Synthesis of a Visibly Emissive 9 -nitro -2,3 -dihydro -1H ...
The Royal Society of Chemistry · S2 Methyl...
22
S1 Benzofuranquinones as Inhibitors of Indoleamine 2,3-Dioxygenase (IDO). Synthesis and Biological Evaluation † Catarina Carvalho, David Siegel, Martyn Inman, Rui Xiong, David Ross and Christopher J. Moody ELECTRONIC SUPPLEMENTARY INFORMATION Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry. This journal is © The Royal Society of Chemistry 2014
Transcript of The Royal Society of Chemistry · S2 Methyl...
S1
Benzofuranquinones as Inhibitors of Indoleamine 2,3-Dioxygenase (IDO).
Synthesis and Biological Evaluation †
Catarina Carvalho, David Siegel, Martyn Inman, Rui Xiong, David Ross
and Christopher J. Moody
ELECTRONIC SUPPLEMENTARY INFORMATION
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2014
S2
Methyl 4,7-dihydro-5-methoxy-2-methyl-4,7-dioxobenzofuran-3-carboxylate 3a
c_car.cjr58_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.106.531.00
7.28
5.82
3.94
3.89
2.70
1.57
S3
Methyl 4,7-dihydro-6-methoxy-2-methyl-4,7-dioxobenzofuran-3-carboxylate 3b
c_car.cjr49_f1_001001r
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.056.251.00
7.28
5.87
3.96
3.88 2.70
1.55
c_car.CJR49_13C_2_002001r
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Nor
mal
ized
Inte
nsity
179.
88
169.
4616
5.26
162.
2915
8.13
148.
66
126.
99
113.
1110
8.23
77.3
377
.01
76.7
059
.90
56.8
952
.35
14.2
812
.64
S4
6-Methoxy-2-methyl-3-(morpholine-4-carbonyl)benzofuran-4,7-dione 3d
m_inm.MI-1927_001001r
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Nor
mal
ized
Inte
nsity
3.162.068.861.00
7.29
5.80
3.90
3.86
3.84 3.
833.
823.
713.
353.
28
2.48
2.45
2.04
1.27 1.
251.
23
m_inm.MI-1927j_002001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
Nor
mal
ized
Inte
nsity
181.
21
168.
8416
1.29
159.
6715
9.40
147.
81
127.
11
115.
34
106.
92
77.3
477
.02
76.7
166
.64
66.5
6 57.0
3
47.3
042
.40
13.0
6
S5
Methyl 4,9-dihydro-2-methyl-4,9-dioxonaphtho[2,3-b]furan-3-carboxylate 3e
m_inm.MI-2569_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.043.032.082.00
8.23
8.22 8.22 8.21
7.80
7.79 7.
787.
777.
29
4.01
2.75
1.61
m_inm.MI-2569_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
Nor
mal
ized
Inte
nsity
178.
7917
3.51
164.
7516
2.55
151.
39
134.
1813
3.73
133.
6712
7.43
126.
54
113.
32
77.3
477
.02
76.7
0
52.3
9
14.2
2
S6
Methyl 4,7-dihydro-2-isopropyl-6-methoxy-4,7-dioxobenzofuran-3-carboxylate 3f
m_inm.MI-2562_001001r
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
6.101.031.00
7.29
5.86
3.96
3.88
3.68 3.
663.
65
1.60
1.39
1.37
m_inm.MI-2562_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Nor
mal
ized
Inte
nsity
180.
15
172.
0816
9.30
162.
48 158.
38
148.
43
127.
09
111.
3910
7.97
77.3
377
.02
76.7
0
56.8
952
.42
27.8
6
20.5
317
.56
S7
Ethyl 4,7-dihydro-6-methoxy-4,7-dioxo-2-phenylbenzofuran-3-carboxylate 3g
m_inm.MI-2579_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.053.082.030.993.122.00
7.90
7.88
7.51
7.29
5.90
4.51
4.50
4.48
3.92
1.59
1.43
1.41
1.40
m_inm.MI-2579_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
Nor
mal
ized
Inte
nsity
180.
