supporting information merging visible-light photoredox ... · for the functionalization and...

Supporting Information

Merging Visible-Light Photoredox and Lewis Acid Catalysis

for the Functionalization and Arylation of Glycine Derivatives

and Peptides

Shaoqun Zhu and Magnus Rueping* Institute of Organic Chemistry, RWTH Aachen University

Landoltweg 1, 52074 Aachen, Germany

General: Unless otherwise noted, all commercially available compounds were used as

provided without further purification. Solvents used in reactions were p.A. grade and dried

only if indicated. Solvents for chromatography were technical grade and distilled prior to use.

Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminium

plates with F-254 indicator, visualised by irradiation with UV light. Column chromatography

was performed using silica gel Merck 60 (particle size 0.063 – 0.2 mm). Solvent mixtures are

understood as volume/volume.

1H-NMR and 13C-NMR were recorded on a Varian VNMR 400 and VNMR 600 spectrometer

in CDCl3. Data are reported in the following order: chemical shift (δ) in ppm; multiplicities

are indicated br (broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet), quint

(quintet), m (multiplet); coupling constants (J) are in Hertz (Hz). Mass spectra (MS-EI, 70

eV) were conducted on a Finnigan SSQ 7000 spectrometer. IR spectra were recorded on a

Perkin Elmer Spectrum 100 FT-IR spectrometer and are reported in terms of frequency of

absorption (cm-1). Glycine ester and glycine derived dipeptides were prepared according to

the literature reports.1-3

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012

General Procedure for the Photoredox Catalyzed Functionalization of Glycine Esters.

In a vial [Ir(ppy)2bpy]PF6 (0.002 mmol), glycine ester 1 (0.2 mmol), Zn(OAc)2 (0.02 mmol)

and indole 2 (0.3 mmol) were dissolved in the solvent indicated and the reaction mixture was

stirred for the time indicated under irradiation with the light source as indicated (fluorescent

bulb Osram Dulux S 11W, distance app. 5cm). The reaction was monitored via TLC

(hexanes: ethyl acetate). Upon consumption of the starting material, the crude mixture was

purified by column chromatography (hexanes: ethyl acetate) to yield the corresponding

products 3a-y.

General Procedure for the Photoredox Catalyzed Functionalization of Dipeptides.

In a vial [Ir(ppy)2bpy]PF6 (0.002 mmol), dipeptide 5 (0.2 mmol), Zn(OAc)2 (0.2 mmol) and

indole 2 (0.3 mmol) were dissolved in MeCN (2 mL) and the reaction mixture was stirred for

the time indicated under irradiation with the light source as indicated (fluorescent bulb Osram

Dulux S 11W, distance app. 5cm). The reaction was monitored via TLC (hexanes: ethyl

acetate). Upon consumption of the starting material the crude mixture was purified by column

chromatography (hexanes: ethyl acetate) to yield the corresponding products 6a-j.

Table 1. Slovent, oxidant and additive screening for the photoredox catalyzed

functionalization of glycine esters.[a]

Ir(ppy)2(bpy)PF6 (1mol%)

11 W fluorescent bulb

+NH Zn(OAc)2 10 mol%, MeCN

1a 2a 3a

Entry Solvent Oxidant Additive Yield(%)[b]

1 MeCN Air none 72% 2 MeCN BrCCl3 none 50%

3 MeCN Oxygen none low conv.

4 MeCN Air NaOAc low conv.

5 MeCN Air N,N-diisopropylethylamine low conv.

6 MeCN Air 4Å MS -

7 Toluene Air none low conv.

8 THF Air none low conv.

9 DMSO Air none -

10 DMF Air none < 10%

11 iPrOH Air none -

12 DCM Air none < 10%

13 NMP Air none -

14 MeCN Air Water (0.5 ml) -

15 EtCN Air none 62% [a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (1 mol%), 11W fluorescent bulb, MeCN (2.0 mL), 48 h. [b] Yield of the isolated product.

Table 2. Lewis acid screening for the photoredox catalyzed functionalization of dipeptides.[a]

Ir(ppy)2(bpy)PF6 (1mol%)HN

11 W fluorescent bulb

+NH Lewis acid X mol%, MeCN

5a 2a6a

Entry Lewis acid X Yield(%)[b]

1 CuBr 10% Trace product

2 CuCl 10% -

3 CuI 10% < 10%

4 Cu(OAc)2 10% Trace product

5 Cu(OTf)2 10% -

6 Zn(OTf)2 10% -

7 Zn(OAc)2 10% 40% conversion

8 Zn(OAc)2 100% 60% [a] Reaction conditions: 5a (0.2 mmol), 2a (0.3 mmol), catalyst (1 mol%), 11W fluorescent bulb, and MeCN (2.0 mL), 48h. [b] Yield of the isolated product.

Characterization of the products.

Ethyl 2-(1H-indol-2-yl)-2-(1H-indol-3-yl)acetate:[4] 1H-NMR (600 MHz, CDCl3): δ = 8.01

(br, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.20 – 7.10

(m, 6H), 5.51 (s, 1H), 4.24 (q, J = 7.2 Hz 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C-NMR (150.8 MHz, CDCl3): δ = 173.4, 136.3, 126.7, 123.3, 122.1,

119.5, 119.3, 113.7, 111.2, 61.1, 40.7, 14.2; IR (neat): ν = 3411, 3011,

1721, 1457, 1216, 755; MS-EI: m/z(%): 245.3 (100%, M+ – CO2Et),

318.3 (M+, 23%), 319.3 (M++1, 5%).

