Chelation-Assisted, Copper(II) Acetate-Accelerated Azide-Alkyne Cycloaddition

Transcription

1 Chelation-Assisted, Copper(II) Acetate-Accelerated Azide-Alkyne Cycloaddition Gui-Chao Kuang, Heather A. Michaels, J. Tyler Simmons, Ronald J. Clark, and Lei Zhu* Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL , USA. Supporting Information Table of Contents: 1. Syntheses and characterizations of carbon azide substrates. S2 2. Syntheses and characterizations of triazole product molecules. S6 3. Effect of competing ligands on the Cu(Ac) 2 -AAC reactions. S11 4. Procedure for preparing T1/Cu(Cl 4 ) 2 complex. S12 5. Procedure for preparing T6/Cu(Cl 4 ) 2 complex. S13 6. Procedure for preparing T6/Zn(Cl 4 ) 2 complex. S H and 13 C MR spectra of new compounds. S14 S1

2 1. Syntheses and characterizations of carbon azide substrates. 4 3 Compound 4. 1 The general procedure for preparing carbon azide substrates can be found in the Experimental Section of the Article. For compound 4, DMS was used as solvent in the reaction in place of CH 3 C. The isolated yield of compound 4 was 29%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 3.38 (t, J = 6.2 Hz, 2H), 2.68 (t, J = 6.3 Hz, 2H), 2.58 (s, 4H), 1.78 (s, 4H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 54.7, 54.0, 50.0, Compound 5. 1 DMS was used as solvent in place of CH 3 C in the reaction. The isolated yield of compound 5 was 73%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 3.32 (t, J = 6.3 Hz, 2H), 2.55 (t, J = 6.2 Hz, 2H), 2.40 (t, J = 4.5 Hz, 4H), (m, 4H), 1.42 (q, J = 5.1 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 57.7, 54.5, 48.3, 25.8, H 2 Br HBr (a) H 2 3 (b) 3 6 Scheme S1. (a) a 3, H 2, 75 ºC, 18 h; (b) Pyridinecarboxaldehyde, ClCH 2 CH 2 Cl, abh(ac) 3, rt, 3 h. 2-Azidoethylamine. 2-Bromoethylamine hydrobromide (5 g, 24.8 mmol) was dissolved in water (35 ml) in a 100-mL round-bottom flask equipped with a magnetic stir bar. To the reaction flask was added sodium azide (3.6 g, 55 mmol) and the reaction was refluxed at 75 ºC overnight (~18 h). The reaction vessel was then removed from the oil bath and cooled to rt before sodium hydroxide (976 mg, 24.4 mmol) was carefully added. The reaction mixture was extracted with CH 2 Cl 2 and the organic fractions were combined. A majority of the solvent was removed on a rotary evaporator with no heating from the water bath. The product is volatile. Therefore, further removal of the residual solvent was not conducted. The crude S2

