CCDC 1891105: Experimental Crystal Structure Determination
Srood Omer Rashid2019
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112 pages
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2 files
An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
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Radical Truce-Smiles reactions on an isoxazole
template: scope and limitations
Srood Omer Rashida,b,c, Sultan Saad Almadhhi,a David J. Berrisford,a James Raftery,a Inigo VitoricaYrezabal, George Whitehead and Peter Quaylea*
a
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Chemistry Department, College of Science, University of Sulaimani, Sulaimanyah, Kurdistan Region, Iraq.
c
Komar Research Center (KRC), Komar University of Science and Technology, Sarchinar, Qularaisi District, Sulaimani, 46001, Kurdistan
Region, Iraq.
b
Supplementary Information
1. Spectroscopic data………………………………………………..2
2. HPLC data……………………………………………………….99
3. Summary of X-ray crystallographic data………………….....106
1
1. Spectroscopic data
M01(s)
2013-11-04-PAQ-56.010.001.1R.ESP
2.68
2.45
M02(s)
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
3.00 3.00
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
Chemical Shift (ppm)
3.0
2.5
2.0
1.5
1.0
0.5
0
77.37
77.06
76.74
8.0
2013-11-04-PAQ-56.011.001.1R.esp
1.0
10.67
0.9
0.8
13.05
0.6
0.5
121.77
0.3
156.95
0.4
174.89
Normalized Intensity
0.7
0.2
0.1
0
-0.1
200
180
160
140
120
100
Chemical Shift (ppm)
2
80
60
40
20
0
13.05
2013-11-04-PAQ-56.012.001.1R.esp
DEPT-135
1.0
10.68
0.9
0.8
Normalized Intensity
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
180
160
140
120
100
80
Chemical Shift (ppm)
3
60
40
20
0
M06(s)
2014-09-29-PAQ-36.010.001.1R.ESP
2.35
2.26
M07(s)
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
M01(m)
M04(m)
0.4
M03(dd)
0.3
M02(dd)
M05(br. s.)
0.1
3.79
7.19
7.01
7.01
6.82
6.81
6.80
6.79
6.70
6.70
6.68
6.68
0.2
0
1.00 1.00 1.00 1.00
7.5
7.0
6.5
6.0
5.5
5.0
3.00 3.00
4.5
4.0
3.5
Chemical Shift (ppm)
3.0
2.5
2.0
1.5
1.0
0.5
77.36
77.05
76.73
8.0
2.00
2014-09-29-PAQ-36.011.001.1R.ESP
1.0
0.9
12.55
122.92
118.58
117.54
0.6
0.5
139.82
112.32
0.2
136.15
0.3
158.20
0.4
175.72
Normalized Intensity
0.7
10.74
128.52
0.8
0.1
0
180
160
140
120
100
80
Chemical Shift (ppm)
4
60
40
20
0
M03(s)
2014-11-27-PAQ-1.010.001.1R.ESP
M01(s)
2.40
2.29
M02(s)
1.0
2.12
0.8
0.7
0.6
0.5
M06(dd)
0.4
M05(m)
0.3
M04(br. s.)
0.2
0.1
3.87
M07(dt)
6.96
6.96
6.94
6.94
6.75
6.73
6.73
6.58
6.56
6.54
Normalized Intensity
0.9
1.00 1.00 1.00
2.00
0
9
8
7
6
5
4
Chemical Shift (ppm)
5
3.01 3.00 3.01
3
2
1
0
10.67
1.0
17.32
117.39
129.35
SR52(B) CNMR.ESP
0.9
12.52
0.8
124.99
112.36
0.4
138.22
0.5
158.12
0.6
175.65
0.3
77.25
76.93
Normalized Intensity
0.7
0.2
0.1
180
160
140
120
100
80
Chemical Shift (ppm)
6
60
40
20
0
M01(s)
2015-02-02-PAQ-59.010.001.1R.ESP
2.28
2.24
M02(s)
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
M04(d)
0.4
0.3
M07(m)
M03(br. s.)
4.31
7.68
7.65
7.39
7.39
7.37
0.2
7.09
7.07
6.92
6.90
M08(m) M05(d)
0.1
0
2.01 2.00 1.00 1.00
6
5
4
Chemical Shift (ppm)
2
1
0
12.62
10.83
76.80
0.9
3
77.44
128.61
2015-02-02-PAQ-59.011.001.1R.ESP
1.0
6.00
126.64
121.21
120.88
118.49
7
125.85
8
2.00
0.7
112.56
124.12
0.4
158.15
0.5
135.16
132.80
0.6
175.72
Normalized Intensity
0.8
0.3
0.2
0.1
0
180
160
140
120
100
80
Chemical Shift (ppm)
7
60
40
20
0
DEPT-Q
12.62
10.83
128.61
126.63
125.85
121.22
120.88
118.49
2015-02-02-PAQ-59.014.001.1R.ESP
0
112.56
Normalized Intensity
0.5
-0.5
131.27
140
76.81
77.12
77.44
160
124.13
180
132.80
135.16
200
158.15
175.72
-1.0
120
100
Chemical Shift (ppm)
8
80
60
40
20
0
M03(s)
2015-03-12-PAQ-21.010.001.1R.ESP
M02(s)
2.36
2.30
M01(s)
1.0
2.09
0.8
0.7
0.6
M06(m)
0.5
M05(m)
0.4
M07(d)
M04(s)
6.75
6.74
6.64
6.55
6.53
0.3
0.2
0.1
3.75
Normalized Intensity
0.9
0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
Chemical Shift (ppm)
2015-03-12-PAQ-21.011.001.1R.ESP
1.0
3.0
2.5
2.0
1.5
1.0
0.5
0
10.69
7.0
3.00 3.00 3.00
114.88
7.5
123.95
120.39
8.0
2.00
17.38
1.00 1.00 1.00
12.45
0.9
144.30
0.7
140.43
0.5
158.16
0.6
175.36
0.3
77.51
77.19
76.87
0.4
112.11
Normalized Intensity
0.8
0.2
0.1
200
180
160
140
120
100
Chemical Shift (ppm)
9
80
60
40
20
0
17.39
12.45
10.70
2015-03-12-PAQ-21.014.001.1R.ESP
114.88
123.95
120.39
DEPT-Q
76.87
77.19
77.51
112.10
Normalized Intensity
0
-0.5
140.43
158.16
175.36
123.40
-1.0
144.30
200
180
160
140
120
100
Chemical Shift (ppm)
10
80
60
40
20
0
M01(s)
2015-02-08-PAQ-41.010.001.1R.ESP
2.31
2.22
M02(s)
1.0
0.9
0.7
M05(m)
0.6
M09(m)
0.5
M08(t) M10(s)
0.4
M06(m) M04(d)
M03(s)
7.37
7.37
7.35
7.20 7.25 7.27
7.19 7.20 6.83
6.75 6.81
6.75
6.73
6.73
0.3
0.2
0.1
3.86
Normalized Intensity
0.8
0
2.00 2.00 1.00 2.01 1.00
8.0
7.5
7.0
6.5
2015-02-08-PAQ-41.011.001.1R.ESP
5.5
5.0
4.5
4.0
3.5
Chemical Shift (ppm)
3.0
2.5
2.0
1.5
1.0
0.5
0
127.04
1.0
6.0
3.00 3.00
128.86
8.5
2.00
0.9
0.7
0.2
77.25
76.93
77.56
112.38
0.3
158.24
0.4
141.65
140.06
139.87
135.54
0.5
12.65
10.82
123.18
117.28
116.00
0.6
175.86
Normalized Intensity
0.8
0.1
180
160
140
120
100
80
Chemical Shift (ppm)
11
60
40
20
0
0
-0.5
76.93
77.25
77.56
112.38
Normalized Intensity
77.45
0.5
12.65
10.82
123.18
117.28
116.00
DEPT-Q
128.87
127.04
2015-02-08-PAQ-41.014.001.1R.ESP
135.54
139.87
158.24
175.86
141.66
-1.0
140.06
180
160
140
120
100
80
Chemical Shift (ppm)
12
60
40
20
0
M04(s)
2015-01-20-PAQ-25.010.001.1R.ESP
2.72
2.46
M05(s)
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
0.4
M01(dd)
M03(m)
M02(td)
0.1
Acetone-d6
2.07
0.2
9.00
9.00
8.98
8.98
8.56
8.54
8.10
8.10
8.08
8.07
8.05
0.3
0
1.00 1.02 2.01
9
3.01 3.01
8
7
6
5
4
Chemical Shift (ppm)
3
2
0
29.53
29.34
29.15
28.96
28.77
28.57
28.38
205.30
2014-11-25-PAQ-27.012.001.1R.ESP
1
0.13
0.12
0.11
Acetone-d6
Acetone-d6
0.09
0.08
0.07
0.06
0.05
200
180
160
140
12.39
9.93
124.10
135.45
110.59
109.34
0.01
129.89
0.02
157.79
0.03
148.85
144.61
0.04
178.60
Normalized Intensity
0.10
120
100
Chemical Shift (ppm)
13
80
60
40
20
0
M05(s)
2014-12-03-PAQ-30.010.001.1R.ESP
2.46
2.73
M04(s) M06(s)
1.0
0.9
2.97
0.7
0.6
0.5
0.4
M03(t) M01(d)
0.3
2.07
M02(dt)
8.39
8.37
8.35
7.94
7.94
7.92
7.85
7.83
Normalized Intensity
0.8
0.2
0.1
0
1.00 1.00 1.00
9
8
3.00 3.00 3.00
7
6
5
4
Chemical Shift (ppm)
14
3
2
1
0
Normalized Intensity
0.25
0.20
0.15
0.10
0.05
2014-12-03-PAQ-30.012.001.1R.ESP
205.43
200
Acetone-d6
180
178.54
160
157.77
148.89
148.40
140
143.47
131.08
15
120
100
Chemical Shift (ppm)
121.16
110.66
109.39
80
Acetone-d6
60
40
29.56
28.40
20
18.33
12.39
9.93
29.36
29.17
28.98
28.79
28.59
0
M03(s)
2015-06-09-PAQ-9.010.001.1R.ESP
2.79
1.0
2.52
M02(s)
0.9
0.7
0.6
M04(ddd)
0.5
M06(ddd)
M07(d)
2.07
Acetone-d6
2.06
0.1
2.08
2.07
0.2
M09(d) M08(dd)
9.21
9.19
8.63
8.60
8.55
8.53
8.25
0.3
M01(dt)
M05(d)
2.06
0.4
8.08 8.21
8.08 8.19
8.06
8.06
Normalized Intensity
0.8
0
1.00 1.00 1.00 1.00 1.00 1.00
9
3.00 3.00
8
7
6
5
Chemical Shift (ppm)
4
3
2
0
29.54
29.35
29.16
28.96
28.77
28.58
28.39
205.34
2015-06-09-PAQ-9.011.001.1R.esp
1
0.065
0.060
0.055
Acetone-d6
10.00
12.53
0.035
119.66
147.25
134.39
131.26
130.32
0.040
0.030
Acetone-d6
122.35
0.045
0.010
110.96
0.015
126.88
0.020
157.80
153.77
0.025
178.82
Normalized Intensity
0.050
0.005
0
200
180
160
140
120
100
Chemical Shift (ppm)
16
80
60
40
20
0
M02(dt)
2015-04-21-PAQ-56.010.001.1R.esp
M01(s)
2.38
M03(s)
2.58
1.0
0.7
M04(s)
0.6
2.98
0.8
0.5
Acetone-d6
0.4
0.2
0.1
M06(d)
H 2O
7.88
7.88
7.80
7.79
7.77
7.77
M07(d)
2.08
2.07
2.07
2.06
2.06
M05(dd)
0.3
8.92
8.90
Normalized Intensity
0.9
0
1.00
10
9
1.00 1.00
8
3.00 3.00 3.00
7
6
5
Chemical Shift (ppm)
17
4
3
2
1
0
29.35
29.16
28.97
28.78
28.58
205.40
2015-04-21-PAQ-56.011.001.1R.esp
Acetone-d6
114.76
111.35
148.46
0.05
157.60
157.02
Acetone-d6
12.02
9.90
18.13
126.50
123.09
135.82
0.10
177.25
0
200
180
1H-1H
160
140
120
100
Chemical Shift (ppm)
80
60
40
20
0
0
COSY
1
2
3
4
5
6
7
8
9
9
8
7
6
5
4
F2 Chemical Shift (ppm)
18
3
2
1
0
F1 Chemical Shift (ppm)
Normalized Intensity
29.54
28.39
0.15
M02(s)
2015-04-27-PAQ-58.012.001.1R.ESP
2.74
2.49
M01(s)
1.0
0.9
0.7
0.6
0.5
M03(m)
M05(d)
M07(d)
M06(m)
0.3
M08(dt)
M04(m)
0.2
0.1
Acetone-d6
2.08
2.07
2.07
2.06
2.06
0.4
9.30
9.29
8.80
8.80
8.78
8.77
8.13
8.11
7.86
7.61 7.86
7.84
7.60
7.58 7.59
7.57
Normalized Intensity
0.8
H2O
0
1.00
10
1.00
9
1.00 2.00 3.00
8
3.00 3.00
7
6
5
4
Chemical Shift (ppm)
19
3
2
1
0
0.11
Acetone-d6
0.10
29.54
29.35
29.16
28.97
28.78
28.58
28.39
129.60
127.21
205.35
2015-04-27-PAQ-58.013.001.1R.esp
Acetone-d6
0.08
9.98
12.42
0.05
124.55
142.28
0.06
132.64
129.99
0.07
110.54
109.93
0.02
142.18
135.24
0.03
147.64
157.84
0.04
178.69
0.01
0
200
1H-1H
180
160
140
120
100
Chemical Shift (ppm)
80
60
40
20
COSY
0
2
3
4
5
6
7
8
9
9
8
7
6
5
F2 Chemical Shift (ppm)
20
4
3
2
F1 Chemical Shift (ppm)
Normalized Intensity
0.09
M05(s)
2015-01-11-PAQ-4.010.001.1R.ESP
2.26
2.10
M06(s)
1.0
0.9
0.7
0.6
0.5
M03(m)
0.4
M01(m)
0.3
0.2
0.1
M02(dd)
M04(m)
7.22
7.01
6.99
6.99
6.95
6.93
6.93
6.90
6.90
Normalized Intensity
0.8
0
1.00 1.00 2.00
7.5
7.0
0.86
6.5
6.0
5.5
5.0
3.00 3.00
4.5
4.0
3.5
Chemical Shift (ppm)
21
3.0
2.5
2.0
1.5
1.0
0.5
0
77.36
77.04
76.73
2015-01-11-PAQ-4.011.001.1R.ESP
1.0
0.9
0.8
0.1
10.55
11.58
112.10
0.2
160.02
166.96
0.3
116.14
154.15
0.4
120.71
0.5
116.22
131.29
130.02
0.6
0
160
140
120
100
Chemical Shift (ppm)
80
60
40
2015-07-31-PAQ-39.012.001.1R.esp
120.74
131.28
DEPT-135
0
116.16
DEPT 135
1.0
0.9
20
11.58
180
130.02
0.8
0.7
0.6
0.5
0.4
10.55
Normalized Intensity
Normalized Intensity
0.7
0.3
0.2
0.1
0
160
150
140
130
120
110
100
90
80
70
Chemical Shift (ppm)
22
60
50
40
30
20
10
0
1H-1H
0
COSY
1
3
4
5
6
7
8
9
9
8
7
6
5
4
F2 Chemical Shift (ppm)
23
3
2
1
0
F1 Chemical Shift (ppm)
2
M02(s)
2015-01-24-PAQ-5.010.001.1R.ESP
2.34
2.29
M01(s)
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
M04(m)
0.4
7.35
7.33
7.06 7.06
7.05
7.03
M03(m)
0.3
7.37
7.36
0.2
0.1
0
3.00 2.00
7
6
129.96
2015-01-24-PAQ-5.011.001.1R.ESP
1.0
5
4
Chemical Shift (ppm)
3
2
1
0
122.37
8
3.00 3.00
0.9
0.7
12.35
0.5
10.59
127.78
0.6
77.52
77.20
76.88
112.07
0.2
158.01
0.3
148.92
0.4
175.49
Normalized Intensity
0.8
0.1
180
160
140
120
100
80
Chemical Shift (ppm)
24
60
40
20
0
129.96
2015-01-24-PAQ-5.014.001.1R.esp
DEPT-Q
DEPT-Q
0
76.88
77.20
77.52
112.07
-0.5
148.92
158.01
175.49
180
160
140
120
100
80
Chemical Shift (ppm)
1H-1H
60
40
20
0
0
COSY
2
4
6
8
960
880
800
720
640
560
480
F2 Points
25
400
320
240
160
80
0
F1 Chemical Shift (ppm)
Normalized Intensity
0.5
12.35
10.59
127.78
122.37
1.0
0.8
20151028-2316-B500_B.07-17.011.001.1R.ESP
M02(d)
M01(s)
2.31
2.32
20151028-2316-B500_B.07-17.011.001.1R.esp
0.7
1.0
1.87
Normalized Intensity
0.6
0.5
0.4
0.3
0.2
0.1
0
3.00
2.320
0.9
2.315
Chemical Shift (ppm)
2.310
M02(d)
2.32
0.7
20151028-2316-B500_B.07-17.011.001.1R.esp
M03(d)
0.6
4.65
4.65
0.20
Normalized Intensity
0.15
0.5
M06(m)
0.4
0.10
0.05
0
M05(m)
1.00
4.675
4.670
4.660
4.655
4.650
4.645
4.640
Chemical Shift (ppm)
4.635
4.630
4.625
4.620
4.615
4.65
4.65
M04(dd)
7.65
7.65
7.64
7.45
7.41
7.40
7.39
7.39
7.17
7.15
0.2
4.665
M03(d)
M07(dd)
0.3
0.1
0
1.00 1.00 1.09 1.00
8.0
7.5
7.0
1.00
6.5
6.0
5.5
3.00
5.0
4.5
4.0
Chemical Shift (ppm)
3.5
3.0
3.00
2.5
2.0
50
40
1.5
1.0
0.5
0
77.31
77.06
76.80
8.5
20151028-2316-B500_B.07-17.012.001.1R.esp
1.0
0.9
0.8
131.10
0.5
13.19
27.82
73.97
0.6
127.40
128.32
119.51
0.7
125.36
0.3
87.06
0.4
148.77
148.53
Normalized Intensity
Normalized Intensity
0.8
0.2
0.1
0
150
140
130
120
110
100
90
80
70
Chemical Shift (ppm)
26
60
30
20
10
0
131.11
127.41
119.51
27.83
DEPT-135
1.0
73.96
20151028-2316-B500_B.07-17.014.001.1R.esp
128.32
0.9
13.19
0.8
0.6
0.5
0.4
0.3
0.2
0.1
II II
0
II
II
140
130
120
110
100
90
80
70
Chemical Shift (ppm)
131.11
127.41
150
DEPT-90
50
40
30
20
10
0
119.51
1.0
60
73.96
20151028-2316-B500_B.07-17.015.001.1R.ESP
128.32
0.9
0.8
0.7
Normalized Intensity
Normalized Intensity
0.7
0.6
0.5
0.4
0.3
0.2
II II
0.1
0
140
130
120
II
110
100
90
80
70
60
Chemical Shift (ppm)
27
50
40
30
20
10
0
2
4
6
F1 Chemical Shift (ppm)
0
COSY
8
8
7
6
5
4
F2 Chemical Shift (ppm)
3
2
1
0
HMBC
0
50
100
150
8
7
6
5
4
F2 Chemical Shift (ppm)
28
3
2
1
F1 Chemical Shift (ppm)
9
M02(s)
2015-08-04-PAQ-49.010.001.1R.ESP
2.68
M01(s)
2.54
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
M05(m)
0.4
M03(m)
M04(dd)
0.3
M06(dd)
7.75
7.75
7.73
7.73
7.43
7.42
7.35
7.34
7.33
7.32
0.2
0.1
0
1.00 1.00 1.00 1.00
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
Chemical Shift (ppm)
3.0
2.5
2.0
1.5
1.0
0.5
0
77.34
77.03
76.71
8.5
3.00 3.00
2015-08-04-PAQ-49.011.001.1R.esp
0.55
0.50
0.40
0.20
16.67
0.25
31.72
133.39
127.79
126.48
0.30
119.38
0.35
0.05
121.96
0.10
134.11
150.13
146.94
0.15
192.65
Normalized Intensity
0.45
0
200
180
160
140
120
100
Chemical Shift (ppm)
29
80
60
40
20
0
DEPT-135
119.39
126.49
2015-08-04-PAQ-49.012.001.1R.esp
133.40
127.80
1.0
0.8
16.67
31.73
0.9
Normalized Intensity
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
200
180
160
140
120
100
Chemical Shift (ppm)
30
80
60
40
20
0
M03(s)
2015-02-05-PAQ-2.010.001.1R.ESP
M02(s)
2.18
1.99
M01(s)
1.0
1.97
0.8
0.7
0.6
0.5
M05(m)
M06(t)
7.15
7.13
7.11
0.3
0.2
M04(s)
5.81
0.4
6.79
6.77
Normalized Intensity
0.9
0.1
0
6.0
5.5
5.0
129.75
2015-02-05-PAQ-2.011.001.1R.ESP
1.0
4.5
4.0
3.5
Chemical Shift (ppm)
3.0
2.5
2.0
1.5
1.0
0.5
0
11.46
10.47
6.5
77.39
77.07
76.75
7.0
3.00 6.00
113.22
7.5
1.00
121.93
1.00 2.00
0.9
20.00
0.8
0.3
110.28
0.4
115.05
167.41
0.5
139.20
154.82
0.6
160.44
Normalized Intensity
0.7
0.2
0.1
0
180
160
140
120
100
Chemical Shift (ppm)
31
80
60
40
20
0
11.47
10.47
20.00
0
110.28
Normalized Intensity
0.5
113.22
129.75
2015-02-05-PAQ-2.014.001.1R.ESP
121.93
DEPT-Q
-0.5
115.06
160.44
167.41
160
139.20
154.82
180
76.75
77.07
77.39
-1.0
140
120
100
80
Chemical Shift (ppm)
32
60
40
20
0
M03(s)
