Eur. J. Org. Chem. 2008 · © WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2008 · ISSN 1434–193X

SUPPORTING INFORMATION

Title: Synthesis of Functionalized Isobenzomorphans by Two-Step Cyclocondensation of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with Isoquinolines Author(s): Mirza A. Yawer, Ibrar Hussain, Jörg-Peter Gütlein, Andreas Schmidt, Haijun Jiao, Helmut Reinke, Anke Spannenberg, Christine Fischer, Peter Langer* Ref. No.: O200800478

Crystal structure analyses

Figure 1. Ortep plot of 4p. The thermal ellipsoids of 50% probability are shown for the non-hydrogen

atoms

Figure 2. Ortep plot of 8b (only one of the two symmetry independent molecules is shown). The thermal

ellipsoids of 50% probability are shown for the non-hydrogen atoms

Figure 3. Ortep plot of 10b. The thermal ellipsoids of 50% probability are shown for the non-hydrogen

atoms

Experimental Section

1H and 13C NMR spectra were taken in CDCl3 at 250, 300, and 500 MHz, respectively. Chemical shifts

are reported in parts per million using the solvent internal standard (chloroform, 7.26 and 77.0 ppm,

respectively). Infrared spectra were recorded on a FTIR spectrometer. Mass spectrometric data (MS) were

obtained by electron ionization (EI, 70 eV), chemical ionization (CI, isobutane) or electrospray ionization

(ESI). Melting points are uncorrected. CH2Cl2 (anhydrous, 99.8%) was purchased directly from ACROS

and used without further purification. Analytical thin layer chromatography was performed on 0.20 mm

60 A silica gel plates. Column chromatography was performed on 60 A silica gel (60 – 200 mesh). All

cyclization reactions were carried out in Schlenk tubes under an argon atmosphere using dried solvents.

Crystallographic data were collected on a Bruker X8Apex with MoKα radiation (λ = 0.71073 Å). Data of

4p were collected on a STOE IPDS II. The structures were solved by direct methods using SHELXS-97

and refined against F2 on all data by full matrix least-squares with SHELXL-97. All non-hydrogen atoms

were refined anisotropically, all hydrogen atoms (for 4p except the H atom attached to oxygen) were

refined in the model at geometrically calculated positions and refined using a riding model.

General procedure for the synthesis of 3a-ad and 5a-e: To a CH2Cl2 solution (40 mL) of isoquinoline

(0.520 g, 4.0 mmol) was added the 1,3-bis-silyl enol ether (8.0 mmol) and methyl or benzyl

chloroformate (0.460 g, 4.8 mmol) at 0 °C. The solution was stirred for 2 h at 0 °C and for 12 h at 20 °C.

A saturated aqueous solution of ammonium chloride (20 mL) was added and the organic and the aqueous

layers were separated. The latter was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers

were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by

chromatography (silica gel, heptanes → heptanes/EtOAc = 2:1).

Methyl 1-[(Z)-2-hydroxy-4-methoxy-4-oxo-2-butenyl]-2(1H)-isoquinoline-carboxylate (3a). Starting

with isoquinoline (0.520 g, 4.00 mmol), 2a (2.080 g, 8.00 mmol) and methyl chloroformate (0.460 g, 4.80

mmol), 3a was prepared as an orange oil (1.000 g, 83%). 1H NMR (300 MHz, CDCl3): δ = 2.25 – 2.41 (m,

1H, NCHCH2, Enol), 2.52 – 2.62 (m, 1H, NCHCH2, Enol), 2.76 (dd, 3J = 6.8 Hz, 2J = 14.4 Hz, 1H,

NCHCH2, Keto), 2.97 (dd, 3J = 6.8 Hz, 2J = 14.4 Hz, 1H, NCHCH2, Keto), 3.29 – 3.56 (m, 2H,

COCH2CO, Keto), 3.66 (s, 3H, OCH3, Keto, Rotamer), 3.68 (s, 3H, OCH3, Keto-Enol, Rotamer), 3.69 (s,

3H, OCH3, Keto-Enol, Rotamer), 3.79 (s, 3H, OCH3, Keto, Rotamer), 3.85 (s, 3H, OCH3, Keto-Enol,

Rotamer), 4.79 (s, 1H, COHCHCO, Enol), 5.61 – 5.98 (m, 2H, NCHCH2, NCHCH), 6.77 – 6.96 (m, 1H,

NCHCH), 7.05 – 7.28 (m, 4H, Ar), 11.91, 11.98 (s, 1H, OH, Rotamer). 13C NMR (75.5 MHz, CDCl3):

δ = 39.8, 40.3 (NCHCH2, Enol, Rotamer), 47.5 (NCHCH2, Keto), 49.2, 49.7 (COCH2CO, Keto), 51.0,

51.6, 51.7 (NCHCH2, Keto-Enol, Rotamer), 52.2, 53.0, 53.3, 53.8 (OCH3, Keto-Enol, Rotamer), 91.2

(COCHCOH, Enol), 108.7, 109.0 (NCHCH, Keto-Enol, Rotamer), 124.1, 124.6, 124.7, 125.9, 126.1,

126.3, 126.9, 127.0, 127.2, 128.0 (NCHCH, CHAr, Keto-Enol, Rotamer), 129.7, 131.1 (CAr), 153.1, 153.3

(NCOO, Keto-Enol, Rotamer), 166.9, 167.3, 172.5, 173.5, 173.8 (CH2COO, COH, Keto-Enol, Rotamer),

199.5 (NCHCH2CO). IR (neat, cm-1): v = 2956 (w), 1714 (s), 1634 (s), 1571 (w), 1447 (s), 1415 (m),

1353 (s), 1328 (s), 1290 (m), 1242 (s), 1200 (s), 1153 (m), 1124 (m), 1025 (w), 981 (w), 949 (w), 775 (m).

MS (EI, 70 eV): m/z (%) = 303 (M+, 2), 255 (5), 188 (100), 144 (37), 129 (11), 103 (8), 60 (8). HRMS

(EI): Anal. Calcd for C16H17NO5 (M+) 303.1101, found 303.1103.

1-(2-N-Methoxycarboyl-1-dihydroisoquinolinyl)-2,4-dioxopentane (3b). Starting with isoquinoline

(0.194 g, 1.50 mmol), 2b (0.732 g, 3.00 mmol) and methyl chloroformate (0.213 g, 2.30 mmol), 3b was

prepared as a yellow oil (0.378 g, 90%). 1H NMR (CDCl3, 300 MHz): δ = 1.92 (s, 3 H, CH3, E, Z), 1.94 (s,

3 H, CH3, E, Z), 2.51 – 2.57 (m, 2 H, CH2, E, Z), 3.69 (s, 3 H, CH3, E, Z), 3.72 (s, 3 H, CH3, E, Z), 5.21 (s,

1 H, CH, E, Z), 5.28 (s, 1 H, CH, E, Z), 5.62–5.91 (m, 2 H, CH, E, Z), 6.72 (d, 3J = 8 Hz, 1 H, CH, E, Z),

6.89 (d, 3J = 8 Hz, 1 H, CH, E, Z), 6.98 – 7.19 (m, 4 H, CH, E, Z), 15.26 (br. s, 1 H, OH, E, Z). 13C NMR

(75 MHz, CDCl3): δ = 25.17, 25.41 (CH3), 42.80, 43.02 (CH2), 53.16, 53.17 (CH) 53.28, 53.76 (CH3),

101.30, 101.41, 108.77, 109.08, 124.10, 124.11, 124.70, 124.83, 125.99, 126.19, 127.00, 127.01, 127.97,

128.07 (CH), 129.83, 130.04, 131.11, 131.25, 153.11, 153.75, 187.41, 188.27, 192.42, 193.50 (C). MS

(EI, 70 eV): m/z = 287 (M+, 1), 188 (100), 144 (52), 129 (20), 193 (14). IR (KBr): v = 3413 (w), 2954 (w),

1716 (s), 1631 (s), 1493 (w), 1450 (s), 1419 (s) cm-1. UV-VIS/NIR (MeCN): λmax (lg ε) = 209.61 (4.16),

225.38 (4.11), 282.68 (4.30) nm. Anal.: Calcd for C16H17NO4: C 66.89, H 5.96, N 4.88; found.: C 66.44,

H 6.37, N 4.61.

Methoxyetthyl 1-[(Z)-2-hydroxy-5-methoxy-4-oxo-2-pentenyl]-2(1H)-isoquinoline-carboxylate (3c).

Starting with isoquinoline (0.194 g, 1.50 mmol), 2c (3.00 mmol) and methyl chloroformate (0.213 g, 2.30

mmol), 3c was prepared as a yellow oil (79%). Due to its unstable nature, the product was immediately

used (without characterization) for the synthesis of 4c.

Methyl 1-[(Z)-2-hydroxy-5-methoxy-4-oxo-2-pentenyl]-2(1H)-isoquinoline-carboxylate (3d). Starting

with isoquinoline (0.520 g, 4.00 mmol), 2d (2.196 g, 8.00 mmol) and methyl chloroformate (0.460 g, 4.80

mmol), 3d was prepared as a yellow viscous oil (0.700 g, 55%). 1H NMR (300 MHz, CDCl3): δ = 2.44

(dd, 2J = 13.1 Hz, 3J = 6.3 Hz, 1H, NCHCH2, Rotamer), 2.54 (dd, 2J = 13.1 Hz, 3J = 7.3 Hz, 1H,

NCHCH2, Rotamer), 2.64 – 2.72 (m, 1H, NCHCH2), 3.36, 3.37 (s, 3H, OCH3, Rotamer), 3.78, 3.80 (s, 3H,

OCH3, Rotamer), 3.93, 3.94 (s, 2H, COCH2O, Rotamer), 5.58, 5.61 (s, 1H, COHCH, Rotamer), 5.71, 5.82

(t, 3J = 7.0 Hz, 1H, NCHCH2, Rotamer), 5.88, 5.98 (d, 3J = 7.8 Hz, 1H, NCHCH, Rotamer), 6.80, 6.96 (d,

3J = 7.8 Hz, 1H, NCHCH, Rotamer), 7.03 – 7.24 (m, 4H, Ar), 15.04 (br, 1H, OH). 13C NMR (75.5 MHz,

CDCl3): δ = 42.7, 43.0 (NCHCH2, Rotamer), 53.27, 53.41, 53.89 (NCHCH2, OCH3, Rotamer), 59.3

(OCH3), 74.0 (CH2OCH3), 98.1 (COHCH), 108.9, 109.2 (NCHCH, Rotamer), 124.2, 124.8, 125.0, 126.0,

126.2, 126.5, 127.1, 128.1 (NCHCH, CHAr, Rotamer), 128.2, 129.9, 130.2, 131.2 (CAr, Rotamer), 153.2,

153.8 (NCOO, Rotamer), 187.1, 187.6 (COH, Rotamer), 193.5, 194.4 (COCH, Rotamer). IR (neat, cm-1):

v = 3106 (w), 3070 (w), 2994 (m), 2950 (m), 2827 (m), 1719 (s), 1630 (s), 1448 (s), 1351 (s), 1331 (s),

1294 (s), 1241 (s), 1198 (s), 1120 (s), 981 (m), 947 (m), 831 (w), 775 (s), 541 (w). MS (EI, 70 eV): m/z

(%) = 317 (M+, 1), 189 (12), 188 (100), 144 (37), 129 (13), 103 (8). Anal. Calcd. for C17H19NO5 (317.34):

C 64.34, H 6.03, N 4.41; found: C 64.46, H 6.01, N 4.28.

Methyl 1-[(Z)-2-hydroxy-4-oxo-4-phenyl-2-butenyl]-2(1H)-isoquinoline-carboxylate (3e). Starting

with isoquinoline (0.520 g, 4.00 mmol), 2e (2.450 g, 8.00 mmol) and methyl chloroformate (0.460 g, 4.80

mmol), 3e was prepared as an orange solid (1.065 g, 76%); mp. = 87-88 oC. 1H NMR (300 MHz, CDCl3):

δ = 2.55 (dd, 2J = 13.0 Hz, 3J = 6.3 Hz, 1H, NCHCH2, Rotamer), 2.67 (dd, 2J = 13.0 Hz, 3J = 7.4 Hz, 1H,

NCHCH2, Rotamer), 2.72 – 2.83 (m, 1H, NCHCH2), 3.75, 3.78 (s, 3H, OCH3, Rotamer), 5.77 (t,

3J = 6.8 Hz, 1H, NCHCH2, Rotamer), 5.86 – 5.93 (m, 2H, NCHCH2, NCHCH, Rotamer), 6.00 (t,

4J = 3.8 Hz, 1H, COCHCOH), 6.83, 7.02 (d, 3J = 7.8 Hz, 1H, NCHCH, Rotamer), 7.07 – 7.24 (m, 4H, Ar),

7.40 – 7.57 (m, 3H, Ar), 7.79 – 7.81 (m, 2H, Ar), 16.03 (br, 1H, OH). 13C NMR (75.5 MHz, CDCl3):

δ = 43.8, 44.1 (CH2, Rotamer), 53.3, 53.5, 54.0 (NCHCH2, OCH3, Rotamer), 97.6, 97.7 (COCHCOH,

Rotamer), 108.9, 109.2 (NCHCH, Rotamer), 124.2, 124.8, 124.9, 126.1, 126.3, 127.1, 127.2, 128.1, 128.2,

128.6, 128.7, 132.4, 132.6 (NCHCH, CHAr, Rotamer), 130.1, 131.3, 134.9, 135.0 (CAr, Rotamer), 153.2,

153.8 (NCOO, Rotamer), 184.3, 185.2 (COH, Rotamer), 190.5, 191.0 (COCH, Rotamer). IR (KBr, cm-1):

v = 1714 (s), 1628 (m), 1572 (m), 1508 (w), 1489 (w), 1448 (m), 1357 (m), 1334 (m), 1292 (w), 1239 (m),

1198 (w), 1122 (w), 769 (m). MS (EI, 70 eV): m/z = 349 (M+, 1), 188 (100), 144 (27), 103 (8), 77 (7).

Anal. Calcd. for C21H19NO4 (349.38): C 72.19, H 5.48, N 4.01; found: C 71.95, H 5.47, N 3.88.

Methyl 1-[(Z)-2-hydroxy-5,5-dimethyl-4-oxo-2-hexenyl]-2(1H)-isoquinoline-carboxylate (3f).

Starting with isoquinoline (0.520 g, 4.00 mmol), 2f (2.290 g, 8.00 mmol) and methyl chloroformate

(0.460 g, 4.80 mmol), 3f was prepared as a dark yellow viscous oil (0.700 g, 55%). 1H NMR (250 MHz,

CDCl3): δ = 1.07, 1.10 (s, 9H, C(CH3)3, Rotamer), 2.39 (dd, 2J = 12.8 Hz, 3J = 6.4 Hz, 1H, CH2, Rotamer),

2.49 – 2.70 (m, 2H, CH2, Rotamer), 3.75, 3.79 (s, 3H, OCH3, Rotamer), 5.34 (s, 1H, CHCOH), 5.68, 5.79

(t, 1H, NCHCH2, Rotamer), 5.85, 5.97 (d, 3J = 7.9 Hz, 1H, NCHCH, Rotamer), 6.79, 6.97 (d, 3J = 7.9 Hz,

1H, NCHCH, Rotamer), 7.05 – 7.24 (m, 4H, Ar), 15.55, 15.68 (br s, 1H, OH, Rotamer). 13C NMR

(75.5 MHz, CDCl3): δ = 27.0, 27.2 (C(CH3)3, Rotamer), 39.4, 39.5 (CCH3, Rotamer), 43.1, 43.5 (CH2,

Rotamer), 53.1, 53.4, 53.4, 54.0 (NCHCH2, OCH3, Rotamer), 97.0 (CHCOH), 108.8, 109.1 (NCHCH,

Rotamer), 124.2, 124.7, 124.8, 126.0, 126.3, 127.0, 127.9, 128.0 (NCHCH, CHAr, Rotamer), 129.9, 130.1,

131.1, 131.3 (CAr, Rotamer), 153.1, 153.7 (NCOO, Rotamer), 188.5, 188.6 (COH, Rotamer), 201.8, 202.4

(CO, Rotamer). IR (neat, cm-1): v = 3105 (w), 3073 (w), 3023 (w), 2966 (m), 2908 (w), 2870 (w), 1719

(s), 1632 (s), 1603 (s), 1573 (m), 1480 (m), 1456 (s), 1442 (s), 1416 (m), 1395 (w), 1355 (s), 1329 (s),

1297 (m), 1271 (m), 1238 (m), 1197 (m), 1123 (m), 1101 (m), 1006 (w), 977 (m), 958 (m), 926 (w), 889

(w), 836 (w), 775 (m), 768 (m). MS (EI, 70 eV): m/z (%) = 329 (M+, 1), 188 (100), 129 (36), 102 (7), 85

(6). HRMS (EI): Anal. Calcd. for C19H23NO4 (M+) 329.1622, found 329.1620.

1-((Z)-4-Hydroxy-2-oxopent-3-enyl)-5-nitro-1H-isoquinoline-2-carboxylic acid methyl ester (3g).

Starting with 5-nitroisoquinoline (0.711 g, 4.00 mmol) in dichloromethane (40 mL), 2b (1.956 g, 8.00

mmol) and methyl chloroformate (0.463 g, 4.80 mmol), 3g was prepared as an orange oil (1.218 g, 92%).

1H NMR (250 MHz, CDCl3): δ = 1.99 (s, 3H, COCH3), 2.47–2.79 (m, 2H, NCHCH2), 3.81 (s, 3H,

CO2CH3), 5.30 (s, 1H, =CHCO), 5.77 (s, 1H, NCH, isomer 1), 5.86 (s, 1H, NCH, isomer 2), 6.61 (d, 3J =

7.8 Hz, 1H, =CH, isomer 1), 6.70 (d, 3J = 7.8 Hz, 1H, =CH, isomer 2), 7.02 (d, 3J = 7.3 Hz, 1H, =CH,

isomer 1), 7.17 (d, 3J = 7.3 Hz, 1H, =CH, isomer 2), 7.19–7.34 (m, 2H, Ar), 7.87 (dd, 3J = 8.1 Hz, 4J =

1.1 Hz, 1H, =CHCNO2), 15.27 (br s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ = 25.0/25.1 (COCH3),

42.1/42.3 (NCHCH2), 52.8 (CO2CH3), 53.4/53.7 (NCH), 101.4 (COCH), 102.6/102.8, 124.6 (CH),

124.9/125.1 (C), 126.6, 128.7/129.4, 131.4/131.8 (Ar–CH), 133.2, 144.4, 152.4/153.0, 186.8/187.5,

192.4/193.2 (C). IR (neat, cm-1): v = 3099 (w), 2957 (m), 2854 (w), 1727 (s), 1619 (s), 1441 (s), 1353 (s),

1118 (s). MS (CI): m/z (%) = 333 ([M+1]+, 1), 275 (1), 234 (15), 233 (100), 203 (5). Anal. Calcd for

C16H16N2O6 (332.31): C 57.83, H 4.85, N 8.43; found: C 57.99, H 4.99, N 8.24.

1-(3-Ethoxycarbonyl-2-oxopropyl)-5-nitro-1H-isoquinoline-2-carboxylic acid methyl ester (3h).

Starting with 5-nitroisoquinoline (0.902 g, 5.08 mmol), 2g (2.740 g, 9.98 mmol) and methyl

chloroformate (0.567 g, 5.99 mmol), 3h was prepared as an orange oil (1.735 g, 94%).

1H NMR (250 MHz, CDCl3): δ = 1.18 (t, 3J = 7.2 Hz, 3H, OCH2CH3), 2.72–2.80 (m, 1H, NCHCH2),

3.06–3.15 (m, 1H, NCHCH2), 3.32 (s, 2H, COCH2), 3.80 (s, 3H, CO2CH3, isomer 1), 3.81 (s, 3H,

CO2CH3, isomer 2), 4.09 (q, 3J = 7.1 Hz, 2H, OCH2CH3), 5.93 (br s, 1H, NCH), 6.62 (br s, 1H, =CH),

7.02 (br s, 1H, Ar / =CH), 7.19–7.29 (m, 1H, Ar), 7.49 (br s, 1H, Ar / =CH), 7.83–7.87 (m, 1H, Ar).

13C NMR (75 MHz, CDCl3): δ = 13.9 (CH2CH3), 46.7, 49.5 (CH2), 50.9 (OCH3), 53.8 (NCH), 61.4

(CH2CH3), 102.7, 124.5/124.8 (CH), 126.5/126.7, 128.6/128.8, 131.1/132.0,(Ar–CH), 133.2, 144.3/144.4,

152.5, 166.5, 171.9/172.3, 199.1 (C). IR (neat, cm-1): v = 3428 (w), 2983 (m), 2959 (m), 1721 (s),

1524 (s), 1352 (s), 1270 (s), 1234 (s), 1117 (m), 1036 (m). MS (NCI): m/z (%) = 362 (M–, 100), 316 (8),

290 (15), 174 (5). Anal. Calcd for C17H18N2O7 (362.33): C 56.35, H 5.01, N 7.73. Found: C 56.22, H 5.01,

N 7.59.

1-((Z)-4-Hydroxy-2-oxo-4-phenylbut-3-enyl)-5-nitro-1H-isoquinoline-2-carboxylic acid methyl ester

(3i): Starting with 5-nitroisoquinoline (0.711 g, 4.00 mmol) in dichloromethane (40 mL), 2e (2.448 g,

8.00 mmol) and methyl chloroformate (0.463 g, 4.80 mmol), 3i was prepared as an orange solid (1.633 g,

94%, mp. = 109 °C). 1H NMR (250 MHz, CDCl3): δ = 2.69–2.85 (m, 2H, NCHCH2), 3.81 (s, 3H,

CO2CH3), 5.86 (s, 1H, =CHCO), 5.95 (br s, 1H, NCH, isomer 1), 5.99 (br s, 1H, NCH, isomer 2), 6.66 (d,

3J = 7.5 Hz, 1H, =CH, isomer 1), 6.75 (d, 3J = 7.5 Hz, 1H, =CH, isomer 2), 7.07 (d, 3J = 7.6 Hz, 1H,

=CH), 7.19–7.26 (m, 1H, Ar), 7.36–7.55 (m, 4H, Ar), 7.78–7.89 (m, 3H, Ar), 15.58 (br s, 1H, OH, isomer

1), 15.68 (br s, 1H, OH, isomer 2). 13C NMR (75 MHz, CDCl3): δ = 43.0/43.3 (NCHCH2), 53.0

(CO2CH3), 53.8 (NCH), 97.6 (COCH), 102.8, 124.6 (CH), 125.0/125.2 (C), 126.7, 127.1, 128.6 (Ar–CH),

129.4 (C), 131.3, 131.5, 132.6 (Ar–CH), 133.2/134.4, 144.4, 152.5/153.0, 184.4/185.0, 189.5/189.9 (C).

