Supporting Information

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1 Supporting Information Efficient Benzimidazolidinone Synthesis via Rhodium-Catalyzed Double-Decarbonylative C C Activation/Cycloaddition between Isatins and Isocyanates Rong Zeng, Peng-hao Chen, and Guangbin Dong* Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States gbdong@cm.utexas.edu Table of Contents General information Preparation of starting materials Double-decarbonylative cut and sew reactions One pot reaction of isatins with azides References X-Ray data Spectra S2 S3-S5 S6-S15 S15-S18 S18 S19-S20 S21-S47 S1

2 Materials: 1,4-dioxane was purchased from Fischer Scientific and distilled freshly over sodium. PhCl was purchased from Alfa Aesar and distilled freshly over P 2 O 5 and freeze-pump-thawed. Other commercially available chemicals were purchased and used without additional purification unless noted otherwise. All reactions were carried out under nitrogen with stirring bar in a rubber septum sealed flask. Reaction temperatures were reported as the temperatures of the bath surrounding the flasks or vials. Sensitive reagents and solvents were transferred under nitrogen into a nitrogen-filled glove-box with standard techniques. Analytical thin-layer chromatography (TLC) was carried out using 0.2 mm commercial silica gel plates (silica gel 60, F254, EMD chemical). Vials (15 x 45 mm 1 dram (4 ml) / x 95 mm 10 dram (40 ml) with PTFE lined cap attached) were purchased from Qorpak and flame-dried or put in an oven overnight and cooled in a dessicator. High-resolution mass spectra (HRSM) were obtained on a Karatos MS9 and are reported as m/z (relative intensity). Accurate masses are reported for the molecular ion [M+Na] +, [M+H] +, [M-H] - or [M] +. Infrared spectra were recorded on a Nicolet 380 FTIR using neat thin film technique. Nuclear magnetic resonance spectra ( 1 H NMR and 13 C NMR) were recorded with a Varian Gemini (400 MHz, 1 H at 400 MHz, 13 C at 100 MHz). Unless otherwise noted, all spectra were acquired in CDCl 3. Chemical shifts are reported in parts per million (ppm, δ), downfield from tetramethylsilane (TMS, δ=0.00 ppm), and are referenced to residual solvent (CDCl 3, δ=7.26 ppm ( 1 H) and ppm ( 13 C)). Coupling constants were reported in Hertz (Hz). Data for 1 H NMR spectra were reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublet of doublets, m = multiplet, coupling constant (Hz), and integration). S2

3 Preparation of starting materials. All the isatin derivatives were synthesized according to known procedures. [1] Ferrocenoyl azide was prepared according to known procedures. [2] 1. Preparation of 2o-P. (zr-10-42) Typical Procedure 1: To a solution of D-α-Tocoperol Succinate (1.06 g, 2.0 mmol) and DMF (1 drop) in DCM (15 ml), oxalyl chloride (0.26 ml, d = 1.455, 3.0 mmol) was added dropwise under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2.5 h and then evaporated to afford the crude product, which was used for next step directly. To a solution of prepared acyl chloride in DCM (20 ml), NaN 3 (278.1 mg, 4.3 mmol) was added. The resulting mixture was stirred at room temperature for 14 h, then diluted with DCM (50 ml), washed with NaCl (sat. aq., 20 ml 1), dried with MgSO 4. Evaporation and flash chromatograph (eluent: hexane/ethyl acetate = 30/1) afforded compound 2o-P (580.6 mg, 52%): 1 H NMR (400 MHz, CDCl 3 ) δ 2.95 (t, J = 6.4 Hz, 2H), (m, 2H), 2.58 (t, J = 6.8 Hz, 2H), 2.09 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H), (m, 2 H), (m, other protons), (m, 12 H); 13 C NMR (100 MHz, CDCl3) δ 179.0, 170.6, 149.5, 140.4, 126.6, 124.9, 123.1, 117.4, 75.0, 39.4, 37.43, 37.41, 37.40, 37.3, 32.8, 32.7, 31.6, 28.4, 28.0, 24.8, 24.4, 22.7, 22.6, 21.0, 20.6, 19.7, 19.6, 12.9, 12.1, 11.8; IR (neat, cm -1 ) 2926, 2868, 2274, 1754, 1723, 1462, 1378, 1156; HRMS (ESI) for C 33 H 53 NO 4 Na (MW = 550, (M+Na-N 2 ) + ): Found: Preparation of 2b- 13 C-P. (zr-10-86b) S3

4 According to Typical Procedure 1, the reaction of benzoic acid- 13 C (368.8 mg, 3 mmol), DCM (15 ml), DMF (1 drop), and oxalyl chloride (0.40 ml, d = 1.455, 4.5 mmol) afforded the crude acyl chloride, which was used for next step directly. The reaction of prepared acyl chloride and NaN 3 (0.61 g, 9.4 mmol) in DCM (20 ml) afforded compound 2b- 13 C-P (221.5 mg, 50%): 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 1 H), (m, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 172.5, (d, J = 1.1 Hz), (d, J = 72.1 Hz), (d, J = 2.5 Hz), (d, J = 4.6 Hz); IR (neat, cm -1 ) 2132, 1654, 1648, 1179; HRMS (EI) for C 13 6 CH 5 ON 3 (MW = 148, M + ): Found: Preparation of 4. [1,3] To a solution of 4-A (1.04 g, 4.8 mmol) in H 2 O (35 ml) and HOAc (0.6 drop), NaOCN (0.76 g) in H 2 O (10 ml) was added dropwise in 5 mins at 35 o C. The resulting mixture was stirred at 35 o C for another 0.5 h and cooled to room temperarure. NaOH (8.07 g) was then added slowly in 10 mins. After stirring for another 10 mins, TBAB (302.2 mg, 1 mmol) and MeI (1.7 ml, 30 mmol) were added. The resulting mixture was stirred at room temperature for 19 h, extracted with DCM (40 ml 3), dried with MgSO 4. Evaporation and flash chromatograph (eluent: S4