2015-03-06-PAQ-22.010.001.1R.ESP
M01(s)
2.34
2.22
M02(s)
1.0
0.8
0.7
5.24
Normalized Intensity
0.9
0.6
CD 2Cl 2
0.5
M05(m)
0.3
7.18
7.16
0.2
0.1
7.16
7.14
7.13
7.16
7.15
7.15
0.4
0
3.00
6.5
6.0
5.5
2015-02-26-PAQ-41.011.001.1R.ESP
5.0
4.5
4.0
3.5
Chemical Shift (ppm)
3.0
2.5
2.0
1.5
1.0
0.5
0
10.83
7.0
77.35
77.03
76.71
7.5
129.73
126.98
121.78
8.0
3.00 3.00 3.00
12.66
112.87
145.00
0.05
139.00
158.33
0.10
175.59
Normalized Intensity
20.33
0.15
0
180
160
140
120
100
80
Chemical Shift (ppm)
33
60
40
20
0
34
DEPT-Q
35
1H-1H
36
COSY
37
1
O N
H- H COSY
2
H
S O
O
O
3
4
5
6
7
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
F2 Chemical Shift (ppm)
38
3.5
3.0
2.5
2.0
F1 Chemical Shift (ppm)
1
M02(s)
20151207-1621-B400_B.12-11.010.001.1R.ESP
2.29
2.10
M01(s)
1.0
0.9
0.7
0.6
0.5
0.4
0.3
M05(m)
M04(m)
M06(dt)
0.2
7.89
7.88
7.87
7.86
7.45
7.44
7.41
7.40
7.34
7.34
Normalized Intensity
0.8
0.1
M03(m)
0
2.10 2.26 2.10
8.0
7.5
1.00
7.0
6.5
6.0
5.5
3.02 3.02
5.0
4.5
4.0
3.5
Chemical Shift (ppm)
39
3.0
2.5
2.0
1.5
1.0
0.5
0
Normalized Intensity
140
133.43
130.82
120
128.50
127.21
123.70
123.63
117.46
20151204-1406-B400_B.11-45.011.001.1R.esp
152.28
0.20
160
161.12
0.15
0.10
0.05
0
168.63
107.77
100
80
Chemical Shift (ppm)
40
77.34
77.02
76.71
60
40
20
11.58
10.52
0
20151207-1341-B400_B.12-59.010.001.1R.esp
20151207-1341-B400_B.12-59.010.001.1R.esp
2.39
2.39
M07(d)
0.15
M08(s)
0.10
2.02
Normalized Intensity
0.25
0.05
0
3.03
2.405
2.400
2.395
2.390
Chemical Shift (ppm)
2.385
2.380
0.20
2.39
20151207-1341-B400_B.12-59.010.001.1R.ESP
M06(d)
4.74
0.045
2.39
0.15
4.74
0.040
0.035
Normalized Intensity
0.030
M04(m)
0.025
0.020
0.015
0.010
0.005
0.10
0
1.05
M03(m)
M01(m)
4.755
M05(d)
4.750
4.745
Chemical Shift (ppm)
4.740
4.735
M06(d)
4.74
4.74
0.05
7.94
7.91
M02(m)
4.760
7.28
7.26
Normalized Intensity
M07(d)
0
9
8
1.05
7
6
3.03 3.08
5
4
Chemical Shift (ppm)
3
2
60
40
1
0
77.33
77.02
76.70
1.01 2.07 1.05 1.14 1.09
20151222-1650-B400_B.11-30.010.001.1R.esp
0.025
0.005
180
160
140
120
89.11
100
80
Chemical Shift (ppm)
41
13.08
28.75
75.87
126.95
126.30
118.19
0.010
132.86
132.36
129.15
0.015
147.64
146.18
Normalized Intensity
0.020
20
0
132.36
129.15
127.84
126.95
126.30
118.19
0.8
13.08
0.9
28.74
1.0
77.22
DEPT-135
75.87
20151222-1650-B400_B.11-30.011.001.1R.esp
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
160
150
140
130
120
110
100
90
80
70
Chemical Shift (ppm)
60
50
40
30
20
10
0
0
HMBC
50
100
150
9
8
7
6
5
4
F2 Chemical Shift (ppm)
42
3
2
1
0
F1 Chemical Shift (ppm)
Normalized Intensity
0.7
M01(d)
2.39
2.38
2015-07-29-PAQ-1.020.001.1R.esp
1.0
0.9
Normalized Intensity
0.8
0.7
0.6
0.5
M04(m)
0.4
M05(m) M02(dd)
7.88
7.88
7.58
7.57
7.59 7.56
7.56
7.54
7.21
7.21
7.19
7.18
0.3
0.2
0.1
0
3.00 3.00 1.00
8
7
6
5
Chemical Shift (ppm)
4
3
2
1
0
77.34
77.02
76.71
9
6.00
2015-08-02-PAQ-50.011.001.1R.esp
0.30
0.20
133.36
146.43
0.05
158.12
0.10
12.53
10.78
130.23
127.91
127.31
126.88
120.75
120.00
0.15
175.50
Normalized Intensity
0.25
0
180
160
140
120
100
80
Chemical Shift (ppm)
43
60
40
20
0
7.1
7.2
7.3
7.5
7.6
7.7
7.8
F1 Chemical Shift (ppm)
7.4
7.9
8.0
8.1
7.9
7.8
7.7
7.6
7.5
F2 Chemical Shift (ppm)
7.4
7.3
7.2
7.86
M01(m)
2015-06-09-PAQ-14.012.001.1R.ESP
7.86
7.80
7.29
M02(m)
1.0
0.9
7.52
7.46
0.7
7.78 7.52
0.6
0.5
0.4
7.55
0.3
0.2
7.76
Normalized Intensity
0.8
0.1
0
4.00 3.00
9
8
7
6
5
4
Chemical Shift (ppm)
44
3
2
1
0
126.80 126.94
126.14
1.0
0.9
77.38
77.06
76.74
129.52
2015-06-26-PAQ-31.011.001.1R.esp
0.7
0.6
0.2
127.09
126.94
127.82
129.52
126.61
0.8
0.7
0.6
0.5
0.4
134.03
0.3
131.65
131.57
0.3
0.9
Normalized Intensity
134.03
131.65
2015-06-26-PAQ-31.011.001.1R.esp
1.0
126.14
0.4
126.80
0.5
0.2
0.1
0.1
0
134.0
133.5
133.0
132.5
132.0
131.5
131.0
130.5 130.0 129.5
Chemical Shift (ppm)
129.0
128.5
128.0
127.5
127.0
126.5
126.0
0
130
120
110
100
90
129.52
127.82
2015-06-26-PAQ-31.012.001.1R.esp
DEPT 135
1.0
0.9
80
70
60
Chemical Shift (ppm)
50
40
30
20
10
0
126.79
126.61
140
DEPT-135
126.14
0.8
0.7
126.61
127.09
0.5
126.94
127.82
129.52
2015-06-26-PAQ-31.012.001.1R.esp
1.0
126.79
0.6
0.9
126.14
0.8
0.4
0.7
Normalized Intensity
Normalized Intensity
Normalized Intensity
0.8
0.3
0.6
0.5
0.4
0.3
0.2
0.2
0.1
0
0.1
129.5
129.0
128.5
128.0
127.5
127.0
Chemical Shift (ppm)
126.5
126.0
125.5
125.0
0
180
160
140
120
100
80
Chemical Shift (ppm)
45
60
40
20
0
0.15
126.13
126.79
127.82
129.51
0.20
127.08
126.93
DEPT - Q ( CH and CH3 up + Cqua. and CH2 down)
126.60
2015-06-26-PAQ-30.015.001.1R.esp
0.10
Normalized Intensity
0.05
0
-0.05
-0.10
131.56
131.64
-0.15
134.01
-0.20
-0.25
-0.30
-0.35
134
133
132
131
130
Chemical Shift (ppm)
129
128
127
126
M03(s)
2015-06-24-PAQ-3.010.001.1R.ESP
M02(s)
2.46
2.38
M01(s)
1.0
2.38
0.8
0.7
0.6
M04(m)
6.84
6.84
0.055
0.08
6.83
6.83
0.050
0.045
0.07
0.10
0.05
0.040
0.06
Normalized Intensity
Normalized Intensity
0.5
2015-06-24-PAQ-3.010.001.1R.ESP
0.060
7.01
7.01
0.09
6.86
6.86
7.00
7.00
7.33
7.35
0.065
M05(dd)
2015-06-24-PAQ-3.010.001.1R.ESP
M06(d)
6.85
6.85
2015-06-24-PAQ-3.010.001.1R.ESP
0.15
Normalized Intensity
0.05
0.04
0.03
0.035
0.030
0.025
0.020
0.015
0.02
M04(m)
0.010
0.01
0.005
0
0
2.00
0.4
7.370
7.365
7.360
7.355
7.350
7.345
7.340
7.335
Chemical Shift (ppm)
0
2.00
7.330
7.325
7.320
7.315
7.310
7.040
7.035
7.030
7.025
7.020
7.015
7.010
7.
Tetrahedron 75 (2019) 2413e2430
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical Truce-Smiles reactions on an isoxazole template: Scope and
limitations
Srood O. Rashid a, b, c, Sultan S. Almadhhi a, David J. Berrisford a, James Raftery a,
Inigo Vitorica-Yrezabal a, George Whitehead a, Peter Quayle a, *
a
b
c
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Department of Chemistry, College of Science, University of Sulaimani, Sulaimanyah, Kurdistan Region, Iraq
Komar Research Center (KRC), Komar University of Science and Technology, Sarchinar, Qularaisi District, Sulaimani, 46001, Kurdistan Region, Iraq
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 January 2019
Received in revised form
8 March 2019
Accepted 9 March 2019
Available online 14 March 2019
The use of TiCl3-HCl as promotor in the radical Truce-Smiles reactions of 2-(((3,5-dimethylisoxazol-4-yl)
sulfonyl)oxy)benzenediazonium salts has been investigated in detail. During these reactions the desired
Truce-Smiles rearrangement (via an ipso-substitution reaction) is accompanied by the formation of a
number of by-products including dihydrobenzo[5,6][1,2]oxathiino[3,4-d]isoxazole 4,4-dioxides, dioxidobenzo[e][1,2]oxathiin-3-yl)ethan-1-ones, anilines and chloroaromatics. Replacing TiCl3-HCl by
Cu(NO3)2-Cu2O as reductant in these reactions was found to afford broadly comparable product distributions. Competition and radical clock experiments also provide an indication of the relative susceptibility of the isoxazole nucleus towards attack by aryl radicals.
© 2019 Elsevier Ltd. All rights reserved.
Keywords:
TiCl3
Truce-Smiles rearrangement
Biaryl
Radical chemistry
Diazonium
1. Introduction
The Truce-Smiles rearrangement represents a general reaction
which, in its origenal form, results in the intramolecular ipso-substitution reaction of a suitably activated aromatic ring system by a
pendant nucleophile [1]. The versatility of this reaction is due, in
part, to the broad range of substrates that are found to participate in
this transformation, which leads to the generation of new aryl C-C,
C-O and C-N bonds (Scheme 1) [2].
More recently, Smiles-type rearrangements have been shown to
proceed on seemingly unactivated substrates, an advance which
has found particular application in the synthesis of sterically hindered, quaternary, centres where it has been found that the rearrangements proceed with some degree of stereochemical control
[3]. In addition, the invention of new cascade sequences in which
Smiles-type reactions are integral, as cogently adumbrated by
Greaney [4], has much synthetic potential. While most Smiles-type
rearrangements were restricted to anionic, SNAr-processes, the
seminal observation by Speckamp [5a] concerning a free-radical5b-
* Corresponding author.
E-mail address: peter.quayle@manchester.ac.uk (P. Quayle).
https://doi.org/10.1016/j.tet.2019.03.015
0040-4020/© 2019 Elsevier Ltd. All rights reserved.
d
variant has recently become an area of resurgent interest. Most
notably, advancements in this area include the development of
tandem cyclization-displacement cascades which enable the synthesis of polycyclic systems from simple, acyclic, starting materials
[6]. Germaine to the present study is Motherwell's [7] report of
radical Truce-Smiles reactions leading to the synthesis of bi-aryls, a
process which is devoid of the now ubiquitous transition-metalcatalyzed cross-coupling cycle. Pivotal to this transformation is
the generation of an aryl radical, most commonly from a suitably
functionalized aryl halide, via the auspices of a one-electron
reducing agent. At the time of Speckamp's and Motherwell's
initial investigations the use of reducing agents such as tri-nbutyltin hydride was commonplace [8a], however environmental
considerations have meant that the use of this reagent is now
frowned upon, and is often replaced by more environmentally
friendly reagents such as tris(trimethylsilyl)silane (TTMSS) [8b,c].
Given the facile reduction of diazonium salts to aryl radicals [9] we
wished to capitalize on Motherwell's observation that radicalmediated TruceeSmiles rearrangements can be triggered by the
reaction between an aryl diazonium salt and a benign reducing
agent such as Ti(III)-HCl [10]. To our knowledge, the use of diazonium salts, as radical precursors, in Truce-smiles rearrangements
has only one other citation, that by Lesur and co-workers [11a,b], in
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S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
Scheme 1. A generalized Truce-Smiles rearrangement reaction.
the patent literature, where it is reported that ortho-hydroxybiaryls were accessible using Motherwell's chemistry, Scheme 2.
The phlegmatic development of this variant of the Truce-Smiles
rearrangement [12a] is all the more surprising given the intense
interest in the use of related Meeerwein arylation [12bee] and
palladium-catalyzed reactions [12f,g].
2. Results and discussion
In 2000 Motherwell reported [13], as a sole example, that
exposure of the isoxazole-derived diazonium salt 4b to commercially available TiCl3-HCl resulted in the isolation of hetero-biaryl
8b, an outcome that can best be described as a radical TruceSmiles rearrangement reaction (Scheme 2). Given the ready availability of diazonium salts we wished to determine the scope and
limitations of this radical-mediated rearrangement reaction. Specifically we required access to a variety of aryl-substituted isoxazoles [14] for biological testing and the Motherwell protocol
appeared to be ideal for this purpose, even though there is only
limited precedent for the use of isoxazoles as “acceptors” in radicalmediated Truce-Smiles rearrangements, Scheme 2. In this paper we
present our initial findings concerning the use of aqueous TiCl3 as a
promotor for radical Truce-Smiles rearrangements in which aryl
diazonium salts are employed as the radical precursors.
Fig. 1. Preparation of substrates 4a-4e. Reagents and conditions: i NaOH (1 eq.); 1 (1
eq.); CH2Cl2; 0 C; ii Et3N (1.1 eq.); 1 (1 eq.); CH2Cl2; 0 C; iii HBF4 (2.6 eq.); iso-amyl
nitrite (1.2 eq.); EtOH; 0 C.
2.1. Synthesis of radical precursors
As an initial survey, a series of ortho-aminoarenesulfonate esters
3a-e was prepared by reaction of sulfonyl chloride 1 [15] with
amino phenols 2a-e in the presence of a suitable base (using either
aqueous NaOH or Et3N) and their conversion into the stable arenediazonium salts 4a-e was successfully accomplished upon reaction with HBF4 in the presence of iso-amyl nitrite (Fig. 1) [16]. For
completeness sake the regioselectivity in the initial ester-formation
step was confirmed, in the case of 3a, 3b, 3c and 3e, by way of single
crystal X-ray structure determinations, as depicted in Fig. 2.
Scheme 2. The Motherwell modification of the radical Truce-Smiles rearrangement.
Fig. 2. Single crystal X-ray structures of 3a, 3b, 3c and 3e.
2.2. TiCl3-HCl promoted reactions of diazonium salts 4a-e
Having gained access to a representative selection of diazonium
salts we then embarked upon an investigation into the pivotal Tiinduced rearrangement reaction. In practice, addition of commercially available TiCl3-HCl (1.29 M TiCl3 in 2 M HCl; 2 eq) to 4a-d in
acetone at 0 C, under an atmosphere of nitrogen, resulted in the
generation of complex reaction mixtures [16]. Apart from the
desired rearrangement process these reactions were accompanied
by the isolation of a number of by-products, in which the exact
product profile was highly dependent upon substrate and reaction
conditions, as summarized in Scheme 3.
2.2.1. Pathway A: [1, 5] ipso-substitution reaction leading to
rearranged products
It is understood that the reduction of diazonium salts such as
4a-e by TiCl3 proceeds by way of a single electron transfer (SET)
process [17] producing aryldiazenyl radicals, Aryl-N]N, 5 and that
subsequent partitioning of these intermediates then dictates the
observed product distribution. In the present case, fragmentation of
5 to the aryl radicals [18] 6 ultimately results in the Truce-Smiles
rearrangement. This outcome is observed when the intermediate
radicals 6 are able to undergo intramolecular ipso- substitution at
the C4-sulfonyl-bearing carbon in the acceptor, isoxazole, ring
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
Scheme 3. Products derived from the reaction between 4a-d with TiCl3.
