zrcl 4 catalyzed c o bond to c n bond formation: synthesis of · 1 zrcl 4 catalyzed c-o bond to c-n...

1

ZrCl4 Catalyzed C-O bond to C-N bond formation: synthesis of

1,2,3-triazoles and their biological evaluation

Gangavaram V. M. Sharma*a, Kandikonda Suresh Kumar

a,c, Buddana

Sudheer Kumarb, Sheri Venkata Reddy

a, Reddy Shetty Prakasham*

b and

Helmut Hugel*c

aOrganic and Biomolecular Chemistry Division,

CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.

(Fax: +91-40-27160387 Email: [email protected])

bBiochemical and Environmental Engineering Sciences,

CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.

(Email: [email protected])

cRoyal Melbourne Institute of Technology, Melbourne VIC 3001, Australia.

(Email: [email protected])

SUPPORTING INFORMATION

CONTENTS

Experimental procedure and details…………………………………………………………...2-11

1H and

13C NMR Spectra of compounds 6-10 and 6a-d to 10a-d……………………………12-36

1H NMR Spectra of a mixture of 6 and 1………………………….…………………………37-41

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1-(Azido(phenyl)methyl)-4-methoxybenzene (6): A stirred solution of alcohol 1 (2.0 g, 9.35 mmol) in acetonitrile

(10 mL) at 0 °C was sequentially treated with azidotrimethylsilane (3.0 mL, 23.38 mmol) and ZrCl4 (0.22 g, 0.93

mmol) and stirred for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x

10 mL). The combined organic layers were washed with brine (10 mL) and dried (Na2SO4). Solvent was evaporated

and the residue purified by column chromatography (60-120 mesh Silica gel, 3% EtOAc in pet. ether) to afford 6

(2.02 g, 90%) as a yellow liquid; IR (CHCl3): 3030, 2091, 1609, 1510, 1243, 1174, 1031 cm-1; 1H NMR (300 MHz,

CDCl3): δ 7.37-733 (m, 2H, ArH), 7.32 (m, 3H, ArH), 7.21 (d, 2H, J = 8.7 Hz, ArH), 6.88 (dt, 2H, J = 2.1, 8.8 Hz,

ArH), 5.67 (s, 1H, ArCH), 3.97 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3): δ 159.2, 139.7, 131.6, 128.6, 128.5,

127.8, 127.1, 113.9, 67.9, 55.1.

5-(Azido(4-methoxyphenyl)methyl)-2-methoxyphenol (7): A stirred solution of alcohol 2 (2.0 g, 7.69 mmol) in

acetonitrile (5 mL) at 0 °C was sequentially treated with azidotrimethylsilane (2.5 mL, 19.23 mmol) and ZrCl4 (0.18

g, 0.77 mmol) and stirred for 30 min. Workup as described for 6 and purification of the residue by column

chromatography (60-120 mesh Silica gel, 5% EtOAc in pet. ether) afforded 7 (1.95 g, 89%) as a yellow liquid; IR

(CHCl3): 3508, 2935, 2838, 2091, 1609, 1505, 1238, 1172, 1024, 833, 757 cm-1; 1H NMR (300 MHz, CDCl3): δ

7.21 (d, 2H, J = 8.4 Hz, ArH), 6.89-6.84 (m, 3H, ArH), 6.81 (m, 2H, ArH), 5.61 (brs, 1H, OH), 5.58 (s, 1H, ArCH),

3.88 (s, 3H, OMe), 3.80 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3): δ 159.1, 146.2, 145.6, 133.1, 131.8, 128.5,

118.9, 113.9, 113.6, 110.4, 67.6, 55.9, 55.2.

1-(Azido(4-methoxyphenyl)methyl)naphthalene (8): A stirred solution of alcohol 3 (2.0 g, 7.58 mmol) in

acetonitrile (10 mL) at 0 °C was sequentially treated with azidotrimethylsilane (2.50 mL, 18.95 mmol) and of ZrCl4

(0.18 g, 0.76 mmol) and stirred for 30 min. Workup as described for 6 and purification of the residue by column


(CHCl3): 3052, 2955, 2836, 2093, 1608, 1510, 1303, 1247, 1174, 1031, 781cm-1; 1H NMR (300 MHz, CDCl3): δ

7.90-7.82 (m, 3H, ArH), 7.65 (d, 1H, J = 7.2 Hz, ArH), 7.53-7.49 (m, 1H, ArH), 7.48-7.40 (m, 2H, ArH), 7.27-7.23

(m, 2H, ArH), 6.88-6.83 (m, 2H, ArH), 6.34 (s, 1H, ArCH) 3.77 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3): δ 159.3,

134.6, 133.9, 131.1, 130.4, 128.8, 126.3, 125.7, 125.5, 125.1, 123.6, 114.0, 65.6, 55.1.