IR (KBr, cm-1): v = 3435 (w), 1711 (s), 1626 (s), 1532 (s), 1360 (s), 1340 (s), 1282 (s), 1226 (m).

MS (CI): m/z (%) = 394 (M+, 1), 234 (21), 233 (100), 158 (9), 143 (42), 59 (14). Anal. Calcd for

C21H18N2O6 (394.38): C 63.96, H 4.60, N 7.10. Found: C 63.65, H 4.66, N 6.72.

5-Bromo-1-(Z)-4-hydroxy-2-oxopent-3-enyl)-1H-isoquinoline-2-carboxylic acid methyl ester (3j):

Starting with 5-bromoisoquinoline (0.849 g, 4.00 mmol), 2b (1.956 g, 8.00 mmol) and methyl

chloroformate (0.463 g, 4.80 mmol), 3j was prepared as a yellow oil (1.072 g, 73%). 1H NMR (250 MHz,

CDCl3): δ = 2.00 (s, 3H, COCH3, isomer 1), 2.00 (s, 3H, COCH3, isomer 2), 2.34–2.66 (m, 2H,

NCHCH2), 3.77 (s, 3H, CO2CH3, isomer 1), 3.80 (s, 3H, CO2CH3, isomer 2), 5.27 (s, 1H, =CHCO,

isomer 1), 5.32 (s, 1H, =CHCO, isomer 2), 5.66 (t, 3J = 6.9 Hz, 1H, NCH, isomer 1), 5.77 (t, 3J = 6.9 Hz,

1H, NCH, isomer 2), 6.21 (d, 3J = 7.9 Hz, 1H, =CH, isomer 1), 6.31 (d, 3J = 7.9 Hz, 1H, =CH, isomer 2),

6.86–7.06 (m, 3H, Ar), 7.42 (d, 3J = 7.4 Hz, 1H, =CH, isomer 1), 7.43 (d, 3J = 7.4 Hz, 1H, =CH, isomer

2), 15.26 (br s, 1H, OH, isomer 1), 15.33 (br s, 1H, OH, isomer 2). 13C NMR (75 MHz, CDCl3):

δ = 25.1/25.3 (COCH3), 42.4/42.6 (NCHCH2), 53.2/53.4 (CO2CH3), 53.5/53.7 (NCH), 101.4/101.4

(COCH), 107.3/107.5 (CH), 120.3/120.4 (C), 125.3/125.5 (CH), 125.9/126.5, 127.9 (Ar–CH),

129.5/129.7 (C), 132.1/132.1 (Ar–CH), 132.9/132.9, 152.8/153.4, 187.1/187.9, 192.4/193.4 (C). IR (neat,

cm-1): v = 3108 (w), 2955 (m), 2852 (w), 1725 (s), 1626 (s), 1447 (s), 1352 (s), 1110 (s). MS (CI): m/z

(%) = 367 (M+, 81Br, 1), 365 (M+, 79Br, 1), 269 (11), 268 (99), 267 (12), 266 (100), 188 (9). Anal. Calcd

for C16H16BrNO4 (366.21): C 52.48, H 4.40, N 3.82. Found: C 52.51, H 4.40, N 3.63.

5-Bromo-1-(3-ethoxycarbonyl-2-oxopropyl)-1H-isoquinoline-2-carboxylic acid methyl ester (3k):

Starting with 5-bromoisoquinoline (0.849 g, 4.00 mmol), 2g (2.196 g, 8.00 mmol) and methyl

chloroformate (0.500 g, 5.29 mmol), 3k was prepared as a pale yellow solid (1.427 g, 90%).

1H NMR (250 MHz, CDCl3): δ = 1.21 (t, 3J = 7.2 Hz, 3H, OCH2CH3), 2.69–2.77 (m, 1H, NCHCH2),

2.96–3.04 (m, 1H, NCHCH2), 3.28 (s, 2H, COCH2, isomer 1), 3.45 (s, 2H, COCH2, isomer 2), 3.80 (s, 3H,

CO2CH3), 4.11 (q, 3J = 7.2 Hz, 2H, OCH2CH3), 5.72–5.88 (m, 1H, NCH), 6.21–6.31 (m, 1H, =CH), 6.85

(s, 1H, =CH, isomer 1), 6.88 (s, 1H, =CH, isomer 2), 6.94–7.02 (m, 2H, Ar), 7.41–7.44 (m, 1H, Ar).

13C NMR (75 MHz, CDCl3): δ = 13.9 (CH2CH3), 47.1, 49.6 (CH2), 51.5 (OCH3), 53.6 (NCH), 61.3

(CH2CH3), 91.8 (CH), 107.3/107.5 (CH), 120.3 (C), 125.8, 128.1 (Ar–CH), 129.4 (C), 132.1 (Ar–CH)

133.0, 152.9/153.1, 166.4/166.7, 172.9/173.1 (C). IR (neat, cm-1): v = 3108 (w), 2982 (w), 2947 (4),

1723 (s), 1626 (s), 1474 (s), 1352 (s), 1273 (s), 1231 (s), 1111 (m), 1036 (m). MS (CI): m/z (%) =

397 (M+, 81Br, 1), 395 (M+, 79Br, 1), 308 (2), 268 (100), 266 (100), 188 (4). Anal. Calcd for C17H18BrNO5

(396.23): C 51.53, H 4.58, N 3.53. Found: C 51.44, H 4.62, N 3.39.

5-Bromo-1-((Z)-4-hydroxy-2-oxo-4-phenylbut-3-enyl)-1H-isoquinoline-2-carboxylic acid methyl

ester (3l): Starting with 5-bromoisoquinoline (0.849 g, 4.00 mmol), 2e (2.448 g, 8.00 mmol) and methyl

chloroformate (0.463 g, 4.80 mmol), 3l was prepared as an orange solid (1.504 g, 88%, mp. = 79 °C).

1H NMR (250 MHz, CDCl3): δ = 2.53–2.82 (m, 2H, NCHCH2), 3.78 (s, 3H, CO2CH3), 5.75 (t, 3J =

6.8 Hz, 1H, NCH, isomer 1), 5.86 (t, 3J = 6.8 Hz, 1H, NCH, isomer 2), 5.94 (s, 1H, =CHCO, isomer 1),

6.01 (s, 1H, =CHCO, isomer 2), 6.26 (d, 3J = 7.9 Hz, 1H, =CH, isomer 1), 6.35 (d, 3J = 7.9 Hz, 1H, =CH,

isomer 2), 6.91–7.13 (m, 2H, Ar), 7.07 (d, 3J = 8.0 Hz, 1H, =CH), 7.40–7.58 (m, 4H, Ar), 7.79–7,83 (m,

2H, Ar), 15.26 (br s, 1H, OH, isomer 1), 15.33 (br s, 1H, OH, isomer 2). 13C NMR (75 MHz, CDCl3):

δ = 43.3/43.6 (NCHCH2), 53.4/53.4 (CO2CH3), 53.6/53.9 (NCH), 97.5/97.6 (COCH), 107.4/107.5 (CH),

120.3/120.4 (C), 125.4/125.6 (CH), 125.9, 126.6, 127.1/128.0, 128.6 (Ar–CH), 129.6/129.8 (C),

132.1/132.2, 132.4/132.6 (Ar–CH), 132.9/133.0, 134.7, 152.9/153.4, 184.4/185.1, 190.0/190.4 (C).

IR (KBr, cm-1): v = 3433 (w), 3114 (w), 2952 (w), 2852 (w), 1708 (s), 1626 (s), 1447 (s), 1358 (s),

1106 (m). MS (NCI): m/z (%) = 429 (M–, 81Br, 20), 427 (M–, 79Br, 20), 362 (10), 349 (18), 161 (78),

81 (97), 79 (100). Anal. Calcd for C21H18BrNO4 (428.28): C 58.89, H 4.24, N 3.27. Found: C 58.89,

H 4.24, N 3.04.

1-[(Z)-2-Hydroxy-4-(4-nitrophenyl)-4-oxo-2-butenyl]-2(1H)-isoquinolinecarboxylic acid methyl

ester (3m). Starting with isoquinoline (0.258 g, 2.00 mmol), 2h (1.054 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3m was prepared as a yellow solid (0.300 g, 43%). 1H NMR

(250 MHz, CDCl3,): δ = 2.47 – 2.65 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.62 (s, 3 H, OCH3, isomer

1), 3.66 (s, 3 H, OCH3, isomer 2), 5.63 (t(br), 3J = 7.6 Hz, 1 H, NCH, isomer 1, isomer 2), 5.70 – 5.85 (m,

1 H, NCH, isomer 1, isomer 2), 5.90 (s(br), 1 H, COCH, isomer 1, isomer 2), 6.69 (d, 3J = 7.5 Hz, 1 H,

CH, isomer 1), 6.87 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 6.96 – 7.12 (m, 4 H, CHAr), 7.79 (d, 3J = 7.8 Hz ,

2 H, CHAr), 8.12 (d, 3J = 7.8 Hz , 2 H, CHAr), 15.58 – 15.71 (m(br), 1 H, OH); 13C NMR (CDCl3,

62 MHz): δC = 44.5 (NCHCH2), 53.3/53.5 (NCH), 53.9 (OCH3), 98.7, 108.9/109.2, 123.7 (CH), 124.2

(2CHAr), 124.9/125.0, 126.0/126.2 (CHAr), 127.2 (CAr), 127.8 (2CHAr), 127.9/128.2, 128.3/129.9 (CHAr),

130.5/130.9, 140.3, 149.8 (CAr), 153.2/153.6 (COH), 179.8/180.9, 193.1/193.9 (CO); IR (neat): v = 3108

(w), 3078 (w), 2994 (w), 2969 (w), 1519 (s), 1434 (s), 1110 (s), 645 (m), 777 (s), 751 (w) cm–1; MS (EI,

70 eV): m/z (%) = 394 (M+, 2), 365 (2), 319 (3), 188 (100), 144 (75), 129 (49), 103 (16); HRMS (EI):

Calcd. for C21H18N2O6: 394.11594; found: 394.11602.

1-[(Z)-4-(4-Chlorophenyl)-2-hydroxy-4-oxo-2-butenyl]-2(1H)-Isoquinoline-carboxylic acid methyl

ester (3n). Starting with isoquinoline (0.258 g, 2.00 mmol), 2i (1.023 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3n was prepared as a red gummy solid (0.530 g, 70%). 1H NMR

(250 MHz, CDCl3,): δ = 2.46 – 2.63 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.65 (s, 3 H, COOCH3,

isomer 1), 3.67 (s, 3 H, COOCH3, isomer 2), 5.66 (m, 1 H, NCH, isomer 1, isomer 2), 5.78 – 5.79 (m, 1 H,

COCH, isomer 1, isomer 2), 5.85 – 5.90 (m, 1 H, CH, isomer 1, isomer 2), 6.74 (d, 3J = 7.6 Hz, 1 H, CH,

isomer 1), 6.91 (m, 1 H, CH, isomer 2), 6.98 – 7.07 (m, 4 H, CHAr), 7.26 (d, 3J = 7.8 Hz, 2 H, CHAr), 7.61

(d, 3J = 7.9 Hz, 2 H, CHAr), 15.90 (s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 43.7/43.9

(NCHCH2), 53.1 (NCH), 53.3/53.9 (COOCH3), 97.4/97.5, 108.7/109.0, 124.1 (CH), 124.7/124.8,

125.9/126.1, 127.0, 128.0/128.1 (CHAr), 128.3 (2CH), 128.7/128.8 (2CHAr), 129.8/130.0, 131.0/131.1,

133.2, 138.4/138.7 (CAr), 153.0/153.6 (COH), 182.8/183.7, 190.5/191.1 (CO); IR (neat): v = 3106 (w),

3066 (w), 2997 (w), 2950 (s), 1704 (s), 1590 (s), 1079 (s), 775 (m), 750 (s), 671 (w) cm–1; MS (EI,

70 eV): m/z (%) = 383 (M+, 2), 292 (5), 201 (3), 188 (100), 144 (33), 129 (12), 103 (6), 77 (3); HRMS

(EI): Calcd. for C21H18ClNO4 : 383.09189; found: 383.09167.

1-[(Z)-4-(4-Fluorophenyl)-2-hydroxy-4-oxo-2-butenyl]-2-(methoxycarbonyl)-isoquinolinium (3o).

Starting with isoquinoline (0.258 g, 2.00 mmol), 2j (0.973 g, 3.00 mmol) and methyl chloroformate

(0.226 g, 2.40 mmol), 3o was prepared as an orange red solid (0.450 g, 68%). 1H NMR (250 MHz,

CDCl3,): δ = 2.39 – 2.72 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.67 (s, 3 H, COOCH3, isomer 1,

isomer 2), 5.77 (m, 1 H, NCH, isomer 1, isomer 2), 5.80 (m, 1 H, COCH, isomer 1, isomer 2), 5.84 – 5.91

(m, 1 H, CH, isomer 1, isomer 2), 6.73 (d, 3J = 7.8 Hz, 1 H, CH, isomer 1), 6.73 (d, 3J = 7.8 Hz, 1 H, CH,

isomer 2), 6.96 – 7.16 (m, 6 H, CHAr), 7.68 – 7.74 (m, 2 H, CHAr), 15.90 (s(br), 1 H, OH); 13C NMR

(CDCl3, 62 MHz): δC = 44.5/44.8 (NCHCH2), 54.2/54.4 (OCH3), 54.5/55.0 (NCH), 98.4/98.5 (COOCH3),

110.0/110.3 (CH), 116.8/117.0 (d, 2J = 20.2 Hz, 2CHAr), 125.3 (CH), 125.9/126.0, 127.2/127.4, 128.2,

129.2/129.3 (CHAr), 130.7 (d, 3J = 6.5 Hz, 2CHAr), 130.8/130.9, 131.1/131.3, 132.3/132.4 (CAr),

154.3/154.9 (COH), 166.4/166.5 (d, 1J = 250.5 Hz, CFAr), 184.9/185.7, 190.8/191.4 (CO); GC-MS (EI,

70 eV): m/z (%) = 367 (M+, 1), 276 (2), 201 (2), 188 (100), 144 (25), 129 (10), 103 (7), 59 (5); HRMS

(EI): Calcd. for C21H18FNO4: 367.12144; found: 367.12160.

1-[(Z)-2-hydroxy-4-(2-methoxyphenyl)-4-oxo-2-butenyl]-2(1H)-isoquinoline-carboxylic acid methyl

ester (3p). Starting with isoquinoline (0.258 g, 2.00 mmol), 2k (1.009 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3p was prepared as a reddish highly viscous oil (0.450 g, 68%). 1H

NMR (250 MHz, CDCl3,): δ = 2.65 – 2.83 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.75 (s, 3 H, OCH3,

isomer 1, isomer 2), 3.84 (s, 3 H, COOCH3, isomer 1, isomer 2), 5.73 – 5.86 (m, 1 H, NCH, isomer 1,

isomer 2), 5.89 – 5.99 (m, 1 H, COCH, isomer 1, isomer 2), 6.24 – 6.29 (m, 1 H, CH, isomer 1&2), 6.81 –

6.89 (m, 1 H, CH, Isomer 1&2), 6.93 – 7.18 (m, 6 H, CHAr) 7.31 – 7.43 (m, 1 H, CHAr), 7.79 (m, 1 H,

CHAr), 16.15 (s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 44.1/44.4 (NCHCH2), 53.1/53.4

(OCH3), 53.4 (NCH), 54.1/55.5 (COOCH3), 102.7, 108.8/109.0, 111.6 (CH), 120.6, 124.2/124.8 (CHAr),

125.2 (CAr), 126.1/126.3, 127.1, 127.9/128.0, 129.9/130.1, 130.7 (CHAr), 131.4/131.6 (CAr), 133.0/133.2

(CHAr), 134.5 (CAr), 153.1/153.8 (COCH3), 158.4 (COH), 182.4/183.5, 190.8/191.5 (CO); GC-MS (EI, 70

eV): m/z (%) = 379 (M+, 1), 201 (1), 188 (100), 144 (23), 129 (8), 103 (5), 77 (6), 59 (4); HRMS (EI):

Calcd. for C22H21NO5: 379.14142; found: 379.14158.

1-[(Z)-2-Hydroxy-4-(2-methylphenyl)-4-oxo-2-butenyl]-2(1H)-isoquinoline carboxylic acid methyl

ester (3q). Starting with isoquinoline (0.258 g, 2.00 mmol), 2l (0.961 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3q was prepared as a yellow solid (0.300 g, 43%). 1H NMR (250

MHz, CDCl3): δ = 2.47 (s, 3 H, CH3, isomer 1, isomer 2), 2.51 – 2.83 (m, 2 H, NCHCH2, isomer 1,

isomer 2), 3.82 (s, 3 H, COOCH3, isomer 1, isomer 2), 5.68 (s, 1 H, COCH, isomer 1, isomer 2), 5.77 –

5.92 (m, 1 H, NCH, isomer 1, isomer 2), 6.02 (d, 3J = 7.5 Hz, 1 H, CH, isomer 1, isomer 2), 6.86 (d, 3J =

7.5 Hz, 1 H, CH, isomer 1), 7.05 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 7.09 – 7.40 (m, 8 H, CHAr), 15.98

(s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 21.9 (CH3), 44.8/45.0 (NCHCH2), 54.6/54.7

(COOCH3), 54.9/55.5 (NCH), 103.1 (CH), 110.1/110.5 (CH), 125.6 (CH), 126.2/126.3, 127.0/127.2,

127.4/127.6, 128.5, 129.4/129.5, 129.6/129.7 (CHAr), 131.3/131.5 (CAr), 132.1/132.2, 132.5/132.6 (CHAr),

132.7/132.8, 137.3/137.4, 138.4 (CAr), 154.5/155.1 (COH), 190.6, 191.2/191.6 (CO); GC-MS (EI, 70 eV):

m/z (%) = 363 (M+, 1), 272 (1), 188 (100), 144 (21), 129 (8), 103 (6), 91 (5), 59 (4); HRMS (EI): Calcd.

for C22H21NO4: 363.14610; found: 363.14600.

1-[(Z)-4-(2-Fluorophenyl)-2-hydroxy-4-oxo-2-butenyl]-2(1H)isoquinolinecarboxylic acid methyl

ester (3r). Starting with 5-ethylisoquinoline (0.258 g, 2.00 mmol), 2m (0.973 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3r was prepared as a deep reddish viscous oil (0.561 g, 76%). 1H

NMR (250 MHz, CDCl3,): δ = 2.41 – 2.74 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.36 (s, 3 H, COOCH3,

isomer 1, isomer 2), 5.64− 5.69 (m, 1 H, NCH, isomer 1), 5.77 − 5.80 (m, 1 H, NCH, isomer 2), 5.86 −

5.89 (m, 1 H, COCH, isomer 1, isomer 2), 6.00 – 6.02 (m, 1 H, CH, isomer 1, isomer 2), 6.73 (d, 3J = 7.5

Hz, 1 H, CH, isomer 1), 6.92 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 6.98 – 7.11 (m, 6 H, CHAr), 7.31 – 7.33

(m, 1 H, CHAr), 7.77 6.73 (ddd, 3J = 7.7 Hz, 3J = 7.7 Hz, 4J = 1.8 Hz,1 H, CHAr), 15.91 (s(br), 1 H, OH);

13C NMR (CDCl3, 62 MHz): δC = 44.9/45.3 (NCHCH2), 54.1/54.3 (NCH), 54.5/55.0 (COOCH3),

103.1/103.5, 109.9/110.1 (CH), 117.4 (d, 2J = 16.2 Hz, CHAr), 124.0/124.2 (CH), 125.2/125.4 (CHAr),

125.9 (d, 3J = 6.1 Hz, CHAr),127.0/127.2, 128.1 (CHAr), 129.1 (d, 3J = 7.2 Hz, CHAr), 129.6 (d, 4J = 1.8

Hz, CHAr),131.0 (CHAr), 132.2/132.3, 134.5, 134.6/134.8 (CAr), 154.1/154.6 (COH), 162.0 (d, 1J = 253.8

Hz, CFAr), 180.6/181.3, 193.0/193.3 (CO); IR (neat): v = 3108 (w), 3078 (w), 2996 (w), 2969 (w), 1519

(s), 1434 (s), 1110 (s), 643 (m), 776 (s) cm–1; GCMS (EI, 70 eV): m/z (%) = 367 (M+, 5), 188 (100), 144

(28), 129 (22), 103 (12), 59 (8). HRMS (EI): Calcd. for C21H18O4FN: 367.12144; found: 367.12076.

1-[(Z)-4-(2-Chlorophenyl)-2-hydroxy-4-oxo-2-butenyl]-2(1H)-isoquinoline carboxylic acid methyl

ester (3s). Starting with isoquinoline (0.258 g, 2.00 mmol), 2n (1.023 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3s was prepared as a yellow oil (0.450 g, 58%). 1H NMR (250 MHz,

CDCl3,): δ = 2.45 – 2.77 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.78 (s, 3 H, COOCH3, isomer 1, isomer

2), 5.72 – 5.77 (m, 1 H, NCH, isomer 1, isomer 2), 5.82 (s, 1 H, COCH, isomer 1), 5.88 (s, 1 H, COCH,

isomer 2), 5.97 (d, 3J = 7.5 Hz, 1 H, CH, isomer 1, isomer 2), 6.80 (d, 3J = 7.5 Hz, 1 H, CH, isomer 1),

6.99 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 7.04 – 7.20 (m, 4 H, CHAr), 7.29 – 7.48 (m, 4 H, CHAr), 15.52

(s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 43.9/44.2 (NCHCH2), 53.8/53.9 (COOCH3),

54.0/54.7 (NCH), 103.2/103.3, 109.4/109.6, 124.7/125.2 (CH), 125.3/125.4, 125.5, 126.7, 127.4, 127.7,

128.6/128.7, 130.4 (CHAr), 130.6 (CAr), 131.1/131.2, 131.6/131.7 (CAr), 132.1/132.3 (CHAr), 136.2 (CAr),

153.6/154.2 (COH), 186.2/187.4, 189.5/190.0 (CO); MS (EI, 70 eV): m/z (%) = 383 (M+, 1), 292 (2), 201

(2), 188 (100), 144 (23), 129 (10), 103 (6), 77 (3); HRMS (EI): Calcd. for C21H18ClNO4: 383.09189;

found: 383.09167.

