M. Pau6ert et al. / Tetrahedron Letters 44 (2003) 4203–4206
4205
Scheme 6. Reagents and conditions: (i) PhCH2Br (2 equiv.), tol, reflux, 2 h (89%), (ii) 14 dissolved in CH3CN/H2O (1/1) then
CHBr3 (1.2 equiv.) and aq KOH (1.1 equiv.), rt, 3 h (76%; white solid, mp: 106–108°C); (iii) see Ref. 7; (iv) Na, liq. NH3, THF,
−78°C, 30 min (95%; white solid, mp: 180–182°C); (v) Me3SiCl (6 equiv.), NaI (6 equiv.), CH3CN, rt, 24 h (98%; white solid, mp:
186–188°C); (vi) tBuOK, DMSO, 50°C, 2 h (40%).
Following these considerations, the synthesis of zate-
bradine (Scheme 6) commences with the quaternarisa-
tion of the dihydroisoquinoline 12 which was
accomplished5 under the action of a slight excess of
benzylbromide at reflux of toluene. The salt 14, isolated
in high yield, was next exposed to the action of an
excess of tribromomethyl anion, generated following
the Duchardt and Kro¨hnke protocol,6 to provide the
addition product 15 in 70% isolated yield.
The potentialities of the reaction were illustrated with a
new synthesis of the anti-anginal compound zate-
bradine 3. It is worth mentioning that, compared to the
azido-Schmidt reaction, our reaction offers additional
synthetic possibilities. Further work is in progress to
understand the scopes and limitations of the reaction
and to best delineate its mechanism.
References
The stage was thus set for the crucial ring homologa-
tion reaction which was carried out by treating 15 with
an aqueous solution of silver nitrate in acetonitrile as
the solvent. Gratifyingly, the expected 3-benzyl-1-
hydroxy - 7,8 - dimethoxy - 1,2,4,5 - tetrahydro - benzo[d]-
azepin-2-one 10b could be isolated7 in 71% yield after
flash chromatography purification. At this stage it is
not without interest to note that: (1) initial attempts to
react tribromomethyl derivatives 1 and 5 with aqueous
silver nitrate in the absence of methanol gave poor yield
of the expected benzo[b]- and benzo[d]azepin-2-ones 2b
and 4b, respectively; (2) the yield for the formation of
10b is significantly higher than the yield (45%) for its
OMe analogue 10a isolated after running the reaction
in a hydromethanolic medium.
1. Pauvert, M.; Dupont, V.; Guingant, A. Synlett 2002,
1350–1352.
2. See for instance: Drugs of the future 1997, 22, 933–934.
3. Spectral data for the 3-benzyl-1,3-dihydro-benzo[d]azepin-
2-one 4a: IR (KBr): 1678 cm−1 1H NMR (200 MHz,
.
CDCl3): l=3.59 (s, 3H, OCH3), 4.45 (br. s, 1H,
CHOCH3), 4.71 and 4.87 (AB system, 2H, J=15.0 Hz,
NCH2), 6.25 (d, 1H, J=9.2 Hz, CHꢀCHꢁN), 6.45 (d, 1H,
J=9.2 Hz, CHꢀCHꢁN), 7.05–7.15 (m, 2H-Ar), 7.20–7.35
(m, 5H-Ar), 7.44 (td, 1H-Ar, J=7.6 Hz and 1.4 Hz), 7.65
(d, 1H-Ar, J=1.4 Hz).13C NMR (50 MHz, CDCl3): l=
50.8, 58.3, 81.1, 117.3, 124.3, 127.0, 127.4, 127.7, 127.8
(2C), 128.4, 128.7 (2C), 129.0, 131.2, 133.7, 136.6, 166.9.
+
MS: m/z (relative intensity)=279 (42) [M ], 264 (9), 220
+
(19), 91 (100), 65 (18). HRMS (SIMS), [M ] calcd for
Compound 10b was next converted to the desired lac-
tame 9 in two high yielding steps featuring N-debenzyl-
ation (16) and benzylic alcohol reduction.8 The final
assembly of zatebradine was then achieved following a
known procedure,9 that is: deprotonation of 9 followed
by alkylation of the resulting anion with the chloro
derivative 17 prepared by reacting the commercially
available [2(3,4-dimethoxy-phenyl)-ethyl]methyl-amine
(N-methylhomo-veratrylamine) with 1-bromo-3-chloro-
ethane.
C18H17NO2: 279.1259; found: 279.1266.
4. (a) Barbier, D.; Marazano, C.; Das, B. D.; Potier, P. J.
Org. Chem. 1996, 61, 9596–9598; (b) Warrener, R. N.; Liu,
L.; Russell, R. A. Tetrahedron 1998, 54, 7485–7496.
5. Beaumont, D.; Waigh, R. D.; Sunbhanich, M.; Nott, M.
W. J. Med. Chem. 1983, 26, 507–515.
6. Duchardt, K. H.; Kro¨hnke, F. Chem. Ber. 1977, 110,
2669–2679.
7. Experimental procedure and spectral data for the 3-benzyl-
1-hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[d]aze-
pin-2-one 10b:
In conclusion, we have shown that treatment of the
1-tribromomethyl-1,2-dihydro-isoquinoline 5 with an
hydroalcoholic solution of silver nitrate effected its
transformation into the 1,3-dihydro-benzo[d]azepin-2-
one 4a. This ring enlargement reaction could also be
accomplished with a 1-tribromomethyl-1,2,3,4-tetra-
hydro-isoquinoline substrate (e.g. 15) to form 1,3,4,5-
tetrahydro-benzo[d]azepin-2-ones (e.g. 10a and 10b).
To
a
well-stirred suspension of the 2-benzyl-6,7-
dimethoxy-1-tribromomethyl-1,2,3,4-tetrahydro-isoquino-
line 15 (300 mg, 0.56 mmol) in CH3CN/H20 (1:1, 10mL) at
−20°C was added an aqueous solution of silver nitrate (280
mg, 3 equiv.) and the mixture was allowed to warm to
room temperature. After 16 h, the mixture was filtered
through a short plug of Celite that was rinsed with
dichloromethane. After removal of the solvents under