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1 1 Supporting Information Cu/Pd Catalyzed Synthesis of Fully Decorated Polycyclic Triazoles: Introducing C H Functionalization to Multicomponent Multicatalytic Reactions (MC) 2 R Zafar Qureshi, Jung Yun Kim, Theodora Bruun, Mark Lautens* Davenport Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6 (Canada) *mlautens@chem.utoronto.ca 1. General Methods 2 2. Azides 2 3. Terminal alkynes 5 4. Internal alkynes 6 5. Intermediate synthesis 7 6. (MC) 2 R H NMR Study Mechanism for palladium catalyzed step Scope Product derivatization NMR spectra 26

2 2 General methods All reagents, starting materials and catalysts were purchased from Sigma Aldrich or Combiblocks and used as received. DMSO was purchased from ACP chemicals and triethylamine was purchased from Sigma Aldrich and used as received. All other solvents were distilled under N 2 prior to use. Unless otherwise noted, reactions were carried out in dry glassware under argon. TLC was performed with EMD TLC Silica gel 60 F254 aluminum sheets. Visualization was accomplished with 254 nm UV light followed by staining with potassium permanganate. Flash and gradient column chromatography was carried out using Silicycle Ultra-Pure mesh silica gel. Melting points were taken on a Fisher- Johns melting point apparatus and are uncorrected. IR spectra were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrometer as neat films or as solutions (CHCl 3 ) on a NaCl plate. Data is presented as frequency of absorption (cm 1 ). 1 H, 19 F and 13 C NMR spectra were recorded at 23 C in CDCl 3 with a Bruker Avance 400 spectrometer, Varian Mercury 400 spectrometer, Varian Unity 500 spectrometer or an Agilent DD2-600 spectrometer. Recorded shifts for protons and carbon NMR are reported in parts per million (δ scale) and are referenced to tetramethylsilane (δ 0). Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, p=pentet, m=multiplet, b=broad), coupling constant (J, Hz) and integration. High resolution mass spectra were obtained from a JEOL AccuTOF model JMS-T1000LC mass spectrometer (DART) or an ABI/Sciex Qstar mass spectrometer (ESI). Azides: Scheme S1: Large scale synthesis of 2-iodobenzyl azide. A mixture of 2-iodotoluene (22 g, 100 mmol), N-bromosuccinimide (20 g, 112 mmol) and benzoyl peroxide (1 g) in benzene (100 ml) was refluxed for 10 h. The reaction was cooled to RT, filtered and the filtrate was washed with Na 2 SO 3, dried with MgSO 4, filtered and concentrated to give crude 2-iodobenzyl bromide. Purification by flash chromatography (Hexanes) gave (60%) of a white solid. The benzyl bromide and NaN 3 (11.8 g, 181 mmol, 3 equiv) were stirred in DMF (100 ml) at RT overnight, diluted with H 2 O (400 ml) and extracted with a 1:1 mixture of EtOAc:Hexanes (250 ml X 4). The organic layer was washed with brine (100 ml X 3), dried with MgSO 4, filtered and concentrated to give pure 2- iodobenzyl azide (15.39 g, 98%).

3 3 Scheme S2: Synthesis of substituted benzyl azides. Typical protocol for the synthesis of azides: To a solution of the 2-iodobenzoic acid derivatives (2 mmol) in THF (0.4 M) at 0 C was added BH 3. SMe 2 (0.28 ml, 3 mmol, 1.5 equiv). The reactions were warmed to RT overnight and quenched with MeOH (1ml), diluted with EtOAc and washed with H 2 O (10 ml) and brine (10 ml). The organic layer was separated and dried with MgSO 4, filtered and concentrated to give the crude benzyl alcohols which were used without further purification. The crude alcohols were dissolved in dry toluene (3 ml). Diphenylphosphoryl azide (1.2 equiv) followed by DBU (1.3 equiv) was added and the reactions were stirred at RT for 1 h. The reactions were diluted with Et 2 O (10 ml), quenched with 2 M HCl (5 ml), and washed with H 2 O (10 ml) and brine (10 ml). The organic layer was separated and dried with MgSO 4, filtered and concentrated to give the crude azides. The azides were purified by flash chromatography (5% EtOAc in Hexanes). 2-iodobenzyl azide, 1a Compound in agreement with literature report (Synthesis, 2013, 45, ). 1 H NMR: (399 MHz, Chloroform-d) δ 7.88 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 1H), 4.46 (s, 2H). 13 C NMR: (100 MHz, cdcl 3 ) δ , , , , , 99.12, (azidomethyl)-1-iodo-4-methylbenzene, S1 1 H NMR: (399 MHz, Chloroform-d) δ 7.73 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), 4.41 (s, 2H), 2.32 (d, J = 0.7 Hz, 3H). 13 C NMR: (100 MHz, cdcl 3 ) δ , , , , , 94.84, 58.93, IR: 2925, 2091, 1466, 1339, 1279, 1262, 1242, 1167, 1012, 930, 746, 808, 746, 709. HRMS: (DART) calc d for C 8 H 9 NI (M + H N 2 ) ; Found (azidomethyl)-4-fluoro-1-iodobenzene, S2 1 H NMR: (399 MHz, Chloroform-d) δ 7.61 (dd, J = 7.9, 2.6 Hz, 1H), 7.34 (dd, J = 8.6, 5.7 Hz, 1H), 7.10 (td, J = 8.3, 2.6 Hz, 1H), 4.43 (s, 2H). 13 C NMR: (100 MHz, Chloroform-d) δ (d, J = Hz), (d, J = 3.4 Hz), (d, J = 8.2 Hz), (d, J = 23.9 Hz), (d, J = 21.1 Hz), (d, J = 8.2 Hz). 19 F NMR: (376 MHz, Chloroform-d) δ (td, J = 7.7, 5.4 Hz). IR: 2094, 1591, 1583, 1479, 1386, 1340, 1263, 1221, 1179, 1029, 861, 813, 777, 663.

4 4 HRMS: (DART) calc d for C 7 H 6 NIF (M + H N 2 ) ; Found (azidomethyl)-4-chloro-2-iodobenzene, S3 1 H NMR: (399 MHz, Chloroform-d) δ 7.87 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.2, 2.1 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 4.43 (s, 2H). 13 C NMR: (100 MHz, cdcl 3 ) δ , , , , , 98.68, IR: 2093, 1578, 1554, 1464, 1373, 1338, 1287, 1243, 1103, 1029, 871, 840, 808, 680. HRMS: (DART) calc d for C 7 H 6 NICl (M + H N 2 ) ; Found Scheme S3: Synthesis of azide S5. S4 (prepared according to Eur. J. Org. Chem. 2014, ) (388 mg, 2 mmol) and NaN 3 (390 mg, 6 mmol) were stirred in DMF (5 ml) at RT overnight, diluted with H 2 O (20 ml) and extracted with a 1:1 mixture of EtOAc:Hexanes (25 ml X 4). The organic layer was washed with brine (20 ml X 3), dried with MgSO 4, filtered and concentrated to give S5 (585 mg, 97%). 5-iodo-4-(iodomethyl)benzo[d][1,3]dioxole, S4 1 H NMR: (400 MHz, Chloroform-d) δ 7.27 (dd, J = 8.2, 0.9 Hz, 1H), 6.50 (dd, J = 8.2, 0.8 Hz, 1H), 6.05 (d, J = 0.9 Hz, 2H), 4.44 (d, J = 1.0 Hz, 2H). 13 C NMR: (101 MHz, CDCl 3 ) δ , , , , , , IR: 3076, 2894, 2775, 1838, 1495, 1450, 1417, 1331, 1247, 1218, 1177, 1147, 1127, 1047, 1002, 923, 864, 804, 738, 666. MP: C HRMS: compound decomposes in mass spectrometer. 4-(azidomethyl)-5-iodobenzo[d][1,3]dioxole, S5