5 hexane/ethyl acetate = 1/1 to 1/2) afforded compound 4-B (1.07 g, 83%): 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (dd, J 1 = 7.9 Hz, J 2 =1.1 Hz, 1H), (m, 1H), 7.16 (dd, J 1 = 8.4 Hz, J 2 = 1.1 Hz, 1H), 3.57 (s, 3H), 3.42 (s, 3H). 13 C (400 MHz, CDCl 3 ) δ 159.8, 150.4, 142.6, 134.1, 130.1, 124.0, 113.2, 113.2, (q, J = 2.0 Hz), (q, J = 2.0 Hz). IR (neat, cm -1 ) 1791, 1659, 1599, 1573, 1478, 1299; HRMS (ESI) for C 10 H 79 9 BrN 2 O 2 Na (MW = 291, (M+Na) + ): Found: To a dried flask were added 4-B (267.1 mg, 1.0 mmol), bis(pinacolato)diboron (288.8 mg, 1.1 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 (82.2 mg, 0.1 mmol, 10 mol%), KOAc (296.6 mg, 3 mmol), and 1,4-dioxane (15 ml) under a nitrogen atmosphere. The resulting mixture was stirred at 100 o C for 17 h, then filtered through celite, washed with ethyl acetate, and evaporated to afford the crude product. Flash chromatograph (eluent: hexane/ethyl acetate = 5/1 to 2/1) afforded compound 4-C, which was used for next step directly. To a dried flask were added compound 4-C, 2-bromo-3-methylpyridine (0.25 ml, d = 1.544, 2.2 mmol), Cs 2 CO 3 (978.8mg, 3 mmol), and Pd(dppf)Cl 2 CH 2 Cl 2 (80.6 mg, 0.1 mmol, 10 mol%) in 1,4-dioxane (15 ml) under a nitrogen atmosphere. The resulting mixture was stirred at 100 o C for36 h, then filtered through celite, washed with ethyl acetate, and evaporated to afford the crude product. Flash chromatograph (eluent: ethyl acetate) afforded compound 4 (154.2mg, 55% for 2 steps): 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.69 (dd, J 1 = 8.5, J 2 = 7.5 Hz, 1H), (m, 1H), 7.28 (dd, J 1 = 8.5 Hz, J 2 = 1.0 Hz, 1H), 7.20 (dd, J 1 = 7.7 Hz, J 1 = 4.9 Hz, 1H), 7.04 (dd, J 1 = 7.5 Hz, J 1 = 1.0 Hz, 1H), 3.63 (s, 3H), 3.30 (s, 3 H), 2.02 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 160.8, 159.3, 150.9, 145.9, 143.1, 141.1, 136.8, 134.2, 130.6, 124.6, 122.2, 113.6, 113.1, 31.2, 28.3, 19.0; IR (neat, cm -1 ) 2925, 1706, 1659, 1593, 1501, 1431, 1376, 1311; HRMS (ESI) for C 16 H 15 N 3 O 2 Na (MW = 304, (M+Na) + ): Found: S5

6 The double decarbonylative cut and sew reactions of isatins 1 with isocyanates 2. Synthesis of 3aa: (zr-9-131, 137) Typical Procedure 2: To a 40 ml vial were added 1a (40.4 mg, 0.16 mmol), [Rh(cod)Cl] 2 (3.9 mg, mmol), and AsPh 3 (9.9 mg, mmol). Then the vial was transferred into nitrogenfilled glovebox via standard glovebox technique. After adding isocyanate 2a (55 μl, d = 1.206, 0.48 mmol) and 1,4-dioxane (4 ml), the vial was sealed and stirred at a pre-heated pie-block at 160 o C for 48 h. Upon reaction completion, the reaction mixture was concentrated under vacuum and directly purified via flash chromatography to give the desired product 3aa (49.5 mg, 93%) (eluent: hexane/ethyl acetate = 1/3 to ethyl acetate): solid; mp: o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.24 (t, J = 7.8 Hz, 1H), (m, 2H), (m, 4H), (m, 2H), 3.52 (s, 3H), 1.92 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ ~ (m); 13 C NMR (101 MHz, CDCl 3 ) δ (d, J = Hz), 155.0, 154.1, 146.4, 136.9, 131.8, 130.7, (d, J = 3.1 Hz), (brs), 126.3, , , (d, J = 44.0 Hz), 114.7(d, J = 22.9 Hz), 107.4, 27.4, 19.1;IR (neat, cm -1 ) 3063, 1712, 1608, 1512, 1469, 1431, 1397, 1300, 1223, 1083; HRMS (ESI) for C 20 H 16 FN 3 ONa (MW = 356, (M+Na) + ): Found: The following compounds were prepared according to Typical Procedure 2. DG N O N Me DG = 3-methyl-2-pyridinyl 3ab (zr-10-20) S6

