amide bond formation via c(sp3)−h activation and co insertion · amide bond formation via...

Supporting information for:

Amide bond formation via C(sp3)−H activation and CO insertion

Huizhen Liu, Gabor Laurenczy, Ning Yan and Paul J. Dyson*

Institut des Sciences et In -1015 Lausanne,

Switzerland

CONTENTS

1 General experimental details

2 Catalytic procedures

3 Product characterization

4 Mechanistic studies

4.1 Influence of aniline concentration

4.2 Radical scavenger studies (reaction in the presence of TEMPO)

4.3 Reaction in the absence of an oxidant (DTBP)

4.4 Reactions in the absence of a catalyst and co-catalyst

4.5 Kinetic isotope effect studies

4.6 ESI-MS of the reaction

5 NMR spectra

1 General experimental details

PdCl2, Pd2(dba)3, Pd(Ph3P)4, DTBP, Ag2O, H2O2 and K2S2O8 were purchased from Alfa Aesar. Xantphos,

triphos, PPh3, Dppe, Dppf, Nixantphos, (±)-Binapo, (R)-Phanephos, 2,2,6,6-tetramethylpiperidine-1-oxyl

(TEMPO), toluene-d8, methanol-d4 and DMSO-d6 were purchased from Aldrich. Tri(o-anisyl)phosphine

was purchased from Alfa Aesar and 1,2-bis(diphenylphosphino)benzene was purchased from Acros. All

other solvents and reagents were purchased from Alfa Aesar. All chemicals were used as received without

further purification. Purification of the products was conducted with technical grade solvents and silica

gel. GC was performed on an Agilent 7890 equipped with a HP-5 column. NMR spectra were recorded at

293 K on a Bruker DMX 400 instrument with TMS as internal standard in methanol-d4. High resolution

mass spectrometry was recorded on a Micromass Q-TOF Ultima API (ESI). Infrared spectra were

recorded on a JASCO FT/IR-4100 spectrometer with MIRacle ATR and a diamond/ZnSe crystal plate

and are reported as cm-1

.

2 Catalytic procedures

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2013

A mixture of PdCl2 (8.8 mg, 0.05 mmol), ligand (0.06 mmol), alkane (15 ml), aniline (1.0 mmol) and

DTBP (di-t-butyl peroxide, 1.2 mmol) was added to a teflon tube that was placed in an autoclave. The

autoclave was purged and charged with CO (50 atm). The reaction mixture was stirred at a required

temperature for 24 h. After cooling the CO was released and the reaction mixture was purified by flash

column chromatography on silica gel to afford the desired product. The yield of the product was

determined by weighing the quality of isolated product or by GC analysis.

3 Product characterization

N,2-diphenylacetamide mp: 115-116oC; IR: 3285, 3061, 2394, 1642, 1596, 1547, 1496, 1465, 1432, 1413,

746, 723, 690; 1H NMR (400 MHz, methanol-d4): δ= 7.56-7.54 (d, 2H), 7.41-7.23 (m, 7H), 7.08 (t, J=

7.4Hz, 1H), 3.69 (s, 2H); 13

C NMR (101 MHz, methanol-d4): δ= 170.90, 138.42, 135.43, 128.72, 128.36,

128.17, 126.52, 123.89, 119.97, 43.29; HRMS (ESI): calculated for C14H13NO [M+H]+ 212.1077, found

212.1075

N,2-diphenylpropanamide mp: 121-122oC; IR: 3254, 1659, 1595, 1541, 1492, 1440, 1371, 1297, 1247,

1202, 1179, 1068, 1028, 935, 902, 748, 717, 693; 1H NMR (400 MHz, methanol-d4): δ= 7.54-7.52 (d, J=

7.6Hz 2H), 7.43-7.41 (d, J= 7.8 Hz, 2H), 7.36-7.23 (m, 5H), 7.10-7.06 (m, 1H), 3.83 (q, J= 7.0Hz, 1H),

