Indium-mediated synthesis of heterobiaryls

Article abstract of DOI:10.1021/jo062638k

The palladium-mediated coupling reaction between triorganoindium reagents and organic electrophiles is extended to the synthesis of heteroaromatic compounds. Both electron-rich and electron-poor heterocycles can act as the organic electrophile or as the organoindium derivative.

Full text of DOI:10.1021/jo062638k

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
fdofdez@umh.es
Table of contents
General procedure for the cross-coupling reaction
S 2
S 3
Synthesis and characterization of compound 8
1
13
H- and C-NMR spectra of compound 8
S 4
Spectroscopic and analytical data of new Heterobiaryls
S 5
1
1
13
H- and C-NMR spectra of new Heterobiaryls
S 8
H-NMR spectra of already known Heterobiaryls
S 15
S 1

General procedure. All reactions were carried out in dried glassware. Tetrahydrofuran
THF) was dried by distillation from sodium and benzophenone. 3-Iodopyridine, 2-
(
iodopyridine, iodobenzene, 2-iodothiophene, 4-iodopyrazole, tert-butyllithium, 2-
thienyllithium, indium (III) choride, tetrakis(triphenylphosphine) palladium (0) and 3,4-
dihydro-2H-pyran are commercially available, and were used as received. 5-Iodo-1-methyl-
1
1
H-pyrazole was prepared according to described procedures.
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)
0.7 mmol) in dry THF was added to a refluxing mixture of the electrophile (2.5 mmol) and
Pd(PPh (0.06 mmol) in dry THF (10 mL). The resulting mixture was refluxed under
3
In
(
3 4
)
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
2 4
washed with water and dried over anhydrous Na SO , filtered, and concentrated. The
residue was purified by flash column chromatography.
1
Effenberger, F.; Krebs, A. J. Org. Chem. 1984, 49, 4687.
S 2

Synthesis of 4-iodo-1-(tetrahydro-2H-2-pyranyl)-1H-pyrazole (8). A solution of 4-
iodopyrazole (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
1
(
4.88g, 88%). H NMR (500 MHz, CDCl
3
) δ 1.61-1.81 (m, 3 H), 1.95-2.05 (m, 3 H), 3.62-
1
3
3
.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); C
NMR (125 MHz, CDCl
3
) δ 21.9, 24.7, 30.2, 57.0, 67.5, 87.5, 132.1, 144.2; MS (EI) m/z:
O: C, 34.55; H, 3.99; N,
+
2
1
78 (M , 42%), 194 (24), 84 (100). Anal. Calcd for C
8
H11IN
2
0.07. Found: C, 34.24; H, 3.97; N, 9.91 %.
S 3

1
1
43.447
31.701
0
0 . 2
9 . 0
7
7
.668
.547
5
5
5
5
.388
.380
.372
.364
8
4
4
4
.045
.026
.021
8
6.859
3
7
0 . 1
0 . 1
3.713
3
3
3
3
.708
.693
.686
.669
6
5
6.846
6.576
6
0 . 3
0 . 3
3.663
2
2
2
2
.070
.064
.056
.046
4
2
9.627
2
.012
2
2
4.203
1.457
1.694
1.691
1
1
1
1
.683
.675
.669
.656
1
.618

Spectroscopic and analytical data of new Heterobiaryls
1
1
-methyl-5-(2-thienyl)-1H-pyrazole (4). H NMR (500 MHz, CDCl
3
) 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 =
1
3
5
3
.2, 1.1 Hz), 7.47 (d, 1 H, J = 1.9 Hz); C NMR (125 MHz, CDCl ) δ 37.7, 106.6, 126.4,
+
1
26.7, 127.5, 131.2, 136.4, 138.3; MS (EI) m/z: 164 (M , 100%), 136 (57), 121 (40), 109
(
23). Anal. Calcd for C
8
H
8
N
2
S·1/2 H
2
O: C, 55.47; H, 5.24; N, 16.17; S, 18.51. Found: C,
5
5.84; H, 4.82; N, 15.90; S, 18.26 %.
1
4
-phenyl-1-(tetrahydro-2H-2-pyranyl)-1H-pyrazole (9). H NMR (500 MHz, CDCl
3
) 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),
13
7
.85 (s, 1 H); C NMR (125 MHz, CDCl
3
) δ 22.2, 24.7, 30.3, 67.6, 87.5, 123.2, 124.3,
+
1
25.4, 126.3, 128.6, 132.3, 136.9; MS (EI) m/z: 228 (M , 27%), 144 (100). Anal. Calcd for
C
14
H
16
N
2
O: C, 73.66; H, 7.06; N, 12.27. Found: C, 73.66; H, 7.08; N, 11.95 %.
1
3
-[1-(tetrahydro-2H-2-pyranyl)-1H-4-pyrazolyl]pyridine (10). H NMR (500 MHz,
CDCl
3
) 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,
1
3
J = 5.4, 1.5 Hz), 8.69 (d, 1 H, J = 1.5 Hz); C NMR (125 MHz, CDCl
3
) δ 22.3, 24.9, 30.6,
+
6
7
7.9, 87.9, 123.6, 124.7, 128.5, 132.1, 132.7, 137.1, 147.0, 147.7; MS (EI) m/z: 229 (M ,
7%), 145 (100), 84 (34). Anal. Calcd for C13
H
15
N
3
O·1/4 H
2
O: C, 66.79; H, 6.68; N, 17.97.
Found: C, 66.62; H, 6.63; N, 17.82 %.
S 5