7 According to Typical Procedure 2, the reaction of 1a (40.0 mg, 0.16 mmol), 2b (52.5 μl, d = 1.09, 0.48 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (9.9 mg, mmol) in 1,4- dioxane (4 ml) at 160 o C for 48 h afforded 3ab (47.9 mg, 93%) (eluent: hexane/ethyl acetate = 1/2 to 1/4): Solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), (m, 9H), 3.51 (s, 3H), 1.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.1, 154.1, 146.2, 136.7, 134.3, 131.7, 130.7, 127.8, 126.8, 126.3, 123.3, 123.2, 122.1, 121.6, 107.2, 27.3, 19.0; IR (neat, cm -1 ) 3064, 1711, 1596, 1501, 1468, 1393, 1220, 1191, 1082; HRMS (ESI) for C 20 H 17 N 3 ONa (MW = 338, (M+Na) + ): Found: (zr-10-7) According to Typical Procedure 2, the reaction of 1a (19.9 mg, 0.08 mmol), 2c (32.3 mg, 0.24 mmol), [Rh(cod)Cl] 2 (2.1 mg, mmol), and AsPh 3 (5.1 mg, mmol) in PhCl (2 ml) at 160 o C for 46 h afforded 3ac (14.5 mg, 47%) (eluent: hexane/ethyl acetate = 1/1 to 1/2): Solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.29 (td, J 1 = 3.9 Hz, J 2 =0.8 Hz, 1 H), (m, 5H), 7.00 (dd, J 1 =7.7 Hz, J 2 =4.7 Hz, 1H), 6.89 (brs, 2H), 3.55 (s, 3H), 1.95 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.0, 153.8, 146.5, 137.0, 133.6, 131.8, 131.0, 130.8, 128.4, 126.2, 123.3,123.2, 122.2, 122.0, 120.6, 107.5, 27.4, 19.1; IR (neat, cm -1 ) 2926, 1712, 1618, 1491, 1467, 1393, 1296, 1221, 1081; HRMS (ESI) for C 20 H BrN 3 O (MW = 394, (M+H) + ): Found: (zr-10-10) According to Typical Procedure 2, the reaction of 1a (40.1 mg, 0.16 mmol), 2d (93.0 mg, 0.48 S7

8 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (9.9 mg, mmol) in 1,4-dioxane (4mL) at 160 o C for 48 h afforded 3ad (60.4 mg, 98%) (eluent: hexane/ethyl acetate = 1/1.5 to 1/3): Solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.67 (d, J = 8.2 Hz, 2H), (m, 1H), (m, 5H), 6.85 (dd, J 1 = 7.7 Hz, J 2 = 4.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.51 (s, 3H), 1.92 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 165.7, 154.9, 153.7, 146.5, 138.6, 137.0, 131.7, 130.9, 129.0, 128.4, 126.3, 125.9, 123.4, 123.4, 122.3, 122.1, 107.4, 60.9, 27.4, 18.9, 14.2; IR (neat, cm -1 ) 2981, 1716, 1603, 1514, 1468, 1393, 1275, 1172, 1101; HRMS (ESI) for C 23 H 21 N 3 O 3 Na (MW = 410, (M+Na) + ): Found: (zr-10-8) According to Typical Procedure 2, the reaction of 1a (40.1 mg, 0.16 mmol), 2e (79.7 mg, 0.48 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (9.9 mg, mmol) in 1,4-dioxane (4 ml) at 160 o C for 46 h afforded 3ae (57.4 mg, quant.) (eluent: hexane/ethyl acetate = 1/2 to 1/3): Solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.86 (d, J = 9.0 Hz,, 2 H), 7.29 (t, J = 7.8 Hz, 1H), (m, 5H), 6.91 (dd, J 1 = 7.7 Hz, J 2 =4.8 Hz, 1H), 3.52 (s, 3H), 1.97 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.8, 153.3, 146.7, 145.4, 140.5, 137.3, 131.8, 131.0, 126.8, 125.5, 123.7, 123.3, 123.0, 122.7, 122.5, 107.8, 27.5, 18.9; IR (neat, cm -1 ) 2928, 1725, 1593, 1501, 1500, 1468, 1392, 1347, 1219, 1082; HRMS (ESI) for C 20 H 17 N 4 O 3 (MW = 361, (M+H) + ): Found: (zr-10-39) S8