1.52 (d, J= 7.0Hz, 3H); 13

C NMR (101 MHz, methanol-d4): δ= 173.94, 141.57, 138.49, 128.33, 122.0,

126.99, 126.63, 123.78, 119.97, 46.78, 17.77; HRMS (ESI): calculated for C15H15NO [M+H]+ 226.1233,

found 226.1232

N,3-diphenylpropanamide mp: 95-96oC; IR: 3321, 3027, 2922, 2857, 1650, 1599, 1525, 1493, 1453, 1440,

1357, 1314, 1243, 1207, 1176, 1139, 1078, 1023, 1001, 968, 907, 750, 697; 1H NMR (400 MHz,

Methanol-d4): δ= 7.52-7.50 (d, J= 9.6 Hz, 2H), 7.32-7.19 (m, 7H), 7.11-7.07 (t, J= 7.4 Hz, 1H), 3.01 (t,

J= 7.7 Hz, 2H), 2.67 (t, 2H). 13

C NMR (101 MHz, methanol-d4): δ= 172.24, 140.75, 138.33, 128.35,

128.10, 128.00, 125.83, 123.81, 119.98, 38.43, 31.43; HRMS (ESI): calculated for C15H15NO [M+H]+

226.1233, found 226.1232


N-Phenylcyclohexanecarboxamide mp: 136–137°C; IR: 3242, 2918, 2849, 2387, 1638, 1596, 1417, 754,

691; 1H NMR (400 MHz, methanol-d4): δ= 7.59-7.50 (d, 2H), 7.30 (t, J= 8.0Hz 2H), 7.08 (t, J= 7.4Hz,

1H), 2.46-2.30 (m, 1H), 1.93-1.82 (m, 5H), 1.64-1.16 (m, 5H); 13

C NMR (101 MHz, methanol-d4):

δ= 176.27,138.62, 128.30, 123.61, 119.92, 45.76, 29.30, 25.55, 25.40; HRMS (ESI): calculated for

C13H17NO [M+H]+ 204.1390, found 204.1388

2-(4-fluorophenyl)-N-phenylacetamide mp: 126-127oC; IR: 3287, 2043, 1642, 1596, 1546, 1487, 1411,

1221, 754, 691; 1H NMR (400 MHz, methanol-d4): δ= 7.57-7.53 (d, 2H), 7.43-7.26 (m,4H), 7.15-7.02 (m,

3H), 3.68 (s, 2H); 13

C NMR (101 MHz, methanol-d4): δ=170.67,163.20, 160.76, 138.39, 131.40, 131.37,

130.55, 130.47, 128.39, 123.91, 119.91, 114.86, 114.65, 42.27; HRMS (ESI): calculated for C14H12FNO

[M+H]+ 230.0983, found 230.0981

2-(4-chlorophenyl)-N-phenylacetamide mp:164-165oC; IR: 3288, 2918, 1664, 1596, 1528, 1491, 1441,

1407, 1343, 1307, 1190, 1093, 1015, 963, 756, 737, 690; 1H NMR (400 MHz, methanol-d4): δ= 7.57-7.54

(m, 2H), 7.37-7.29 (m,6H), 7.12-7.09 (t, J= 7.4 Hz, 1H), 3.68 (s, 2H); 13


δ=170.32, 138.35, 134.22, 132.39, 130.44, 128.39, 123.94, 119.90, 42.39; HRMS (ESI): calculated for

C14H12ClNO [M+H]+ 246.086, found 246.0686

N-(3-nitrophenyl)-2-phenylacetamide mp: 130-131oC; IR: 3241, 3189, 2921, 1652, 1605, 1529, 1494,

1433, 1345, 1261, 801, 733, 682; 1H NMR (400 MHz, methanol-d4): δ= 8.63 (s, 1H), 7.98-7.90 (dd, J=

9.0Hz, 2H), 7.58-7.54 (t, J= 8.3 Hz, 1H), 7.41-7.21 (m, 5H), 3.74 (s, 2H); 13

C NMR (101 MHz, methanol-

d4): δ= 171.25, 148.39, 139.88, 134.96, 129.45, 128.76, 128.23, 126.67, 125.07, 118.02, 114.00, 43.29;

