M. Beller et al.
FULL PAPER
[M+1]+, 404 (53) [M+1ÀCO]+, 322 (50), 294 (33), 232 (57);HRMS
1, C-10), 131.8 (q, 2J(C,F) = 32.2 Hz;C-4), 129.7 (C-11), 127.6 (C-2),
128.1 (q, 3J(C,F) = 3.8 Hz;C-3), 114.0 (C-12), 60.6 (C-8), 55.4 (OMe),
53.6, 52.9, 47.8, 42.3, 32.7 (C-9) ppm;IR (KBr): n˜ = 2959, 2930, 2823,
1640, 1512, 1439, 1327, 1250, 1165, 1119, 1065, 847, 603 cmÀ1;MS (70 eV,
EI): m/z (%): 392 (0.3) [M]+, 272 (20), 271 (100) [MÀBnOMe]+, 216
(18), 173 (56), 145 (20);HRMS (70 eV, EI) calcd for C 21H23F3N2O2:
392.17117;found 392.17041.
(70 eV, EI) calcd for C23H22F4N3O: 432.16989;found 432.16513.
N-(2-Pyrazylcarbonyl)-N’-[2-(4-fluorophenyl)ethyl]piperazine
(11 f):
White crystals; Rf = 0.38 (AcOEt/MeOH 9:1);m.p. 96 8C; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d = 8.84 (s, 1H;3-H), 8.52 (s, 1H;Ar),
8.44 (s, 1H;Ar), 7.04 (dd, 3J(H,H) = 8.7 Hz, 4J(H,F) = 5.5 Hz, 2H;13-
H), 6.85 (t, 3J(H,H) = 3J(H,F) = 8.7 Hz, 2H;14-H), 3.75 (t, 2J(H,H) =
2J(H,H) = 4.9 Hz, 2H;pip.), 3.54 (t, 2J(H,H) = 3J(H,H) = 5 Hz, 2H;
pip.), 2.68 (m, 2H;10-H), 2.53 2.48 (m, 4H;11-H, pip.), 2.43 (t, 2J(H,H)
N-(1-Isoquinolylcarbonyl)-N’-[2-(4-tolyl)ethyl]piperazine (11k): Light
yellow solid; Rf
=
0.62 (AcOEt/MeOH 9:1);m.p. 110 8C; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d = 8.43 (d, 3J(H,H) = 5.8 Hz, 1H;3-
H), 7.96 (dd, 3J(H,H) = 8.4 Hz, 5J(H,H) = 0.9 Hz, 1H;8-H), 7.77 (d,
3J(H,H) = 8.3 Hz, 1H;5-H), 7.64 (ddd, 3J(H,H) = 8.4 Hz, 3J(H,H) =
7 Hz, 4J(H,H) = 1 Hz, 1H;7-H), 7.60 (d, 3J(H,H) = 5.8 Hz, 1H;4-H),
7.54 (ddd, 3J(H,H) = 8.3 Hz, 3J(H,H) = 6.9 Hz, 4J(H,H) = 1.2 Hz, 1H;
=
3J(H,H) = 5.0 Hz, 2H;pip.) ppm; 13C NMR (100 MHz, CDCl3, 258C):
d = 164.9 (C-7), 161.2 (d, 1J(C,F) = 241.7 Hz;C-15), 149.2 (C-2), 145.4,
145.2, 142.5, 135.5 (d, 4J(C,F) 3.8 Hz;C-12), 129.9 (d, 3J(C,F)
=
=
7.6 Hz;C-13), 115.0 (d, 2J(C,F) = 20.8 Hz;C-14), 60.0 (C-10), 53.3, 52.5,
47.0, 42.3, 32.5 (C-11) ppm;IR (KBr): n˜ = 2936, 2811, 1637, 1509, 1443,