3 azide product was used directly in the next step. 1 H MR (300 MHz, DMS-d 6 ): δ/ppm 3.25 (d, J = 6.0 Hz, 2H), 2.71 (d, J = 6.0 Hz, 2H). Compound Azidoethylamine obtained from the previous step (2.13 g, 24.8 mmol) was dissolved in 1,2-dichloroethane (50 ml) in a 100-mL round-bottom equipped with a magnetic stir bar. To the flask was added pyridinecarboxaldehyde (2.67 g, 25 mmol). The reaction was allowed to stir at rt for 30 min before sodium triacetoxyborohydride (6.36 g, 30 mmol) was slowly added and the reaction was allowed to stir at rt for ~3 h. The reaction was extracted with CH 2 Cl 2 and the crude 1 H MR showed complete conversion of 2-azidoethylamine. However, there was a 1:1 mixture of 6 and the secondary amine by-product. Rather than separating the two components, the product mixture was re-dissolved in 1,2-dichloroethane and the reductive amination was carried out again. The reaction mixture was extracted with CH 2 Cl 2 and crude 1 H MR showed nearly pure product with a small fraction of unreacted pyridinecarboxaldehyde. The product was purified on a alumina column to afford a dark yellow oil 6 in 39% yield (2.56 g, 9.6 mmol) over two steps from 2-bromoethylamine hydrobromide. 1 H MR (300 MHz, CDCl 3 ): δ/ppm 8.48 (d, J = 4.6 Hz, 2H), 7.63 (tt, J = 1.4, 7.6 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.11 (t, J = 6.0 Hz, 2H), 3.84 (s, 4H), 3.29 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H). F (a) F Br + F Br Br (b) F F Scheme S2. (a) BS, AIB, CCl 4, reflux, overnight. (b) a 3, DMS, 18-crown-6, Bu 4 I, 70 ºC, overnight. 2-Bromomethyl-6-fluoropyridine and 2,2-dibromomethyl-6-fluoropyridine. 2-Fluoro-6-methylpyridine (2.08 g, 19.2 mmol), BS (3.44 g, 19.2 mmol) and AIB (0.30 g, 1.92 mmol) were dissolved in CCl 4 (30 ml). The solution was heated to reflux for overnight under argon protection before cooling down to rt. The solvent was removed under vacuum S3

4 and the residue was partitioned between H 2 and CH 2 Cl 2. The combined organic fractions were dried over anhydrous a 2 S 4, after which solvent was removed via evaporation under vacuum. 2-Bromomethyl-6-fluoropyridine and 2,2-dibromomethyl-6-fluoropyridine were isolated using silica chromatography eluted by hexanes/ch 2 Cl 2 (1/1). 2-Bromomethyl-6-fluoropyridine 3 was obtained at 40% (1.45 g). 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.80 (q, J = 7.6 Hz, 1H), 7.32 (dd, J = 2.5, 2.0 Hz, 1H), 6.88 (dd, J = 2.5, 2.6 Hz, 1H), 4.47 (s, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 164.3, 161.2, 155.5, 142.0, 141.9, 109.2, 108.7, 32.2 (More 13 C signals were recorded than the number of distinct carbon atoms due to the splitting of 19 F-bonded carbon. 2-Dibromomethyl-6-fluoropyridine was obtained at 15% (0.54 g). 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.88 (q, J = 7.9 Hz, 1H), 7.64 (dd, J = 2.0, 2.0 Hz, 1H), 6.91 (dd, J = 2.8, 2.7 Hz, 1H), 6.54 (s, 1H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 163.3, 160.1, 157.0, 156.9, 142.5, 118.7, 110.6, 110.1, 39.3 (More 13 C signals were recorded than the number of distinct carbon atoms due to the splitting of 19 F-bonded carbon). HRMS (ESI): calcd. (C 6 H 4 Br 2 F+H + ) , found Compound 8. 2-Bromomethyl-6-fluoropyridine (380 mg, 2 mmol) was dissolved in DMS (5 ml). 18-Crown-6 (catalytic amount), Bu 4 I (catalytic amount), and a 3 were added sequentially. The solution was heated to 70 ºC and stirred overnight before cooling down to rt. EtAc (50 ml) was added into the reaction mixture and the white precipitate was removed by filtration. The solution was washed with basic brine (3 50 ml, ph 11) and saturated H 4 Cl solution (2 50 ml) sequentially. The organic portion was dried over anhydrous a 2 S 4 before solvent was evaporated under vacuum to afford compound 8 (238 mg, 78%). 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.68 (q, J = 7.6 Hz, 1H), 7.09 (dd, J = 2.5, 2.0 Hz, 1H), 6.75 (dd, J = 2.5, 2.6 Hz, 1H), 4.29 (s, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 164.6, 161.4, 154.8, 141.9, 141.8, 118.9, 109.0, 108.5, 54.7 (More 13 C signals were recorded than the number of distinct carbon atoms due to the splitting of 19 F-bonded carbon). MS (CI) calcd. (C 6 H 5 F 4 +H + ) 152.1, found Compound 9 was prepared using the same procedure for synthesizing compound 8. The isolated yield was 70%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.90 (q, J = 7.9 Hz, 1H), 7.31 (dd, J = 2.1, 2.2 Hz, 1H), 6.99 (dd, J = 2.6, 2.7 Hz, 1H), 5.69 (s, 1H). 13 C MR (75 MHz, S4

