6.5 Hz, 2H, -CH2CH2O), 3.65 (dd, J = 11.8, 7.9
Hz, 1H, HaxC-4), 2.14 (dd, J = 13.4, 7.9 Hz, 1H, HeqC-5), 1.99 (dd, J =
13.4, 12.4 Hz, 1H, HaxC-5), 1.87-1.76, 1.55-1.43 and 1.37-1.26 (3 m, 2H,
2H and 10H, CH2), 1.41 and 1.37 (2 s, 3H and 3H, 2 CH3), 0.91 (t, J =
6.4 Hz, 3H, CH3-CH2-). 13C NMR (75 MHz, DEPT135, CDCl3) δ 165.48
(C=O), 163.13 (C-1’), 154.47 (C-3), 139.41 (i-C6H5), 131.66 (C-3’),
129.11, 128.24 and 127.48 (o,m,p-C6H5), 121.82 (C-4’), 114.10 (C-2’),
74.97 (C-6), 68.25 and 64.30 (2 CH2O), 40.42 (С-5), 38.10 (С-4), 31.89,
29.55, 29.35, 29.11 and 25.99 (7 CH2), 28.40 and 22.70 (2 CH3), 14.11
(CH3). Anal. calcd. for C29H39NO4: C, 74.81; H, 8.44; N, 3.01. Found C,
74.65; H, 8.60; N, 2.94.
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl 2-oxo-
2H-chromene-3-carboxylate (3m). Prepared according to general
procedure (ii) from coumarin-3-carboxylic acid (95 mg, 0.5 mmol) and
bis(oxy)enamine 1a (0.5 mmol). Yield: 162 mg (79%). White solid. Mp =
136-137oC (pentane-Et2O). Rf = 0.43 (AcOEt-hexane = 1 : 1). 1H NMR
(300 MHz, Chloroform-d) δ 8.47 (s, 1H, HC-4’), 7.80-7.52 and 7.42-7.15
(2 m, 2H and 7H, HC-5’, HC-6’, HC-7’ HC-8’ and o,m,p-C6H5), 4.69 (s,
2H, CH2O), 3.82 (dd, J = 11.2, 9.1 Hz, 1H, HaxC-4), 2.14 (dd, J = 12.7,
9.1 Hz, 1H, HeqC-5), 1.97 (t, J = 12.7, 11.2 Hz, 1H, HaxC-5), 1.40 and
1.36 (2 s, 3H and 3H, 2 CH3). 13C NMR (75 MHz, CDCl3) δ 162.57,
155.30, 156.48 and 154.11 (C=O, C-2’, C-3 and C-8a), 139.46 (i-C6H5),
149.33, 134.56, 129.67, 129.16, 128.43, 127.52, 124.93, 116.81 (C-4’, C-
5’, C-6’, C-7’, C-8’ and o,m,p-C6H5), 117.85 and 117.65 (C-4a’ and C-3’),
75.36 (C-6), 65.25 (CH2O), 40.29 (C-5), 37.84 (C-4), 28.42 and 22.72 (2
CH3). Anal. calcd. for C23H21NO5: C, 70.58; H, 5.41; N, 3.58. Found C,
70.37; H, 5.48; N, 3.59.
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl 3-(1H-
indol-3-yl)propanoate (3n). Prepared according to general procedure
(ii) from 3-indolepropionic acid (Oxigon®) (94 mg, 0.5 mmol) and
bis(oxy)enamine 1a (0.5 mmol). Yield: 133 mg (68%). Oil. Rf = 0.24
(AcOEt-hexane = 1 : 3). 1H NMR (300 MHz, Chloroform-d) δ 8.04 (br s,
1H, HN-1’), 7.61 (d, J = 7.7 Hz, 1H, HC-7’), 7.39 (d, J = 8.0 Hz, 1H, HC-
4’), 7.36-7.14 (m, 5H, m,p-C6H5, HC-5’ and HC-6’), 7.12 (d, J = Hz, 2H,
o-C6H5), 6.98 (s, 1H, HC-2’), 4.47 (s, 2H, CH2O) 3.47 (dd, J = 12.3, 7.8
Hz, 1H, HaxC-4), 3.06 and 2.70 (2 t, J = 7.6 Hz and J = 7.6 Hz, 2H and
2H, CH2-CH2), 2.07 (dd, J = 13.5, 7.9 Hz, 1H, HeqC-5), 1.92 (dd, J = 13.5,
12.3 Hz, 1H, HaxC-5), 1.39 and 1.29 (2 s, 3H and 3H, 2 CH3). 13C NMR
(75 MHz, CDCl3) δ 172.63 (C=O), 154.37 (C-3), 139.32 and 136.43 (C-
7a’ and i-C6H5), 129.13, 128.26 and 127.55 (o,m,p-C6H5), 127.17 (C-3a’),
122.00, 121.68, 119.27 and 118.60 (C-2’, C-4’, C-5’ and C-6’), 114.47 (C-
3’), 111.37 (C-7’), 75.16 (С-6), 64.10 (CH2O), 40.32 (C-5), 37.97 (C-4),
34.58 and 20.60 (CH2-CH2), 28.43 and 22.74 (2 CH3). Anal. calcd. for
C24H26N2O3: C, 73.82; H, 6.71; N, 7.17. Found C, 73.83; H, 6.86; N, 6.99.