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1-(1-Azidoethyl)-4-methoxybenzene (9): A stirred solution of alcohol 4 (2.0 g, 13.16 mmol) in acetonitrile (10

mL) at 0 °C was sequentially treated with azidotrimethylsilane (4.30 mL, 32.90 mmol) and ZrCl4 (0.30 g, 1.31

mmol) and stirred for 30 min. Workup as described for 6 and purification of the residue by column chromatography

(60-120 mesh Silica gel, 5% EtOAc in pet. ether) afforded 9 (2.02 g, 87%) as a yellow liquid; IR (CHCl3): 2931,

2837, 2096, 1512, 1244, 1177, 1033, 831 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.25 (d, 2H, J = 8.7 Hz, ArH), 6.90

(d, 2H, J = 8.7 Hz, ArH), 4.56 (q, 1H, J = 6.8 Hz, ArCH), 3.81 (s, 3H, OMe), 1.50 (d, 3H, J = 6.4 Hz, CH3); 13C

NMR (75 MHz, CDCl3): δ 159.2, 132.6, 127.5, 113.9, 60.5, 55.0, 21.2.

1-(1-Azido-3-methylbutyl)-4-methoxybenzene (10): A stirred solution of alcohol 5 (2.0 g, 10.31 mmol) in

acetonitrile (10 mL) at 0 °C was sequentially treated with azidotrimethylsilane (3.3 mL, 25.78 mmol) and ZrCl4

(0.24 g, 1.03 mmol) and stirred for 30 min. Workup as described for 6 and purification of the residue by column


(CHCl3): 2956, 2931, 2869, 2837, 2091, 1611, 1512, 1244, 1175, 1033, 830 cm-1; 1H NMR (500 MHz, CDCl3): δ

7.23 (d, 2H, J = 8.5 Hz, ArH), 6.91 (d, 2H, J = 8.5 Hz, ArH), 4.42 (t, 1H, J = 7.4 Hz, ArCH), 3.81 (s, 3H, OMe),

1.77-1.70 (m, 1H, CH), 1.67-1.51 (m, 2H, CH2), 0.92 (d, 6H, J = 7.6 Hz, 2 x CH3); 13C NMR (75 MHz, CDCl3): δ

159.3, 131.7, 128.0, 113.9, 63.8, 54.9, 44.7, 24.8, 22.3, 22.1.

1-((4-Methoxyphenyl)(phenyl)methyl)-4-phenyl-1H-1,2,3-triazole (6a): A solution of azide 6 (0.20 g, 0.84

mmol) and phenyl acetylene 11a (0.09 mL, 0.84 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with

sodium-ascorbate (0.01g, 0.04 mmol) followed by CuSO4.5H2O (0.02 g, 0.08 mmol) at room temperature and stirred

for 8 h. Solvent was evaporated from the reaction mixture, residue diluted with water (5 mL) and extracted with

EtOAc (2 x 10 mL) organic layer was washed with brine (5 mL) and dried (Na2SO4). Solvent was evaporated and

purified the residue by column chromatography (60-120 mesh Silica gel, 15% EtOAc in pet. ether) to afford 6a

(0.27 g, 95%) as a white solid; mp 157-159 oC; IR (CHCl3): 3032, 2928, 1609, 1512, 1456, 1250, 1178, 1030, 763,

739 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.81 (d, 2H, J = 7.2 Hz, ArH), 7.60 (s, 1H, CH), 7.45-7.21 (m, 6H, ArH),

7.17-7.07 (m, 5H, ArH, ArCH), 6.91 (d, 2H, J = 8.7 Hz, ArH), 3.82 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3): δ

129.6, 128.8, 128.7, 128.4, 128.1, 127.7, 125.6, 119.5, 114.3, 67.6, 55.3; HRMS (ESI+) m/z calcd for C22H20N3O

(M+ + H) 342.16009, found 342.16022.

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4-Hexyl-1-((4-methoxyphenyl)(phenyl)methyl)-1H-1,2,3-triazole (6b): A solution of azide 6 (0.20 g, 0.84 mmol)

and n-octyne 11b (0.12 mL, 0.84 mmol) in t-BuOH (1 mL) and water (1mL) was treated with sodium-ascorbate

(0.01g, 0.04 mmol) followed by CuSO4.5H2O (0.02 g, 0.08 mmol) at room temperature and stirred for 8 h. Workup

as described for 6a and purification of the residue by column chromatography (60-120 mesh Silica gel, 20% EtOAc

in pet. ether) afforded 6b (0.27 g, 92%) as a pale yellow solid; mp 72-74 oC; IR (CHCl3): 3019, 2926, 2854, 2315,

1514, 1215, 752, 667 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.42-7.30 (m, 3H, ArH, CH), 7.14-7.00 (m, 6H, ArH,

ArCH), 6.88 (d, 2H, J = 8.7 Hz, ArH), 3.81 (s, 3H, OMe), 2.69 (t, 2H, J = 7.6 Hz, CH2), 1.75-1.53 (m, 2H, CH2)

1.42-1.19 (m, 6H, 3 x CH2), 0.86 (t, 3H, J = 6.4 Hz, CH3); 13C NMR (75 MHz, CDCl3): δ 159.5, 148.1, 138.7,

130.3, 129.5, 128.7, 128.2, 127.6, 120.4, 114.1, 67.2, 55.2, 31.4, 29.3, 28.8, 25.7, 22.4, 13.9; HRMS (ESI+) m/z

calcd for C22H28N3O (M+ + H) 350.22269, found 350.22284.