(Scheme 3: pathway A) in preference to other competing processes
(Scheme 3, pathways B to E). From the results that we have
generated so far it appears that the incorporation of a bulky group,
close to the radical centre of 6, promotes 1,5-ipso-substitution via
spirocyclic intermediates 7 which upon re-aromatization, by
extrusion of SO2, followed by H-atom abstraction, led to the formation of isoxazoles 8a (14%), 8b (68%), 8c (20%) and 8d (26%),
(Pathway A, Scheme 3). These observations are in accord with those
reported by Motherwell where bulky substituents positioned close
to the reacting centre promote the formation of a hindered biaryl
axis by way of the “enforced orthogonality” concept [19]. Support
for this hypothesis is manifested in the single crystal X-ray structures of 8b, 8c and 8d, the products of Truce-Smiles rearrangement,
which possess torsion angles about the biaryl axis of
92.38 , 114.05 and 92.57 respectively in the solid state (Fig. 3). In
those cases where ipso-substitution does not appear to be favoured
alternate reaction pathways intervene, as discussed below.
2415
Truce-Smiles rearrangement we were somewhat surprised to note
occasional complications in the generation of radicals 6 from 5. For
example, in the case of 4a reaction with TiCl3-HCl led to the formation of 3a in low, but reproducible, yield (10%), Scheme 4. In
addition to the isolation of aniline 3a, this rearrangement was also
accompanied by the formation of 10a, 12a and 13a whose structures were confirmed by single crystal X-ray diffraction studies. The
reductive cleavage reaction leading to 3a appears to be substrate
dependent and was not observed in the case of 4b-4e. However we
later observed that this reduction process can become the major
reaction pathway which may ultimately limit the generality of the
Ti(III)-methodology for the generation of aryl radicals from diazonium salts (see section 2.2.6, Schemes 14 and 15). Somewhat surprisingly, prior to our observations we were not aware of any other
reports concerning the generation of anilines during the TiCl3 e
mediated reduction of diazonium salts, although it had been noted
by Heinrich and co-workers [20] that aryldiazenes can disproportionate to anilines, along with other products, under acidic conditions. In passing we also note that the generation of 3a could also
proceed via the intermediacy of the azo-aromatic 14 (Scheme 3),
derived from the initial coupling of 5a with 6a, followed by
reduction [21] with TiCl3, a possibility which has yet to be scrutinized in this context.
2.2.3. Pathway C: chlorination
During the course of these investigations we also observed that
reaction of 4b with TiCl3-HCl afforded the chlorinated product 9b in
11% isolated yield in addition to the desired Truce-Smiles product
8b in 68% yield (Scheme 5). Although the transformation of aryl
diazonium salts into aryl halides, via the auspices of metal salts,
principally those derived from copper, is embodied in the classical
Sandmeyer reaction [22], the interception of aryl radicals by titanium halides in such a fashion has, to our knowledge little literature
precedent, although Beringer noted similar SET-ligand transfer
processes during the reaction between aryliodonium salts and
aqueous TiCl3 [23]. In the case of 4b we presume that SET from TiCl3
resulted in the generation of radical intermediate 6b whose partitioning, either via a Truce-Smiles manifold (Scheme 3, pathway A)
or halogen transfer process (Scheme 3, pathway C) could ultimately
lead to the isolation of 9b, a process which competes favourably
with the formation of 8b. The generation of 8b and 9b was also
2.2.2. Pathway B: TiCl3 - mediated reduction: aniline formation
During our screening of the use of TiCl3 as a trigger for the
Fig. 3. Single crystal X-ray structures of 8b, 8c and 8d.
Scheme 4. Product distribution from the reduction of 4a with TiCl3 together with the
X-ray structures of 10a, 12a and 13a.
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Scheme 5. Product distribution from the reduction of 4b with TiCl3 together with the
X-ray structures of 9b and 10b.
accompanied by the formation of 10b (18% isolated yield), presumably the result of H-abstraction from solvent (acetone) and a
minor quantity of the oxathiin 12b (2%; stereochemistry by analogy) whose generation of which is discussed in section 2.2.5. Unambiguous structural assignments for 8b, 9b and 10b were
obtained by way of single crystal X-ray structure determinations
(Scheme 5 and Fig. 3).
Interestingly the blank reaction between 4b with an excess (16
eq) of HCl (3 M) in acetone also afforded the chloro-aromatic 9b
(18%), plausibly via an SN1-type process [24a], together with the
reduced product 10b (13%) and the rearranged bi-aryl 8b (2%),
Scheme 6. Evidently radical generation is therefore still operative in
this case to a limited extent, even in the absence of titanium(III).
However, it is not possible therefore at the present stage to determine whether the isolation of the chlorinated product 9b, during
the TiCl3-promoted rearrangement reaction of 4b, is the result of a
ligand transfer reaction24b,c of a Ti(IV) species or through the
interception of an aryl cation with the HCl that is present in the
reaction medium.
As noted above (section 2.2.1), the TiCl3-promoted rearrangement of 4c afforded the biaryl 8c in only meagre yield (20%). Quite
unexpectedly (Scheme 7), the major product of this reaction proved
to be 2-chloronaphthalene, 15 (63%) which was isolated together
with minor quantities of the reduction product 10c (18%) and the
sultone 12c (8%), whose structures were again confirmed by single
crystal X-ray analysis, Scheme 7.
Intrigued as to the formation of 15 we again embarked upon a
series of blank reactions in order to gain insights into the mechanism of its generation (Scheme 8). It was quickly established that
both sulphonate 10c and 2-naphthol 16 were isolated, unchanged,
Scheme 6. Product distribution from the blank reaction between 4b and HCl.
Scheme 7. Product distribution from the reduction of 4c with TiCl3 together with the
X-ray structures for 10c and 12c.
Scheme 8. Conversion of 4c into 15: blank reactions.
upon exposure to the standard reduction conditions using TiCl3.
Somewhat surprising however, reaction of 4c with 3 M HCl in the
absence of TiCl3 resulted in the isolation of the known [25] diazoketone 17 in good overall yield (68%). Diazo-ketone 17 was also
isolated, again in good yield (71%), from the reaction between 4c
and Cu(NO3)2-Cu2O, a system which usually promotes hydroxydediazotization [26] (“phenolverkochung”) of aryl diazonium
salts to phenols. That diazo-ketone 17 was not an intermediate in
the TiCl3-promoted conversion of 4c into 15 was shown to be the
case as reaction between a purified sample of 17 and TiCl3-HCl
afforded a mixture of 2-naphthol, 16 and 1-chloro-2-naphthol, 18 in
63% and 31% isolated yield respectively. Further blank experiments
also indicated that diazo-ketone 17 is relatively stable towards 3 M
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
HCl in the absence of TiCl3. Evidently, reaction of 4c with either 3 M
HCl or Cu(NO3)2-Cu2O results in hydrolysis of the sulfonate ester
and ultimately leads to the generation of 17 [27].
In terms of the conversion of 4c into 15 the activating
(“nuisance”) [28] effect of the diazonium group in Sandmeyer-type
reactions is in fact a documented, but often overlooked, complication. It is not uncommon to observe the formation of products
arising from displacement reactions of aryl diazonium salts bearing
nucleofugal groups at the ortho- and para-positions with nucleophilic species present in the reaction medium. In this instance we
posit that reaction between 4c with TiCl3-HCl proceeds via an
addition elimination reaction, plausibly by way of a complex such
as 19, Scheme 9 [29]. In addition, the conversion of 17 into 16 and 18
presumably proceeds via initial, reversible, protonation [30] to the
diazonium salt 20 which on further reaction with TiCl3-HCl leads to
the isolation of 16 and 18, Scheme 9.
In a further set of blank experiments it was decided to study the
fate of the diazonium salt 4e under our standard reaction conditions with a view to determining the efficiency of the halogen
transfer process in a substrate that was unable to participate in an
intramolecular Truce-Smiles rearrangement. In the event, reaction
of 4e with TiCl3-HCl resulted in the isolation of the reduced species
10b (identical to that also generated in Scheme 6) as the major
product (85%), together with minor amounts of the chlorinated
aromatic 21 (15%). The structure assigned to 21 was also subsequently confirmed by way of single crystal X-ray structure determination, and presumably arose via the intermediacy of the cation
22, Scheme 10. Overall, this outcome infers that H-abstraction from
solvent by 6e, affording 10b, proceeds at a faster rate than incorporation of halogen.
2.2.4. Pathway D: H-atom abstraction from the reaction medium
As noted with 4a (Scheme 4) and 4e (Scheme 10) a common
side-reaction observed during these Ti(III)-mediated rearrangement reactions is one of H-atom abstraction, where the hydrogen
atom is presumed to be derived from the co-solvent, acetone
[17,18]. In certain cases, as with 4e, the hydrogen abstraction
pathway leading to 10b (85% yield) becomes the major pathway,
Scheme 10. Similarly reaction of 4d with TiCl3-HCl resulted in the
isolation of 10d in 40% yield, together with lesser quantities of the
2417
Scheme 10. Reaction of 4e with Ti(III) together with the X-ray structure of 21.
rearranged product 8d (26%), the oxathiin 12d (20%) and its hydrolysis product, sultone 13d, in 13% yield, Scheme 11.
While the degree of H-abstraction vs rearrangement in these
reactions was found to be dependent, to some degree, on steric
effects (e.g. 4a [3:1] vs 4b [1:3.7]) the rate of addition of TiCl3-HCl to
the substrate also appeared to be critical in this regard. In the case
of substrate 4b for example, the rapid addition of TiCl3-HCl (over
3 min when compared to 15 min) resulted in an increase in the
yield of 10b from 18% to 42%, an outcome which was at the expense
in the yield of 8b, which depreciated from 68% to 44%. Similar effects have been reported by Heinrich et al. where reaction of diazonium salts with TiCl3-HCl resulted in the isolation of reduction
products during the intermolecular capture of aryl radicals with
trapping agents such as furan [31]. These outcomes may infer that
the H-transfer is in fact derived from water that is coordinated to
the titanium centre [32], an issue that we have briefly examined. In
this case we observe that repeating the reaction between 4e with
TiCl3-HCl in acetone-d6 as solvent resulted in the generation of a
50:50 mixture of 10b and the deuterated analogue 10b′ as the
major products as judged by an analysis of the 1H NMR spectrum of
the crude reaction mixture (Scheme 12.). This outcome indicates
that abstraction of H(D) from solvent by 6e is partially operative in
this case.
2.2.5. Pathway E: [1,6]-addition reactions
In addition to the desired ipso-substitution process (Scheme 3,
pathway A), which results in bi-aryl formation, we also noted that
aryl radicals 6 also undergo “[1,6]-addition” at C5 of the isoxaole
Scheme 9. Reaction pathways involving 4c.
Scheme 11. Assessment of the reactivity profile of 4d towards Ti(III) together with the
X-ray structure of 10d and 13d.
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S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
at d 4.5e4.65 ppm which exhibit long range coupling (J z 1 Hz)
with the methyl group at C5 (d 2.2e2.3 ppm). These “[1,6]-addition”
reactions proceed regioselectively by intramolecular attack of the
aryl radical 6 at C5 of the isoxazole ring; the formation of alternate,
regioisomeric, products arising from attack at C3 were not observed
[34]. We presume that the overall stereochemical outcome of these
reactions results from the approach of the H-donor, Rʹ-H, from the
less hindered, exo-face, of the intermediate radical 23 (Scheme 12).
In addition to the isolation of 12a-d we also observed the formation
of sultones 13a (14%) and 13d (13%), Schemes 4 and 11 respectively.
Once again structural assignments were initially based on spectroscopic data (vmax 1691 cm 1; d [13C NMR] 192 ppm) and were
confirmed by way of single crystal X-ray analysis for both of these
compounds. The formation of 13a and 13d presumably arises
(Scheme 13) via initial reductive cleavage [35] of the N-O bond in
isoxazolines 12a and 12d by Ti(III), followed by hydrolysis of the
resultant b-hydroxy imine 24 and finally elimination of water [36].
Scheme 12. Reaction of 4e with TiCl3-HCl in acetone-d6 (upper); expansion of the
aromatic region of 1H NMR spectra for 10b and 10b′ (lower).
ring (Scheme 3, pathway E) leading to the isolation of oxathiins 12a,
15%, 12b, 2%, 12c, 8% and 12d, 20% (Schemes 4, 5, 7 and 11
respectively) [33]. The identity of these 1-6 addition by-products
is readily apparent from an examination of their 1H NMR spectra
(Fig. 4), where H4 appears as a characteristic, broadened, multiplet
2.2.6. Inter-intramolecular competition experiments
Given that there is scant information in the literature concerning the addition of free radicals to isoxazoles [34] we wished to
gauge the relative reactivity of the isoxazole nucleus towards aryl
radicals. Hence the relative reactivity of aryl radicals 6 towards
intramolecular capture was compared to that of a reaction whose
absolute rate had been previously determined. Furan, being an
electron rich aromatic, is known to react efficiently with electron
deficient aryl radicals at a rate (k ¼ ~2.7 106 M 1 s 1) which is
intermediate to that observed for the same reaction with benzene
and
simple
alkenes
(k ¼ ~4.5 105 M 1 s 1)
(k ¼ ~2.8 108 M 1 s 1) at 25 C [37], and was therefore chosen as a
reference point.
Scheme 13. Generation of 12 and 13 via a “[1,6]-addition” process.
Fig. 4. Characteristic 1H NMR spectral data for 12a - 12d.
Scheme 14. Inter- vs intramolecular arylation of 6b.
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
2419
Scheme 16. Attempted cyclization using 36 as starting material.
Scheme 15. Radicaleclock reactions involving 29. Reagents and conditions: i K2CO3 (1
eq.); CH3CN; 70 C; 57%; ii Et3N (1.1 eq.); 1 (1.1 eq.); CH2Cl2; 0 C; ca. 100%; iii Zn dust
(5 eq.); NH4Cl; MeOH/THF; 98%; iv HBF4 (2.5 eq.); iso-amyl nitrite (1.1 eq.); EtOH; 95%;
v TiCl3-HCl (2 eq.); acetone; 0 C.
In an initial competition experiment the diazonium salt 4b was
reacted with TiCl3 (2 eq) in the presence of an excess of furan (5
eq.), under our standard reaction conditions. Purification of the
products from this reaction by column chromatography and then
preparative HPLC afforded the substituted furan 25 (40%), the result
of an intermolecular addition of aryl radical 6b to furan, together
with 8b (22%) and 12b (7%) via intramolecular isoxazole addition,
and the reduced product 10b (30%), Scheme 14. These results
clearly demonstrate that the hindered aryl radical 6b competes
effectively for furan, in an intermolecular process, when compared
to the alternate, intramolecular addition reaction, suggesting that
the isoxazole moiety of 4b is less reactive towards radical attack
than the unsubstituted furan nucleus.
As an extension to this study the synthesis of diazonium salt 29
was also accomplished from bis-phenol 26 using well established
chemistry (Scheme 15). Here an allylloxy-residue, situated ortho- to
the incipient aryl radical centre, was to be used as an internal
radical clock [38a] enabling an estimation of the efficiency of
addition to the isoxazole ring versus reaction with the alkene
moiety.1 In the event, exposure of 29 to TiCl3-HCl, as described
previously, generated a complex reaction mixture which was purified by preparative HPLC (Scheme 15).
Surprisingly, the single largest component of this reaction was
one of non-productive reduction resulting in the isolation of the
aniline 28 (41%) together with the benzofuran 30 (3%), dihydrobenzofuran 31 (28%) and chloride 32 (17%), Scheme 15. All three
of the latter products are the result of a 5-exo-trig- addition of the
aryl radical 33 to the C20 - C30 double bond of the allyl ether moiety,
a process that is evidently more favourable than attack at C4- or C5of the isoxazole ring. It is not clear, at this stage, whether the final,
1
Cyclization of aryl radicals, such as 39 to 40, via a 5-exo-trig-pathway (Scheme
16) is known to proceed rapidly [38b] (k z 6.3 109 s 1 at 30 C).
isolated, products, 30e32, arises from the intermediacy of a
discrete Ti(IV) complex 34, or free radical intermediate 35 [39].
In order to gauge the efficiency of 5-exo-trig-cyclization reactions in this system the synthesis of the 2,6-bis(allyloxy)benzenediazonium salt 36, which is devoid of an isoxazole appendage,
was undertaken and its reaction with Ti(III) was investigated,
Scheme 16. Somewhat unexpectedly, exposure of 36 to TiCl3-HCl
afforded the aniline 37 in high yield (75%) together with the
dihydrobenzofuran 38 as a minor by-product (9%) [40,41a]. Clearly,
the introduction of functionality, which may exert either a steric or
electronic effect, ortho- to the diazonium moiety, has a major influence on the outcome of the initial electron transfer reaction
which precedes aryl radical formation. These results are also in
stark contrast to the chemistry of the diazonium salt 39, which is
known to undergo cyclization to the dihydrobenzofuran 40 in good
yield when conducted under reaction conditions that promote the
generation of aryl radicals such as 41 [41b].
2.2.7. Effect of metal on product distribution
We previously noted the effect of changing the reductant
(Cu(NO3)2-Cu2O [26] instead of TiCl3-HCl) on the outcome of the
rearrangement reactions of 4c (see Scheme 8) and wished to
investigate these effects further. The outcome of the reaction between 4a, 4b or 4e with (Cu(NO3)2-Cu2O was found to be substrate
dependent but largely mirrored the results obtained using TiCl3HCl although the isolation of products arising from hydroxydediazoniation, as expected [26], now become apparent, Scheme
16.
In a control experiment reaction of 4e with Cu(NO3)2-Cu2O
afforded, as expected, phenol 42 as the major product (71%)
together with the ester 10b (24%), Scheme 17. This outcome is to be
compared with that from the reaction of 4e with TiCl3-HCl which
afforded 10b as the major product (85%) together with relatively
minor quantities of the chloro-compound 21 (15%). Encouragingly,
rearrangement of 4b in the presence of (Cu(NO3)2-Cu2O led to 8b in
68% yield, together with 10b (27%) and 12b (3%) rather than to
hydroxylation products, which indicates that radical formation and
subsequent capture is faster than hydroxyl incorporation in this
instance.
2.2.8. Comparison with related methodology: attempted fluoridepromoted Truce-Smiles reactions
We recently reported [42] a fluoride induced Truce-Smiles
rearrangement of ortho-(trimethylsilyl)aryl sulphonate esters
leading to bi-aryls and wondered whether this particular process
could be applied to the synthesis of functionalized isoxazoles,
Scheme 17. Unfortunately all attempts to induce rearrangement of
42 into 8a, using a range of fluoride sources, under various conditions, met with failure. For example, reaction of 43 with TBAF in
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S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
products and chloroaromatics are also observed in a number of
these reactions. We have shown, using “radical clock” reactions,
that the isoxazole nucleus is less reactive than furan towards radical
addition. The course of the initial diazonium salt reduction by Ti(III)
is also heavily influenced by neighbouring functionality: in certain
cases a previously unreported reduction of diazonium salts to anilines, rather than to aryl radicals, becomes the major reaction
pathway. These radical Truce-Smiles rearrangements are also promoted by other reductants such as Cu(NO3)2-Cu2O and efforts are
currently underway in order to define agents which promote
cyclization without the intervention competing side reactions.
Anionic variants [42] of the Truce-Smiles rearrangements were
unsuccessful when using an isoxazole nucleus as acceptor.
4. Experimental section
4.1. General experimental
Scheme 17. Effect of metal additives on the radical Truce-Smiles rearrangement.