5 CDCl 3 ): δ (ppm) 164.6, 161.3, 152.6, 142.4, 142.3, 118.1, 110.9, 110.4, 77.4 (More 13 C signals were recorded than the number of distinct carbon atoms due to the splitting of 19 F-bonded carbon). Compound 10 was prepared using the same procedure for synthesizing 3 10 compound 4. The isolated yield was 48%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 3.28 (t, J = 6.7 Hz, 2H), 2.33 (t, J = 7.0 Hz, 6H), (m, 2H), 1.54 (t, J = 5.1 Hz, 4H), 1.39 (s, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 56.0, 54.4, 49.6, 26.2, 25.8, Compound 11 4 was prepared using the same procedure for synthesizing compound 4. The isolated yield was 69%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 8.56 (d, J = 4.8 Hz, 1H), (m, 1H), (m, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.33 (t, J = 6.9 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 157.8, 149.4, 136.4, 123.4, 121.7, 50.5, Br H (a) 3 H 12 Scheme S3. (a) a 3, H 2, rt, 42 h, 54%. Compound This is a common procedure for the preparation of compounds 12 and 13. Bromoacetic acid (1.389 g, 10 mmol) was dissolved in H 2 (10 ml) followed by the addition of 18-crown-6 (catalytic amount) and tetrabutylammonium iodide (catalytic amount) sequentially. The reaction flask was kept in an ice bath before a 3 (1.30 g, 20 mmol) was added. The reaction mixture was stirred for 42 h at rt and partitioned between an acidic aqueous solution (ph 1.9) and CH 2 Cl 2. The combined organic fractions were dried over anhydrous a 2 S 4 before the solvent was evaporated under vacuum to afford compound 12 (0.545 g, 54%). 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.60 (s, 1H), 3.97 (s, 2H). S5

6 3 13 H Compound The isolated yield was 75%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 11.9 (s, 1H), 3.57 (t, J = 6.4 Hz, 2H), 2.63 (t, J = 6.4 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 177.4, 46.2, The procedure for preparing compounds 14, 15, and 17 is the same as that for synthesizing compound Compound The isolated yield was 86%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.33 (t, J = 7.4 Hz, 2H), (m, 3H), 4.16 (t, J = 5.1 Hz, 2H), 3.60 (t, J = 4.9 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 158.0, 129.4, 121.2, 114.4, 66.7, Ph Compound The isolated yield was 57%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) (m, 5H), 4.59 (s, 2H), 3.67 (t, J = 4.5 Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 137.6, 128.3, 127.6, 127.5, 73.1, 68.7, S 3 17 Compound 17. The isolated yield was 64%. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 3.42 (t, J = 7.0 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.55 (q, J = 7.4 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 50.9, 30.6, 26.0, MS (CI): calcd. (C 4 H 9 3 S+H + ) 132.1, found Syntheses and characterizations of triazole product molecules. T0 Compound T0. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.75 (d, J = 8.7 Hz, 2H), 7.65 (s, 1H), 6.95 (d, J = 8.7 Hz, 2H), 4.37 (t, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.93 (t, J = 7.1 Hz, 2H), 1.24 (dd, J = 4.0, 7.7 Hz, 10H), 0.86 (t, J = 6.2 Hz, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.5, 147.5, 126.9, 123.4, 118.4, 114.1, 55.2, 50.3, 31.6, 30.3, 28.9, 28.8, 26.4, 22.5, HRMS (ESI): calcd. (C 17 H H + ) , found S6