Ethyl 2-(1H-indol-3-yl)-2-(phenylamino)acetate: 24h, 74% yield, 1H-NMR (400 MHz,

CDCl3): δ = 8.12 (br, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0

Hz, 1H), 7.24 – 7.20 (m, 2H), 7.18 – 7.12 (m, 3H), 6.73 – 6.69 (m,

1H), 6.64 – 6.62 (m, 2H), 5.38 (s, 1H), 4.75 (br, 1H), 4.30 – 4.04

(m, 2H), 1.21 (t, J = 7.2 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): δ

= 172.5, 146.5, 136.5, 129.2, 125.8, 123.0, 122.5, 120.0, 119.6, 118.0, 113.4, 112.7, 111.3,

61.6, 54.2, 14.1; IR (neat): ν = 3410, 3010, 2980, 1728, 1603, 1504, 1313, 1218, 1187, 1019,

693, 666, 532; MS-EI: m/z(%): 221.3 (100%, M+ – CO2Et), 294.3 (M+, 14%), 295.3 (M++1,

Ethyl 2-(1H-indol-3-yl)-2-(p-tolylamino)acetate: 30h, 72% yield, 1H-NMR (600 MHz,

CDCl3): δ = 8.17 (br, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.35 (d, J =

8.4 Hz, 1H), 7.26 – 7.16 (m, 3H), 6.98 (m, 2H), 6.59 (m, 2H), 5.38

(s, 1H), 4.63 (br, 1H), 4.30 – 4.11 (m, 2H), 2.23 (s, 3H), 1.23 (t,

J = 7.2 Hz, 3H); 13C-NMR (150.8 MHz, CDCl3): δ = 172.7, 144.3,

136.5, 129.7, 127.3, 125.8, 123.0, 122.5, 120.0, 119.6, 113.6, 112.7, 111.4, 61.5, 54.6, 14.1;

IR (neat): ν = 3407, 3009, 2921, 1729, 1617, 1518, 1307, 1216, 1191, 1018, 812, 754, 666,

506; MS-EI: m/z(%): 235.3 (100%, M+ – CO2Et), 308.3 (M+, 24%), 309.3 (M++1, 5%).

Isopropyl 2-(1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 73% yield, 1H-NMR (400 MHz,

8.0 Hz, 1H), 7.24 – 7.13 (m, 3H), 6.97 – 6.95 (m, 2H), 6.59 – 6.55

(m, 2H), 5.34 (s, 1H), 5.08 – 5.02 (m, 1H), 3.98 (br, 1H), 2.22 (s,

3H), 1.28 (d, J = 6.4 Hz, 3H), 1.08 (t, J = 6.0 Hz, 3H); 13C-NMR

(100.6 MHz, CDCl3): δ = 172.2, 144.3, 136.5, 129.7, 127.2, 125.8,

122.9, 122.4, 119.8, 119.7, 113.5, 112.8, 111.3, 69.2, 54.7, 21.8 (d, J = 32.8 Hz, 1C), 20.4; IR

(neat): ν = 3407, 2982, 2930, 1725, 1616, 1519, 1305, 1216, 1103, 949, 813, 754, 667, 506;

MS-EI: m/z(%): 235.3 (100%, M+ – CO2iPr), 322.3 (M+, 18%), 323.4 (M++1, 5%).

Methyl 2-(1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 71% yield, 1H-NMR (400 MHz,

Hz, 1H), 7.24 – 7.14 (m, 3H), 6.97 – 6.95 (m, 2H), 6.58 – 6.55 (m,

2H), 5.38 (s, 1H), 4.60 (br, 1H), 3.72 (s, 3H), 2.21 (s, 3H); 13C-NMR

(100.6 MHz, CDCl3): δ = 173.2, 144.2, 136.4, 129.7, 127.4, 125.8,

123.0, 122.5, 120.1, 119.4, 113.5, 112.6, 111.4, 54.4, 52.5, 20.4; IR (neat): ν = 3409, 3015,

2954, 1736, 1616, 1519, 1308, 1216, 1100, 985, 812, 757, 667, 506; MS-EI: m/z(%): 235.3

(100%, M+ – CO2Me), 294.4 (M+, 38%), 295.3 (M++1, 7%).

Tert-butyl 2-(1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 45% yield, 1H-NMR (400 MHz,

Hz, 1H), 7.28 – 7.14 (m, 3H), 6.96 – 6.94 (m, 2H), 6.57 – 6.54 (m,

2H), 5.27 (s, 1H), 4.58 (br, 1H), 2.22 (s, 3H), 1.40 (s, 9H); 13C-

NMR (100.6 MHz, CDCl3): δ = 171.8, 144.4, 136.5, 129.6, 127.0,

126.0, 122.8, 122.3, 119.8, 119.7, 113.5, 113.3, 111.2, 82.0, 55.1, 27.9, 20.4; IR (neat): ν =

3408, 3008, 2979, 1724, 1616, 1519, 1154, 812, 757, 667, 506; MS-EI: m/z(%): 235.4 (100%,

M+ – CO2tBu), 336.4 (M+, 38%), 337.4 (M++1, 19%).