5 5 1 H NMR: (399 MHz, Chloroform-d) δ 7.34 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.02 (s, 2H), 4.44 (s, 3H). 13 C NMR: (100 MHz, cdcl 3 ) δ , , , , , , 89.03, IR: 2894, 2783, 2090, 1497, 1450, 1338, 1242, 1158, 1098, 1046, 1016, 927, 874, 842, 797, 761, 700, 654. HRMS: (DART) calc d for C 8 H 7 NO 2 I (M + H N 2 ) ; Found Terminal alkynes: bis-tert-butyl pent-4-yn-1-ylcarbamate, S6 Prepared according to US Patent: , B1, cyclopenta-2,4-dien-1-yl(2-((prop-2-yn-1-yloxy)methyl)cyclopenta-2,4-dien-1-yl)iron, S7 Prepared according to New J. Chem. 2014, 38, (tert-butyl) 2-(prop-2-yn-1-yl) (S)-pyrrolidine-1,2-dicarboxylate, S8 Prepared according to J. Org. Chem. 2010, 75, benzoyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione, S9

6 6 Prepared according to Eur. J. Med. Chem. 2013, 70, (3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-(prop-2-yn-1- yloxy)tetrahydrofuro[2,3-d][1,3]dioxole, S10 Prepared according to Angew. Chem. Int. Ed. 2015, 54, (3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-3-(prop-2-yn-1- yloxy)hexadecahydro-1h-cyclopenta[a]phenanthrene, S11 Prepared according to Patent: WO2009/49370 A1, Internal alkynes: Figure S1: Internal alkyne used in (MC) 2 R (prepared according to Org. Lett. 2002, 4, ).

7 7 diethyl 3,3'-(ethyne-1,2-diyl)dibenzoate, S12 1 H NMR: (399 MHz, Chloroform-d) δ 8.22 (td, J = 1.7, 0.6 Hz, 1H), 8.03 (ddd, J = 7.8, 1.2, 0.7 Hz, 1H), 7.71 (dt, J = 7.7, 1.3 Hz, 1H), 7.44 (tt, J = 7.8, 0.5 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13 C NMR: (100 MHz, cdcl 3 ) δ , , , , , , , 89.19, 61.25, IR: 2981, 1715, 1603, 1579, 1487, 1431, 1367, 1321, 1278, 1266, 1236, 1166, 1149, 1100, 1079, 1020, 998, 943, 911, 863, 816, 749, 681. MP: C HRMS: (ESI) calc d for C 27 H 26 N 3 (M + H) ; Found ,2-di(thiophen-3-yl)ethyne, S13 1 H NMR: (399 MHz, Chloroform-d) δ 7.50 (dd, J = 3.0, 1.2 Hz, 2H), 7.29 (dd, J = 5.0, 3.0 Hz, 2H), 7.18 (dd, J = 5.0, 1.2 Hz, 2H). 13 C NMR: (100 MHz, cdcl 3 ) δ , , , , IR: 3100, 1570, 1539, 1476, 1353, 1183, 1076, 960, 867, 829, 775, 693. MP: C HRMS: (DART) calc d for C 10 H 6 S 2 (M + H) ; Found All other starting materials are commercial. Intermediate synthesis: Scheme S4: Synthesis of intermediate 3a. A mixture of 1-iodobenzyl azide, 1a (2.59 g, 10 mmol), 1-hexyne, 2a (1.14 ml, 10 mmol), triethylamine (2.8 ml, 20 mmol) and CuI (1.9 g, 10 mmol) is stirred in THF (50 ml) at RT overnight. The reaction was

8 8 filtered, concentrated and purified by column chromatography (10% EtOAc in Hexanes) to the give 2.95 g (87%) 3a as a white solid. 4-butyl-1-(2-iodobenzyl)-1H-1,2,3-triazole, 3a Compound in agreement with literature report (Synthesis, 2013, 45, ). 1 H NMR: (300 MHz, Chloroform-d) δ 7.89 (dd, J = 8.3, 1.3 Hz, 1H), 7.32 (td, J = 7.6, 1.3 Hz, 1H), 7.28 (s, 1H), 7.04 (ddt, J = 8.2, 3.6, 1.7 Hz, 2H), 5.58 (s, 2H), (m, 2H), (m, 2H), 1.37 (dq, J = 14.4, 7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , 98.43, 58.13, 58.13, 31.47, 25.36, 22.27, (MC) 2 R: Scheme S5: (MC) 2 R. Typical protocol: 2-iodobenzyl azide, 1a (142.5 mg, 0.55 mmol, 1.1 equiv) was added a 2 dram amber vial with a Teflon coated stirbar under air. CuI (4.7 mg, 25.0 µmol, 5 mol % Cu), the Herrmann-Beller palladacycle (11.7 mg, 12.5 µmol, 5 mol % Pd), diphenylacetylene, 5a (178.2 mg, 1 mmol, 2 equiv) and PivOH (25.5 mg, 0.25 mmol, 50 mol %) were added to the vial followed by 1-hexyne, 1a (57.4 µl, 0.5 mmol, 1 equiv), triethylamine (348.5 µl, 2.5 mmol, 5 equiv) and DMSO (2 ml, 0.25 M, ppm H 2 O by KF titration). The vial was purged with Argon, capped, Teflon taped and then heated to 120 C for 24h. For optimization reactions: The vial was cooled to RT and diluted with 10 ml solution of a 1:1 mixture of EtOAc:Hexanes and washed with 20 ml saturated NaCl solution. The aqueous layer was extracted with 10 ml of the 1:1 EtOAc:Hexanes solution twice. The organic layers were combined, dried with MgSO 4 and filtered into a flask containing 1 ml of a 20 mm solution (in THF) of trimethoxybenzene. The filtrate was concentrated and yields were obtained through NMR spectroscopy.