31
169.
0016
2.80
159.
3315
8.65
147.
77
131.
0912
8.90
127.
46
113.
0310
7.44
77.3
477
.02
76.7
162
.40 57
.02
13.8
9
S8
tert-Butyl 4,7-dihydro-6-methoxy-2-methyl-4,7-dioxobenzofuran-3-carboxylate 3c
m_inm.MI-2601_001001r
9 8 7 6 5 4 3 2 1Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
10.383.113.131.00
7.29
5.85
3.88
2.67
1.64
m_inm.MI-451-J_002001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Nor
mal
ized
Inte
nsity
179.
89
164.
4116
0.94
158.
09
148.
39
127.
22
108.
19
82.7
077
.33
77.0
276
.70
56.8
1
28.1
327
.66 14
.17
S9
4,7-Dihydro-6-methoxy-2-methyl-4,7-dioxobenzofuran-3-carboxylic acid 4
m_inm.MI-2607_001001r
11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.133.141.00
7.28
6.00
3.98
2.86
m_inm.MI-2607N_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
185.
79
169.
4616
7.99 16
0.70
160.
69
147.
24
125.
33
112.
8610
5.93
77.3
5 77.0
376
.71
57.6
9
14.5
2
S10
4,7-Dihydro-3-hydroxymethyl-5-methoxy-2-methylbenzofuran-4,7-dione 5a
c_car.cjr86_2_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.100.843.152.061.00
7.28
5.81 4.
64
3.89
2.44
1.57
S11
Methyl 4,7-dihydroxy-6-methoxy-2-methylbenzofuran-3-carboxylate 10b
c_car.cjr54_av3400_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
1.282.763.131.000.980.99
9.78
8.70
6.41
3.94 3.
78
3.31
2.66
2.50
c_car.cjr54_av400_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
168.
1016
2.54
147.
10
141.
97
124.
81
108.
6410
7.63
97.2
6
57.1
053
.53
40.6
040
.40
40.1
939
.97
39.7
739
.56
39.3
5
15.1
7
S12
4,7-Dihydro-3-hydroxymethyl-6-methoxy-2-methylbenzofuran-4,7-dione 5b
c_car.cjr83_3_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.514.122.291.00
7.28
5.85
4.62
3.90
2.45
c_car.cjr83_13c_001001r
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
Nor
mal
ized
Inte
nsity
184.
61
168.
47
160.
1415
6.71
148.
27
129.
44
121.
01
106.
35
77.3
377
.01
76.7
0
57.1
154
.93
12.3
5
S13
4,9-Dihydro-3-(hydroxymethyl)-2-methylnaphtho[2,3-b]furan-4,9-dione 5c
m_inm.MI-2582_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.220.722.042.032.01
8.25 8.25
8.23 8.19
7.80 7.
797.
79 7.78
7.29
4.71
2.51
m_inm.MI-2582_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
Nor
mal
ized
Inte
nsity
183.
28
172.
97
156.
03
134.
3713
3.76
132.
8012
7.04
120.
74
77.3
377
.01
76.7
0
55.0
3 12.2
7
S14
4,7-Dihydro-3-(hydroxymethyl)-2-isopropyl-6-methoxybenzofuran-4,7-dione 5d
m_inm.MI-2568_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
6.331.034.022.051.00
7.29
5.85
4.64
3.91
3.21 3.
203.
18 1.61
1.37
1.35
m_inm.MI-2568_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
Nor
mal
ized
Inte
nsity
184.
82
168.
4216
4.79
160.
22
148.
17
129.
49 119.
30
106.
29
77.3
477
.02
76.7
0
57.1
154
.65
26.9
821
.03
S15
4,7-Dihydro-5-Methoxy-3-(methoxymethyl)-2-methylbenzofuran-4,7-dione 6
S16
4,7-Dihydro-3-(2,4,6-trifluorophenoxy)methyl-5-methoxy-2-methylbenzofuran-4,7-dione 7a
CJR300 13C-NMR 3-((2,4,6-TRIFLUOROPHENOXY)METHYL)-5-METHOXY-2-METHYLBENZOFURAN-4,7-DIONE 215.MRC
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
Nor
mal
ized
Inte
nsity
177.
