Supporting Information For s3

Supporting Information

Experimental and spectroscopic data for:

Green oxidations: Titanium dioxide induced

tandem oxidation coupling reactions

Vineet Jeena and Ross S. Robinson*

Department of Chemistry, University of KwaZulu-Natal, Scottsville,

Pietermaritzburg, 3209, South Africa

[email protected]

General

1H and 13C NMR spectra were obtained using a Bruker Avance 400 operating at either at 400 or 100 MHz using CDCl3 as an internal standard. Data are expressed in parts per million relative to residual solvent. All J values given in Hz.

Low resolution electron impact (EI) mass spectra were recorded on

Thermofinnigan trace GC, coupled with PolarisQ mass spectra. IR spectra were recorded on Perkin-Elmer Spectrum One. Absorption maxima are expressed in wavenumbers (cm−1). Radial chromatography was performed on the Harrison

Research Chromatatron (Model 7924T) with the solvent system delivered by gravity flow using a 1 mm layer of Merck silica gel (7749).

1 The α-hydroxyketone 1b was synthesized from the corresponding methyl ketone using the method described by Moriarty et al. [1] PE refers to petroleum ether with a boiling point range 40–60 °C. Microwave

All microwave reactions were conducted on a CEM Focused MicrowaveTM

Synthesis system which uses an infrared sensor located below the microwave cavity floor to measure temperature.

Temperature/Time Profile for 2-phenylquinoxaline (3a)

2  Reaction temperature and profile was monitored every minute during a

5 min run.

 After the 5 min, the reaction vessel was rapidly cooled to 50 °C by the

instrument.

 Once a temperature of 50 °C was reached, the instrument stopped

cooling and released the residual pressure.

General procedure for the synthesis of quinoxalines (table 2, entries i-vii)

2-Phenylquinoxaline (3a) 2-Hydroxyacetophenone (0.068 g, 0.50 mmol), o- phenylenediamine (0.054 g, 0.50 mmol), TiO2 (0.040 g, 0.50 mmol) and 2,2,6,6-

Tetramethylpiperidine-1-oxyl (TEMPO) (0.008 g, 0.050 mmol) were added to a sealed 10 mL CEM Discover® reaction vial equipped with a magnetic stirrer bar.

The reaction vial was irradiated (at 150 W with cooling) for 10 min (2 x 5 min) at

150 °C, after which the vessel was rapidly cooled to 50 °C by the unit. The reaction mixture was diluted with dichloromethane (DCM) and passed through a short silica plug. The solvent was removed in vacuo to produce a crude product

3 which was purified using radial chromatography (3 : 1 PE : EtOAc) to produce the title compound 3a (0.089 g, 87%) as an orange solid: Rf 0.46 (3 : 1 PE : EtOAc);

−1 1 νmax (neat) 1599, 1541, 1488, 1445, 1305 cm ; H NMR (400 MHz, CDCl3) 7.53–

7.58 (3H, m), 7.78–7.80 (2H, m), 8.16 (2H, m), 8.21 (m, 2H), 9.34 (1H, s); δ C

(100 MHz) 127.5, 127.6, 129.2, 129.6, 129.7, 130.2, 130.4, 136.8, 141.4, 142.4,

143.2, 151.9; m/z (EI) 206 (M+). Data consistent with literature [2].

2-Cyclohexylquinoxaline (3b) Prepared by the procedure given for 3a using 1- cyclohexyl-2-hydroxyethanone 1b [1] (0.106 g, 0.50 mmol) and o- phenylenediamine (0.054 g, 0.50 mmol). Purified using radial chromatography (2:

1 PE : EtOAc) to produce the title compound 3b (0.064 g, 60%) as a brownish

−1 solid: Rf 0.80 (2 : 1 PE : EtOAc); vmax (neat) 1559, 1491, 1449, 1368 cm ;

1 H NMR (400 MHz, CDCl3) δH 1.38–2.07 (10H, m), 2.99 (1H, tt, J = 12.0 Hz J =

3.5 Hz), 7.72 (2H, m); 8.07 (2H, m); 8.78 (1H, s); δC (100 MHz) 25.9, 26.4, 32.3,

45.0, 128.9, 128.9, 129.1, 129.9, 141.4, 142.1, 144.9, 161.1 m/z (EI) 212 (M+).

Data consistent with literature [2].

