Supporting Information

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1 Supporting Information Synthesis of Pyrrole-Fused C,N-Cyclic Azomethine Imines and Pyrazolopyrrolopyrazines: Analysis of Their Aromaticity Using Nucleus-Independent Chemical Shifts Values Merve Sinem Özer, Nurettin Menges,, Selbi Keskin,,ǁ Ertan Şahin, Metin Balci *, Department of Chemistry, Middle East Technical University, Ankara, Turkey Faculty of Pharmacy, Yüzüncü Yil University, Van, Turkey Department of Chemistry, Atatürk University, 25240, Erzurum, Turkey ǁ Department of Chemistry, Giresun University, Giresun, Turkey Table of Content Page 1. Experimental Section S2 2. General Procedure for compound 12a-h S2 3. General Procedure for compound 13a-h S5 4. General Procedure for compound S7 5. NMR Spectra S10 6. Theoretical Calculations S33 7. Methodology S33 8. Theoretical Coordinates for compound 13a,c,d,f, and S33 9. X-Ray structure determination of 13d S References S42 S1

2 Experimental Section General Methods. NMR spectra were recorded on a 400 MHz spectrometer. Infrared (IR) spectra were recorded in the range cm -1 via ATR diamond. Melting points were determined using a melting point apparatus and were uncorrected. Mass spectra were recorded by LC-MS TOF electrospray ionization technique. Column chromatography was performed on silica gel (60-mesh), TLC was carried out on 0.2 mm silica gel 60 F 254 analytical aluminum plates. Evaporation of solvents was performed at reduced pressure, using a rotary vacuum evaporator. General Procedure for compound 12a-h. Pyrrole aldehyde 9 or 10 (1 equiv.) and hydrazide 11a-e (1 equiv) were stirred in 5 ml EtOH at room temperature for 24 h. Evaporation of the solvent gave the corresponding products 12a-h. N'-((1-(Prop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)formohydrazide (12a): Pyrrole aldehyde 9 (0.50 g, 3.76 mmol) and formohydrazide (0.23 g, 3.76 mmol) were reacted as described above. After evaporation of the solvent the residue was crystallized from CHCl 3 in petroleum ether atmosphere to give the product 12a as brown crystals (0.66 g, 100%, NMR yield), mp C. 1 H NMR (400 MHz, CDCl 3 ) δ 9.75 (bd, J = 8.8 Hz, 1H), 8.71 (d, J = 10.3 Hz, 1H), 7.79 (s, 1H), 7.04 (dd, J = 2.3, 1.8 Hz, 1H), 6.49 (dd, J = 3.8, 1.7 Hz, 1H), 6.21 (dd, J = 3.7, 2.8 Hz, 1H), 5.13 (d, J = 2.5 Hz, 2H), 2.42 (t, J = 2.5 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 179.8, 165.2, 139.3, 127.0, 117.8, 109.5, 78.4, 73.9, 38.8; IR (ATR, cm -1 ) 3186, 1676, 1473, 1396, 1362, 1276, 1069, 1021, 776, 710, 650; HRMS for C 9 H 10 N 3 O [M+H] + : Found: (E/Z)-N'-((1-(Prop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)acetohydrazide (12b). Pyrrole aldehyde 9 (0.53 g, 4.00 mmol) and acetohydrazide (0.30 g, 4.00 mmol) were reacted as described above. After evaporation of the solvent the residue was crystallized from ethanol to give the product 12b as white sponge crystals (0.76 g, 100%, crude yield). According to NMR calculation, E-isomer 74%, Z-isomer is 26%. E-isomer; 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), 7.89 (s, 1H), 7.05 (dd, J = 2.4, 2.0 Hz, 1H), 6.43 (dd, J = 3.7, 1.7 Hz, 1H), 6.11 (dd, J = 3.6, 2.8 Hz, 1H), 5.10 (d, J = 2.4 Hz, 2H), 3.35 (t, J = 2.4 Hz, 1H), 2.16 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 171.6, 135.5, 126.8, 126.5, 115.3, 108.7, 79.9, 75.2, 38.0, Z-isomer; 1 H NMR (400 MHz, DMSO-d 6 ) S2