9 9 For scope reactions: The vial was cooled to RT and the contents directly loaded onto a column (3cm x 20cm) and purified using mixtures of EtOAc in Hexanes. The pale yellow foams obtained from chromatography can be crystallized by slow evaporation from a 1:2 mixture of DCM:Hexanes. Large scale reaction: A 75 ml pressure flask was charged with 2-iodobenzyl azide, 1a (1.42 g, 5.5 mmol, 1.1 equiv), CuI (47.6 mg, 0.25 mmol, 5 mol % Cu), HBP (117.2 mg, mmol, 5 mol % Pd), diphenylacetylene, 5a (1.78 g, 10 mmol, 2 equiv), PivOH (255.3 mg, 2.5 mmol, 50 mol %), 1-hexyne, 2a (574 µl, 5.0 mmol, 1 equiv), triethylamine (3.48 ml, 25 mmol, 5 equiv) and DMSO (20 ml, 0.25M, 345 ppm H 2 O by KF titration) under air. The green mixture was flushed with Argon, capped and heated to 120 C for 24h. The flask was cooled to RT, diluted with 100 ml mixture of EtOAc:Hexanes (1:1), washed with 100 ml saturated NaCl solution. The aqueous layer was extracted with 100 ml of the 1:1 EtOAc:Hexanes solution twice. The organic layers were combined, dried with MgSO 4, filtered and concentrated. The black residue was purified by column chromatography (5 20% EtOAc in Hexanes) to give 1.53g (78%) 7a along with 1.04 g (94% recovery) 5a. 3-butyl-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7a Yield: 145 mg, 74%. Room temperature: 1 H NMR: (500 MHz, Chloroform-d) δ 7.46 (ddd, J = 7.5, 1.5, 0.6 Hz, 1H), 7.38 (ddd, J = 7.8, 1.4, 0.5 Hz, 1H), 7.32 (td, J = 7.4, 1.4 Hz, 1H), (m, 1H), (m, 4H), (m, 6H), 5.62 (broad s, 2H), 2.02 (broad s, 2H), 1.15 (broad s, 2H), 1.03 (dq, J = 14.8, 7.3 Hz, 2H), 0.69 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , 52.73, 31.37, 25.45, 22.45, IR: 2955, 2928, 2857, 1506, 1219, 1078, 772, 751, 740, 698, 415. MP: C HRMS: (ESI) calc d for C 27 H 26 N 3 (M + H) ; Found *Alkyl protons appear as broad singlets at room temperature which can be resolved at -40 o C At -40 o C: 1 H NMR: (600 MHz, Chloroform-d) δ 7.50 (d, J = 7.5 Hz, 1H), 7.42 (dd, J = 8.1, 2.2 Hz, 1H), 7.36 (td, J = 7.4, 1.4 Hz, 1H), (m, 5H), (m, 6H), 5.90 (d, J = 13.9 Hz, 1H), 5.43 (d, J = 13.1 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 0.68 (t, J = 7.3 Hz, 3H).

10 10 13 C NMR: (151 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 52.58, 31.45, 25.37, 22.49, H NMR study: Scheme S6: (MC) 2 R for 1 H NMR study. 2-iodobenzyl azide, 1a (28.5 mg, 0.11 mmol, 1.1 equiv), CuI (0.96 mg, 5.0 µmol, 5 mol % Cu), HBP (2.3 mg, 2.5 µmol, 5 mol % Pd), diphenylacetylene, 5a (35.6 mg, 0.2 mmol, 2 equiv), PivOH (5.1 mg, 0.05 mmol, 50 mol %), 1-hexyne, 2a (11.5 µl, 0.1 mmol, 1 equiv), triethylamine (70 µl, 0.5 mmol, 5 equiv) and DMSO d6 (0.4 ml, 0.25 M, ppm H 2 O by KF titration) were added to a 5 mm NMR tube and purged with Ar. A spectrum was taken at RT, then the probe was heated to 120 C. Spectra were taken every 15 mins for 2 h at the beginning of the experiment and then every hour for the remainder of the experiment. At the first time point at 120 C, 1a has reacted with 2a to form 3a. The excess azide degrades over the next few hours. The conversion of 3a to 7a is then observed. The reaction was purified by column chromatography (10 30% EtOAc in Hexanes) to give 30 mg (77%) of 7a, which closely matched the final NMR yield of 80%.

11 % NMR Yield Reaction Progression Time (hours) Figure S2: Plot of yield versus time for azide 1a, intermediate 3a and product 7a. Mechanism for palladium catalyzed step: Scheme S7: (MC) 2 R with 3,3-dideutereo hexyne. The reaction was run using standard conditions with 3,3-dideutereo hexyne, 2a-d (J. Org. Chem. 2005, 7, ) to give 7a-d with 92% D. Scope: 3-butyl-8-methyl-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7b

12 12 Yield: 142 mg, 70%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.27 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), (m, 4H), (m, 6H), 7.05 (ddd, J = 8.1, 1.9, 0.8 Hz, 1H), 5.57 (broad s, 2H), 2.33 (s, 3H), 2.01 (broad s, 2H), 1.15 (broad s, 2H), 1.03 (h, J = 7.3 Hz, 2H), 0.69 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 52.72, 31.39, 25.43, 22.43, 20.93, IR: 2955, 2928, 1615, 1599, 1497, 1464, 1441, 1219, 1072, 1031, 846, 826, 750, 705, 697. MP: C HRMS: (ESI) calc d for C 28 H 28 N 3 (M + H) ; Found butyl-8-fluoro-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7c Yield: 112 mg, 55%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 1H), (m, 4H), (m, 7H), (m, 1H), 5.60 (broad s, 2H), 2.03 (broad s, 2H), 1.17 (broad s, 2H), 1.04 (h, J = 7.3 Hz, 2H), 0.69 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , (d, J = 2.1 Hz), (d, J = 7.9 Hz), , , , , , (d, J = 2.9 Hz), , , , , , , , , , , , , 51.92, 31.32, 25.38, 22.38, F NMR: (377 MHz, Chloroform-d) δ (m). IR: 2956, 2929, 2860, 1610, 1577, 1489, 1465, 1441, 1265, 1201, 1074, 1000, 925, 878, 843, 803, 754, 725, 701. MP: C HRMS: (DART) calc d for C 27 H 25 N 3 F (M + H) ; Found butyl-7-chloro-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7d

13 13 Yield: 113 mg, 53%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.40 (dd, J = 8.2, 0.5 Hz, 1H), (m, 1H), 7.29 (dd, J = 8.1, 2.1 Hz, 1H), (m, 10H), 5.59 (broad s, 2H), 2.00 (braod s, 2H), 1.15 (broad s, 2H), 1.03 (dq, J = 14.8, 7.4 Hz, 2H), 0.69 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 52.04, 31.34, 25.39, 22.42, IR: 2956, 2927, 2858, 1596, 1560, 1485, 1465, 1441, 1206, 1075, 889, 836, 821, 803, 750, 699. MP: C HRMS: (DART) calc d for C 27 H 25 N 3 Cl (M + H) ; Found butyl-6,7-diphenyl-12H-[1,3]dioxolo[4',5':3,4]benzo[1,2-e][1,2,3]triazolo[1,5-a]azepine, 7e Yield: 133 mg, 61%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 4H), (m, 6H), 6.82 (dd, J = 8.4, 0.7 Hz, 1H), 6.67 (dd, J = 8.4, 0.6 Hz, 1H), 6.03 (s, 2H), 5.67 (broad s, 2H), 2.01 (t, J = 7.9 Hz, 2H), 1.14 (p, J = 7.5 Hz, 2H), 1.03 (h, J = 7.3 Hz, 2H), 0.69 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , 44.82, 31.38, 25.39, 22.40, IR: 2957, 2928, 2859, 1600, 1473, 1459, 1441, 1251, 1209, 1177, 1058, 1041, 1007, 931, 837, 818, 748, 698, 667. MP: C HRMS: (DART) calc d for C 28 H 26 N 3 O 2 (M + H) ; Found (4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)butanenitrile, 7f Yield: 176 mg, 88%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.47 (ddd, J = 7.5, 1.5, 0.6 Hz, 1H), 7.39 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 7.34 (td, J = 7.4, 1.4 Hz, 1H), (m, 1H), (m, 10H), 5.63 (broad s, 2H), 2.17 (t, J = 7.4 Hz, 2H), 2.10 (t, J = 7.3 Hz, 2H), (m, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , 52.80, 24.47, 24.23,

