Versatile assembly of the 2-carboxybenzo[b]azepine ring system

Article abstract of DOI:10.1016/S0040-4039(01)00073-9

A suitable 2-carboxybenzo[b]azepine derivative was designed as a potential novel antagonist of the strychnine-insensitive glycine binding site of the NMDA receptor. This compound was synthesized via an N-aryl allylglycine, a useful intermediate efficiently prepared from the starting aniline derivative, followed by a short and unusual elaboration of the allyl double bond.

Full text of DOI:10.1016/S0040-4039(01)00073-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2027–2029
Versatile assembly of the 2-carboxybenzo[b]azepine ring system
Simone A. Giacobbe† and Romano Di Fabio*
GlaxoWellcome S.p.A., Medicines Research Center, Via Fleming 4, I-37135 Verona, Italy
Received 27 November 2000; revised 22 December 2000; accepted 10 January 2001
Abstract—A suitable 2-carboxybenzo[b]azepine derivative was designed as a potential novel antagonist of the strychnine-insensi-
tive glycine binding site of the NMDA receptor. This compound was synthesized via an N-aryl allylglycine, a useful intermediate
efficiently prepared from the starting aniline derivative, followed by a short and unusual elaboration of the allyl double bond.
© 2001 Elsevier Science Ltd. All rights reserved.
Neurons are highly vulnerable to the very signalling
mechanisms that support their ability to receive, pro-
cess and relay information. Neuronal damage can result
from excessive exposure to excitatory amino acids1
(EAA) and from ingress of abnormally high amounts of
Ca2+. Indeed, several pathological conditions of the
central nervous system, such as stroke,2 Huntington’s
disease,3 Alzheimer’s disease4 and neurotrauma5 seem
to involve, among other factors, the over-activation of
the receptor subtype responding to the exogenous ago-
binding site associated with the NMDA receptor. Dur-
ing the search for novel classes of ligands of this
binding site, the benzoazepine derivative 2 was iden-
tified as an alternative template that would additionally
enable us to better define the topological requirements
of the receptor binding pocket.10
To synthesize this novel class of compounds our plan,
as shown in Scheme 1, was to enshrine the whole
substitution pattern of the product in a late intermedi-
ate II, and to effect the cyclization as the last step via a
Heck-type reaction. The double bond of II would be
built via a Horner–Emmons reaction on aldehyde III,
which derives retrosynthetically from the substituted
N-phenyl allylglycine IV. This intermediate can be
derived from V through the addition of an allylmetal to
a suitable aldimine, a reaction set up in house for the
synthesis of tetrahydroquinoline derivatives.11
nist N-methyl-D
-aspartic acid (NMDA).6 This receptor,
and in particular the modulatory glycine binding site
associated with it,7 is now widely recognized as being a
potentially attractive target (Fig. 1).
A sustained effort conducted in our laboratories8 over
the last few years has resulted in the identification of
2-carboxyindole derivatives such as 19 (GV150526) as
potent and selective antagonists acting at the glycine
To that end, the reaction of aniline derivative 3 with
ethylglyoxal overnight in refluxing toluene, with
azeotropic removal of water using a Dean–Stark
apparatus, gave the intermediate imine 4 which was,
after evaporation of the solvent, dissolved in dry
CH2Cl2 and treated at −78°C with TiCl4 (1.2 equiva-
lents), followed by the dropwise addition of allyl-
tributyltin (1.2 equivalents). After 1 h the reaction was
complete and compound 5 was isolated in 78% overall
yield from 3 after purification by flash chromatography.
The original synthetic plan, shown in Scheme 1, which
called for a hydroboration-oxidation of intermediate
IV, was rendered impracticable by the failure of any
attempt at protecting the poorly nucleophilic secondary
amino group. To overcome this issue the alternative
route shown in Scheme 2 was envisaged. In this event,
the double bond of 5 was oxidized to the corresponding
Figure 1.
Keywords: glycine antagonists; synthesis; 2-carboxybenzo[b]azepine;
allylmetalation reaction.
* Corresponding
author.
Fax:
0039-045-9218196;
e-mail:
rdf26781@glaxowellcome.co.uk
Present address: European Patent Office, Ehrardtstrasse 27,
Munich, Germany.
†
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00073-9