1018, 733 cmÀ1;MS (70 eV, EI): m/z (%): 314 (5) [M]+, 206 (49), 205 (72)
[MÀBnF]+, 177 (21), 150 (40), 123 (18), 107 (27), 98 (100), 79 (59), 56
6-H), 7.05 6.97 (m, 4H;15-H, 16-H), 3.92 (t, 3J(H,H)
= =
2J(H,H)
5.1 Hz, 2H;pip.), 3.20 (t, 3J(H,H) = 2J(H,H) = 5.2 Hz, 2H;pip.), 2.73
2.61 (m, 4H;12-H, pip.), 2.55 (m, 2H;13-H), 2.37 (t, 2J(H,H) = 3J(H,H)
= 5.1 Hz, 2H;pip.), 2.22 (s, 3H;Me) ppm; 13C NMR (100 MHz, CDCl3,
258C): d = 166.8 (C-9), 155.4 (C-1), 141.9 (C-3), 136.8, 136.6, 135.8,
131.0, 129.3 (C-16), 128.7 (C-15), 128.3, 127.2, 126.0, 125.7 and 121.5 (C-
8a, C-5), 60.4 (C-12), 53.5, 52.9, 46.8, 41.8, 33.0 (C-13), 21.1 (CH3) ppm;
IR (neat): n˜ = 2924, 2809, 1644, 1585, 1471, 1443, 1250, 998, 828, 811,
751, 734, 704 cmÀ1;MS (70 eV, EI): m/z (%): 359 (5) [M]+, 255 (18), 254
(100) [MÀMeBn]+, 199 (15), 128 (42);HRMS (70 eV, EI) calcd for
C23H26N3O: 360.20759;found 360.20617.
(24);HRMS (70 eV, EI) calcd for
314.15607.
C 17H19FN4O: 314.15430;found
N-(4-Indolylcarbonyl)-N’-[2-(4-fluorophenyl)ethyl]piperazine
Yellow solid; Rf
0.62 (AcOEt/MeOH 9:1);m.p. 80 8C; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d = 8.98 (s, 1H;NH), 7.24 (dd, 3J(H,H)
7.2, 4J(H,H)
1.8 Hz, 1H;Ar), 7.10 7.00 (m, 5H;Ar), 6.87 (t,
(11 g):
=
=
=
3J(H,H) = 3J(H,F) = 8.7 Hz, 2H;15-H), 6.41 (t, 3J(H,H) = 4J(H,H) =
2.9 Hz, 3H;Ar), 3.82 (br, 2H;pip.), 3.32 (br, 2H;pip.), 2.68 (m, 2H;11-
H), 2.55 (br, 2H;pip.), 2.51 (m, 2H;12-H), 2.31 (br, 2H;pip.) ppm; 13C
NMR (100 MHz, CDCl3, 258C): d = 170.6 (C-8), 161.6 (d, 1J(C,F) =
242.6 Hz;C-16), 136.2 (C-7a), 135.8 (d, 4J(C,F) = 3.8 Hz;C-13), 130.2
(d, 3J(C,F) = 7.6 Hz;C-14), 127.7, 125.7, 125.3, 121.6, 118.5, 115.3 (d,
2J(C,F) = 20.8 Hz;C-15), 112.8 (C-7), 101.3 (C-3), 60.4 (C-11), 54.0, 53.2,
47.6, 42.2, 32.8 (C-12) ppm;IR (nujol): n˜ = 3400 (NH), 2956, 2816, 1625,
1599, 1508, 1463, 999, 825, 758 cmÀ1;MS (70 eV, EI): m/z (%): 352 (100)
[M+1]+, 242 (40), 144 (23);HRMS (70 eV, EI) calcd for C 21H23FN3O:
352.18253;found 352.17824.