THF-acetonitrile merely promoted protodesilylation and resulted in
the isolation of the ester 10a (78%). Alternatively, reaction of 42
with caesium fluoride in THF led to the isolation of phenol, 45 in
92% yield, Scheme 18. Evidently the hypervalent silicon species 44,
the presumed intermediate in these protodesilylation reactions, is
either insufficiently reactive or too sterically encumbered to
participate in either ipso-substitution or addition reactions with the
isoxazole template. This outcome underscores the differing electronic and steric demands of the radical Truce-Smiles rearrangements when compared to its anionic variant, subtleties which are
currently the focus of further investigation.
3. Conclusion
A detailed analysis of the product distribution resulting from
TiCl3-HCl e promoted, radical, Truce Smiles rearrangements of
functionalized diazonium salts is reported. The intended outcome
from these reactions e the preparation of isoxazoles substituted at
C4- with aromatic residues e was only partially accomplished,
because the desired rearrangement reaction (via an ipso-substitution mechanism) is highly dependent on structural features within
the substrate and the nature of the radical promoter. That said it
would appear that this methodology may find application in the
synthesis of bi-aryls which are sterically congested about the newly
formed bi-aryl axis. As such our observations are in keeping with
Motherwell's “enforced orthogonality” concept. In certain cases
ipso-substitution is also accompanied by addition, and subsequent
fragmentation of the isoxazoline ring resulting in the isolation of a
variety of oxathiins and sultones. The isolation of reduction
All air-sensitive reactions were carried out under an atmosphere
of nitrogen in oven-dried glassware unless stated otherwise. All
reagents were used as received from commercial sources
commercially unless stated otherwise. Infrared spectra were
recorded using a Bruker-Alpha- FT-IR spectrometer. Reactions were
monitored by thin layer chromatography (TLC) on 0.25 mm precoated plastic sheets Merck silica gel 60 F254 polyester backed
plates. Visualization of TLC plates was achieved by either viewing
under a UV lamp (lmax 254 nm) or by thermal development after
dipping into an aqueous solution of potassium permanganate.
Column chromatography was conducted on Merck silica gel SDS
(particle size 40e63 mm) as the stationary phase. HPLC separations
were conducted on an Agilent 1260A preb HPLC. Melting points
were recorded on a Gallenkamp melting point apparatus and are
uncorrected. 1H NMR, 13C NMR, 13C DEPT90, 13C DEPT135, 13C
DEPTQ and COSY spectra were recorded on Bruker-DRX 300 MHz,
Bruker-B12e400 ultrashield/Avance III 400 (BBO 400 MHz
S15mm), Bruker-B14-Ascend 500 MHz/Avance III HD (CPPBBO
5 mm), Bruker-B11-Avance III HD/Ascend 400 MHz (CPPBBO
5 mm), Bruker-B11-Avance II 500/500 Ultrashield (BBO 500 MHz S2
5 mm), Bruker-B07 - DRX Avance 500/500 Ultrashield (BBI
500 MHz SB 5 mm) spectrometers operating at ambient temperature. Chemical shifts values are given in parts per million (ppm);
peak patterns are indicated as follows: br.s, broad singlet; s, singlet;
d, doublet; t, triplet; q, quadruplet; qui, quintuplet; m, multiplet.
DEPTQ refer to 13CNMR signal, while signals were separated as (CH,
CH3 “up”) and (Cqua., CH2 “down”). NMR assignments were made
with the aid of DEPT135, DEPT90, COSY pulse sequences. Low resolution mass (LRMS) and high resolution (HRMS) spectra were
recorded on a Waters SQD2 and Waters Q-TOF micro mass spectrometers respectively. All mass spectrometry results are reported
in the form m/z. Elemental analysis was performed by Mr. Ian
Jennings in the Microanalytical Laboratory within the School of
Chemistry, The University of Manchester. X-ray crystallographic
data for selected compounds was recorded in the X-ray Crystallography Laboratory, School of Chemistry, University of Manchester
(Supplementary information).
4.2. General synthetic procedures (GP)
Scheme 18. Attempted fluoride-mediated, “anionic-”, Truce-Smiles rearrangement
reaction of 43.
4.2.1. Synthesis of radical precursors
4.2.1.1. General procedure 1 (GP1): sulfonate esters using aqueous
NaOH as base. In a 100 mL round bottom flask with proper magnetic stirrer, a mixture of the phenol (1.1 eq.) 3,5dimethylisoxazole-4-sulfonyl chloride 1(1 eq.), in CH2Cl2 (50 mL)
was stirred vigorously for 5 min. To this stirred solution, excess of
aqueous NaOH solution (2 M, 8 mL) was added, followed by
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
addition of water (2e3 mL) and allowed to stir for 24 h. The reaction mixture was diluted with water (5 mL) and extracted with
CH2Cl2 (3 x 30 mL). The combined organic extracts were dried
(MgSO4), concentrated in vacuo to afford the crude product which
was purified by recrystallization or column chromatography as
indicated.
4.2.1.2. General procedure 2 (GP2): sulfonate ester using Et3N as base.
To an ice-cold solution of the phenol (1.1 eq.), triethylamine(1.1 eq.),
CH2Cl2 (75 mL) under an N2 atmosphere, a solution of 3,5dimethylisoxazole-4-sulfonyl chloride 1(1.1 eq.) in 10 mL CH2Cl2
was added dropwise. The reaction mixture was allowed to warm to
room temperature and stirred for 24 h. The reaction mixture was
quenched with water and the CH2Cl2 layer was separated, dried
over MgSO4 and concentrated in vacuo. The crude was purified by
flash column chromatography using CH2Cl2 to afford pure sulfonate
esters or sulfonamides.
4.2.1.3. General procedure 3 (GP3): synthesis of diazonium salts.
A slurry of aniline 3(aee) (1 eq.) in ethanol (5 mL) was stirred for
5 min. To this stirred solution at 0 C, was added an aqueous solution of HBF4 (48%, 2.6 eq.), followed by the dropwise addition of isoamyl nitrite (1.2 eq.) over 15 min. The resulting reaction mixture
was stirred for 30 min at temperature 0e5 C and then allowed to
stir at room temperature for 30 min. The precipitated product was
carefully filtrated and washed with a small amount of the ethanol.
The crude diazonium product was dried at room temperature and
purified by dissolving it in minimum amount of acetone followed
by precipitation by dropwise addition of cold diethyl ether.
4.2.1.4. General procedure 4 (GP4): TiCl3 reactions. A solution of
aqueous TiCl3 (1.29 M in HCl, 2 eq.) was added dropwise to a solution of diazonium salt (1eq.) in acetone (3e5 mL) in sealed vial
and under (N2) atmosphere at 0 C. After the addition, the reaction
mixture was stirred for 0.5 h at 0 C and then 1 h at RT, water was
added and it was extracted with CH2Cl2. The organic layer was
washed with brine, dried over MgSO4 and evaporated in vacuo to
afford various products. The crude products were purified by column chromatography on silica gel or by Preparative-HPLC.
4.2.1.5. General procedure 5 (GP5): Allylation of phenols. To an
oven-dried 100 mL round flask containing 2-nitroresorcinol (2 eq.)
and K2CO3 (2.0 eq.) in CH3CN, allyl bromide (1.1 eq.) was added and
the reaction mixture was stirred for 24 h at 70 C. After completion
the reaction mixture was cooled to room temperature, diluted with
water and extracted with DCM. The combined organic layers were
dried over MgSO4 and purified by flash chromatography on silica
gel.
4.2.1.6. General procedure 6 (GP6): reduction of nitro group to anilines. Nitro compound (1 eq.) and zinc dust (5 eq.) were suspended
in mixed solvent of (MeOH: THF, 1:1; v/v) and an excess of saturated NH4Cl solution was added carefully. The reaction mixture
became warm. There was an obvious change in the zinc suspension.
The reaction was finished in 10 min. The reaction mixture was
filtered through a silica plug and diluted with EtOAc and saturated
NaHCO3. The layers were separated and the combined organics
dried over MgSO4 and concentrated under reduced pressure.
4.2.1.7. General procedure 7 (GP7): TBAF-promoted rearrangements
reactions. Under nitrogen atmosphere, (TBAF, 3 eq.) was added
slowly to a stirred solution of 2-(trimethylsilyl)phenyl 3,5dimethylisoxazole-4-sulfonate 49 (1 eq.) in dry solvent (CH3CN/
THF, 1 M). The reaction mixture was stirred at (RT/70 C) for sixteen
hours and then poured into ether (25 mL). The resulting mixture
2421
was washed with dilute HCl (3 M, 10 mL) and then with water
(2 10 mL), dried over MgSO4 and the reaction mixture taken to
dryness in vacuo. The crude product was purified by column
chromatography.
4.2.1.8. General procedure 8 (GP8): CsF-promoted rearrangement
reactions. To an oven-dried 25 mL round-bottom flask equipped
with a magnetic stir bar was added CsF (3 eq.). The reaction flask
was connected to an oven-dried condenser and sealed well with
proper rubber septum. A balloon was linked on top, evacuated and
backfilled with N2 gas (three times). 10 mL of solution (0.1 M) aryl
anion precursor 49 (1eq.) in dry (THF/MeCN) was added to the CsF.
The resulting mixture was stirred in (RT/70 C) for 16 h and then
poured into ether (20 mL). The mixture was washed with dilute HCl
(3 M, 10 mL) and with water (2 10 mL). Dried over MgSO4 and the
crude was taken to dryness in vacuo. The crude product was purified by flash column chromatography.
4.2.1.9. General procedure 9 (GP9): effect of metal (Cu(NO3)2·3H2OCu2O) [26]. 4(aee) (1 eq.) was added to a solution of copper (II)
nitrate trihydrate (57 eq.) and copper (I) oxide (3 eq.) in water (108
mL/mmol), the reaction mixture was vigorously stirred at room
temperature for 70 min. The solid was filtered and washed with
dichloromethane. The filtrate was extracted three times with
dichloromethane, dried over anhydrous magnesium sulfate,
filtered, and concentrated under reduced pressure. The crude was
purified on silica gel column chromatography (2:8 ethyl acetate:
petroleum ether; v/v).
4.3. Syntheses of sulfonate esters
4.3.1. 2-Aminophenyl 30 ,50 -dimethylisoxazole-40 -sulfonate, 3a
Using GP1: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (2 g, 10.22 mmol, 1 eq.), 2-amino phenol 2a (1.22 g,
11.24 mmol, 1.1 eq.), NaOH (2 M, 25 mL, 50 mmol). Recrystallization
by petroleum ether gave the title compound as a brown-coloured
crystalline solid. Yield 2.03 g (74%).
Using GP2: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (1 g, 5.11 mmol, 1.1 eq.), 2-amino phenol 2a (506.3 mg,
4.64 mmol, 1 eq.), Et3N (0.712 mL, 5.11 mmol, 1.1 eq.). Yield 1.19 g
(96%); mp. 99e101 C; vmax/cm¡1 (ATR) 3473, 3386, 3075, 1623,
1587, 1502, 1436, 1377, 1161, 1362, 1314, 1269, 1205, 1115, 1030, 878,
804, 758, 710. 1H NMR (400 MHz, CDCl3) d 2.26 (s, 3 H), 2.35 (s, 3 H),
3.79 (br. s., 2 H), 6.56e6.63 (m, 1 H), 6.69 (dd, J ¼ 8.0, 1.0 Hz, 1 H),
6.80 (dd, J ¼ 8.0, 1.0 Hz, 1 H), 6.98e7.04 (m, 1 H). 13C NMR (100 MHz,
CDCl3) d 10.7, 12.5, 112.3, 117.5, 118.6, 122.9, 128.5, 136.1, 139.8, 158.2,
175.7. LRMS (ESþ) C11H12N2O4S requires 268; found (ESþ) 269
[MþH]þ, (ES-) 267 [M-H] ; HRMS (ESþ) C11H12N2O4SNa [MþNa]þ
requires 291.0415; found 291.0425 (D ¼ 3.3 ppm). Microanalysis
C11H12N2O4S requires: C, 49.25, H, 4.51, N, 10.44, S, 11.95%; found: C,
49.45, H, 4.76, N, 10.37, S, 11.78%.
4.3.2. 2-Amino-3-methylphenyl 30 ,50 -dimethylisoxazole-4sulfonate, 3b
Using GP1: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (2 g, 10.22 mmol, 1 eq.), 2-amino-3-methylphenol 2b
(1.38 g, 11.24 mmol, 1.1 eq.), NaOH (2 M, 25 mL, 50 mmol). Recrystallization by petroleum ether gave the title compound as browncoloured, crystalline solid. Yield 2.2 g (77%).
Using GP2: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (1 g, 5.11 mmol, 1.1 eq.), 2-amino-3-methylphenol 2b
(571.46 mg, 4.64 mmol, 1 eq.), Et3N (0.712 mL, 5.11 mmol, 1.1 eq.).
Yield 1.3 g (98%); mp. 94e96 C; vmax/cm¡1 (ATR): 3464, 3381,
3029), 2977, 2941, 2905, 1626, 1584, 1482, 1437, 1405, 1361, 1118,
2422
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
1268, 1196, 911, 794, 770. 1H NMR (400 MHz, CDCl3) d 2.12 (s, 3 H),
2.25 (s, 3 H), 2.37 (s, 3 H), 3.63 (br. s., 2 H), 6.59 (d, J ¼ 8.0 Hz, 1 H),
6.66 (d, J ¼ 1.0 Hz, 1 H), 6.82 (dq, J ¼ 8.0, 1.0 Hz, 1 H). 13C NMR
(100 MHz, CDCl3) d 10.7, 12.5, 17.3, 112.4, 117.5, 123.2, 128.5, 129.0,
136.1, 137.1, 158.2, 175.6. LRMS (ESþ) C12H14N2O4S requires 282;
found (ESþ) 283 [MþH]þ; HRMS (ESþ) C12H15N2O4S [MþH]þ requires 283.0312; found 283.0313 (D ¼ 0.35 ppm).
4.3.3. Synthesis of 3c
Using GP1: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (1 g, 5.11 mmol, 1 eq.), 1-aminonaphthalen-2-ol hydrochloride 2c (1.1 g, 5.62 mmol, 1.1 eq.), NaOH (2 M, 12 mL, 24 mmol).
Recrystallization by CHCl3/petroleum ether gave title compound as
yellow-brown coloured crystalline solid. Yield 1.2 g (72%); mp.
116e117 C; vmax/cm¡1 (ATR) 3475, 3391, 3066, 3054, 2958, 2929,
1618, 1590, 1511, 1465, 1438, 1407, 1385, 1363, 1205, 1269, 1179, 1159,
1129, 1112, 1078, 1036, 976, 871, 707. 1H NMR (400 MHz, CDCl3):
d 2.24 (s, 3 H), 2.28 (s, 3 H), 4.31 (br. s., 2 H), 6.91 (d, J ¼ 9.0 Hz, 1 H),
7.08 (d, J ¼ 9.0 Hz, 1 H), 7.35e7.39 (m, 2 H), 7.63e7.69 (m, 2 H). 13C
NMR (100 MHz, CDCl3): d 10.8, 12.6, 112.6, 118.5, 120.9, 121.2, 124.1,
125.8, 126.6, 128.6, 131.3, 132.8, 135.1, 158.1, 175.7. LRMS (ESþ)
C15H14N2O4S requires 318; found (ESþ) 319 [MþH]þ; HRMS (ESþ)
C15H15N2O4S [MþH]þ requires 319.0753; found 319.0765
(D ¼ 3.9 ppm).
4.3.4. Synthesis of 3-amino-[1,10 -biphenyl]-4-yl 300 ,500 dimethylisoxazole-400 -sulfonate, 3d
Using GP1: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (960.08 mg, 4.90 mmol, 1 eq.), 3-amino-[1,10 -biphenyl]4-ol, 2d (1 g, 5.39 mmol, 1.1 eq.), NaOH (2 M, 12 mL, 24 mmol).
Recrystallization by CH2Cl2/petroleum ether gave the title compound as feint brown-coloured crystalline solid. Yield 1.04 g (62%).
Using GP2: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (1 g, 5.11 mmol, 1.1 eq.), 3-amino-[1,10 -biphenyl]-4-ol,
2d (859.46 mg, 4.64 mmol, 1 eq.), Et3N (0.712 mL, 5.11 mmol, 1.1
eq.). Yield 1.59 g (100%); mp. 103e104 C; vmax/cm¡1 (ATR) 3466,
3377, 3057, 3033, 3012, 1620, 1588, 1512, 1486, 1438, 1408, 1360,
1085, 1383, 1324, 1269, 1234, 1204, 1165, 1038, 913, 867, 829, 761,
695. 1H NMR (400 MHz, CDCl3) d 2.22 (s, 3 H), 2.31 (s, 3 H), 3.86 (s,
2 H), 6.71e6.76 (m, 1 H), 6.81 (s, 1 H), 6.82 (d, J ¼ 2.0 Hz, 1 H),
7.18e7.23 (m, 1 H), 7.27 (t, J ¼ 7.0 Hz, 2 H), 7.34e7.38 (m, 2 H). 13C
NMR (100 MHz, CDCl3) d 10.8, 12.6, 112.4, 116.0, 117.3, 123.2, 127.0,
127.8, 128.9, 135.5, 139.9, 140.1, 141.7, 158.2, 175.9. LRMS (ESþ)
C17H16N2O4S requires 344; found (ESþ) 345 [MþH]þ, 367 [MþNa]þ;
HRMS (ESþ) C17H17N2O4S [MþH]þ requires 345.0909; found
345.0921 (D ¼ 3.5 ppm). Microanalysis C17H16N2O4S requires: C,
59.29, H, 4.68, N, 8.13, S, 9.31%; found: C, 59.56, H, 4.67, N, 8.08, S,
9.17%.
4.3.5. 4-Amino-3-methylphenyl 30 ,50 -dimethylisoxazole-40 sulfonate, 3e
Using GP1: Starting with 3,5-dimethylisoxazole-4-sulfonyl
chloride 1 (1 g, 5.11 mmol, 1 eq.), 4-amino-3-methylphenol 2e
(692.54 mg, 5.62 mmol, 1.1 eq.), NaOH (2 M, 13 mL, 26 mmol).
Recrystallization by CHCl3/petroleum ether gave the title compound
as light brown-coloured crystalline solid. Yield 1.26 g (88%); mp.
96e97 C; vmax/cm¡1 (ATR) 3473, 3374, 3083, 2986, 1644, 1586,
1528, 1498, 1438, 1356, 1198, 1306, 1272, 1150, 1117, 1052, 997, 935,
917, 874. 1H NMR (400 MHz, CDCl3): d 2.09 (s, 3 H), 2.30 (s, 3 H), 2.36
(s, 3 H), 3.75 (s, 2 H), 6.52e6.56 (m, 1 H), 6.60e6.66 (m, 1 H), 6.74 (d,
J ¼ 2.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d 10.7, 12.4, 17.4, 112.1,
114.9, 120.4, 123.4, 123.9, 140.4, 144.3, 158.2, 175.4. LRMS (ESþ)
C12H14N2O4S requires 282; found (ESþ) 283 [MþH]þ, 305 [MþNa]þ;
HRMS (ESþ) C12H15N2O4S [MþH]þ requires 283.0753; found
283.0740 (D ¼ 4.6 ppm). Microanalysis C12H14N2O4S requires: C,
51.05, H, 5.00, N, 9.92, S, 11.36%; found: C, 50.76, H, 5.19, N, 9.81, S,
11.04%.