14 14 IR: 3019, 1599, 1575, 1488, 1440, 1353, 1324, 1206, 1074, 1030, 1001, 883, 851, 815, 741, 698, 666. MP: C HRMS: (DART) calc d for C 27 H 23 N 4 (M + H) ; Found (4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)methanol, 7g Yield: 79 mg, 43%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 1H), (m, 2H), (m, 1H), (m, 10H), 5.64 (broad s, 2H), 4.08 (d, J = 5.1 Hz, 2H), 1.72 (broad s, 1H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 56.30, IR: 3355, 3054, 3019, 1598, 1489, 1441, 1355, 1216, 1074, 1026, 883, 820, 756, 746, 698. MP: C HRMS: (DART) calc d for C 24 H 20 N 3 O (M + H) ; Found ,5-diphenyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7gthp Yield: 119 mg, 53%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.47 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H), (m, 2H), (m, 1H), (m, 10H), 5.64 (broads, 2H), 4.28 (s, 2H), 3.76 (broad s, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), (m, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 97.86, 61.51, 60.04, 52.75, 30.16, 25.33, IR: 2945, 1599, 1489, 1464, 1441, 1322, 1201, 1118, 1075, 1054, 1024, 970, 905, 869, 814, 755, 751, 698. MP: C HRMS: (DART) calc d for C 29 H 28 N 3 O 2 (M + H) ; Found

15 15 2-(4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)ethan-1-ol, 7h Yield: 135 mg, 72%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.47 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 7.8, 1.3 Hz, 1H), (m, 1H), (m, 1H), (m, 4H), (m, 6H), 5.63 (broad s, 2H), 3.59 (q, J = 6.0 Hz, 2H), (m, 1H), 2.18 (broad s, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , 60.85, 52.81, 28.44, IR: 3361, 3055, 3020, 2930, 1599, 1575, 1488, 1440, 1362, 1322, 1207, 1148, 1074, 1046, 1001, 882, 863, 822, 740, 697. MP: C HRMS: (DART) calc d for C 25 H 22 N 3 O (M + H) ; Found (2-((tert-butyldimethylsilyl)oxy)ethyl)-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7h-tbs Yield: 102 mg, 41%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 1H), 7.36 (ddd, J = 7.8, 1.4, 0.4 Hz, 1H), 7.31 (td, J = 7.4, 1.4 Hz, 1H), (m, 1H), (m, 4H), (m, 6H), 5.61 (broad s, 2H), 3.50 (broad s, 2H), 2.27 (broad s, 2H), 0.73 (s, 9H), (s, 6H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 62.35, 52.71, 29.14, 25.83, 18.16, IR: 2953, 2927, 2855, 1600, 1575, 1488, 1471, 1463, 1441, 1387, 1360, 1253, 1212, 1098, 1040, 1005, 917, 835, 753, 740, 697, 665. MP: C HRMS: (DART) calc d for C 31 H 36 N 3 OSi (M + H) ; Found (4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)propan-1-ol, 7i

16 16 Yield: 145 mg, 74%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.47 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H), 7.38 (ddd, J = 7.8, 1.4, 0.5 Hz, 1H), 7.33 (td, J = 7.5, 1.4 Hz, 1H), (m, 2H), (m, 4H), (m, 6H), 5.62 (broad s, 2H), 3.39 (t, J = 6.1 Hz, 2H)i, 2.16 (t, J = 7.3 Hz, 2H), 1.86 (broad s, 1H), 1.41 (ddd, J = 7.2, 6.1, 1.2 Hz, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 62.07, 52.80, 31.17, IR: 3279, 2950, 2863, 1487, 1449, 1433, 1372, 1202, 1150, 1051, 1042, 1014, 921, 890, 864, 821, 777, 757, 743, 729, 697, 673. MP: C HRMS: (DART) calc d for C 26 H 24 N 3 O (M + H) ; Found (4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)propan-2-ol, 7j Yield: 63 mg, 32%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 2H), (m, 6H), (m, 6H), 5.83 (d, J = 13.7 Hz, 1H), 5.42 (d, J = 13.7 Hz, 1H), 2.11 (s, 1H), 1.24 (s, 3H), 1.08 (s, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 69.49, 52.51, 30.32, IR: 3567, 3443, 3054, 3019, 2977, 2926, 1599, 1575, 1489, 1441, 1380, 1363, 1324, 1219, 1166, 1147, 1075, 1056, 1001, 957, 883, 862, 754, 742, 698. MP: C HRMS: (DART) calc d for C 26 H 24 N 3 O (M + H) ; Found Bis-tert-butyl (3-(4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)propyl)carbamate, 7k

17 17 Yield: 74 mg, 25%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.46 (ddd, J = 7.6, 1.4, 0.7 Hz, 1H), 7.36 (ddd, J = 7.9, 1.4, 0.5 Hz, 1H), 7.32 (td, J = 7.4, 1.4 Hz, 1H), (m, 1H), (m, 4H), (m, 6H), 5.61 (broad s, 2H), 3.35 (t, J = 7.4 Hz, 2H), 2.00 (broad s, 2H), (m, 2H), 1.38 (s, 18H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , 81.83, 52.73, 45.88, 28.60, 27.95, IR: 2979, 2932, 1781, 1740, 1694, 1488, 1441, 1393, 1367, 1287, 1133, 853, 756, 698. MP: C HRMS: (DART) calc d for C 36 H 41 N 4 O 4 (M + H) ; Found tert-butyl (3-(4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)propyl)carbamate, 7l Yield: 88 mg, 36%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.46 (ddd, J = 7.6, 1.5, 0.5 Hz, 1H), 7.38 (ddd, J = 7.8, 1.4, 0.5 Hz, 1H), 7.33 (td, J = 7.4, 1.4 Hz, 1H), (m, 1H), (m, 4H), (m, 6H), 5.61 (broad s, 2H), 4.34 (broad s, 1H), (m, 2H), (m, 2H), 1.41 (s, 9H), 1.32 (broads, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , 78.82, 52.76, 39.77, 28.92, 28.42, IR: 3364, 3059, 2975, 2930, 1699, 1505, 1489, 1441, 1364, 1247, 1164, 1075, 740, 698. MP: C HRMS: (DART) calc d for C 31 H 33 N 3 O 2 (M + H) ; Found ,5-diphenyl-3-(pyridin-3-yl)-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7m