Benzyl 2-(1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 83% yield, 1H-NMR (400 MHz,

8.4 Hz, 1H), 7.28 – 7.11 (m, 9H), 6.96 – 6.94 (m, 2H), 6.58 –

6.55 (m, 2H), 5.44 (s, 1H), 5.25 (d, J = 12.0 Hz, 1H), 5.10 (d, J =

12.0 Hz, 1H), 4.60 (br, 1H), 2.22 (s, 3H); 13C-NMR (100.6 MHz,

CDCl3): δ = 172.6, 144.2, 136.4, 135.4, 129.7, 128.4, 128.2,128.1, 127.4, 125.8, 123.0, 122.5,

120.0, 119.6, 113.6, 112.5, 111.3, 67.1, 54.6, 20.4; IR (neat): ν = 3471, 3419, 3352, 3018,

1733, 1519, 1216, 809, 757, 668, 507; MS-EI: m/z(%): 235.3 (100%, M+ – CO2Bn), 370.3

(M+, 30%), 371.3 (M++1, 19%).

Ethyl 2-(1H-indol-3-yl)-2-((4-methoxyphenyl)amino)acetate: 36h, 76% yield, 1H-NMR

(400 MHz, CDCl3): δ = 8.15 (br, 1H), 7.83 (d, J = 7.6 Hz, 1H),

7.36 (d, J = 8.4 Hz, 1H), 7.24 – 7.13 (m, 3H), 6.76 – 6.72 (m,

2H), 6.63 – 6.59 (m, 2H), 5.32 (s, 1H), 4.47 (br, 1H), 4.28-

4.08 (m, 2H), 3.71 (s, 3H), 1.20 (t, J = 7.2 Hz, 1H); 13C-NMR

(100.6 MHz, CDCl3): δ = 172.7, 152.5, 140.8, 136.4, 125.8, 122.9, 122.5, 120.0, 119.6, 114.8

(2C), 112.9, 111.3, 61.5, 55.7, 55.2, 14.1; IR (neat): ν = 3407, 3003, 2937, 2907, 1730, 1513,

1459, 1302, 1239, 1191, 1099, 1031, 823, 757, 668, 507; MS-EI: m/z(%): 251.3 (100%, M+ –

CO2Et), 324.3 (M+, 34%), 325.3 (M++1, 8%).

Ethyl 2-((4-chlorophenyl)amino)-2-(1H-indol-3-yl)acetate: 48h, 76% yield, 1H-NMR (600

MHz, CDCl3): δ = 8.17 (br, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.37

(d, J = 8.4 Hz, 1H), 7.25 – 7.16 (m, 3H), 7.09 – 7.06 (m, 2H),

6.56 – 6.53 (m, 2H), 5.34 (s, 1H), 4.80 (br, 1H), 4.29-4.10 (m,

2H), 1.21 (t, J = 7.2 Hz, 1H); 13C-NMR (150.8 MHz, CDCl3): δ

= 172.2, 145.0, 136.5, 129.0, 125.7, 123.0, 122.6, 121.4, 120.1, 119.5, 114.5, 112.2, 111.4,

61.7, 54.3, 14.1; IR (neat): ν = 3407, 3003, 2937, 2907, 1730, 1513, 1459, 1302, 1239, 1191,

1099, 1031, 823, 757, 668, 507; MS-EI: m/z(%): 255.3 (100%, M+ – CO2Et), 328.3 (M+,

23%), 329.3 (M++1, 8%).

Benzyl 2-(1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 68% yield, 1H-NMR (400

MHz, CDCl3): δ = 7.77 (d, J = 8.0 Hz, 1H), 7.34 – 7.10 (m, 8H), 7.01

(s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.57 – 6.53 (m, 2H), 5.41 (d, J =

6.0 Hz, 1H), 5.25 (d, J = 12.0 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H),

4.56 (d, J = 6.0 Hz, 1H), 3.70 (s, 3H), 2.21 (s, 3H); 13C-NMR (100.6

MHz, CDCl3): δ = 172.7, 144.3, 137.2, 135.5, 129.7, 128.4, 128.2

(2C), 127.6, 127.3, 126.3, 122.1, 119.7, 119.6, 113.5, 110.8, 109.4, 67.1, 54.5, 32.8, 20.4; IR

(neat): ν = 3404, 3036, 2923, 1735, 1613, 1519, 1466, 1380, 1317, 1163, 1020, 963, 812, 744,

608, 507; MS-EI: m/z(%): 249.3 (100%, M+ – CO2Bn), 384.4 (M+, 16%), 385.4 (M++1, 4%).

Ethyl 2-(1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 48h, 60% yield, 1H-NMR (600

MHz, CDCl3): δ = 7.83 (d, J = 7.8 Hz, 1H), 7.32 – 6.57 (m, 8H), 5.35

(s, 1H), 4.60 (s, 1H), 4.29 – 4.10 (m, 2H), 3.74 (s, 3H), 2.22 (s, 3H),

1.23 (t, J = 6.8 Hz, 3H); 13C-NMR (150.8 MHz, CDCl3): δ = 172.8,

144.3, 137.3, 129.7, 127.5, 127.2, 126.3, 122.0, 119.7, 119.5, 113.5,

111.1, 109.4, 61.4, 54.5, 32.8, 20.4, 14.1; IR (neat): ν = 3404, 3036,

2923, 1735, 1613, 1519, 1466, 1380, 1317, 1163, 1020, 963, 812, 744, 608, 507; MS-EI:

m/z(%): 249.4 (100%, M+ – CO2Et), 322.4 (M+, 16%), 323.4 (M++1, 4%).