7 T1 Compound T1. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 8.62 (d, J = 4.5 Hz, 1H), 7.76 (s, 1H), 7.70 (td, J = 1.8, 7.8 Hz, 3H), 7.22 (t, J = 7.2 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.69 (s, 2H), 3.83 (s, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.5, 154.5, 149.6, 147.9, 137.2, 126.9, 123.2, 123.1, 122.3, 119.2, 114.1, 55.5, HRMS (ESI): calcd. (C 15 H H + ) , found Ph T3 Compound T3. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) (m, 3H), 7.42 (d, J = 7.4 Hz, 4H), 7.17 (d, J = 7.5 Hz, 3H), 7.06 (d, J = 8.7 Hz, 2H), 5.73 (s, 2H), 5.35 (s, 2H), 3.96 (s, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.5, 148.1, 135.3, 128.9, 128.1, 126.8, 126.7, 122.8, 118.7, 114.0, 55.1, 49.9, HRMS (ESI): calcd. (C 20 H H + ) , found T4a Compound T4a. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.79 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.48 (t, J = 6.5 Hz, 2H), 3.81 (s, 3H), 2.97 (s, 2H), 2.55 (s, 4H), 1.77 (s, 4H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.4, 147.4, 126.9, 123.5, 119.2, 114.1, 55.5, 55.2, 54.0, 49.3, HRMS (ESI): calcd. (C 15 H H + ) , found Compound T4b. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) T4b 8.70 (d, J = 9.3 Hz, 1H), (m, 9H), 4.65 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 2.64 (s, 4H), 1.83 (s, 4H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 147.2, 131.4, 131.2, 130.9, 128.6, 128.0, 127.7, 127.3, 127.1, 126.0, 125.7, 125.3, 125.1, 125.0, 124.8, 123.5, 55.6, 54.1, 49.6, HRMS (ESI): calcd. (C 24 H H + ) , found T5 Compound T5. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.83 (s, 1H), 7.72 (d, J = 6.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.45 (t, J = 6.4 Hz, 2H), 3.81 (s, 3H), 2.75 (t, J = 6.4 Hz, 2H), 2.43 (s, 4H), (m, 4H), (m, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.3, 147.2, 126.8, 123.5, 119.4, 114.0, 58.1, 55.1, 54.4, 47.7, 25.9, HRMS (ESI): calcd. (C 16 H H + ) S7

8 , found Py Py T6 Br Compound T6. Azide 6 (53 mg, mmol) was added to a vial equipped with a magnetic stir bar. To the vial was added 4-bromophenylacetylene (34.7 mg, mmol). MeH (500 μl) was added and stirring was turned on. Simultaneously, aqueous Cu(Ac) 2 (0.4 M, 25 L, 0.01 mmol) was added to the vial. After 10 min, TLC analysis showed complete conversion of the acetylene reactant. The reaction mixture was diluted with CH 2 Cl 2 and the solvent was then removed by rotary evaporation. The residue was loaded on a short plug of alumina gel and the product was isolated in 88%. 1 H MR (300 MHz, CDCl 3 ): δ/ppm 8.52 (d, J = 4.6 Hz, 2H), 8.00 (s, 1H), (m, 4H), 7.52 (td, J = 1.6, 6.1 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.13 (m, 2H), 4.51 (t, J = 5.6 Hz, 2H), 3.88 (s, 4H), 3.09 (t, J = 5.8 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ/ppm 158.6, 149.3, 146.4, 136.7, 132.2, 130.1, 127.3, 123.4, 122.5, 121.9, 121.0, 60.3, 53.8, HRMS (ESI): calcd. (C 22 H 21 Br 6 +H + ) , found Ph Ph Compound T H MR (300 MHz, CDCl 3 ): δ (ppm) 7.29 (m, 6H), 7.20 (t, J = 6.4 Hz, 3H), 7.01 (t, J = 7.6 Hz, 6H), 6.80 (s, 3H), 4.11 (m, 6H), 3.35 (m, 6H). T7 Ph Compound T8. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 8.04 F T8 (s, 1H), (m, 3H), 7.10 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 2.5 Hz, 1H), 5.77 (s, 2H), 3.99 (s, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 164.6, 161.4, 159.6, 153.3, 153.2, 148.1, 142.3, 142.2, 126.9, 123.0, 119.5, 119.4, 114.1, 109.6, 109.1, 55.2, 54.5 (More 13 C signals were recorded than the number of distinct carbon atoms due to the splitting of 19 F-bonded carbon). HRMS (ESI): calcd. (C 15 H 13 F 4 +H + ) , found S8