9 According to Typical Procedure 2, the reaction of 1a (40.2 mg, 0.16 mmol), 2f (83 μl, d = 1.476, 0.48 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (10.5 mg, mmol) in 1,4- dioxane (4 ml) at 160 o C for 48 h afforded 3af (69.2 mg, 96%) (eluent: hexane/ethyl acetate = 2/1 to 1/1): oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (dd, J 1 = 4.9 Hz, J 2 =1.6 Hz, 1H), (m, 3H), (m, 2H), 7.09 (dd, J 1 =7.9 Hz, J 2 =1.1 Hz, 1H), 7.03 (dd, J 1 =7.8 Hz,J 1 = 1.1 Hz, 1H), 6.82 (dd, J 1 =7.8 Hz, J 1 =4.8 Hz, 1H), 3.48 (s, 3H), 2.05 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ C NMR (100 MHz, CDCl 3 ) δ 154.1, 153.6, 146.7, 137.8, 136.5, (q, J = 33.0 Hz), 131.5, 131.1, (brs), 126.6, 123.6, 123.0, (q, J = Hz), , 122.4, (m), 107.8, 27.5, 18.9; IR (neat, cm -1 ) 3056, 1719, 1606, 1478, 1465, 1400, 1279, 1179, 1133; HRMS (ESI) for C 22 H 15 F 6 N 3 ONa (MW = 474, (M+Na) + ): Found: (zr-10-1) According to Typical Procedure 2, the reaction of 1a (40.1 mg, 0.16 mmol), 2g (86.8 mg, 0.48 mmol), [Rh(cod)Cl] 2 (3.9 mg, mmol), and AsPh 3 (10.5 mg, mmol) in 1,4-dioxane (4 ml) at 160 o C for 44 h afforded 3ag (56.3 mg, 94%) (eluent: hexane/ethyl acetate = 1/3 to ethyl acetate): Solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 4.6 Hz, 1H), (m, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.85 (dd, J 1 = 7.7 Hz, J 2 = 4.8 Hz, 1H), (m, 2H), 6.48 (d, J = 8.9 Hz, 1H), 3.62 (s, 3H), 3.56 (s, 3H), 3.51 (s, 3H), 1.98 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.9, 153.9, 152.7, 149.2, 145.6, 136.4, 131.8, 130.9, 126.9, 123.5, 123.3, 122.7, 122.1, 121.2, 115.8, 114.8, 111.7, 107.1, 55.6, 55.5, 27.4, 19.0; IR (neat, cm -1 ) 2936, 1715, 1512, 1471, 1452, 1389, 1301, 1229, 1175, 1080, 1044; HRMS (ESI) for C 22 H 22 N 3 O 3 (MW = 376, (M+H) + ): Found: S9

10 DG N O N Me DG = 3-methyl-2-pyridinyl 3ah (zr-10-22) According to Typical Procedure 2, the reaction of 1a (40.2 mg, 0.16 mmol), 2h (82.4 mg, 0.48 mmol), [Rh(cod)Cl] 2 (3.9 mg, mmol), and AsPh 3 (10.2 mg, mmol) in PhCl (4 ml) at 160 o C for 48 h afforded 3ah (46.2 mg, 79%) (eluent: hexane/ethyl acetate = 1/2 to 1/4): Solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 9 H), 6.85 (d, J = 8.7 Hz, 1H), 6.66 (brs, 1H), 6.45 (brs, 1H), 3.52 (s, 3H), 1.59 (brs, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.4, 154.0, 145.3, 136.1, 133.8, 131.4, 131.0, 130.2, 128.5, 127.7, 127.3, 126.4, 125.9, 124.7, 123.7, 122.9, 121.6, 121.5, 107.3, 27.5, 19.3; IR (neat, cm -1 ) 3271, 3054, 1713, 1630, 1560, 1463, 1430, 1404, 1296, 1227, 1089; HRMS (ESI) for C 24 H 19 N 3 ONa (MW = 388, (M+Na) + ): Found: (zr-9-139) According to Typical Procedure 2, the reaction of 1a (39.8 mg, 0.16 mmol), 2i (44 μl, d = 0.94, 0.48 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (9.8 mg, mmol) in 1,4- dioxane (4 ml) at 160 o C for 48 h afforded 3ai (43.3 mg, 98%) (eluent: hexane/ethyl acetate = 1/3 to ethyl acetate): oil; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.58 (ddd, J 1 = 7.7 Hz, J 2 =1.7 Hz, J 3 = 0.8 Hz, 1H), (m, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.01 (dd, J 1 = 7.9 Hz, J 2 = 1.2 Hz, 1H), 6.90 (dd, J 1 = 7.7 Hz, J 2 = 1.2 Hz, 1H), 5.33 (ddt, J 1 = 17.2 Hz, J 2 = 10.3 Hz, J 3 = 5.1 Hz, 1H), 4.77 (dq, J 1 = 10.4 Hz, J 2 = 1.6 Hz, 1H), (m, 1H), 4.23 (brs, 1H), 3.98 (brs, 1H), 3.46 (s, 3H), 2.13 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 156.2, 154.6, 146.1, 138.0, 133.0, 132.4, 131.0, 126.1, 123.0, 122.9, 122.8, 120.8, 115.7, 107.0, 44.2, 27.3, 19.6; IR (neat, cm -1 ) 3062, 2928, 1707, 1618, 1471, 1443, 1398, 1169, 1090; HRMS (ESI) for C 17 H 17 N 3 ONa (MW = 302, (M+Na) + ): Found: S10