3417
5.44
159.
8715
9.01
149.
9114
7.34
124.
74
114.
7810
5.46
101.
0510
0.78
100.
51
77.3
177
.00
76.6
864
.74 56
.82
29.6
8 12.0
5
S17
4,9-Dihydro-2-methyl-3-(2,4,6-trifluorophenoxy)methylnaphtho[2,3-b]furan-4,9-dione 7b
m_inm.MI-2605_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.102.092.082.082.00
8.24
8.21
8.15 7.78 7.
77 7.76
7.75
7.28
6.72 6.
706.
68
5.36
2.56
m_inm.mi2605_001001r
220 200 180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
Nor
mal
ized
Inte
nsity
181.
36
173.
25
160.
4115
5.34
151.
12
133.
8813
3.77
133.
1913
1.53
126.
85
115.
65
101.
0410
0.82
100.
61
77.2
877
.02
76.7
7
65.0
0
29.7
1
12.3
5
S18
4,7-Dihydro-3-hydroxymethyl-2-methyl-5-(pentylamino)benzofuran-4,7-dione 8a
c_car.cjr233_1_001001r
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.104.193.032.302.000.960.93
7.29
5.87
5.31
4.63
3.20
3.18
3.17
3.15
2.41
1.73 1.
711.
701.
401.
391.
390.
970.
960.
94
c_car.cjr233_001001r
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Nor
mal
ized
Inte
nsity
180.
7617
5.18
152.
9414
7.93
118.
95 95.8
0
77.3
577
.03
76.7
1
55.0
6
43.0
8
29.1
427
.81
22.3
113
.93
11.8
5
S19
4,7-Dihydro-5-(3-(dimethylamino)propylamino)-3-(hydroxymethyl)-2-methylbenzofuran-4,7-dione 8b
c_car.cjr231_f2_2_001001r
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
2.079.482.242.081.000.94
7.28
5.26
4.61
3.29
3.28
2.56
2.40
2.37
1.90 1.
88
1.27
S20
4,7-Dihydro-3-(2,4,6-trifluorophenoxy)methyl-5-(3-(dimethylamino)propylamino)-2-methylbenzofuran-4,7-dione 8c
c_car.cjr301_f1_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
3.306.582.092.082.001.02
7.29
6.71
6.68
6.66
5.27
5.20
3.26
3.25
2.50
2.48
2.41
2.32
1.86 1.
851.
83
c_car.cjr301_f1_1_001001r
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.05
0.10
0.15
0.20
Nor
mal
ized
Inte
nsity
178.
9817
5.14
156.
8815
2.98
149.
02
122.
45 113.
8410
1.00 10
0.73
94.9
5
77.3
377
.01
76.7
065
.01
57.9
8
45.1
942
.80 24
.67
11.7
3
S21
4,7-Dihydro-5-(2-(Dimethylamino)ethylamino)-2-(hydroxymethyl)-3-methylbenzofuran-4,7-dione 8d
c_car.cjr454_2_001001r
10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
9.322.162.000.990.92
7.28
6.51
5.26
4.66
3.18
3.17 2.65 2.
63
2.32
2.29
2.03
c_car.cjr454_2_dpx400_001001r
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
Nor
mal
ized
Inte
nsity
179.
1317
5.29
153.
98
148.
52
123.
3611
7.29
96.1
1
77.3
577
.03
76.7
1
56.4
354
.82
45.0
839
.91
8.53
S22
Methyl 4,7-dihydroxy-6-methoxy-2-methylbenzofuran-3-carboxylate 10a
c_car.cjr62_001001r
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0.05
0.10
0.15
0.20
0.25
0.30
Nor
mal
ized
Inte
nsity
168.
1216
3.91
143.
1413
4.38
131.
89
115.
39
101.
40 57.5
553
.56
40.6
240
.42
40.2
040
.00
39.7
939
.58
39.3
7
15.4
8
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