9 F T9 Compound T9. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 8.33 (s, 1H), 8.23 (s, 2H), 7.94 (q, J = 7.9 Hz, 1H), 7.75 (d, J = 8.6 Hz, 4H), 7.26 (d, J = 6.2 Hz, 1H), 7.07 (dd, J = 2.5, 2.5 Hz, 1H), 6.95 (d, J = 8.4 Hz, 4H), 3.83 (s, 6H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 164.8, 161.6, 160.0, 150.4, 150.2, 142.9, 142.8, 127.2, 122.3, 120.1, 118.9, 114.3, 111.9, 111.4, 74.1, 55.3 (More 13 C signals were recorded than the number of distinct carbon atoms due to the splitting of 19 F-bonded carbon). HRMS (ESI): calcd. (C 24 H 20 F 7 2 +H + ) , found T10a Compound T10a. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.74 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.43 (t, J = 6.8 Hz, 2H), 3.82 (s, 3H), (m, 6H), (m, 2H), 1.59 (t, J = 5.3 Hz, 4H), 1.43 (s, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.4, 147.3, 126.8, 123.3, 119.1, 114.1, 55.1, 54.3, 49.6, 48.1, 27.2, 25.7, HRMS (ESI): calcd. (C 17 H H + ) , found T10b H Compound T10b. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.55 (s, 1H), 4.79 (s, 2H), 4.41 (t, J = 7.0 Hz, 2H), (m, 6H), (m, 2H), (m, 4H), 1.43 (d, J = 4.9 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 147.7, 121.9, 56.1, 55.2, 54.3, 48.2, 27.3, 25.7, HRMS (ESI): calcd. (C 11 H H + ) , found T11a Compound T11a. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 8.55 (d, J = 4.6 Hz, 1H), 7.64 (d, J = 8.9 Hz, 2H), (m, 1H), 7.47 (s, 1H), (m, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 8.9 Hz, 2H), 4.81 (t, J = 7.0 Hz, 2H), 3.78 (s, 3H), 3.38 (t, J = 7.0 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.3, 156.8, 149.4, 147.0, 136.6, 126.7, 123.6, 123.2, 121.9, 119.2, 114.0, 55.1, 49.1, HRMS (ESI): calcd. (C 16 H H + ) , found S9

10 T11b H Compound T11b. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 8.51 (d, J = 4.4 Hz, 1H), (m, 1H), 7.41(s, 1H), (m, 1H), 7.02 (d, J = 7.7 Hz, 1H), 4.74 (t, J = 7.0 Hz, 2H), 4.66 (s, 2H), 3.32 (t, J = 7.0 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 156.6, 149.2, 147.5, 136.7, 123.6, 122.2, 122.0, 55.9, 49.1, HRMS (ESI): calcd. (C 10 H H + ) , found H T12 Compound T12. 1 H MR (300 MHz, DMS-d 6 ): δ (ppm) 8.42 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.28 (s, 2H), 3.77 (s, 3H). 13 C MR (75 MHz, DMS-d 6 ): δ (ppm) 168.6, 159.0, 146.2, 126.5, 123.2, 121.7, 114.3, 55.1, HRMS (ESI): calcd. (C 11 H H + ) , found H T13 Compound T13. 1 H MR (300 MHz, DMS-d 6 ): δ (ppm) 8.44 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.56 (t, J = 6.7 Hz, 2H), 3.76 (s, 3H), 2.93 (t, J = 6.7 Hz, 2H). 13 C MR (75 MHz, DMS-d 6 ): δ (ppm) 171.3, 158.5, 145.6, 125.9, 122.9, 120.1, 113.8, 54.6, 45.0, HRMS (ESI): calcd. (C 12 H H + ) , found T14 Compound T14. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.88 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.26 (t, J = 8.5 Hz, 2H), (m, 5H), 4.79 (t, J = 5.0 Hz, 2H), 4.38 (t, J = 5.0 Hz, 2H), 3.84 (s, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.6, 157.8, 147.8, 129.6, 127.0, 123.3, 121.7, 119.8, 114.6, 114.2, 66.4, 55.3, HRMS (ESI): calcd. (C 17 H H + ) , found Ph T15 Compound T15. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.80 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 4.58 (t, J = 5.0 Hz, 2H), 4.51 (s, 2H), 3.86 (d, J = 5.0 Hz, 2H), 3.84 (s, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 159.5, 147.5, 137.3, 128.5, 127.9, 127.7, 127.0, 123.5, 119.9, 114.2, 73.4, 68.5, 55.3, HRMS (ESI): S10