11 (zr-10-65) According to Typical Procedure 2, the reaction of 1a (40.2 mg, 0.16 mmol), 2j (40μL, d = 0.89, 0.50 mmol), [Rh(cod)Cl] 2 (3.9 mg, mmol), and AsPh 3 (10.2mg, mmol) in 1,4- dioxane (4 ml) at 160 o C for 48 h afforded 3aj (38.6 mg, 90%) (eluent: hexane/ethyl acetate = 1/3 to ethyl acetate): solid;v o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.24 (dd, J = 7.5, 4.6 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.98 (dd, J = 7.8, 0.9 Hz, 1H), 6.89 (dd, J 1 = 7.7 Hz, J 2 =0.8 Hz, 1H), (m, 4H), 3.30 (brs, 1H), 2.14 (s, 3H), 0.76 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 156.3, 154.5, 146.4, 137.7, 132.5, 130.8, 125.9, 123.0, 122.7, 122.5, 120.7, 107.0, 37.0, 27.1, 19.2, 13.8; IR (neat, cm -1 ) 2975, 1707, 1473, 1449, 1400, 1383, 1082; HRMS (ESI) for C 16 H 17 N 3 ONa (MW = 290, (M+Na) + ): Found: DG N O N Me DG = 3-methyl-2-pyridinyl 3ak (zr-10-41) According to Typical Procedure 2, the reaction of 1a (39.3 mg, 0.16 mmol), 2k (59μL, d = 1.078, 0.48 mmol), [Rh(cod)Cl] 2 (3.9 mg, mmol), and AsPh 3 (9.9mg, mmol) in 1,4-dioxane (4 ml) at 160 o C for 48 h afforded 3ak (48.2 mg, 94%) (eluent: hexane/ethyl acetate = 1/2 to 1/4): solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (ddt, J 1 = 4.7 Hz, J 2 =1.6 Hz, J 3 = 0.7 Hz, 1H), 7.27 (ddt, J 1 = 7.8 Hz, J 1 = 1.5 Hz, J 1 = 0.8 Hz, 1H), 7.16 (dd, J = 7.7 Hz, J 1 = 4.8 Hz, 1H), 7.11 (td, J 1 = 7.8 Hz, J 2 = 0.5 Hz, 1H), (m, 4H), 6.79 (dd, J 1 = 7.7 Hz, J 2 = 1.0 Hz, 1H), 6.46 (d, J = 7.4 Hz, 2 H), 5.21 (d, J = 16.3 Hz, 1H), 4.46 (d, J = 16.3 Hz, 1H), 3.54 (s, 3H), 1.58 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.9, 155.1, 145.6, 137.9, 136.9, 133.4, 131.2, 127.9, 126.8, 125.9, 125.6, 123.2, 123.1, 122.7, 120.8, 107.0, 45.4, 27.4, 18.9; IR (neat, cm -1 ) 3032, 1707, 1618, 1496, 1471, 1444, 1399, 1360, 1167, 1094; HRMS (ESI) for C 21 H 19 N 3 ONa S11

12 (MW = 352, (M+Na) + ): Found: (zr-10-17) According to Typical Procedure 2, the reaction of 1a (40.6 mg, 0.16 mmol), 2l (38μL, d = 0.898, 0.48 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (10.6 mg, mmol) in 1,4- dioxane (4 ml) at 160 o C for 44 h afforded 3al (38.7 mg, 74%) (eluent: hexane/ethyl acetate = 1/2 to 1/3): solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (dd, J 1 = 4.8 Hz, J 2 = 1.1 Hz, 1H), 7.56 (ddd, J 1 = 7.7 Hz, J 2 = 1.6 Hz, J 3 = 0.7 Hz, 1H), 7.23 (dd, J 1 = 7.7 Hz, J 2 = 4.8 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.01 (dd, J 1 = 7.9 Hz, J 2 = 1.1 Hz, 1H), 6.89 (dd, J 1 = 7.7 Hz, J 2 = 1.1 Hz, 1H), 4.32 (brs, 2H), 3.81 (q, J = 6.8 Hz, 2H), 3.45 (s, 3H), 2.13 (s, 3H), 1.05 (t, J = 7.1 Hz, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 167.8, 155.5, 154.5, 146.2, 138.0, 133.4, 131.0, 122.9, 122.6, 121.0, 107.3, 60.9, 43.5, 27.3, 19.5, 13.9; IR (neat, cm -1 ) 2983, 1749, 1712, 1619, 1497, 1473, 1440, 1400, 1208, 1170, 1023; HRMS (ESI) for C 18 H 19 N 3 O 3 Na (MW = 348, (M+Na) + ): Found: (zr-10-56) According to Typical Procedure 2, the reaction of 1b (37.2 mg, 0.16 mmol), 2k (60μL, d = 1.078, 0.48 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (10.5 mg, mmol) in PhCl (4 ml) at 160 o C for 48 h afforded 3bk (35.9 mg, 73%, 94% of purity) (eluent: hexane/ethyl acetate = 1/2 to 1/3): 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (d, J = 4.8 Hz, 1H), (m, 1H), (m, 1H), 7.13 (t, J = 7.8 Hz, 1H), (m, 6 H), 6.45 (d, J = 7.3 Hz, 2 H), 5.11 (s, 2 H), 3.53 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 157.3, 155.2, 148.1, 136.7, 136.1, 131.1, 127.9, 126.6, 125.9, 125.8, 124.6, 124.6, 124.0, 122.1, 120.9, 107.4, 45.8, 27.5; IR (neat, cm -1 ) 3061, 1707, 1618, 1585, 1496, 1462, 1442, 1398, 1164, 1104; HRMS (ESI) for C 20 H 17 N 3 ONa (MW = S12

