Palladium-Catalyzed Direct Coupling of Azoles with Trialkoxy (aryl)silanes

General Procedure A: Under air atmosphere, a round-bottom flask was charged with Pd(OAc)2 (2.8 mg, 5 mol %), Cu(OAc)2·H2O (0.10 g, 0.50 mmol), and AgF (64 mg, 0.50

168

by using microliter syringes. After the addition of DMF (2.5 mL) the reaction mixture was stirred for 5 min at room temperature and then heated at 120 °C for the given time. After cooling to r.t., the reaction mixture was poured into a saturated aqueous NaCl solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, and the volatile components were evaporated in a rotary evaporator. Purification of the crude product by column chromatography (silica gel, eluent: n-pentane/Et2O = 15:3) yielded the 2-aryl-

azoles 3.

2-Phenylbenzothiazole (3a)

Following General Procedure A, benzothiazole 2 (29 µL, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 9 h to give 3a (49.1 mg, 93 %).

S N

3a

Known compound [CAS Reg. No. 883-93-2]; the NMR spectroscopic data agree with those reported in ref. [S1].1H NMR (CDCl3, 400 MHz): δ = 7.35–7.40 (m, 1 H), 7.46–7.50 (m, 4

H), 7.88–7.91 (m, 1 H), 8.05–8.11 ppm (m, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 121.6,

123.2, 125.2, 126.3, 127.6, 129.0, 131.0, 133.6, 135.1, 154.2, 168.1 ppm; mp 113–113.5 °C.

2-(p-Tolyl)benzothiazole (3b)

Following General Procedure A, benzothiazole 2 (29 µL, 0.25 mmol) reacted with 1b (0.11 mL, 0.50 mmol) for 12 h to afford 3b (48.3 mg, 86 %).

[S1] a) H. Hachiya, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11, 1737-1740; b) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D. Larsen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 3674-3675.

169

S N

3b

Known compound [CAS Reg. No. 16112-21-3]; the 1H NMR spectroscopic data agree with those reported in ref. [S1]. 1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H), 7.28 (d, J = 8.4 Hz,

2 H), 7.34–7.37 (m, 1 H), 7.45–7.48 (m, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 8.04 ppm (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): δ = 21.5, 121.5, 123.0,

125.0, 126.2, 127.5, 129.7, 131.0, 134.9, 141.4, 154.2, 168.2 ppm; mp 70.5–72 °C.

2-(4-Methoxyphenyl)benzothiazole (3c)

Following General Procedure A, benzothiazole 2 (29 µL, 0.25 mmol) reacted with 1c (0.11 mL, 0.50 mmol) for 20 h to produce 3c (50.0 mg, 83 %).

S N MeO

3c

Known compound [CAS Reg. No. 6265-92-5]; the NMR spectroscopic data agree with those reported in ref. [S2]. 1_{H NMR (CDCl} 3, 400 MHz): δ = 3.87 (s, 3 H), 6.99 (d, J = 8.8 Hz, 2 H), 7.31–7.35 (m, 1 H), 7.43–7.47 (m, 1 H), 7.85–7.87 (m, 1 H), 8.00–8.03 ppm (m, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 55.5, 114.4, 121.5, 122.8, 124.8, 126.2, 126.4, 129.1, 134.9, 154.2, 161.9, 167.8 ppm; mp 119–121 °C (ref. [S3]: mp 119–120 °C). 2-(4-(Trifluoromethyl)phenyl)benzothiazole (3d)

Following General Procedure A, benzothiazole 2 (29 µL, 0.25 mmol) reacted with 1d (0.13 g, 0.50 mmol) for 18 h to afford 3d (60.6 mg, 87 %).

[S2] Spectral Database of Organic Compounds (SDBSWeb:

http://riodb01.ibase.aist.go.jp/sdbs/), National Institute of Advanced Industrial Science and Technology (AIST), Japan, 07.04.2010; SDBS No.: 51357.

170

S N F₃C

3d

Known compound [CAS Reg. No. 134384-31-9]; the NMR spectroscopic data agree with those reported in ref. [S1]. 1H NMR (CDCl3, 400 MHz): δ = 7.42 (t, J = 8.2 Hz, 1 H), 7.52 (t,

J = 7.8 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.92 (d, J = 8.4 Hz, 1 H), 8.09 (d, J = 7.2 Hz, 1 H), 8.19 ppm (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 121.7, 123.6, 123.8 (q, 1JC,F

= 272 Hz), 125.8, 126.0 (q, 3JC,F = 3.8 Hz), 126.7, 127.8, 132.5 (q, 2JC,F = 33 Hz), 135.2,

136.8, 154.1, 166.0 ppm; mp 157–159 °C (ref. [S1]: mp 161–162 °C).

2-Phenylbenzoxazole (3e)

Following General Procedure A, benzoxazole (30 mg, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 12 h to give 3e (45.3 mg, 93 %).