4 2,3-Diphenylquinoxaline (3c) Prepared using the procedure given for 3a using benzoin (0.106 g, 0.50 mmol) and o-phenylenediamine (0.054 g, 0.50 mmol) but irradiated for 20 min. Purified using radial chromatography (9 : 1 PE : EtOAc) to give the title compound 3c (0.114 g, 81%) as a yellow solid: Rf 0.59 (9 : 1 PE :

−1 1 EtOAc); νmax (neat) 1596, 1514, 1448, 1346 cm ; H NMR (400 MHz, CDCl3) δH

7.34–7.36 (6H, m), 7.52–7.54 (4H, m), 7.78 (2H, m), 8.19 (2H, m); δ C (100 MHz)

128.2, 128.8, 129.2, 129.8, 129.9, 139.1, 141.2, 153.5; m/z (EI) 282 (M+). Data consistent with literature [2].

1,2,3,4-Tetrahydrophenazine (3d) Prepared using the procedure given for 3a using 2-hydroxycyclohexanone dimer (0.057 g, 0.500 mmol) and o- phenylenediamine (0.054 g, 0.50 mmol). Purified using radial chromatography

(1 : 1 PE : EtOAc) to give the title compound 3d (0.810 g, 88%) as a white solid:

−1 Rf 0.54 (1 : 1 PE : EtOAc); νmax (neat) 1459, 1423, 1384, 1330, 1291, 1238 cm ;

1 H NMR (400 MHz, CDCl3) δH 2.04 (4H, m), 3.16 (4H, m), 7.65 (2H, m), 7.97 (2H,

+ m); δC (100 MHz) 22.8, 33.2, 128.3, 128.9, 141.2, 154.1; m/z 184 (M ). Data consistent with literature [3].

N N 3e

2-/3-Phenylpyrido[2,3-b]pyrazine (3e) Prepared using the procedure given for

3a using 2-hydroxyacetophenone and 2,3-diaminopyridine 2b (0.054g,

0.50 mmol) but irradiated for 20 min. Purified using radial chromatography

(EtOAc) to give the title compound 3e (0.087 g, 83%) as a brown solid, as a mixture of regioisomers with 3-phenylpyrido[2,3-b]pyrazine predominating: Rf

−1 1 0.70 (EtOAc); νmax (neat) 1645, 1561, 1457, 1419, 1363, 1327 cm ; H NMR (400

MHz) 3-phenylpyrido[2,3-b]pyrazine δH 7.55–7.60 (3H, m), 7.69 (1H, dd, J = 8.3

Hz, J = 4.2 Hz), 8.32–8.35 (2H, m), 8.48 (1H, dd, J = 8.3 Hz, J = 1.8 Hz), 9.18

(1H, dd, J = 4.1 Hz, J = 1.8 Hz), 9.45 (1H, s); δC (100 MHz) 124.7, 128.0, 129.1,

131.0, 135.7, 136.7, 138.1, 144.3, 150.8, 153.4; 154.4. 2-phenylpyrido[2,3- b]pyrazine δH (400 MHz) 7.53–7.60 ( 3H, m), 7.73 (1H, dd, J = 8.4 Hz, J = 4.2

Hz), 8.21–8.24 (2H, m), 8.51 (1H, dd, J = 8.4 Hz J = 1.8 Hz), 9.17 (1H, dd J = 4.1

Hz J = 1.8 Hz), 9.55 (1H, s); δC (100 MHz) 125.5, 127.6, 129.2, 130.7, 135.8,

137.5, 138.5, 146.2, 150.4, 152.9, 154.6; m/z 207 (M+). Data consistent with literature [2].

6 2,3-Diphenylpyrido[2,3-b]pyrazine (3f) Prepared using the procedure given for

3a using benzoin (0.106g, 0.50mmol) and 2,3-diaminopyridine (0.054 g,

0.50 mmol) but irradiated for 20 min. Purified using radial chromatography (9:1

DCM:EtOAc) to produce the title compound 3f (0.076 g, 54%) as a yellow solid Rf

−1 1 0.30 (9:1 DCM:EtOAc); νmax (neat) 1588, 1545, 1430, 1382, 1328 cm ; H NMR

(400 MHz) δH 7.31–7.41 (6H, m), 7.56 (2H, d, J = 7.8 Hz), 7.64 (2H, d, J = 7.8

Hz), 7.74–7.76 (1H, dd, J = 8.4 Hz J = 4.1 Hz), 8.55–8.57 (1H, d, J = 8.2 Hz),

9.19 (1H, d, J = 4.2 Hz); δC (100 MHz) 125.2, 128.2, 128.5, 129.4, 129.6, 129.8,

130.3, 136.2, 138.0, 138.5, 149.4, 153.6, 155.0, 156.6; m/z 283 (M+). Data consistent with literature [4].