Ethyl 2-(1-(tert-butyldimethylsilyl)-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 42%

yield, 1H-NMR (400 MHz, CDCl3): δ = 7.80 – 7.77 (m, 1H), 7.50

– 6.56 (m, 8H), 5.34 (s, 1H), 4.51 (s, 1H), 4.28 – 4.11 (m, 2H),

2.21 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.58 (d, J = 3.2

Hz, 6H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.8, 144.5, 141.6,

129.7 (2C), 129.2, 127.3, 121.9, 120.0, 119.4, 114.5, 114.1, 113.6,

61.3, 54.7, 26.2, 20.4, 19.4, 14.2, –4.0; IR (neat): ν = 3401, 2920, 2854, 1726, 1622, 1579,

1544, 1452, 1383, 1064, 794, 741, 592; MS-EI: m/z(%): 349.4 (100%, M+ – CO2Et), 422.5

(M+, 18%), 423.5 (M++1, 7%).

Isopropyl 2-(1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 55% yield, 1H-NMR

(400 MHz, CDCl3): δ = 7.82 – 7.80 (m, 1H), 7.31 – 6.54 (m, 8H),

5.30 (s, 1H), 5.09 – 4.98 (m, 1H), 4.58 (s, 1H), 3.73 (s, 3H), 2.21

(s, 3H), 1.28 (d, J = 6.0 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H); 13C-

NMR (100.6 MHz, CDCl3): δ = 172.3, 144.4, 137.3, 129.7, 127.5,

127.1, 126.4, 121.9, 119.8, 119.4, 113.5, 111.2, 109.4, 69.1, 54.7,

32.9, 21.8 (d, J = 32.2 Hz, 1C), 20.4; IR (neat): ν = 3404, 2922, 2422, 1728, 1615, 1524,

1462, 1381, 1103, 815, 746, 612; MS-EI: m/z(%): 249.4 (100%, M+ – CO2iPr), 336.4 (M+,

19%), 337.4 (M++1, 4%).

Methyl 2-(5-fluoro-1H-indol-3-yl)-2-(p-tolylamino)acetate: 72h, 56% yield, 1H-NMR (400

MHz, CDCl3): δ = 8.18 (br, 1H), 7.47 – 7.44 (m, 1H), 7.26 – 6.53

(m, 7H), 5.30 (s, 1H), 4.62 (br, 1H), 3.70 (s, 3H), 2.21 (s, 3H); 13C-

NMR (100.6 MHz, CDCl3): δ = 173.0, 159.1 (d, J = 235.5 Hz, 1C),

144.0, 132.9, 129.8, 127.5, 126.2 (d, J = 10.0 Hz, 1C), 124.7,

113.6, 112.8 (d, J = 4.6 Hz, 1C), 112.1 (d, J = 9.6 Hz, 1C), 111.2

(d, J = 26.0 Hz, 1C), 104.6 (d, J = 24.0 Hz, 1C), 54.3, 52.6, 20.4; IR (neat): ν = 3412, 2920,

2856, 1733, 1623, 1582, 1452, 1384, 1066, 804, 723, 617; MS-EI: m/z(%): 253.3 (100%, M+

– CO2Me), 312.3 (M+, 52%), 313.3 (M++1, 12%).

Methyl 2-(6-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 48h, 82% yield, 1H-NMR (400

MHz, CDCl3): δ = 8.02 (br, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.16 –

6.55 (m, 7H), 5.36 (s, 1H), 4.61 (br, 1H), 3.73 (s, 3H), 2.47 (s, 3H),

2.22 (s, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 173.2, 144.2,

136.9, 132.5, 129.7, 127.3, 123.6, 122.4, 121.9, 119.1, 113.5, 112.5,

111.3, 54.5, 52.5, 21.7, 20.4; IR (neat): ν = 3425, 2920, 2855, 1731,

1629, 1579, 1546, 1384, 1065, 879, 670; MS-EI: m/z(%): 249.3 (100%, M+ – CO2Me), 308.3

(M+, 55%), 309.3 (M++1, 12%).

Methyl 2-(5-cyano-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 75% yield, 1H-NMR (400

MHz, CDCl3): δ = 8.72 (br, 1H), 8.20 – 8.19 (m, 1H), 7.45 –

6.53 (m, 7H), 5.36 (s, 1H), 3.75 (s, 3H), 3.70 (br, 1H), 2.22 (s,

3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.5, 143.7, 138.2,

129.8 (2), 127.8, 125.6, 125.3 (2), 120.5, 113.7, 113.6, 112.4,

103.2, 54.2, 52.8, 20.4; IR (neat): ν = 3424, 2920, 2854, 2222, 1734, 1625, 1579, 1543, 1448,

1384, 1064, 879, 643; MS-EI: m/z(%): 260.4 (100%, M+ – CO2Me), 319.4 (M+, 55%), 320.4

(M++1, 12%).