(1-((4-Methoxyphenyl)(phenyl)methyl)-1H-1,2,3-triazol-4-yl)methanol (6c): A solution of azide 6 (0.20 g, 0.836

mmol) and propargyl alcohol 11c (0.05 mL, 0.831 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with


for 8 h. Workup as described for 6a and purification of the residue by column chromatography (60-120 mesh Silica

gel, 50% EtOAc in pet. ether) afforded 6c (0.21g, 85%) as a yellow syrup; IR (CHCl3): 2923, 2852, 2319, 1513,

772, 699 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.39 (s, 1H, CH), 7.38-7.30 (m, 3H, ArH), 7.11-7.00 (m, 5H, ArH,

ArCH ), 6.88 (d, 2H, J = 7.9 Hz, ArH), 4.78 (s, 2H, CH2), 3.80 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3): δ 159.6,

147.4, 138.3, 129.9, 129.5, 128.7, 128.3, 127.6, 121.8, 114.2, 67.6, 56.0, 55.2; HRMS (ESI+) m/z calcd for

C17H17N3O2Na (M+ + Na) 318.12130, found 318.12105.

tert. Butyl (1-((4-methoxyphenyl)(phenyl)methyl)-1H-1,2,3-triazol-4-yl)methylcarbamate (6d): A solution of

azide 6 (0.20 g, 0.70 mmol) and 11d (0.13 g, 0.84 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with

sodium-ascorbate (0.01 g, 0.04 mmol) followed by CuSO4.5H2O (0.02 g, 0.08 mmol) at room temperature and

stirred for 8 h. Workup as described for 6a and purification of the residue by column chromatography (60-120 mesh

Silica gel, 30% EtOAc in pet. ether) afforded 6d (0.30 g, 92%) as a white solid; mp 105-107 oC; IR (CHCl3): 2922,

2852, 2315, 1515, 1214, 754, 667 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.45 (m, 5H, ArH, CH), 7.13-6.99 (m, 4H,

ArH, ArCH), 6.88 (d, 2H, J = 8.3 Hz, ArH), 5.17-5.01 (brs, 1H, NH), 4.37 (d, 2H, J = 5.8 Hz, CH2), 3.81 (s, 3H,

OMe), 1.41 (s, 9H, 3 x CH3); 13C NMR (75 MHz, CDCl3): 159.6, 155.7, 145.0, 138.4, 130.0, 129.5, 128.8, 128.3,

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127.6, 121.8, 114.2, 79.6, 67.6, 55.3, 36.1, 28.3; HRMS (ESI+) m/z calcd for C22H26N4O3Na (M+ + Na) 417.18971,

found 417.18931.

2-Methoxy-5-((4-methoxyphenyl)(4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenol (7a): A solution of azide 7

(0.20 g, 0.70 mmol) and phenyl acetylene 11a (0.07 g, 0.70 mmol) in t-BuOH (1 mL) and water (1mL) was treated

with sodium-ascorbate (0.01 g, 0.03 mmol) followed by CuSO4.5H2O (0.02 g, 0.07 mmol) at room temperature and


Silica gel, 15% EtOAc in pet. ether) afforded 7a (0.26 g, 97%) as a yellow solid; mp 168-170 oC; IR (CHCl3): 3020,

2317, 1214, 742, 667 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.81 (d, 2H, J = 7.2 Hz, ArH), 7.60 (s, 1H, CH), 7.53-

7.21 (m, 4H, ArH), 7.08 (d, 2H, J = 8.7 Hz, ArH), 7.03 (s, 1H, ArCH), 6.9 (dd, 2H, J = 8.7, 2.3 Hz, ArH), 6.69 (d,

1H, J = 1.3 Hz, ArH), 6.62 (dd, 1H, J = 8.3, 1.3 Hz, ArH), 5.75 (brs, 1H, OH), 3.82 (s, 6H, 2 x OMe); 13C NMR (75

MHz, CDCl3): δ 159.6, 147.3, 146.7, 145.9, 131.5, 130.5, 130.3, 129.2, 128.7, 128.1, 125.6, 119.8, 119.5, 114.3,

114.2, 110.7, 67.7, 55.9, 55.3; HRMS (ESI+) m/z calcd for C23H21N3O3Na (M+ + Na) 410.14751, found 410.14551.

5-((4-Hexyl-1H-1,2,3-triazol-1-yl)(4-methoxyphenyl)methyl)-2-methoxyphenol (7b): A solution of azide 7 (0.20

g, 0.70 mmol) and n-octyne 11b (0.1 mL, 0.70 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodim-

ascorbate (0.01 g, 0.15 mmol) followed by CuSO4.5H2O (0.02 g, 0.07 mmol) at room temperature and stirred for 8

h. Workup as described for 6a and purification of the residue by column chromatography (60-120 mesh Silica gel,

20% EtOAc in pet. ether) afforded 7b (0.27 g, 97%) as a yellow syrup; IR (CHCl3): 2924, 2853, 2316, 1215, 771,

667 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.12 (s, 1H, CH), 7.02 (d, 2H, J = 8.4 Hz, ArH), 6.94 (s, 1H, ArH), 6.87

(m, 3H, ArH), 6.62 (s, 1H, ArCH), 6.56 (d, 1H, J = 7.9 Hz, ArH), 3.81 (s, 3H, OMe), 3.79 (s, 3H, OMe), 2.69 (t,

2H, J = 7.4 Hz, CH2), 1.71-1.57 (m, 2H, CH2) 1.44-1.21 (m, 6H, 3 x CH2), 0.86 (t, 3H, J = 5.45 Hz, CH3); 13C NMR

(75 MHz, CDCl3): δ 159.4, 148.1, 146.8, 145.7, 130.6, 130.4, 129.1, 120.9, 120.4, 114.5, 114.1, 110.6, 67.2, 55.8,

31.4, 29.3, 28.8, 25.7, 22.4, 13.9; HRMS (ESI+) m/z calcd for C23H29N3O3Na (M+ + Na) 418.21011, found

418.20992.