1-[(Z)-2-Hydroxy-4-(2-naphthyl)-4-oxo-2-butenyl]-2(1H)-isoquinoline-carboxylic acid methyl ester

(3t). Starting with 5-ethylisoquinoline (0.258 g, 2.00 mmol), 2o (1.05 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3t was prepared as a reddish highly viscous oil (0.325 g, 41%). 1H

NMR (250 MHz, CDCl3,): δ = 2.35 – 2.69 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.65 (s, 3 H, COOCH3,

isomer 1), 3.67 (s, 3 H, COOCH3, isomer 2), 5.66 (s, 1 H, COCH, isomer 1, isomer 2), 5.73 – 5.78 (m, 1

H, NCH, isomer 1, isomer 2), 5.86 (d, 3J = 7.7 Hz, 1 H, CH, isomer 1, isomer 2), 6.70 (d, 3J = 7.7 Hz, 1 H,

CH, isomer 1), 6.87 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 6.94 – 7.10 (m, 4 H, CHAr), 7.30 – 7.46 (m, 4 H,

CHAr), 7.69 – 7.78 (m, 2 H, CHAr), 8.16 – 7.20 (m, 1 H, CHAr), 15.98 (s(br), 1 H, OH); 13C NMR (CDCl3,

62 MHz): δC = 43.2/43.4 (NCHCH2), 53.3/53.4 (COOCH3), 53.6/54.2 (NCH), 102.7/102.8, 124.2, 1024.7

(CH), 124.8/124.9, 125.4/125.5, 126.1, 126.3, 127.0 (CHAr), 127.1 (2CHAr), 127.3, 128.1/128.2, 128.4,

130.0 (CHAr), 130.2, 131.1/131.2, 131.7/131.9, 133.7, 134.3/134.4 (CAr), 153.2/153.1 (COH), 188.5/189.0,

189.5/190.4 (CO); IR (neat): v = 3054 (w), 2952 (w), 2926 (w), 2849 (w), 1710 (s), 1593 (s), 1118 (s),

972 (m), 772 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) = 399 (M+, 1), 308 (1), 212 (1), 188 (100), 155 (4),

144 (18), 129 (7), 103 (5), 77 (2), 59 (3); HRMS (EI): Calcd. for C25H21NO4 : 399.14720; found:

399.14691.

1-[(Z)-2-Hydroxy-4-(2-naphthyl)-4-oxo-2-butenyl]-2(1H)-isoquinoline-carboxylic acid methyl ester

(3u). Starting with isoquinoline (0.258 g, 2.00 mmol), 2p (1.05 g, 3.00 mmol) and methyl chloroformate

(0.226 g, 2.40 mmol), 3u was prepared as a reddish solid (0.561 g, 76%). 1H NMR (250 MHz, CDCl3,): δ

= 2.43 – 2.73 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.64 (s, 3 H, COOCH3, isomer 1, isomer 2), 5.63 –

5.69 (m, 1 H, NCH, isomer 1, isomer 2), 5.75 (s, 1 H, COCH, isomer 1), 5.79 (s, 1 H, COCH, isomer 2),

5.93 – 6.01 (m, 1 H, CH, isomer 1, isomer 2), 6.61 (d, 3J = 7.5 Hz, 1 H, CHAr, isomer 1), 6.91 (d, 3J = 7.5

Hz, 1 H, CHAr, isomer 2), 6.95 – 7.11 (m, 4 H, CHAr), 7.39 – 7.44 (m, 2 H, CHAr), 7.69 – 7.81 (m, 4 H,

CHAr), 8.21 (m, 1 H, CHAr), 15.95 (s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 43.9/44.2

(NCHCH2), 53.3/53.4 (NCH), 53.6/54.0 (COOCH3), 97.9, 108.9/109.1, 123.1 (CH), 124.2, 124.8,

126.1/126.3, 126.7, 127.1, 127.7, 128.1, 128.3, 128.4 (CHAr), 129.3 (2CHAr), 130.0/130.1, 131.2/131.3,

132.1/132.2, 132.6, 135.3 (CAr), 153.2/153.1 (COH), 184.1/184.8, 190.6/190.9 (CO); IR (neat): v = 3052

(w), 3027 (w), 2955 (w), 2918 (w), 1714 (s), 1633 (m), 1116 (s), 972 (w), 783 (s) cm–1; GC-MS (EI,

70 eV): m/z (%) = 399 (M+, 1), 308 (1), 188 (100), 144 (20), 127 (6), 103 (5), 59 (3); HRMS (EI): Calcd.

for C25H21NO4: 399.14651; found: 399.14696.

1-[(Z)-2-Hydroxy-4-oxo-4-(3,4,5-trimethoxyphenyl)-2-butenyl]-2(1H)-isoquinoline-carboxylic acid

methyl ester (3v). Starting with isoquinoline (0.258 g, 2.00 mmol), 2q (1.185 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3v was prepared as a yellow highly viscous oil (0.300 g, 34%). 1H

NMR (250 MHz, CDCl3,): δ = 2.46 – 2.69 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.68 (s, 3 H,

COOCH3, isomer 1), 3.70 (s, 3 H, COOCH3, isomer 2), 3.70 (m, 9 H, OCH3 isomer 1&2), 5.68 (m, 1 H,

NCH, isomer 1, isomer 2), 5.76 – 5.85 (m, 1 H, COCH, isomer 1, isomer 2), 5.92 (d, 3J = 7.5 Hz, 1 H, CH,

isomer 1, isomer 2), 6.75 (d, 3J = 7.6 Hz, 1 H, CH, isomer 1) 6.92 (m, 1 H, CH, isomer 2), 6.97 – 7.22 (m,

6 H, CHAr), 16.01 (s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 41.3/41.7 (NCHCH2), 51.3/51.5

(NCH), 54.3 (3OCH3), 58.9 (COOCH3), 95.3/95.5, 102.6, 106.9/107.107.1 (CH), 122.3, 122.8/122.9,

124.1/124.3 (CHAr), 125.0 (CAr), 126.0/126.1, 128.0/128.2 (CHAr), 128.4 (CAr), 129.2/129.3 (CHAr),

140.0/140.1 (CAr), 151.2 (3COCH3Ar), 151.8 (COH), 183.0/183.8, 186.6/187.1 (CO); IR (neat): v = 2997

(w), 2951 (w), 2939 (w), 2836 (w), 1709 (s), 1570 (s), 1119 (s), 999 (s), 773 (s) cm–1; HRMS (EI): Calcd.

for C24H25O7N: 439.16255; found: 439.16281.

1-[(Z)-2-Hydroxy-4-oxo-4-(2-pyridyl)-2-butenyl]-2(1H)-isoquinoline-carboxylic acid methyl ester

(3w). Starting with isoquinoline (0.258 g, 2.00 mmol), 2r (1.009 g, 3.00 mmol) and methyl chloroformate

(0.226 g, 2.40 mmol), 3w was prepared as a reddish highly viscous oil (0.450 g, 68%). 1H NMR (250

MHz, CDCl3,): δ = 2.46 – 2.77 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.64 (s, 3 H, COOCH3, isomer 1,

isomer 2), 5.65 – 5.71 (m, 1 H, NCH, isomer 1, isomer 2), 5.80 – 5.90 (m, 1 H, CH, isomer 1, isomer 2),

6.62 (s, 1 H, COCH, isomer 1, isomer 2), 6.73 (d, 3J = 7.2 Hz, 1 H, CH, isomer 1), 6.89 (d, 3J = 7.2 Hz, 1

H, CH, isomer 2), 6.91 – 7.08 (m, 4 H, CHAr), 7.26 – 7.29 (m, 1 H, CHAr), 7.65 – 7.70 (m, 1 H, CHAr),

7.92 – 7.96 (m, 1 H, CHAr), 8.51 – 7.70 (m, 1 H, CHAr), 15.56 (s(br), 1 H, OH); 13C NMR (CDCl3, 62

MHz): δC = 43.8/44.2 (NCHCH2), 53.1/53.2 (OCH3), 53.5/53.8 (NCH), 98.0, 108.8/109.1, 122.1 (CH),

124.2, 124.8/124.9, 126.1/126.2 (CHAr), 126.4, 127.0/127.1 (CAr), 128.0, 129.9/130.1 (CHAr), 131.3 (CAr),

137.1 (CHAr), 148.8/149.1 (CAr), 151.9 (CHAr), 153.1/153.6 (COH), 182.0/182.5, 192.0/192.2 (CO); IR

(neat): v = 3106 (w), 3055 (w), 2952 (w), 2851 (w), 1709 (s), 1564 (s), 1119 (s), 772 (s) cm–1; GC-MS (EI,

70 eV): m/z (%) = 350 (M+, 5), 274 (3), 188 (100), 144 (56), 129 (19, 103 (9), 78 (10), 59 (7); HRMS

(EI): Calcd. for C20H18N2O4: 350.12611; found: 350.12617.

1-[(Z)-2-Hydroxy-4-oxo-4-(2-thienyl)-2-butenyl]-2(1H)-isoquinoline-carboxylic acid methyl ester

(3x). Starting with isoquinoline (0.258 g, 2.00 mmol), 2s (0.937 g, 3.00 mmol) and methyl chloroformate

(0.226 g, 2.40 mmol), 3x was prepared as a reddish highly viscous oil (0.150 g, 22%). 1H NMR

(250 MHz, CDCl3,): δ = 2.07 – 2.42 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.42 (s, 3 H, COOCH3,

isomer 1, isomer 2), 5.36– 5.41 (m, 1 H, NCH, isomer 1, isomer 2), 5.47 (s, 1 H, COCH, isomer 1, isomer

2), 5.54 (d, 3J = 7.5 Hz, 1 H, CH, isomer 1), 5.65 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 6.48 (d, 3J = 7.5 Hz,

1 H, CH, isomer 1), 6.66 (d, 3J = 7.5 Hz, 1 H, CH, isomer 2), 6.71 – 6.91 (m, 5 H, CHAr), 7.24 (m, 2 H,

CHAr), 16.01 (s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 42.4/42.9 (NCHCH2), 53.6/53.7 (NCH),

53.9/54.4 (OCH3), 98.0, 109.2/109.4, 124.5 (CH), 125.1/125.2, 126.4/126.6, 127.4/127.5, 128.4/128.5,

128.6/128.7 (CHAr), 130.2/130.4 (CAr), 130.7/131.1 (CHAr), 131.4/131.5 (CAr), 132.9/133.2 (CHAr),

142.0/142.2 (CAr), 153.6/154.1 (COH), 182.6/183.0, 184.4/184.9 (CO); IR (neat): v = 3112 (w), 3034 (w),

2972 (w), 2826 (w), 1698 (s), 1598 (s), 1158 (s), 954 (s), 774 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) =

355 (M+, 36), 337 (18), 264 (92), 188 (100), 170 (15), 170 (15), 144 (18), 11 (86), 83 (8), 59 (14);

HRMS (EI): Calcd. for C19H17NO4S: 355.08728; found: 355.08637.

1-[(Z)-4-(4-Chlorophenyl)-2-hydroxy-4-oxo-2-butenyl]-2-(methoxycarbonyl)-5-nitro-isoquinoline

(3y). Starting with 5-nitroisoquinoline (0.348 g, 2.00 mmol), 2i (1.023 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3y was prepared as a red gummy solid (0.486 g, 54%). 1H NMR

(250 MHz, CDCl3,): δ = 2.71 – 2.73 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.76 (s, 3 H, COOCH3,

isomer 1&2), 5.78 (m, 1 H, NCH, isomer 1, isomer 2), 5.84 (m, 1 H, COCH, isomer 1, isomer 2), 6.56 –

6.68 (m, 1 H, CH, isomer 1&2), 6.99 − 7.02 (m, 1 H, CH isomer 1&2), 7.14 − 7.20 (m, 2 H, CHAr), 7.29 –

7.35 (m, 2 H, CHAr), 7.65 − 7.69 (m, 2 H, CHAr), 7.79 − 7.83(m, 1 H, CHAr), 15.87 (s, 1 H, OH);

13C NMR (CDCl3, 62 MHz): δC = 43.9 (NCHCH2), 53.9 (NCH), 54.7 (COOCH3), 98.4, 103.8, 125.6,

(CH), 127.7, (CHAr), 129.4 (2CHAr), 129.9 (2CHAr). 131.4 (CHAr), 132.2 (CAr), 133.133.9 (CHAr), 134.1

(2CAr), 139.9, 145.4 (CAr), 153.5 (COH), 184.1/184.8, 190.5/191.0 (CO); IR (neat): v = 3035 (w), 3011

(w), 2957 (w), 2855 (w), 1711 (s), 1590 (s), 1223 (s), 1098 (s), 762 (s) cm–1; MS (EI, 70 eV): m/z (%) =

430 ([M+], 37Cl, 2), 428 ([M+], 35Cl, 6), 246 (2), 233 (100), 187 (15), 158 (25), 143 (80), 128 (15), 59

(34); HRMS (EI): Calcd. for C21H17ClNO6 ([M+], 35Cl): 428.07697; found: 428.07756.

1-[4-(4-Fluorophenyl)-2,4-dioxobutyl]-2(1H)-isoquinolinecarboxylic acid methyl ester (3z). Starting

with 5-nitroisoquinoline (0.348 g, 2.00 mmol), 2j (0.973 g, 3.00 mmol) and methyl chloroformate (0.226

g, 2.40 mmol), 3z was prepared as an orange red solid (0.590 g, 72%). 1H NMR (300 MHz, CDCl3): δ =

2.51 – 2.61 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.69 (s, 3 H, COOCH3, isomer 1, isomer 2), 5.77 (m,

1 H, NCH, isomer 1, isomer 2), 5.82 (s, 1 H, COCH, isomer 1, isomer 2), 6.55 – 6.62 (m, 1 H, CH,

isomer 1, isomer 2), 6.95 (m, 1 H, CH, isomer 1, isomer 2), 6.97 – 7.00 (m, 2 H, CHAr), 7.08 – 7.14 (m, 1

H, CHAr), 7.24 – 7.26 (m, 1 H, CHAr), 7.67 – 7.77 (m, 3 H, CHAr), 15.52 (s(br), 1 H, OH); 13C NMR

(CDCl3, 75 MHz): δC = 43.9/44.2 (NCHCH2), 54.2 (NCH), 55.0 (COOCH3), 98.5, 104.0 (CH), 117.0 (d,

2J = 17.9 Hz, 2CHAr), 125.9 (CH), 127.9, 130.1 (CHAr), 130.8 (d, 4J = 2.2 Hz, 2CHAr), 132.1/132.2

(CHAr), 132.7, 134.4, 145.7 (CAr), 153.8/154.3 (COH), 166.5 (d, 1J = 209.6 Hz, CFAr), 185.1/185.7,

189.9/190.4 (CO); IR (neat): v = 3110 (w), 3030 (w), 2971 (w), 2836 (w), 1695 (s), 1597 (s), 1155 (s),

951 (s), 771 (s) cm–1; MS (EI, 70 eV): m/z (%) = 414 (M+, 50), 343 (25), 281 (10), 195 (100), 165 (12),

123 (70).

1-[(Z)-2-Hydroxy-4-(2-methylphenyl)-4-oxo-2-butenyl]-5-nitro-2(1H)-isoquinolinecarboxylic acid

methyl ester (3aa). Starting with 5-nitroisoquinoline (0.348 g, 2.00 mmol), 2l (0.961 g, 3.00 mmol) and

methyl chloroformate (0.226 g, 2.40 mmol), 3aa was prepared as a yellow gummy solid (0.580 g, 71%).

1H NMR (300 MHz, CDCl3,): δ = 2.48 (s, 3 H, CH3, isomer 1, isomer 2), 2.65 – 2.81 (m, 2 H, NCHCH2,

isomer 1, isomer 2), 3.89 (s, 3 H, COOCH3, isomer 1, isomer 2), 5.72 (s, 1 H, COCH, isomer 1, isomer 2),

5.90 – 6.00 (m, 1 H, NCH, isomer 1, isomer 2), 6.70 – 6.76 (m, 1 H, CH, isomer 1, isomer 2), 7.10 – 7.13

(m, 1 H, CH, isomer 1, isomer 2), 7.23 – 7.45 (m, 6 H, CHAr), 7.92 (d, 3J = 6.7 Hz , 1 H, CHAr), 15.89

(s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 22.0 (CH3), 44.2/44.3 (NCHCH2), 54.5 (NCH), 54.2

(COOCH3), 103.1, 104.0, 126.0 (CH), 126.5 (CAr), 127.2, 128.1, 129.7, 130.3, 130.8, 132.4, 132.9 (CHAr),

134.7, 137.0, 138.6, 145.8, (CAr), 153.9/154.5 (COH), 189.8/190.4, 190.7/191.5 (CO); IR (neat): v = 3065

(w), 3015 (w), 2954 (w), 2928 (w), 1716 (s), 1519 (s), 1265 (s), 966 (s), 759 (s) cm–1. MS (EI, 70 eV):

m/z (%) = 408 (M+, 35), 393 (14), 340 (15), 271 (28), 210 (33), 195 (53), 177 (30), 135 (12), 123 (100),

111 (18), 69 (63), 57 (86), 43 (58).

1-[(Z)-4-(2-Fluorophenyl)-2-hydroxy-4-oxo-2-butenyl]-2-(methoxycarbonyl)-5-nitro-isoquinoline

(3ab). Starting with 5-nitroisoquinoline (0.348 g, 2.00 mmol), 2m (0.973 g, 3.00 mmol) and methyl

chloroformate (0.226 g, 2.40 mmol), 3ab was prepared as a yellow solid (0.345 g, 41%). 1H NMR (250

MHz, CDCl3,): δ = 2.70 – 2.73 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.76 (s, 3 H, COOCH3, isomer 1,

isomer 2), 5.79− 5.89 (m, 1 H, NCH, isomer 1,isomer 2), 6.01 (m, 1 H, COCH, isomer 1, isomer 2), 6.58

– 6.71 (m, 1 H, CH, isomer 1&2), 6.99 – 7.02 (m, 1 H, CH, isomer 1, isomer 2), 7.07 − 7.21 (m, 3 H, CH,

CHAr), 7.32 – 7.42 (m, 2 H, CHAr), 7.81 − 7.85 (m, 2 H, CHAr), 15.83 (s(br), 1 H, OH); 13C NMR (CDCl3,

62 MHz): δC = 43.2/43.4 (NCHCH2), 52.9/53.4 (NCH), 53.6/53.8 (COOCH3), 102.1 (CH), 102.3 (d, 3J =

12.0 Hz, CHAr), 102.5 (CH), 116.6 (d, 2J = 21.0 Hz, CHAr), 124.5 (d, 4J = 3.0 Hz, CHAr), 124.7 (CH),

126.7, 127.1, 127.3/128.8, 130.0 (CHAr), 131.3/131.5, 133.3, 133.9, 144.5 (CHAr), 153.0 (COH), 161.5 (d,

1J = 247.4 Hz, CFAr), 180.0, 191.3 (CO); GC-MS (EI, 70 eV): m/z (%) = 414 (M+, 50), 343 (30), 281 (15),

255 (10), 195 (100), 123 (99), 57 (50).

1-[(Z)-4-(2-Chlorophenyl)-2-hydroxy-4-oxo-2-butenyl]-5-nitro-2(1H)-isoquinoline-carboxylic acid

methyl ester (3ac). Starting with 5-nitroisoquinoline (0.348 g, 2.00 mmol), 2n (0.961 g, 3.00 mmol) and

methyl chloroformate (0.226 g, 2.40 mmol), 3ac was prepared as a orange solid (0.520 g, 56%). 1H NMR

(250 MHz, CDCl3,): δ = 2.45 – 2.61 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.69 (s, 3 H, COOCH3,

isomer 1, isomer 2), 5.69 (s, 1 H, COCH, isomer 1, isomer 2), 5.75 – 5.80 (m, 1 H, NCH, isomer 1,

isomer 2), 6.49 – 6.60 (m, 1 H, CH, isomer 1, isomer 2), 6.80 – 6.92 (m, 1 H, CH, isomer 1, isomer 2),

7.05 – 7.26 (m, 5 H, CHAr), 7.32 – 7.35 (m, 1 H, CHAr), 7.74 (dd, 3J = 7.5 Hz, 4J = 1.0 Hz, 1 H, CHAr),

15.30 (s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 43.2/43.5 (NCHCH2), 53.7 (NCH), 54.4

(COOCH3), 103.4, 125.3 (CH), 125.7 (CAr), 127.4 (CH), 127.5, 129.3, 130.0, 130.4, 131.3, 131.8, 132.2

(CHAr), 132.5, 133.8, 136.0, 145.1 (CAr), 153.2/153.6 (COH), 186.7/187.4, 188.6/188.9 (CO); IR (neat):

v = 3067 (w), 3002 (w), 2954 (w), 2851 (w), 1719 (s), 1604 (s), 1519 (s), 1115 (m), 967 (s), 759 (s) cm–1;

MS (EI, 70 eV): m/z (%) = 430 ([M+], 37Cl, 1), 428 ([M+], 35Cl, 3), 246 (2), 233 (100), 187 (15), 158 (25),

143 (80), 128 (15), 59 (34); HRMS (EI): Calcd. for C21H17ClNO6 ([M+], 35Cl): 428.07697; found:

428.07756.

1-[(Z)-2-Hydroxy-4-(2-naphthalenyl)-4-oxo-2-butenyl]-5-nitro-2(1H)-isoquinoline-carboxylic acid

methyl ester (3ad). Starting with 5-nitroisoquinoline (0.348 g, 2.00 mmol), 2p (0.973 g, 3.00 mmol) and

methyl chloroformate (0.226 g, 2.40 mmol), 3ad was prepared as an yellow solid (0.500 g, 56%). 1H

NMR (250 MHz, CDCl3,): δ = 2.73 – 2.76 (m, 2 H, NCHCH2, isomer 1, isomer 2), 3.75 (s, 3 H, COOCH3,

isomer 1, isomer 2), 5.82 – 5.91 (m, 1 H, CH, isomer 1, isomer 2), 6.01 – 6.06 (m, 1 H, NCH, isomer 1,

isomer 2), 6.59 – 6.70 (m, 1 H, COCH, isomer1&2), 7.15 (m, 1 H, CH, isomer 1, isomer 2), 7.33 (d, 3J =

7.7 Hz, 1 H, CHAr), 7.45 – 7.51 (m, 2 H, CHAr), 7.76 – 7.86 (m, 6 H, CHAr), 8.27 (m, 1 H, CHAr), 16.05

(s(br), 1 H, OH); 13C NMR (CDCl3, 62 MHz): δC = 43.0 (NCHCH2), 53.1/53.4 (NCH), 53.8 (COOCH3),

97.9, 102.8, 122.9 (CH), 124.7 (CHAr), 125.1 (CAr), 126.7, 126.8, 127.7 (CHAr), 128.3 (2CHAr), 128.5

(CHAr), 128.7 (CAr), 129.3 (CHAr), 129.5 (CAr), 131.4, 131.7 (CHAr), 132.6, 133.3, 135.3 (CAr), 144.5

(COH), 184.4/184.6, 189.6/189.8 (CO); IR (neat): v = 1704 (w), 1615 (m), 1521 (w), 1185 (w), 977 (w),

761 (w) cm–1; GC-MS (EI, 70 eV): m/z (%) = 444 (M+, 2), 410 (2), 233 (100), 203 (36), 155 (11), 143

(35), 127 (14), 69 (18); HRMS (EI): Calcd. for C25H20N2O4 : 444.13159; found: 444.13132.