HRMS (ESI): calculated for C14H12N2O3 [M+H]+ 257.0928, found 257.0926

N-(3-cyanophenyl)-2-phenylacetamide mp: 156-157oC; IR: 3319, 2236, 1685, 1590, 1547, 1424, 1125,

893, 791, 692, 679, 658; 1H NMR (400 MHz, methanol-d4): δ= 8.07-8.06 (d, J= 1.6Hz, 1H), 7.82-7.79 (d,

J= 9.6Hz, 1H), 7.51-7.43 (m, 2H), 7.36-7.28 (m, 5H), 3.72 (s, 2H); 13

C NMR (101 MHz, methanol-d4): δ=


171.25, 148.39, 139.88, 134.96, 129.45, 128.76, 128.23, 126.67, 125.07, 118.02, 114.00, 43.29; HRMS

(ESI): calculated for C15H12N2O [M+H]+ 237.103, found 237.1028

N-(4-cyanophenyl)-2-phenylacetamide mp: 168-169oC; IR: 3326, 2226, 1680, 1593, 1517, 1502, 1495,

1432, 1377, 1170, 858, 731; 1H NMR (400 MHz, methanol-d4): δ= 7.70-7.78 (d, J= 9.0Hz, 2H), 7.68-7.66

(d, J= 9.0Hz, 2H), 7.36-7.27 (m, 5H), 3.73 (s, 2H); 13

C NMR (101 MHz, methanol-d4): δ= 171.24, 143.01,

134.93, 132.81, 128.74, 128.23, 126.67, 119.53, 118.38, 106.28, 43.35; HRMS (ESI): calculated for

C15H12N2O [M+H]+ 237.103, found 237.1026

N-(3-fluorophenyl)-2-phenylacetamide mp: 107-108oC; IR: 3257, 1657, 1602, 1545, 1489, 1441, 1412,

1351, 1199, 853, 771, 709, 691, 674; 1H NMR (400 MHz, methanol-d4): δ= 7.55-7.53 (d, J= 11.1Hz,

1H), 7.36-7.24 (m, 7H), 6.84-6.80 (m, 1H), 3.69 (s, 2H); 13

C NMR (101 MHz, methanol-d4): δ= 171.02,

164.07, 161.65, 140.21, 135.17, 129.79, 129.70, 128.75, 128.21, 126.59, 115.05, 110.21, 110.00, 106.85,

106.59, 43.30; HRMS (ESI): calculated for C14H12FNO [M+H]+ 230.0983, found 230.0981

N-(4-fluorophenyl)-2-phenylacetamide mp: 140-141oC; IR: 3256, 1650, 1615, 1546, 1496, 1405, 837, 828,

799, 722, 696; 1H NMR (400 MHz, methanol-d4): δ= 7.57-7.54 (d, J= 8.0 Hz, 2H), 7.40-7.36 (m,2H),

7.33-7.29 (m, 2H), 7.12-7.05(m, 3H), 3.68 (s, 2H); 13

C NMR (101 MHz, methanol-d4): δ= 170.88, 160.55,

158.11, 135.34, 134.62, 128.72, 128.20, 126.57, 121.83, 121.75, 114.95, 114.72, 43.18; HRMS (ESI):

calculated for C14H12FNO [M+H]+ 230.0983, found 230.0981

N-(3-chlorophenyl)-2-phenylacetamide mp: 97-98oC; IR: 3247, 1654, 1588, 1524, 1479, 1404, 1345,

1286, 865, 773, 722, 696, 676; 1H NMR (400 MHz, methanol-d4): δ= 7.57-7.54 (d, J=8.0 Hz, 2H), 7.40-

7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.12-7.05(m, 3H), 3.68 (s, 2H); 13


170.88, 160.55, 158.11, 135.34, 134.62, 128.72, 128.20, 126.57, 121.83, 121.75, 114.95, 114.72, 43.18;

HRMS (ESI): calculated for C14H12ClNO [M+H]+246.0687, found 246.0686


N-(4-chlorophenyl)-2-phenylacetamide mp: 165-166oC; IR: 3285, 3028, 2918, 2465, 2394, 1647, 1491,