Methyl 3-(2-methoxy-2-oxo-1-(p-tolylamino)ethyl)-1H-indole-5-carboxylate: 36h, 67%

yield, 1H-NMR (400 MHz, CDCl3): δ = 8.59 (br, 1H), 8.56

(d, J = 8.0 Hz, 1H), 7.92 – 6.54 (m, 7H), 5.41 (s, 1H), 3.93

(s, 3H), 3.72 (s, 3H), 3.62 (br, 1H), 2.20 (s, 3H); 13C-NMR

(100.6 MHz, CDCl3): δ = 173.0, 168.1, 144.0, 139.0, 129.8,

127.6, 125.4, 124.4, 123.9, 122.3, 122.2, 114.2, 113.6, 111.2, 54.1, 52.6, 51.9, 20.4; IR (neat):

ν = 3364, 2920, 2854, 2575, 1729, 1687, 1624, 1582, 1437, 1384, 1065, 751, 621; MS-EI:

m/z(%): 293.4 (100%, M+ – CO2Me), 352.3 (M+, 25%), 353.3 (M++1, 5%).

Methyl 2-(2-phenyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 65% yield, 1H-NMR (400

MHz, CDCl3): δ = 8.24 (br, 1H), 7.94 – 7.91 (m, 1H), 7.71 – 6.38

(m, 12H), 5.47 (s, 1H), 4.73 (br, 1H), 3.75 (s, 3H), 2.19 (s, 3H); 13C-

NMR (100.6 MHz, CDCl3): δ = 173.2, 144.0, 137.3, 135.8, 132.0,

129.6, 129.0, 128.8, 128.6, 127.0, 126.6, 122.6, 120.4, 120.0, 113.3,

111.1, 108.5, 53.9, 52.5, 20.3; IR (neat): ν = 3411, 2920, 2854,

2025, 1734, 1449, 1384, 1062, 878, 742; MS-EI: m/z(%): 311.3 (100%, M+ – CO2Me), 370.4

(M+, 22%), 371.4 (M++1, 6%).

MHz, CDCl3): δ = 8.05 (br, 1H), 7.66 – 7.64 (m, 1H), 7.23 – 6.54 (m,

7H), 5.37 (s, 1H), 4.61 (br, 1H), 3.72 (s, 3H), 2.46 (s, 3H), 2.20 (s,

3H); 13C-NMR (100.6 MHz, CDCl3): δ = 173.2, 144.2, 136.0, 129.7,

127.3, 125.3, 123.1, 122.7, 120.5, 120.3, 117.1, 113.5, 113.2, 54.5,

52.5, 20.4, 16.5; IR (neat): ν = 3411, 3014, 2922, 2861, 1735, 1616,

1519, 1439, 1311, 1212, 1011, 811, 755; MS-EI: m/z(%): 249.3 (100%, M+ – CO2Me), 308.3

(M+, 54%), 309.4 (M++1, 11%).

Methyl 2-(5-iodo-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 52% yield, 1H-NMR (400

MHz, CDCl3): δ = 8.26 (br, 1H), 8.13(d, J = 8.0 Hz, 1H), 7.46 –

6.53 (m, 7H), 5.30 (s, 1H), 4.56 (br, 1H), 3.73 (s, 3H), 2.21 (s, 3H),

2.20 (s, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.9, 143.9,

135.5, 130.9, 129.8, 128.3, 128.2, 127.6, 123.8, 119.8, 113.6, 113.3,

112.0, 83.7, 54.2, 52.6, 20.4; IR (neat): ν = 3402, 3014, 2923, 2865,

1733, 1614, 1519, 1448, 1309, 1217, 1004, 804, 757, 596, 504; MS-EI: m/z(%): 361.2 (100%,

M+ – CO2Me), 420.2 (M+, 44%), 421.2 (M++1, 8%).

Methyl 2-(5-bromo-1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 68% yield, 1H-

NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 6.0 Hz, 1H), 7.35 – 6.55

(m, 7H), 5.30 (s, 1H), 4.62 (br, 1H), 3.75 (s, 3H), 3.72 (s, 3H),

2.23 (s, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.9, 144.0,

135.9, 129.7, 128.7, 127.9, 127.5, 125.0, 122.1, 113.5, 113.1,

111.0, 110.8, 54.1, 52.6, 33.0, 20.4; IR (neat): ν = 3403, 3014,

2924, 1865, 1738, 1616, 1520, 1471, 1435, 1380, 1307, 864, 800, 757, 616, 507; MS-EI:

m/z(%): 327.2 (100%, M+ – CO2Me), 386.2 (M+, 39%), 387.2 (M++1, 11%).

Methyl 2-(5-bromo-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 54% yield, 1H-NMR (400

MHz, CDCl3): δ = 8.28 (br, 1H), 7.94 (m, 1H), 7.31 – 6.55 (m,

7H), 5.32 (s, 1H), 4.24 (br, 1H), 3.75 (s, 3H), 2.23 (s, 3H); 13C-

NMR (100.6 MHz, CDCl3): δ = 172.9, 144.0, 135.1, 129.8, 127.6,

127.5, 125.4, 124.2, 122.0, 113.6, 113.4, 112.8, 112.4, 54.2, 52.6,

20.4; IR (neat): ν = 3401, 3016, 2922, 2865, 1734, 1614, 1520, 1451, 1310, 1380, 1217, 1107,

882, 804, 757, 602, 505; MS-EI: m/z(%): 313.2 (100%, M+ – CO2Me), 372.2 (M+, 42%),

373.2 (M++1, 9%).