13 338, (M+Na) + ): Found: (zr-10-72) According to Typical Procedure 2, the reaction of 1c (37.2 mg, 0.1 mmol), 2k (37μL, d = 1.078, 0.3 mmol), [Rh(cod)Cl] 2 (2.5 mg, mmol), and AsPh 3 (6.2mg, 0.02 mmol) in PhCl (3 ml) at 160 o C for 46 h afforded 3ck (13.9 mg, 41%) (eluent: hexane/ethyl acetate = 1.8/1): 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 1.0 Hz, 1H), (m, 1 H), (m, 4H), 6.97 (dd, J 1 = 7.8 Hz, J 2 = 1.4 Hz, 1H), (m, 4H), 6.36 (d, J = 7.2 Hz, 2H), 4.88 (s, 2H), 3.56 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.9, 141.5, 136.0, 135.0, 132.4, 128.6, 127.7, 127.4, 127.0, 126.7, 125.5, 125.1, 124.1, 122.2, 121.3, 121.3, 120.6, 109.9, 107.8, 45.5, 27.7; IR (neat, cm -1 ) 2926, 1712, 1618, 1483, 1416, 1400, 1379, 1166; HRMS (ESI) for C 22 H 19 N 4 O (MW = 355, (M+H) + ): Found: (zr-10-56) According to Typical Procedure 2, the reaction of 1d (24.6 mg, 0.16 mmol), 2k (37μL, d = 1.078, 0.3 mmol), [Rh(cod)Cl] 2 (2.6 mg, mmol), and AsPh 3 (6.3 mg, 0.02 mmol) in PhCl (3 ml) at 160 o C for 48 h afforded 3dk (27.1 mg, 84%) (eluent: hexane/ethyl acetate = 1/1 to 1/3): 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (ddd, J 1 = 4.9 Hz, J 2 = 1.8 Hz, J 3 = 0.9 Hz, 1H), 7.32 (td, J 1 = 7.7 Hz, J 2 = 1.8 Hz, 1H), 7.17 (ddd, J 1 = 7.6 Hz, J 2 = 4.9 Hz, J 3 = 1.2 Hz, 1H), (m, 3H), 6.99 (q, J = 8.0 Hz, 2H), 6.76 (dt, J 1 = 7.7 Hz, J 2 = 1.1 Hz, 1H), (m, 2H), 5.02 (d, J = 16.8 Hz, 1H), 4.35 (d, J = 16.6 Hz, 1H), 3.50 (s, 3H), 1.96 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.7, 155.2, 148.8, 136.9, 135.4, 129.8, 128.9, 127.9, , , 126.1, 125.3, 123.6, 122.7, 122.2, 107.1, 45.3, 27.4, 19.8; IR (neat, cm -1 ) 2925, 1707, 1616, 1585, 1473, 1440, 1400, 1170, 1069; HRMS (ESI) for C 21 H 19 N 3 ONa (MW = 352, (M+Na) + ): Found: S13

14 (zr-10-56) According to Typical Procedure 2,the reaction of 1e (51.1 mg, 0.16 mmol), 2k (60μL, d = 1.078, 0.49 mmol), [Rh(cod)Cl] 2 (3.9 mg, mmol), and AsPh 3 (9.9mg, mmol) in PhCl (4 ml) at 160 o C for 46 h afforded 3ek (56.7 mg, 90%) (eluent: hexane/ethyl acetate = 2/1 to 1/1): solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 6H), 7.18 (dd, J 1 = 7.7 Hz, J 2 = 4.8 Hz, 1H), (m, 4H), 6.93 (dd, J 1 = 7.9 Hz, J 2 = 1.3 Hz, 1H), 6.76 (dd, J 1 = 7.7 Hz, J 2 = 1.3 Hz, 1H), 6.47 (dt, J 1 = 8.6 Hz, J 2 = 1.8 Hz, 2H), 5.31 (d, J = 20.0 Hz, 2H), 5.13 (d, J = 15.7 Hz, 1H), 4.49 (d, J = 16.2 Hz, 1H), 1.58 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.9, 155.2, 145.6, 138.0, 136.9, 136.2, 133.5, 130.4, 128.7, 128.0, 127.7, 127.4, 126.9, 126.0, 125.5, 123.4, 123.2, 122.7, 120.9, 107.9, 45.6, 45.1, 19.0; IR (neat, cm -1 ) 3032, 2927, 1705, 1604, 1465, 1442, 1405, 1358, 1176, 1028; HRMS (ESI) for C 27 H 23 N 3 ONa (MW = 428, (M+Na) + ): Found: (zr-10-71) According to Typical Procedure 2, the reaction of 1f (24.6 mg, 0.1 mmol), 2k (37μL, d = 1.078, 0.3 mmol), [Rh(cod)Cl] 2 (2.5 mg, mmol), and AsPh 3 (6.8mg, 0.02 mmol) in PhCl (3 ml) at 160 o C for 46 h afforded 3fk (17.6 mg, 55%) (eluent: hexane/ethyl acetate = 1/2 to 1/4 to ethyl acetate): 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, J = 4.5 Hz, 1H), 8.05 (d, J = 5.3 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.22 (dd, J 1 = 7.7 Hz, J 2 = 4.7 Hz, 1H), 7.07 (dd, J 1 = 8.3 Hz, J 2 = 6.3 Hz, 1H), 7.00 (t, J = 7.4 Hz, 2H), 6.73 (d, J = 5.3 Hz, 1H), 6.44 (d, J = 7.3 Hz, 2H), 5.18 (brs, 1H), 4.55 (brs, 1H), 3.62 (s, 3H), 1.62 (s, 3H).; 13 C NMR (100 MHz, CDCl 3 ) δ 154.6, 153.7, 146.0, 145.0, 140.0, , , 133.1, 128.8, 128.0, 127.1, 125.6, 123.4, 120.5, 118.3, 45.2, 26.4, 18.7; IR (neat, cm -1 ) 2929, 1718, 1624, 1486, 1439, 1398, 1169; HRMS (ESI) for S14