1392, 1316, 1092, 1009, 961, 826, 803, 715, 699; 1H NMR (400 MHz, methanol-d4): δ= 7.57-7.54 (d, J=

8.0 Hz, 2H), 7.40-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.12-7.05(m, 3H), 3.68 (s, 2H); 13

C NMR (101 MHz,

methanol-d4): δ= 170.86, 137.29, 135.24, 128.73, 128.65, 128.35, 128.19, 126.59, 121.17, 43.27; HRMS

(ESI): calculated for C14H12ClNO [M+H]+ 246.0687, found 246.0686

2-phenyl-N-(m-tolyl)acetamide mp: 92-93oC; IR: 3262, 3029, 2918, 1648, 1611, 1590, 1532, 1496, 1452,

1409, 1342, 1285, 1265, 1225, 1195, 968, 768, 688; 1H NMR (400 MHz, methanol-d4): δ= 7.39-7.15 (m,

7H), 6.93-6.92 (d, J= 7.5Hz, 2H), 3.68 (s, 2H), 2.32 (s, 1H); 13

C NMR (101 MHz, methanol-d4):δ= 170.87,

138.34, 138.29, 135.47, 128.71, 128.22, 128.17, 126.52, 124.63, 120.52, 117.08, 43.30, 20.12; HRMS

(ESI): calculated for C15H15NO [M+H]+ 226.1234, found 226.1224

2-phenyl-N-(P-tolyl)acetamide mp: 133-134oC; IR: 3297, 1654, 1603, 1535, 1513, 1492, 1454, 1405,

1334, 1307, 1259, 818, 707; 1H NMR (400 MHz, methanol-d4): δ= 7.44-7.10 (m, 9H), 3.66 (s, 2H), 2.29

(s,3H); 13

C NMR (101 MHz, methanol-d4): δ= 170.80, 135.81, 135.51, 133.63, 128.83, 128.71, 128.16,

126.51, 120.03, 43.25, 19.49; HRMS (ESI): calculated for C15H15NO [M+H]+ 226.1234, found 226.1224

N-(3-methoxyphenyl)-2-phenylacetamide mp: 89-90oC ;

1H NMR (400 MHz, Methanol-d4): δ= 7.41 –

7.03 (m, 8H), 6.66 (d, 1H), 3.78 (s, 3H), 3.68 (s, 2H); 13

C NMR (101 MHz, methanol-d4): 170.70, 156.59,

135.55, 131.35, 128.69, 128.17, 126.51, 121.73, 113.53, 54.44, 43.14; HRMS (ESI): calculated for

C15H15NO2 [M+H]+ 242.1181, found 242.1175


N-(4-methoxyphenyl)-2-phenylacetamide mp: 128-129oC;

1H NMR (400 MHz, Methanol-d4): δ= 7.57 –

7.02 (m, 7H), 6.88 (d, J = 9.1 Hz, 2H), 3.78 (s, 3H), 3.66 (s, 2H); 13


170.94, 160.10, 139.58, 135.39, 129.11, 128.73, 128.18, 126.54, 112.01, 109.44, 105.65, 54.25, 43.35;

HRMS (ESI): calculated for C15H15NO2 [M+H]+ 242.1181, found 242.1184

N-(3,5-bis(trifluoromethyl)phenyl)-2-phenylacetamide mp: 130-131oC;

1H NMR (400 MHz, Methanol-

d4): δ= 8.23 (s, 2H), 7.65 (s, 1H), 7.41 – 7.25 (m, 3H), 3.75 (s, 1H).; 13


δ= 170.94, 160.10, 139.58, 135.39, 129.11, 128.73, 128.18, 126.54, 112.01, 109.44, 105.65, 54.25, 43.35;

HRMS (ESI): calculated for C16H11F6NO [M+H]+ 348.0823, found 348.0820

1,3-diphenylurea mp: 168-169oC; IR: 3298, 2928, 1647, 1594, 1540, 1493, 1439, 1390, 1296, 1231, 1202,

