Supporting Information
Indium-Mediated Synthesis of Heterobiaryls Enrique Font-Sanchis, Francisco Javier Céspedes-Guirao, Ángela Sastre-Santos, and Fernando Fernández-Lázaro* División de Química Orgánica, Instituto de Bioingeniería, Universidad Miguel Hernández, Avda. Ferrocarril s/n, 03202 Elche (Alicante), Spain
[email protected] Table of contents General procedure for the cross-coupling reaction
S2
Synthesis and characterization of compound 8
S3
1
S4
H- and 13C-NMR spectra of compound 8
Spectroscopic and analytical data of new Heterobiaryls
S5
1
H- and 13C-NMR spectra of new Heterobiaryls
S8
1
H-NMR spectra of already known Heterobiaryls
S1
S 15
General procedure. All reactions were carried out in dried glassware. Tetrahydrofuran (THF) was dried by distillation from sodium and benzophenone. 3-Iodopyridine, 2iodopyridine,
iodobenzene,
2-iodothiophene,
4-iodopyrazole,
tert-butyllithium,
2-
thienyllithium, indium (III) choride, tetrakis(triphenylphosphine) palladium (0) and 3,4dihydro-2H-pyran are commercially available, and were used as received. 5-Iodo-1-methyl1H-pyrazole was prepared according to described procedures.1 Preparation of organolithium compounds. A commercial solution of t-BuLi in pentane (4.2 mmol, 1.7 M) was diluted with dry THF (10 mL) and cooled to -78 ºC. To the resulting solution was slowly added the corresponding aryl iodide (2.1 mmol) in dry THF (2 mL). The mixture was stirred for 2 hours. Preparation of organoindium compounds. A 50 mL round-bottomed flask with a stir bar and indium (III) chloride (0.7 mmol) was dried under a positive argon pressure with a heat gun. After cooling, dry THF (10 mL) was added. The mixture was added to the previously described solution of the organolithium compound at -78 ºC and stirred for 1 hour, the cooling bath was removed, and the reaction mixture was warmed to room temperature. Procedure for the cross-coupling reaction. One third of the previous solution of (Ar)3In (0.7 mmol) in dry THF was added to a refluxing mixture of the electrophile (2.5 mmol) and Pd(PPh3)4 (0.06 mmol) in dry THF (10 mL). The resulting mixture was refluxed under argon atmosphere overnight, and the reaction quenched by addition of methanol. The mixture was concentrated, and diethyl ether (50 mL) was added. The organic phase was washed with water and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography. 1
Effenberger, F.; Krebs, A. J. Org. Chem. 1984, 49, 4687. S2
Synthesis of 4-iodo-1-(tetrahydro-2H-2-pyranyl)-1H-pyrazole (8). A solution of 4iodopyrazole (3.88 g, 20 mmol) and dihydropyran (2.5 g, 20 mmol) in dichloromethane (150 mL) containing pyridinium toluene-p-sulphonate (0.5g, 2 mmol) was stirred for 24 hours at room temperature. Then, the solution was diluted with ethyl acetate and washed to remove the catalyst. The organic phase was dried and concentrated. The residue was purified by flash column chromatography (hexane: ethyl acetate; 2:1) to afford an oil (4.88g, 88%). 1H NMR (500 MHz, CDCl3) δ 1.61-1.81 (m, 3 H), 1.95-2.05 (m, 3 H), 3.623.76 (m, 1 H), 4.01-4.04 (m, 1 H), 5.37-5.41 (m, 1 H), 7.52 (s, 1 H), 7.68 (s, 1 H);
13
C
NMR (125 MHz, CDCl3) δ 21.9, 24.7, 30.2, 57.0, 67.5, 87.5, 132.1, 144.2; MS (EI) m/z: 278 (M+, 42%), 194 (24), 84 (100). Anal. Calcd for C8H11IN2O: C, 34.55; H, 3.99; N, 10.07. Found: C, 34.24; H, 3.97; N, 9.91 %.