Methyl 2-(1,2-dimethyl-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 50% yield, 1H-NMR

(400 MHz, CDCl3): δ = 7.90 (br, 1H), 7.78 – 6.52 (m, 8H), 5.29 (s,

1H), 4.57 (br, 1H), 3.70 (s, 3H), 2.48 (s, 3H), 2.21 (s, 3H); 13C-NMR

(100.6 MHz, CDCl3): δ = 172.9, 144.0, 135.1, 129.8, 127.6, 127.5,

125.4, 124.2, 122.0, 113.6, 113.4, 112.8, 112.4, 54.2, 52.4, 20.4, 12.1;

IR (neat): ν = 3401, 3016, 2922, 2865, 1734, 1614, 1520, 1451, 1310, 1380, 1217, 1107, 882,

804, 757, 602, 505; MS-EI: m/z(%): 249.2 (100%, M+ – CO2Me), 308.2 (M+, 42%), 309.2

(M++1, 9%).

Methyl 2-(5-methoxy-1H-indol-3-yl)-2-(p-tolylamino)acetate: 36h, 69% yield, 1H-NMR

(400 MHz, CDCl3): δ = 8.05 (br, 1H), 7.27 – 6.56 (m, 8H), 5.34

(s, 1H), 4.53 (br, 1H), 3.87 (s, 3H), 3.75 (s, 3H), 2.22 (s, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 173.2, 154.4, 144.3, 131.5,

129.7, 127.4, 126.2, 123.7, 113.5, 112.9, 112.4, 112.1, 101.1,

55.9, 54.4, 52.5, 20.4; IR (neat): ν = 3403, 3005, 2922, 2856,

1734, 1618, 1518, 1481, 1383, 1307, 1211, 1176, 1028, 925, 809, 755, 638, 505; MS-EI:

m/z(%): 265.3 (100%, M+ – CO2Me), 324.3 (M+, 57%), 325.3 (M++1, 11%).

MHz, CDCl3): δ = 8.06 (br, 1H), 7.59 – 6.57 (m, 8H), 5.36 (s, 1H),

4.55 (br, 1H), 3.74 (s, 3H), 2.48 (s, 3H), 2.23 (s, 3H); 13C-NMR

(100.6 MHz, CDCl3): δ = 173.3, 144.3, 134.7, 129.7, 129.5, 127.3,

126.0, 124.2, 123.1, 118.9, 113.5, 112.1, 111.0, 54.4, 52.5, 21.5,

20.4; IR (neat): ν = 3350, 2970, 2922, 1736, 1614, 1517, 1461, 1378, 1306, 1232, 1119, 949,

814, 756, 615; MS-EI: m/z(%): 249.3 (100%, M+ – CO2Me), 308.3 (M+, 60%), 309.3 (M++1,

Methyl 2-(p-tolylamino)-2-(2,4,6-trimethoxyphenyl)acetate: 36h, 71% yield, 1H-NMR

(400 MHz, CDCl3): δ = 6.94 – 6.92 (m, 2H), 6.66 – 6.64 (m, 2H), 6.12

(s, 2H), 5.67 (s, 1H), 4.77 (br, 1H), 3.84 (s, 6H), 3.78 (s, 3H), 3.67 (s,

3H), 2.20 (s, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 173.5, 160.9,

158.7, 145.0, 129.5, 126.9, 114.0, 108.5, 91.0, 55.9, 55.3, 52.3, 51.2,

20.4; IR (neat): ν = 3404, 3011, 2945, 2848, 1742, 1606, 1521, 1459,

1304, 1216, 1120, 813, 756, 665; MS-EI: m/z(%): 286.3 (100%, M+ –

CO2Me), 345.3 (M+, 11%), 346.3 (M++1, 3%).

Ethyl 2-(2-(1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 60% yield, 1H-NMR

(600 MHz, CDCl3): δ = 8.44 (br, 1H), 7.64 – 6.61 (m,

10H), 5.09 (s, 2H), 4.32– 4.28 (m, 1H), 4.20 – 4.16 (m,

1H), 3.90 – 3.86 (m, 1H), 2.27 (s, 3H), 1.25 (t, J = 7.2 Hz,

3H); 13C-NMR (150.8 MHz, CDCl3): δ = 172.7, 169.8,

144.7, 136.4, 129.9, 128.6, 125.7, 123.5, 122.6, 120.1,

118.8, 113.9, 113.2, 111.6, 61.5, 57.6, 41.2, 20.4, 14.1; IR (neat): ν = 3377, 3239, 2982, 2917,

2858, 1732, 1657, 1618, 1515, 1451, 1348, 1206, 1111, 810, 738, 671; MS-EI: m/z(%): 235.3

(100%, M+ – CONHCH2CO2Et), 365.3 (M+, 7%), 366.3 (M++1, 2%).