1
1
-(tetrahydro-2H-2-pyranyl)-4-(2-thienyl)-1H-pyrazole (11). H NMR (500 MHz,
CDCl ) 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),
.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),
3
5
7
1
1
3
.72 (s, 1 H), 7.78 (s, 1 H); C NMR (125 MHz, CDCl
3
) δ 22.2, 24.8, 30.4, 67.7, 87.6,
+
17.2, 122.6, 123.0, 124.5, 127.5, 134.7, 137.2; MS (EI) m/z: 234 (M , 13%), 150 (100).
Anal. Calcd for C12
H
14
N
2
OS·1/2 H
2
O: C, 59.23; H, 6.21; N, 11.51; S, 13.18. Found: C,
5
9.61; H, 6.47; N, 11.22; S, 12.91 %.
1
1
-methyl-5-phenyl-1H-pyrazole (12). H NMR (500 MHz, CDCl
3
) δ 3.87 (s, 3 H), 6.29
1
3
(
d, 1 H, J = 1.8 Hz), 7.38-7.45 (m, 5 H), 7.51 (d, 1 H, J = 1.8 Hz); C NMR (125 MHz,
+
CDCl
3
) δ 37.3, 105.9, 128.3, 128.5, 128.6, 130.6, 138.3, 143.4; MS (EI) m/z: 158 (M ,
1
00%), 130 (33), 115 (26), 103 (27), 77 (20). Anal. Calcd for C10
H
10
N
2
·1/2 H
2
O: C, 71.83;
H, 6.63; N, 16.75. Found: C, 72.14; H, 6.26; N, 16.34 %.
1
3
6
8
3
1
-(1-methyl-1H-5-pyrazolyl)pyridine (13). H NMR (500 MHz, CDCl
3
) δ 3.91 (s, 3 H),
.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),
13
3
.65 (dd, 1 H, J = 4.9, 1.6 Hz), 8.70 (d, 1 H, J = 1.6 Hz); C NMR (125 MHz, CDCl ) δ
+
7.4, 106.7, 123.3, 126.7, 135.8, 138.7, 139.9, 149.2, 149.4; MS (EI) m/z: 159 (M , 100%),
31 (92), 104 (46), 78 (21). Anal. Calcd for C
H
9 9
N
3
2
·1/2 H O: C, 64.27; H, 5.99; N, 24.98.
Found: C, 64.52; H, 5.58; N, 24.60 %.
S 6

1
2
-(1-methyl-1H-5-pyrazolyl)pyridine (14). H NMR (500 MHz, CDCl
3
) 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
1
3
3
Hz), 7.38-7.41 (m, 1 H), 8.33 (d, 1 H, J = 4.8 Hz); C NMR (125 MHz, CDCl ) δ 39.2,
+
1
06.3, 122.1, 122.6, 136.5, 137.9, 141.1, 149.0, 149.8; MS (EI) m/z: 159 (M , 67%), 158
(
9 9 3
100), 131 (20), 104 (54), 78 (28). Anal. Calcd for C H N : C, 67.91; H, 5.70; N, 26.40.
Found: C, 67.67; H, 5.74; N, 26.81 %.
S 7

NMR spectra of new Heterobiaryls
1-methyl-5-(2-thienyl)-1H-pyrazole (4)
N
N
S
CH3
1
0.0
5.0
0.0
ppm (t1)
2
00
150
100
50
0
ppm (t1)
S 8

7
7
.848
.826
6
9 . 1
7
.489
6
0
2
0 . 2
0 . 2
0 . 1
7.475
7
7
7
.362
.346
.331
7
7
.231
.217
1
1
36.915
32.283
5
.409
1
1
28.615
26.280
5.403
5.390
5.384
0
0 . 1
1
1
1
25.415
24.296
23.213
4.084
4
4
.064
.058
6
3
0 . 1
0 . 1
3
.732
3.727
3
3
3
3
.710
.705
.687
.682
8
7.534
7
7
7
7.255
7.000
6.746
2
2
2
.144
.139
.136
0 2 . 3
1 . 3
6
7.567
2
2
2
2
2
2
2
2
.104
.097
.070
.048
.040
.036
.032
.024
7
3
0.310
1
.715
2
2
4.758
2.179
1.708
1.695
1
.676
1
1
1
.613
.607
.595