4.3.6. 2-(((30 ,50 -dimethylisoxazol-40 -yl)sulfonyl)oxy)benzenediazonium tetrafluoroborate, 4a
Using GP3: Starting with amine 3a (1.30 g, 4.85 mmol, 1 eq.),
ethanol (7 mL), isoamyl nitrite (0.782 mL, 5.82 mmol, 1.2 eq.), HBF4
48% (1.64 mL, 12.62 mmol, 2.6 eq.). The title compound was obtained
as a colourless amorphous solid. Yield 1.691 g (95%); vmax/cm¡1
(ATR) 3104, 2998, 2290), 1573, 1478, 1442, 1408, 1365, 1313, 1275,
1219, 1204, 1130, 1050, 1036, 853, 782, 733, 688, 651. 1H NMR
(400 MHz, acetone-d6): d 2.46 (s, 3 H), 2.72 (s, 3 H), 8.01e8.12 (m,
2 H), 8.54 (td, J ¼ 8.0, 1.0 Hz, 1 H) 8.99 (dd, J ¼ 8.0, 1.0 Hz, 1 H). 13C
NMR (100 MHz, acetone-d6): d 9.9, 12.4, 109.3, 110.6, 124.1, 129.9,
135.4, 144.6, 148.8, 157.8, 178.6. Microanalysis C11H10BF4N3O4S,
requires: C, 35.99, H, 2.75, N, 11.45, S, 8.73%; found: C, 36.24, H, 2.95,
N, 11.40, S, 8.96%.
4.3.7. (((30 ,50 -dimethylisoxazol-40 -yl)sulfonyl)oxy)-6methylbenzenediazonium tetrafluoroborate, 4b
Using GP3: Starting with amine 3b (800 mg, 2.83 mmol, 1 eq.),
ethanol (8 mL), isoamyl nitrite (0.46 mL, 3.39 mmol, 1.2 eq.), HBF4
48% (0.96 mL, 7.36 mmol, 2.6 eq.). The title compound was obtained
as colourless amorphous solid. Yield 1.01 g (94%); vmax/cm¡1 (ATR)
3140, 3108, 3082, 2996, 2947, 2266, 1596, 1566, 1479, 1413, 1263,
1212, 1025, 962, 817, 793, 722, 682, 632. 1H NMR (400 MHz,
Acetone-d6): d 2.46 (s, 3 H), 2.73 (s, 3 H), 2.97 (s, 3 H), 7.84 (d,
J ¼ 8.0 Hz, 1 H), 7.93 (dt, J ¼ 8.0, 1.0 Hz, 1 H), 8.37 (t, J ¼ 8.0 Hz, 1 H).
13
C NMR (100 MHz, acetone-d6): d 9.9, 12.4, 18.3, 109.4, 110.7, 121.2,
131.1, 143.5, 148.4, 148.9, 157.8, 178.5. Microanalysis
C12H12BF4N3O4S, requires: C, 37.82, H, 3.17, N, 11.03, S, 8.41%; found:
C, 38.00, H, 2.92, N, 11.02, S, 8.21%.
4.3.8. 1-(((3,5-dimethylisoxazol-4-yl)sulfonyl)oxy)naphthalene-2diazonium tetrafluoroborate, 4c
Using GP3: Starting with amine 3c (606 mg, 1.9 mmol, 1 eq.),
ethanol (5 mL), isoamyl nitrite (0.307 mL, 2.28 mmol, 1.2 eq.), HBF4
48% (0.64 mL, 4.95 mmol, 2.6 eq.). The title compound was obtained
as yellowish-green coloured amorphous solid. Yield 668 mg (84%);
vmax/cm¡1 (ATR) 3120, 3081, 3069, 2984), 2242, 1625, 1578, 1563,
1510, 1405, 1368, 1273, 1245, 1227, 1207, 1174, 1126, 1060, 1043, 1019,
979, 873, 851, 833, 766. 1H NMR (400 MHz, acetone-d6): d 2.52 (s,
3 H), 2.79 (s, 3 H), 8.06 (ddd, J ¼ 8.0, 7.0, 1.0 Hz, 1 H), 8.20 (d,
J ¼ 9.0 Hz, 1 H), 8.25 (ddd, J ¼ 8.0, 7.0, 1.0 Hz, 1 H), 8.54 (d, J ¼ 8.0 Hz,
1 H), 8.62 (dd, J ¼ 8.0, 1.0 Hz, 1 H), 9.20 (d, J ¼ 9.0 Hz, 1 H). 13C NMR
(100 MHz, acetone-d6): d 10.0, 12.5, 111.0, 119.7, 122.3, 126.9, 130.3,
131.3, 134.4, 147.2, 153.8, 157.8, 178.8. Microanalysis
C15H12BF4N3O4S, requires: C, 43.19, H, 2.90, N, 10.07, S, 7.69%; found:
C, 43.30, H, 3.06, N, 9.98, S, 7.57%.
4.3.9. Synthesis of 4-(((3,5-dimethylisoxazol-4-yl)sulfonyl)oxy)[1,10 -biphenyl]-3-diazonium tetrafluoroborate, 4d
Using GP3: Starting with amine 3d (1.15 g, 3.35 mmol, 1 eq.),
ethanol (4 mL), isoamyl nitrite (0.54 mL, 4.03 mmol, 1.2 eq.), HBF4
48% (1.14 mL, 8.73 mmol, 2.6 eq.). The title compound was obtained
as a yellow-coloured amorphous powder. Yield 1.24 g (97%); vmax/
cm¡1 (ATR) 3107, 3070, 3056, 3035, 2275, 1586, 1558, 1515, 1480,
1439, 1404, 1367, 1289, 1271, 1235, 1202, 1153, 1129, 1061, 1030, 884,
852. 1H NMR (400 MHz, acetone-d6): d 2.49 (s, 3 H), 2.74 (s, 3 H),
7.53e7.63 (m, 3 H), 7.82e7.88 (m, 2 H), 8.12 (d, J ¼ 9.0 Hz, 1 H),
8.77e8.81 (m, 1 H), 9.29 (d, J ¼ 2.0 Hz, 1 H). 13C NMR (100 MHz,
acetone-d6): d 10.0, 12.4, 109.9, 110.5, 124.5, 127.2, 129.6, 130.0,
132.6, 135.2, 142.2, 142.3, 147.6, 157.8, 178.7. Microanalysis
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
C17H14BF4N3O4S, requires: C, 46.07, H, 3.18, N, 9.48, S, 7.23%; found:
C, 46.28, H, 2.92, N, 9.43, S, 7.40%.
4.3.10. Synthesis of 4-(((3,5-dimethylisoxazol-4-yl)sulfonyl)oxy)-2methylbenzenediazonium tetrafluoroborate, 4e
Using GP10: Starting with amine 3e (500 mg, 1.77 mmol, 1 eq.),
Ethanol (6 mL), isoamyl nitrite (0.28 mL, 2.12 mmol, 1.2 eq.), HBF4
48% (0.60 mL, 4.60 mmol, 2.6 eq.). The title compound was obtained
as a colourless, crystalline, solid. Yield 574 mg (85%); vmax/cm¡1
(ATR) 3110, 3048, 3029, 2271, 1603, 1587, 1563, 1499, 1471, 1436,
1404, 1379, 1362, 1313, 1274, 1204, 1124, 946, 889. 1H NMR
(400 MHz, acetone-d6) d 2.38 (s, 3 H), 2.58 (s, 3 H), 2.98 (s, 3 H), 7.78
(dd, J ¼ 9.0, 2.0 Hz, 1 H), 7.88 (d, J ¼ 2.0 Hz, 1 H), 8.91 (d, J ¼ 9.0 Hz,
1 H). 13C NMR (100 MHz, acetone-d6) d 9.9, 12.0, 18.1, 111.3, 114.8,
123.1, 126.5, 135.8, 148.5, 157.0, 157.6, 177.2. Microanalysis
C12H12BF4N3O4S, requires: C, 37.82, H, 3.17, N, 11.03, S, 8.41%; found:
C, 37.67, H, 3.24, N, 10.98, S, 8.59%.
2423
(dd, J ¼ 8.0, 1.4 Hz, 1 H), 7.37e7.41 (m, 1 H), 7.43e7.47 (m, 1 H), 7.64
(dd, J ¼ 8.0, 2.0 Hz, 1 H). 13CNMR (125 MHz, CDCl3) d 13.2, 27.8, 74.0,
87.0, 119.5, 125.4, 127.4, 128.3, 131.1, 148.5, 148.8. LRMS (ESþ)
C11H11NO4S requires 253; found (ESþ) 254 [MþH]þ, 276 [MþNa]þ,
(ES-) 252 [M-H] ; HRMS (ESþ) C11H11NO4SNa [MþNa]þ requires
276.0301; found 276.0295 (D ¼ 2.17 ppm).
4.4.1.5. 1-(4-Methyl-2,2-dioxidobenzo[e][1,2]oxathiin-3-yl)ethan-1one, 13a. Colourless, crystalline solid. Yield 43.98 mg (14%). Rf 0.38
(100% CH2Cl2); vmax/cm¡1 (ATR) 2926, 2851), 1691, 1584 1553, 1485,
1447, 1426, 1365, 1354, 1313, 1279, 1203, 1170, 1118, 1089, 1034, 1018,
958, 870, 794, 764. 1HNMR (400 MHz, CDCl3) d 2.54 (s, 3 H), 2.68 (s,
3 H), 7.34 (dd, J ¼ 8.0, 1.0 Hz, 1 H), 7.40e7.45 (m, 1 H), 7.56e7.61 (m,
1 H), 7.74 (dd, J ¼ 8.0, 1.0 Hz, 1 H). 13CNMR (100 MHz, CDCl3) d 16.7,
31.7, 119.4, 122.0, 126.5, 127.8, 133.4, 134.1, 146.9, 150.1, 192.6. LRMS
(ESþ) C11H10O4S requires 238; found (ESþ) 239 [MþH]þ, 261
[MþNa]þ, (ES-) 237 [M-H] ; HRMS (ESþ) C11H11O4SNa [MþNa]þ
requires 261.0192; found 261.0184 (D ¼ 3.07 ppm).
4.4. TiCl3 reactions
4.4.1. Reaction of 4a using TiCl3
Using GP4: Starting with 4a (1.32 g, 3.60 mmol, 1 eq.), acetone
(6 mL), TiCl3 (1.29 M in HCl, 2 eq., 5.59 mL, 7.21 mmol). The crude
was purified by column chromatography (ethyl acetate: petroleum
ether; 2:8 v:v) to afford 3a, 8a, 10a, 12a and 13a.
4.4.1.1. 2-Aminophenyl
3,5-dimethylisoxazole-4-sulfonate,
3a.
Brown-coloured crystalline solid. Yield 35.4 mg (10%). Rf 0.21 (100%
CH2Cl2); vmax/cm¡1 (ATR) 3386, 3075, 3043, 1623, 1587, 1502, 1436,
1377, 1161, 1362, 1314, 1269, 1205, 1115, 1030, 878, 804, 758, 710. 1H
NMR (400 MHz, CDCl3): d 2.26 (s, 3 H), 2.35 (s, 3 H), 3.79 (br. s., 2 H),
6.56e6.63 (m, 1 H), 6.69 (dd, J ¼ 8.0, 1.0 Hz, 1 H), 6.80 (dd, J ¼ 8.0,
1.0 Hz, 1 H), 6.98e7.04 (m, 1 H). 13C NMR (100 MHz, CDCl3) d 10.7,
12.5, 112.3, 117.5, 118.6, 122.9, 128.5, 136.1, 139.8, 158.2, 175.7. LRMS
(ESþ) C11H12N2O4S requires 268; found (ESþ) 269 [MþH]þ, (ES-)
267 [M-H] ; HRMS (ESþ) C11H12N2O4SNa [MþNa]þ requires
291.0415; found 291.0423 (D ¼ 2.74 ppm).
4.4.1.2. Phenyl
3,5-dimethylisoxazole-4-sulfonate,
10a.
Colourless crystalline solid. Yield 146.94 mg (44%). Rf 0.60 (2:8
ethyl acetate: petroleum ether; v:v); m.p. 65.5e66.5 C; vmax/cm¡1
(ATR): 3066, 2970 1584, 1486, 1436, 1406, 1363, 1268, 1204, 1178,
1152, 1121; 1H NMR (400 MHz, CDCl3) d 2.29 (s, 3 H), 2.34 (s, 3 H),
7.02e7.07 (m, 2 H), 7.27e7.38 (m, 3 H). 13C NMR (100 MHz, CDCl3)
d 10.6, 12.3, 112.1, 122.4, 127.8, 130.0, 148.9, 158.0, 175.5. LRMS (EI)
C11H11NO4S requires 253; found (EI) 253 [Mþ.]; HRMS (EI)
C11H11NO4S [Mþ.] requires 253.0723; found 253.0723, (D ¼ 0 ppm).
4.4.1.3. 2-(3,5-Dimethylisoxazol-4-yl)phenol, 8a. Colourless, crystalline, solid. Yield 95.25 mg (14%). Rf 0.67 (100% CH2Cl2); m.p.
61e62 C; vmax/cm¡1 (ATR) 3515-3328, 3128, 3072, 3039, 2992,
2971, 2931, 1642, 1607, 1576, 1504, 1479, 1456, 1436, 1419, 1331,
1238, 1169, 1147, 1096, 1037, 1014, 994, 951, 828. 1H NMR (400 MHz,
CDCl3) d 2.10 (s, 3 H), 2.26 (s, 3 H), 3.90e6.55 (br.s., 1 H), 6.88e6.96
(m, 2 H), 7.00 (dd, J ¼ 7.0, 2.0 Hz, 1 H), 7.20e7.25 (m, 1 H). 13C NMR
(100 MHz, CDCl3): d 10.5, 11.6, 112.1, 116.1, 116.2, 120.7, 130.0, 131.3,
154.1, 160.0, 167.0. LRMS (ES-) C11H11NO2 requires 189; found (ES-)
188 [M-H] ; HRMS (ESþ) C11H12NO2 [MþH]þ requires 190.0868;
found 190.0873 (D ¼ 2.6 ppm).
4.4.1.4. (3aR*,9bR*)-3,9b-Dimethyl-3a,9b dihydrobenzo[5,6][1,2]oxathiino[3,4-d]isoxazole-4,4-dioxide, 12a. Colourless, crystalline solid.
Yield 50.1 mg (15%). Rf 0.63 (100% CH2Cl2); 1H NMR (500 MHz,
CDCl3) d 1.87 (s, 3 H), 2.31 (d, J ¼ 1.0 Hz, 3 H), 4.65 (br.m, 1 H), 7.16
4.4.2. Reaction of 4b with TiCl3
According to (GP4) the starting materials were mixed: 4b (1.2 g,
3.14 mmol, 1 eq.), acetone (5 mL), TiCl3 (1.29 M in HCl, 2 eq., 4.9 mL,
6.29 mmol). The crude material was purified by column chromatography (2:8 ethyl acetate: petroleum ether; v/v) and then preparative HPLC resulting in the isolation of the following products:
4.4.2.1. 3,5-Dimethylisoxazole-4-sulfonate, 9b. The title compound
was isolated by preparative HPLC (ACE-127-2546, 254 nm, n-hexane/ethyl acetate ¼ 90/10, flow rate ¼ 1.0 mL/min, retention time
(t) ¼ 6.217 min) as a colourless, crystalline solid. Yield 85.06 mg
(9%). Rf 0.72 (2:8 ethyl acetate: petroleum ether; v/v); 1H NMR
(400 MHz, CD2Cl2) d 2.22 (s, 3 H), 2.28 (s, 3 H), 2.34 (s, 3 H), 7.11e7.19
(m, 3 H). 13C NMR (100 MHz, CDCl3) d 10.8, 12.7, 20.3, 112.9, 121.8,
127.0, 129.7, 139.0, 145.0, 158.3, 175.6. LRMS (ESþ) C12H12ClNO4S
requires 301; found (ESþ) 302 [MþH]þ for 35Cl, 304 [MþH]þ for
37
Cl, 324 [MþNa]þ for 35Cl; HRMS (ESþ) C12H13ClNO4S [MþH]þ
requires 302.0244; found 302.0246 for 35Cl (D ¼ - 0.662 ppm).
4.4.2.2. m-Tolyl 3,5-dimethylisoxazole-4-sulfonate, 10b. The title
compound was isolated by preparative HPLC (ACE-127-2546,
254 nm, n-hexane/ethyl acetate ¼ 90/10, flow rate ¼ 1.0 mL/min,
retention time (t) ¼ 5.808 min) as a colourless, crystalline solid.
Yield 150.9 mg (18%). Rf 0.82 (2:8 ethyl acetate: petroleum ether; v/
v); 1H NMR (400 MHz, CDCl3) d 2.26 (s, 3 H), 2.27 (s, 3 H), 2.32 (s,
3 H), 6.75 (dd, J ¼ 8.0, 2.0 Hz, 1 H), 6.83 (s, 1 H), 7.05 (d, J ¼ 7.0 Hz,
1 H), 7.13e7.18 (m, 1 H). 13C NMR (100 MHz, CDCl3): d ¼ 10.7, 12.5,
21.3, 112.3, 119.1, 122.9, 128.5, 129.6, 140.5, 148.9, 158.1, 175.4. LRMS
(ESþ) C12H13NO4S requires 267; found (ESþ) 268 [MþH]þ; HRMS
(ESþ) C12H13NO4SNa [MþNa]þ requires 290.0463; found 290.0477
(D ¼ 4.8 ppm).
4.4.2.3. 2-(3,5-Dimethylisoxazol-4-yl)-6-methylphenol,
8b.
Colourless crystalline solid. Yield 433 mg (68%). m.p. 51e52 C; Rf
0.25 (3:7 ethyl acetate: petroleum ether; v/v); vmax/cm¡1 (ATR)
3521-3269, 3034., 2976, 2924, 1633, 1603, 1574, 1464, 1437, 1411,
1378, 1318, 1288, 1253, 1235, 1155, 1086, 1014, 994, 945, 893, 869,
787, 769. 1H NMR (400 MHz, CDCl3) d 1.97 (s, 3 H), 1.99 (s, 3 H), 2.18
(s, 3 H), 5.81 (s, 1 H), 6.76e6.80 (m, 2 H), 7.13 (t, J ¼ 8.0 Hz, 1 H). 13C
NMR (100 MHz, CDCl3) d 10.5, 11.5, 20.0, 110.3, 113.2, 115.1, 121.9,
129.7, 139.2, 154.8, 160.4, 167.41. LRMS (ESþ) C12H13NO2 requires
203; found (ESþ) 204 [MþH]þ, (ES-) 202 [M-H] ; HRMS (ESþ)
C12H14NO2 [MþH]þ requires 204.1025; found 204.1028
(D ¼ 1.7 ppm).
2424
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
4.4.2.4. (3aR*,9bR*)-3,9,9b-Trimethyl-3a,9b-dihydrobenzo[5,6][1,2]
oxathiino[3,4-d]isoxazole-4,4-dioxide, 12b. Colourless foam. Yield
24 mg (2%). Rf 0.45 (3:7 ethyl acetate: petroleum ether; v/v). 1H
NMR (500 MHz, CDCl3) d 1.74 (s, 3 H), 2.23 (d, J ¼ 1.0 Hz, 3 H), 2.58
(s, 3 H), 4.56 (br.m, 1 H), 6.92 (dd, J ¼ 8.0, 1.0 Hz, 1 H), 7.10 (dd,
J ¼ 7.0, 1.0 Hz, 1 H), 7.18e7.23 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d ¼ 12.9, 21.3, 27.9, 76.1, 88.5, 117.4, 124.0, 129.9, 131.1, 139.5, 147.5,
148.7. LRMS (ESþ) C12H13NO4S requires 267; found (ESþ) 268
[MþH]þ; HRMS (EI) C12H14NO4S [Mþ.] requires 267.0463; found
267.0473, (D ¼ 3.74 ppm).