3 δ (s, 1H), 8.08 (s, 1H), 7.06 (dd, J = 2.5, 1.8 Hz, 1H), 6.48 (dd, J = 3.7, 1.7 Hz, 1H), 6.14 (dd, J = 3.6, 2.8 Hz, 1H), 5.20 (d, J = 2.5 Hz, 2H), 3.40 (t, J = 2.5 Hz, 1H), 1.91 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.0, 138.5, 126.5, 126.4, 114.7, 109.1, 79.7, 75.7, 37.1, 21.6.; IR (ATR, cm -1 ) 3248, 1675, 1427, 1390, 1348, 1125, 1031, 885, 726, 669, 548; HRMS for C 10 H 12 N 3 O [M+H] + : Found: N -((1-(Prop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)benzohydrazide (12c). Pyrrole aldehyde 9 (0.50 g, 3.76 mmol) and benzoyl hydrazide (0.51 g, 3.76 mmol) were reacted as described above. After evaporation of the solvent the residue was crystallized from CHCl 3 in petroleum ether atmosphere to give the product 12c as white crystals (0.55 g, 58%), mp C. 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), 8.40 (s, 1H), 7.90 (dd, J = 7.1, 1.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.12 (d, J = 1.8 Hz, 1H), 6.55 (dd, J = 3.6, 1.5 Hz, 1H), 6.18 (dd, J = 3.4, 3.0 Hz, 1H), 5.28 (d, J = 2.3 Hz, 2H), 3.43 (t, J = 2.3 Hz, 1H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 162.6, 140.5, 133.6, 131.5, 128.4, 127.4, 126.7, 126.6, 115.1, 109.2, 79.7, 75.7, 37.1; IR (ATR, cm -1 ) 3289, 1646, 1602, 1559, 1397, 1279, 1124, 1060, 718, 685, 632; HRMS for C 15 H 14 N 3 O [M+H] + : Found: Methyl-N'-((1-(prop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)benzenesulfonohydrazide N O N S NH O (12d). Pyrrole aldehyde 9 (0.13 g, mmol) and p- toluenesulfonyl hydrazide (0.19 g, mmol) were reacted as described above. After evaporation of the solvent the residue was crystallized from CHCl 3 in petroleum ether atmosphere to give the product 12d as brownish crystals in quantitative yield (0.30 g, 100%, NMR yield), mp C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.02 (dd, J = Hz, 1H), 6.38 (dd, J = 3.8, 1.7 Hz, 1H), 6.14 (dd, J = 3.8, 2.8 Hz, 1H), 4.99 (d, J = 2.5 Hz, 2H), 2.40 (s, 3H), 2.37 (t, J = 2.6 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 144.3, 142.2, 135.3, 129.8, 128.2, 127.1, 125.7, 118.0, 109.4, 78.4, 73.9, 38.6, 21.7; IR (ATR, cm -1 ) 3248, 1540, 1395, 1355, 1308, 1161, 1020, 930, 804, 736, 659, 547, 526; HRMS for C 15 H 16 N 3 O 2 S [M+H] + : Found: (E/Z)-N'-((1-(prop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)thiophene-2-carbohydrazide N O N C NH S (12e). Pyrrole aldehyde 9 (0.27 g, 2.00 mmol) and thiophene-2- S3