8
8
.697
.692
8
8
8
.251
.246
.235
0 0 . 1
9
9 . 0
9 . 0
8.230
.156
7.830
8
8
9 0 . 2
7
7
.824
.817
147.691
147.026
137.062
132.719
132.117
2 0 . 1
7.798
.790
7
7.781
7.197
7.181
7
.171
1
1
28.522
24.716
7.155
123.633
5
5
5
5
.420
.412
.388
.380
9 9 . 0
87.865
4
.060
5
0 . 1
1 . 1
3.774
7
7
7
7.256
7.002
6.748
3
3
3
.735
.728
.723
2
67.866
3
3
.703
.690
2
2
.114
.041
0 1 . 6
30.609
1.717
2
4.922
2.307
2

7
7
7
.783
.725
.260
7
7
7
.170
.168
.160
0
0 . 2
9 . 2
7
.073
4
7.066
7
.064
7
.020
1
1
1
1
37.163
34.730
27.472
24.468
7.012
7.009
7
.002
0 0 . 1
5.404
5
5
5
.397
.386
.379
1
1
23.020
22.565
1
17.240
5
0 . 1
1 . 1
4.091
4
4
.071
.065
5
3
3
3
3
.742
.737
.720
.714
8
7.609
7
7
7
6
7.255
7.000
6.746
7.673
1
2 . 3
3.698
3
.692
5 4 . 3
2
2
2
2
.122
.112
.104
.097
2
2
2
1
.051
.044
.036
.728
3
0.399
1.706
1
1
.693
.686
2
2
4.821
2.219
1
1
.631
.626

7
7
.512
.508
1 0 . 6
7.440
.426
7.408
1
1
43.510
38.407
7
7
7
.404
.394
1
1
1
1
30.645
28.667
28.587
28.357
7
.512
7.508
7 9 . 0
1 0 .
6
7.440
6.298
6.294
7
.426
.408
7
7
7
.404
.394
1
05.955
7
7
7
7.255
7.000
6.746
0 0 . 3
3
.877
3
7.379

8
8
.708
.704
8
.659
1
0 . 2
8.656
8
8
.649
.646
7
7
7
7
7
7
7
.757
.753
.741
.737
.734
.550
.547
1
2
0 . 1
0 . 1
1
1
49.436
49.246
8 0 . 1
1
1
1
1
39.959
38.723
35.782
26.760
7
7
7
.418
.408
.402
7 9 . 0
1
23.349
7.393
6
6
.377
.373
1
06.694
7
7
7
7.254
7.000
6.745
0
0 . 3
3
.911
3
7.459

4
9 . 0
8.661
8.652
7.724
7.720
7.708
7.705
2 0 . 1
9 . 1
4
7
7
.566
.550
1
1
49.791
48.982
0 1 . 1
7
7
.504
.500
1
1
1
41.081
37.894
36.526
9 9 . 0
7
7
7
7
.231
.221
.216
.206
1
1
22.628
22.152
6
.570
1
06.291
6.566
7
7
7
7.255
7.000
6.746
0 0 . 3
4.220
3
9.196

NMR spectra of already known Heterobiaryls
3-(2-thienyl)pyridine (1)
N
S
10.0
5.0
0.0
ppm (t1)
S 15

[
2,2']bithienyl (2)
S
S
10.0
5.0
0.0
ppm (t1)
S 16

7
7
7
7
.714
.690
.462
.436
0 0 . 2
4
1 . 2
9 . 2
7.411
3
7.380
7.365
7.338
7.314
7.297
8 9 . 0
7
7
7
.139
.127
.110

8
8
.858
.854
8
8
8
.602
.599
.592
7
6
9 . 0
9 . 0
8.589
7
7
7
7
7
.889
.885
.882
.874
.869
0
1
0 . 1
0 . 6
7
7
.595
.580
7
7
7
.501
.486
.471
7
7
7
7
7
7
.426
.411
.380
.370
.364
.354

8
8
.870
.866
0
7
0 . 1
0 . 1
8.685
8
8
8
.682
.676
.673
8
1
0 . 1
1 . 1
7.933
7
7
7
7
7
.928
.925
.917
.913
.909
7
7
7
7
.463
.453
.447
.437

8
8
.766
.757
8
8
8
8
.694
.691
.684
.681
0 0 . 1
8
8
8
8
8
8
.370
.366
.362
.354
.350
.346
7
1 . 2
9 . 0
6
3 0 . 2
7
7
.837
.834
4
0 . 1
0 . 1
8
7.823
7.819
7.800
7.784
7
7
7
7
.455
.446
.439
.430
7
7
7
7
7
7
7
7
.345
.343
.335
.333
.330
.328
.321
.318