1-{[2-(4-Tolyl)ethyl]piperazin-1-yl}isoquinoline (12k): Yellow solid; Rf
0.50 (AcOEt/MeOH 9:1);m.p. 119 8C, H NMR (400 MHz, CDCl3, 258C,
TMS): d = 8.07 (d, 3J(H,H) = 5.8 Hz, 1H;3-H), 8.01 (d, 3J(H,H) =
=
1
8.3 Hz, 1H;8-H), 7.66 (d, 3J(H,H)
=
7.9 Hz, 1H;5-H), 7.51 (ddd,
3J(H,H) = 8.3 Hz, 3J(H,H) = 7.0 Hz, 4J(H,H) = 1.2 Hz, 1H;7-H), 7.41
3
3
3
(ddd, J(H,H) = 7.9 Hz, J(H,H) = 6.9 Hz, J(H,H) = 1.2 Hz, 1H;6-H),
7.16 (d, 3J(H,H) = 5.8 Hz, 1H;4-H), 7.09 6.99 (m, 4H;15-H, 16-H),
2
3.41 (t, J(H,H) = 3J(H,H) = 4.6 Hz, 4H;pip.), 2.80 2.71 (m, 6H;11-H,
pip.), 2.66 2.60 (m, 2H;12-H), 2.61 (s, 3H;Me) ppm;
(100 MHz, CDCl3, 258C): d 161.5 (C-1), 140.9 (C-3), 138.3, 137.4,
13C NMR
N-(5-Indolylcarbonyl)-N’-[2-(4-fluorophenyl)ethyl]piperazine
(11h):
=
Yellow solid; Rf
=
0.60 (AcOEt/MeOH 9:1);m.p. 97 8C; 1H NMR
135.8, 129.8 (C-6), 129.3 (C-15), 128.8 (C-14), 127.3, 126.2, 125.8, 121.9
(C-8a), 116.0, 61.0 (C-11), 53.6 (C-9), 51.4 (C-10), 32.3 (C-12), 21.2
(Me) ppm;IR (KBr): n˜ = 2925, 2841, 2811, 1621, 1557, 1499, 1448, 1404,
1367, 1007, 814, 750 cmÀ1;MS (70 eV, EI): m/z (%): 331 (12) [M]+, 226
(35) [MÀMeBn]+, 187 (57), 171 (52), 169 (22), 157 (100), 145 (23), 128
(26), 118 (17), 82 (16);HRMS (70 eV, EI) calcd for C 22H26N3: 332.21267;
found 332.21060.
(400 MHz, CDCl3, 258C, TMS): d = 9.73 (s, 1H;NH), 7.60 (s, 1H;Ar),
7.17 6.95 (m, 5H;Ar), 6.84 (t, 3J(H,H) = 3J(H,F) = 8.5 Hz, 2H;15-H),
6.37 (br, 1H;3-H), 3.76 3.32 (br, 4H;pip.), 2.63 (m, 2H;11-H), 2.48 (m,
2H;12-H), 2.50 2.30 (br, 4H;pip.) ppm; 13C NMR (100 MHz, CDCl3,
258C): d = 172.3 (C-8), 161.4 (d, 1J(C,F) = 241.7 Hz;C-16), 136.7 (C-
4
7a), 135.6 (d, J(C,F) = 2.8 Hz;C-13), 130.0 (d, 3J(C,F) = 7.6 Hz;C-14),
2
127.3, 126.3, 126.1, 120.9, 120.0, 115.2 (d, J(C,F) = 20.9 Hz;C-15), 111.5
(C-7), 102.4 (C-3), 60.4 (C-11), 53.2, 47.9, 42.4, 32.5 (C-12) ppm;IR
(KBr): n˜ = 3417 (NH), 2923, 2854, 1625, 1603, 1509, 1436, 1024, 823,
750 cmÀ1;MS (70 eV, EI): m/z (%): 351 (0.4) [M]+, 242 (47), 144 (100),
116 (17);HRMS (70 eV, EI) calcd for C 21H23FN3O: 352.18253;found
352.18034.
Acknowledgement
We acknowledge financial support from the BMBF (™Life Science Catal-
ysis and Engineering∫), the state of Mecklenburg-Western Pomerania,
and the Fonds der Chemischen Industrie (FCI). The Alexander von
Humboldt foundation is thanked for a grant for K. K., OMG is thanked
for gifts of palladium compounds. Prof. Dr. M. Michalik, Dr. C. Fischer,
C. Mewes, H. Baudisch, A. Lehmann, and S. Buchholz are thanked for
their excellent analytical support.