4 carbohydrazide (0.28 g, 2.00 mmol) were reacted as described above. After evaporation of the solvent, the residue was crystallized from MeOH to give the product 12e as pale yellow needles and sponge crystals in quantitative yield (0.51 g, 100%, NMR yield). E-isomer 63%; Z-isomer 37%. E-isomer; 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), 8.36 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.85 (d, J = 4.9 Hz, 1H), (m, 1H), 7.11 (s, 1H), 6.56 (s, 1H), 6.18 (t, J = 3.0 Hz, 1H), 5.25 (s, 2H), 3.44 (s, 1H); 13 C NMR (101 MHz, DMSO-d 6 ) δ , 138.5, 136.7, 134.1, 134.0, 133.8, 126.4, 114.4, 109.2, 79.5, 76.2, 37.0; Z-isomer; 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 9.4 Hz, 1H), (m, 1H), 7.11 (s, 1H), 6.64 (s, 1H), 6.18 (t, J = 3.0 Hz, 1H), 5.15 (s, 2H), 3.48 (s, 1H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 157.3, 140.3, 131.5, 128.5, 128.0, 126.8, 126.6, 115.2, 109.2, 79.7, 75.8, 37.2; IR (ATR, cm -1 ) 3225, 1624, 1558, 1520, 1416, 1328, 1299, 1132, 844, 804, 707; HRMS for C 13 H 12 N 3 OS [M+H] + : Found: N'-((1-(3-phenylprop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)benzohydrazide (12f). Pyrrole aldehyde 10 (209 mg, mmol) and benzoylhydrazine (136 mg, mmol) were reacted as described above. After evaporation of the solvent, the residue was crystallized from MeOH to give the product 12f as white crystals (298 mg, 91%), mp C. 1 H NMR (400 MHz, DMSO-d 6 ) δ (s, 1H), 8.47 (s, 1H), 7.92 (dd, J = 7.0, 1.4 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.46 (dd, J = 7.2, 2.3 Hz, 2H), 7.37 (d, J = 1.6 Hz, 2H), 7.36 (d, J = 1.5 Hz, 2H), 7.23 (d, J = 1.8 Hz, 1H), 6.59 (dd, J = 3.6, 1.5 Hz, 1H), 6.21 (dd, J = 3.4, 2.9 Hz, 1H), 5.55 (s, 2H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 162.7, 140.7, 133.6, 131.5, 128.8, 128.6, 128.4, 127.5, 126.8, 126.7, 121.8, 115.2, 109.2, 85.4, 84.2, 48.6, 37.9; IR (ATR, cm -1 ) 3212, 3053, 1644, 1614, 1543, 1464, 1346, 1289, 1077, 720, 693; HRMS for C 21 H 18 N 3 O [M+H] + : Found: N'-((1-(3-phenylprop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)thiophene-2-carbohydrazide (12g). Pyrrole aldehyde 10 (209 mg, mmol) and thiophene-2- carbohydrazide (142 mg, mmol) were reacted as described above. After evaporation of the solvent the residue was crystallized from MeOH to give the product 12g as pale yellow crystals (303 mg, 91%, crude yield), mp C. 1 H NMR (400 MHz, CDCl 3 ) δ 1 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.64 (s, 1H), 7.43 (d, J = 6.1 Hz, 2H), (m, 3H), 7.17 (s, 1H), 7.14 (s, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 5.43 (s, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 163.0, 138.6, 135.1, 133.6, 133.4, (2C), 128.8, 128.4, S4