1-(3-Methoxycarbonyl-2-oxo-propyl)-1H-isoquinoline-2-carboxylic acid benzyl ester (5a). Starting

with isoquinoline (0.516 g, 4.00 mmol), 2a (2.112 g, 8.00 mmol) and benzyl chloroformate (0.819 g, 4.80

mmol), 5a was prepared as a pale yellow solid (1.099 g, 72%, mp. = 98–100 °C). 1H NMR (250 MHz,

CDCl3): δ = 2.67–2.81 (m, 1H, NCHCH2), 2.93–3.04 (m, 1H, NCHCH2), 3.37 (s, 2H, COCH2, isomer 1),

3.50 (s, 2H, COCH2, isomer 2), 3.61 (s, 3H, CO2CH3, isomer 1), 3.66 (s, 3H, CO2CH3, isomer 2), 5.21 (s,

2H, NCO2CH2, isomer 1), 5.25 (s, 2H, NCO2CH2, isomer 2), 5.80–5.97 (m, 2H, NCH, =CH), 6.82 (d, 3J =

7.7 Hz, 1H, =CH, isomer 1), 6.84 (d, 3J = 7.7 Hz, 1H, =CH, isomer 2), 7.04–7.35 (m, 9H, Ar). 13C NMR

(63 MHz, CDCl3): δ = 47.7, 49.4 (CH2), 51.8 (OCH3), 52.3 (NCHCH2), 68.2 (CO2CH2), 108.9 (NCHCH),

124.2 (NCHCH), 124.9, 125.0, 126.5, 127.4, 128.1, 128.4, 128.6 (Ar–CH), 129.8 131.2, 135.7, 152.6,

167.4, 199.6 (C). IR (ATR, cm-1): v = 2949 (w), 1758 (m), 1702 (s), 1632 (m), 1452 (m), 1417 (s), 1388

(s), 1350 (s), 1323 (s), 1276 (s), 1241 (s), 1191 (m), 1119 (s), 1073 (s), 1028 (m), 1008 (m), 984 (s), 945

(m), 778 (s), 757 (s), 736 (s), 695 (s), 577 (m), 551 (m), 529 (s). HRMS (TOF): m/z (%) calcd for

C22H21NO5Na+ ([M+Na]+): 402.13119, found: 402.13055. Anal. Calcd for C22H21NO5 (379.41): C 69.64,

H 5.58, N 3.69; found: C 70.01, H 5.68, N 3.47.

1-(3-Methoxycarbonyl-2-oxo-propyl)-5-nitro-1H-isoquinoline-2-carboxylic acid benzyl ester (5b).

Starting with 5-nitroisoquinoline (1.045 g, 6.00 mmol), 2a (3.168 g, 12.00 mmol) and benzyl

chloroformate (1.228 g, 7.20 mmol), 5b was prepared as a yellow highly viscous oil (2.089 g, 82%). 1H

NMR (250 MHz, CDCl3): δ = 2.57–2.82 (m, 1H, NCHCH2), 3.06–3.15 (m, 1H, NCHCH2), 3.23–3.52 (m,

2H, COCH2), 3.66 (s, 3H, CO2CH3, isomer 1), 3.69 (s, 3H, CO2CH3, isomer 2), 5.24 (s, 2H, NCO2CH2),

5.98 (br s, 1H, CH, ), 6.61–6.72 (m, 1H, CH), 7.04–7.07, m, 1H, CH), 7.23–7.54 (m, 7H, Ar), 7.86–7.90

(m, 1H, Ar). 13C NMR (63 MHz, CDCl3): δ = 46.8, 49.4 (CH2), 51.1 (OCH3), 52.4 (NCHCH2), 68.7

(CO2CH2), 103.0 (NCHCH), 124.7 (NCHCH), 127.0, 128.3, 128.7, 128.7, 129.8, 132.1 (Ar–CH), 133.1,

133.3 135.2, 144.6, 152.0, 167.1, 199.0 (C). IR (ATR, cm-1): v = 2952 (w), 1709 (s), 1657 (w), 1619 (s),

1520 (s), 1452 (m), 1414 (m), 1387 (s), 1323 (s), 1260 (s), 1227 (s), 1180 (s), 1154 (s), 1104 (s), 962 (m),

914 (m), 865 (m), 758 (s), 736 (s), 697 (s), 603 (m), 579 (m), 549 (m). MS (EI): m/z (%) = 424 (M+, 5),

309 (49), 265 (84), 257 (22), 174 (28), 144 (49), 116 (27), 92 (66), 91 (100). Anal. Calcd for C22H20N2O7

(424.40): C 62.26, H 4.75, N 6.60; found: C 62.43, H 4.73, N 6.50.

5-Bromo-1-((Z)-4-hydroxy-2-oxo-pent-3-enyl)-1H-isoquinoline-2-carboxylic acid benzyl ester (5c).

Starting with 5-bromoisoquinoline (0.500 g, 2.40 mmol), 2c (1.176 g, 4.80 mmol) and benzyl

chloroformate (0.492 g, 2.88 mmol), 5c was prepared as a yellow viscous oil (0.958 g, 90%). 1H NMR

(250 MHz, CDCl3): δ = 1.97 (s, 3H, CH3), 2.16–2.65 (m, 2H, NCHCH2), 5.10–5.32 (m, 3H, CO2CH2,

COCH=), 5.70 (t, 3J = 6.9 Hz, 1H, NCH, isomer 1), 5.80 (t, 3J = 7.0 Hz, 1H, NCH, isomer 2), 6.22 (d, 3J

= 8.0 Hz, 1H, =CH, isomer 1), 6.33 (d, 3J = 8.0 Hz, 1H, =CH, isomer 2), 6.91–7.08 (m, 3H, Ar), 7.36–

7.45 (m, 5H, Ar, 1H, =CH), 15.27 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ = 25.2/25.4 (CH3),

42.4/42.8 (CH2), 53.3/53,8 (NCHCH2), 68.3 (CO2CH2), 101.4/101.5 (COCH), 107.5/107.7 (NCHCH),

120.4/120.5 (CBr), 125.4/125.6 (NCHCH), 125.9, 126.5, 127.9/128.0, 128.2/128.3, 128.4/128.6 (Ar–CH),

129.6/129.7 (C), 132.1/132.2 (Ar–CH), 132.9/133.0, 135.4/135.6, 152.3/152.9, 186.8/187.7, 192.7/193.6

(C). IR (ATR, cm-1): v = 2955 (w), 1709 (s), 1621 (s), 1554 (m), 1497 (m), 1446 (s), 1410 (m), 1385 (s),

1343 (s), 1321 (s), 1299 (s), 1262 (s), 1216 (s) 1199 (s), 1133 (m), 1099 (s), 942 (br s), 758 (s), 695 (s),

649 (m), 607 (m), 581 (m), 550 (m), 533 (m). MS (EI): m/z (%) = 443 (M+, 81Br, 1), 441 (M+, 79Br, 1) 344

(14), 342 (15), 300 (31), 298 (31), 209 (78), 207 (78), 128 (53), 91 (100). Anal. Calcd for C22H20BrNO4

(442.30): C 59.74, H 4.56, N 3.17; found: C 59.53, H 4.33, N 2.87.

1-[3-(2-Methoxy-ethoxycarbonyl)-2-oxo-propyl]-1H-isoquinoline-2-carboxylic acid benzyl ester (5d).

Starting with isoquinoline (0.516 g, 4.00 mmol), 2d (2.433 g, 8.00 mmol) and benzyl chloroformate

(0.819 g, 4.80 mmol), 5d was prepared as a yellow oil (1.674 g, 99%). 1H NMR (250 MHz, CDCl3): δ =

2.54–3.24 (m, 2H, NCHCH2), 3.33 (s, 3H, CH3), 3.36–3.39 (m, 2H, COCH2CO2), 3.49–3.62 (m, 2H,

CO2CH2CH2), 4.21–4.31 (m, 2H, CO2CH2CH2), 5.20–5.29 (m, 2H, CO2CH2Ph), 5.78–5.99 (m, 2H, NCH,

=CH), 6.82 (d, 3J = 7.2 Hz, 1H, =CH, isomer 1), 6.93 (d, 3J = 6.3 Hz, 1H, =CH, isomer 2), 6.92–7.39 (m,

9H, Ar). 13C NMR (63 MHz, CDCl3): δ = 47.6/47.8, 49.5/49.9 (CH2), 51.7 (NCHCH2), 58.9/59.0, (CH3),

64.2, 68.0/68.1, 70.1/70.2 (CH2), 108.9/109.2 (NCHCH), 124.2 (NCHCH), 124.8/125.0, 126.5,

127.0/127.1, 127.3, 128.1, 128.3/128.3, 128.5 (Ar–CH), 129.7, 132.2 135.7, 152.5, 166.5/166.9, 199.5

(C). IR (ATR, cm-1): v = 2890 (w), 1704 (s), 1630 (s), 1455 (m), 1415 (m), 1388 (s), 1314 (s), 1232 (s),

1199 (s), 1117 (s), 1094 (s), 1032 (s), 979 (m), 943 (m), 848 (w), 776 (s), 754 (s), 734 (s), 697 (s). MS

(EI): m/z (%) = 423 (M+, 4), 264 (67), 220 (94), 129 (82), 91 (100). HRMS (EI): calcd for C24H25NO6

(M+): 423.16764, found 423.16748.

Benzyl 1-[(1E)-1,3-dimethyl-1,3-butadienyl]-2(1H)-isoquinolinecarboxylate (5e). Starting with

isoquinoline (0.520 g, 4.00 mmol), 2c (1.366 g, 5.60 mmol) and benzyl chloroformate (0.819 g, 4.80

mmol), 5e was prepared as a yellow solid (1.674 g, 99%), mp. = 109–110 °C. 1H NMR (250 MHz,

CDCl3): δ = 1.97 (s, 3H, CH3, Enol), 2.04 (s, 3H, CH3, Keto), 2.43 (m, 1H, NCHCH2), 2.63 (m, 1H,

NCHCH2), 5.08 – 5.34 (m, 3H, OCH2, COHCH), 5.73, 5.82 (t, 3J = 6.9 Hz, 1H, NCHCH2, Rotamer), 5.86,

5.98 (d, 3J = 7.8 Hz, 1H, NCHCH, Rotamer), 6.84, 6.98 (d, 3J = 7.8 Hz, 1H, NCHCH, Rotamer), 7.05 –

7.21 (m, 5H, Ar), 7.36, 7.38 (m, 4H, Ar), 15.30 (br, 1H, OH). 13C NMR (75.5 MHz, CDCl3): δ = 25.3,

25.4 (CH3, Rotamer), 42.8, 43.1 (NCHCH2, Rotamer), 53.4, 53.8 (NCHCH2, Rotamer), 68.0, 68.1 (OCH2,

Rotamer), 101.3, 101.4 (COHCH, Rotamer), 108.9, 109.3 (NCHCH, Rotamer), 124.1, 124.7, 124.7, 124.9,

126.0, 126.2, 127.0, 127.1, 128.0, 128.1, 128.2, 128.3, 128.6 (CHAr, NCHCH, Rotamer), 129.8, 130.0,

131.2, 131.3, 135.6, 135.8 (CAr, Rotamer), 152.5, 153.1 (NCOO, Rotamer), 187.2, 188.1 (COH, Rotamer),

192.6, 193.6 (COCH3).IR (KBr, cm-1): v = 3099 (w), 3066 (w), 3040 (w), 3015 (w), 2971 (w), 2959 (w),

2925 (w), 2901 (w), 1708 (s), 1629 (s), 1569 (m), 1491 (m), 1470 (m), 1457 (m), 1417 (m), 1397 (s),

1349 (m), 1328 (s), 1290 (m), 1264 (m), 1227 (m), 1212 (m), 1204 (m), 1157 (m), 1125 (m), 1093 (m),

1001 (w), 978 (m), 960 (w), 943 (m), 862 (w), 815 (w), 776 (s), 755 (s), 695 (m), 594 (w), 558 (w), 450

(w). MS (EI, 70 eV): m/z (%) = 363 (M+, 1), 264 (33), 220 (66), 170 (6), 144 (4), 129 (18), 91 (100), 65

(6), 43 (7). Anal. Calcd. for C22H21NO4 (363.41): C 72.71, H 5.82, N 3.85; found: C 72.75, H 5.91, N

3.60.

General procedure for the synthesis of 4a-ad and 6a-e. To a CH2Cl2 solution (6 mL) of 3 or 5 (1.5

mmol) was added TFA (3.0 mmol) and the solution was stirred for 12 h at 20 °C. The solution was

concentrated in vacuo and the residue was purified by chromatography (silica gel, hexane →

hexane/EtOAc = 2:1). The product was dried for 16 h at 50 °C and 0.01 mbar to remove hydrolyzed 2.

Due to the amide resonance and formation of E/Z-isomers, doubling of some signals was observed. In all

products, the 1,3-dicarbonyl moiety resides in the enolic form.

Methyl 11-hydroxy-13-(1-methoxyvinyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-10-

carboxylate (4a). Starting with 3a (0.735 g, 2.40 mmol), dichloromethane (12 mL) and TFA (0.550 g,

4.80 mmol), 4a was isolated as a colorless solid (0.270 g, 37%, mp. = 117-119 °C). 1H NMR (300 MHz,

CDCl3): δ = 2.35 (2 d, 2J = 17.8 Hz, 1H, CH2COH, Rotamer), 2.83 (d, 2J = 16.6 Hz, 1H, CH2CAr), 2.94 –

3.07 (m, 1H, CH2COH), 3.19 – 3.29 (m, 1H, CH2CAr), 3.73, 3.75 (s, 3H, OCH3, Rotamer), 3.81, 3.82 (s,

3H, OCH3, Rotamer), 5.26 (d, 3J = 5.5 Hz, 1H, NCHCCO, Rotamer), 5.36 (d, 3J = 6.2 Hz, 1H, NCHCAr,

Rotamer), 5.39 (d, 3J = 5.5 Hz, 1H, NCHCCO, Rotamer), 5.48 (d, 3J = 6.2 Hz, 1H, NCHAr, Rotamer),

7.07 – 7.19 (m, 4H, Ar), 12.05 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3): δ = 33.4, 33.9 (CH2CAr,

Rotamer), 36.9, 37.3 (CH2COH, Rotamer), 44.5, 45.0 (NCHCCO, Rotamer), 48.5, 49.2 (NCHCAr,

Rotamer), 51.7 (OCH3), 52.8 (OCH3), 99.6, 99.9 (CCOO, Rotamer), 126.3, 126.6, 127.3, 127.4, 129.5,

129.8 (CHAr, Rotamer), 132.1, 132.5, 136.1, 136.3 (CAr, Rotamer), 154.3, 154.4 (NCOO, Rotamer), 170.0

(COH), 170.6, 170.8 (CCOO, Rotamer). IR (KBr, cm-1): v = 2954 (br, w), 1601 (s), 1617 (m), 1413 (m),

1385 (w), 1334 (s), 1098 (m), 1265 (m), 1221 (s), 1115 (m), 1066 (m), 1021 (m), 819 (w), 766 (m), 673

(w). MS (EI, 70 eV): m/z (%) = 303 (M+, 36), 212 (100), 188 (12), 180 (13), 116 (6), 114 (7). Anal. Calcd.

for C16H17NO5 (303.31): C 63.36, H 5.65, N 4.62; found: C 63.49, H 5.97, N 4.81.

1-[11-Hydroxy-13-(1-methoxyvinyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraen-10-yl]-1-

ethanone (4b). Starting with 3b (0.933 g, 3.25 mmol), dichloromethane (16 mL) and TFA (0.741 g,

6.50 mmol), 4b was isolated as a colorless solid (0.839 g, 90%, mp. = 120-122 °C). 1H NMR (300 MHz,

CDCl3): δ = 2.28 (s, 3H, CH3), 2.46 (d, 2J = 18.0 Hz, 1H, CH2, Rotamer), 2.47 (d, 2J = 18.0 Hz, 1H, CH2,

Rotamer), 2.74 (d, 2J = 16.3 Hz, 1H, CH2), 2.98 – 3.12 (m, 1H, CH2), 3.32 – 3.44 (m, 1H, CH2), 3.75,

3.78 (s, 3H, OCH3, Rotamer), 5.33 (d, 3J = 5.3 Hz, 1H, NCH, Rotamer), 5.39 (d, 3J = 6.1 Hz, 1H, NCH,

Rotamer), 5.47 (d, 3J = 5.3 Hz, 1H, NCH, Rotamer), 5.51 (d, 3J = 6.1 Hz, 1H, NCH, Rotamer), 7.08 –

7.26 (m, 4H, Ar), 16.15 (s, 1H, OH, Rotamer), 16.18 (s, 1H, OH, Rotamer). 13C NMR (75.5 MHz,

CDCl3): δ = 23.8 (CH3), 34.5, 35.0 (CH2, Rotamer), 39.8, 40.2 (CH2, Rotamer), 45.6, 46.2 (NCH,

Rotamer), 48.6, 49.2 (NCH, Rotamer), 53.0 (OCH3), 109.5 (NCHCCO), 126.4, 126.8, 127.5, 127.7, 129.7,

130.0 (CHAr, Rotamer), 131.0, 131.5, 136.2, 136.3 (CAr, Rotamer), 154.5 (NCOO), 183.0, 183.7 (COH,

Rotamer), 194.0, 194.4 (CO, Rotamer). IR (KBr, cm-1): v = 1709 (s), 1605 (m), 1493 (m), 1451 (s), 1412

(s), 1332 (s), 1307(s), 1258 (m), 1234 (m), 1199 (w), 1114 (m), 1025 (m), 978 (m), 758 (m), 685 (w). MS

(EI, 70 eV): m/z (%) = 287 (M+, 45), 196 (100), 188 (15), 114 (12), 59 (8). Anal. calcd. for C16H17NO4

(287.31): C 66.89, H 5.96, N 4.88; found: C 66.82, H 6.33, N 5.21.

2-Methoxyethyl 11-hydroxy-13-(1-methoxyvinyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-

10-carboxylate (4c). Starting with 3c (0.775 g, 2.23 mmol), dichloromethane (8 mL) and TFA (0.510 g,

4.46 mmol), 4c was isolated as a colorless viscous oil (0.192 g, 25%). 1H NMR (300 MHz, CDCl3):

δ = 2.36 (dd, 2J = 17.8 Hz, 3J = 1.1 Hz, 1H, CH2COH), 2.87 (d, 2J = 16.7 Hz, 1H, CH2CAr), 2.84 – 3.05

(m, 1H, CH2COH), 3.19 – 3.29 (m, 1H, CH2CAr), 3.43 (s, 3H, CH2OCH3), 3.67 (m, 2H, CH2OCH3), 3.73,

3.75 (s, 3H, NCOOCH3, Rotamer), 4.29 – 4.44 (m, 2H, COOCH2), 5.35 (d, 3J = 5.1 Hz, 1H, NCHCCOO,

Rotamer), 5.37 (d, 3J = 5.8 Hz, 1H, NCHCAr, Rotamer), 5.43 (d, 3J = 5.1 Hz, 1H, NCHCCOO, Rotamer),

5.48 (d, 3J = 5.8 Hz, 1H, NCHCAr, Rotamer), 7.07 – 7.26 (m, 4H, Ar), 12.01, 12.02 (s, 1H, OH, Rotamer).

13C NMR (75.5 MHz, CDCl3): δ = 33.4, 33.9 (CH2CAr, Rotamer), 37.1, 37.5 (CH2COH, Rotamer), 44.6,

45.2 (NCHCCOO, Rotamer), 48.6, 49.2 (NCHCAr, Rotamer), 52.8 (OCH3), 59.0 (OCH3), 63.5, 70.3

(COOCH2, CH2OCH3), 99.7, 99.9 (CCOO, Rotamer), 126.3, 126.6, 127.3, 127.4, 129.6, 129.9 (CHAr,

Rotamer), 132.3, 132.7, 136.1, 136.3 (CAr, Rotamer), 154.3, 154.4 (NCOO, Rotamer), 170.1, 170.3

(CCOO, Rotamer), 171.1 (COH). IR (neat, cm-1): v = 2982 (w), 2953 (w), 2893 (w), 2878 (w), 1705 (s),

1658 (s), 1619 (m), 1452 (s), 1413 (m), 1333 (s), 1296 (s), 1263 (s), 1220 (s), 1198 (s), 1168 (m), 1125

(s), 1066 (m), 1025 (m), 978 (w), 826 (w), 802 (w), 766 (w), 740 (w), 672 (w). MS (EI, 70 eV): m/z

(%) = 347 (M+, 17), 256 (100), 188 (66), 180 (27), 144 (18), 115 (12). Anal. Clacd. for C18H21NO6

(347.36): C 62.24, H 6.09, N 4.03; found: C 62.14, H 6.27, N 4.42.