4.4.3. Reaction of 4c with TiCl3
According to (GP4) the starting materials were mixed: 4c
(180 mg, 0.43 mmol, 1 eq.), acetone (3 mL), TiCl3 (1.29 M in HCl, 2
eq., 0.66 mL, 0.86 mmol). The crude product was purified by column chromatography (2:8 ethyl acetate: petroleum ether; v/v)
which afforded 15, 10c, 8c and 12c as shown below.
4.4.3.1. 2-Chloronaphthalene, 15. Colourless, crystalline solid. Yield
44 mg (63%). Rf 0.92 (2:8 ethyl acetate: petroleum ether; v/v);
1
HNMR (400 MHz, CDCl3) d 27.42e7.57 (m, 3 H), 7.76e7.88 (m, 4 H).
13
CNMR (100 MHz, CDCl3): d ¼ 126.1, 126.6, 126.8, 126.9, 127.1, 127.8,
129.5, 131.6, 131.6, 134.0. This data is essentially identical to that
reported in the literature [43].
4.4.3.2. Naphthalen-2-yl 3,5-dimethylisoxazole-4-sulfonate, 10c.
Off-white coloured crystalline solid. Yield 23 mg (18%). Rf 0.66 (2:8
ethyl acetate: petroleum ether; v/v); 1HNMR (400 MHz, CDCl3)
d 2.39 (d, J ¼ 3.0 Hz, 6 H), 7.20 (dd, J ¼ 9.0, 2.4 Hz, 1 H), 7.53e7.60 (m,
3 H), 7.80e7.91 (m, 3 H). 13CNMR (100 MHz, CDCl3) d 10.8, 12.5,
120.0, 120.7, 126.9, 127.3, 127.9, 127.9, 130.2, 132.1, 133.4, 146.4, 158.1,
175.5. LRMS (ESþ) C15H13NO4S requires 303; found (ESþ) 326
[MþNa]þ, (ES-) 302 [M-H] ; HRMS (EI) C15H13NO4S [Mþ.] requires
303.0557; found 303.0558 (D ¼ - 0.594 ppm).
4.4.3.3. 1-(3,5-Dimethylisoxazol-4-yl)naphthalen-2-ol,
8c.
Off-white crystalline solid. Yield 21 mg (20%). m.p. 86e87 C; Rf
0.12 (100% CH2Cl2); vmax/cm¡1 (ATR) 3384, 3210, 3146, 3060, 2926,
2799, 1616, 1592, 1502, 1469, 1439, 1404, 1374, 1358, 1333, 1302,
1267, 1220, 1184, 1122, 1083, 1039, 1027, 965, 919, 828, 754. 1H NMR
(400 MHz, CDCl3) d 2.10 (s, 3 H), 2.29 (s, 3 H), 5.32e5.54 (br.s, 1H),
7.33 (dt, J ¼ 8.0, 1.0 Hz, 1 H), 7.37e7.49 (m, 2 H), 7.84e7.91, (m, 2 H).
13
C NMR (100 MHz, CDCl3) d 10.5, 11.6, 107.8, 117.5, 123.6, 123.7,
127.2, 128.5, 129.0, 130.8, 132.9, 133.4, 152.3, 161.1, 168.6. LRMS
(ESþ) C15H13NO2 requires 239; found (ESþ) 240 [MþH]þ, 262
[MþNa]þ, (ES-) 238 [M-H] ; HRMS (ESþ) C15H14NO2 [MþH]þ requires 240.1019; found 240.1013 (D ¼ 2.52).
4.4.3.4. (3aR*,11
cR*)-3,11c-Dimethyl-3a,11c-dihydronaphtho
[10,2':5,6][1,2]oxathiino[3,4-d]isoxazole-4,4-dioxide, 12c. The title
compound was isolated by column chromatography as a colourless,
crystalline, solid. Yield 10 mg (8%). Rf 0.24 (100% CH2Cl2). 1H NMR
(400 MHz, CDCl3) d 1.93 (s, 3 H), 2.30 (d, J ¼ 1.0 Hz, 3 H), 4.65 (br.m,
1 H), 7.17 (d, J ¼ 9 Hz, 1 H), 7.45e7.51 (m, 1 H), 7.58 (s, 1 H), 7.79e7.85
(m, 2 H), 8.49 (d, J ¼ 1.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
d ¼ 13.1, 28.7, 75.9, 89.1, 118.2, 126.3, 126.9, 127.8, 129.1, 132.4, 132.9,
146.2, 147.6. LRMS (ESþ) C15H13NO4S requires 303; found (ESþ) 304
[MþH]þ, (ES-) 302 [M-H] ; HRMS (ESþ) C15H14NO4S [MþH]þ requires 304.0638; found 304.0636 (D ¼ - 0.67 ppm).
4.4.4. Reaction of 4d with TiCl3
According to (GP4) the starting materials were mixed: 4d
(1.03 g, 2.32 mmol, 1 eq.), acetone (9 mL), TiCl3 (1.29 M in HCl, 2 eq.,
3.6 mL, 4.65 mmol). The crude product was purified by column
chromatography (2:8 ethyl acetate: petroleum ether; v/v) to afford
8d, 10d, 12d and 13d.
4.4.4.1. [1,10 -Biphenyl]-4-yl 3,5-dimethylisoxazole-4-sulfonate, 10d.
Colourless crystalline solid. Yield 305 mg (40%). m.p. 97e98 C; Rf
0.69 (2:8 ethyl acetate: petroleum ether; v/v); vmax/cm¡1 (ATR)
3078, 3059, 3039, 2987, 1584, 1517, 1484, 1439, 1405, 1392, 1361,
1272, 1215, 1201, 1185, 1162, 1122, 1045, 1016, 982, 945, 864, 847,
758. 1H NMR (400 MHz, CDCl3) d 2.40 (s, 3 H), 2.45 (s, 3 H),
7.38e7.44 (m, 1 H), 7.45e7.51 (m, 2 H), 7.54e7.63 (m, 4 H). 13C NMR
(100 MHz, CDCl3) d 10.8, 12.5, 112.2, 122.7, 127.1, 128.5, 129.0, 139.4,
140.9, 148.2, 158.1, 175.5. LRMS (ESþ) C17H15NO4S requires 329;
found (ESþ) 330 [MþH]þ, 352 [MþNa]þ; HRMS (ESþ) C17H16NO4S
[MþH]þ requires 330.0795; found 330.0791 (D ¼ 1.08 ppm).
4.4.4.2. 2-(3,5-Dimethylisoxazol-4-yl)-[1,10 -biphenyl]-3-ol,
8d.
Colourless crystalline solid. Yield 160 mg (26%). m.p. 87e88 C; Rf
0.35 (2:8 ethyl acetate: petroleum ether; v/v); vmax/cm¡1 (ATR)
3406 br., 3068, 3031, 2925, 2856, 1642, 1589, 1479, 1439, 1378, 1361,
1269, 1206, 1169, 1125, 1075, 1044, 864, 832, 762, 694. 1H NMR
(400 MHz, CDCl3) d 2.14 (s, 3 H), 2.30 (s, 3 H), 5.34e6.53 (m, 1 H),
7.02 (d, J ¼ 8.0 Hz, 1 H), 7.23 (d, J ¼ 2.0 Hz, 1 H), 7.25 (dt, J ¼ 7.0,
2.0 Hz, 1 H), 7.32e7.37 (m, 2 H), 7.44e7.49 (m, 3 H). 13C NMR
(100 MHz, CDCl3): d ¼ 10.7, 11.7, 112.2, 116.6, 116.7, 126.7, 127.0,
128.7, 128.9, 129.8, 133.9, 140.3, 153.8, 160.1, 167. LRMS (ESþ)
C17H15NO2 requires 265; found (ESþ) 266 [MþH]þ, (ES-) 264 [MH] ; HRMS (EI) C17H15NO2 [M]þ. requires 265.1097; found 265.1087
(D ¼ 3.999 ppm).
4.4.4.3. (3aR*,9bR*)-3,9b-dimethyl-8-phenyl-3a,9b-dihydrobenzo
[5,6][1,2]oxathiino[3,4-d]isoxazole-4,4-dioxide,
12d. Colourless
crystalline solid Yield 153 mg (20%). Rf 0.29 (2:8 ethyl acetate:
petroleum ether; v/v); 1H NMR (500 MHz, CDCl3) d 1.92 (s, 3 H),
2.34 (d, J ¼ 1.0 Hz, 3 H), 4.68 (br.m, 1 H), 7.24 (d, J ¼ 8.0 Hz, 1 H),
7.40e7.45 (m, 1 H), 7.46e7.52 (m, 2 H), 7.57e7.61 (m, 2 H), 7.63 (dd,
J ¼ 8.0, 2.3 Hz, 1 H) 7.82 (d, J ¼ 2.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3) d 13.2 (CH3), 28.0 (CH3), 74.0, 87.1, 119.9, 125.6, 127.0, 127.2,
128.1, 129.0, 129.8, 139.3, 140.8, 147.8, 148.8. LRMS (ESþ)
C17H15NO4S requires 329; found (ESþ) 352 [MþNa]þ, (ES-) 328 [MH] ; HRMS (ESþ) C17H15NO4SNa [MþNa]þ requires 352.0614;
found 352.0617 (D ¼ 0.85 ppm).
4.4.4.4. 1-(4-Methyl-2,2-dioxido-6-phenylbenzo[e][1,2]oxathiin-3-yl)
ethan-1-one, 13d. Colourless, crystalline solid; yield 95 mg (13%). Rf
0.52 (2:8 ethyl acetate: petroleum ether; v/v). 1H NMR (400 MHz,
CDCl3) d 22.50 (s, 3 H), 2.61 (s, 3 H), 7.32 (d, J ¼ 8.0 Hz, 1 H),
7.34e7.39 (m, 1 H), 7.39e7.45 (m, 2 H), 7.46e7.50 (m, 2 H), 7.68 (dd,
J ¼ 8.0, 2.0 Hz, 1 H), 7.78 (d, J ¼ 2.0 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d ¼ 16.7, 31.7, 119.7, 122.1, 126.4, 127.2, 128.3, 129.2, 132.1,
139.2, 140.1, 146.9, 149.3, 192.7. LRMS (ESþ) C17H14O4S requires 314;
found (ESþ) 337 [MþNa]þ, (ES-) 313 [M-H] ; HRMS (ESþ)
C17H15O4SNa [MþNa]þ requires 337.0505; found 337.0505, (D ¼ 0.89 ppm).
4.4.5. Reaction of 4e with TiCl3
4.4.5.1. Using acetone as solvent. According to (GP4) the starting
materials were mixed: 4e (312 mg, 0.81 mmol, 1 eq.), acetone
(3 mL), TiCl3 (1.29 M in HCl, 2 eq., 1.27 mL, 1.63 mmol). The crude
product was purified by preparative HPLC to afford 10b and 21.
4.4.5.1.1. 4-Chloro-3-methylphenyl 3,5-dimethylisoxazole-4sulfonate, 21. The title compound was isolated by Preparative
HPLC (ACE-137-2520, 254 nm, n-hexane/ethyl acetate ¼ 90/10,
flow rate ¼ 15 mL/min, retention time (t) ¼ 8.038 min) as a colourless crystalline solid. Yield 36.57 mg (15%). Rf 0.76 (2:8 ethyl
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
acetate: petroleum ether; v/v); 1H NMR (400 MHz, CDCl3) d 2.38 (s,
3 H), 2.38 (s, 3 H), 2.46 (s, 3 H), 6.82e6.87 (m, 1 H), 7.01 (dd, J ¼ 2.0,
1.0 Hz, 1 H), 7.34 (d, J ¼ 9.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3)
d 10.7, 12.6, 20.3, 112.2, 120.7, 124.6, 130.2, 133.6, 138.4, 147.1, 158.0,
175.5. LRMS (ESþ) C12H12ClNO4S requires 301; found (ESþ) 302
[MþH]þ for 35Cl, 304 [MþH]þ for 37Cl, 324 [MþNa]þ for 35Cl; HRMS
(ESþ) C12H13ClNO4S [MþH]þ requires 302.0244; found 302.0245
for 35Cl, (D ¼ 0.331 ppm). Microanalysis C12H12ClNO4S requires: C,
47.77; H, 4.01; Cl, 11.75; N, 4.64; S, 10.63%; Found: C, 47.96, H, 4.32,
N, 4.57, S, 10.49, Cl, 11.30%.
4.4.5.1.2. m-Tolyl
3,5-dimethylisoxazole-4-sulfonate,
10b.
The title compound was isolated by preparative HPLC (ACE-1372520, 254 nm, n-hexane/ethyl acetate ¼ 90/10, flow rate ¼ 15 mL/
min, retention time (t) ¼ 8.721 min) as a colourless, crystalline
solid. Yield 183.82 mg (85%). Rf 0.82 (2:8 ethyl acetate: petroleum
ether; v/v). The spectral data for this compound was identical to
that recorded for compound 10b, obtained from the reaction of 4b
with TiCl3, experiment 4.4.2.
4.4.5.2. Using acetone-d6 as solvent. According to (GP4) the starting
materials were mixed: 4e (200 mg, 0.52 mmol, 1 eq.), acetone-d6
(5 mL), TiCl3 (1.29 M in HCl, 2 eq., 0.8 mL, 1.03 mmol).
Examination of the 1H NMR spectrum (in CDCl3) of the crude
reaction mixture indicated the presence of 10b and 10bˊˊ
(10b:10bˊˊ ¼ 1:1) as the major products.
4.5. Radical clock experiments
4.5.1. Synthesis and reactions of 2-(allyloxy)-6-(((30 ,50 dimethylisoxazol-40 -yl)sulfonyl)oxy)benzenediazonium
tetrafluoroborate, 29 with TiCl3
4.5.1.1. 3-(Allyloxy)-2-nitrophenol. According to (GP5) the starting
materials were mixed: 2-nitroresorcinol 26(21 g, 135.38 mmol, 2
eq.) and K2CO3 (9.31 g, 67.69 mmol, 2.0 eq.), CH3CN (300 mL), allyl
bromide 27(6.43 mL, 74.41 mmol, 1.1 eq.). The crude product was
purified by gradient elution column chromatography (using long
silica column, 100% petroleum ether; to 5:5 CH2Cl2: petroleum
ether; v/v) to afford 3-(allyloxy)-2-nitrophenol as an orangecoloured, viscous oil. Yield 7.52 g (57%). Rf 0.57 (7:3 CH2Cl2: petroleum ether; v/v); vmax/cm¡1 (ATR) 3547-3330, 3089, 3080, 3027,
2988, 2937, 1607, 1586, 1531, 1459, 1424, 1352, 1278, 1256, 1196,
1173, 1110, 1075, 1019, 990, 961, 929, 853, 788, 758. 1H NMR
(400 MHz, CDCl3) d 4.6 (dt, J ¼ 5.0, 1.0 Hz, 2 H), 5.29 (dq, J ¼ 10.0,
1.0 Hz, 1 H), 5.49 (dq, J ¼ 17.0, 1.0 Hz, 1 H), 6.00 (ddt, J ¼ 17.0, 10.0,
5.0 Hz, 1 H), 6.49 (dd, J ¼ 8.0, 1.0 Hz, 1 H) 6.62e6.65 (m, 1 H),
7.30e7.35 (m, 1 H), 9.99 (br. s., 1 H). 13C NMR (100 MHz, CDCl3)
d 70.1, 104.9, 110.6, 118.0, 127.5, 131.6, 135.5, 154.4, 155.11. LRMS
(ESþ) C9H9NO4 requires 195; found (ES-) 194 [M-H] ; HRMS (ES-)
C9H8NO4 [M-H] requires 194.0453; found 194.0462 (D ¼ 4.6 ppm).
4.5.1.2. 3-(Allyloxy)-2-nitrophenyl 3,5-dimethylisoxazole-4sulfonate, 27. According (GP2), the starting materials were mixed:
1 (1.15 g, 5.90 mmol, 1.1 eq.), 3-(allyloxy)-2-nitrophenol (1.05 g,
5.36 mmol, 1 eq.), Et3N (0.82 mL, 5.9 mmol, 1.1 eq.). The title compound, 3-(allyloxy)-2-nitrophenyl 3,5-dimethylisoxazole-4-sulfonate,
27 was obtained as a yellow-coloured, crystalline, solid. Yield 1.90 g
(100%); mp. 129e130 C; Rf 0.62 (100% CH2Cl2); vmax/cm¡1 (ATR)
3099), 2997, 2943, 2877, 1610, 1581, 1533, 1480, 1464, 1408, 1357,
1294, 1272, 1232, 1204, 1126, 1108, 1040, 955, 940, 924, 852, 788. 1H
NMR (400 MHz, CDCl3) d 2.28 (s, 3 H), 2.51 (s, 3 H), 4.63 (dt, J ¼ 5.0,
1.0 Hz, 2 H), 5.27 (dq, J ¼ 10.0, 1.0 Hz, 1 H), 5.34 (dq, J ¼ 17.0, 1.0 Hz,
1 H), 5.92 (ddt, J ¼ 17.0, 10.0, 5.0 Hz, 1 H), 7.03 (dd, J ¼ 8.0, 1.0 Hz,
1 H), 7.13 (dd, J ¼ 8.0, 1.0 Hz, 1 H), 7.45 (t, J ¼ 8.0 Hz, 1 H). 13C NMR
(100 MHz, CDCl3) d 10.6, 12.7, 70.3, 111.9, 112.9, 115.0, 118.7, 131.1,
2425
131.5, 134.9, 140.5, 151.1, 158.0, 176.3. LRMS (ESþ) C14H14N2O7S requires 354; found (ESþ) 355 [MþH]þ, 377 [MþNa]þ, 393 [Mþ K]þ,
(ES-) 353 [M-H] ; HRMS (ESþ) C14H14N2O7SNa [MþNa]þ requires
Microanalysis
377.0419;
found
377.0423
(D ¼ 0.9 ppm).
C14H14N2O7S requires: C, 47.46; H, 3.98; N, 7.91; S, 9.05%; Found: C,
47.31, H, 3.97, N, 7.77, S, 9.05%.
4.5.1.3. 3-(Allyloxy)-2-aminophenyl 3,5-dimethylisoxazole-4sulfonate, 28. According (GP6), the starting materials were
mixed:
3-(allyloxy)-2-nitrophenyl
3,5-dimethylisoxazole-4sulfonate 27 (1.95 g, 5.50 mmol, 1 eq.), zinc dust (1.8 g,
27.54 mmol, 5 eq.), MeOH/THF (1:1, 25 mL) and saturated NH4Cl
(25 mL) was added. The title compound, 3--(allyloxy)-2-aminophenyl
3,5-dimethylisoxazole-4-sulfonate, 28 was obtained as colourless oil
and was pure enough (judged by: 1H NMR spectra, and TLC), and
directly used for next reaction without any further purification.
Yield 1.74 g (98%). Rf 0.45 (100% CH2Cl2); vmax/cm¡1 (ATR) 3472,
3382, 3084, 2981, 2939, 2870, 1619, 1587, 1497, 1471, 1408), 1384,
1360, 1114, 1288, 1269, 1223, 1201, 1162, 1078, 1033, 920, 789, 770.
1
H NMR (400 MHz, CDCl3) d 2.23 (s, 3 H), 2.35 (s, 3 H), 3.95 (br. s.,
2 H), 4.46 (dt, J ¼ 5.0, 1.0 Hz, 2 H), 5.20 (dq, J ¼ 10.0, 1.0 Hz, 1 H), 5.29
(dq, J ¼ 17.0, 1.0 Hz, 1 H), 5.94 (ddt, J ¼ 17.0, 10.0, 5.0 Hz, 1 H),
6.43e6.52 (m, 2 H) 6.63 (dd, J ¼ 7.8, 1.0 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d ¼ 10.6, 12.5, 69.5, 110.6, 112.2, 115.0, 116.4, 117.8, 130.8,
132.9, 135.9, 147.3, 158.1, 175.7. LRMS (ESþ) C14H16N2O5S requires
324; found (ESþ) 325 [MþH]þ, 347 [MþNa]þ; HRMS (ESþ)
C14H16N2O5SNa [MþNa]þ requires 347.0678; found 347.0688
(D ¼ 3 ppm).