5 126.8, 126.5, 122.4, 117.6, 109.7, 86.0, 83.8, 39.4; IR (ATR, cm -1 ) 2875, 1637, 1514, 1423, 1399, 1281, 1223, 1070, 1028, 689, 645; HRMS for C 19 H 16 N 3 OS [M+H] + : Found: N'-((1-(3-phenylprop-2-yn-1-yl)-1H-pyrrol-2-yl)methylene)formohydrazide (12h). O Pyrrole aldehyde 10 (209 mg, mmol) and formohydrazide (60 mg, N NH H mmol) were reacted as described above. After evaporation, it was N re-crystallized from MeOH to give the product as brown crystals (221 mg, 88%, NMR yield), mp C. 1 H NMR (400 MHz, CDCl 3 ) δ (bs, 1H), 8.75 (d, J = 9.3 Hz, 1H), 7.88 (s, 1H), 7.44 (dd, J = 7.1, 2.2 Hz, 2H), 7.32 (m, 3H), 7.15 (bs, 1H), 6.52 (dd, J = 3.4, 1.2 Hz), 6.23 (t, J = 3.1 Hz), 5.34 (s, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.6, 139.7, 131.9, 128.7, 128.5, 126.9, 126.0, 122.4, 117.6, 109.3, 85.7, 83.6, 39.6; IR (ATR, cm -1 ) 1684, 1425, 1359, 1283, 1219, 1172, 1115, 751, 716, 687; HRMS for C 15 H 14 N 3 O [M+H] + : Found: General Procedure for pyrrole-fused C,Nˈ-cyclic azomethine imine derivatives 13a-h. Hydrazone 12a-h (0.10 g, 0.53 mmol) and 5 mole % CF 3 SO 3 Ag were stirred in 3 ml of CHCl 3 at room temperature for 3 hours. The solvent was evaporated to give the desired cyclization products 13a-h. (3-Methylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)(formyl)amide (13a) Hydrazone 12a (0.10 g, NCHO 0.57 mmol) was reacted as described above to give dark red oily N compund (0.10 g, 89%, NMR yield). 1 H NMR (400 MHz, CDCl 3 ) δ N CH (s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.20 (dd, J = 3.3, 1.0 Hz, 1H), (m, 1H), 2.46 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 191.5, 165.2, 139.4, 130.0, 125.8, 120.1, 118.5, 112.2, 15.8; IR (ATR, cm -1 ) 2917, 1653, 1558, 1541, 1541, 1457, 1419, 1173, 1078, 718; HRMS for C 9 H 10 N 3 O [M+H] + : Found: Acetyl(3-methylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)amide (13b) Hydrazone 12b (0.10 g, 0.53 mmol) was reacted as described above to give red dark oily compound (0.10 g, 99%, NMR yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.14 (d, J = 4.1 Hz, 1H), 7.05 (dd, J = 4.4, 2.4 Hz, 1H), 2.37 (s, 3H), 2.11 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.9, 139.7, 130.2, 125.8, 120.5, 120.0, 118.5, 112.3, 22.2, 15.5; IR (ATR, cm -1 ) 1653, 1558, 1541, 1419, 1373, 1273, 1242, 719; HRMS for C 10 H 11 N 3 O [M+H] + : Found: S5