18 18 Yield: 146 mg, 71%. 1 H NMR: (500 MHz, Chloroform-d) δ 8.47 (d, J = 2.1 Hz, 1H), (m, 1H), (m, 3H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), 5.70 (broad s, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , , IR: 3055, 3022, 1599, 1573, 1488, 1441, 1410, 1362, 1215, 1146, 1101, 1029, 1005, 808, 749, 739, 696. MP: C HRMS: (DART) calc d for C 28 H 21 N 4 (M + H) ; Found ((((3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1Hcyclopenta[a]phenanthren-3-yl)oxy)methyl)-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7n Yield: 195 mg, 53%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.45 (ddd, J = 7.5, 1.5, 0.6 Hz, 1H), (m, 2H), (m, 2H), (m, 10H), 5.62 (s, 2H), 3.91 (s, 2H), 2.92 (tt, J = 11.1, 4.6 Hz, 1H), 1.94 (dt, J = 12.5, 3.4 Hz, 1H), 1.80 (dtd, J = 13.3, 9.4, 5.9 Hz, 1H), (m, 1H), (m, 1H), 1.44 (dt, J = 13.6, 5.1 Hz, 1H), (m, 8H), 0.89 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 2.3 Hz, 3H), 0.85 (d, J = 2.3 Hz, 3H), (m, 1H), 0.73 (s, 2H), 0.63 (s, 3H), 0.55 (ddd, J = 12.3, 10.4, 4.0 Hz, 1H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 77.97, 60.76, 56.51, 56.29, 54.36, 52.76, 44.74, 42.59, 40.05, 39.52, 36.95, 36.18, 35.79, 35.70, 35.48, 34.44, 32.10, 28.82, 28.25, 28.01, 27.95, 24.21, 23.83, 22.82, 22.56, 21.20, 18.67, 12.24, [α] D 20 = +0.12, c = 1.0 CHCl 3. IR: 2930, 2864, 1494, 1470, 1442, 1382, 1075, 759, 741, 697. MP: C HRMS: (DART) calc d for C 51 H 66 N 3 O (M + H) ; Found (tert-butyl) 2-((4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)methyl) (S)-pyrrolidine- 1,2-dicarboxylate, 7o

19 19 Yield: 233 mg, 83%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.48 (ddd, J = 7.3, 1.4, 0.6 Hz, 1H), (m, 2H), (m, 1H), (m, 10H), 5.64 (broads, 2H), (m, 2H), (m, 0.4H), (m, 0.6H), (m, 2H), (m, 1H), (m, 3H), 1.46 (s, 4H), 1.22 (s, 5H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 79.77, 79.53, 58.84, 58.55, 58.09, 57.48, 52.82, 46.49, 46.22, 30.72, 29.82, 28.45, 28.10, 24.09, [α] D 20 = -0.12, c = 0.5 CHCl 3. IR: 3055, 2976, 2930, 1746, 1693, 1489, 1477, 1442, 1395, 1365, 1159, 1122, 1087, 966, 756, 743, 699. MP: C HRMS: (DART) calc d for C 34 H 35 N 4 O 4 (M + H) ; Found *Signals for both 1 H NMR and 13 C NMR were split due to rotomeric effects 3-((((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3- d][1,3]dioxol-6-yl)oxy)methyl)-4,5-diphenyl-10h-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7p Yield: 185 mg, 61%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.48 (ddd, J = 7.5, 1.4, 0.5 Hz, 1H), (m, 2H), (m, 1H), (m, 10H), (m, 3H), 4.26 (d, J = 3.7 Hz, 1H), 4.19 (broads, 2H), 4.08 (dd, J = 6.8, 3.1 Hz, 1H), (m, 3H), 3.72 (dt, J = 3.2, 0.5 Hz, 1H), 1.58 (broad s, 1H), 1.44 (s, 3H), 1.40 (s, 3H), 1.36 (s, 2H), 1.22 (s, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , 81.74, 81.62, 80.83, 72.58, 66.76, 62.90, 52.79, 26.75, 26.16, [α] D 20 = +0.24, c = 0.5 CHCl 3.

20 20 IR: 2987, 1489, 1442, 1372, 1213, 1163, 1069, 1018, 845, 741, 698. MP: C HRMS: (DART) calc d for C 36 H 38 N 3 O 6 (M + H) ; Found ((4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepin-3-yl)methyl)pyrimidine-2,4(1H,3H)-dione, 7q Yield: 171 mg, 74%. 1 H NMR: (500 MHz, Chloroform-d) δ 8.40 (s, 1H), 7.48 (ddd, J = 7.4, 1.4, 0.5 Hz, 1H), (m, 2H), (m, 1H), (m, 4H), (m, 6H), 6.98 (d, J = 8.0 Hz, 1H), 5.66 (broad s, 2H), 5.50 (dd, J = 8.0, 2.4 Hz, 1H), (m, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , 52.91, IR: 3172, 3055, 1680, 1489, 1442, 1388, 1361, 1266, 1223, 759, 742, 700. MP: C HRMS: (DART) calc d for C 28 H 22 N 5 O 2 (M + H) ; Found cyclopenta-2,4-dien-1-yl(2-(((4,5-diphenyl-10h-benzo[e][1,2,3]triazolo[1,5-a]azepin-3- yl)methoxy)methyl)cyclopenta-2,4-dien-1-yl)iron, 7r Yield: 147 mg, 52%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.46 (ddd, J = 7.5, 1.4, 0.6 Hz, 1H), 7.33 (ddd, J = 7.5, 6.8, 1.8 Hz, 1H), (m, 2H), (m, 10zH), 5.63 (s, 2H), 4.11 (s, 2H), (m, 9H), 3.88 (s, 2H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 69.52, 68.37, 68.35, 68.27, 62.78, IR: 3059, 3005, 2919, 2854, 1666, 1599, 1488, 1441, 1411, 1261, 1235, 1217, 1065, 1000, 819, 740, 697. MP: C HRMS: (DART) calc d for C 35 H 30 N 3 OFe (M + H) ; Found

21 21 3-butyl-4,5-di-p-tolyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7s Yield: 110 mg, 52%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.43 (dd, J = 7.5, 1.4 Hz, 1H), 7.34 (dd, J = 7.9, 1.4 Hz, 1H), 7.28 (td, J = 7.4, 1.4 Hz, 1H), 7.22 (td, J = 7.6, 1.5 Hz, 1H), (m, 2H), (m, 4H), (m, 2H), 5.58 (broad s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 2.01 (broad s, 2H), (m, 2H), 1.04 (h, J = 7.3 Hz, 2H), 0.69 (t, J = 7.2 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 52.67, 31.40, 25.45, 22.47, 21.13, 21.11, IR: 3023, 2957, 2926, 2858, 1506, 1448, 1211, 1109, 1022, 816, 756. MP: C HRMS: (DART) calc d for C 29 H 30 N 3 (M + H) ; Found butyl-4,5-bis(4-(trifluoromethyl)phenyl)-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7t Yield: 180 mg, 68%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 5H), (m, 3H), (m, 4H), 5.65 (broad s, 2H), 2.01 (t, J = 7.8 Hz, 2H), 1.12 (broad s, 2H), 1.02 (h, J = 7.3 Hz, 2H), 0.67 (t, J = 7.2 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 52.77, 31.35, 25.55, 22.43, F NMR: (377 MHz, CDCl 3 ) δ , IR: 2961, 2932, 2874, 1616, 1406, 1327, 1167, 1126, 1067, 804, 760. MP: C HRMS: (DART) calc d for C 29 H 24 N 3 F 6 (M + H) ; Found butyl-4,5-bis(4-chlorophenyl)-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7u