O N

3e

Known compound [CAS Reg. No. 833-50-1]; the NMR spectroscopic data agree with those reported in ref. [S4]. 1H NMR (CDCl3, 400 MHz): δ = 7.32–7.36 (m, 2 H), 7.50–7.53 (m, 3

H), 7.56–7.58 (m, 1 H), 7.75–7.78 (m, 1 H), 8.24–8.26 ppm (m, 2 H); 13C NMR (CDCl3, 100

MHz): δ = 110.6, 120.0, 124.6, 125.1, 127.2, 127.6, 128.9, 131.5, 142.1, 150.8, 163.0 ppm; mp 100–102.5 °C.

5-Chloro-2-phenylbenzoxazole (3f)

Following General Procedure A, 5-chloro-benzoxazole (40 mg, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 17 h to furnish 3f (50.9 mg, 89 %).

171

O

N Cl

3f

Known compound [CAS Reg. No. 1019-90-5]; the NMR spectroscopic data agree with those reported in ref. [S4]. 1H NMR (CDCl3, 400 MHz): δ = 7.29–7.33 (m, 1 H), 7.47–7.54 (m, 4

H), 7.73 (s, 1 H), 8.22 ppm (d, J = 6.8 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 111.3,

120.0, 125.4, 126.7, 127.8, 129.0, 130.0, 131.9, 143.3, 149.4, 164.4 ppm; mp 104–104.5 °C.

5-Methyl-2-phenylbenzoxazole (3g)

Following General Procedure A, 5-methyl-benzoxazole (34 mg, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 9 h to furnish 3g (45.9 mg, 88 %).

O N

3g

Known compound [CAS Reg. No. 7420-86-2]; the NMR spectroscopic data agree with those reported in ref. [S4]. 1H NMR (CDCl3, 600 MHz): δ = 2.47 (s, 3 H), 7.14–7.15 (m, 1 H), 7.44

(d, J = 7.8 Hz, 1 H), 7.49–7.52 (m, 3 H), 7.53–7.54 (m, 1 H), 8.22–8.24 ppm (m, 2 H); 13C NMR (CDCl3, 151 MHz): δ = 21.5, 109.9, 119.9, 126.2, 127.3, 127.5, 128.9, 131.4, 134.4,

142.3, 149.0, 163.1 ppm; mp 101.5–103 °C.

5-Methyl-2-(p-tolyl)benzoxazole (3h)

Following General Procedure A, 5-methyl-benzoxazole (34 mg, 0.25 mmol) reacted with 1b (0.11 mL, 0.50 mmol) for 9 h to furnish 3h (45.1 mg, 81 %).

O N

172

Known compound [CAS Reg. No. 16155-94-5]; the NMR spectroscopic data agree with those reported in ref. [S5]. 1H NMR (CDCl3, 400 MHz): δ = 2.42 (s, 3 H), 2.46 (s, 3 H), 7.12 (d, J =

8.4 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0, 1 H), 7.51–7.52 (m, 1 H), 8.11 ppm (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 21.5, 21.6, 109.8, 119.7, 124.5, 126.0,

127.5, 129.6, 134.3, 141.9, 142.3, 148.9, 163.4 ppm; mp 136–137.5 °C.

2-(4-Methoxyphenyl)-5-methylbenzoxazole (3i)

Following General Procedure A, 5-methyl-benzoxazole (34 mg, 0.25 mmol) reacted with 1c (0.11 mL, 0.50 mmol) for 9 h to furnish 3i (50.7 mg, 85 %).

O N MeO

3i

Known compound [CAS Reg. No. 35876-70-1]; 1H NMR (CDCl3, 400 MHz): δ = 2.46 (s, 3

H), 3.87 (s, 3 H), 7.01 (d, J = 8.8 Hz, 2 H), 7.11 (d, J = 9.2 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.50 (s, 1 H), 8.16 ppm (d, J = 8.8 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 21.5, 55.4,

109.7, 114.3, 119.5, 119.8, 125.7, 129.3, 134.2, 142.4, 148.9, 162.2, 163.2 ppm; mp 104.5– 105.5 °C.

2-Phenyloxazole (3j)

Following General Procedure A, oxazole (17 µL, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 8 h to furnish 3j (30.7 mg, 85 %).

O N

3j

[S5] a) L. Ackermann, S. Barfüsser, J. Pospech, Org. Lett. 2010, 12, 724–726; b) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, O. Saidi, J. M. J. Williams, Org. Lett.

173

Known compound [CAS Reg. No. 20662-88-8]; 1H NMR (CDCl3, 400 MHz): δ = 7.22 (s, 1

H), 7.42–7.46 (m, 3 H), 7.69 (t, J = 0.6 Hz, 1 H), 8.02–8.05 ppm (m, 2 H); 13C NMR (CDCl3,

100 MHz): δ = 126.3, 127.5, 128.4, 128.8, 130.3, 138.5, 162.0 ppm.

6-Nitro-2-phenylbenzothiazole (3k)

In analogy to General Procedure A, 6-nitro-benzothiazole (45 mg, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) in the presence of 10 mol-% Pd(OAc)2 for 48 h in 1,4-dioxane

under O2 (1 atm). The crude product was purified by column chromatography (silica gel,

eluent: n-pentane/ethyl acetate/triethylamine in a 15:4:1 ratio) to furnish 3k (37.7 mg, 59 %).