1177, 1156, 1027, 893, 750, 693; 1H NMR (400 MHz, DMSO-d6 : δ= 8.67 (s, NH, 2H), 7.46-7.44 (d, J=

8.4Hz, 4H), 7.30-7.26 (t, J= 7.7Hz, 4H), 6.99-6.95 (t, J= 7.0Hz, 2H); 13

C NMR (101 MHz, DMSO-d6):

δ= 154.19, 139.08, 128.45, 122.44, 119.01; HRMS (ESI): calculated for C13H12N2O [M+H]+ 223.0983,

found 223.0987

4 Mechanistic studies

4.1 Influence of aniline concentration

A mixture of PdCl2 (8.8 mg, 0.05 mmol), Xantphos (34.7 mg, 0.12 mmol), toluene, the appropriate amine

(1.0 mmol) and DTBP (1.2mmol) was added to a teflon tube that was placed in an autoclave. The

concentration of aniline was modified by varying the amount of toluene used. The autoclave was purged

and charged with CO (50 atm). The reaction mixture was stirred at 125oC for 24 h. After reaction the

system was cooled and the CO released. The yield of the product(s) was determined by GC analysis with

n-decane as an internal standard.

Table S1. Influence of aniline concentration.


Entry The concentration of aniline

(mol/L) Yield of 3

a (%) Yield of 4

a (%)

1 0.5 28 63

2 0.2 48 40

3 0.1 62 32

4 0.07 66 21

5 0.05 53 18

Reaction conditions: aniline (1 mmol), PdCl2 (5 mol% based on aniline), Xantphos (120 mol % based on PdCl2), Oxidant

(120 mol% based on aniline), CO (50 atm), 24 h, aYields were determined by GC analysis relative to the aniline with n-decane

as internal standard.

4.2 Radical scavenger studies (reaction in the presence of TEMPO)

A mixture of PdCl2 (8.8 mg, 0.05 mmol), Xantphos (34.7 mg, 0.012 mmol), toluene (15 ml), aniline (1.0

mmol), DTBP (1.2 mmol) and TEMPO (156 mg, 1.0 mmol) was added into a teflon tube which was

placed in an autoclave. The autoclave was purged and charged with CO (50 atm). The reaction mixture

was stirred at 125oC for 24 h. After cooling the CO was released and the reaction mixture analyzed (no

desired product was observed).

4.3 Reaction in the absence of an oxidant (DTBP)

A mixture of PdCl2 (8.8 mg, 0.005 mmol), toluene (15 ml), aniline (1 mmol), was added to a teflon tube

which was placed in an autoclave. Then the autoclave was purged and charged with CO (50 atm). The

reaction mixture was stirred at 125oC for 24 h. The system as cooled and the CO released and the reaction

mixture analyzed, no desired product was observed.

4.4 Reactions in the absence of a catalyst and co-catalyst

A mixture of toluene (15 ml), aniline (1.0 mmol) and DTBP (1.2 mmol) was added to a teflon tube which

was placed in an autoclave. The autoclave was purged and charged with CO (50 atm). The reaction

mixture was stirred at 125oC for 24 h. After cooling the CO was released and the reaction mixture

analyzed. 1,2-diphenylethane was obtained in 13% yield based on DTBP (presumably as result of

homocoupling of benzyl radicals).

4.5 Kinetic isotope effect studies


A mixture of PdCl2 (8.8 mg, 0.005 mmol), Xantphos (34.7 mg, 0.006 mmol), toluene (7.5 ml), aniline

(1.0 mmol) and DTBP (1.2 mmol) was added to a teflon tube which was placed in an autoclave. The

autoclave was purged and charged with CO (50 atm). The reaction mixture was stirred at 125oC for 2 h,

cooled, and the CO released. The reaction mixture was analyzed by GC with n-decane used as the internal

standard. The desired product was obtained in 18% yield.

A mixture of PdCl2 (8.8 mg, 0.005 mmol), Xantphos (34.7 mg, 0.006 mmol), toluene-d8 (7.5 ml), aniline

(1.0 mmol) and DTBP (1.2mmol) was added to a teflon tube which was placed in an autoclave. The

autoclave was purged and charged with CO to 50 atm. The reaction mixture was stirred at 125oC for 2 h,

then cooled, and the CO released. The reaction mixture was analyzed by GC with n-decane as an internal

standard. The desired product was obtained in 7% yield.

