RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2015, 348, 100–112
M. R. Simic et al.
Archiv der Pharmazie
–
–
–
2.33 (m, 1H, CH C CH ), 2.38–2.48 (m, 2H, CH C CH , H C-6),
d ¼ 21.1 (C-8), 39.6 (C-14), 47.4 (C-7), 59.6 (C-5), 60.7 (C-13b),
–
2
2
2
2
2
–
2.85 (dt, 1H, J ¼ 12.0 and 5.0 Hz, H2C-6), 3.08–3.11 (m, 1H, HC-
2), 3.59 (d, 1H, J ¼ 15.0 Hz, CH2Ar), 3.92 (d, 1H, J ¼ 15.0 Hz,
108.5, 110.8, 114.8 ( CH ), 118.2, 119.4, 121.0, 121.6, 127.5,
–
2
127.6, 129.1, 129.4, 135.9, 136.5, 142.6, 147.8 ppm; IR (ATR)
CH2Ar), 5.01–5.06 (m, 2H, CH ), 5.64 (dq, 1H, J ¼ 10.0 and
nmax ¼ 3206, 3058, 2850, 1622, 1454, 1345, 1323, 1162 cmꢂ1
;
–
–
2
2.0 Hz, HC-3), 5.81–5.90 (m, 2H, CH CH , HC-4), 7.08 (td, 1H,
MS (EI, 70 eV): m/z ¼ 300.1 [M]þ, 171.1, 154.1, 130.1, 115.1,
91.1; HRMS (ESI, [MþH]þ): calcd. for C21H21N2 301.16993,
found 301.17034.
–
–
2
J ¼ 7.5 and 1.5 Hz, ArH), 7.27 (td, 1H, J ¼ 8.0 and 0.5 Hz, ArH),
7.51 (dd, 1H, J ¼ 8.0 and 1.0 Hz, ArH), 7.58 (dd, 1H, J ¼ 7.0 and
0.5 Hz, ArH) ppm; 13C NMR (125 MHz, CDCl3) d ¼ 24.5 (C-5),
–
–
37.9 (CH C CH ), 46.7 (C-6), 57.7 (CH Ar), 59.3 (C-2), 116.3
13-Methylene-5,6,8,13,14,14a-hexahydroisoquino[2,1-b]-
[2]benzazepine (7a)
2
2
2
–
–
( CH ), 124.2 (C-4), 125.4, 127.2, 128.0, 129.6 (C-3), 130.3,
2
–
–
132.4, 135.8 (C CH ), 138.9 ppm; IR (ATR) n
¼ 1437, 1022,
Compound 7a was synthesised from 6a following the general
procedure for Heck reaction. The product was isolated after
flash chromatography (SiO2, petroleum ether/diethyl ether
saturated with aqueous ammonia 4:1) as a pale yellow semi-
solid in 60% yield. Spectral data were found to be identical
with the ones described by Cleghorn et al. [11].
910, 746, 667 cmꢂ12; MS (EI, 70 eV): m/z ¼ 291.1 [M]þ, 250.0,
169.0, 90.1; HRMS (ESI, [MþH]þ): calcd. for C15H19BrN
292.06954, found 292.06984.
max
1-(2-Bromobenzyl)-4-allyl-piperidine (10b)
Colourless oil, Rf ¼ 0.24 (petroleum ether/diethyl ether 95:5);
1H NMR (500 MHz, CDCl3): d ¼ 1.25–1.30 (m, 3H, H2C-3, H2C-5,
HC-4), 1.65 (dd, 2H, J ¼ 12.0 and 1.5 Hz, H2C-3, H2C-5), 2.00
Rf ¼ 0.27 (petroleum ether/diethyl ether saturated with
aqueous ammonia 4:1); 1H NMR (500 MHz, CDCl3): d ¼ 2.63
(dd, 1H, J ¼ 14.0 and 3.0 Hz, H2C-14), 2.73–2.89 (m, 4H, H2C-6,
H2C-5, H2C-14), 2.99–3.04 (m, 1H, H2C-6), 3.95 (d, 1H, J ¼ 14.5
Hz, H2C-8), 4.27 (d, 1H, J ¼ 14.5 Hz, H2C-8), 4.33 (dd, 1H,
–
(t, 2H, J ¼ 6.5 Hz, CH C CH ), 2.03–2.08 (m, 2H, H C-2, H C-6),
–
2
2
2
2
2.88 (brd, 2H, J ¼ 11.5 Hz, H2C-2, H2C-6), 3.56 (s, 2H, CH2Ar),
–
–
–
4.97–5.01 (m, 2H, CH ), 5.74–5.82 (m, 1H, CH CH ), 7.07
J ¼ 11.0 and 2.5 Hz, H-14a), 5.14 (d, 1H, J ¼ 2.0 Hz, CH ), 5.25
–
–
–
2
2
2
(s, 1H, CH ), 7.08–7.28 (m, 8H, ArH) ppm; 13C NMR (125 MHz,
–
2
–
(td, 1H, J ¼ 8.0 and 2.0 Hz, ArH), 7.26–7.27 (m, 1H, ArH), 7.48
(dd, 1H, J ¼ 7.5 and 1.5 Hz, ArH), 7.51 (dd, 1H, J ¼ 8.0 and
1.0 Hz, ArH) ppm; 13C NMR (125 MHz, CDCl3) d ¼ 32.2 (2C, C-3,
CDCl3) d ¼ 29.9 (C-6), 40.6 (C-14), 43.4 (C-5), 60.4 (C-8), 64.8
–
(C-14a), 114.9 ( CH ), 125.5, 126.2, 126.9, 127.1, 127.5, 129.0,
–
2
–
C-5), 35.7 (C-4), 41.0 (CH C CH ), 54.0 (2C, C-2, C-6), 62.1
129.1, 133.9, 135.9, 139.3, 143.5, 149.2 ppm; IR (ATR)
nmax ¼ 3017, 2907, 2159, 2024, 1137, 745 cmꢂ1; MS (EI,
70 eV): m/z ¼ 261.1 [Mþ], 232.1, 132.1, 115.0.