5-((4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)(4-methoxyphenyl)methyl)-2-methoxyphenol (7c): A solution of

azide 7 (0.20 g, 1.53 mmol) and propargyl alcohol 11c (0.04 mL, 0.70 mmol) in t-BuOH (1 mL) and water (1 mL)

was treated with sodium-ascorbate (0.01 g, 0.03 mmol) followed by CuSO4.5H2O (0.02 g, 0.07 mmol) at room

temprature and stirred for 8 h. Workup as described for 6a and purification of the residue by column

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chromatography (60-120 mesh Silica gel, 50% EtOAc in pet. ether) afforded 7c (0.21 g, 87%) as a yellow syrup; IR

(CHCl3): 3019, 2922, 2852, 2313, 1214, 768, 667 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.39 (s, 1H, CH), 7.03 (d, J

= 7.9 Hz, 2H, ArH), 6.96 (s, 1H, ArH), 6.88 (d, 3H, J = 7.9 Hz, ArH), 6.65 (s, 1H, ArCH), 6.57 (d, 1H, J = 7.9 Hz,

ArH), 5.90-5.72 (brs, 1H, OH), 4.77 (s, 2H, CH2) 3.80 (s, 3H, OMe), 3.79 (s, 3H, OMe); 13C NMR (75 MHz,

CDCl3): δ 159.5, 147.2,146.8, 145.8, 130.2, 129.9, 129.1, 121.8, 120.9, 114.6, 114.1, 110.7, 67.5, 55.9, 55.3, 56.2;

HRMS (ESI+) m/z calcd for C18H19N3O4Na (M+ + Na) 364.12678, found 364.12451.

tert. Butyl(1-((3-hydroxy-4-methoxyphenyl)(4-methoxyphenyl)methyl)-1H-1,2,3-triazol-4-yl)methylcarbamate

(7d): A solution of azide 7 (0.20 g, 0.70 mmol) and 11d (0.11 g, 0.70 mmol) in t-BuOH (1 mL) and water (1 mL)

was treated with Na-ascorbate (0.01g, 0.03 mmol) followed by CuSO4.5H2O (0.02 g, 0.07 mmol) at room

temperature and stirred for 8 h. Workup as described for 6a and purification of the residue by column

chromatography (60-120 mesh Silica gel, 30% EtOAc in pet. ether) afforded 7d (0.28 g, 91%) as a yellow syrup; IR

(CHCl3): 2924, 2853, 2316, 1215, 771, 667 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.37 (s, 1H, CH), 7.02 (d, 2H, J =

8.5 Hz, ArH), 6.95 (s, 1H, ArCH), 6.91-6.84 (m, 3H, ArH), 6.63 (d, 1H, J = 1.7 Hz, ArH), 6.60-6.53 (dd, 1H, J =

8.1, 1.7 Hz, ArH), 5.76 (brs, 1H, NH ), 5.17-5.04 (brs, 1H, OH), 4.37 (d, J = 5.8 Hz, 2H, CH2), 3.81 (s, 3H, OMe),

3.79 (s, 3H, OMe), 1.41 (s, 9H, 3 x CH3) ; 13C NMR (75 MHz, CDCl3): δ 159.6, 155.7, 146.6, 145.9, 138.4, 131.5,

130.2, 129.2, 121.8, 119.7, 114.2 (2C), 110.6, 77.2, 67.3, 60.4, 55.9, 55.3, 55.3, 28.3; HRMS (ESI+) m/z calcd for

C23H28N4O5Na (M+ + Na) 463.19519, found 463.19299.

1-((4-Methoxy phenyl) (naphthalen-1-yl) methyl)-4-phenyl-1H-1,2,3-triazole (8a): A solution of azide 8 (0.20 g,

0.69 mmol) and phenyl acetylene 11a (0.07 mL, 0.69 mmol) in t-BuOH (1 mL) and water (1mL) was treated with



Silica gel, 15% EtOAc in pet. ether) afforded 8a (0.25 g, 94%) as a white solid; mp 172-174 oC; IR (CHCl3): 2957,

1609, 1511, 1251, 1177, 1030, 757, 693 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.92-7.82 (m, 4H, ArH, CH), 7.79 (d,

2H, J = 7.8 Hz, ArH), 7.53-7.33 (m, 6H, ArH), 7.29 (t, 1H, J = 7.2 Hz, ArH), 7.11 (d, 2H, J = 8.3 Hz, ArH), 6.95-

6.87 (m, 3H, ArH, ArCH), 3.81 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3): δ 159.7, 147.3, 134.1, 133.8, 130.6,

130.5, 129.7, 129.5, 129.4, 128.9, 128.7, 128.1, 127.1, 126.1, 125.7, 125.6, 125.1, 123.0, 120.1, 114.4, 64.7, 55.3;

HRMS (ESI+) m/z calcd for C52H43N6O2 (2M+ + H) 783.34420, found 783.34424.