22 22 Yield: 156 mg, 68%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.45 (d, J = 6.8 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 4H), (m, 2H), 5.59 (broad s, 2H), 2.03 (broad s, 2H), 1.17 (broad s, 2H), 1.06 (dq, J = 14.7, 7.3 Hz, 2H), 0.72 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 52.68, 31.37, 25.50, 22.45, IR: 2956, 2928, 2859, 1592, 1488, 1395, 1214, 1148, 1089, 1015, 818, 793, 752, 666. MP: C HRMS: (DART) calc d for C 27 H 24 N 3 Cl 2 (M + H) ; Found butyl-4,5-di-m-tolyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7v Yield: 136 mg, 65%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.45 (dd, J = 7.5, 1.4 Hz, 1H), 7.36 (dd, J = 7.9, 1.3 Hz, 1H), 7.30 (td, J = 7.4, 1.4 Hz, 1H), (m, 1H), (m, 1H), 7.04 (dd, J = 7.4, 0.9 Hz, 2H), 7.01 (dt, J = 2.5, 0.8 Hz, 1H), (m, 4H), 5.61 (broad s, 2H), 2.25 (s, 3H), 2.21 (s, 3H), 2.02 (broad s, 2H), 1.15 (broad s, 2H), 1.03 (h, J = 7.3 Hz, 2H), 0.70 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , 52.69, 31.44, 25.45, 22.48, 21.37, 21.22, IR: 2955, 2826, 2859, 1602, 1583, 1486, 1464, 1453, 1434, 1210, 1095, 880, 834, 789, 750, 710, 698. MP: C HRMS: (DART) calc d for C 29 H 30 N 3 (M + H) ; Found butyl-4,5-bis(3-(trifluoromethyl)phenyl)-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7w

23 23 Yield: 159 mg, 60%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 2H), (m, 3H), (m, 1H), (m, 2H), (m, 4H), 5.66 (broad s, 2H), 2.02 (t, J = 8.0 Hz, 2H), 1.15 (broad s, 2H), 1.02 (h, J = 7.6 Hz, 2H), 0.68 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 52.80, 31.39, 25.58, 22.37, F NMR: (377 MHz, CDCl 3 ) δ , IR: 2959, 2932, 1487, 1432, 1330, 1252, 1164, 1123, 1094, 1072, 907, 796, 753, 702. MP: C HRMS: (DART) calc d for C 29 H 24 N 3 F 6 (M + H) ; Found diethyl 3,3'-(3-butyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine-4,5-diyl)dibenzoate, 7x Yield: 174 mg, 65%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.89 (td, J = 1.8, 0.5 Hz, 1H), (m, 3H), (m, 1H), 7.44 (ddd, J = 7.6, 1.8, 1.2 Hz, 1H), (m, 2H), 7.30 (td, J = 7.8, 0.6 Hz, 1H), (m, 3H), 5.67 (broad s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 2.00 (broad s, 2H), 1.37 (t, J = 7.2 Hz, 6H), 1.16 (broad s, 2H), 1.03 (dt, J = 14.9, 7.3 Hz, 2H), 0.68 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , , , , , , 61.18, 61.16, 52.79, 31.40, 25.51, 22.41, 14.30, 14.29, IR: 2957, 1715, 1581, 1446, 1433, 1367, 1288, 1241, 1219, 1106, 1082, 1022, 747, 700. MP: C HRMS: (DART) calc d for C 33 H 34 N 3 O 4 (M + H) ; Found

24 24 3-butyl-4,5-di(thiophen-3-yl)-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 7y Yield: 146 mg, 72%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.43 (ddd, J = 7.4, 1.6, 0.5 Hz, 1H), 7.40 (ddd, J = 7.7, 1.5, 0.5 Hz, 1H), 7.32 (td, J = 7.4, 1.5 Hz, 1H), 7.28 (dd, J = 7.7, 1.5 Hz, 1H), 7.24 (dd, J = 4.9, 3.0 Hz, 1H), 7.16 (dd, J = 5.0, 3.0 Hz, 1H), 7.12 (dd, J = 2.9, 1.3 Hz, 1H), 7.02 (dd, J = 3.0, 1.3 Hz, 1H), 6.94 (dd, J = 4.9, 1.3 Hz, 1H), 6.79 (dd, J = 5.0, 1.3 Hz, 1H), 5.55 (broad s, 2H), 2.08 (broad s, 2H), 1.30 (broad s, 2H), 1.10 (dq, J = 14.7, 7.4 Hz, 2H), 0.74 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 52.61, 31.28, 25.38, 22.48, IR: 3102, 2956, 2928, 2859, 1488, 1451, 1434, 1356, 1206, 1081, 868, 843, 776, 755, 735, 657. HRMS: (DART) calc d for C 23 H 22 N 3 S 2 (M + H) ; Found ethyl 3-butyl-4-phenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine-5-carboxylate, 7z Yield: 142 mg, 73%. 1 H NMR: (500 MHz, Chloroform-d) δ (m, 1H), (m, 1H), (m, 7H), 5.54 (broad s, 2H), 3.93 (q, J = 7.2 Hz, 2H), 1.89 (broad s, 2H), 1.23 (p, J = 7.5 Hz, 2H), 0.99 (h, J = 7.4 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H), 0.66 (t, J = 7.3 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , 61.49, 52.69, 31.31, 25.13, 22.35, 13.54, IR: 2957, 2930, 2872, 1721, 1717, 1368, 1263, 1231, 1024, 762, 701. MP: C HRMS: (ESI) calc d for C 24 H 26 N 3 O 2 (M + H) ; Found Product derivatization:

25 25 Scheme S8: Derivatization of product 7a. To a solution of 7a (50 mg, 0.13 mmol) and alkyl bromide (1-bromobutane 56 µl, 4 equiv; 1,5- dibromopentane 43 µl, 2.5 equiv) in THF (5 ml) at -78 C was added nbuli (0.1 ml, 2.5 M in Hexanes, 2 equiv). The reactions were warmed to RT overnight, concentrated and purified by column chromatography (10% EtOAc in Hexanes) to give the alkylated products as white foams. 3,10,10-tributyl-4,5-diphenyl-10H-benzo[e][1,2,3]triazolo[1,5-a]azepine, 12 Yield: 63 mg, 97%. 1 H NMR: (500 MHz, Chloroform-d) δ 7.60 (dd, J = 8.2, 1.3 Hz, 1H), 7.39 (dd, J = 8.0, 1.4 Hz, 1H), 7.31 (ddd, J = 8.2, 7.2, 1.5 Hz, 1H), (m, 4H), (m, 7H), 3.28 (s, 1H), (m, 3H), (m, 7H), (m, 14H), 0.69 (t, J = 7.1 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , 69.04, 33.38, 31.25, 30.81, 27.28, 26.41, 25.68, 23.35, 23.15, 22.50, 14.23, IR: MP: C HRMS: (DART) calc d for C 35 H 42 N 3 (M + H) ; Found butyl-4,5-diphenylspiro[benzo[e][1,2,3]triazolo[1,5-a]azepine-10,1'-cyclohexane], 13 Yield: 48 mg, 83%.