15 C 20 H 18 N 4 ONa (MW = 353, (M+Na) + ): Found: One-pot reaction of isatins with organic azides. Synthesis of 3aa from 4-fluorobenzoyl azide. Typical Procedure 3: To a dried 40 ml vial were added 4-fluorobenzoyl azide (39.9 mg, 0.24 mmol) and PhCl (0.5 ml) under nitrogen atmosphere. Then the vial was sealed and heated at 110 o C. After 3 h, the resulting crude product was mixed with 1a (20.0 mg, 0.08 mmol), [Rh(cod)Cl] 2 (2.0 mg, mmol), AsPh 3 (5.1 mg, mmol), and 1,4-dioxane (2 ml) in glove box. The vial was sealed and stirred at a pre-heated pie-block at 160 o C for 37 h. Upon reaction completion, the reaction mixture was concentrated under vacuum and directly purified via flash chromatography to give the desired product 3aa (18.3 mg, 69%) (eluent: hexane/ethyl acetate = 1/2 to 1/3): 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 7.24 (t, J = 7.8 Hz, 1H), (m, 2H), (m, 4H), 6.70 (brs, 2H), 3.52 (s, 3H), 1.91 (s, 3H); 19 F NMR (376 MHz, CDCl 3 ) δ ~ (m). The following compounds were prepared according to Typical Procedure 3. (zr-10-16) According to Typical Procedure 3, the reaction of ferrocenoyl azide (164.2 mg, 0.64 mmol) in S15

16 toluene (1 ml) afforded a mixture, which directly reacted with 1a (40.2 mg, 0.16 mmol), [Rh(cod)Cl] 2 (4.0 mg, mmol), and AsPh 3 (10.2mg, mmol) in 1,4-dioxane (4 ml) at 160 o C for 43 h afforded 3am (28.9 mg, 43%) (eluent: hexane/ethyl acetate = 2/1 to 1/1): 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1 H), 7.61 (dd, J 1 =7.7 Hz, J 2 =0.9 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 1H), 7.31 (dd, J 1 = 7.7 Hz, J 2 =4.8 Hz, 1H), 6.98 (dd, J 1 =7.8 Hz, J 2 =0.9 Hz, 1H), 6.82 (dd, J 1 =7.9 Hz, J 2 =0.9 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1 H), 3.94 (s, 4H), 3.26 (s, 3H), 2.17 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 157.8, 157.7, 146.9, 146.3, 144.0, 136.4, 136.3, 132.8, 131.0, 124.0, 122.3, 120.2, 108.0, 98.0, 72.7, 70.3, 70.2, 69.8, 69.5, 69.3, 66.0, 25.9, 19.0; IR (neat, cm -1 ) 2925, 1707, 1603, 1582, 1459, 1363, 1301, 1087; HRMS (ESI) for C 24 H 21 N 3 OFeNa (MW = 446, (M+Na) + ): Found: (zr-12-35) According to Typical Procedure 3, the reaction of 4-acetylbenzoyl azide (57.4 mg, 0.3 mmol) in PhCl (1 ml) afforded a mixture, which directly reacted with 1a (24.4 mg, 0.1 mmol), [Rh(cod)Cl] 2 (2.6 mg, mmol), and AsPh 3 (6.6 mg, 0.02 mmol) in 1,4-dioxane (3 ml) at 160 o C for 48 h afforded 3an (23.4 mg, 68%) (eluent: hexane/ethyl acetate = 2/1 to 1/1 to ethyl acetate): 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 4.7 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), (m, 1H), (m, 5H), 6.87 (dd, J = 7.7, 4.8 Hz, 1H), 3.54 (s, 3H), 2.51 (s, 3H), 1.95 (s, 3H).; 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , , , , , , 27.63, 26.77, 19.16; IR (neat, cm -1 ) 2925, 1712, 1683, 1600, 1468, 1429, 1391, 1267, 1175, 1082, 914, 841, 787, 732; HRMS (ESI) for C 22 H 19 N 3 O 2 Na (MW = 380, (M+Na) + ): Found: S16