11 calcd. (C 18 H H + ) , found EtS T17 Compound T17. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.76 (s, 1H), 7.74 (d, J = 10.1 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.54 (t, J = 6.9 Hz, 2H), 3.82 (s, 3H), 3.01 (t, J = 6.9 Hz, 2H), 2.48 (q, J = 7.3 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 160.0, 147.9, 127.4, 123.7, 119.7, 114.6, 55.7, 50.6, 32.1, 26.6, HRMS (ESI): calcd. (C 13 H 17 3 S+H + ) , found S T20 H Compound T20. 1 H MR (300 MHz, CDCl 3 ): δ (ppm) 7.63 (s, 1H), 4.77 (d, J = 5.5 Hz, 2H), 4.51 (t, J = 6.9 Hz, 2H), 3.25 (s, 1H), 2.96 (t, J = 7.0 Hz, 2H), 2.47 (q, J = 7.4 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H). 13 C MR (75 MHz, CDCl 3 ): δ (ppm) 147.6, 122.2, 56.3, 50.0, 31.6, 26.1, HRMS (ESI): calcd. (C 7 H 13 3 S+H + ) , found Effect of competing ligands on the Cu(Ac) 2 -AAC reactions. (1) Cu(Ac) 2 tb uh rt 2-Picolylazide 1 (13.4 mg, 0.1 mmol), phenylacetylene (10.2 mg, 0.1 mmol), and tbuh (250 μl) were added to four different 2-dram sample vials, to each vial different amounts of pyridine (vial 1: 0 equiv.; vial 2: 1 equiv., 7.9 mg, 0.1 mmol; vial 3: 10 equiv., 79 mg, 1 mmol; vial 4: 30 equiv., 237 mg, 3 mmol) were added, followed by addition of Cu(Ac) 2 (50 μl, 0.1 M solution in H 2, 5 μmol). The reaction mixtures were stirred at rt and monitored by TLC (CH 2 Cl 2 /EtAc = 10/1) once every 10 min during the first hour and every 30 min in the next seven hours. The results were summarized in Table S1. S11