S3
ppm (t1)
ppm (t1) 200
N N
O
131.701 2.00
7.547
100 0.98 5.0
4.045 4.026 4.021 1.07 1.03
66.846 56.576 50
3.06 3.04
S4
86.859
29.627 0.0
24.203 21.457
5.388 5.380 5.372 5.364
0
3.713 3.708 3.693 3.686 3.669 3.663 2.070 2.064 2.056 2.046 2.012 1.694 1.691 1.683 1.675 1.669 1.656 1.618
NMR spectra of 8
7.668
4-iodo-1-(tetrahydro-2H-2-pyranyl)-1H-pyrazole (8)
I
10.0
150 143.447
Spectroscopic and analytical data of new Heterobiaryls
1-methyl-5-(2-thienyl)-1H-pyrazole (4). 1H NMR (500 MHz, CDCl3) δ 3.97 (s, 3 H), 6.38 (d, 1 H, J = 1.9 Hz), 7.09-7.11 (m, 1 H), 7.15 (dd, 1 H, J = 3.6, 1.1 Hz), 7.38 (dd, 1 H, J = 5.2, 1.1 Hz), 7.47 (d, 1 H, J = 1.9 Hz); 13C NMR (125 MHz, CDCl3) δ 37.7, 106.6, 126.4, 126.7, 127.5, 131.2, 136.4, 138.3; MS (EI) m/z: 164 (M+, 100%), 136 (57), 121 (40), 109 (23). Anal. Calcd for C8H8N2S·1/2 H2O: C, 55.47; H, 5.24; N, 16.17; S, 18.51. Found: C, 55.84; H, 4.82; N, 15.90; S, 18.26 %.
4-phenyl-1-(tetrahydro-2H-2-pyranyl)-1H-pyrazole (9). 1H NMR (500 MHz, CDCl3) δ 1.61-1.71 (m, 3 H), 2.03-2.10 (m, 3 H), 3.68-3.73 (m, 1 H), 4.06-4.08 (m, 1 H), 5.37-5.41 (m, 1 H), 7.20-7.23 (m, 1 H), 7.33-7.36 (m, 2 H), 7.48 (d, 2 H, J = 7.5 Hz), 7.82 (s, 1 H), 7.85 (s, 1 H);
13
C NMR (125 MHz, CDCl3) δ 22.2, 24.7, 30.3, 67.6, 87.5, 123.2, 124.3,
125.4, 126.3, 128.6, 132.3, 136.9; MS (EI) m/z: 228 (M+, 27%), 144 (100). Anal. Calcd for C14H16N2O: C, 73.66; H, 7.06; N, 12.27. Found: C, 73.66; H, 7.08; N, 11.95 %.
3-[1-(tetrahydro-2H-2-pyranyl)-1H-4-pyrazolyl]pyridine (10). 1H NMR (500 MHz, CDCl3) δ 1.61-1.72 (m, 3 H), 2.04-2.11 (m, 3 H), 3.69-3.74 (m, 1 H), 4.06-4.08 (m, 1 H), 5.38-5.42 (m, 1 H), 7.17 (m, 1 H), 7.78 (s, 1 H), 7.80 (m, 1 H), 8.15 (s, 1 H), 8.24 (dd, 1 H, J = 5.4, 1.5 Hz), 8.69 (d, 1 H, J = 1.5 Hz); 13C NMR (125 MHz, CDCl3) δ 22.3, 24.9, 30.6, 67.9, 87.9, 123.6, 124.7, 128.5, 132.1, 132.7, 137.1, 147.0, 147.7; MS (EI) m/z: 229 (M+, 77%), 145 (100), 84 (34). Anal. Calcd for C13H15N3O·1/4 H2O: C, 66.79; H, 6.68; N, 17.97. Found: C, 66.62; H, 6.63; N, 17.82 %. S5
1-(tetrahydro-2H-2-pyranyl)-4-(2-thienyl)-1H-pyrazole (11).
1
H NMR (500 MHz,
CDCl3) δ 1.60-1.71 (m, 3 H), 2.02-2.12 (m, 3 H), 3.68-3.73 (m, 1 H), 4.05-4.08 (m, 1 H), 5.37-5.39 (m, 1 H), 6.99-7.01 (m, 1 H), 7.06 (d, 1 H, J = 3.5 Hz), 7.15 (d, 1 H, J = 5.1 Hz), 7.72 (s, 1 H), 7.78 (s, 1 H);
13
C NMR (125 MHz, CDCl3) δ 22.2, 24.8, 30.4, 67.7, 87.6,
117.2, 122.6, 123.0, 124.5, 127.5, 134.7, 137.2; MS (EI) m/z: 234 (M+, 13%), 150 (100). Anal. Calcd for C12H14N2OS·1/2 H2O: C, 59.23; H, 6.21; N, 11.51; S, 13.18. Found: C, 59.61; H, 6.47; N, 11.22; S, 12.91 %.