6 Benzoyl(3-methylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)amide (13c). Hydrazone 12c (0.10 g, 0.40 mmol) was reacted as described above to give reddish oily compound (0.10 g, 100%, NMR yield). 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1H), (m, 2H), 7.94 (bs, 1H), 7.63 (bd, J = 2.1 Hz, 1H), (m, 3H), 7.11 (bd, A-part of AB-system, J = 4.4 Hz, 1H), 7.06 (dd, B-part of AB-system, J = 4.4, 2.4 Hz, 1H), 2.48 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.0, 139.0, 137.6, 130.4, 130.1, 128.1, 128.0, 126.0, 119.2, 118.9, 118.4, 110.6, 15.8; IR (ATR, cm -1 ) 1653, 1558, 1370, 1246, 1160, 1028, 745, 636. (3-Methylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)(tosyl)amide (13d). Hydrazone 12d (0.30 g, mmol) and 1 wt % AuCl 3 were stirred in 3 ml of CHCl 3 at room NTs N temperature for 3 hours. The solvent was evaporated to give the product N CH 13d as green powder (0.30 g, 100%, NMR yield), mp C. 1 3 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.41 (d, J = 0.7 Hz, 1H), 8.04 (t, J = 1.2 Hz, 1H), (m, 3H), (m, 3H), 2.32 (s, 3H), 1.82 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 141.6, 141.4, 140.4, 130.0, 129.2, 125.9, 125.6, 120.9, 119.5, 118.9, 112.2, 20.8, 15.0; IR (ATR, cm -1 ) 3079, 1653, 1558, 1424, 1268, 1136, 1083, 1039, 918, 753, 656, 535; HRMS for C 15 H 16 N 3 O 2 S [M+H] + : : Found (3-Methylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)(thiophene-2-carbonyl)amide (13e) Hydrazone 12e (0.10 g, 0.39 mmol) was reacted as described above to give reddish oily compound (0.10 g, 90%, NMR yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (s, 1H), 7.92 (s, 1H), 7.79 (d, J = 3.5 Hz, 1H), 7.67 (s, 1H), 7.34 (d, J = 4.9 Hz, 1H), 7.16 (d, J = 4.3 Hz, 1H), 7.09 (dd, J = 4.3, 2.4 Hz, 1H), 7.07 (dd, J = 4.7, 4.0 Hz, 1H), 2.44 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.9, 140.0, 139.8, 130.3, 129.8, 128.6, 127.6, 125.8, 120.3, 120.0, 118.5, 112.4, 15.6; IR (ATR, cm -1 ) 3078, 1652, 1558, 1458, 1418, 1252, 1160, 1027, 717, 636; HRMS for C 13 H 12 N 3 OS [M+H] + : Found: Benzoyl(3-benzylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)amide (13f) Hydrazone 12f (100 mg, 0.31 mmol) was reacted as described above to give dark red oily compound (79 mg, 78%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.15 (s, 1H), 8.16 (d, J = 7.3 Hz, 2H), 7.55 (s, 1H), (m, 8H), 7.26 (d, J = 1.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.07 (dd, J = 3.9, 2.3 Hz, 1H), 4.25 (s, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 170.6, 139.6, 136.9, 135.6, 134.2, 130.5, 129.9, 129.2, 128.2, 128.1, 127.6, 125.7, 119.9, 119.6, 119.4, 111.4, 34.9; IR (ATR, cm -1 ) 3062, S6

7 2919, 1653, 1527, 1343, 1281, 1252, 1155, 1028, 696; HRMS for C 21 H 18 N 3 O [M+H] + : Found: (3-Benzylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)(thiophene-2-carbonyl)amide (13g) Hydrazone 12g (50 mg, 0.15 mmol) was reacted as described above. After evaporation of the solvent, the column chromatography was carried out on silica gel (10 g) eluting with hexane/etoac (1:1) followed by EtOAc to give 13g as dark red oily compund (27 mg, 54%, NMR yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.52 (s, 1H), 7.37 (s, 1H), (m, 7H), 6.96 (dd, J = 4.4, 2.3 Hz, 1H), 6.94 (dd, J = 4.8, 3.9 Hz, 1H), 4.05 (s, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.7, 140.7, 134.9, 133.9, 130.2, 129.8, 129.5, 129.5, 129.2, 127.8, 127.7, 125.6, 121.6, 120.6, 119.4, 113.6, 34.7; IR (ATR, cm -1 ) 2916, 1653, 1579, 1510, 1415, 1314, 1280, 1208, 1028, 719, 703; HRMS for C 19 H 16 N 3 OS [M+H] + : Found: (3-Benzylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)(formyl)amide (13h) Hydrazone 12h (50 mg, 0.20 mmol) was reacted as described above. After evaporation of the solvent, the column chromatography was carried out on 10 g silica gel eluting with hexane/etoac (1:1) followed by EtOAc to give dark red oily compound 13h (47 mg, 93%, NMR yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.17 (s, 1H), 7.54 (s, 1H), (m, J = 6.9 Hz, 6H), 7.17 (d, J = 4.3 Hz, 1H), 7.07 (dd, J = 4.4, 2.4 Hz, 1H), 4.20 (s, 2H); 13 C NMR (101 MHz, CDCl 3 ) δ 175.5, 164.8, 140.0, 134.7, 133.7, 130.0, 129.4, 127.9, 125.6, 121.4, 120.7, 119.5, 34.7; IR (ATR, cm -1 ) 2919, 1676, 1654, 1492, 1355, 1256, 1074, 1028, 725, 697; HRMS for C 15 H 14 N 3 O [M+H] + : Found: General Procedure for Cycloaddition Reactions: Synthesis of Dipolaphile (1 mmol) was added to a solution of (3-methylpyrrolo[1,2-a]pyrazin-2-ium-2-yl)(tosyl)amide (13d) (1 mmol) in 15 ml of toluene. The resulting mixture was heated at the reflux temperature for 18 h. After cooling to room temperature, the solvent was evaporated under the reduced pressure. The crude product was purified over silica gel eluting with hexane/etoac (10:1 2:1) to give the product. 5-Methylpyrazolo[1,5-a]pyrrolo[2,1-c]pyrazine-1-carbonitrile (14) (3-Methylpyrrolo[1,2- a]pyrazin-2-ium-2-yl)(tosyl)amide (13d) (140 mg, 0.46 mmol) and S7