2028
S. A. Giacobbe, R. Di Fabio / Tetrahedron Letters 42 (2001) 2027–2029
Scheme 1.
Scheme 2. (a) HCOCO2Et (1.1 equiv.), toluene, reflux, overnight; (b) TiCl4 (1.2 equiv.), allyltributyltin (1.2 equiv.), CH2Cl2,
−78°C; (c) OsO4 (0.1 equiv.), NMO (2 equiv.), THF/H2O (9:1), rt, 5 h; (d) (i) LiOH (2 equiv.), EtOH/H2O (4:1), rt, 2 h; (ii) HCl
(1N), THF, 24 h; (e) (COCl)2 (1.5 equiv.), DMSO (3 equiv.), TEA (3.5 equiv.), CH2Cl2, −78°C, 1 h; (f) (Ph3PCHCONHPh)+Br−
(1.2 equiv.), DBU (1.2 equiv.), CH3CN, rt, 1 h; (g) (i) Bu3SnH (1.7 equiv.), Pd(PPh3)4 (0.03 equiv.), THF, rt, 4 h; (ii) TMSCHN2,
CH2Cl2/MeOH (4:1), rt, 30 min; (h) Pd(PPh3)4 (0.05 equiv.), TEA (2 equiv.), DMF, 80°C, 1 h; (i) LiOH (2 equiv.), EtOH/H2O
(4:1) rt, 1 h.