4.6 ESI-MS of the reaction

ESI-MS/MS spectra were recorded on BrukerMicroTOF-QII mass equipped with a standard ESI ion

source. The basic ESI conditions were: vacuum, 3.7×10-7

mbar; Capillary voltage, 4500 V; Dry Heater

temperature, 180oC. Data acquisition and analysis were done with the Bruker Daltonicsmicro TOF control

(version3.0) software package.

Following a standard catalytic run for 2 h the reaction mixture was diluted with methanol and analyzed by

ESI-MS. A peak at 775.2 was observed that corresponds to the species [(Xantphos)PdCH2Ph]+.

Figure 1. The peak envelope in the ESI–MS a) assigned to [(Xantphos)PdCH2Ph]+; b) shows the

theoretical spectrum.

770 772 774 776 778 780 782 784

773.2

774.2

775.2

776.2

777.2

778.2

779.2

a)

770 772 774 776 778 780 782 784

774.15

775.15

776.15

777.15

778.15

779.15773.15

b)


5 NMR spectra

1H NMR of N, 2-diphenylacetamide


13C NMR of N, 2-diphenylacetamide


1H NMR of N, 2-diphenylpropanamide


13C NMR of N, 2-diphenylpropanamide


1H NMR of N, 3-diphenylpropanamide


13C NMR of N, 3-diphenylpropanamide


1H NMR of N-phenylcyclohexanecarboxamide


13C NMR of N-phenylcyclohexanecarboxamide


1H NMR of 2-(4-fluorophenyl)-N-phenylacetamide


13C NMR of 2-(4-fluorophenyl)-N-phenylacetamide


1H NMR of 2-(4-chlorophenl)-N-phenylacetamide


13C NMR of 2-(4-chlorophenl)-N-phenylacetamide


1H NMR of N-(3-nitrophenyl)-2-phenylacetamide


13C NMR of N-(3-nitrophenyl)-2-phenylacetamide


1H NMR of N-(3-cyanophenyl)-2-phenylacetamide


13C NMR of N-(3-cyanophenyl)-2-phenylacetamide


1H NMR of N-(4-cyanophenyl)-2-phenylacetamide


13C NMR of N-(4-cyanophenyl)-2-phenylacetamide


1H NMR of N-(3-fluorophenyl)-2-phenylacetamide


13C NMR of N-(3-fluorophenyl)-2-phenylacetamide


1H NMR of N-(4-fluorophenyl)-2-phenylaceamide


13C NMR of N-(4-fluorophenyl)-2-phenylaceamide


1H NMR of N-(3-chlorophenyl)-2-phenylacetamide


13C NMR of N-(3-chlorophenyl)-2-phenylacetamide


1H NMR of N-(4-chlorophenyl)-2-phenylacetamide


13C NMR of N-(4-chlorophenyl)-2-phenylacetamide


1H NMR of 2-phenyl-N-(m-tolyl)acetamide


13C NMR of 2-phenyl-N-(m-tolyl)acetamide


1H NMR of 2-phenyl-N-(p-tolyl)acetamide


13C NMR of 2-phenyl-N-(p-tolyl)acetamide


1H NMR of N-(3-methoxyphenyl)-2-phenylacetamide


13C NMR of N-(3-methoxyphenyl)-2-phenylacetamide


1H NMR of N-(4-methoxyphenyl)-2-phenylacetamide


13C NMR of N-(4-methoxyphenyl)-2-phenylacetamide


1H NMR of N-(3,5-bis(trifluoromethyl)phenyl)-2-phenylacetamide


13C NMR of N-(3,5-bis(trifluoromethyl)phenyl)-2-phenylacetamide


1H NMR of 1, 3-diphenylurea


13C NMR of 1, 3-diphenylurea


amide bond formation via c(sp3)−h activation and co insertion · amide bond formation via...

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