26 26 1 H NMR: (500 MHz, Chloroform-d) δ 7.67 (d, J = 8.0 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 7H), (m, 1H), (m, 1H), 2.79 (ddd, J = 14.1, 10.2, 4.0 Hz, 1H), 2.48 (dtd, J = 13.8, 9.9, 4.9 Hz, 1H), (m, 1H), (m, 2H), 1.92 (ddd, J = 14.3, 10.1, 5.7 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 3H), 0.70 (t, J = 7.2 Hz, 3H). 13 C NMR: (126 MHz, cdcl 3 ) δ , , , , , , , , , , , , , , , , , , , 65.44, 33.97, 33.00, 31.29, 25.63, 25.57, 23.47, 22.70, 22.52, IR: 2955, 2929, 2855, 1489, 1441, 751, 699. MP: C HRMS: (DART) calc d for C 32 H 34 N 3 (M + H) ; Found NMR Spectra:

27 27

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70 Figure S3: Crystal structure of product 7z. 70

71 71 Table 1. Crystal data and structure refinement for d1619. Identification code Empirical formula d1619 Formula weight Temperature Wavelength Crystal system C24 H25 N3 O2 147(2) K Å Orthorhombic Space group P Unit cell dimensions a = (2) Å a= 90. b = (5) Å b= 90. c = (7) Å g = 90. Volume (12) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 824 Crystal size x x mm 3 Theta range for data collection to Index ranges Reflections collected <=h<=5, -20<=k<=20, -27<=l<=27 Independent reflections 3655 [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 3655 / 0 / 272 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.01(7) Extinction coefficient n/a Largest diff. peak and hole and e.å -3

72 72 Table 2. Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for d1619. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) O(1) 1046(3) 5999(1) 4834(1) 47(1) O(2) 4794(4) 6129(1) 4360(1) 45(1) N(1) 5002(3) 3493(1) 3749(1) 25(1) N(2) 4974(4) 2807(1) 3478(1) 32(1) N(3) 3149(4) 2843(1) 3081(1) 31(1) C(1) 6756(4) 3673(1) 4228(1) 29(1) C(2) 5226(4) 3770(1) 4777(1) 28(1) C(3) 5715(5) 3291(1) 5251(1) 37(1) C(4) 4280(5) 3360(1) 5753(1) 46(1) C(5) 2307(6) 3890(2) 5777(1) 50(1) C(6) 1827(5) 4386(1) 5315(1) 39(1) C(7) 3328(4) 4339(1) 4809(1) 28(1) C(8) 2929(4) 4913(1) 4333(1) 25(1) C(9) 2824(3) 4759(1) 3758(1) 23(1) C(10) 3191(4) 3979(1) 3530(1) 22(1) C(11) 2019(4) 3554(1) 3097(1) 25(1) C(12) -136(4) 3770(1) 2698(1) 30(1) C(13) 663(4) 3847(1) 2063(1) 36(1) C(14) -1586(6) 4074(2) 1674(1) 53(1) C(15) -881(7) 4136(2) 1045(1) 79(1) C(16) 2339(4) 5374(1) 3316(1) 24(1) C(17) 4043(4) 5450(1) 2851(1) 28(1) C(18) 3714(4) 6033(1) 2445(1) 36(1) C(19) 1638(5) 6528(1) 2488(1) 38(1) C(20) -99(5) 6447(1) 2939(1) 37(1) C(21) 257(4) 5876(1) 3356(1) 30(1) C(22) 2745(4) 5737(1) 4537(1) 31(1) C(23) 4438(18) 6983(3) 4486(2) 49(2)

73 73 C(24) 5937(16) 7407(2) 4072(2) 51(2) C(24A) 4400(20) 7430(4) 4102(3) 44(2) C(23A) 5549(18) 6869(4) 4573(3) 38(2) Table 3. Bond lengths [Å] and angles [ ] for d1619. O(1)-C(22) 1.203(3) O(2)-C(22) 1.325(3) O(2)-C(23A) 1.426(8) O(2)-C(23) 1.517(5) N(1)-N(2) 1.342(2) N(1)-C(10) 1.358(2) N(1)-C(1) 1.461(2) N(2)-N(3) 1.316(2) N(3)-C(11) 1.364(2) C(1)-C(2) 1.503(3) C(1)-H(1A) C(1)-H(1B) C(2)-C(3) 1.394(3) C(2)-C(7) 1.394(3) C(3)-C(4) 1.379(3) C(3)-H(3A) C(4)-C(5) 1.374(4) C(4)-H(4A) C(5)-C(6) 1.390(3) C(5)-H(5A) C(6)-C(7) 1.403(3) C(6)-H(6A) C(7)-C(8) 1.494(2) C(8)-C(9) 1.352(2) C(8)-C(22) 1.506(3) C(9)-C(10) 1.461(2) C(9)-C(16) 1.493(2) C(10)-C(11) 1.381(3) C(11)-C(12) 1.494(3)

74 74 C(12)-C(13) 1.526(3) C(12)-H(12A) C(12)-H(12B) C(13)-C(14) 1.521(3) C(13)-H(13A) C(13)-H(13B) C(14)-C(15) 1.498(4) C(14)-H(14A) C(14)-H(14B) C(15)-H(15A) C(15)-H(15B) C(15)-H(15C) C(16)-C(21) 1.389(3) C(16)-C(17) 1.394(3) C(17)-C(18) 1.385(3) C(17)-H(17A) C(18)-C(19) 1.379(3) C(18)-H(18A) C(19)-C(20) 1.381(3) C(19)-H(19A) C(20)-C(21) 1.391(3) C(20)-H(20A) C(21)-H(21A) C(23)-C(24) 1.433(8) C(23)-H(23A) C(23)-H(23B) C(24)-H(24A) C(24)-H(24B) C(24)-H(24C) C(24A)-C(23A) 1.573(11) C(24A)-H(24D) C(24A)-H(24E) C(24A)-H(24F) C(23A)-H(23C) C(23A)-H(23D)

75 75 C(22)-O(2)-C(23A) 125.1(4) C(22)-O(2)-C(23) 110.1(3) N(2)-N(1)-C(10) (15) N(2)-N(1)-C(1) (15) C(10)-N(1)-C(1) (15) N(3)-N(2)-N(1) (14) N(2)-N(3)-C(11) (15) N(1)-C(1)-C(2) (16) N(1)-C(1)-H(1A) C(2)-C(1)-H(1A) N(1)-C(1)-H(1B) C(2)-C(1)-H(1B) H(1A)-C(1)-H(1B) C(3)-C(2)-C(7) (18) C(3)-C(2)-C(1) (18) C(7)-C(2)-C(1) (15) C(4)-C(3)-C(2) 120.4(2) C(4)-C(3)-H(3A) C(2)-C(3)-H(3A) C(5)-C(4)-C(3) 119.5(2) C(5)-C(4)-H(4A) C(3)-C(4)-H(4A) C(4)-C(5)-C(6) 121.0(2) C(4)-C(5)-H(5A) C(6)-C(5)-H(5A) C(5)-C(6)-C(7) 120.0(2) C(5)-C(6)-H(6A) C(7)-C(6)-H(6A) C(2)-C(7)-C(6) (17) C(2)-C(7)-C(8) (16) C(6)-C(7)-C(8) (18) C(9)-C(8)-C(7) (16) C(9)-C(8)-C(22) (16) C(7)-C(8)-C(22) (15) C(8)-C(9)-C(10) (15) C(8)-C(9)-C(16) (16)

76 76 C(10)-C(9)-C(16) (15) N(1)-C(10)-C(11) (15) N(1)-C(10)-C(9) (16) C(11)-C(10)-C(9) (17) N(3)-C(11)-C(10) (16) N(3)-C(11)-C(12) (16) C(10)-C(11)-C(12) (16) C(11)-C(12)-C(13) (17) C(11)-C(12)-H(12A) C(13)-C(12)-H(12A) C(11)-C(12)-H(12B) C(13)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(14)-C(13)-C(12) (18) C(14)-C(13)-H(13A) C(12)-C(13)-H(13A) C(14)-C(13)-H(13B) C(12)-C(13)-H(13B) H(13A)-C(13)-H(13B) C(15)-C(14)-C(13) 113.6(2) C(15)-C(14)-H(14A) C(13)-C(14)-H(14A) C(15)-C(14)-H(14B) C(13)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(14)-C(15)-H(15A) C(14)-C(15)-H(15B) H(15A)-C(15)-H(15B) C(14)-C(15)-H(15C) H(15A)-C(15)-H(15C) H(15B)-C(15)-H(15C) C(21)-C(16)-C(17) (17) C(21)-C(16)-C(9) (16) C(17)-C(16)-C(9) (16) C(18)-C(17)-C(16) (19) C(18)-C(17)-H(17A) 119.7