Methyl 11-hydroxy-10-(2-methoxyacetyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4d). Starting with 3d (0.531 g, 2.40 mmol), dichloromethane (12 mL) and TFA (0.381 g,

3.35 mmol), 4d was isolated as a colorless solid (0.364 g, 69%, mp. = 143-144 °C). 1H NMR (300 MHz,

CDCl3): δ = 2.47 (d, 2J = 18.1 Hz, 1H, CHCH2, Rotamer), 2.48 (d, 2J = 18.1 Hz, 1H, CHCH2, Rotamer),

2.74 (d, 2J = 16.4 Hz, 1H, CHCH2), 3.04 (m, 1H, CHCH2), 3.39 (m, 1H, CHCH2), 3.51 (s, 3H, CH2OCH3),

3.75, 3.78 (s, 3H, NCOOCH3, Rotamer), 4.32 (m, 2H, COCH2), 5.39 (d, 3J = 5.5 Hz, 1H, NCH), 5.50 („t“,

3J = 5.5 Hz, 1H, NCH, Rotamer), 7.08 – 7.21 (m, 4H, Ar), 15.59, 15.65 (s, 1H, OH, Rotamer). 13C NMR

(75.5 MHz, CDCl3): δ = 34.9, 35.4 (CHCH2, Rotamer), 39.3, 39.5 (CHCH2, Rotamer), 44.2, 44.7 (NCH,

Rotamer), 48.1, 48.7 (NCH, Rotamer), 53.1 (OCH3), 60.0 (OCH3), 72.9, 73.1 (COCH2, Rotamer), 108.5

(CCO), 126.4, 126.7, 126.8, 127.6, 127.7, 129.7, 129.9 (CHAr, Rotamer), 130.9, 131.4, 136.0, 136.1 (CAr,

Rotamer), 154.4 (NCOO), 180.8, 182.1 (COH, Rotamer), 193.1, 193.8 (COCH2, Rotamer). IR (KBr, cm-

1): v = 1702 (s), 1632 (m), 1583 (m), 1458 (s), 1434 (w), 1419 (m), 1379 (w), 1345 (m), 1343 (m), 1305

(m), 1284 (w), 1253 (m), 1230 (w), 1196 (m), 1121 (s), 1029 (m), 979 (w), 765 (m), 738 (w), 694 (w).

MS (EI, 70 eV): m/z (%) = 317 (M+, 10), 272 (94), 226 (32), 194 (26), 188 (100), 144 (23), 114 (15), 87

(18), 59 (20). Anal. calcd. for C17H19NO5 (317.34): C 64.34, H 6.03, N 4.41; found: C 64.10, H 6.03, N

4.30.

Methyl 10-benzoyl-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-carboxylate

(4e). Starting with 3e (0.441 g, 1.26 mmol), dichloromethane (6 mL) and TFA (0.290 g, 2.52 mmol), 4e

was isolated as a deep red solid (0.372 g, 85%, mp. = 170-171 °C). 1H NMR (300 MHz, CDCl3): δ = 2.32

(d, 2J = 16.5 Hz, 1H, CH2), 2.56 (d, 2J = 17.9 Hz, 1H, CH2, Rotamer), 2.56 (d, 2J = 17.9 Hz, 1H, CH2,

Rotamer), 2.98 (m, 1H, CH2), 3.14 (m, 1H, CH2), 3.77, 3.79 (s, 3H, OCH3, Rotamer), 5.40, 5.52 (d,

3J = 5.9 Hz, 1H, NCH, Rotamer), 5.62, 5.81 (d, 3J = 5.4 Hz, 1H, NCH, Rotamer), 6.97 (m, 1H, Ar), 7.09

– 7.22 (m, 3H, Ar), 7.46 – 7.59 (m, 5H, Ar), 16.40 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3): δ = 34.7,

35.1 (CH2, Rotamer), 40.8, 41.2 (CH2, Rotamer), 45.2, 45.8 (NCH, Rotamer), 48.5, 49.0 (NCH, Rotamer),

53.0, 53.2 (OCH3, Rotamer), 109.2, 109.3 (NCHCCO, Rotamer), 126.4, 126.7, 126.7, 127.0, 127.5, 127.7,

128.9, 129.7, 129.9, 130.6 (CHAr, Rotamere), 131.0, 131.5, 136.0, 136.1, 136.5, 136.7 (CAr, Rotamer),

154.6, 154.7 (NCOO, Rotamer), 187.1, 187.9, 190.0, 190.3 (CCO, COH, Rotamer). IR (KBr, cm-1):

v = 1698 (s), 1619 (m), 1455 (s), 1411 (m), 1341 (m), 1313 (m), 1243 (w), 1199 (w), 1119 (w), 1024 (w),

768 (w), 745 (w), 694 (w), 650 (w), 513 (w), 446 (w). MS (EI, 70 eV): m/z (%) = 349 (M+, 35), 331 (21),

258 (100), 188 (53), 105 (44), 97 (16), 57 (35). Anal. calcd. for C21H19NO4 (349.38): C, 72.19; H, 5.48; N,

4.01; found: C, 72.22; H, 5.92; N, 4.20.

Methyl 10-(2,2-dimethylpropanoyl)-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4f). Starting with 3f (0.564 g, 1.71 mmol), dichloromethane (7 mL) and TFA

(0.390 g, 3.42 mmol), 4f was isolated as a colorless solid (0.402 g, 71%, mp. = 122-123 °C). 1H NMR

(250 MHz, CDCl3): δ = 1.18, 1.20 (s, 9H, C(CH3)3, Rotamer), 2.47 (m, 2J = 14.0 Hz, 1H, CH2, Rotamer),

2.77 (d, 2J = 16.8 Hz, 1H, CH2), 3.29 – 3.43 (m, 2H, CH2), 3.75, 3.82 (s, 3H, OCH3, Rotamer), 3.93 (d,

3J = 3.4 Hz, 1H, COCHCO), 4.90, 5.10 (d, 3J = 6.9 Hz, 1H, NCHCH2CO, Rotamer), 5.63, 5.73 (m,

3J = 3.4 Hz, 1H, NCHCH, Rotamer), 6.98 – 7.08 (m, 2H, Ar), 7.15 – 7.21 (m, 2H, Ar). 13C NMR

(75.5 MHz, CDCl3): δ = 25.7 (C(CH3)3), 34.0, 34.4 (CH2, Rotamer), 46.0, 46.1 (C(CH3)3, Rotamer), 47.8,

48.2 (CH2, Rotamer), 49.7, 50.4 (OCH3, Rotamer), 51.6, 51.8 (NCH, Rotamer), 52.9, 53.1 (NCH,

Rotamer), 62.2, 62.3 (COCHCO, Rotamer), 126.1, 126.4, 127.1, 127.2, 127.6, 127.7, 129.0, 129.4 (CHAr,

Rotamer), 129.5, 130.0, 135.6, 135.7 (CAr, Rotamer), 154.8, 155.0 (NCOO, Rotamer), 203.9, 208.3, 208.3

(COCH, COC, Rotamer). IR (KBr, cm-1): v = 3008 (w), 2984 (m), 2956 (m), 2934 (w), 2874 (w), 2845

(w), 1710 (s), 1690 (s), 1491 (w), 1479 (m), 1448 (s), 1408 (s), 1367 (w), 1361 (m), 1342 (s), 1329 (s),

1311 (m), 1296 (m), 1265 (w), 1248 (m), 1237 (m), 1215 (m), 1194 (m), 1182 (m), 1130 (w), 1111 (s),

1095 (m), 1058 (m), 1040 (m), 1012 (m), 983 (m), 954 (w), 793 (w), 769 (s), 722 (w), 686 (w), 636 (w),

533 (w), 489 (w). MS (EI, 70 eV): m/z (%) = 329 (M+, 21), 272 (4), 245 (5), 227 (6), 202 (5), 188 (100),

170 (9), 154 (21), 116 (8), 57 (26), 42 (8). Anal. calcd. for C19H23NO4 (329.39): C, 69.28; H, 7.04; N,

4.25; found: C, 68.87; H, 7.14; N, 4.02.

10-Acetyl-11-hydroxy-6-nitro-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-13-carboxylic acid

methyl ester (4g). Starting with 3g (0.598 g, 1.80 mmol), dichloromethane (12 mL) and TFA (0.410 g,

3.60 mmol), 4g was isolated as a white solid (0.494 g, 83%, mp. = 175 °C). 1H NMR (250 MHz, CDCl3):

δ = 2.27 (s, 3H, COCH3), 2.45 (dd, 2J = 18.1 Hz, 3J = 1.0 Hz, 1H, NCHCH2), 3.03 (dd, 2J = 17.8 Hz, 3J =

1.1 Hz, 1H, NCHCH2), 3.05–3.14 (m, 1H, NCHCH2), 3.58 (dd, 2J = 17.8 Hz, 3J = 5.7 Hz, 1H, NCHCH2),

3.77 (s, 3H, CO2CH3, isomer 1), 3.79 (s, 3H, CO2CH3, isomer 2), 5.38–5.61 (m, 2H, NCH), 7.38–7.41 (m,

2H, Ar), 7.88–7.92 (m, 1H, Ar), 15.50 (s, 1H, OH, isomer 2), 15.52 (s, 1H, OH, isomer 2). 13C NMR (75

MHz, CDCl3): δ = 23.9 (COCH3), 32.4/32.9, 39.5/39.8 (NCHCH2), 44.6/45.3, 48.5/49.2 (NCH),

53.2/53.4 (CO2CH3), 108.9 (C), 124.4, 127.3 (Ar–CH), 127.8 (C), 131.6/131.9 (Ar–CH), 139.2,

149.8/149.9, 154.2, 181.9/182.6, 194.5/194.8 (C). IR (Nujol, cm-1): v = 1699 (s), 1526 (s), 1358 (s), 1303

(s), 1213 (m), 1108 (m). MS (CI): m/z (%) = 333 ([M+1]+, 20), 234 (15), 233 (100), 203 (12). Anal. Calcd

for C16H16N2O6 (332.31): C 57.83, H 4.85, N 8.43; found: C 57.70, H 4.91, N 8.18.

11-Hydroxy-6-nitro-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-10,13-dicarboxylic acid 10-

ethyl ester 13-methyl ester (4h). Starting with 3h (1.087 g, 3.00 mmol) and TFA (0.684 g, 6.00 mmol),

4h was isolated as a slightly yellow solid (0.509 g, 47%, mp. = 161 °C). 1H NMR (250 MHz, CDCl3):

δ = 1.34 (t, 3J = 7.2 Hz, 3H, CO2CH2CH3), 2.33 (dd, 2J = 17.7 Hz, 3J = 1.3 Hz, 1H, NCHCH2), 2.96–3.13

(m, 2H, NCHCH2), 3.44 (dd, 2J = 18.1 Hz, 3J = 4.7 Hz, 1H, NCHCH2), 3.74 (s, 3H, CO2CH3, isomer 1),

3.76 (s, 3H, CO2CH3, isomer 2), 4.25 (q, 3J = 7.0 Hz, 2H, CO2CH2CH3), 5.28–5.56 (m, 2H, NCH), 7.31–

7.42 (m, 2H, Ar), 7.82–7.86 (m, 1H, Ar), 12.14 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ = 14.1

(CO2CH2CH3), 31.3/31.7, 36.7/37.1 (NCHCH2), 43.6/44.2, 48.5/49.2 (NCH), 53.0 (CO2CH3), 61.0

(CO2CH2CH3), 99.5/99.9 (C), 124.0, 126.8 (Ar–CH), 128.5/128.9 (C), 131.3/131.7 (Ar–CH), 139.1/139.2,

149.9/150.0, 153.9/154.2, 169.1/169.9, 170.0/170.1 (C). IR (KBr, cm-1): v = 2979 (w), 2952 (w), 1704 (s),

1521 (s), 1346 (s), 1263 (s), 1224 (s), 1062 (m). MS (CI): m/z (%) = 363 ([M+1]+, 46), 362 (8), 317 (7),

234 (14), 233 (100). Anal. Calcd for C17H18N2O7 (362.33): C 56.35, H 5.01, N 7.73. Found: C 56.43,

H 5.08, N 7.46.

10-Benzoyl-11-hydroxy-6-nitro-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-13-carboxylic

acid methyl ester (4i). Starting with 3i (0.394 g, 1.00 mmol) and TFA (0.228 g, 2.00 mmol), 4i was

isolated as a slightly yellow solid (0.368 g, 93%, mp. = 184–185 °C). 1H NMR (250 MHz, CDCl3):

δ = 2.55 (dd, 2J = 18.0 Hz, 3J = 1.2 Hz, 1H, NCHCH2), 2.65 (dd, 2J = 18.0 Hz, 3J = 1.4 Hz, 1H, NCHCH2),

3.15 (d, 2J = 17.6 Hz, 1H, NCHCH2), 3.18 (d, 2J = 17.9 Hz, 1H, NCHCH2), 3.80 (s, 3H, CO2CH3), 5.48–

5.86 (m, 2H, NCH), 7.26–7.88 (m, 8H, Ar), 15.34 (br s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ =

32.5/32.9, 40.3/40.8 (NCHCH2), 44.3/45.0, 48.4/49.1 (NCH), 53.2/53.3 (CO2CH3), 108.8/108.8 (C),

124.2, 126.5/126.8, 127.2, 128.9, 130.8/130.9, 131.4/131.7 (Ar–CH), 134.0, 136.0/136.1, 138.8/139.0,

149.8/149.9, 154.3, 185.6/186.3, 190.7/191.0 (C). IR (Nujol, cm-1): v = 1700 (s), 1526 (s), 1355 (s),

1306 (s), 1035 (m). MS (CI): m/z (%) = 394 (M+, 24), 258 (100), 233 (82), 105 (68). Anal. Calcd for

C21H18N2O6 (394.38): C 63.96, H 4.60, N 7.10. Found: C 63.76, H 4.64, N 6.96.

10-Acetyl-6-bromo-11-hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-13-carboxylic

acid methyl ester (4j). Starting with 3j (0.364 g, 0.99 mmol) and TFA (0.250 g, 2.19 mmol), 4j was

isolated as a white solid (0.323 g, 89%, mp. = 148 °C). 1H NMR (250 MHz, CDCl3): δ = 2.30 (s, 3H,

COCH3), 2.46 (d, 2J = 18.0 Hz, 1H, NCHCH2), 2.85 (d, 2J = 16.9 Hz, 1H, NCHCH2), 2.98–3.18 (m, 2H,

NCHCH2), 3.75 (s, 3H, CO2CH3, isomer 1), 3.76 (s, 3H, CO2CH3, isomer 2), 5.37 (d, 3J = 4.0 Hz, 1H,

NCH), 5.50 (d, 3J = 4.4 Hz, 1H, NCH), 7.07–7.47 (m, 3H, Ar), 15.49 (s, 1H, OH, isomer 1), 15.52 (s, 1H,

OH, isomer 2). 13C NMR (75 MHz, CDCl3): δ = 23.8 (COCH3), 35.7/36.2, 39.4/39.8 (NCHCH2),

45.4/46.0, 48.4/49.0 (NCH), 53.0 (CO2CH3), 109.3/109.5 (C), 125.5,/125.8 (Ar–CH), 126.0/126.2 (C),

127.9/127.9 (Ar–CH), 131.2 (C), 131.6/131.7 (Ar–CH), 138.6/138.8, 154.2, 182.2/182.8, 194.4/194.7 (C).

IR (Nujol, cm-1): v = 1712 (s), 1700 (s), 1605 (br, m), 1353 (s), 1325 (s), 1306 (s). MS (CI): m/z (%) =

368 ([M+1]+, 81Br, 20), 366 ([M+1]+, 79Br, 21), 268 (100), 266 (100), 188 (23), 97 (16). Anal. Calcd for

C16H16BrNO4 (366.21): C 52.48, H 4.40, N 3.82. Found: C 52.66, H 4.41, N 3.63.

6-Bromo-11-hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-10,13-dicarboxylic acid

10-ethyl ester 13-methyl ester (4k). Starting with 3k (0.792 g, 2.00 mmol) and TFA (0.456 g,

4.00 mmol), 4k was isolated as a colourless solid (0.472 g, 60%, mp. = 154–155 °C). 1H NMR (250 MHz,

CDCl3): δ = 1.38 (t, 3J = 7.0 Hz, 3H, CO2CH2CH3), 2.35 (dd, 2J = 17.9 Hz, 3J = 1.1 Hz, 1H, NCHCH2),

2.91–3.10 (m, 3H, NCHCH2), 3.73 (s, 3H, CO2CH3, isomer 1), 3.75 (s, 3H, CO2CH3, isomer 2), 4.19–

4.39 (m, 2H, CO2CH2CH3), 5.28–5.48 (m, 2H, NCH), 7.02–7.10 (m, 2H, Ar), 7.43–7.45 (m, 1H, Ar),

12.15 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ = 14.3 (CO2CH2CH3), 34.8/35.3, 36.8/37.2 (NCHCH2),

44.5/45.0, 48.6/49.2 (NCH), 52.9 (CO2CH3), 60.7 (CO2CH2CH3), 99.9/100.2 (C), 125.5/125.8 (Ar–CH),

126.0/126.2 (C), 127.5, 131.5/131.6 (Ar–CH), 132.4/132.8, 138.7/138.9, 154.3, 169.4, 170.2/170.3 (C).

IR (Nujol, cm-1): v = 1708 (s), 1659 (s), 1349 (s), 1329 (s), 1291 (s), 1213 (s), 1064 (s). MS (CI): m/z (%)

= 398 ([M+1]+, 81Br, 53), 396 ([M+1]+, 79Br, 53), 268 (99), 266 (100), 226 (14), 188 (19). Anal. Calcd for

C17H18BrNO5 (396.23): C 51.53, H 4.58, N 3.53. Found: C 51.64, H 4.61, N 3.40.

10-Benzoyl-6-bromo-11-hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-13-carboxylic

acid methyl ester (4l). Starting with 3l (0.704 g, 1.64 mmol) and TFA (0.448 g, 3.93 mmol), 4l was

isolated as a pale yellow solid (0.664 g, 94%, mp. = 146 °C). 1H NMR (250 MHz, CDCl3): δ = 2.50 (d, 2J

= 17.1 Hz, 1H, CHCH2), 2.55 (dd, 2J = 17.9 Hz, 3J = 1.0 Hz, 1H, CHCH2), 2.72–2.81 (m, 1H, CHCH2),

3.11–3.23 (m, 1H, CHCH2), 3.77 (s, 3H, CO2CH3, isomer 1), 3.79 (s, 3H, CO2CH3, isomer 2), 5.38–5.82

(m, 2H, NCH), 7.07–7.54 (m, 8H, Ar), 15.29 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ = 36.0/36.4,

40.5/40.9 (NCHCH2), 45.1/45.7, 48.4/49.0 (NCH), 53.0/53.2 (CO2CH3), 109.2/109.3 (C), 125.5/126.6,

126.8, 127.8/127.9, 128.8, 130.6/130.7 (Ar–CH), 131.2 (C), 131.7/131.7 (Ar–CH), 136.3/136.4, 138.4,

138.6, 154.4, 186.3/187.0, 190.4/190.7 (C). IR (Nujol, cm-1): v = 1715 (s), 1602 (m), 1559 (m), 1323 (m),

1307 (m), 1116 (m), 1029 (m). MS (CI): m/z (%) = 430 ([M+1]+, 81Br, 17), 428 ([M+1]+, 79Br, 18),

268 (96), 266 (100), 188 (25), 69 (21). Anal. Calcd for C21H18BrNO4 (428.28): C 58.89, H 4.24, N 3.27.

Found: C 58.87, H 4.36, N 3.04.

Methyl 11-hydroxy-10-(4-nitrobenzoyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4m). Starting with 3m (0.169 g, 0.43 mmol) and TFA (0.097 g, 085 mmol), 4m was

isolated as a colourless solid (0.100 g, 60%). 1H NMR (CDCl3, 250 MHz): δ = 2.19 (d, 2J = 16.1 Hz, 1 H,

CHCH2), 2.53 (d, 2J = 19.0, Hz, 1 H, CHCH2), 2.91 – 3.17 (m, 2 H, CHCH2), 3.71 (s, 3 H, CO2CH3,

isomer 1&2), 5.22 − 5.41 (m, 1 H, NCH), 5.46 – 5.59 (m, 1 H, NCH), 6.90 − 6.93 (s, 1 H, CHAr), 7.05 −

7.15 (s, 3 H, CHAr), 7.61 − 7.71 (m, 2 H, CHAr), 8.30 − 8.33 (m, 2 H, CHAr),16.05 (s, 1 H, OH). 13C NMR

(CDCl3, 62 MHz): δC = 34.9/35.3, 40.8/41.3 (CHCH2), 45.0/45.7, 48.3/49.0 (NCH), 53.1/53.4 (CO2CH3),

109.5 (C), 124.2 (2CHAr), 124.4, 126.7/126.9, 127.8/127.9, 128.2, 129.6/129.9, 130.3 (CHAr), 130.7,

135.6, 142.0, 148.8 (CAr), 154.6 (C-OH), 187.3/187.6, 188.3/189.0 (C=O); MS (EI, 70 eV): m/z (%) =

394 ([M+], 19), 376 (23), 346 (6), 303 (100), 273 (30), 188 (92), 180 (19), 120 (71), 92 (12), 73 (11), 57

(20).; HRMS (EI): Calcd. for C21H18O6N2: 394.11594; found: 394.11665.

Methyl 10-(4-chlorobenzoyl)-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4n). Starting with 3n (0.420 g, 1.09 mmol) and TFA (0.249 g, 2.10 mmol), 4n was isolated

as a colourless solid (0.290 g, 69%). 1H NMR (CDCl3, 250 MHz): δ = 2.15 (d, 2J = 17.0 Hz, 1 H,

CHCH2), 2.42 (d, 2J= 19.5, Hz, 1 H, CHCH2), 2.82 – 3.06 (m, 2 H, CHCH2), 3.63 (s(br), 3 H, CO2CH3,

isomer 1&2), 5.25 − 5.39 (m, 1 H, NCH), 5.41 – 5.62 (m, 1 H, NCH), 6.82 − 6.85 (m, 1 H, CHAr), 6.93 −

7.06 (m, 3 H, CHAr), 7.31 − 7.43 (m, 4 H, CHAr), 16.17 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC =

34.8/35.2, 40.9/41.2 (CHCH2), 45.1/45.7, 48.4/49.0 (NCH), 53.0/53.4 (CO2CH3), 109.3 (C), 126.4,

126.7/126.8, 127.6/127.7, 128.3, 128.6, 129.2, 129.7/129.9, 130.7 (CHAr), 131.1, 134.9, 135.8, 136.8

(CAr), 154.3/154.6 (C-OH), 187.4/188.1, 188.6/188.9 (C=O); IR (neat): v = 3034 (w), 3000 (w), 2990 (w),

2838 (w), 1691 (s), 1447 (s), 1313 (s), 1023 (s), 759 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) = 385 ([M+],

37Cl, 8), 383 ([M+], 35Cl, 21), 294 (37Cl, 33), 383 (35Cl, 100), 188 (68), 139 (51), 111 (25), 91 (6), 59 (11);

HRMS (EI): Calcd. for C21H18O4ClN, ([M+], 35Cl): 383.09189; found: 383.09192.