S N

NO₂

3k

Known compound [CAS Reg. No. 38338-23-7]; the NMR spectroscopic data agree with those reported in ref. [S3]. 1H NMR (CDCl3, 400 MHz): 1H NMR (CDCl3, 400 MHz): δ = 7.51–

7.55 (m, 3 H), 8.10–8.14 (m, 3 H), 8.36 (dd, J = 9.0 Hz, J = 2.4 Hz, 1 H), 8.83 ppm (dd, J = 2.4 Hz, J = 0.4 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): δ = 118.2, 121.9, 123.3, 127.9, 129.3,

132.2, 132.7, 135.3, 144.9, 157.8, 173.8 ppm.; mp 177.5–180 °C

2-Phenylthiazole (3l) and 2,2’-bithiazole

Following General Procedure A, thiazole (18 µL, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 8 h to furnish 3l (20.5 mg, 51 %) and 2,2’-bithiazole (4.6 mg, 22 %).

S N 3l S N S N 2,2'-bithiazole

3l: Known compound [CAS Reg. No. 1826-11-5]; 1H NMR (CDCl3, 400 MHz): δ = 7.31 (d, J

= 3.2 Hz, 1 H), 7.40–7.45 (m, 3 H), 7.85 (d, J = 3.2 Hz, 1 H), 7.94–7.97 ppm (m, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 118.8, 126.6, 128.9, 130.0, 133.6, 143.7, 168.4 ppm.

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2,2’-bithiazole: Known compound [CAS Reg. No. 13816-21-2]; 1H NMR (CDCl3, 400 MHz):

δ = 7.42 (d, J = 3.2 Hz, 2 H), 7.88 ppm (d, J = 3.2 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): δ =

120.9, 143.9, 161.7 ppm; mp 99–101.5 °C.

1-Methyl-2-phenyl-benzimidazole (3m)

Following General Procedure A, 1-methyl-benzimidazole (33 mg, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) in the presence of 10 mol-% Pd(OAc)2 for 20 h under O2 (1 atm ).

The crude product was purified by column chromatography (silica gel, eluent: n-pentane/ethyl acetate/triethylamine in a 15:4:1 ratio) to furnish 3m (42.1 mg, 81 %).

N N

3m

Known compound [CAS Reg. No. 2622-63-1]; the 13C NMR spectroscopic data agree with those reported in ref. [S6]. 1H NMR (CDCl3, 400 MHz): δ = 3.86 (s, 3 H), 7.28–7.34 (m, 2 H),

7.38–7.40 (m, 1 H), 7.50–7.53 (m, 3 H), 7.75–7.77 (m, 2 H), 7.82–7.84 ppm (m, 1 H); 13_C

NMR (CDCl3, 100 MHz): δ = 31.7, 109.6, 119.8, 122.5, 122.8, 128.2, 128.7, 129.5, 129.8,

136.5, 142.8, 153.7 ppm.

8-Phenyl-caffeine (5) = 3,7-dihydro-1,3,7-trimethyl-8-phenyl-1H-purine-2,6-dione

Following General Procedure A, caffeine 4 (49 mg, 0.25 mmol) reacted with 1a (0.12 mL, 0.50 mmol) for 9 h. The crude product was purified by column chromatography (silica gel, eluent: n-pentane/ethyl acetate/triethylamine in a 15:4:1 ratio) to afford 5 (41.8 mg, 62 %).

[S6] Spectral Database of Organic Compounds (SDBSWeb:

http://riodb01.ibase.aist.go.jp/sdbs/), National Institute of Advanced Industrial Science and Technology (AIST), Japan, 07.04.2010; SDBS No.: 22471.

175 N N N N Me _O O Me Me 5

Known compound [CAS Reg. No. 6439-88-9]; the NMR spectroscopic data agree with those reported in ref. [S7]. 1_{H NMR (CDCl}

3, 400 MHz): δ = 3.42 (s, 3 H), 3.62 (s, 3 H), 4.04 (s, 3

H), 7.50–7.52 (m, 3 H), 7.66–7.68 ppm (m, 2 H); 13C NMR (CDCl3, 100 MHz): δ = 28.0,

29.8, 33.9, 108.5, 128.4, 128.9, 129.2, 130.4, 148.3, 151.7, 152.1, 155.6 ppm; mp 178.6– 179.5 °C (ref. [S7b]: mp 180–181 °C).

Details of the crystal structure determination of 5 are reported in Chapter 4.5.5.

4.5.4 Palladium-Catalyzed Direct Coupling of Azoles with Allyl-