12 Table S1. The time for completion of reactions with different equivalents of pyridine added. 0 equiv. 1 equiv. 10 equiv. 30 equiv. Time for completion 10 min 4 hour 7 hour > 24 hour (2) 3 tb uh Cu(A c) 2 rt -(2-Azidoethyl)pyrrolidine 4 (14.0 mg, 0.1 mmol), phenylacetylene (10.2 mg, 0.1 mmol), and tbuh (250 μl) were added to four different 2-dram sample vials. To each vial different equivalents of -methylpyrrolidine (vial 1: 0 equiv.; vial 2: 1 equiv., 8.5 mg, 0.1 mmol; vial 3: 10 equiv., 85 mg, 1 mmol; vial 4: 30 equiv., 255 mg, 3 mmol) were added, followed by addition of Cu(Ac) 2 (50 μl, 0.1 M solution in H 2, 5 μmol). The mixtures were stirred at rt and monitored by TLC (CH 2 Cl 2 /EtAc = 1/1) once every 2 min in the first 10 min, every 15 min in the next one hour, and every 30 min in the next four hours. The results were summarized in Table S2. Table S2. The time for completion of the reactions with different equivalents of -methylpyrrolidine added. 0 equiv. 1 equiv. 10 equiv. 30 equiv. Time for completion 2 min 15 min 2 hour > 20 hour 4. Procedure for preparing T1/Cu(Cl 4 ) 2 complex. The acetonitrile solutions of compound T1 (0.15 M, 2.5 ml) and Cu(Cl 4 ) 2 (0.075 M, 2.5 ml) were added to a round-bottom flask and stirred for 20 min, after which the solvent was removed. The resulting copper complex was washed with diethyl ether 3 times. After the ether washes, the copper complex was once again dissolved in acetonitrile and filtered S12

13 through a piece of glass microfiber filter paper. After filtration, the acetonitrile solution was subjected to diffusion of diethyl ether. After 3 days dark green crystals formed and a sample crystal was analyzed via X-ray diffraction in preliminary form showing perchlorate ion or acetonitrile as apical ligands (data not included due to poor quality). The remaining crystals were kept in the vial. Two days later, a second crystal was removed from the vial and its structure was determined by X-ray diffraction revealing that two water molecules had displaced the acetonitrile and perchlorate ligands. 5. Procedure for preparing T6/Cu(Cl 4 ) 2 complex. Compound T6 (54 mg, 0.12 mmol) was dissolved in spectrophotometric grade CH 3 C in a sample vial. Cu(Cl 4 ) 2 6H 2 (46 mg, 0.12 mmol) was added and the mixture was gently sonicated. The solvent was then removed in vacuo. The resulting solid was washed three times with diethyl ether. After the ether was decanted, the solid was then re-dissolved in CH 3 C. The solution was passed through a plug of fiberglass filter paper. Diethyl ether was slowly diffused into the CH 3 C solution which led to the formation of single crystals of the copper complex suitable for X-ray crystallographic analysis. 6. Procedure for preparing T6/Zn(Cl 4 ) 2 complex. Compound T6 (50 mg, 0.11 mmol) was dissolved in a Zn(Cl 4 ) 2 solution in spectrophotometric CH 3 C (14 ml, 10.5 mm, mmol). The mixture was gently sonicated before the solvent was removed in vacuo. The resulting solid was washed three times with diethyl ether. After the ether was decanted, the solid was then re-dissolved in CH 3 C. The solution was passed through a plug of fiberglass filter paper. Diethyl ether was slowly diffused into the CH 3 C solution which led to the formation of single crystals of the zinc complex suitable for X-ray crystallographic analysis. S13

14 7. 1 H and 13 C MR spectra of new compounds. S14

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38 References: (1) Carboni, B.; Vaultier, M.; Carrié, R. Tetrahedron Lett. 1988, 29, (2) adler, A.; Hain, C.; Diederichsen, U. Eur. J. rg. Chem. 2009, (3) Machkour, A.; Mandon, D.; Lachkar, M.; Welter, R. Inorg. Chem. 2004, 43, (4) Boyer, J. H. J. Am. Chem. Soc. 1951, 73, (5) Dyke, J. M.; Groves, A. P.; Morris, A.; gden, J. S.; Dias, A. A.; liveira, A. M. S.; Costa, M. L.; Barros, M. T.; Cabral, M. H.; Moutinho, A. M. C. J. Am. Chem. Soc. 1997, 119, (6) Grandjean, C.; Boutonnier, A.; Guerreiro, C.; Fournier, J.; Mulard, L. A. J. rg. Chem. 2005, 70, (7) Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X.; Chen, M.; Fang, L.; Sun, D.; Wang, P. G. J. Med. Chem. 2008, 51, (8) Balderman, D.; Kalir, A. Synthesis 1978, (9) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. rg. Lett. 2004, 6, S38