Methyl 10-(4-fluorobenzoyl)-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4o). Starting with 3o (0.164 g, 0.43 mmol) and TFA (0.87 g, 0.09 mmol), 4o was isolated as

a colourless solid (0.110 g, 67%). 1H NMR (CDCl3, 250 MHz): δ = 2.23 (d, 2J = 16.5 Hz, 1 H, CHCH2),

2.48 (d, 2J = 18.0 Hz, 1 H, CHCH2), 2.89 – 3.12 (m, 2 H, CHCH2), 3.69 (s, 3 H, CO2CH3, isomer 1&2),

5.31 − 5.45 (m, 1 H, NCH), 5.50 – 5.72 (m, 1 H, NCH), 6.88 (m, 1 H, CHAr), 7.03 − 7.15 (m, 5 H, CHAr),

7.44 – 7.52 (m, 2 H, CHAr), 16.28(s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC = 34.7/35.1, 40.7/41.1

(CHCH2), 45.2/45.8, 48.2/49.0 (NCH), 53.0/53.1 (CO2CH3), 109.2 (C), 116.1 (d, 2J = 25.0 Hz, 2CHAr),

126.4/126.7, 127.5/127.6, 129.1/129.2 (CHAr), 129.5 (d, 3J = 9.5 Hz, 2CHAr), 130.7/131.2 (CHAr),

131.6/131.7, 132.7/132.8, 135.9/136.0 (CAr), 154.7 (C-OH), 163.9 (d, 1J = 248.0 Hz, CFAr), 187.1/187.9,

188.7/188.9 (C=O); IR (neat): v = 2957 (w), 2935 (w), 2919 (w), 2851 (w), 1691 (s), 1446 (s), 1235 (s),

1022 (s), 758 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) = 376 ([M+], 22), 349 (17), 276 (100), 188 (39), 144

(15), 123 (50), 115 (12), 95 (16), 77 (5), 59(10). HRMS (EI): Calcd. for C21H18O4NF: 367.12144; found:

367.12113.

Methyl 11-hydroxy-10-(2-methoxybenzoyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4p). Starting with 3p (0.210 g, 0.553 mmol) and TFA (0.126 g, 1.107 mmol), 4p was

isolated as a colourless solid (0.190 g, 69%). 1H NMR (CDCl3, 250 MHz): δ = 2.23 (d, 2J= 17.5 Hz. 1 H,

CHCH2), 2.46 (d, 2J= 17.5 Hz, 1 H, CHCH2), 2.77 – 2.88 (m, 1 H, CHCH2), 2.99 − 3.12 (m,1 H, CHCH2),

3.64 (s, 3H, OCH3), 3.83 (s, 3 H, CO2CH3, isomer 1&2), 5.19 – 5.31 (m, 1 H, NCH), 5.34 – 5.43 (m, 1 H,

NCH), 6.86 – 7.18 (m, 7 H, CHAr), 7.33 – 7.39 (m, 1 H, CHAr), 16.03 (s, 1 H, OH). 13C NMR (CDCl3, 62

MHz): δC = 34.4/34.9, 40.3/40.7 (CHCH2), 45.3/45.9, 48.3/48.9 (NCH), 52.4 (OCH3), 55.4/55.6

(CO2CH3), 110.8 (C), 111.3/111.5, 120.9/121.0, 126.5/126.6, 127.4/127.5, 128.1, 129.5/129.8 (CHAr),

131.5/131.6 (2CHAr), 132.1, 136.2, 136.3, 154.2/154.4 (CAr), 155.0/155.3 (C-OH), 184.5/185.0,

190.9/191.3 (C=O); IR (neat): v = 2956 (w), 2925 (w), 2910 (w), 2841 (w), 1693 (s), 1442 (s), 1225 (s),

1012 (s), 750 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) = 379 ([M+], 27), 361 (13), 330 (7), 288 (100), 258

(6), 212 (8), 188 (30), 135 (59), 115 (14), 77(21), 59 (7); HRMS (EI): Calcd. for C22H21O5N: 379.14142;

found: 379.14091.

Methyl 11-hydroxy-10-(2-methylbenzoyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4q). Starting with 3q (0.277 g, 0.76 mmol) and TFA (0.173 g, 1.50 mmol), 4q was isolated

as a colourless solid (0.201 g, 72%). 1H NMR (CDCl3, 250 MHz): δ = 2.21 − 2.23 (m, 1 H, CHCH2), 2.25

(s, 3H, CH3), 2.49 (d, 2J = 17.5, 1 H, CHCH2), 2.78 – 2.86 (m, 1 H, CHCH2), 2.98 – 3.13 (m, 1 H,

CHCH2), 3.65 (s, 3 H, CO2CH3, isomer 1&2), 5.08 – 5.28 (m, 1 H, NCH), 5.32 – 5.47 (m, 1 H, NCH),

6.89 – 6.91 (m, 1 H, CHAr), 7.01 – 7.10 (m, 3 H, CHAr), 7.14 – 7.29 (m, 4 H, CHAr), 16.20 (s, 1 H, OH).

13C NMR (CDCl3, 62 MHz): δC = 17.0/17.1 (CH3), 32.5/32.9, 39.1/39.5 (CHCH2), 43.5/44.2, 46.6/47.1

(NCH), 50.9 (CO2CH3), 108.0 (C), 124.0, 124.2 (CAr), 124.4, 124.7, 125.7, 127.5, 127.7, 128.9, 129.2,

129.7 (CHAr), 132.4, 133.8/134.0 (CAr), 152.4 (C-OH), 186.1/186.8, 188.9/189.3 (C=O); GC-MS (EI, 70

eV): m/z (%) = 363 ([M+], 24), 345 (11), 272 (100), 218 (14), 188 (13), 180 (26), 119 (26), 77(5), 65 (9);

HRMS (EI): Calcd. for C22H21O4N: 363.14651; found: 363.14570.

Methyl 10-(2-fluorobenzoyl)-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4r). Starting with 3r (0.430 g, 1.17 mmol) and TFA (0.226 g, 2.34 mmol), 4r was isolated

as a light yellow solid (0.350 g, 81%). 1H NMR (CDCl3, 250 MHz): δ = 2.24 (d, 2J = 19.5 Hz, 1 H,

CHCH2), 2.49 (d, 2J = 18.0, 1 H, CHCH2), 2.87 – 2.98 (m, 1 H, CHCH2), 3.06 – 3.12 (m, 1 H, CHCH2),

3.66 (s, 3 H, CO2CH3, isomer 1&2), 5.18 – 5.30 (m, 1 H, NCH), 5.37 – 5.44 (m, 1 H, NCH), 6.90 – 7.23

(m, 8 H, CHAr), 15.93 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC = 34.6/35.1, 40.6/41.1 (CHCH2),

45.2/45.8, 48.3/48.9 (NCH), 52.9 (CO2CH3), 110.7 (C), 116.4/116.7 (2CHAr), 124.7 (d, 4J = 3.1 Hz,

CHAr), 126.3 (CAr), 126.6/126.7, (CHAr), 127.5 (d, 3J = 7.2 Hz, CHAr), 128.6, 129.6/129.9 (CHAr),

131.0/131.4 (CAr), 132.1 (d, 3J =7.9 Hz, CHAr), 135.9/136.0 (CAr), 154.4/154.5 (C-OH), 158.0/158.2 (d, 1J

= 245.0 Hz, CFAr), 186.4/186.8, 186.9/187.3 (C=O); IR (neat): v = 2957 (w), 2930 (w), 2915 (w), 2848

(w), 1693 (s), 1448 (s), 1210 (s), 1022 (s), 754 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) = 367 ([M+], 70),

349 (45), 276 (100), 258 (20), 188 (73), 123 (83), 95 (37), 57(32).; HRMS (EI): Calcd. for C21H18O4NF:

367.12144; found: 367.12106

Methyl 10-(2-chlorobenzoyl)-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4s). Starting with 3s (0.350 g, 0.911 mmol) and TFA (0.2079 g, 1.823 mmol), 4s was

isolated as a colourless solid (0.274 g, 78%). 1H NMR (CDCl3, 250 MHz): δ = 2.37 (d, 2J = 16.1 Hz. 1 H,

CHCH2), 2.51 (d, 2J = 18.9 Hz, 1 H, CHCH2), 2.84− 2.90 (m,1 H, CHCH2), 3.01 – 3.15 (m, 1 H, CHCH2),

3.67 (s, 3 H, CO2CH3, isomer 1&2), 5.11 – 5.25 (m, 1 H, NCH), 5.35 – 5.46 (m, 1 H, NCH), 6.96 (m, 1 H,

CHAr), 7.04 – 7.19 (m, 3 H, CHAr), 7.34 – 7.47 (m, 4 H, CHAr), 15.88 (s, 1 H, OH). 13C NMR (CDCl3, 62

MHz): δC = 34.2/34.8, 40.6/41.1 (CHCH2), 45.5/46.2, 48.3/49.0 (NCH), 50.9 (CO2CH3), 110.1 (C), 126.3

(CAr), 126.6/126.7, 127.7 (CHAr), 127.6/127.7 (CAr), 127.9, 128.8, 129.6/129.9, 130.4/130.7, 130.9, 131.0

(CHAr), 131.6, 135.9/136.0 (CAr), 154.6 (C-OH), 186.6/187.0, 189.1 (C=O); GC-MS (EI, 70 eV): m/z (%)

= 385 ([M+], Cl37 7), 343 ([M+], Cl35 20), 365 (11), 348 (10), 330 (12), 292 (100), 212 (10), 188 (20), 139

(30), 115 (12), 77(5); HRMS (EI): Calcd. for C21H18O4NCl: 383.09189 ([M+], Cl35); found: 383.09184.

Methyl 11-hydroxy-10-(2-naphthoyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4t). Starting with 3t (0.399 g, 1.00 mmol) and TFA (0.228 g, 2.00 mmol), 4t was isolated as

a slightly yellow solid (0.307 g, 77%). 1H NMR (CDCl3, 250 MHz): δ = 2.33 (d, 2J = 15.5 Hz, 1 H,

CHCH2), 2.60 (d, 2J = 18.5 Hz, 1 H, CHCH2), 3.01 – 3.34 (m, 1 H, CHCH2), 3.35 − 3.51 (m,1 H,

CHCH2), 3.72 (s, 3 H, CO2CH3, isomer 1), 3.83 (s, 3 H, CO2CH3, isomer 2), 5.25 − 5.44 (m, 1 H, NCH),

5.79 – 5.96 (m, 1 H, NCH), 6.94 − 7.24 (m, 4 H, CHAr), 7.56 – 7.71 (m, 2 H, CHAr), 7.85 – 8.13 (m, 4 H,

CHAr), 8.20 (s, 1 H, CHAr), 16.18 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC = 34.8/35.3, 40.8/41.2

(CHCH2), 45.2/45.8, 48.4/49.1 (NCH), 53.0/53.1 (CO2CH3), 109.1 (C), 123.7/123.8, 126.3/126.4, 126.6,

126.9, 127.0, 127.2, 127.4, 127.6/127.7, 127.8/127.9, 128.8/128.9, 129.7/129.9 (CHAr), 130.9, 131.4,

132.6, 133.9/134.1, 135.9/136.1 (CAr), 154.7 (C-OH), 187.1/187.1, 189.8/190.3 (C=O IR (neat): v = 3061

(w), 3042 (w), 2956 (w), 2849 (w), 1699 (s), 1443 (s), 1219 (s), 1006 (s), 750 (s) cm–1; GC-MS (EI, 70

eV): m/z (%) = 399 ([M+], 63), 382 (12), 356 (5), 308 (100), 280 (11), 253 (19), 212 (23), 188 (15), 155

(44), 127 (42), 116(27), 91 (10), 59 (12); HRMS (EI): Calcd. for C25H21O4N: 399.14651; found:

399.14617.

Methyl 11-hydroxy-10-(1-naphthoyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4u). Starting with 3u (0.115 g, 0.28 mmol) and TFA (0.067 g, 0.57 mmol), 4u was isolated

as a colourless solid (0.080 g, 70%). 1H NMR (CDCl3, 250 MHz): δ = 2.00 − 2.07 (m, 1 H, CHCH2), 2.53

(d, 2J = 15.0 Hz, 1 H, CHCH2), 2.59 – 2.69 (m, 1 H, CHCH2), 3.04 − 3.19 (m,1 H, CHCH2), 3.56 (s, 3 H,

CO2CH3, isomer 1), 3.63 (s, 3 H, CO2CH3, isomer 2), 5.18 (m, 1 H, NCH), 5.31 – 5.43 (m, 1 H, NCH),

6.75 (m, 1 H, CHAr), 7.01 – 7.15 (m, 3 H, CHAr), 7.38 – 7.50 (m, 4 H, CHAr), 7.67 (m, 1 H, CHAr), 7.83−

7.91 (m, 2 H, CHAr), 16.08 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC = 34.8/35.2, 41.1/41.6 (CHCH2),

45.7/46.2, 48.5/49.1 (NCH), 52.9/53.4 (CO2CH3), 110.9 (C), 124.5/124.6, 124.7, 125.1, 126.4 (CHAr),

126.9 (2CHAr), 127.1/127.3, 127.5/127.6, 128.5, 129.5, 129.8 (CHAr), 130.2, 131.1, 131.7, 133.3/133.6,

135.9/136.0 (CAr), 154.5 (C-OH), 188.6, 190.1/190.5 (C=O); GC-MS (EI, 70 eV): m/z (%) = 399 ([M+],

50), 382 (10), 356 (15), 308 (100), 280 (41), 253 (19), 212 (20), 188 (12), 155 (44), 127 (4); HRMS (EI):

Calcd. for C25H21O4N: 399.14651; found: 399.14617.

Methyl 11-hydroxy-10-(3,4,5-trimethoxybenzoyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4v). Starting with 3v (0.180 g, 0.41 mmol) and TFA (0.093 g, 0.82 mmol), 4v

was isolated as a colourless solid (0.100 g, 55%). 1H NMR (CDCl3, 250 MHz): δ = 2.29 (d, 2J = 15.7 Hz,

1 H, CHCH2), 2.46 (d, 2J = 15.5, Hz, 1 H, CHCH2), 2.73 – 2.99 (m, 1 H, CHCH2), 3.09 – 3.18 (m, 1 H,

CHCH2), 3.70 (s, 3 H, CO2CH3, isomer 1), 3.73 (s, 3 H, CO2CH3, isomer 2) 3.83 − 3.87 (m(br), 9 H, OCH3,

isomer 1&2), 5.14 − 5.45 (m, 1 H, NCH), 5.60 – 5.90 (m, 1 H, NCH), 6.70 (s, 1 H, CHAr), 6.78 (s, 1 H,

CHAr), 7.00 − 7.19 (m, 4 H, CHAr), 16.21 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC = 34.9/35.3,

40.5/40.9 (CHCH2), 45.1/45.8, 48.4/49.0 (NCH), 53.0 (OCH3), 56.2/56.3 (CO2CH3), 61.0, 64.2/64.4

(OCH3), 108.9/109.1 (C), 126.4/126.6, 127.2/127.3, 127.5/127.6, 129.5/129.7, 129.9/130.0, 130.4/130.5

(CHAr), 131.7/131.8, 135.5/135.9, 139.9, 153.0, 153.5, 154.4 (CAr), 154.7 (C-OH), 186.9/187.0,

190.4/190.5 (C=O); MS (EI, 70 eV): m/z (%) = 439 ([M+], 80), 348 (100), 294 (25), 212 (7), 188 (61), 85

(8), 71 (12), 57 (22); HRMS (EI): Calcd. for C24H25O7N: 439.16255; found: 439.16281

Methyl 11-hydroxy-10-(2-pyridinylcarbonyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-

13-carboxylate (4w). Starting with 3w (0.300 g, 0.85 mmol) and TFA (0.195 g, 1.71 mmol), 4w was

isolated as a yellow oil (0.080g, 27%). 1H NMR (CDCl3, 250 MHz): δ = 2.49 (d, 2J = 17.9 Hz, 1H,

CHCH2), 2.78 − 2.85 (m, 1H, CHCH2), 3.01 – 3.16 (m, 1 H, CHCH2), 3.18 − 3.29 (m,1 H, CHCH2), 3.66

(s, 3 H, CO2CH3, isomer 1&2), 5.34 − 5.48 (m, 1 H, NCH), 5.81 – 6.05 (m, 1 H, NCH), 6.94 − 7.07 (m, 4

H, CHAr), 7.43 – 7.47 (m, 1 H, CHAr), 7.86 – 7.95 (m, 1 H, CHAr), 8.08 − 8.14 (s, 1 H, CHAr), 8.54 (m, 1

H, CHAr), 15.59 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC = 35.0, 40.9/41.4 (CHCH2), 45.8/46.3,

48.6/49.1 (NCH), 52.8 (CO2CH3), 111.1 (C), 124.7, 125.3, 126.2/126.5, 127.2/127.4, 129.6, 130.0, 133.0,

133.4 (CHAr), 136.3/136.4, 138.2, 138.6 (CAr), 154.4/154.8 (C-OH), 183.2, 192.2 (C=O); GC-MS (EI, 70

eV): m/z (%) = 350 ([M+], 34), 275 (4), 259 (100), 188 (66), 162 (7), 144 (9), 106 (11), 78 (28), 59 (4);

HRMS (EI): Calcd. for C20H18O4N2: 350.12611; found: 350.12604.

Methyl 11-hydroxy-10-(2-thienylcarbonyl)-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-

carboxylate (4x). Starting with 3x (0.120 g, 0.35 mmol) and TFA (0.045 g, 0.40 mmol), 4x was isolated

as a reddish viscous oil (0.041g, 34%). 1H NMR (CDCl3, 250 MHz): δ = 2.45− 2.47 (m, 1 H, CHCH2

isomer 1), 2.51 − 2.54 (m, 1 H, CHCH2 isomer 2), 2.76 (d, 2J= 15.0 Hz, 1 H, CHCH2 isomer 1), 2.83 (d,

2J= 15.0 Hz, 1 H, CHCH2 isomer 2), 3.01− 3.21 (m, 1 H, CHCH2 isomer 1&2), 3.32− 3.40 (m, 1 H,

CHCH2 isomer 1&2), 3.69 (s, 3 H, CO2CH3, isomer 1), 3.74 (s, 3 H, CO2CH3, isomer 2), 5.36 − 5.40 (m,

1 H, NCH isomer 1&2), 5.87 – 6.03 (m, 1 H, NCH isomer 1&2), 6.97 − 7.18 (m, 5 H, CHAr), 7.61 – 7.77

(m, 2 H, CHAr). 13C NMR (CDCl3, 62 MHz): δC = 34.8/35.4, 40.9/41.3 (CHCH2), 45.0/45.7, 48.2/48.7

(NCH), 53.0 (CO2CH3), 108.1 (C), 126.3/126.7, 127.3/127.6, 128.5, 129.7/130.0, 131.7/131.9, 133.0,

133.8 (CHAr), 135.4, 136.4, 140.3 (CAr), 154.6/155.1 (C-OH), 178.8/179.4, 187.2/188.1 (C=O); IR (neat):

v = 3097 (w), 2990 (w), 2948 (w), 2851 (w), 1690 (s), 1448 (s), 1249 (s), 1022 (s), 749 (s) cm–1; GC-MS

(EI, 70 eV): m/z (%) = 355 ([M+], 36), 337 (15), 264 (86), 188 (100), 180 (37), 170 (10), 144 (15), 111

(68), 97 (19), 83 (21), 69 (25), 57 (29); HRMS (EI): Calcd. for C19H17NO4S: 355.08728; found:

355.08729.

Methyl 10-(4-chlorobenzoyl)-11-hydroxy-6-nitro-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4y). Starting with 3y (0.399 g, 1.00 mmol) and TFA (0.229 g, 2.01 mmol), 4y

was isolated as a light yellow solid (0.300g, 75%). 1H NMR (CDCl3, 250 MHz): δ = 2.48 (d, 2J = 19.0 Hz,

1 H, CHCH2), 2.58 (d, 2J = 18.0 Hz, 1 H, CHCH2), 3.05 – 3.27 (m, 2 H, CHCH2), 3.67 (s, 3 H, CO2CH3,

isomer 1), 3.74 (s, 3 H, CO2CH3, isomer 2), 5.17 − 5.44 (m, 1 H, NCH), 5.54 – 5.81 (m, 1 H, NCH), 7.29

− 7.45 (m, 5 H, CHAr), 7.79 – 7.89 (m, 2 H, CHAr), 16.13 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC =

32.6/33.0, 40.4/40.8 (CHCH2), 44.3/45.0, 48.4/49.1 (NCH), 53.3/53.4 (CO2CH3), 108.9 (C), 124.3,

127.3/127.4, 128.2/128.3, 128.5, (CHAr), 129.3 (2CHAr), 130.2 (CHAr), 131.1/131.8, 134.4, 137.3, 138.8,

149.9 (CAr), 154.3 (C-OH), 185.9/186.5, 189.5/189.6 (C=O); IR (neat): v = 3082 (w), 3009 (w), 2954 (w),

2852 (w), 1699 (s), 1445 (s), 1221 (s), 1013 (s), 768 (s) cm–1; GCMS (EI, 70 eV): m/z (%) = 430 ([M++1],

37Cl, 1), 428 ([M++1], 35Cl, 3), 390 (100), 312 (35), 256 (30), 210 (10); HRMS (EI): Calcd. for

C21H17O6N2: ([M+], 35Cl), 428.07697; found: 428.07755.

Methyl 10-(4-fluorobenzoyl)-11-hydroxy-6-nitro-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4z). Starting with 3z (0.396 g, 1.04 mmol) and TFA (0.237 g, 2.08 mmol), 4z

was isolated as a colourless solid (0.220g, 55%). 1H NMR (CDCl3, 250 MHz): δ = 2.42 (d, 2J = 15.0 Hz,

1 H, CHCH2), 2.53 (d, 2J = 15.8 Hz, 1 H, CHCH2), 2.99 – 3.23 (m, 2 H, CHCH2), 3.62 (s, 3 H, CO2CH3,

isomer 1), 3.68 (s, 3 H, CO2CH3, isomer 2), 5.12 − 5.38 (m, 1 H, NCH), 5.49 – 5.74 (m, 1 H, NCH), 7.03

− 7.09 (m, 2 H, CHAr), 7.26 − 7.50 (m, 3 H, CHAr), 7.74 – 7.88 (m, 2 H, CHAr), 16.09 (m(br), 1 H, OH).

13C NMR (CDCl3, 62 MHz): δC = 32.6/33.0, 40.4/40.7 (CHCH2), 44.3/45.0, 48.4/49.1 (NCH), 53.2/53.4

(CO2CH3), 108.7/108.9 (C), 116.3 (d, 2J = 21.0 Hz, 2CHAr), 124.4/124.7, 127.2/127.3, 127.9/128.3

(CHAr), 129.2 (d, 3J = 8.4 Hz, CHAr), 129.5 (d, 3J = 10.0 Hz, CHAr), 131.5/131.7, 132.3, 138.3/138.8,

148.9/149.8 (CAr), 154.4 (C-OH), 162.1 (d, 1J = 241.8 Hz, CFAr), 185.6/186.4, 189.5/189.8 (C=O); IR

(neat): v = 3079 (w), 3002 (w), 2954 (w), 2815 (w), 1698 (s), 1444 (s), 1224 (s), 1032 (s), 784 (s) cm–1;

MS (EI, 70 eV): m/z (%) = 412 ([M+], 11), 382 (10), 364 (28), 276 (100), 233 (69), 203 (35), 180 (13),

123 (99), 95 (34); HRMS (EI): Calcd. for C21H18O6N2F: 412.10652; found: 412.10666.