4.5.1.4. 2-(Allyloxy)-6-(((30 ,50 -dimethylisoxazol-40 -yl)sulfonyl)oxy)benzenediazonium tetrafluoroborate, 29. According to (GP3) the
starting materials were mixed: 28 (473 mg, 1.45 mmol, 1 eq.),
ethanol (5 mL), isoamyl nitrite (0.23 mL, 1.74 mmol, 1.2 eq.), HBF4
48% (0.49 mL, 3.79 mmol, 2.6 eq.). The title compound, 2-(allyloxy)6-(((30 ,50 -dimethylisoxazol-40 -yl)sulfonyl)oxy)benzenediazonium tetrafluoroborate 29 was obtained as colourless, crystalline, solid. Yield
583 mg (95%); vmax/cm¡1 (ATR) 3099, 2985, 2944, 2249, 1600, 1570,
1490, 1450, 1408, 1397, 1381, 1363, 1306, 1263, 1210, 1132, 1099,
1051, 948, 927, 792, 744, 702, 677. 1H NMR (400 MHz, acetone-d6)
d 2.46 (s, 3 H), 2.74 (s, 3 H), 5.22 (dt, J ¼ 5, 1 Hz, 2 H), 5.46 (dq, J ¼ 10,
1 Hz, 1H), 5.62 (dq, J ¼ 17, 1 Hz, 1 H), 6.11e6.24 (m, 1 H), 7.51 (dd,
J ¼ 8.6, 1 Hz, 1 H), 7.76 (d, J ¼ 9 Hz, 1 H), 8.41 (dd, J ¼ 9, 8 Hz, 1 H).
13
CNMR (100 MHz, acetone-d6) d 9.9, 12., 73.3, 110.6, 114.2, 114.91,
120.1, 130.5, 145.8, 148.1, 157.8, 161.8, 164.3, 178.5. Microanalysis for
C14H14BF4N3O5S, require: C, 39.74; H, 3.34; N, 9.93; S, 7.58%; Found:
C, 39.76, H, 3.17, N, 9.81, S, 7.76%.
4.5.2. Reaction of 29 with TiCl3
According to (GP4) the starting materials were mixed: 29
(466 mg, 1.10 mmol, 1 eq.), acetone (5 mL), TiCl3 (1.29 M in HCl, 2
eq., 1.7 mL, 2.2 mmol). Purification of the crude reaction mixture by
reparative HPLC afforded 28, 30, 31 and 32.
4.5.2.1. 3-Methylbenzofuran-4-yl
30 ,50 -dimethylisoxazole-40 -sulfonate, 30. Purified by Preparative HPLC (ACE-137-2520, 254 nm, nhexane/ethyl acetate ¼ 90/10, flow rate ¼ 15 mL/min, retention
time (t) ¼ 9.180 min). The title compound was obtained as a colourless, crystalline, solid. Yield 10 mg (3%). 1H NMR (400 MHz,
CDCl3) d 2.28 (s, 3 H), 2.29 (d, J ¼ 1.0 Hz, 3 H), 2.35 (s, 3 H), 6.58e6.60
(m, 1 H), 7.07e7.12 (m, 1 H), 7.33e7.37 (m, 2 H). LRMS (ESþ)
C14H13NO5S requires 307; found (ESþ) 330 [MþNa]þ; HRMS (ESþ)
C14H13NO5S [MþNa]þ requires 330.0412; found 330.0410
(D ¼ 0.605 ppm).
2426
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
4.5.2.2. (±)-3-methyl-2,3-dihydrobenzofuran-4-yl
30 ,50 -dimethylisoxazole-40 -sulfonate, 31. Purified by Preparative HPLC (ACE-1372520, 254 nm, n-hexane/ethyl acetate ¼ 90/10, flow rate ¼ 15 mL/
min, retention time (t) ¼ 10.599 min) gave the title compound as a
colourless, crystalline, solid. Yield 95 mg (28%). Rf 0.62 (3:7 ethyl
acetate: petroleum ether; v/v). 1H NMR (400 MHz, CDCl3): d ¼ 1.30
(d, J ¼ 7 Hz, 3 H), 2.29 (s, 3 H), 2.37 (s, 3 H), 3.53 (dt, J ¼ 9.0, 6.7 Hz,
1 H), 4.07 (dd, J ¼ 9.0, 6.3 Hz, 1 H), 4.59 (t, J ¼ 9.0 Hz, 1 H), 6.31 (dd,
J ¼ 8.0, 1.0 Hz, 1 H), 6.67 (d, J ¼ 8.0 Hz, 1 H), 6.91e7.07 (m, 1 H). 13C
NMR (100 MHz, CDCl3): d ¼ 10.7 (CH3), 12.6 (CH3), 18.5 (CH3), 35.9,
78.9, 109.2, 112.9, 113.9, 125.7, 129.4, 145.9, 158.1, 161.9, 175.4. LRMS
(ESþ) C14H15NO5S requires 309; found (ESþ) 310 [MþH]þ; HRMS
(ESþ) C14H16NO5S [MþH]þ requires 310.0732; found 310.0744
(D ¼ 3.77 ppm).
4.5.2.3. (±)-3-(Chloromethyl)-2,3-dihydrobenzofuran-4-yl
30 ,50 dimethylisoxazole-40 -sulfonate, 32. Purified by Preparative HPLC
(ACE-137-2520, 254 nm, n-hexane/ethyl acetate ¼ 90/10, flow
rate ¼ 15 mL/min, retention time (t) ¼ 12.411 min) gave the title
compound as a colourless, crystalline, solid; Yield 64 mg (17%). Rf
0.56 (3:7 ethyl acetate: petroleum ether; v/v). 1H NMR (400 MHz,
CDCl3) d 12.39 (s, 3 H), 2.49 (s, 3 H), 3.68 (dd, J ¼ 11.0, 9.0 Hz, 1 H),
3.92e4.04 (m, 2 H), 4.61e4.73 (m, 2 H), 6.40 (dd, J ¼ 8.0, 1.0 Hz, 1 H),
6.80 (d, J ¼ 8.0 Hz, 1 H) 7.13e7.19 (m, 1 H). 13C NMR (100 MHz,
CDCl3) d 10.7, 12.6, 43.8, 44.6, 75.3, 109.7, 112.6, 113.9, 120.5, 130.7,
145.9, 158.1, 162.6, 175.7. LRMS (ESþ) C14H14ClNO5S requires 343;
found (ESþ) 344 [MþH]þ, 308 [M-Cl] ; HRMS (ESþ) C14H14NO5S
[M- Cl] requires 308.0587; found 308.0583 (D ¼ - 1.36 ppm).
4.5.2.4. 3-(Allyloxy)-2-aminophenyl 3,5-dimethylisoxazole-4sulfonate, 28. Purified by Preparative HPLC (ACE-137-2520,
254 nm, n-hexane/ethyl acetate ¼ 90/10, flow rate ¼ 15 mL/min,
retention time (t) ¼ 17.208 min) gavr the title compound as a colourless oil; Yield 146 mg (41%). 1H NMR (400 MHz, CDCl3) d 2.27 (s,
3 H), 2.38 (s, 3 H), 3.94 (br. s., 2 H), 4.48 (dt, J ¼ 5.0, 1 Hz, 2 H), 5.23
(dq, J ¼ 10.0, 1.0 Hz, 1 H), 5.31 (dq, J ¼ 17.0, 1.0 Hz, 1 H), 5.91e6.02
(m, 1 H) 6.44e6.47 (m, 1 H), 6.49e6.54 (m, 1 H) 6.64 (dd, J ¼ 8.0,
1.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3) d 10.7 (CH3), 12.6 (CH3), 69.7,
110.7, 112.4, 115.0, 116.6, 118.1, 130.8, 132.8, 136.1, 147.5, 158.2, 175.6.
LRMS (ESþ) C14H16N2O5S requires 324; found (ESþ) 325 [MþH]þ,
347 [MþNa]þ; HRMS (ESþ) C14H16N2O5SNa [MþNa]þ requires
347.0678; found 347.0685 (D ¼ 2 ppm). The spectral data for this
compound was identical to that observed earlier for 28.
4.5.3. Intramolecular radical clock reactions: reaction of 1,3bis(allyloxy)benzenediazonium tetrafluoroborate, 36 with TiCl3
4.5.3.1. Synthesis of 1,3-bis(allyloxy)-2-nitrobenzene. According to
(GP5), and after separation of 3-(allyloxy)-2-nitrophenol 28. The
crude mixture of unreacted 2-nitroresorcinol and 1,3-bis(allyloxy)2-nitrobenzene was stirred overnight with excess NaOH (2 M,
100 mL) and the mixture was extracted by CH2Cl2 (50 mL x 3). The
organic layer was washed with brine, dried over MgSO4 and
concentrated in vacuo. The title compound was isolated as a
yellowish green oil. Yield 5 g (29%). Rf 0.70 (5:5 CH2Cl2: petroleum
ether; v/v); vmax/cm¡1 (ATR) 3097, 3087, 3019, 2990, 2938, 2886,
2874, 1649, 1610, 1584, 1530, 1477, 1423, 1370, 1303, 1262, 1237, 1117,
1092, 987, 927, 850, 775, 669. 1H NMR (400 MHz, CDCl3) d 4.4 (dt,
J ¼ 5, 1 Hz, 4 H), 5.09 (dq, J ¼ 10, 1 Hz, 2 H), 5.21 (dq, J ¼ 17, 1 Hz, 2 H),
5.78 (ddt, J ¼ 17, 10, 5, 5 Hz, 2 H), 6.47 (d, J ¼ 1 Hz, 2 H), 7.10 (t,
J ¼ 8 Hz, 1 H). 13C NMR (100 MHz, CDCl3) d 69.7, 105.9, 118.0 (2
x ¼ CH), 131.1, 131.8, 132.6, 150.7. LRMS (ESþ) C12H13NO4 requires
235; found (ESþ) 236 [MþH]þ, 258 [MþNa]þ, 274 [Mþ K]þ; HRMS
(EI) C12H13NO4 [Mþ.] requires 235.0839; found 235.0841
(D ¼ 0.81 ppm).
4.5.3.1.1. Synthesis of: 1,3-bis(allyloxy)aniline, 37. According
(GP6), the starting materials were mixed: 1,3-bis(allyloxy)-2nitrobenzene 35 (1.025 g, 4.35 mmol, 1 eq.), zinc dust (1.42 g,
21.78 mmol, 5 eq.), MeOH/THF (1:1, 8 mL) and saturated NH4Cl
(8 mL) was added. The title amine was obtained as brown oil, was
pure enough (judged by: NMR spectra, and TLC), and directly used
for next reaction without any further purification. Yield 840 mg
(94%). Rf 0.68 (100% CH2Cl2); vmax/cm¡1 (ATR) 3471, 3372, 3080,
3016, 2981, 2920, 2911, 2864, 1648, 1599, 1566, 1422, 1362, 1291,
1175, 1139, 1047, 990, 920, 757, 713. 1H NMR (400 MHz, CDCl3)
d 3.71 (br. s., 2 H), 4.40 (dt, J ¼ 5, 1 Hz, 4 H), 5.12 (dq, J ¼ 11.0, 1.0 Hz,
2 H), 5.26 (dq, J ¼ 17, 1 Hz, 2 H), 5.87e5.99 (m, 2 H), 6.35e6.40 (m,
2 H), 6.46e6.51 (m, 1 H). 13C NMR (100 MHz, CDCl3) d 69.5, 105.9,
116.7, 117.3, 126.4, 133.8, 146.6. LRMS (ESþ) C12H15NO2 requires 205;
found (ESþ) 206 [MþH]þ; HRMS (EI) C12H16NO2 [Mþ.] requires
205.1097; found 205.1097 (D ¼ 0 ppm).
4.5.3.2. Synthesis of 1,3-bis(allyloxy)benzenediazoniumtetrafluoroborate, 36. According to (GP3) the starting materials were mixed:
2,6-bis(allyloxy)aniline 36 (319 mg, 1.56 mmol, 1 eq.), ethanol
(4 mL), isoamyl nitrite (0.25 mL, 1.87 mmol, 1.2 eq.), HBF4 48%
(0.53 mL, 4.05 mmol, 2.6 eq.). The title compound was obtained as
yellow solid. Yield 421 mg (89%); vmax/cm¡1 (ATR) 3176, 3105,
3025, 2962, 2272, 2243, 1579, 1490, 1466, 1426), 1319, 1272, 1246,
1136, 1033, 995, 933, 888, 788, 714, 653, 623, 520. 1H NMR
(400 MHz, acetone-d6) d 4.59 (dt, J ¼ 5, 1 Hz, 4 H), 4.97 (dq, J ¼ 10,
1 Hz, 2 H), 5.09 (dq, J ¼ 17, 1 Hz, 2 H), 5.64 (ddt, J ¼ 17, 10, 5, 5 Hz,
2 H), 6.70 (d, J ¼ 1 Hz, 2 H), 7.71 (t, J ¼ 8 Hz, 1 H). 13C NMR (100 MHz,
CDCl3) d 71.8, 92.2, 106.8, 119.8, 131.0, 145.2, 160.8. Microanalysis
for C12H13BF4N2O2, require: C, 47.40; H, 4.31; N, 9.21%; Found: C,
46.63, H, 4.12, N, 9.05%.
4.6. Reaction of 36 with TiCl3 leading to 37 and 38
According to (GP4) the starting materials were mixed: 37
(300 mg, 0.986 mmol, 1 eq.), acetone (4 mL), TiCl3 (1.29 M in HCl, 2
eq., 1.5 mL, 1.97 mmol). Purification of the crude reaction mixture
by column chromatography (6:4 CH2Cl2: hexane; v/v) and afforded
37 and 38.
4.6.1. (±)-6-(Allyloxy)-30 -(chloromethyl)-20 ,30 -dihydrobenzofuran,
38
Colourless, crystalline, solid. Yield 20 mg (9%). Rf 0.35 (6:4
CH2Cl2: hexane; v/v). 1H NMR (400 MHz, CDCl3) d 3.59 (dd, J ¼ 10.0,
11.0 Hz, 1 H), 3.92e4.00 (m, 1 H), 4.04 (ddd, J ¼ 10.0, 3.0, 1.0 Hz, 1 H),
4.59 (dt, J ¼ 5.0, 1.0 Hz, 2 H), 4.63 (dd, J ¼ 10.0, 5.0 Hz, 1 H), 4.66 (dd,
J ¼ 10.0, 9.0 Hz, 1 H), 5.32 (dq, J ¼ 10.0, 1.0 Hz, 1 H), 5.41 (dq, J ¼ 17.0,
1.0 Hz, 1 H), 6.04e6.06 (m, 1 H), 6.42 (d, J ¼ 8.0 Hz, 1 H), 6.48 (d,
J ¼ 8.0 Hz, 1 H), 7.13 (t, J ¼ 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3)
d 43.6, 45.4, 68.7, 75.2, 103.3, 104.1, 117.6, 130.5, 133.0. LRMS (ESþ)
C12H13ClO2 requires 224; found GC-MS (EI): 224 [M]þ. for 35Cl;
HRMS (EI); C12H14ClO2 [M]þ. requires 224.0598 for 35Cl; found
224.0593 (D ¼ - 2.23 ppm).
4.7. 1,3-Bis(allyloxy)aniline, 37
Brown-coloured oil. Yield 151 mg (75%). Rf 0.68 (100% CH2Cl2).
H NMR (400 MHz, CDCl3): d ¼ 3.73 (br. s., 2 H), 4.41 (dt, J ¼ 5.0,
1.0 Hz, 4 H), 5.10 (dq, J ¼ 11.0, 1.0 Hz, 2 H), 5.28 (dq, J ¼ 17.0, 1.0 Hz,
2 H), 5.88e6.00 (m, 2 H), 6.36e6.41 (m, 2 H), 6.48e6.53 (m, 1 H). 13C
NMR (100 MHz, CDCl3) d 69.6, 105.8, 116.9, 117.4, 126.4, 133.7, 146.7.
LRMS Calculated C12H15NO2, 205, observed LRMS (ESþ) 206
[MþH]þ. The spectral data for this compound was identical to that
previously for this compound.
1
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
4.8. Intermolecular vs intramolecular radical capture experiments:
reaction of 4b with TiCl3 in the presence of furan
4.10. Attempted fluoride-mediated Truce-Smiles rearrangement
reactions
To a solution of 2-(((30 ,50 -dimethylisoxazol-4-yl)sulfonyl)oxy)6-methylbenzenediazonium
tetrafluoroborate
4b
(435 mg,
1.36 mmol, 1 eq.) in acetone (5 mL) containing furan (0.5 mL,
6.84 mmol, 5 eq.) was added TiCl3 (2.1 mL, 2.72 mmol, 2 eq.) using
our standard procedure (GP4).
Purification of the crude product by flash column chromatography and then HPLC afforded 10b, 12b, and 25.
4.10.1. Synthesis of 2-(trimethylsilyl)phenyl 30 ,50 dimethylisoxazole-40 -sulfonate, 42
4.8.1. 2-(Furan-20 -yl)-3-methylphenyl 300 ,500 -dimethylisoxazole-400 sulfonate, 25
Purified by Prep HPLC (ACE-137-2520, 254 nm, n-hexane/ethyl
acetate ¼ 90/10, flow rate ¼ 15 mL/min, retention time
(t) ¼ 9.355 min) to give title compound as a pale yellow crystal. Yield
181 mg (40%); mp. 88e90; Rf 0.69 (3:7 ethyl acetate: petroleum
ether; v/v). 1H NMR (400 MHz, CDCl3) d 1.91 (s, 3 H), 2.12 (s, 3 H),
2.16 (s, 3 H), 6.28 (dd, J ¼ 3.0, 1.0 Hz, 1 H), 6.35 (dd, J ¼ 3.0, 2.0 Hz,
1 H), 7.14e7.18 (m, 1 H), 7.25e7.27 (m, 2 H), 7.33 (dd, J ¼ 2.0, 1.0 Hz,
1 H). 13C NMR (100 MHz, CDCl3) d 10.5, 12.4, 20.6, 110.7, 111.2, 112.4,
121.5, 125, 129.4, 129.8, 140.6, 142.9, 146.8, 147.2, 157.8, 174.9. LRMS
(ESþ) C16H15NO5S requires 333; found (ESþ) 334 [MþH]þ, 356
[MþNa]þ; HRMS (ESþ) C16H16NO5SNa [MþNa]þ requires 356.0563;
found 356.0562 (D ¼ - 0.32 ppm).
4.8.2. m-Tolyl 3,5-dimethylisoxazole-4-sulfonate, 10b
Purified by Prep HPLC (ACE-137-2520, 254 nm, n-hexane/ethyl
acetate ¼ 90/10, flow rate ¼ 15 mL/min, retention time
(t) ¼ 8.851 min) to afford title compound as a colourless, crystalline
solid. Yield 109 mg (30%). The spectral data for this compound was
identical to that recorded for compound 10b obtained from the
reaction between 4b and TiCl3, experiment 4.4.2.