–
2
2
–
(CH Ar), 115.6 ( CH ), 124.5, 127.1, 128.1, 130.5, 132.5, 137.1
–
2
2
–
–
(C CH ), 138.2 ppm; IR (ATR) nmax ¼ 2917, 1463, 910, 747
2
cmꢂ1; MS (EI, 70 eV): m/z ¼ 293.1 [M]þ, 252.1, 169.0; HRMS
(ESI, [MþH]þ): calcd. for C15H21BrN 294.08519, found
294.08621.
2,3-Dimethoxy-13-methylene-5,6,8,13,14,14a-
hexahydroisoquino[2,1-b][2]benzazepine (7b)
Compound 7b was synthesised from 6b following the general
procedure for Heck reaction. The product was isolated after
flash chromatography (SiO2, petroleum ether/ether saturated
with aqueous ammonia 1:1) as a yellow semi-solid in 70%
yield. Spectral data were found to be identical with the ones
described by Cleghorn et al. [11].
General procedure for the preparation of benzazepine
derivatives by Heck reaction
A mixture of aryl bromide (0.3 mmol), Pd(OAc)2 (10 mol%),
PPh3 (20 mol%) and K2CO3 (1.5 eq) in dry toluene (8 mL) was
refluxed under nitrogen atmosphere for 12 h. The solvent was
removed under reduced pressure and the residue was
dissolved in DCM (40 mL), washed with water (2 ꢁ 10 mL),
dried (Na2SO4) and filtered. The solvent was then removed
under reduced pressure and the residue was purified by flash
chromatography (SiO2).
Rf ¼ 0.13 (petroleum ether/diethyl ether saturated with
aqueous ammonia 4:1). 1H NMR (500 MHz, CDCl3): d ¼ 2.61
(dd, 1H, J ¼ 15.0 and 3.5 Hz, H2C-14), 2.68 (dt, 1H, J ¼ 15.0 and
3.5 Hz, H2C-14), 2.76–2.87 (m, 3H, H2C-5, H2C-6), 2.91–2.97
(m, 1H, H2C-5), 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.93
(d, 1H, J ¼ 15.0 Hz, H2C-8), 4.24–4.28 (m, 2H, H-14a, H2C-8),
–
–
–
15-Methylene-7,8,13,13b,14,15-hexahydro-5H-indolo-
[20,30:3,4]pyrido[1,2-b][2]benzazepine (3)
Compound 3 was synthesised from 2 following the general
procedure for Heck reaction. The product 3 was isolated after
flash chromatography (SiO2, petroleum ether/diethyl ether
7:3) as a yellow amorphous solid in 36% yield.
5.16 (d, 1H, J ¼ 2.0 Hz, CH2 ), 5.26 (s, 1H, CH ), 6.57 (s, 1H,
–
2
ArH), 6.63 (s, 1H, ArH), 7.17–7.26 (m, 4H, ArH) ppm; 13C NMR
(125 MHz, CDCl3): d ¼ 28.6 (C-5), 40.5 (C-6), 43.5 (C-14), 55.8
(OCH3), 56.1 (OCH3), 60.3 (C-8), 64.4 (C-14a), 109.9, 111.4, 114.8,
126.1, 127.2, 127.5, 129.1, 131.4, 135.9, 143.5, 147.1, 147.6,
149.2 ppm; IR (ATR) nmax ¼ 1517, 1463, 1257, 1225, 853, 766
cmꢂ1;MS(EI, 70eV):m/z ¼ 321.2 [M]þ, 192.1, 130.1, 115.1;HRMS
(ESI,[MþH]þ):calcd.forC21H24NO2 322.18016,found322.18144.
m.p.: 123–125°C; Rf ¼ 0.26 (petroleum ether/diethyl ether
7:3); 1H NMR (500 MHz, CDCl3): d ¼ 2.72–2.86 (m, 4H, H2C-8,
H2C-14), 2.97–3.08 (m, 2H, H2C-7), 4.01 (d, 1H, J ¼ 15.0 Hz, H2C-
5), 4.13 (d, 1H, J ¼ 15.0 Hz, H2C-5), 4.34 (dd, 1H, J ¼ 10.5 and
6-Methyl-13-methylene-5,6,8,13,14,14a-
hexahydroisoquino[2,1-b][2]benzazepine (7c)
–
3.5 Hz, H-13b), 5.24 (s, 2H, CH ), 7.07–7.16 (m, 2H, ArH), 7.18–
–
2
7.25 (m, 3H, ArH), 7.31 (m, 2H, ArH), 7.47 (d, 1H, J ¼ 8.0 Hz,
Compound 7c was synthesised from 6c following the general
procedure for Heck reaction. The products 7c and 7d were
ArH), 7.86 (brs, 1H, N-H) ppm; 13C NMR (125 MHz, CDCl3)
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108