Methyl 11-hydroxy-10-(2-methylbenzoyl)-6-nitro-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4aa). Starting with 3aa (0.410 g, 1.09 mmol) and TFA (0.248 g, 2.18 mmol),

4aa was isolated as a colourless solid (0.355g, 69%. 1H NMR (CDCl3, 250 MHz): δ = 2.18 (s, 3 H, CH3),

2.49 (d, 2J = 15.0 Hz, 1 H, CHCH2), 2.52 (d, 2J = 15.1, Hz, 1 H, CHCH2), 2.92 – 2.98 (m, 2 H, CHCH2),

3.70 (s, 3 H, CO2CH3, isomer 1&2), 5.13 − 5.32 (m, 1 H, NCH), 5.41 – 5.55 (m, 1 H, NCH), 7.11 − 7.34

(m, 6 H, CHAr), 7.75 − 7.79 (m, 1 H, CHAr), 16.17 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC =

18.8/19.0 (CH3), 32.0/32.4, 40.7/41.2 (CHCH2), 44.7/45.3, 48.6/49.3 (NCH), 53.2 (CO2CH3), 109.4/109.6

(C), 124.1 (CHAr), 125.9 (CAr), 126.2, 127.4, 128.3, 130.2, 131.1, 131.5/131.8 (CHAr), 134.2, 135.2,

138.8/138.9, 149.9/150.1 (CAr), 154.1/154.3 (C-OH), 186.7/187.3, 191.8/192.2 (C=O); HRMS (EI): Calcd.

for C22H20O6N2: 408.13159; found: 408.13276.

Methyl 10-(2-fluorobenzoyl)-11-hydroxy-6-nitro-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4ab). Starting with 3ab (0.210 g, 0.55 mmol) and TFA (0.125 g, 1.10 mmol),

4ab was isolated as a slightly yellow solid (0.180 g, 86%). 1H NMR (CDCl3, 250 MHz): δ = 2.50 (d, 2J=

15.8 Hz, 1 H, CHCH2), 2.60 (d, 2J= 15.8 Hz, 1 H, CHCH2), 3.05 – 3.20 (m, 2 H, CHCH2), 3.72 (s, 3 H,

CO2CH3, isomer 1&2), 5.30 − 5.43 (m, 1 H, NCH), 5.46 – 5.57 (m, 1 H, NCH), 7.15 − 7.34 (m, 5 H,

CHAr), 7.43 (m, 1 H, CHAr), 7.78 – 7.82 (m, 1 H, CHAr), 15.89 (s(br), 1 H, OH). 13C NMR (CDCl3, 62

MHz): δC = 32.2/32.8, 40.2/40.7 (CHCH2), 44.3/45.0, 48.2/49.0 (NCH), 53.2 (CO2CH3), 110.4 (C),

116.4/116.8, 124.3, 125.1, 127.3 (CHAr), 128.3 (CAr), 128.4 (d, 2J = 16.5 Hz, CHAr), 129.1 (CHAr), 131.6

(d, 4J = 2.3 Hz, CHAr), 132.5 (d, 3J = 8.2 Hz, CHAr) 139.0 (2CAr), 149.6 (CAr), 154.4 (C-OH), 185.5/185.8,

187.5 (C=O); MS (CI, 70 eV): m/z (%) = 413 ([M+1], 23), 393 (24), 363 (15), 233 (100), 203 (15);

HRMS (CI): Calcd. for C21H19O6N2F: 413.10652; found: 413.10666.

Methyl 10-(2-chlorobenzoyl)-11-hydroxy-6-nitro-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-

pentaene-13-carboxylate (4ac). Starting with 3ac (0.416 g, 1.05 mmol) and TFA (0.239 g, 2.09 mmol),

4ac was isolated as a light yellow solid (0.205 g, 60%). 1H NMR (CDCl3, 250 MHz): δ = 2.45 (d, 2J =

16.7 Hz. 1 H, CHCH2), 2.66 (d, 2J = 14.6 Hz, 1 H, CHCH2), 2.94− 3.10 (m, 2 H, CHCH2), 3.64 (s, 3 H,

CO2CH3, isomer 1&2), 5.09 – 5.24 (m, 1 H, NCH), 5.37 – 5.50 (m, 1 H, NCH), 7.14 (m, 1 H, CHAr), 7.27

– 7.42 (m, 5 H, CHAr), 7.72 – 7.76 (m, 1 H, CHAr), 15.78 (s, 1 H, OH). 13C NMR (CDCl3, 62 MHz): δC =

31.9/32.5, 40.2/40.7 (CHCH2), 44.6/45.2, 48.4/49.1 (NCH), 53.2 (CO2CH3), 109.6 (C), 124.2, 127.4,

127.7, 127.9, 128.3, 130.5, 131.3 (CHAr), 131.7, 133.1, 135.1, 139.0, 149.9 (CAr), 154.3 (C-OH), 185.8,

189.8 (C=O); IR (neat): v = 3011 (w), 1990 (w), 2956 (w), 2849 (w), 1698 (s), 1443 (s), 1219 (s), 1029

(s), 731 (s) cm–1; GC-MS (CI, 70 eV): m/z (%) = 431 ([M++1], 37Cl, 3), 429 ([M++1], 35Cl, 10), 391 (100),

313 (30), 257 (35), 211 (20); HRMS (EI): Calcd. for C21H17O6N2: ([M+], 35Cl), 428.07697; found:

428.07755.

Methyl 11-hydroxy-10-(2-naphthoyl)-6-nitro-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-

13-carboxylate (4ad). Starting with 3ad (0.443 g, 1.00 mmol) and TFA (0.228 g, 2.00 mmol), 4ad was

isolated as a yellowish solid (0.280 g, 63%). 1H NMR (CDCl3, 250 MHz): δ = 2.49 (d, 2J = 17.5 Hz, 1 H,

CHCH2), 2.61 (d, 2J = 19.0 Hz, 1 H, CHCH2), 3.02 – 3.11 (m, 2 H, CHCH2), 3.73 (s, 3 H, CO2CH3,

isomer 1&2), 5.41− 5.56 (m, 1 H, NCH), 5.70 – 5.91 (m, 1 H, NCH), 7.18 (m, 1 H, CHAr), 7.21 – 7.36 (m,

2 H, CHAr), 7.46 – 7.53 (m, 3 H, CHAr), 7.75 − 8.03 (m, 4 H, CHAr), 16.22 (s, 1 H, OH). 13C NMR

(CDCl3, 62 MHz): δC = 34.8/35.2, 41.1/41.6 (CHCH2), 45.7/46.2, 48.5/49.1 (NCH), 52.9/53.4 (CO2CH3),

110.9 (C), 124.5/124.6, 124.7, 125.1, 126.4 (CHAr), 126.9 (2CHAr), 127.1/127.3, 127.5/127.6, 128.5,

129.5, 129.8 (CHAr), 130.2, 131.1, 131.7, 133.3/133.6, 135.9/136.0 (CAr), 154.5 (C-OH), 188.6,

190.1/190.5 (C=O); IR (neat): v = 3033 (w), 3014 (w), 2958 (w), 2852 (w), 1702 (s), 1528 (s), 1340 (s),

1029 (s), 771 (s) cm–1; GC-MS (EI, 70 eV): m/z (%) = 444 ([M+], 10), 425 (16), 385 (10), 308 (90), 257

(13), 233 (37), 180 (40), 155 (100), 143 (29), 125 (43), 59 (11); HRMS (EI): Calcd. for C25H20O6N2:

444.13159; found: 444.13172.

11-Hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene-10,13-dicarboxylic acid 13-benzyl

ester 10-methyl ester (6a). Starting with 5a (0.997 g, 2.63 mmol) and TFA (0.600 g, 5.26 mmol), 6a was

isolated as a colourless solid (0.340 g, 34%, mp. = 54–56 °C). 1H NMR (250 MHz, CDCl3): δ = 2.35 (dd,

2J = 17.9 Hz, 3J = 7.1 Hz, 1H, NCHCH2), 2.78–3.32 (m, 3H, NCHCH2), 3.81 (s, 3H, CO2CH3), 5.07–5.26

(m, 2H, CO2CH2), 5.29–5.51 (m, 2H, NCH), 7.06–7.21 (m, 4H, Ar), 7.31–7.37 (m, 5H, Ar), 12.05 (s, 1H,

OH). 13C NMR (75 MHz, CDCl3): δ = 33.6/34.0, 37.1/37.5 (NCHCH2), 44.6/45.2, 48.7/49.3 (NCH), 51.7

(CO2CH3), 67.3/67.5 (CO2CH2), 99.6/100.1 (C), 126.3/126.4, 126.6, 127.4/127.5, 127.9, 128.1/128.2,

128.5, 129.6/129.9 (Ar–CH), 132.2/132.6, 136.1/136.3, 136.5, 153.8/153.9, 170.0, 170.7/170.9 (C). IR

(ATR, cm-1): v = 2951 (w), 1697 (s), 1655 (s), 1614 (m), 1496 (w), 1424 (s), 1321 (s), 1295 (s), 1257 (s),

1217 (s), 1201 (s), 1113 (s), 1096 (s), 1063 (s), 1014 (s), 976 (m), 811 (m), 758 (s), 734 (s), 693 (s), 670

(s), 624 (m), 611 (m), 591 (m), 572 (m). MS (EI): m/z (%) = 379 (M+, 26), 288 (33), 244 (49), 212 (39),

91 (100). HRMS (EI): calcd for C22H21NO5 (M+): 379.14142; found: 379.14077.

11-Hydroxy-6-nitro-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-10,13-dicarboxylic acid

13-benzyl ester 10-methyl ester (6b). Starting with 5b (2.002 g, 4.7 mmol) and TFA (1.072 g, 9.40

mmol), 6b was isolated as a white solid (0.859 g, 43%, mp. = 171–172 °C). 1H NMR (250 MHz, CDCl3):

δ = 2.34 (dd, 2J = 17.8 Hz, 3J = 7.9 Hz, 1H, NCHCH2), 2.94–3.12 (m, 2H, NCHCH2), 3.40–3.55 (m, 1H,

NCHCH2), 3.80 (s, 3H, CO2CH3), 5.09–5.26 (m, 2H, CO2CH2), 5.34–5.59 (m, 2H, NCH), 7.35–7.38 (m,

7H, Ar), 7.85–7.89 (dd, 3J = 7.0 Hz, 4J = 2.5 Hz, 1H, Ar), 12.09 (s, 1H, OH). 13C NMR (75 MHz,

CDCl3): δ = 31.6/32.0, 36.8/37.2 (NCHCH2), 43.7/44.3, 48.7/49.4 (NCH), 52.0 (CO2CH3), 67.7/67.8

(CO2CH2), 99.5/99.9 (C), 124.2, 127.0, 128.0/128.2, 128.4/128.6, 128.9, 131.4/131.8 (Ar–CH),

136.0/136.1, 139.1/139.3, 149.9/150.1, 153.5/153.7, 169.2, 170.1, 170.4/170.5 (C). IR (ATR, cm-1): v =

2956 (w), 1689 (s), 1659 (s), 1614 (m), 1524 (s), 1431 (s), 1415 (s), 1356 (s), 1323 (s), 1304 (s), 1290 (s),

1264 (m), 1217 (s), 1111 (s), 1066 (m), 1024 (s), 1001 (m), 971 (m), 953 (m), 911 (m), 862 (m), 822 (m),

808 (m), 770 (m), 749 (s), 730 (s), 694 (s), 676 (s). MS (EI): m/z (%) = 424 (M+, 9), 288 (8), 257 (11),

244 (25), 91 (100). Anal. Calcd for C22H20N2O7 (424.40): C, 62.26; H, 4.75; N, 6.60. Found: C, 61.96; H,

4.68; N, 6.53.

10-Acetyl-6-bromo-11-hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-13-carboxylic

acid benzyl ester (6c). Starting with 5c (0.885 g, 2.00 mmol) and TFA (0.456 g, 4.00 mmol), 6c was

isolated as a white solid (0.845 g, 95%, mp. = 51–53 °C). 1H NMR (250 MHz, CDCl3): δ = 2.26 (s, 3H,

CH3, isomer 1), 2.31 (s, 3H, CH3, isomer 2), 2.42 (dd, 2J = 18.1 Hz, 3J = 5.5 Hz, 1H, NCHCH2), 2.83 (s,

1H, NCHCH2, isomer 1), 2.89 (s, 1H, NCHCH2, isomer 2), 2.96–3.23 (m, 2H, NCHCH2), 5.09–5.29 (m,

2H, CO2CH2), 5.40–5.54 (m, 2H, NCH), 7.06–7.10 (m, 2H, Ar), 7.35 (br s, 5H, Ar), 7.44–7.48 (m, 1H,

Ar) 16.11 (s, 1H, OH, isomer 1), 16.13 (s, 1H, OH, isomer 2). 13C NMR (75 MHz, CDCl3): δ = 23.9

(CH3), 35.9/36.3, 39.5/39.9 (NCHCH2), 45.5/46.2, 48.6/49.1 (NCH), 67.8 (CO2CH2), 109.4/109.5 (C),

125.6/125.9 (Ar–CH), 126.0/126.2 (C), 127.9/128.0, 128.1, 128.3, 128.6 (Ar–CH), 131.2/131.6 (C),

131,7/131.8 (Ar–CH), 136.0/136.1, 138.6/138.8, 153.7, 182.2/182.9, 194.3/194.8 (C). IR (ATR, cm-1): v

= 2945 (w), 1694 (s), 1586 (m), 1567 (m), 1497 (m), 1409 (s), 1379 (m), 1336 (s), 1299 (s), 1247 (s),

1207 (s), 1175 (m), 1126 (m), 1096 (s), 1017 (s), 973 (s), 912 (m), 875 (m), 826 (m), 794 (m), 757 (s),

737 (s), 695 (s), 686 (s), 630 (m), 611 (m), 590 (m), 573 (m). MS (EI): m/z (%) = 443 (M+, 81Br, 22), 441

(M+, 79Br, 22) 308 (18), 306 (19), 272 (38), 228 (69), 91 (100). Anal. Calcd for C22H20BrNO4 (442.30): C,

59.74; H, 4.56; N, 3.17. Found: C, 59.43; H, 4.60; N, 2.95.

11-Hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-10,13-dicarboxylic acid 13-benzyl

ester 10-(2-methoxy-ethyl) ester (6d). Starting with 5d (1.523 g, 3.60 mmol) and TFA (0.820 g, 7.20

mmol), 6d was isolated as a colourless viscous oil (0.503 g, 33%). 1H NMR (250 MHz, CDCl3): δ = 2.35

(dd, 2J = 17.8 Hz, 3J = 6.2 Hz, 1H, NCHCH2), 2.83–3.09 (m, 2H, NCHCH2), 3.18–3.32 (m, 1H,

NCHCH2), 3.38 (s, 3H, OCH3, isomer 1), 3.42 (s, 3H, OCH3, isomer 2), 3.62–3.67 (m, 2H, CO2CH2CH2),

4.25–4.44 (m, 2H, CO2CH2CH2), 5.07–5.24 (m, 2H, CO2CH2Ar), 5.34–5.51 (m, 2H, NCH), 7.06–7.20 (m,

4H, Ar), 7.35 (br s, 5H, Ar), 12.00 (s, 1H, OH, isomer 1), 12.02 (s, 1H, OH, isomer 2). 13C NMR (75

MHz, CDCl3): δ = 33.5/33.9, 37.1/37.5 (NCHCH2), 44.7/45.2, 48.7/49.2 (NCH), 59.0 (OCH3), 63.5,

67.3/67.4, 70.2/70.3 (CH2) 99.7/99.9 (C), 126.3/126.3, 126.6, 127.3/127.5, 127.8, 128.0/128.1,

128.5/128.5, 129.6/129.9 (Ar–CH), 132.2/132.7, 136.1/136.3 136.3/136.5, 153.7/153.8, 170.0/170.2,

171.0 (C). IR (ATR, cm-1): v = 2896 (w), 1697 (s), 1653 (s), 1614 (m), 1496 (w), 1417 (s), 1321 (s), 1294

(s), 1256 (s), 1216 (s), 1198 (s), 1114 (s), 1096 (s), 1062 (s), 1014 (s), 979 (m), 910 (m), 818 (m), 758 (s),

736 (s), 693 (s), 671 (m). MS (EI): m/z (%) = 423 (M+, 63), 332 (88), 288 (100), 212 (97), 91 (82). Anal.

Calcd for C24H25NO6 (423.17): C, 68.07; H, 5.95; N, 3.31. Found: C, 67.82; H, 6.07; N, 3.12.

Benzyl 10-acetyl-11-hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,8,10-pentaene-13-carboxylate

(6e). Starting with 5e (0.600 g, 1.65 mmol) and TFA (0.376 g, 3.30 mmol), 6e was isolated as a

colourless viscous oil (0.505 g, 84%). 1H NMR (250 MHz, CDCl3): δ = 2.22, 2.27 (s, 3H, CH3, Rotamer),

2.46 (dd, 2J = 18.0 Hz, 3J = 5.2 Hz, 1H, NCHCH2), 2.75 (d, 2J = 16.4 Hz, 1H, NCHCH2), 3.00, 3.08 (dd,

2J = 18.0 Hz, 3J = 6.1 Hz, 1H, NCHCH2, Rotamer), 3.37 (m, 1H, NCHCH2), 5.18 (m, 2H, OCH2), 5.39 (d,

3J = 5.2 Hz, 1H, NCH, Rotamer), 5.43 (d, 3J = 6.1 Hz, 1H, NCH, Rotamer), 5.48 – 5.54 (m, 2H, NCH,

Rotamer), 7.07 – 7.09 (m, 2H, Ar), 7.18 – 7.21 (m, 2H, Ar), 7.35 (m, 5H, Ar), 16.15, 16.17 (s, 1H, OH,

Rotamer). 13C NMR (62.9 MHz, CDCl3): δ = 23.7 (CH3), 34.5, 35.0, 39.8, 40.2 (NCHCH2, Rotamer),

45.6, 46.3, 48.6, 49.1 (NCH, Rotamer), 67.5, 67.6 (OCH2, Rotamer), 109.3, 109.4 (CCO, Rotamer), 126.4,

126.7, 126.8, 127.5, 127.6, 127.8, 128.1, 128.2, 128.6, 129.7, 129.9 (CHAr, Rotamer), 130.9, 131.4, 136.0,

136.2, 136.3 (CAr, Rotamer), 153.9 (NCOO), 182.9, 183.6 (COH, Rotamer), 194.0, 194.4 (COCH3,

Rotamer).IR (ATR, cm-1): v = 3063 (w), 3030 (w), 2943 (w), 2930 (w), 2897 (w), 2848 (w), 2837 (w),

1694 (s), 1585 (m), 1496 (w), 1453 (m), 1421 (m), 1379 (m), 1364 (m), 1324 (m), 1301 (s), 1255 (m),

1232 (m), 1203 (m), 1114 (m), 1093 (m), 1012 (m), 974 (m), 912 (m), 878 (m), 787 (w), 743 (s), 696 (s),

682 (s), 621 (m), 610 (m), 570 (m), 543 (m). MS (EI, 70 eV): m/z (%) = 363 (M+, 13), 345 (3), 318 (3),

272 (7), 228 (30), 210 (13), 186 (3), 168 (4), 130 (4), 115 (5), 91 (100), 77 (2), 65 (7), 43 (8). HRMS

(EI): Calcd. for (C22H21NO4 (M+) 363.14651, found 363.146091.

General procedure for the synthesis of 7a-e: To a stirred methanol suspension (25 mL) of Pd/C (0.1

equiv.) was added 6a-e (1.0 equiv.). The reaction mixture was set under hydrogen atmosphere and stirred

for 24 h at 20 °C. The reaction mixture was filtered (celite) and the filtrate was concentrated in vacuo.

The residue was purified by chromatography (silica gel, heptanes → heptanes/EtOAc = 0:1).

11-Hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-10-carboxylic acid methyl ester

(7a). Starting with 6a (0.275 g, 0.72 mmol), 7a was isolated as a pale yellow solid (0.150 g, 85%), mp. =

134–135 °C. 1H NMR (250 MHz, CDCl3): δ = 2.31 (dd, 2J = 17.9 Hz, 3J = 1.1 Hz, 1H, NCHCH2), 2.80 (d,

2J = 16.8 Hz, 1H, NCHCH2), 2.92 (dd, 2J = 17.9 Hz, 3J = 6.1 Hz, 1H, NCHCH2), 3.16 (dd, 2J = 16.8 Hz,

3J = 5.6 Hz, 1H, NCHCH2), 3.79 (s, 3H, CO2CH3), 4.27 (d, 3J = 5.5 Hz, 1H, NCH), 4.37 (d, 3J = 6.0 Hz,

1H, NCH), 7.02–7.18 (m, 4H, Ar), 11.89 (br s, 1H, OH). 13C NMR (75 MHz, CDCl3): δ = 34.7, 38.2

(NCHCH2), 45.2, 49.8 (NCH), 51.5 (CO2CH3), 101.2 (C), 126.1, 126.7, 127.0, 129.8 (Ar–CH), 132.8,

138.3, 170.4, 171.2 (C). IR (ATR, cm-1): v = 3314 (w), 3214 (w), 2925 (w), 1651 (s), 1609 (s), 1442 (s),

1417 (m), 1377 (m), 1347 (m), 1327 (m), 1291 (s), 1264 (s), 1244 (m), 1215 (s), 1197 (s), 1074 (s), 986

(m), 849 (m), 834 (s), 815 (s), 792 (m), 775 (s), 758 (s), 738 (s), 675 (m), 635 (m), 588 (m). MS (EI): m/z

(%) = 245 (M+, 19), 154 (97), 129 (91), 57 (100), 43 (91). HRMS (EI): calcd for C14H15NO3 (M+):

245.10464, found 245.10539. Anal. Calcd for C14H15NO3 (245.27): C 68.56, H 6.61, N 5.71; found: C

68.48, H 6.12, N 5.38.