8 acrylonitrile (30 µl, 0.46 mmol) were reacted as described above. White needles from chloroform/hexane (40 mg, 44%), mp.: C. 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (s, 1H), 7.30 (bs, 1H), 7.27 (dd, J = 2.7, 1.3 Hz, 1H), 7.18 (bd, J = 4.0 Hz, 1H), 6.76 (dd, J = 4.0, 2.7 Hz, 1H), 2.58 (d, J = 1.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 143.1, 136.4, 122.0, 120.0, 116.8, 114.1, 113.8, 112.0, 105.3, 83.3, 14.7; IR (KBr, cm-1) 3100, 2223, 1587, 1443, 1421, 989, 882, 824, 728, 710, 644; HRMS for C 11 H 9 N 4 [M+H] + : calculated , found: HRMS for C 11 H 9 N 4 [M+H] + : Found: Methylpyrazolo[1,5-a]pyrrolo[2,1-c]pyrazine-1-carbaldehyde (15) (3- Methylpyrrolo-[1,2-a]pyrazin-2-ium-2-yl)(tosyl)amide (13d) (150 mg, 0.5 mmol) and acrolein (33 µl, 0.5 mmol) were reacted as described above. The crude product was purified over silica gel eluting with hexane/etoac (5:1 2:1) to give 15. White powder from (50 mg, 50%) mp C. 1 H- NMR (400 MHz, CDCl 3 ) δ (s, 1H), 8.23 (s, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.33 (s, 1H), 7.30 (dd, J = 2.6, 1.4 Hz, 1H), 6.75 (dd, J = 4.0, 2.6 Hz, 1H), 2.59 (d, J = 1.1 Hz, 3H); 13 C- NMR (101 MHz, CDCl 3 ) δ 182.9, 144.3, 133.4, 121.4, 121.3, , 116.2, 113.3, 112.1, , 14.9; IR (KBr, cm -1 ) 3101, 1661, 1565, 1532, 1360, 1235, 805, 726, 645; HRMS for [M+H] + : C 11 H 10 N 3 O Found: Methyl 5-methylpyrazolo[1,5-a]pyrrolo[2,1-c]pyrazine-1-carboxylate (16) (3-Methyl-pyrrolo-[1,2-a]pyrazin-2-ium-2-yl)(tosyl)amide (13d) (150 mg, 0.5 mmol) and acrolein (50 µl, 0.5 mmol) were reacted as described above. The crude product was purified over silica gel eluting with hexane/etoac (10:1 3:1) to give 16. White needles, (50 mg, 44%) from diethyl ether, mp C. 1 H-NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.70 (ddd, J = 4.0, 1.4, 0.7 Hz, 1H), 7.23 (bs, 1H), 7.22 (dd, J = 2.6, 1.4 Hz, 1H), 6.70 (dd, J = 4.0, 2.6 Hz, 1H), 3.93 (s, 3H), 2.55 (d, J = 1.2 Hz, 3H); 13 C-NMR (101 MHz, CDCl 3 ) δ , 143.2, 134.4, 121.7, 121.3, 116.6, 112.9, 111.5, 108.8, 106.0, 51.4, 14.9; IR (KBr, cm - 1) 2923, 1713, 1578, 1535, 1422, 1266, 1246, 1130, 1050, 992, 769, 701, 625; HRMS for C 12 H 12 N 3 O 2 [M+H] + : Found: Dimethyl 5-methylpyrazolo[1,5-a]pyrrolo[2,1-c]pyrazine-1,2-dicarboxylate (17) (3- Methyl-pyrrolo-[1,2-a]pyrazin-2-ium-2-yl)(tosyl)amide (13d) (170 mg, 0.56 mmol) and dimethyl acetylenedicarboxylate (71 µl, 0.56 mmol) were reacted as described above. The crude product was purified over silica gel eluting with hexane/etoac (10:1 2:1). S8