Ethyl 2-(2-(1-(tert-butyldimethylsilyl)-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate:

48h, 68% yield, 1H-NMR (600 MHz, CDCl3): δ = 7.67 –

7.61 (m, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.40 (s, 1H), 7.20 –

6.63 (m, 6H), 5.08 (s, 1H), 4.35 – 4.29 (m, 1H), 4.29

(br,1H), 4.21 – 4.18 (m, 2H), 3.91 – 3.87 (m, 1H), 2.27 (s,

3H), 1.26 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.61 (s, 6H); 13C-NMR (150.8 MHz, CDCl3): δ = 172.5, 169.6, 144.8, 141.6, 130.3, 129.8, 129.1, 128.5,

122.0, 120.1, 118.8, 115.2, 114.3, 113.9, 61.3, 57.8, 41.2, 26.3, 20.4, 19.4, 14.1, –4.0; IR

(neat): ν = 3457, 3020, 2402, 1742, 1678, 1512, 1384, 1215, 759, 669; MS-EI: m/z(%): 349.4

(100%, M+ – CONHCH2CO2Et), 479.4 (M+, 20%), 480.4 (M++1, 13%).

Ethyl 2-(2-(6-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 62% yield, 1H-NMR (600 MHz, CDCl3): δ = 8.27 (br, 1H), 7.63 – 6.60

(m, 9H), 5.06 (s, 1H), 4.31 – 4.27 (m, 1H), 4.20 – 4.16 (m,

2H), 3.91 – 3.87 (m, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 1.26

(t, J = 7.2 Hz, 1H), 0.93 (s, 9H), 0.61 (s, 6H); 13C-NMR

(150.8 MHz, CDCl3): δ = 172.7, 169.8, 144.8, 136.9, 132.5,

129.8, 128.5, 123.6, 122.8, 121.9, 118.4, 113.9, 113.1, 111.5, 61.4, 57.7, 41.2, 20.4, 14.2,

14.1; IR (neat): ν = 3379, 2982, 2924, 2865, 1740, 1664, 1518, 1453, 1382, 1300, 1209, 860,

807, 755, 587, 507; MS-EI: m/z(%): 249.3 (100%, M+ – CONHCH2CO2Et), 379.3 (M+, 6%),

380.3 (M++1, 2%).

Isopropyl 2-(2-(1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 63% yield, 1H-

NMR (400 MHz, CDCl3): δ = 8.50 (br, 1H), 7.66 – 6.60 (m,

10H), 5.09 (s, 1H), 5.08 – 5.02 (m, 1H), 4.30 – 4.24 (m, 1H),

3.89 – 3.83 (m, 1H), 2.27 (s, 3H), 1.23 (t, J = 5.6 Hz, 6H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.7, 169.3, 144.8,

136.4, 129.9, 128.5, 125.7, 123.5, 122.5, 120.1, 118.7, 113.9,

113.2, 111.6, 69.3, 57.6, 41.4, 21.7, 20.4; IR (neat): ν = 3379, 2982, 2928, 2868, 1733, 1664,

1519, 1459, 1378, 1217, 1106, 814, 750, 504; MS-EI: m/z(%): 235.4 (100%, M+ –

CONHCH2CO2iPr), 379.4 (M+, 8%), 380.4 (M++1, 2%).

Isopropyl 2-(2-(5-bromo-1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate:

48h, 51% yield, 1H-NMR (400 MHz, CDCl3): δ = 7.41 –

7.31 (m, 1H), 7.58 – 6.59 (m, 7H), 5.08 – 5.02 (m, 1H),

5.00 (s, 1H), 4.28 – 4.22 (m, 1H), 3.87 – 3.82 (m, 1H),

3.72 (s, 3H), 2.56 (s, 3H), 1.22 (t, J = 5.6 Hz, J = 5.6 Hz,

6H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.4, 169.0,

144.8, 137.6, 136.0, 131.7, 129.8, 129.0, 128.5, 128.4, 126.2, 122.6, 120.4, 120.0, 114.0,

111.3, 109.4, 69.2, 57.3, 41.6, 21.7, 20.4; IR (neat): ν = 3373, 2980, 2927, 2022, 1736, 1670,

1517, 1472, 1378, 1296, 1212, 1106, 1035, 940, 755; MS-EI: m/z(%): 327.3 (100%, M+ –

CONHCH2CO2iPr), 471.3 (M+, 7%), 472.3 (M++1, 2%).

Isopropyl 2-(2-(2-phenyl-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 50%

yield, 1H-NMR (400 MHz, CDCl3): δ = 8.44 (br, 1H),

7.89 – 7.84 (m, 2H), 7.76 – 7.74 (m, 2H), 7.42 – 7.15

(m, 6H), 6.99 – 6.97 (m, 2H), 6.56 – 6.54 (m, 2H), 5.16

(s, 1H), 5.09 – 5.03 (m, 1H), 4.42 (br, 1H), 4.17 – 4.11

(m, 1H), 3.99 – 3.93 (m, 1H), 2.23 (s, 3H), 1.22 (t, J =

5.6 Hz, 6H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.4, 169.0, 144.7, 137.6, 136.0, 131.7,

129.8, 129.0, 128.9, 128.5, 128.4, 126.2, 122.6, 120.4, 120.0, 114.0, 111.3, 109.4, 69.2, 57.3,

41.6, 21.7, 20.4; IR (neat): ν = 3464, 2922, 2861, 2442, 1949, 1734, 1663, 1616, 1382, 1100,

1023, 935, 683; MS-EI: m/z(%): 311.3 (100%, M+ – CONHCH2CO2iPr), 455.3 (M+, 15%),

456.3 (M++1, 6%).