6-Amino-11-hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-10-carboxylic acid

methyl ester (7b). Starting with 6b (0.795 g, 1.87 mmol), 7b was isolated as a brownish solid (0.502 g,

97%), mp. = 129–130 °C. 1H NMR (250 MHz, CDCl3): δ = 2.34 (dd, 2J = 18.0 Hz, 3J = 1.0 Hz, 1H,

NCHCH2), 2.50 (d, 2J = 16.3 Hz, 1H, NCHCH2), 2.75 (dd, 2J = 16.3 Hz, 3J = 5.8 Hz, 1H, NCHCH2), 2.91

(dd, 2J = 18.0 Hz, 3J = 6.3 Hz, 1H, NCHCH2), 3.53 (br s, 2H, NH2), 3.78 (s, 3H, CO2CH3), 4.32 (d, 3J =

6.1 Hz, 1H, NCH), 4.37 (d, 3J = 5.6 Hz, 1H, NCH), 6.54 (d, 3J = 7.5 Hz, 1H, Ar), 6.55 (d, 3J = 7.9 Hz, 1H,

Ar), 6.99 (t, 3J = 7.7 Hz, 1H, Ar), 11.99 (br s, 1H, OH). 13C NMR (63 MHz, CDCl3): δ = 30.0, 37.9

(NCHCH2), 44.9, 49.8 (NCH), 51.5 (CO2CH3), 101.4 (C), 113.3, 117.1, (Ar–CH), 117.5 (C), 126.5 (Ar–

CH), 139.2, 144.7, 170.7, 171.2 (C). IR (ATR, cm-1): v = 2913 (w), 1651 (s), 1609 (s), 1587 (s), 1465 (m),

1435 (m), 1415 (m), 1348 (m), 1292 (s), 1220 (s), 1194 (s), 1075 (s), 1044 (m), 994 (m), 961 (m), 942

(m), 885 (m), 819 (m), 782 (s), 763 (s), 727 (s), 651 (s), 635 (m), 579 (m). MS (CI): m/z (%) = 261

([M+1]+, 100), 229 (7), 177 (10), 145 (24), 117 (16). HRMS (CI): calcd for C14H16N2O3 (M+): 260.11554,

found 260.11559.

1-(11-Hydroxy-13-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraen-10-yl)-1-ethanone (7c). Starting with

6c (0.758 g, 1.72 mmol), 7c was isolated as a slightly brownish solid (0.508 g, 96%), mp. = 192–193 °C.

1H NMR (300 MHz, CDCl3): δ = 2.27 (s, 3H, CH3), 2.57 (d, 2J = 18.3 Hz, 1H, NCHCH2), 2.87 (d, 2J =

16.9 Hz, 1H, NCHCH2), 3.67 (d, 2J = 16.4 Hz, 1H, NCHCH2), 3.92 (d, 2J = 15.4 Hz, 1H, NCHCH2), 4.97

(br s, 2H, NCH), 7.13–7.30 (m, 4H, Ar), 10.05–10.15 (br d, 1H, NCH), 16.05 (s, 1H, OH). 13C NMR (75

MHz, DMSO): δ = 27.1 (CH3), 31.8, 37.6 (NCHCH2), 45.1, 47.6 (NCH), 107.3 (C), 127.1, 127.2, 128.5,

129.6 (Ar–CH), 129.9, 132.8, 174.0, 196.3 (C). IR (ATR, cm-1): v = 2908 (m), 2720 (m), 2676 (m), 2642

(m), 2617 (m), 2576 (m), 2480 (m), 1574 (s), 1495 (m), 1446 (s), 1430 (m), 1402 (s), 1363 (s), 1341 (s),

1260 (m), 1219 (m), 1204 (m), 1173 (m), 1016 (m), 969 (s), 923 (m), 863 (w), 789 (m), 767 (s), 741 (s),

648 (m), 530 (m). MS (CI): m/z (%) = 230 ([M+1]+, 100), 130 (52), 101 (30). HRMS (ESI): calcd for

C14H16N2O3 ([M+1]+): 230.11756, found 230.11714

11-Hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-10-carboxylic acid 2-

methoxyethyl ester (7d). Starting with 6d (0.330g, 0.78 mmol), 7d was isolated as a brownish solid

(0.208 g, 72%, mp. = 56–58 °C). 1H NMR (250 MHz, CDCl3): δ = 2.30 (dd, 2J = 17.9 Hz, 3J = 0.7 Hz, 1H,

NCHCH2), 2.83 (d, 2J = 17.2 Hz, 1H, NCHCH2), 2.91 (dd, 2J = 17.9 Hz, 3J = 6.1 Hz, 1H, NCHCH2), 3.16

(dd, 2J = 16.9 Hz, 3J = 5.5 Hz, 1H, NCHCH2), 3.41 (s, 3H, OCH3), 3.64 (t, 3J = 4.7 Hz, 2H, CO2CH2CH2),

4.30–4.37 (m, 2H, NCH), 4.34 (t, 3J = 4.7 Hz, 2H, CO2CH2CH2), 7.02–7.18 (m, 4H, Ar), 11.94 (br s, 1H,

OH). 13C NMR (75 MHz, CDCl3): δ = 34.6, 38.2 (NCHCH2), 45.2, 49.7 (NCH), 58.9 (COCH3), 63.2

(CO2CH2CH2), 70.4 (CO2CH2CH2), 101.3 (C), 125.9, 126.6, 126.9, 129.8 (Ar–CH), 132.9, 138.3, 170.6,

170.7 (C). IR (ATR, cm-1): v = 3189 (w), 2928 (m), 2895 (m), 2878 (m), 1645 (s), 1615 (s), 1492 (w),

1452 (m), 1413 (m), 1384 (m), 1366 (m), 1350 (m), 1328 (m), 1292 (s), 1262 (s), 1237 (m), 1217 (s),

1197 (s), 1123 (s), 1074 (s), 1038 (s), 999 (m), 972 (m), 956 (m), 945 (m), 858 (m), 829 (s), 806 (s), 781

(s), 759 (s), 735 (s), 682 (m), 676 (m), 639 (m), 586 (m), 561 (m). MS (EI): m/z (%) = 289 ([M+1]+, 13),

198 (66), 130 (49), 129 (100), 128 (26), 102 (36), 58 (33), 45 (48). Anal. Calcd for C16H19NO4 (289.33):

C 66.42, H 6.62, N 4.84; found: C 66.37, H 6.67, N 5.51.

1-(11-Hydroxy-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraen-10-yl)-ethanone (7e). Starting

with 6e (0.758 g, 1.72 mmol), 7e was isolated as a slightly brownish solid (0.508 g, 96%, mp. = 192–

193 °C). 1H NMR (300 MHz, CDCl3): δ = 2.27 (s, 3H, CH3), 2.57 (d, 2J = 18.3 Hz, 1H, NCHCH2), 2.87

(d, 2J = 16.9 Hz, 1H, NCHCH2), 3.67 (d, 2J = 16.4 Hz, 1H, NCHCH2), 3.92 (d, 2J = 15.4 Hz, 1H,

NCHCH2), 4.97 (br s, 2H, NCH), 7.13–7.30 (m, 4H, Ar), 10.05–10.15 (br d, 1H, NCH), 16.05 (s, 1H,

OH). 13C NMR (75 MHz, DMSO): δ = 27.1 (CH3), 31.8, 37.6 (NCHCH2), 45.1, 47.6 (NCH), 107.3 (C),

127.1, 127.2, 128.5, 129.6 (Ar–CH), 129.9, 132.8, 174.0, 196.3 (C). IR (ATR, cm-1): v = 2908 (m), 2720

(m), 2676 (m), 2642 (m), 2617 (m), 2576 (m), 2480 (m), 1574 (s), 1495 (m), 1446 (s), 1430 (m), 1402 (s),

1363 (s), 1341 (s), 1260 (m), 1219 (m), 1204 (m), 1173 (m), 1016 (m), 969 (s), 923 (m), 863 (w), 789 (m),

767 (s), 741 (s), 648 (m), 530 (m). MS (CI): m/z (%) = 230 ([M+1]+, 100), 130 (52), 101 (30). HRMS

(ESI): calcd for C14H16N2O3 ([M+1]+): 230.11756, found 230.11714

General procedure for the decarboxylation of 4a,h,k. To a solution of 9 (1.40 mmol) in wet DMSO

(13 mL, 2% of water) was added LiCl (2.94 mmol) and the solution was stirred for 8 h at 130 °C. After

cooling to 20 °C, CH2Cl2 (30 mL) was added and the mixture was washed with water (1 x 20 mL) and

brine (1 x 20 mL). The combined aqueous layers were extracted with CH2Cl2 (3 x 50 mL). The combined

organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was

purified by chromatography (silica gel, heptanes → heptanes/EtOAc = 2:1).

11-Oxo-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-13-carboxylic acid methyl ester (8a).

Starting with 6a (0.418 g, 1.40 mmol) and LiCl (0.125 g, 2.94 mmol) in DMSO (13 mL, 2% water), 8a

was isolated as a colourless solid (0.159 g, 46%); mp. = 127–130 °C. 1H NMR (250 MHz, CDCl3):

δ = 2.37 (m, 1H, COCH2), 2.49 (m, 1H, COCH2), 2.68 – 2.91 (m, 3H, COCH2, NCHCH2CAr), 3.36 (br dd,

2J = 17.7 Hz, 3J = 6.1 Hz, 1H, NCHCH2CAr), 3.80 (s, 3H, OCH3), 5.07 (br m, 3J = 6.1 Hz, 1H,

NCHCH2CAr, Rotamers), 5.20 (br m, 1H, NCHCH2CAr, Rotamers), 5.58 (br m, 1H, COCH2CHCAr,

Rotamers), 5.70 (br m, 1H, COCH2CHCAr, Rotamers), 7.03 – 7.07 (br m, 2H, Ar), 7.15 – 7.19 (m, 2H,

Ar). 13C NMR (75.5 MHz, CDCl3): δ = 33.6, 33.9 (CH2, Rotamers), 46.7, 46.9 (CH2, Rotamers), 47.1,

47.6 (NCH, Rotamers), 48.9, 49.2 (CH2, Rotamers), 51.6, 51.9 (NCH, Rotamers), 53.1 (OCH3), 126.2,

126.5, 127.0, 127.8, 129.3, 129.6 (CHAr, Rotamers), 130.4, 130.8, 135.2, 135.4 (CAr, Rotamers), 154.9

(NCOO), 206.9 (CO). IR (KBr, cm-1): v = 3048 (w), 3005 (w), 2956 (w), 2933 (w), 2908 (w), 2852 (w),

1712 (s), 1693 (s), 1493 (w), 1455 (s), 1412 (s), 1347 (m), 1326 (m), 1279 (m), 1220 (m), 1208 (m), 1119

(m), 1045 (m), 989 (w), 763 (m), 682 (w). MS (EI, 70 eV): m/z (%) = 245 (M+, 20), 202 (4), 188 (100),

144 (31), 128 (12), 115 (13), 91 (4), 77 (3), 59 (4). Anal. Calcd. for C14H15NO3 (245.27): C, 68.56; H,

6.16; N, 5.71. Gefunden: C, 68.23; H, 6.35; N, 5.39.

6-Nitro-11-oxo-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-13-carboxylic acid methyl ester (8b).

Starting with 4h (0.313 g, 0.86 mmol) and LiCl (0.076 g, 1.80 mmol) in DMSO (8 mL, 2% water), 8b

was isolated as a colourless solid (0.137 g, 44%); mp. = 104–106 °C. 1H NMR (250 MHz, CDCl3):

δ = 2.38 (m, 1H, COCH2), 2.50 (m, 1H, COCH2), 2.73 – 2.94 (m, 2H, COCH2), 3.06 (dd, 2J = 18.6 Hz,

3J = 0.9 Hz, 1H, NCHCH2CAr), 3.60 (dd, 2J = 18.6 Hz, 3J = 7.0 Hz, 1H, NCHCH2CAr), 3.83 (s, 3H,

OCH3), 5.15 (br m, 1H, NCH, Rotamers), 5.27 (br m, 1H, NCH, Rotamers), 5.69 (br m, 1H, NCH,

Rotamers), 5.81 (br m, 1H, NCH, Rotamers), 7.36 – 7.42 (m, 2H, Ar), 7.91 (m, 1H, Ar). 13C NMR

(75.5 MHz, CDCl3): δ = 31.4, 31.7 (CH2, Rotamers), 46.3, 46.6 (CH2, Rotamers), 46.8 (NCH), 48.6, 48.9

(CH2, Rotamers), 51.6, 52.0 (NCH, Rotamers), 53.4 (OCH3), 124.6, 127.7, 131.6, 131.9 (CHAr,

Rotamers), 126.9, 127.2, 138.3(br), 149.2 (br) (CAr, Rotamers), 154.7 (br, NCOO), 205.9 (CO). IR (KBr,

cm-1): v = 3076 (w), 3050 (w), 2998 (w), 2957 (w), 2924 (w), 2856 (w), 1697 (s), 1611 (w), 1576 (w),

1525 (s), 1446 (s), 1410 (m), 1359 (s), 1331 (m), 1273 (m), 1229 (m), 1204 (m), 1106 (m), 1056 (m),

1033 (m), 997 (w), 946 (w), 891 (w), 824 (w), 804 (w), 769 (m), 738 (w), 714 (w). MS (EI, 70 eV): m/z

(%) = 290 (M+, 12), 233 (100), 187 (3), 158 (8), 143 (25), 115 (12), 89 (4), 77 (4), 59 (8). Anal. Calcd. for

C14H14N2O5 (290.27): C, 57.93; H, 4.86; N, 9.65. Found: C, 58.05; H, 4.99; N, 9.45.

6-Brom-11-oxo-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-13-carboxylic acid methyl ester (8c).

Starting with 4k (0.243 g, 0.61 mmol) and LiCl (0.054 g, 1.28 mmol) in DMSO (6 mL, 2% water), 8c

was isolated as a colourless solid (0.123 g, 62%); mp. = 132–133 °C. 1H NMR (250 MHz, CDCl3):

δ = 2.39 (m, 1H, COCH2), 2.49 (m, 1H, COCH2), 2.71 – 2.89 (m, 2H, COCH2), 2.79 (d, 2J = 18.0 Hz, 1H,

NCHCH2CAr), 3.15 (br dd, 2J = 18.0 Hz, 3J = 7.0 Hz, 1H, NCHCH2CAr), 3.80 (s, 3H, OCH3), 5.12 (br m,

1H, NCH, Rotamers), 5.25 (br m, 1H, NCH, Rotamers), 5.57 (br m, 1H, NCH, Rotamers), 5.69 (br m, 1H,

NCH, Rotamers), 7.04 – 7.10 (m, 2H, Ar), 7.44 (m, 1H, Ar). 13C NMR (75.5 MHz, CDCl3): δ = 34.8,

35.2 (CH2, Rotamers), 46.9, 47.0 (CH2, Rotamers), 47.1, 47.6 (NCH, Rotamers), 48.6, 48.9 (CH2,

Rotamers), 51.6, 51.9 (NCH, Rotamers), 53.2 (OCH3), 125.4, 125.7, 128.2, 131.9 (CHAr, Rotamers),

130.7, 131.1, 137.7 (br) (CAr), 154.7 (NCOO), 206.4 (CO). IR (KBr, cm-1): v = 3000 (w), 2954 (w), 2924

(w), 1699 (s), 1567 (w), 1450 (s), 1415 (s), 1326 (m), 1267 (w), 1134 (w), 1105 (m), 1051 (m), 1032 (m),

975 (w), 790 (w), 763 (m), 717 (w), 652 (w), 484 (w). MS (EI, 70 eV): m/z (%) = 325 (M+, 81Br, 30), 323

(M+, 79Br, 31), 268 (81Br, 95), 266 (79Br, 100), 224 (81Br, 21), 222 (79Br, 23), 208 (9), 143 (25), 116 (18),

115 (41), 89 (7), 59 (15). HRMS (EI): calcd. for C14H14BrNO3 (M+, 79Br) 323.01516, found 323.01433.

Synthesis of 9 and of 10a-c. To a CH2Cl2 solution of 4d (2.80 mmol) was added pyridine (5.60 mmol) at

−78 °C. To the solution was dropwise added trifluoromethanesulfonic acid anhydride (3.36 mmol) at

−78 °C. The solution was allowed to warm to 20 °C during 4 h with stirring. The solvent was removed in

vacuo and the residue was purified by chromatography (silica gel, heptanes → heptanes / EtOAc = 2:1) to

give 9. The product was dried in vacuo and directly used for the synthesis of 10a-c. To a 1,4-dioxane

solution (2.5 mL) of 9 (1.00 mmol) were added the boronic acid (1.30 mmol), potassium phosphate

(1.60 mmol) and tetrakis(triphenylphosphane)-palladium(0) (0.03 mmol) at 20 °C. The solution was

stirred under reflux for 20 h. After cooling to 20 °C, an aqueous solution of ammonium chloride was

added (3 mL) and to the mixture was added CH2Cl2 (15 mL). The organic and the aqueous layer were

separated and the latter was extracted with CH2Cl2 (20 mL). The combined organic layers were dried

(Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by

chromatography (silica gel, heptane → heptane-EtOAc = 2:1).

10-Acetyl-11-phenyl-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-13-carboxylic acid methyl

ester (10a). Starting with 4d (0.804 g, 2.80 mmol), pyridine (0.443 g, 5.6 mmol) and

trifluoromethanesulfonic anhydride (0.948 g, 3.36 mmol) in CH2Cl2 (28 mL), 9 was isolated as a slightly

yellow oil (0.906 g, 77%). Starting with 9 (0.419 g, 1.00 mmol), phenylboronic acid (0.159 g, 1.30 mmol),

potassium phosphate (0.340 g, 1.60 mmol) and tetrakis(triphenylphosphane)-palladium(0) (0.035 g,

0.03 mmol) in 1,4-dioxane (2.5 mL), 10a was isolated as a colourless solid (0.197 g, 57%); mp. = 97–

98 °C. 1H NMR (250 MHz, CDCl3): δ = 1.55, 1.56 (s, 3H, COCH3, Rotamers), 2.21, 2.24 (s, 3H, COCH3,

Rotamers), 2.66 (m, 2H, CH2), 3.13 (m, 2H, CH2), 3.68, 3.74, 3.76 (s, 3H, OCH3), 5.27 – 5.59 (m, 2H,

NCH), 6.97 – 7.00 (m, 2H, Ar), 7.07 – 7.20 (m, 5H, Ar), 7.27 – 7.29 (m, 2H, Ar), 7.45 (m, 1H, Ar). 13C

NMR (75.5 MHz, CDCl3): δ = 31.0 (COCH3), 33.0, 33.3, 34.7, 34.9 (CH2, Rotamers), 40.8, 41.1 (CH2,

Rotamers), 47.4, 47.8, 49.0, 49.7, 50.0, 50.7, 51.3, 51.5, 52.7 (NCH, OCH3, Rotamers), 126.2, 126.4,

126.5, 127.2, 127.6, 127.7, 128.6, 129.3, 129.6 (CHAr, Rotamers), 132.4, 132.9, 136.8, 136.9, 137.8,

138.0, 140.6, 142.5, 143.1, 144.4 (CAr, CCO, CCAr, Rotamers), 154.3, 154.5 (NCOO, Rotamers), 202.3,

202.6 (COCH3). IR (KBr, cm-1): v = 3021 (w), 2953 (w), 2886 (w), 2847 (w), 1693 (s), 1672 (s), 1628

(w), 1491 (w), 1453 (s), 1415 (m), 1352 (m), 1334 (m), 1323 (m), 1286 (w), 1251 (m), 1236 (m), 1190

(w), 1119 (m), 1029 (m), 764 (m), 745 (m), 705 (m). MS (EI, 70 eV): m/z = 347 (M+, 100), 304 (10), 288

(23), 272 (36), 256 (83), 229 (50), 215 (8), 204 (22), 188 (74), 115 (11), 59 (4). Anal. Calcd. for

C22H21NO3 (347.41): C, 76.06; H, 6.09; N, 4.03. Found: C, 75.78; H, 6.16; N, 3.87.

10-Acetyl-11-(4-methoxy-phenyl)-13-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraene-13-

carboxylic acid methyl ester (10b). Starting with 9 (0.456 g, 1.09 mmol), p-(methoxyphenyl)boronic

acid (0.215 g, 1.41 mmol), potassium phosphate (0.369 g, 1.74 mmol) and tetrakis(triphenylphosphane)-

palladium(0) (0.038 g, 0.03 mmol) in 1,4-dioxane (2.5 mL), 10b was isolated as a colourless solid

(0.226 g, 55%); mp. = 152–157 °C. 1H NMR (250 MHz, CDCl3): δ = 1.58 (s, 3H, COCH3, Rotamers),

2.26 (s, 3H, COCH3, Rotamers), 2.51 – 2.77 (m, 2H, CH2), 3.02 – 3.30 (m, 2H, CH2), 3.75, 3.77 (s, 6H,

OCH3), 5.39 (d, 3J = 5.2 Hz, 1H, NCH, Rotamers), 5.51 (d, 3J = 5.2 Hz, 1H, NCH), 5.57 (d, 3J = 5.2 Hz,

1H, NCH, Rotamers), 6.78 – 6.83 (m, 2H, Ar), 6.90 – 6.94 (m, 2H, Ar), 7.06 (br, 1H, Ar), 7.18 – 7.19 (m,

3H, Ar). 13C NMR (75.5 MHz, CDCl3): δ = 31.0 (COCH3), 33.0, 33.3, 40.6, 40.9 (CH2, Rotamers), 47.6,

48.0, 49.2, 49.9 (NCH, Rotamers), 52.8, 53.0, 55.0, 55.3 (CArOCH3 ,NCOOCH3, Rotamers), 114.1, 126.4

(br), 126.5 (br), 127.2, 129.2 (br), 129.4 (br) (CHAr, Rotamers), 132.6 (br), 137.0 (br), 137.6 (br), 142.7,

143.9 (CAr, CCAr, CCO), 154.3, 154.6 (NCOO, Rotamers), 160.2 (CArOCH3), 202.8, 203.1 (COCH3,

Rotamers). IR (KBr, cm-1): v = 3018 (w), 2954 (w), 2899 (w), 2848 (w), 1701 (s), 1662 (m), 1608 (m),

1512 (m), 1447 (m), 1405 (m), 1332 (m), 1298 (m), 1247 (m), 1230 (m), 1177 (m), 1121 (w), 1041 (m),

1022 (m), 827 (w), 750 (w). MS (EI, 70 eV): m/z (%) = 377 (M+, 100), 286 (62), 259 (43), 214 (7), 188

(38), 115 (8), 69 (4). HRMS (EI): calcd. for C23H23NO4 (M+) 377.16216, found 377.161758.