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl
nicotinate (3j). Prepared according to general procedure (ii) from
nicotinic acid (61.5 mg, 0.5 mmol) and bis(oxy)enamine 1a (0.5 mmol).
Yield: 94 mg (58%). Oil. Rf = 0.24 (AcOEt-hexane = 1 : 1). 1H NMR (300
MHz, Chloroform-d) δ 9.13 (d, J = 2.3 Hz, 1H, HC-2’), 8.76 (d, J = 4.8 Hz,
1H, HC-6’), 8.19 (dt, J = 7.9, 2.1 Hz, 1H, HC-4’), 7.47-7.08 (m, 6H, o,m,p-
C6H5 and HC-5’), 4.73 (s, 2H, CH2O), 3.61 (dd, J = 12.1, 7.8 Hz, 1H,
HaxC-4), 2.12 (dd, J = 13.6, 7.8 Hz, 1H, HeqC-5), 1.96 (dd, J = 13.6, 12.1
Hz, 1H, HaxC-5), 1.38 and 1.33 (2 s, 3H and 3H, 2 CH3). 13C NMR (75
MHz, CDCl3) δ 164.34 (C=O), 153.53 (C-3), 153.46 and 150.75 (C-2’ and
C-6’), 139.13 (i-C6H5), 137.14 (C-4’), 129.17, 128.17 and 127.59 (o,m,p-
C6H5), 125.63 (C-3’), 123.31 (C-5’), 75.15 (C-6), 64.85 (CH2O), 40.26 (C-
5), 38.15 (C-4), 28.33 and 22.72 (2 CH3). HRMS: calcd. for
[C19H20N2O3Na]+ 347.1366; found 347.1361 ([M+H]+).
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl furan-
2-carboxylate (3k). Prepared according to general procedure (i) from 2-
furanoic acid (56 mg, 0.5 mmol) and bis(oxy)enamine 1a (0.5 mmol).
Yield: 114 mg (73%). White solid. Mp = 84-87oC (pentane-Et2O). Rf = 0.4
(AcOEt-hexane = 1 : 3). 1H NMR (300 MHz, Chloroform-d) δ 7.60 (d, J =
1.5 Hz, 1H, HC-5’), 7.39-7.25 (m, 3H, m,p-C6H5), 7.22 (d, J = 7.6 Hz, 2H,
o-C6H5), 7.15 (d, J = 3.5 Hz, 1H, HC-3’), 6.52 (dd, J = 3.5, 1.5 Hz, 1H,
HC-4’), 4.69 (d, J = 12.6 Hz, 1H, CH2O), 4.64 (d, J = 12.6 Hz, 1H, CH2O),
3.63 (dd, J = 12.0, 7.9 Hz, 1H, HaxC-4), 2.13 (dd, J = 13.6, 7.9 Hz, 1H,
HeqC-5), 1.97 (dd, J = 13.6, 12.0 Hz, 1H, HaxC-5), 1.40 and 1.35 (2 s, 3H
and 3H, 2 CH3). 13C NMR (75 MHz, JMOD, CDCl3) δ 157.84 and 153.89
(C=O and C-3), 146.54 (C-5’), 144.15 (C-2’), 139.23 (i-C6H5), 129.16,
128.29 and 127.58 (o,m,p-C6H5), 118.31 and 111.87 (C-3’ and C-4’),
75.14 (C-6), 64.34 (CH2O), 40.32 (C-5), 38.05 (C-4), 28.41 and 22.76 (2
6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)methyl
(tert-
butoxycarbonyl)glycylglycylglycinate (3o). To a stirred solution of
bis(oxy)enamine 1a (75 mg, 0.26 mmol) in CH2Cl2 (0.9 mL) was added
N-tbutoxycarbonyl-glycyl-glycyl-glycine (75 mg, 0.26 mmol) at r.t. The
mixture was stirred for 96 h at r.t., and then concentrated in vacuum. The
residue was subjected to column chromatography on silica gel (eluent
hexane-AcOEt = 5 : 1→1 : 1 → 0 : 1 → AcOEt-MeOH = 10 : 1 → 5 : 1) to
give 67 mg (53%) of product 3o. Also, a fraction containing 23 mg (40%)
of 5a was obtained. Oil. Rf = 0.05 (AcOEt-hexane = 1 : 1). 1H NMR (300
MHz, Chloroform-d) δ 7.43-7.08 (m, 7H, o,m,p-C6H5, 2 NH), 5.59 (t, J =
5.8 Hz, 1H, NHBoc), 4.52 (d, J = 12.8 Hz, 1H, CH2O), 4.46 (d, J = 12.8
Hz, 1H, CH2O), 3.99 (m, 2H, CH2N), 3.94 (d, J = 5.6 Hz, 2H, CH2N), 3.81
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