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4-Hexyl-1-((4-methoxyphenyl)(naphthalen-1-yl)methyl)-1H-1,2,3-triazole (8b): A solution of azide 8 (0.20 g,

0.69 mmol) and n-octyne 11b (0.1 mL, 0.69 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodium-



20% EtOAc in pet. ether) afforded 8b (0.25 g, 91%) as a yellow syrup; IR (CHCl3): 2926, 2854, 1610, 1511, 1250,

1177, 1034, 784, 757 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.90-7.80 (m, 3H, ArH), 7.76 (s, 1H, CH), 7.51-7.37 (m,

3H, ArH), 7.07-7.03 (m, 2H, ArH), 7.02 (s, 1H, ArCH), 6.90-6.86 (m, 2H, ArH), 6.85-6.82 (m, 1H, ArH), 3.80 (s,

3H, OMe), 2.67 (t, 2H, J = 7.6 Hz, CH2), 1.65-1.58 (m, 2H, CH2) 1.33-1.22 (m, 6H, 3 x CH2), 0.85 (t, 3H, J = 5.5

Hz, CH3 ); 13C NMR (125 MHz, CDCl3): δ 159.5, 148.0, 134.4, 133.8 130.7, 130.1, 129.3, 128.8, 126.9, 126.0,

125.6, 125.1, 123.1, 121.2, 114.3, 77.2, 64.4, 55.2, 31.4, 29.3, 28.8, 25.7, 22.5, 13.9; HRMS (ESI+) m/z calcd for

C26H29N3ONa (M+ + Na) 422.22028, found 422.21792.

(1-((4-Methoxyphenyl)(naphthalen-1-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (8c): A solution of azide 8

(0.20 g, 0.69 mmol) and propargyl alcohol 11c (0.04 mL, 0.69 mmol) in t-BuOH (1 mL) and water (1 mL) was

treated with sodium-ascorbate (0.01 g, 0.03 mmol) followed by CuSO4.5H2O (0.02 g, 0.07 mmol) at room


chromatography (60-120 mesh Silica gel, 50% EtOAc in pet. ether) afforded 8c (0.21 g, 87%) as a yellow solid; mp

90-92 oC; IR (CHCl3): 3306, 2926, 1610, 1512, 1251, 1177, 1031, 785, 754 cm-1 ; 1H NMR (500 MHz, CDCl3): δ

7.98-7.75 (m, 4H, CH), 7.56-7.35 (m, 3H, ArH), 7.30 (s, 1H, CH), 7.06 (d, 2H, J = 8.7 Hz, ArH), 6.93-6.81 (m, 3H,

2 ArH, ArCH), 4.76 (s, 2H, CH2) 3.80 (s, 3H, OMe), 2.33 (brs, 1H, OH); 13C NMR (75 MHz, CDCl3): δ 159.6,

147.1, 133.8, 133.7, 130.4, 129.4, 129.3, 128.8, 126.9, 126.1 125.6, 125.1, 12.8 114.4, 77.2, 64.8, 55.9, 55.2, 29.6;

HRMS (ESI+) m/z calcd for C42H39N6O4 (2M+ + H) 691.30273, found 691.30292.

tert. Butyl(1-((4-methoxy phenyl)(naphthalen-1-yl)methyl)-1H-1,2,3-triazol-4-yl) methyl carbamate (8d): A

solution of azide 8 (0.20 g, 0.69 mmol) and 11d (0.11 g, 0.69 mmol) in t-BuOH (1 mL) and water (1 mL) was

treated with sodium-ascorbate (0.01 g, 0.03 mmol) followed by CuSO4.5H2O (0.02 g, 0.07 mmol) at room


chromatography (60-120 mesh Silica gel, 30% EtOAc in pet. ether) afforded 8d (0.27 g, 89%) as a light yellow

solid; mp 66-68 oC; IR (CHCl3): 3351, 2928, 1700, 1168, 1229, 1170, 1031, 753 cm-1; 1H NMR (500 MHz, CDCl3):

8

δ 7.91-7.84 (m, 2H, ArH), 7.81 (d, 1H, J = 8.9 Hz, ArH), 7.77 (s, 1H, CH) 7.51-7.42 (m, 2H, ArH), 7.41-7.36 (m,

1H, ArH), 7.28 (s, 1H, ArCH), 7.07-7.02 (m, 2H, ArH), 6.90-6.28 (m, 2H, ArH), 6.85-6.82 (m, 1H, ArH), 5.13-5.00

(brs, 1H, NH), 4.35 (d, 2H, J = 5.6 Hz, CH2), 3.80 (s, 3H, OMe), 1.39 (s, 9H, 3 x CH3); 13C NMR (75 MHz, CDCl3):

δ 159.7, 155.7, 134.0, 133.8, 130.6, 129.8, 129.5, 129.3, 128.9, 127.0, 126.1, 125.7, 125.1, 122.9, 122.5, 114.4, 79.6,


1-(1-(4-Methoxyphenyl)ethyl)-4-phenyl-1H-1,2,3-triazole (9a): A solution of azide 9 (0.20 g, 1.12 mmol) and

phenyl acetylene 11a (0.12 mL, 1.12 mmol) in t-BuOH (1 mL) and water (1mL) was treated with sodium-ascorbate