N-(4-Indolylcarbonyl)-N’-[2-(4-methoxyphenyl)ethyl]piperazine
(11i):
Yellow solid; Rf
=
0.58 (AcOEt/MeOH 9:1);m.p. 143 8C; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d = 9.57 (s, 1H;NH), 7.15 (dd, 3J(H,H)
= 6 Hz, 4J(H,H) = 3.2 Hz, 1H, Ar), 7.03 6.97 (m, 4H;Ar), 6.91 (t,
3J(H,H) = 4J(H,H) = 2.6 Hz, 1H;Ar), 6.71 (d, 3J(H,H) = 8.7 Hz, 2H;
14-H), 6.35 (br, 1H;3-H), 3.92 3.74 (br, 2H;pip.), 3.65 (s, 3H;OMe),
3.38 3.22 (br, 2H;pip.), 2.63 (m, 2H;11-H), 2.60 2.45 (br, 2H;pip.),
2.49 (m, 2H;12-H), 2.40 2.22 (br, 2H;pip.) ppm; 13C NMR (100 MHz,
CDCl3, 258C): d = 170.7 (C-8), 158.0 (C-16), 136.1 and 132.0 (C-7a, C-
13), 129.6 (C-14), 127.3 and 125.9 (C-2, C-4), 125.1 (C-3a), 121.2 and
118.2 (C-5, C-6), 113.9 (C-15), 112.9 (C-7), 100.7 (C-3), 60.5 (C-11), 55.2
(OCH3), 53.8, 53.0, 47.5, 42.1, 32.5 (C-12) ppm;IR (KBr): n˜ = 3247
(NH), 2934, 1653, 1608, 1512, 762, 735 cmÀ1;MS (70 eV, EI): m/z (%):
364 (100) [M+1]+, 243 (12), 242 (76), 144 (31);HRMS (70 eV, EI) calcd
for C22H25N3O2: 363.19467;found 363.19280.
[1] a) J. Tsuji, Palladium Reagents and Catalysts: Innovations in Organic
Synthesis, Wiley, Chichester, 1995;b) F. Diederich, P. J. Stang, Metal
Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1998;
c) M. Beller, C. Bolm, Transition Metals for Organic Synthesis,
Wiley-VCH, Weinheim, 1998.
[2] H.-U. Blaser, F. Spindler, M. Studer, Appl. Catal. A 2001, 221, 119.
[3] a) H. Bˆttcher, H. Greiner, J. Harting, G. Bartoszyk, C. Seyfried, C.
van Amsterdam (Merck Patent GmbH, Germany), DE 19934433,
2001;b) H. Bˆttcher, G. Bartoszyk, J. Harting, C. van Amsterdam,
C. Seyfried (Merck Patent GmbH, Germany), DE 10102053, 2002;
c) H. Crassier, H. Bˆttcher, U. Eckert, A. Bathe, S. Emmert
(Merck Patent GmbH, Germany), DE 10102944, 2002.
N-[4-(Trifluoromethyl)phenylcarbonyl]-N’-[2-(4-methoxyphenyl)-ethyl]-
piperazine (11j): Colorless crystals; Rf = 0.62 (AcOEt/MeOH 9:1);m.p.
1008C; 1H NMR (400 MHz, CDCl3, 258C, TMS): d = 7.66 (d, 3J(H,H)
=
8.1 Hz, 2H;2-H), 7.50 (d, 3J(H,H)
= 8.1 Hz, 2H;3-H), 7.09 (d,
3J(H,H) = 8.5 Hz, 2H;12-H), 6.81 (d, 3J(H,H) = 8.5 Hz, 2H;11-H),
3.81 (br, 2H;pip.), 3.76 (s, 3H;OMe), 3.39 (br, 2H;pip.), 2.72 (m, 2H;
8-H), 2.59 (m, 4H;pip., 9-H), 2.43 (br, 2H;pip.) ppm;
(100 MHz, CDCl3, 258C): d = 168.9 (C-5), 158.2 (C-13), 139.6, 132.0 (C-
[4] H. Bˆttcher, J. Marz, H. Greiner, J. Harting, G. Bartoszyk, C. Sey-
fried, C. van Amsterdam (Merck Patent GmbH, Germany), WO
2001007434, 2001.
13C NMR
756
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2004, 10, 746 757