1-methyl-5-phenyl-1H-pyrazole (12). 1H NMR (500 MHz, CDCl3) δ 3.87 (s, 3 H), 6.29 (d, 1 H, J = 1.8 Hz), 7.38-7.45 (m, 5 H), 7.51 (d, 1 H, J = 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 37.3, 105.9, 128.3, 128.5, 128.6, 130.6, 138.3, 143.4; MS (EI) m/z: 158 (M+, 100%), 130 (33), 115 (26), 103 (27), 77 (20). Anal. Calcd for C10H10N2·1/2 H2O: C, 71.83; H, 6.63; N, 16.75. Found: C, 72.14; H, 6.26; N, 16.34 %.
3-(1-methyl-1H-5-pyrazolyl)pyridine (13). 1H NMR (500 MHz, CDCl3) δ 3.91 (s, 3 H), 6.37 (d, 1 H, J = 1.9 Hz), 7.39-7.41 (m, 1 H), 7.55 (d, 1 H, J = 1.9 Hz), 7.73-7.75 (m, 1 H), 8.65 (dd, 1 H, J = 4.9, 1.6 Hz), 8.70 (d, 1 H, J = 1.6 Hz); 13C NMR (125 MHz, CDCl3) δ 37.4, 106.7, 123.3, 126.7, 135.8, 138.7, 139.9, 149.2, 149.4; MS (EI) m/z: 159 (M+, 100%), 131 (92), 104 (46), 78 (21). Anal. Calcd for C9H9N3·1/2 H2O: C, 64.27; H, 5.99; N, 24.98. Found: C, 64.52; H, 5.58; N, 24.60 %.
S6
2-(1-methyl-1H-5-pyrazolyl)pyridine (14). 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3 H), 6.25 (d, 1 H, J = 1.9 Hz), 6.88-6.91 (m, 1 H), 7.18 (d, 1 H, J = 1.9 Hz), 7.24 (d, 1 H, J = 7.9 Hz), 7.38-7.41 (m, 1 H), 8.33 (d, 1 H, J = 4.8 Hz);
13
C NMR (125 MHz, CDCl3) δ 39.2,
106.3, 122.1, 122.6, 136.5, 137.9, 141.1, 149.0, 149.8; MS (EI) m/z: 159 (M+, 67%), 158 (100), 131 (20), 104 (54), 78 (28). Anal. Calcd for C9H9N3: C, 67.91; H, 5.70; N, 26.40. Found: C, 67.67; H, 5.74; N, 26.81 %.
S7
ppm (t1)
100
S8 37.669
10.0 ppm (t1) 77.255 77.000 76.746
106.631
126.690 126.366
127.497
131.226
136.395
3.10
150
0.96
200
2.00
0.93 0.98 138.322
S 3.967
6.384 6.380
7.114 7.107 7.104 7.097
7.384 7.376 7.374 7.157 7.150
7.471 7.467
NMR spectra of new Heterobiaryls
1-methyl-5-(2-thienyl)-1H-pyrazole (4)
N N
CH3
5.0 0.0
50
0
10.0 ppm (t1)
ppm (t1) 200
N
1.96 1.02 2.00 2.06 1.00 1.06 1.03 77.255 77.000 76.746
3.20
67.567
3.17 50
0.0
24.758 22.179
7.362 7.346 7.331
5.409 5.403 5.390 5.384 4.084 4.064 4.058 3.732 3.727 3.710 3.705 3.687 3.682 2.144 2.139 2.136 2.104 2.097 2.070 2.048 2.040 2.036 2.032 2.024 1.715 1.708 1.695 1.676 1.613 1.607 1.595
4-phenyl-1-(tetrahydro-2H-2-pyranyl)-1H-pyrazole (9)
5.0
100
S9
87.534
30.310
N
O
150 124.296 123.213
7.489 7.475
7.231 7.217
136.915 132.283 128.615 126.280 125.415
7.848 7.826
0
10.0 ppm (t1)
200 ppm (t1)
8.697 8.692 1.00 0.98 0.99
8.156
2.09
N
1.02
150
147.691 147.026 137.062 132.719 132.117
N
128.522 124.716
0.99 5.0
100
5.420 5.412 5.388 5.380
4.060 1.05
77.256 77.002 76.748
1.12
67.866
3.774 3.735 3.728 3.723 3.703 3.690
50
6.10
S 10
87.865
N
O
123.633
7.830 7.824 7.817 7.798 7.790 7.781 7.197 7.181 7.171 7.155
2.114 2.041 1.717
30.609 24.922 22.307
3-[1-(tetrahydro-2H-2-pyranyl)-1H-4-pyrazolyl]pyridine (10)