77 77 C(16)-C(17)-H(17A) C(19)-C(18)-C(17) (19) C(19)-C(18)-H(18A) C(17)-C(18)-H(18A) C(18)-C(19)-C(20) (18) C(18)-C(19)-H(19A) C(20)-C(19)-H(19A) C(19)-C(20)-C(21) (19) C(19)-C(20)-H(20A) C(21)-C(20)-H(20A) C(16)-C(21)-C(20) (19) C(16)-C(21)-H(21A) C(20)-C(21)-H(21A) O(1)-C(22)-O(2) (19) O(1)-C(22)-C(8) (19) O(2)-C(22)-C(8) (16) C(24)-C(23)-O(2) 107.9(4) C(24)-C(23)-H(23A) O(2)-C(23)-H(23A) C(24)-C(23)-H(23B) O(2)-C(23)-H(23B) H(23A)-C(23)-H(23B) C(23)-C(24)-H(24A) C(23)-C(24)-H(24B) H(24A)-C(24)-H(24B) C(23)-C(24)-H(24C) H(24A)-C(24)-H(24C) H(24B)-C(24)-H(24C) C(23A)-C(24A)-H(24D) C(23A)-C(24A)-H(24E) H(24D)-C(24A)-H(24E) C(23A)-C(24A)-H(24F) H(24D)-C(24A)-H(24F) H(24E)-C(24A)-H(24F) O(2)-C(23A)-C(24A) 102.4(5) O(2)-C(23A)-H(23C) 111.3

78 78 C(24A)-C(23A)-H(23C) O(2)-C(23A)-H(23D) C(24A)-C(23A)-H(23D) H(23C)-C(23A)-H(23D) Symmetry transformations used to generate equivalent atoms:

79 79 Table 4. Anisotropic displacement parameters (Å 2 x 10 3 ) for d1619. The anisotropic displacement factor exponent takes the form: -2p 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 O(1) 49(1) 48(1) 45(1) -15(1) 8(1) 12(1) O(2) 63(1) 31(1) 42(1) -13(1) 13(1) -16(1) N(1) 28(1) 22(1) 24(1) 3(1) 1(1) 4(1) N(2) 39(1) 23(1) 32(1) 0(1) 1(1) 3(1) N(3) 36(1) 25(1) 31(1) -1(1) -1(1) 1(1) C(1) 26(1) 32(1) 29(1) 5(1) -3(1) 0(1) C(2) 29(1) 28(1) 26(1) 3(1) -4(1) -9(1) C(3) 47(1) 32(1) 32(1) 6(1) -9(1) -9(1) C(4) 69(2) 42(1) 28(1) 10(1) -3(1) -14(1) C(5) 68(2) 57(1) 25(1) 3(1) 12(1) -17(1) C(6) 44(1) 45(1) 27(1) -1(1) 6(1) -7(1) C(7) 31(1) 31(1) 21(1) 0(1) -2(1) -10(1) C(8) 23(1) 26(1) 27(1) -1(1) 2(1) -3(1) C(9) 20(1) 23(1) 25(1) 0(1) 3(1) -1(1) C(10) 23(1) 22(1) 22(1) 4(1) 3(1) 0(1) C(11) 26(1) 24(1) 26(1) 0(1) 2(1) 0(1) C(12) 27(1) 30(1) 32(1) -5(1) -3(1) 0(1) C(13) 38(1) 38(1) 30(1) 1(1) -1(1) -2(1) C(14) 54(2) 65(2) 39(1) 3(1) -11(1) 5(1) C(15) 81(2) 113(3) 43(1) 23(2) -12(2) -8(2) C(16) 27(1) 20(1) 24(1) -2(1) -3(1) -2(1) C(17) 29(1) 29(1) 26(1) 1(1) -1(1) 2(1) C(18) 41(1) 38(1) 29(1) 7(1) -1(1) -4(1) C(19) 50(1) 28(1) 36(1) 8(1) -12(1) -1(1) C(20) 39(1) 26(1) 47(1) -2(1) -11(1) 9(1) C(21) 28(1) 28(1) 35(1) -4(1) -1(1) 2(1) C(22) 36(1) 32(1) 24(1) -3(1) -3(1) 1(1) C(23) 76(4) 22(2) 49(3) -18(2) 9(3) -9(2) C(24) 65(5) 25(2) 64(3) -6(2) 4(2) -2(2)

80 80 Table 5. Hydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for d1619. x y z U(eq) H(1A) H(1B) H(3A) H(4A) H(5A) H(6A) H(12A) H(12B) H(13A) H(13B) H(14A) H(14B) H(15A) H(15B) H(15C) H(17A) H(18A) H(19A) H(20A) H(21A) H(23A) H(23B) H(24A) H(24B) H(24C) H(24D) H(24E) H(24F)

81 81 H(23C) H(23D)

82 82 Table 6. Torsion angles [ ] for d1619. C(10)-N(1)-N(2)-N(3) 0.1(2) C(1)-N(1)-N(2)-N(3) (15) N(1)-N(2)-N(3)-C(11) 0.3(2) N(2)-N(1)-C(1)-C(2) (18) C(10)-N(1)-C(1)-C(2) 66.1(2) N(1)-C(1)-C(2)-C(3) (19) N(1)-C(1)-C(2)-C(7) -59.8(2) C(7)-C(2)-C(3)-C(4) 1.7(3) C(1)-C(2)-C(3)-C(4) (19) C(2)-C(3)-C(4)-C(5) 2.0(3) C(3)-C(4)-C(5)-C(6) -3.6(4) C(4)-C(5)-C(6)-C(7) 1.5(4) C(3)-C(2)-C(7)-C(6) -3.7(3) C(1)-C(2)-C(7)-C(6) (18) C(3)-C(2)-C(7)-C(8) (18) C(1)-C(2)-C(7)-C(8) -6.2(3) C(5)-C(6)-C(7)-C(2) 2.2(3) C(5)-C(6)-C(7)-C(8) (2) C(2)-C(7)-C(8)-C(9) 45.8(3) C(6)-C(7)-C(8)-C(9) (2) C(2)-C(7)-C(8)-C(22) (19) C(6)-C(7)-C(8)-C(22) 45.9(2) C(7)-C(8)-C(9)-C(10) -2.1(3) C(22)-C(8)-C(9)-C(10) (18) C(7)-C(8)-C(9)-C(16) (18) C(22)-C(8)-C(9)-C(16) -4.5(3) N(2)-N(1)-C(10)-C(11) -0.4(2) C(1)-N(1)-C(10)-C(11) (16) N(2)-N(1)-C(10)-C(9) (16) C(1)-N(1)-C(10)-C(9) 0.5(3) C(8)-C(9)-C(10)-N(1) -40.3(3) C(16)-C(9)-C(10)-N(1) (17) C(8)-C(9)-C(10)-C(11) 139.4(2) C(16)-C(9)-C(10)-C(11) -40.8(3)