N N 3g

6,7,8,9-Tetrahydropyrido[2,3-b]quinoxaline (3g) Prepared using the procedure given for 3a using 2-hydroxycyclohexanone dimer (0.057 g, 0.50 mmol), 2,3- diaminpyridine (0.054 g, 0.50 mmol) but irradiated for 20 min. Purified using radial chromatography (9:1 DCM: EtOAc) to produce the title compound 3g

(0.052 g, 56%) as a purple solid Rf 0.40 (9:1 DCM:EtOAc); νmax (neat) 2926, 2858,

−1 1 1459, 1425, 1380, 1327, 1261 cm ; H NMR (400 MHz) δH 2.05 (4H, m), 3.22

(2H, m), 3.25 (2H, m), 7.59–7.62 (1H, dd, J = 8.3 Hz J = 4.2 Hz), 8.30–8.33 (1H, dd, J = 8.3 Hz J = 1.6 Hz), 9.05 (1H, dd, J = 3.9 Hz J = 1.5 Hz) δC (100 MHz)

7 22.4, 22.6, 33.1, 33.4, 124.3, 136.1, 137.2, 150.1, 152.8, 155.7, 157.9; m/z 185

(M+). Compound has been previously reported [5].

References:

1. Moriarty, R. M.; Berglund, B. A.; Penmasta, R. Tetrahedron Lett. 1992, 33,

6065–6068. doi:10.1016/S0040-4039(00)60007-2

2. Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Org. Biomol. Chem. 2004, 2,

788–796. doi:10.1039/b315689c

3. Petukhov, P. A.; Tkachev, A. V. Tetrahedron. 1997, 53, 9761–9768.

doi:10.1016/S0040-4020(97)00623-6

4. Mohsenzadeh, F.; Aghapoor, K.; Darabi, H. R. J. Braz. Chem. Soc. 2007,

18, 297–303. doi:10.1590/S0103-50532007000200009.

5. Antoniotti, S.; Duňach, E. Tetrahedron Lett. 2002, 43, 3971–3973.

doi:10.1016/S0040-4039(02)00715-3

8 0 1 7 4 0 7 9 5 8 5 4 4 0 2 3 4 1 6 6 2 8 1 4 2 1 0 0 9 8 8 6 6 5 3 3 0 8 7 8 7 6 6 4 3 3 2 2 1 1 1 7 5 5 5 5 2 2 1 1 1 1 1 8 7 5 5 ...... 9 8 8 8 8 8 8 8 8 8 8 8 8 7 7 7 7 7 7 7 7 7 N

10 9 8 7 ppm

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 ppm 0 9 5 4 5 5 3 8 1 7 2 3 1 6 5 2 9 1 3 4 7 3 2 6 6 0 8 ...... 3 0 6 9 7 7 . N 1 3 2 1 6 0 0 9 9 . . 2 2 2 7 5 4 4 4 3 3 3 2 2 7 6 1 1 1 1 1 1 1 1 1 1 1 1 7 7 7

200 180 160 140 120 100 80 60 40 20 0 ppm

N 6 6 0 7 2 2 3 7 9 2 3 4 1 4 5 3 8 4 3 5 4 2 1 1 4 1 8 6 3 3 0 0 7 7 9 0 0 0 0 9 9 9 9 9 7 7 7 7 5 4 3 ...... 3b ...... 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 6 9 6 8 3 9 5 8 6 3 4 0 4 0 6 0 6 5 4 2 2 1 0 9 7 8 8 7 7 6 6 5 5 4 7 0 0 0 0 0 0 0 0 0 7 7 7 7 7 7 6 ...... 8 8 8 8 8 8 8 8 8 8 7 7 7 7 7 7 7

3.0 2.5 2.0 1.5 ppm

9.0 8.5 8.0 7.5 ppm

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 ppm 6 1 8 7 7 6 4 2 0 9 0 3 8 0 9 9 0 2 8 8 . . . 0 3 8 . . . . . 3 1 4 2 1 9 9 8 8 . . . . 6 4 2 5 2 5 4 4 2 2 2 6