9 White crystals from chloroform in petroleum ether atmosphere (60 mg, 37%), mp C. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.54 (bd, J = 3.9 Hz, 1H), 7.31 (bs, 1H), 7.24 (dd, J = 2.7, 1.4 Hz, 1H), 6.71 (dd, J = 3.9, 2.7 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 2.57 (d, J = 0.9 Hz, 3H); 13 C-NMR (101 MHz, CDCl 3 ) δ 163.8, 162.9, 145.9, 134.8, 121.6, 120.6, 117.1, 113.1, 112.7, 109.0, 105.1, 53.0, 52.0, 14.8; IR (KBr, cm -1 ) 2956, 1707, 1566, 1436, 1422, 1353, 1267,1183, 1072, 771, 732; HRMS for C 14 H 13 N 3 NaO 4 [M+Na] + : Found: S9

10 NMR Spectra N O H N C NH N O H N C NH Figure 1. 1 H and 13 C NMR Spectra of 12a in CDCl 3 (400 MHz) S10

11 Figure 2. 1 H and 13 C NMR Spectra of 12b in DMSO (400 MHz) S11

12 N O N C NH N O N C NH Figure 3. 1 H and 13 C NMR Spectra of 12c in DMSO (400 MHz) S12

13 N O N S NH O N O N S NH O Figure 4. 1 H and 13 C NMR Spectra of 12d in CDCl 3 (400 MHz) S13

14 Figure 5. 1 H and 13 C NMR Spectra of 12e in DMSO (400 MHz) S14

15 Figure 6. 1 H and 13 C NMR Spectra of 12f in DMSO (400 MHz) S15

16 Figure 7. 1 H and 13 C NMR Spectra of 12g in CDCl 3 (400 MHz) S16

17 Figure 8. 1 H and 13 C NMR Spectra of 12h in CDCl 3 (400 MHz) S17

18 Figure 9. 1 H and 13 C NMR Spectra of 13a in CDCl 3 (400 MHz) S18

19 Figure H and 13 C NMR Spectra of 13b in CDCl 3 (400 MHz) S19

20 N O N C N N O N C N Figure H and 13 C NMR Spectra of 13c in CDCl 3 (400 MHz) S20

21 Figure H and 13 C NMR Spectra of 13d in DMSO (400 MHz) S21

22 Figure H and 13 C NMR Spectra of 13e in CDCl 3 (400 MHz) S22

23 Figure H and 13 C NMR Spectra of 13f in CDCl 3 (400 MHz) S23

24 Figure H and 13 C NMR Spectra of 13g in CDCl 3 (400 MHz) S24

25 Figure H and 13 C NMR Spectra of 13h in CDCl 3 (400 MHz) S25

26 Figure 17: 1 H and 13 C NMR Spectra of 14 in CDCl 3 (400 MHz) S26

27 f1 (ppm) f1 (ppm) Figure 18: 1 H and 13 C NMR Spectra of 15 in CDCl 3 (400 MHz) S27

28 f1 (ppm) Figure 19: DEPT 90 and DEPT 135 Spectra of 14 in CDCl 3 (400 MHz) S28