8.251 8.246 8.235 8.230
0.0
0
ppm (t1)
ppm (t1)
S
10.0
200
2.00 2.94 1.00 5.0
123.020 122.565 117.240
1.05
100
1.15
77.255 77.000 76.746 67.673
3.21 3.45
S 11
87.609
50 0.0
30.399 24.821 22.219
N
O
150 137.163 134.730 127.472 124.468
7.725 7.260 7.170 7.168 7.160 7.073 7.066 7.064 7.020 7.012 7.009 7.002 5.404 5.397 5.386 5.379 4.091 4.071 4.065 3.742 3.737 3.720 3.714 3.698 3.692 2.122 2.112 2.104 2.097 2.051 2.044 2.036 1.728 1.706 1.693 1.686 1.631 1.626
1-(tetrahydro-2H-2-pyranyl)-4-(2-thienyl)-1H-pyrazole (11)
N
7.783
0
10.0 ppm (t1)
200 ppm (f1)
N N
CH3
7.70 ppm (t1)
150
7.512 7.508
7.60
6.01
143.510
7.512
7.50
130.645 128.667 128.587 128.357
7.508
0.97
7.440 7.426
6.01 7.40
7.408
6.298 6.294
7.404 7.394
105.955 7.30
100
5.0 7.20
S 12 77.255 77.000 76.746
3.00
50 37.379
3.877
1-methyl-5-phenyl-1H-pyrazole (12)
138.407
7.440 7.426 7.408 7.404 7.394
0
0.0
10.0 ppm (t1)
ppm (t1)
N
200
8.708 8.704 2.01 1.08 1.02 1.01 0.97
123.349
106.694
7.757 7.753 7.741 7.737 7.734 7.550 7.547 7.418 7.408 7.402 7.393 6.377 6.373
100
5.0 3.00
S 13
77.254 77.000 76.745
50 37.459
3.911
3-(1-methyl-1H-5-pyrazolyl)pyridine (13)
135.782 126.760
N
138.723
N
139.959
CH3
150
149.436 149.246
8.659 8.656 8.649 8.646
0
0.0
10.0 ppm (t1)
ppm (t1) 200
N N
CH3
7.566 7.550
0.94 1.94 1.02 1.10
7.504 7.500
141.081 137.894
0.99
122.628 122.152
7.231 7.221 7.216 7.206
106.291
6.570 6.566
136.526
100
5.0 3.00
S 14
77.255 77.000 76.746
50 39.196
4.220
2-(1-methyl-1H-5-pyrazolyl)pyridine (14)
148.982
N
150
149.791
8.661 8.652 7.724 7.720 7.708 7.705
0
0.0
0.96 3.03
0.97
1.03
1.00
10.0 ppm (t1) 7.021 7.004 6.992
7.763 7.756 7.750 7.737 7.729 7.724 7.254 7.238 7.204 7.188 7.178 7.162
8.414 8.409 8.398 8.393
8.781 8.774
NMR spectra of already known Heterobiaryls 3-(2-thienyl)pyridine (1)
N
S
5.0
S 15 0.0
6.899 6.886 6.882 6.870
7.079 7.061 7.052
[2,2']bithienyl (2)
S S
1.12 2.00
10.0 ppm (t1)
5.0
0.0
S 16
ppm (t1) 10.0
S
2.00 0.98 2.93 2.14
7.139 7.127 7.110
5.0
S 17
2-phenylthiophene (3)
7.714 7.690 7.462 7.436 7.411 7.380 7.365 7.338 7.314 7.297
0.0
10.0 ppm (t1)
N
8.858 8.854 8.602 8.599 8.592 8.589 7.889 7.885 7.882 7.874 7.869 7.595 7.580
0.97 0.96 1.00 6.01 5.0
S 18
3-phenylpyridine (5)
7.501 7.486 7.471 7.426 7.411 7.380 7.370 7.364 7.354
0.0
10.0 ppm (f1)
N 8.870 8.866
N
8.685 8.682 8.676 8.673 7.933 7.928 7.925 7.917 7.913 7.909
1.07 1.00 1.08 1.11 5.0
S 19
[3,3']bipyridinyl (6)
7.463 7.453 7.447 7.437
0.0
10.0 ppm (t1)
8.766 8.757
N
1.00 2.17
N
8.694 8.691 8.684 8.681 8.370 8.366 8.362 8.354 8.350 8.346 7.837 7.834 7.823 7.819 7.800 7.784
0.96 2.03 1.08 1.04 5.0
S 20
7.345 7.343 7.335 7.333 7.330 7.328 7.321 7.318
[2,3']bipyridinyl (7)
7.455 7.446 7.439 7.430
0.0