(0.01 g, 0.06 mmol) followed by CuSO4.5H2O (0.03 g, 0.11 mmol) was added and stirred for 8 h. Workup as

described for 6a and purification of the residue by column chromatography (60-120 mesh Silica gel, 15% EtOAc in

pet. ether) afforded 9a (0.29 g, 93%) as a white solid; mp 122-124 oC; IR (CHCl3): 3019, 1515, 1214, 742, 697, 626

cm-1; 1H NMR (300 MHz, CDCl3): δ 7.80-7.77 (m, 2H, ArH), 7.58-7.57 (m, 1H, ArH), 7.42-7.26 (m, 5H, CH, ArH),

6.92-6.87 (m, 2H, ArH), 5.87-5.80 (q, 1H, J = 6.8 Hz, ArCH), 3.79 (s, 3H, OMe), 1.99 (d, 3H, J = 6.8 Hz, CH3); 13C

NMR (75 MHz, CDCl3): δ 159.5, 147.4, 131.7, 130.6, 128.6, 127.8, 127.7, 125.5, 118.2, 114.2, 59.6, 55.2, 21.2;

HRMS (ESI+) m/z calcd for C17H18N3O (M+ + H) 280.14444, found 280.14442.

4-Hexyl-1-(1-(4-methoxyphenyl)ethyl)-1H-1,2,3-triazole (9b): A solution of azide 9 (0.20 g, 1.13 mmol) and n-

octyne 11b (0.16 mL, 1.13 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodium-ascorbate (0.01 g,

0.06 mmol) followed by CuSO4.5H2O (0.03 g, 0.11 mmol) at room temperature and stirred for 8 h. Workup as

described for 6a and purification of the residue by column chromatography (60-120 mesh Silica gel, 20% EtOAc in

pet. ether) afforded 9b (0.30 g, 93%) as a pale yellow solid; mp 43-45 oC; IR (CHCl3): 2928, 2856, 1612, 1514,

1249, 1034, 833, 749 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.22 (d, 2H, J = 8.7 Hz, ArH), 7.12 (s, 1H, CH), 6.86 (d,

2H, J = 8.7 Hz, ArH), 5.73 (q, 1H, J = 7.2 Hz, ArCH), 3.79 (s, 3H, OMe), 2.66 (t, 2H, J = 7.6 Hz, CH2), 1.92 (d,

3H, J = 6.8 Hz, CH3), 1.64-1.57 (m, 2H, CH2), 1.34-1.28 (m, 6H, 3 x CH2) 0.86 (m, 3H, CH3) ; 13C NMR (75

MHz, CDCl3): δ 159.3, 148.1, 132.1, 127.6, 118.9, 114.0, 59.2. 55.1, 31.3, 29.2, 28.7, 25.6, 22.3, 21.2, 13.8; HRMS

(ESI+) m/z calcd for C17H26N3O (M+ + H) 280.20704, found 280.20688.

(1-(1-(4-Methoxyphenyl)ethyl)-1H-1,2,3-triazol-4-yl)methanol (9c): A solution of azide 9 (0.20 g, 1.13 mmol)

and propargyl alcohol 11c (0.06 mL, 1.13 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodium-

9

ascorbate (0.01 g, 0.11 mmol) followed by CuSO4.5H2O (0.03 g, 0.11 mol) at room temperature and stirred for 8 h.

Workup as described for 6a and purification of the residue by column chromatography (60-120 mesh Silica gel,

50% EtOAc in pet. ether) afforded 9c (0.23 g, 89%) as a yellow syrup; IR (CHCl3): 2921, 2851, 2310, 1514, 1259,

1218, 1140, 772 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.38 (s, 1H, CH), 7.23 (d, 2H, J = 8.43 Hz, ArH), 6.89 (d,

2H, J = 8.43 Hz, ArH) 5.77 (q, 1H, J = 6.9 Hz, ArCH), 4.75 (s, 2H, CH2), 3.80 (s, 3H, OMe), 1.95 (d, 3H, J = 6.9

Hz , CH3), 1.82-1.66 (bs, 1H, OH); 13C NMR (75 MHz, CDCl3): δ 159.5, 147.5, 131.5, 127.8, 120.4, 114.2, 59.7,

55.8, 55.2, 21.1; HRMS (ESI+) m/z calcd for C12H16N3O2 (M+ + H) 234.12370, found 234.12392.

tert. Butyl (1-(1-(4-methoxyphenyl)ethyl)-1H-1,2,3-triazol-4-yl)methylcarbamate (9d): A solution of azide 9

(0.20 g, 1.13 mmol) and 11d (0.17 g, 1.13 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodium-



30% EtOAc in pet. ether) afforded 9d (0.34 g, 91%) as a white solid; mp 124-126 oC; IR (CHCl3): 3019, 2926,

2855, 1214, 746, 667 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.37 (s, 1H, CH), 7.21 (d, 2H, J = 8.3 Hz, ArH), 6.88 (d,

2H, J = 8.3 Hz, ArH), 5.74 (q, 1H, J = 6.8 Hz, ArCH), 5.20-5.07 (brs, 1H, NH), 4.34 (d, 2H, J = 5.6 Hz, CH2), 3.80

(s, 3H, OMe), 1.93 (d, 3H, J = 6.8 Hz, CH3) 1.41 (s, 9H, 3 x CH3); 13C NMR (75 MHz, CDCl3): δ 159.6, 115.7,

145.2, 131.7, 127.8, 120.3, 114.2, 79.6, 59.7, 55.3, 36.1, 28.3, 21.2; HRMS (ESI+) m/z calcd for C17H25N4O3 (M+ +

H) 333.19212, found 333.19204.