Ethyl 2-(2-(7-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 76% yield, 1H-NMR (400 MHz, CDCl3): δ = 8.34 (br, 1H), 7.65 – 7.62

(m, 1H), 7.49 – 7.32 (m, 2H), 7.07 – 6.60 (m, 6H), 5.09 (s,

1H), 4.32– 4.26 (m, 1H), 4.21 – 4.15 (m, 2H), 3.92 – 3.86

(m, 1H), 2.46 (s, 3H), 2.27 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.7, 169.7, 144.8,

136.0, 129.8, 128.5, 125.3, 123.2, 123.1, 120.8, 120.4, 116.4, 113.9, 113.7, 61.4, 57.8, 41.2,

20.4, 16.5, 14.1; IR (neat): ν = 3391, 2921, 2857, 2421, 2232, 1738, 1663, 1517, 1443, 1384,

1208, 1103, 1026, 809, 753; MS-EI: m/z(%): 249.5 (100%, M+ – CONHCH2CO2Et), 379.5

(M+, 17%), 380.5 (M++1, 12%).

Methyl 2-(2-(1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 66% yield, 1H-NMR

(400 MHz, CDCl3): δ = 8.47 (br, 1H), 7.67 – 7.61 (m,

2H), 7.37 – 6.61 (m, 8H), 5.09 (s, 1H), 4.34 – 4.27 (m,

1H), 3.93 – 3.87 (m, 1H), 3.72 (s, 3H), 2.27 (s, 3H); 13C-

NMR (100.6 MHz, CDCl3): δ = 172.8, 170.2, 144.7,

136.4, 129.9, 128.6, 125.7, 123.5, 122.6, 120.1, 118.7,

113.9, 113.1, 111.6, 57.7, 52.3, 41.0, 20.4; IR (neat): ν = 3380, 3013, 2924, 2859, 2131, 1744,

1664, 1618, 1518, 1439, 1381, 1216, 1108, 1012, 812, 751; MS-EI: m/z(%): 235.3 (100%, M+

– CONHCH2CO2Me), 351.3 (M+, 11%), 352.3 (M++1, 3%).

Ethyl 2-(2-(2-phenyl-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h, 52% yield, 1H-NMR (400 MHz, CDCl3): δ = 8.39 (br, 1H), 7.88 – 7.85

(m, 2H), 7.77 – 7.35 (m, 6H), 7.24 – 6.54 (m, 6H), 5.16 (s,

1H), 4.41 (br, 1H), 4.20 – 4.16 (m, 2H), 4.15 – 4.13 (m,

1H), 4.03 – 3.97 (m, 1H), 2.23 (s, 3H), 1.23 (t, J = 7.2 Hz,

3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.5, 169.5,

144.7, 137.6, 136.0, 131.7, 129.7, 129.0, 128.9, 128.5, 128.4, 126.1, 122.6, 120.3, 120.0,

114.0, 111.3, 109.4, 61.4, 57.3, 41.4, 20.4, 14.1; IR (neat): ν = 3374, 2924, 2523, 1887, 1738,

1667, 1516, 1455, 1382, 1213, 1116, 1023, 923, 809, 752, 701, 507; MS-EI: m/z(%): 311.4

(100%, M+ – CONHCH2CO2Et), 441.5 (M+, 15%).

Ethyl 2-(2-(5-bromo-1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetamido)acetate: 48h,

55% yield, 1H-NMR (400 MHz, CDCl3): δ = 7.75 – 7.74

(m, 1H), 7.62 – 7.27(m, 3H), 7.19 – 6.60 (m, 5H), 5.01 (s,

1H), 4.33 – 4.27 (m, 1H), 4.23 – 4.18 (m, 2H), 3.92 – 3.85

(m, 1H), 3.74 (s, 3H), 2.27 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.3, 169.6, 144.5,

135.9, 129.9, 129.0, 128.7, 127.9, 125.1, 121.5, 113.9, 113.3, 111.5, 111.1, 61.5, 57.3, 41.2,

33.1, 20.4, 14.1; IR (neat): ν = 3401, 3019, 2924, 2402, 1740, 1676, 1516, 1471, 1383, 1215,

1024, 928, 759, 670; MS-EI: m/z(%): 327.3 (100%, M+ – CONHCH2CO2Et), 457.4 (M+

(Br79), 15%), 459.4 (M+ (Br81), 17%).

References:

[1] J. Xie, Z.-Z. Huang, Angew. Chem. Int. Ed. 2010, 49, 10181.

[2] L. Zhao, O. Basle, C.-J. Li, Proc. Natl. Acad. Sci. USA. 2009, 106, 4106.

[3] L. Zhao, C.-J. Li, Angew. Chem. Int. Ed. 2008, 47, 7075.

[4] M. Soueidan, J. Collin, R. Gil, Tetrahedron Lett, 2006, 47, 5467.

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