29 Figure 20: COSY and HSQC Spectra of 15 in CDCl 3 (400 MHz) S29

30 Figure 21: HMBC Spectra of 15 in CDCl 3 (400 MHz) S30

31 Figure 22: 1 H and 13 C NMR Spectra of 16 in CDCl 3 (400 MHz) S31

32 Figure 23: 1 H and 13 C NMR Spectra of 17 in CDCl 3 (400 MHz) S32

33 THEORETICAL CALCULATIONS 1. Methodology The quantum chemical calculations were performed using the Gaussian 09 program package 1 and the structures were fully optimized at the RHF/6-311 G(d,p) level of theory without constraints. NICS values were computed on the basis of RHF/6-311 G(d,p) geometries of molecules using the gaugeincluding atomic orbital (GIAO) method at the RHF/6-311 G(d,p) theory level. 1b-d Coordinates for 13a Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C N H H H C C H C C H H H N N H C O H Coordinates for 13c Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C N S33

34 6 1 H H H C C H C C H H H N N H C O C C C C H C H C H H H Coordinates for 13d Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C N H H H C C H C C H H H N S34

35 18 7 N S C C C C H C H C H H C H H H O O H Coordinates 13f Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C N H H H C C H C C H H N N H C O C C C C H S35

36 26 6 C H C H H H C C C C H C H C H H H Coordinates for 14 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C C C C H H H H C H H H N N C C N H C N Coordinates for 15 S36

37 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C C C C H H H H C H H H N N C C N H C H O Coordinates for 16 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C C C C H H H H C H H H N N S37

38 18 6 C C N H C O O H Coordinates for 17 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C C C C H H H H C H H H N N C C N C O O C O O C H H H C H H H Coordinates for 23 S38

39 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C C N H H H H H Coordinates for 24 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C C N H H H H N Coordinates for 25 Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z C C N C C N H H H H S39

40 X-Ray structure determination of 13d For the crystal structure determination, single-crystal of compound 13d was used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a twodimensional area IP detector). Graphite-monochromated Mo-K α radiation (λ = Å) and oscillation scans technique with w = 5º for one image were used for data collection. The lattice parameters were determined by the least-squares methods on the basis of all reflections with F 2 > 2σ(F 2 ). Integration of the intensities, correction for Lorentz and polarization effects and cell refinement was performed using CrystalClear (Rigaku/MSC Inc.,2005) software. 2 The structures were solved by direct methods using SHELXS-97 3 and refined by a full-matrix least-squares procedure using the program SHELXL All nonhydrogen atoms were refined anisotropically and H atoms were positioned geometrically and refined using a riding model. The final difference Fourier maps showed no peaks of chemical significance. Crystal data for 13d: C 15 H 15 N 3 O 2 S, crystal system, space group: triclinic, P-1; (no:2); unit cell dimensions: a = (2), b = (3), c = (4) Å, α= (1), β = (2), γ = (1) Å; volume: (5) Å 3 ; Z = 2; calculated density: 1.39 g/cm 3 ; absorption coefficient: mm -1 ; F(000): 316; θ-range for data collection º ; refinement method: full matrix least-square on F 2 ; data/parameters: 2009/192; goodness-of-fit on F 2 : 1.031; final R-indices [I > 2σ(I)]: R 1 = 0.047, wr 2 = 0.106; largest diff. peak and hole: and e Å -3. S40

41 Fig. 1. Up: Mercury drawing of the molecule 13d. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å) ; S1-O (2), S1-O (2), S1-C (2), S1-N (2), N3-N (3), N2-C (3), N2-C (3), N1-C (3). Down: C-H N interaction along the a-axis Crystallographic data that were deposited in CSD under CCDC registration number contain the supplementary crystallographic data for this Letter. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre (CCDC) via S41

42 and are available free of charge upon request to CCDC, 12 Union Road, Cambridge, UK (fax: , References References (1) (a) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian, Inc.: Wallingford, CT, (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785; (d) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200. (2) Rigaku/MSC, Inc.: 9009 new Trails Drive, The Woodlands, TX (3) Sheldrick, G. M. SHELXS97 and SHELXL97; University of Göttingen: Germany, S42