N 1 1 1 1 1 1 1 1 4 3 2 2

200 180 160 140 120 100 80 60 40 20 0 ppm

10 2 3 5 7 9 0 3 4 0 7 7 2 7 0 4 0 5 0 8 7 7 4 3 2 1 5 3 9 8 8 6 2 6 5 2 1 1 1 7 7 7 7 5 5 5 5 5 3 3 3 3 ...... 8 8 8 8 7 7 7 7 7 7 7 7 7 7 7 7 7 N

8.2 8.0 7.8 7.6 7.4 ppm

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 ppm 7 4 0 2 4 1 9 4 4 2 1 9 8 2 7 2 ...... 3 1 9 8 8 N 9 9 9 5 4 3 2 2 2 2 2 1 1 1 1 1 1 1 1

200 180 160 140 120 100 80 60 40 20 0 ppm

11 2 7 9 4 5 8 9 9 1 3 5 5 4 3 8 7 6 5 7 7 6 5 8 4 6 7 9 6 6 5 1 3 9 9 9 9 6 6 6 6 6 4 3 2 ...... 8 6 5 1 0 0 0 N 7 7 7 7 7 7 7 7 7 7 7 1 0 0 ...... 3 3 2 2 2 2 2 N

4.0 3.5 3.0 2.5 2.0 1.5 ppm

8.0 7.5 ppm

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 ppm 4 3 1 4 1 2 9 3 0 0 . . 8 N . . 2 4 1 . 8 8 . 5 4 2 2 3 2 N 1 1 1 1 3 2

200 180 160 140 120 100 80 60 40 20 0 ppm

12 7 4 2 8 2 7 7 0 3 8 2 7 2 7 2 8 1 7 1 8 0 9 0 0 9 9 4 0 6 3 5 2 4 9 7 0 8 6 4 2 2 1 0 3 1 1 8 0 9 6 5 5 8 8 1 9 7 5 3 3 0 7 0 8 5 1 1 5 4 4 3 3 2 2 2 7 7 7 6 6 5 5 5 4 1 1 5 4 4 3 3 2 7 6 6 5

N ...... 9 9 9 9 9 9 8 8 8 8 8 8 8 8 8 8 8 8 8 8 7 7 7 7 7 7 7 7 7 7 7 7

9.5 9.0 8.5 8.0 7.5 ppm

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 ppm 9 6 6 7 6 9 9 2 2 5 5 7 1 6 8 7 6 8 5 9 1 5 5 3 3 8 7 3 1 2 4 0 4 7 8 6 9 6 1 1 9 6 5 6 ...... 4 4 3 2 0 0 6 4 8 8 7 6 5 5 0 0 9 9 7 7 5 4 5 5 5 4 4 3 3 3 3 3 3 2 2 2 5 5 5 3 3 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 ppm

13 0 8 9 0 0 2 8 0 7 0 9 9 2 2 3 4 5 1 2 4 9 8 6 4 6 4 3 2 5 3 7 5 1 9 8 7 6 5 3 1 1 1 5 5 7 7 7 7 6 6 5 5 4 3 3 3 3 3 3 3 ......

N 9 9 8 8 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7

9.5 9.0 8.5 8.0 7.5 7.0 ppm

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 ppm 6 6 8 1 2 6 5 5 9 9 3 7 8 8 9 4 1 3 8 5 4 1 5 5 4 9 3 1 ...... 4 8 6 0 9 9 8 5 6 3 9 7 9 8 5 3 3 3 2 2 2 2 5 5 4 3 2 2

N 1 1 1 1 1 1 1 1 1 1 1 1 1 1

200 180 160 140 120 100 80 60 40 20 0 ppm

14 5 1 1 1 2 3 5 7 5 5 5 0 3 2 1 4 4

N 5 5 4 4 2 2 0 0 2 1 0 9 5 8 6 5 4 0 0 0 3 6 2 0 0 0 3 3 3 6 6 5 1 0 ...... 9 9 9 9 8 8 8 8 7 7 7 7 3 3 2 2 2 N N

9.0 8.5 8.0 7.5 ppm 3.5 3.0 2.5 ppm

9 8 7 6 5 4 3 2 1 0 ppm 6 6 3 0 3 6 6 8 6 8 1 2 0 2 3 7 1 0 ...... 4 0 6 4

N 7 5 2 0 7 6 4 . . . . 5 5 5 5 3 3 2 3 3 2 2 1 1 1 1 1 1 1 3 3 2 2 N N

200 180 160 140 120 100 80 60 40 20 0 ppm