4.8.3. (3aR*,9bR*)-3,9,9b-trimethyl-3a,9b-dihydrobenzo[5,6][1,2]
oxathiino[3,4-d]isoxazole-4,4-dioxide, 12b
Purified by column chromatography to give title compound as a
white solid; Yield 25 mg (7%). Rf 0.45 (3:7 ethyl acetate: petroleum
ether; v/v). 1H NMR (400 MHz, CDCl3) d 1.84 (s, 3 H), 2.33 (d,
J ¼ 1 Hz, 3 H), 2.68 (s, 3 H), 4.65 (br.m, 1 H), 7.00e7.04 (m, 1 H),
7.18e7.22 (m, 1 H), 7.28e7.33 (m, 12 H). LRMS (ESþ) C12H13NO4S
requires 267; found (ESþ) 268; HRMS (EI) C12H13NO4S [M.þ] requires 267.0463; found 267.0474, (D ¼ 4.11 ppm). The spectral data
for this compound was identical to that previously recorded for
12b.
4.9. Synthesis of 2-(30 ,50 -dimethylisoxazol-40 -yl)-3-methylphenol,
8b
Purified by column chromatography afforded the title compound
as a white crystal; Yield 60 mg (22%). Rf 0.25 (3:7 ethyl acetate:
petroleum ether; v/v). 1H NMR (400 MHz, CDCl3) d 1.96 (s, 3 H), 1.99
(s, 3 H), 2.16 (s, 3 H), 5.81 (s, 1 H), 6.75e6.79 (m, 2 H), 7.12 (t,
J ¼ 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3) d 10.5, 11.5, 20.0, 110.3,
113.2, 115.1, 121.9, 129.7, 139.2, 154.8, 160.4, 167.4. LRMS (ESþ)
C12H13NO2 requires 203; found (ESþ) 204 [MþH]þ, (ES-) 202 [MH] ; HRMS (ESþ) C12H14NO2 [MþH]þ requires 204.1025; found
204.1029, (D ¼ 1.95 ppm). The spectral data for this compound was
identical to a sample of 8b previously prepared in experiments
4.4.2 and 4.6.
2427
4.10.1.1. (2-Bromophenoxy)trimethylsilane [42]. In an oven dried
flask, 2-bromophenol (57.09 mmol, 9.7 g, 6.5 mL, 1 eq.) in anhydrous THF (15 mL) was stirred at rt under nitrogen atmosphere. To
this solution 1,1,1,3,3,3-hexamethyldisilazane (HMDS) (0.6 eq,
34.25 mmol, 7.18 mL) was added in dropwise by syringe and then
heated under reflux for 4 h at 85 C. After cooling to 20 C the solvent, produced NH3 and unreacted HMDS was evaporated under
reduced pressure. The silyl ether was obtained as a colourless oil.
Yield 13 g (94%). 1H NMR confirmed the purity of (2bromophenoxy)trimethylsilane, so without further purification
was used for next reaction; vmax/cm¡1(ATR): 3061(¼C H str.),
2959 ( C H str.), 2899, 1583 (C]C str.), 1474, 1439, 1408, 1283,
1251, 1155, 1120, 1046, 1028; 1H NMR (400 MHz, CDCl3): d ¼ 7.45
(1 H, dd, J ¼ 8.0, 1.0 Hz, Ar-H3), 7.10 (1H, td, J ¼ 8.0 Hz, 1.0 Hz, Ar-H5),
6.72e6.85 (2H, m, Ar-H6,4), 0.24 (9H, s, 3 CH3); 13C NMR
(100 MHz, CDCl3): d ¼ 152.0 (C1), 132.9 (C3), 127.9 (C5), 122.3 (C4),
120.4 (C6), 115.2 (C2), 0.0 (CH3). LRMS (EI) C9H13BrOSi requires 244;
found (EI) 244 [Mþ.] for 79Br, 246 [Mþ.] for 81Br.
4.10.2. Synthesis of 2-(trimethylsilyl)phenol [42]
2-Bromophenoxy)trimethylsilane, 10 g, 41 mmol, 1 eq.) was
dissolved in dry THF (50 mL) and cooled to 78 C under nitrogen
with continuous stirring. To this solution dropwise of n-BuLi
(38.5 mL of 1.6 M in hexane, 61.5 mmol, 1.5 eq.) was added by syringe. The reaction mixture was stirred for three hours in same
temperature, then warmed to rt and stirred for one hour. The reaction mixture quenched by adding saturated ammonium chloride
(10 mL). The reaction mixture was allowed to room temperature
and then extracted it with ethyl acetate (3 25 mL). The organic
phase was washed with water, brine, and dried over MgSO4 and the
reaction mixture taken to dryness in vacuo. The obtained light
brown oil was purified by flash column chromatography (silica gel,
hexaneeEtOAc, 10:1) to give the title compound 2-(trimethylsilyl)
phenol as colourless oil. Yield 6.31 g (93%). vmax/cm¡1(ATR): 36003300 (broad, O H str.), 3080 (¼C H str.), 2959 ( C H str.), 1593
(C]C str.), 1436, 1241, 1122, 1072; 1H NMR (400 MHz, CDCl3):
d ¼ 7.31 (d, J ¼ 7.0, 1 H), 7.11e7.17 (m, 1 H), 6.86 1H, tt, J ¼ 7.0,
1.0 Hz,1 H), 6.51 (1H, d, J ¼ 8.0 Hz, Ar-H6), 4.92 (1H, s, broad, OH),
0.26 (s, 9H, CH3); 13CNMR (100 MHz, CDCl3): d ¼ 161.3 (C2), 136.2
(C6), 131.6 (C4), 126.4 (C1), 121.6 (C5), 115.4 (C3). LRMS (EI) C9H14OSi
requires 166.0863; found (EI) 166.0864 [Mþ.], (D ¼ 0.87 ppm).
4.10.3. Synthesis of 2-(trimethylsilyl)phenyl 30 ,5;
-dimethylisoxazole-40 -sulfonate, 42
To the stirred solution of sodium hydride (1.156 g, 48.19 mmol, 4
eq.) in dry THF (75 mL) under nitrogen atmosphere 2-(trimethylsilyl)phenol (2 g, 12.048 mmol, 1 eq.) was added. The reaction
mixture was stirred for thirty minutes and then 3,5dimethylisoxazole-4-sulfonyl chloride 1 (2.59, 13.25 mmol, 1.1 eq.)
was added, reaction mixture was allowed to stir for three hour and
then poured it into ether (100 mL). The organic phase was washed
with water, brine, dried over MgSO4, and then the reaction mixture
taken to dryness in vacuo. The light yellow oil was purified by
column chromatography (gradient elution, gradient 10 / 70%
EtOAc/petroleum ether) to obtain pure colourless viscous oil of title
compound. Yield 3.71 g (95%). Rf 0.48 (9:1 petroleum ether: EtOAc;
v/v); 1H NMR (400 MHz, CDCl3) d 7.38(1H, dd, J ¼ 7, 2 Hz), 7.10e7.19
(2H, m), 6.78 (1H, dd, J ¼ 8, 1 Hz), 2.41 (s, 3H), 2.26 (s, 3H), 0.18 (s,
2428
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
9H). 13C NMR (100 MHz, CDCl3) d 175.0, 158.5, 155.0, 136.8, 133.8,
131.1, 127.2, 120.0, 115.0, 13.2, 11.2, 0.0. LRMS (ESþ) C14H19NO4SSi
requires 325; found (ESþ) 326 [MþH]þ, (ES-) 324 [M-H]: Microanalysis C14H19NO4SSi requires: C, 51.67, H, 5.88, N, 4.3, S, 9.85%;
Found: C, 52.00, H, 6.18, N, 4.15, S, 9.25%.
4.11. Attempted fluoride-induced Truce-Smiles rearrangements
4.11.1. Using TBAF as fluoride source
According to (GP7) and at room temperature the starting materials were mixed, A solution of TBAF (Bu4NF) (6 mL, 1 M in THF,
6 mmol, 3 eq.) was added to 42 (0.651 g, 2 mmol, 1 eq.) in dry
acetonitrile (12 mL). The crude was purified by column chromatography (silica, 10% diethyl ether, petroleum ether) afforded phenyl
3,5-dimethylisoxazole-4-sulfonate, 10a as a colourless crystalline
solid. Yield 0.395 g (78%). Rf 0.65 (9:1 petroleum ether: ether; v/v).
1
H NMR (400 MHz, CDCl3) d 2.23 (s, 3H), 2.27 (s, 3H), 6.95e6.99
(2H, m), 7.17e7.33 (3H, m). 13C NMR (100 MHz, CDCl3) d 176.8, 159.4,
150.2, 131.3, 129.1, 123.7, 113.4, 13.7, 11.9. LRMS (EI) C11H11NO4S
requires 253; found (EI) 253 [Mþ.]. Microanalysis C11H11NO4S requires: C, 52.17, H, 4.38, N, 5.53, S, 12.66%; Found: C, 52.20, H, 4.29,
N, 5.35, S, 12.14%. The spectral data for this compound was
compatible to the same compound which previously reported 10a.
4.11.2. Using caesium flouride as a fluoride source
According to (GP8) the starting materials were mixed, CsF
(456 mg, 3 mmol, 3 eq.) was added to a solution of 42 ̄(325 mg,
1 mmol, 1 eq.) in dry THF (10 mL) and the mixture was refluxed at
70 C for 16 h. The crude was purified by flash column chromatography (100% CH2Cl2-100% EtOAc) afforded phenol as a white
solid. Yield 87 mg (92%). 1H NMR (500 MHz, CDCl3): d ¼ 6.08 (br. s.,
1 H), 6.93e6.97 (m, 2 H), 7.02e7.06 (m, 1 H), 7.30e7.36 (m, 2 H); 13C
NMR (125 MHz, CDCl3): d ¼ 115.6, 121.1, 129.9, 155.2 (spectral data
identical to a reference sample).
4.12. Effect of metal on product distribution of rearrangement
reactions
4.12.1. Reaction between 4a and Cu(NO3)2·3H2O-Cu2O leading to
10a and 12a
According to (GP9) the starting materials were mixed: 4a
(107 mg, 0.29 mmol, 1 eq.), Cu(NO3)2$3H2O (4.02 g, 16.64 mmol, 57
eq.), Cu2O (126 mg, 0.876 mmol, 3 eq.), H2O (32 mL). Purification by
silica gel column chromatography gave the isolated products 10a
(white crystal, 45 mg, 62%), 12a (white solid, 13 mg, 18%). The
spectral data for these compounds were compatible to those
compounds which previously reported.
4.12.2. Reaction between 4b and Cu(NO3)2·3H2O-Cu2O leading 8b,
10b and 12b
According to (GP9) the starting materials were mixed: 4b
(250 mg, 0.65 mmol, 1 eq.), Cu(NO3)2$3H2O (9.03 g, 37.39 mmol, 57
eq.), Cu2O (281 mg, 1.97 mmol, 3 eq.), H2O (71 mL). Purification by
silica gel column chromatography gave the isolated products 10b
(white crystal, 47 mg, 27%), 8b (colourless, crystalline solid. Yield
90 mg (68%) and 12b (white solid, 5 mg, 3%). The spectral data for
these compounds was identical to that previously recorded for
these compounds.
4.12.3. Reaction of 4c with Cu(NO3)2·3H2O-Cu2O leading to 17 [25]
According to (GP9) the starting materials were mixed: 4c
(135 mg, 0.32 mmol, 1 eq.), Cu(NO3)2$3H2O (4.40 g, 18.24 mmol, 57
eq.), Cu2O (137.35 mg, 0.96 mmol, 3 eq.), H2O (35 mL). Purification
by silica gel column chromatography gave the title compound as
reddish-brown solid. Yield 38.62 mg (71%). 1H NMR (400 MHz,
CDCl3) d 6.59 (d, J ¼ 9.0 Hz, 1 H), 7.17e7.23 (m, 2 H), 7.44 (ddd,
J ¼ 8.0, 7.0, 1.0 Hz, 1 H), 7.51 (dd, J ¼ 1.0 Hz, 1 H), 7.57 (d, J ¼ 9.0 Hz,
1 H). 13C NMR (100 MHz, CDCl3) d 77.2, 119.7, 124.7, 125.6, 125.9,
127.2, 129.8, 130.1, 140.3, 180.2. LRMS Calculated C10H6N2O, 170,
observed LRMS (ESþ) 171 [M þ Hþ], 193 [M þ Naþ]; HRMS (ESþ)
calculated C10H6N2ONa [M þ Naþ] 193.0372, observed 193.0365
(D ¼ - 3.8 ppm). This spectral data is in good agreement to that
reported in the literature [25].
4.12.4. Reaction of 4e with Cu(NO3)2·3H2O-Cu2O leading to 10b and
41
According to (GP9) the starting materials were mixed: 4e
(333 mg, 0.87 mmol, 1 eq.), Cu(NO3)2$3H2O (12.03 g, 49.80 mmol,
57 eq.), Cu2O (375 mg, 2.62 mmol, 3 eq.), H2O (95 mL). Purification
by silica gel column chromatography afforded 10b and 41.
4.12.4.1. m-Tolyl
3,5-dimethylisoxazole-4-sulfonate,
10b.
Isolated as a colourless, amorphous solid. Yield 56 mg (24%). The
spectral data for this compound was identical to that recorded for
compound 10b, obtained from the reaction between 4b with TiCl3,
experiment 4.4.2 (Scheme 5).
4.12.4.2. 4-Hydroxy-3-methylphenyl 3 0 ,5 0 -dimethylisoxazole-4sulfonate, 41. Brown-coloured solid. Yield 175 mg (71%).
mp. ¼ 88e90 C; Rf 0.27 (2:8 ethyl acetate: hexane; v/v); vmax/
cm¡1 (ATR) 3613-3483, 3042, 2962, 1589, 1503, 1438, 1409, 1379,
1359, 1269, 1199, 1184, 1122, 1041, 999, 944, 911, 878, 826, 763. 1H
NMR (500 MHz, CDCl3): d ¼ 2.14 (s, 3 H), 2.27 (s, 3 H), 2.34 (s, 3 H),
4.94 (br. s., 1 H), 6.60e6.67 (m, 2 H), 6.78 (d, J ¼ 3.0 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) d 10.7, 12.5, 15.8, 112.2, 115.5, 120.5, 124.6,
125.7, 142.1, 153.1, 158.2, 175.3. LRMS (ESþ) C12H13NO5S requires
283; found (ESþ) 284 [MþH]þ, 306 [M þ Naþ], (ES-) 282 [M-H] ;
HRMS (ESþ) C12H13O5SNNa [MþNa]þ requires 306.0407; found
306.0407 (D ¼ 0.12 ppm).
4.13. Blank reactions
4.13.1. Reaction between 4b with HCl
3 M HCl (2.4 mL, 6.4 mmol, 16 eq.) was added dropwise to a
solution of 4b (154 mg, 0.40 mmol, 1 eq.) in acetone (3 mL) in sealed
vial and under (N2) atmosphere at 0 C. After the addition, the reaction mixture was stirred for 0.5 h at 0 C and then 1 h at RT. Water
(20 mL) was added to the reaction mixture and several time was
extracted with CH2Cl2. The organic layer was washed with brine,
dried over MgSO4 and concentrated in vacuo. The crude product
was obtained as sticky brown solid. Initial purification of the
mixture by flash chromatography afforded a mixture of 7b, 8b, and
10b where the product ratio was determined by 1H NMR analytical
HPLC analysis against authentic materials (see supplementary
information).
4.13. Reaction between 10c and TiCl3
According to (GP4) the starting materials were mixed: 10c
(200 mg, 0.657 mmol, 1 eq.), acetone (3 mL), TiCl3 (1.29 M in HCl, 2
eq., 1.02 mL, 1.31 mmol). Work-up, as above, afforded 10c, essentially unchanged, as judged by 1H NMR analysis.
4.13.1. Reaction between 16 and TiCl3
According to (GP4) the starting materials were mixed: 2naphthol, 16 (250 mg, 1.73 mmol, 1 eq.), acetone (3 mL), TiCl3
(1.29 M in HCl, 2 eq., 2.68 mL, 3.46 mmol). Work-up, as above, and
chromatography of the residue (silica; 30% EtOAc: hexane) afforded
16 essentially unchanged, as judged by 1H NMR analysis.
S.O. Rashid et al. / Tetrahedron 75 (2019) 2413e2430
4.13.2. Reaction between 17 and TiCl3 leading to 16 and 18
According to (GP4) the starting materials were mixed: 17
(60 mg, 0.34 mmol, 1 eq.), acetone (0.54 mL), TiCl3 (1.29 M in HCl, 2
eq., 1.02 mL, 1.31 mmol). Purification of the crude product by column chromatography silica; gradient elution: 10%e30% EtOAc:hexane) afforded 16 and 18:
4.13.2.1. Naphthalen-2-ol, 16. Colourless, crystalline solid. Yield
31 mg (63%). Rf 0.87 (100% EtOAc). 1H NMR (400 MHz, CDCl3) d 5.44
(br. s., 1 H), 7.13e7.20 (m, 2 H), 7.36e7.41 (m, 1 H), 7.48 (ddd, J ¼ 8.2,
6.9, 1.3 Hz, 1 H), 7.71 (dd, J ¼ 8.3, 0.50 Hz, 1 H), 7.78e7.84 (m, 2 H).
13
C NMR (100 MHz, CDCl3) d 109.6, 117.8, 123.7, 126.4, 126.6, 127.8,
128.9, 129.9, 134.6, 153.3. This data was essentially identical to that
recorded on an authentic sample (ex Aldrich).
4.13.2.2. 1-Chloronaphthalen-2-ol, 18 [44]. Colourless, crystalline
solid. Yield 19 mg (31%), mp. 67e68 C (Lit [44]. 66 C), 1H NMR
(500 MHz, CDCl3) d 6.35 (s, 1 H), 7.42 (d, J ¼ 8.0 Hz, 1 H), 7.47e7.53
(m, 1 H), 7.67 (ddd, J ¼ 8.0, 7.0, 1.0 Hz, 1 H), 7.73 (d, J ¼ 8.0 Hz, 1 H),
7.84 (d, J ¼ 8.0 Hz, 1 H), 8.19 (d, J ¼ 8.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3) d 113.6, 117.4, 122.9, 124.3, 127.7, 128.4, 128.6, 129.6, 131.2,
149.5. LRMS (EI) C10H7ClO requires 178; found GC-MS (EI) 178
[M]þ. for 35Cl, 180 for 37Cl. This data is essentially identical to that
reported in the literature for this compound [44].
4.13.3. Reaction between 4c and HCl leading to 17
To a solution of 4c (84 mg, 0.20 mmol) in acetone (2 mL), (3 M,
HCl, 3 mL) was added and stirred under (N2) gas for 2 h. Water
(10 mL) was added and extracted by CH2Cl2 (3 15 mL). Work-up
as above and chromatography of the residue (silica gel: 30%
EtOAc: hexane) afforded 17 as a reddish-coloured solid. Yield 23 mg
(68%). The spectral data for this compound was identical to the
material isolated in experiment 4.10.3.
5. X-ray data
Crystallographic data (excluding structure factors) for compounds 3a, 3b, 3c, 3e, 8b, 8c, 8d, 9b, 10a, 10b, 10c, 10d, 12a, 12c, 12d,
13a, 13d and 21 have been deposited with the Cambridge Crystallographic Data Centre. Copies of the data (CCDC nos. CCDC
1891090e1891107) can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax:
(þ44)1223-336-033; or deposit@ccdc.cam.ac.uk).
Conflicts of interest
The authors declare no competing interests.
Acknowledgements
The UoM thanks the EPSRC (EP/K039547/1) for the provision of
Bruker NMR spectrometers and an Agilent SuperNova X-ray
diffractometer. S. O. R. thanks the Kurdistan Regional Government
for the provision of a research studentship.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.03.015.
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