1-(1-(4-Methoxyphenyl)-3-methylbutyl)-4-phenyl-1H-1,2,3-triazole (10a): A solution of azide 10 (0.20 g, 0.91

mmol) and phenyl acetylene 11a (0.17 g, 0.91 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodium-

ascorbate (0.08 g, 0.04 mmol) followed by CuSO4.5H2O (0.02 g, 0.09 mmol) at room temperature and stirred for 8 h.

Workup as described for 6a and purification of the residue by column chromatography (60-120 mesh Silica gel,

15% EtOAc in pet. ether) afforded 10a (0.27 g, 91%) as a white solid; mp 111-113 oC; IR (CHCl3): 3722, 3641,

2924, 2314, 1215, 770, 667 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.80 (d, 2H, J = 7.2 Hz, ArH), 7.66 (s, 1H, CH),

7.43-7.21 (m, 5H, ArH), 6.89 (d, 2H, J = 8.7 Hz, ArH), 5.71 (t, 1H, J = 7.6 Hz, ArCH), 3.80 (s, 3H, OMe), 2.44-

2.31 (ddd, 1H, J = 6.4, 8.7, 13.9 Hz, CH), 2.25-2.05 ( m, 1H, CH), 1.47 (m, 1H, CH), 0.98 (dd, 6H, J = 6.8, 13.2 Hz,

2 x CH3); 13C NMR (75 MHz, CDCl3): δ 159.6, 147.5, 131.0, 130.6, 128.7, 128.3, 127.9, 125.5, 118.1, 114.2, 62.7,

55.2, 43.9, 24.8, 22.3, 22.2; HRMS (ESI+) m/z calcd for C20H23N3ONa (M+ + Na) 344.17333, found 344.17205.

10

4-Hexyl-1-(1-(4-methoxyphenyl)-3-methylbutyl)-1H-1,2,3-triazole (10b): A solution of azide 10 (0.20 g, 0.91

mmol) and n-octyne 11b (0.13 mL, 0.91 mmol) in t-BuOH (1 mL) and water (1 mL) was treated with sodium-



20% EtOAc in pet. ether) afforded 10b (0.29 g, 96%) as a pale yellow solid; mp 58-60 oC; IR (CHCl3): 2924, 2854,

2314, 1219, 772 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.27 (d, 2H, J = 8.7 Hz, ArH), 7.17 (s, 1H, CH), 6.87 (d, 2H,

J = 8.7 Hz, ArH), 5.62 (t, 1H, J = 7.9 Hz, ArCH), 3.79 (s, 3H, OMe), 2.65 (t, 2H, J = 7.9 Hz, CH2), 2.35-2.21 (ddd,

1H, J = 6.8, 8.3, 13.9 Hz, CH), 2.12-2.00 (m, 1H, CH), 1.68-1.53 (m, 1H, CH), 1.48-1.13 (m, 8H, 4 x CH2), 1.0-0.77

(m, 9H, 3 x CH3); 13C NMR (75 MHz, CDCl3): δ 159.4, 148.3, 131.3, 128.2, 118.9, 114.1, 62.3, 55.2, 43.9, 31.4,

29.3, 28.5, 25.7, 24.7, 22.4, 22.2, 13.9; HRMS (ESI+) m/z calcd for C20H32N3O (M+ + H) 330.25399, found

330.25409.

(1-(1-(4-Methoxyphenyl)-3-methylbutyl)-1H-1,2,3-triazol-4-yl)methanol (10c): A solution of azide 10 (0.20 g,

0.91 mmol) and propargyl alcohol 11c (0.05 mL, 0.91mmol) in t-BuOH (1 mL) and water (1 mL) was treated with



Silica gel, 20% EtOAc in pet. ether) afforded 10c (0.21 g, 86%) as a yellow syrup; IR (CHCl3): 2921, 2851, 2310,

1514, 1259, 1218, 1140, 772 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.47 (s, 1H, CH), 7.29 (d, 2H, J = 8.7 Hz, ArH),

6.88 (d, 2H, J = 8.7 Hz, ArH), 5.65 (t, 1H, J = 7.9 Hz, ArCH), 4.74 (s, 2H, CH2), 3.79 (s, 3H, OMe), 2.30 (ddd, 1H,

J = 6.8, 8.5, 13.9 Hz, CH), 2.18-2.03 (m, 1H, CH), 1.41 (m, 1H, CH), 0.95 (dd, 6H, J = 6.6 Hz, J = 10.9 Hz, 2 x

CH3); 13C NMR (75 MHz, CDCl3): δ 159.6, 149.9, 130.7, 128.3, 120.3, 114.3, 62.8, 56.2, 55.3, 43.8, 24.7, 22.2;

HRMS (ESI+) m/z calcd for C15H22N3O (M+ + H) 276.17065, found 276.17090.