S. A. Giacobbe, R. Di Fabio / Tetrahedron Letters 42 (2001) 2027–2029
2029
diol 6 to give, as expected, a 1:1 mixture of syn and anti
diastereoisomers, which were in turn cyclized to g-lac-
tone 7 in 77% overall yield. Oxidation of the primary
alcohol was carried out following the Swern procedure,
and the aldehyde derivative 8 was used crude in the
next step. Under Horner–Emmons conditions, this
intermediate was coupled to the requisite phosphonate
affording the a,b-unsaturated carbamoyl derivative 9 in
50% yield (over two steps) as a 8:2 mixture of syn and
anti diasteroisomers, in which the stereochemistry of
the double bond was partially controlled (E/Z=84:16).
From here, the route to the product proceeded through
the reductive opening of the g-lactone ring, a reaction
in which the allylic CꢀO bond is chemoselectively
cleaved, leaving the aromatic CꢀI bond unscathed. This
reaction was successfully accomplished by reacting 9
with Bu3SnH in the presence of a catalytic amount of
Pd(PPh3)4 in THF.12 The following treatment with
TMSCHN2 in CH2Cl2/MeOH gave a 1:1 mixture of
desired product 10 and the corresponding isomer 11,
where the double bond had migrated to the b,g-posi-
tion, in 70% total yield after purification by flash
chromatography. The last hurdle having been over-
come, we set out to complete the synthesis by ring-clos-
ing via a Heck-type reaction. When 10 was treated with
Pd(PPh3)4 and triethylamine in DMF, the benzazepine
derivative 12 was isolated, in which, as expected, the E
stereochemistry of the double bond was completely
controlled.13 The final deprotection of the methyl ester
afforded the desired product 2 in 60% yield, over the
last two steps.14
5. Faden, A.; Demediuk, P.; Panter, S.; Vink, R. Science
1989, 244, 798.
6. The NMDA Receptor; Collingridge, G. L.; Watkins, J.
C., Eds.; Oxford University Press: Oxford, 1994.
7. (a) McBain, C. J.; Kleckner, N. W.; Wyrick, S.;
Digledine, R. Mol. Pharmacol. 1989, 33, 2944; (b) Carter,
A. J. Drugs Future 1992, 17, 595; (c) Kemp, J. A.; Leeson,
P. D. TiPS 1993, 14, 20; (d) Leeson, P. D.; Iversen, L. L.
J. Med. Chem. 1994, 37, 4053.
8. (a) Di Fabio, R.; Capelli, A. M.; Conti, N.; Cugola, A.;
Feriani, A.; Gastaldi, P.; Gaviraghi, G.; Hewkin, C. T.;
Micheli, F.; Missio, A.; Mugnaini, M.; Pecunioso, A.;
Quaglia, A. M.; Ratti, E.; Rossi, L.; Tedesco, G.; Trist,
D. G.; Reggiani, A. J. Med. Chem. 1997, 40, 841; (b)
Giacobbe, S. A.; Baraldi, D.; Di Fabio, R. Biorg. Med.
Chem. Lett. 1998, 8, 1689. For the synthesis and the
biological characterization of other series of indole-2-car-
boxylate derivatives, see: (c) Hewkin, C. T.; Di Fabio, R.;
Conti, N.; Cugola, A.; Gastaldi, P.; Micheli, F.; Quaglia,
A. M. Arch. Pharm. Med. Chem. 1999, 332, 55; (d)
Micheli, F.; Di Fabio, R.; Capelli, A. M.; Cugola, A.;
Curcuruto, O.; Feriani, A.; Gastaldi, P.; Gaviraghi, G.;
Marchioro, C.; Orlandi, A.; Pozzan, A.; Quaglia, A. M.;
Reggiani, A.; van Amsterdam, F. Arch. Pharm. Med.
Chem. 1999, 332, 73; (e) Giacobbe, S. A.; Di Fabio, R.;
Baraldi, D.; Cugola, A.; Donati, D. Synth. Commun.
1999, 29, 3125; (f) Di Fabio, R.; Conti, N.; De Magistris,
E.; Feriani, A.; Provera, S.; Sabbatini, F. M.; Reggiani,
A.; Rovatti, L.; Barnaby, R. J. J. Med. Chem. 1999, 42,
3486.
9. (a) Di Fabio, R.; Cugola, A.; Donati, D.; Feriani, A.;
Gaviraghi, G.; Ratti, E.; Trist, D. G.; Reggiani, A. Drugs
Future 1998, 23, 61; (b) Di Fabio, R.; Cugola, A.; Donati,
D.; Feriani, A.; Gaviraghi, G.; Ratti, E.; Trist, D. G.;
Reggiani, A. Book of Abstracts, 211th ACS National
Meeting, New Orleans, LA, March 1996, abstract 107.
10. For an alternative seven-membered ring scaffold explored
to identify novel glycine antagonists, see: Di Fabio, R.;
Antolini, M.; Bertani, B.; Conti, N.; Donati, D.; Feriani,
A.; Messeri, T.; Missio, A.; Pasquarello, A.; Pentassuglia,
G.; Quaglia, A. M.; Reggiani, A.; Sabbatini, F. Book of
Abstracts, 217th ACS National Meeting, Anaheim, CA,
March 1999, abstract 278.
In conclusion, an efficient synthesis of a novel 2-car-
boxybenzo[b]azepine derivative was set up avoiding the
drawbacks associated with the need for protecting the
poorly reactive secondary aromatic amino group.
The pharmacological profile of this novel glycine antag-
onist will be reported in due course.
Acknowledgements
The authors would like to thank the personnel of the
Mass Spectrometry, NMR Spectroscopy and the Ana-
lytical Chemistry Group for spectral and other analyti-
cal data.
11. Di Fabio, R.; Alvaro, G.; Bertani, B.; Giacobbe, S. A.
Can. J. Chem. 2000, 78, 809.
12. (a) Keinan, E.; Greenspoon, N. Tetrahedron Lett. 1982,
23, 241; (b) Keinan, E.; Gleize, P. A. Tetrahedron Lett.
1982, 23, 477.
13. For a related example of intramolecular cis addition/syn
elimination reaction, see: (a) Nagasawa, K.; Zako, Y.;
Ishihara, H.; Shimizu, I. Tetrahedron Lett. 1991, 32, 4937;
(b) Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I. J.
Org. Chem. 1993, 58, 2523.
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14. 1H NMR (400 MHz, acetone-d6) l 7.76 (m, 2H), 7.32 (m,
2H), 7.22 (m, 1H), 7.10 (m, 1H), 7.06 (m, 1H), 6.75 (m,
1H), 6.40 (s, 1H), 4.17 (dd, J=12.4 Hz, 4.8 Hz, 1H), 4.06
(m, 1H), 2.67 (m, 1H), 2.52 (m, 1H), 2.18 (m, 1H); IR
(Nujol) wmax (cm−1) 3383, 1736, 1647; MS (FAB) m/z 357
[M+H]+.
.