17 (zr-10-48) According to Typical Procedure 3, the reaction of 2o-P(166.6 mg, 0.3 mmol) in PhCl (1 ml) afforded 2o, which direcly reacted with 1a (24.8 mg, 0.1 mmol), [Rh(cod)Cl] 2 (2.6 mg, mmol), and AsPh 3 (6.3 mg, 0.02 mmol) in 1,4-dioxane (3 ml) at 160 o C for 48 h afforded 3ao (60.8 mg, 85%) (eluent: hexane/ethyl acetate = 3/1 to 1/1): oil; 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (dd, J 1 = 4.9 Hz, J 2 = 1.6 Hz, 1H), (m, 1H), (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.04 (dd, J 1 =7.9 Hz, J 2 = 1.2 Hz, 1H), 6.95 (dd, J 1 = 7.7 Hz, J 2 = 1.2 Hz, 1H), 3.99 (brs, 2H), 3.48 (s, 3H), (m, 4H), 2.21 (s, 3H), 2.06 (s, 3H), 1.89 (s, 3H), 1.85 (s, 3H), (m, 2H), (m, all other protons), (m, 12H); 13 C NMR (100 MHz, CDCl 3 ) δ168.9, 155.9, 154.5, 149.3, 146.8, 140.1, 138.1, 132.6, 131.0, 126.4, 125.7, 124.7, 123.4, , , 122.6, 121.2, 117.3, 107.3, 75.0, 39.3, 37.9, 37.4, 37.4, 37.3, 32.8, 32.7, 32.5, 28.0, 27.3, 24.8, 24.4, 22.7, 22.6, 21.0, 20.5, 19.7, 19.6, 19.3, 13.1, 12.2, 11.8; IR (neat, cm -1 ) 2926, 1753, 1711, 1460, 1385, 1146; HRMS (ESI) for C 46 H 65 N 3 O 4 Na (MW = 746, (M+Na) + ): Found: (zr-11-16) According to Typical Procedure 3, the reaction of 2b- 13 C-P (50.0 mg, 0.34 mmol) in PhCl (0.7 ml) at 100 o C for 2 h afforded 2b- 13 C, which directly reacted with 1a (25.3 mg, 0.1 mmol), [Rh(cod)Cl] 2 (2.5 mg, mmol), and AsPh 3 (6.8mg, 0.02 mmol) in 1,4-dioxane (3 ml) at 160 o C for 48 h afforded 3ab- 13 C (27.5 mg, 87%) (eluent: hexane/ethyl acetate = 1/2 to 1/4): solid; o C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (dd, J 1 = 4.9 Hz, J 2 = 1.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), (m, 8H), 6.86 (dd, J 1 = 7.7 Hz, J 2 =4.8 Hz, 1H), 3.53 (d, J = 3.1 Hz, 3H), S17

18 1.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.1, 154.1, 146.2, 136.7, (d, J = 1.5 Hz), 131.7, (d, J = 5.7 Hz), 127.8, 126.8, (d, J = 6.2 Hz), (d, J = 3.3 Hz), 123.2, 122.1, 121.7, (d, J = 3.4 Hz), 27.3 (d, J = 1.7 Hz), 19.0; IR (neat, cm -1 ) 3063, 2926, 1671, 1619, 1596, 1501, 1468, 1386, 1296, 1220, 1191, 1082; HRMS (ESI) for C CH 17 N 3 ONa (MW = 339, (M+Na) + ): Found: References: [1] Zeng, R.; Dong, G. J. Am. Chem. Soc. 2015, 137, [2] Cormode, D. P.; Evans, A. J.; Davis, J. J.; Beer, P. D. Dalton Trans.,2010, 39, [3] For synthesis of 5-bromoquinazoline-2,4(1H,3H)-dione, see: Bristol-Myers Company; Johnson, J. A.; Lloyd, J.; Finlay, H.; Jiang, J.; Neels, J.; Dhondi, N. K.; Gunaga, P.; Banerjee, A.; Adisechan, A. Patent: WO2011/28741 A1, S18

19 Identification code ZR Empirical formula C20 H16 F N3 O Formula weight Temperature 100(2) K Wavelength Å Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = (5) Å = 90. b = 7.219(2) Å = (4). c = (6) Å = 90. Volume (9) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 696 Crystal size x x mm 3 Theta range for data collection to Index ranges -14<=h<=19, -10<=k<=10, -24<=l<=24 Reflections collected Independent reflections 4765 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4765 / 0 / 228 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient n/a Largest diff. peak and hole and e.å -3 S19

20 Identification code ZR Empirical formula C18 H19 N3 O3 Formula weight Temperature 100(2) K Wavelength Å Crystal system Monoclinic Space group P 21/n Unit cell dimensions a = (3) Å = 90. b = (3) Å = (5). c = (5) Å = 90. Volume (9) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 688 Crystal size x x mm 3 Theta range for data collection to Index ranges -15<=h<=14, -15<=k<=15, -20<=l<=19 Reflections collected Independent reflections 4641 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4641 / 0 / 220 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient n/a Largest diff. peak and hole and e.å -3 S20

21 S21

22 S22

23 S23

24 S24

25 S25

26 S26

27 S27

28 S28

29 S29

30 S30

31 S31

32 S32

33 MeO DG OMe N O N Me DG = 3-methyl-2-pyridinyl 3ag S33

34 S34

35 S35

36 S36

37 S37

38 S38

39 S39 (94% of purity)

40 S40

41 S41

42 S42

43 S43

44 S44

45 S45

46 S46

47 S47