tert. Butyl (1-(1-(4-methoxy phenyl)-3-methyl butyl)-1H-1,2,3-triazol-4-yl) methyl carbamate (10d): A solution

of azide 10 (0.20 g, 0.91 mmol) and 11d (0.14 g, 0.91mmol) in t-BuOH (1 mL) and water (1 mL) was treated with


for 8 h. Workup as described for 6a and purification of the residue by column chromatography (60-120 mesh Silica

gel, 30% EtOAc in pet. ether) afforded 10d (0.32 g, 93%) as a pale yellow solid; mp 104-106 oC; IR (CHCl3): 3020,

2318, 1214, 745, 667 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.43 (s, 1H, CH), 7.27 (d, 2H, J = 8.5 Hz, ArH), 6.87 (d,

11

2H, J = 8.5 Hz, ArH), 5.63 (t, 1H, J = 7.9 Hz, ArCH), 5.10-5.01 (brs, 1H, NH), 4.34 (d, 2H, J = 5.9 Hz, CH2), 3.79

(s, 3H, OMe), 2.29 (m, 1H, CH), 2.07 (m, 1H, CH), 1.66 (m, 1H, CH), 1.41 (s, 9H, 3 x CH3), 0.95 (dd, J = 6.5, 18.5

Hz, 6H, 2 x CH3); 13C NMR (75 MHz, CDCl3): δ 159.5, 155.7, 145.1, 130.9, 128.2, 120.3, 114.2, 79.5, 62.7, 55.2,


12

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O

N3

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

Figure S1: 1H NMR Spectrum of 6 (300 MHz, CDCl3)

13

C NMR Spectrum of 6 (75 MHz, CDCl3)

13

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

50506060707080809090100100110110120120130130140140

MeO

NN

N

Ph

Figure S2: 1H NMR Spectrum of 6a (500 MHz, CDCl3)

13

C NMR Spectrum of 6a (75 MHz, CDCl3)

14

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

MeO

NN

N

Figure S3:1H NMR Spectrum of 6b (300 MHz, CDCl3)

13

C NMR Spectrum of 6b (75 MHz, CDCl3)

101020203030404050506060707080809090100100110110120120130130140140150150160160

15

-0.5-0.50.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

50506060707080809090100100110110120120130130140140150150160160

MeO

NN

N

OH

Figure S4: 1H NMR Spectrum of 6c (500 MHz, CDCl3)

13

C NMR Spectrum of 6c (75 MHz, CDCl3)

16

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MeO

NN

N

NHBoc

-0.5-0.50.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

FigureS5: 1H NMR Spectrum of 6d (500 MHz, CDCl3)

13C NMR Spectrum of 6d (75 MHz, CDCl3)

17

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

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OMe

OH

MeO

N3


13


18

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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MeO

NN

N

Ph

OH

MeO


13


19

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MeO

NN

N

OH

MeO

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

Figure S8: 1

H NMR Spectrum of 7b (300 MHz, CDCl3)

13


20

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5

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MeO

NN

N

MeO

OH

OH

Figure S9:1H NMR Spectrum of 7c (500 MHz, CDCl3)

13


21

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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MeO

NN

N

NHBoc

O OH

Figure S10: 1H NMR Spectrum of 7d (300 MHz, CDCl3)


22

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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N3

O

Figure S11:1H NMR Spectrum of 8 (300 MHz, CDCl3)

13


23

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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OMe

N

N

N

Ph


13


24

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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OMe

N

N

N

Figure S13: 1H NMR Spectrum of 8b (500 MHz, CDCl3)

13C NMR Spectrum of 8b (125 MHz, CDCl3)

25

-0.5-0.50.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

NN

N

O

OH

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Figure S14: 1

H NMR Spectrum of 8c (500 MHz, CDCl3)

13


26

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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N

N

N

NHBoc


13

C NMR Spectrum of 8d (75 MHz, CDCl3)

27

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O

N3


13


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MeO

NN

N

Ph


13C NMR Spectrum of 9a (75 MHz, CDCl3)

29

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MeO

NN

N

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13C NMR Spectrum of 9b (75 MHz, CDCl3)

30

0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.5


13


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13

C NMR Spectrum of 9d (75 MHz, CDCl3)

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O

N3


13C NMR Spectrum of 10 (75 MHz, CDCl3)

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MeO

N NN

Ph

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13


34

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NN

N


13


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MeO

N NN

OH


13


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0.00.00.50.51.01.01.51.52.02.02.52.53.03.03.53.54.04.04.54.55.05.05.55.56.06.06.56.57.07.07.57.58.08.0

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MeO

NN

N

NHBoc



37

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Figure S26: 1H NMR Spectrum of a mixture of 6 and 1 (300 MHz, CDCl3), Reaction in CH2Cl2

38

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Figure S27: 1H NMR Spectrum of a mixture of 6 and 1 (300 MHz, CDCl3), Reaction in Toluene

39

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Figure S28: 1H NMR Spectrum of a mixture of 6 and 1 (300 MHz, CDCl3), Reaction in 1,4 Dioxane

40

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Figure S29: 1H NMR Spectrum of a mixture of 6 and 1 (300 MHz, CDCl3), Reaction in CH3CN

41

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Figure S30: 1H NMR Spectrum of a mixture of 6 and 1 (300 MHz, CDCl3), Reaction in Nitromethane

zrcl 4 catalyzed c o bond to c n bond formation: synthesis of · 1 zrcl 4 catalyzed c-o bond to c-n...

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