Solid-phase synthesis of dibenzoxazepinones

Article abstract of DOI:10.1016/j.tetlet.2003.09.037

Two novel solid-phase routes to the pharmaceutically relevant dibenzoxazepinone nucleus are described. In one, a key cyclisation step involves intramolecular phenolate displacement of an activated aryl fluoride. In the second, the tricyclic nucleus is pre

Full text of DOI:10.1016/j.tetlet.2003.09.037

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8169–8172
Solid-phase synthesis of dibenzoxazepinones
Neal D. Hone,* James I. Salter and John C. Reader
Millennium Pharmaceuticals Ltd, Granta Park, Great Abington, Cambridge CB1 6ET, UK
Received 1 July 2003; revised 13 August 2003; accepted 3 September 2003
Abstract—Two novel solid-phase routes to the pharmaceutically relevant dibenzoxazepinone nucleus are described. In one, a key
cyclisation step involves intramolecular phenolate displacement of an activated aryl fluoride. In the second, the tricyclic nucleus
is prepared in solution prior to derivatisation on resin.
© 2003 Elsevier Ltd. All rights reserved.
The dibenzoxazepinone ring system exhibits a range of
biological activity such as antidepressant activity,1 HIV
reverse transcriptase inhibition,2 anticonvulsant
activity3 as well as antipsychotic,3 vasopressin4 and
dopamine D4 antagonist5 activity. The number of pub-
lished routes to these compounds is small and only one
example discloses a solid-phase route.6 The latter route
describes the synthesis of a small library of 16 com-
pounds although the opportunities for product diver-
sification are limited by using the ring amide nitrogen
as a linkage point. The use of 2-aminophenols further
reduces synthetic flexibility due to limited commercial
availability of such compounds.
tion represents the second point of diversity in a library
synthesis. The resultant secondary aniline 6 was then
acylated with 2-fluoro-5-nitrobenzoic acid. This step
required considerable optimisation. A single acylation
step using a variety of coupling reagents and additives
led to incomplete acylation and varying degrees of
product purity. A double acylation frequently led to
some bis-acylation (O and N). The optimal conditions
involved a double acylation with DIC-HOBt, followed
by hydrolysis of any ester formed using potassium
carbonate in DMF. Cyclisation of 7 was effected using
5% DBU in DMF following the conditions outlined in
ref. 1 to give the resin bound tricyclic product 8. The
synthesis was performed using 2 g resin, portions of
which were cleaved after each step with the products
To increase the ability to diversify products on solid-
phase, an alternative strategy was investigated (Scheme
1). The commercially available formylindole resin 17
was reductively aminated with n-propylamine in 1%
acetic acid in DMF using sodium triacetoxyborohy-
dride. This amination step represents the first point of
diversity in a library synthesis based on this scheme.
The resultant secondary amine 2 was acylated with
4-fluoro-3-nitrobenzoic acid in DCM using DIC. Con-
version of the fluoro-compound 3 to a phenol 4 was
achieved using acetic acid and cesium carbonate in
DMF at 70°C. This reaction presumably proceeds
through fluorine displacement by the acetate followed
by hydrolysis of the resultant active ester. Nitro group
reduction was achieved using tin(II) chloride in DMF
buffered with 2,6-lutidine. The indolyl linkage is very
acid labile and the inclusion of lutidine prevented pre-
mature product loss. The aniline 5 was reductively
alkylated with 4-chlorobenzaldehyde in 1% acetic acid
in DMF using sodium cyanoborohydride. This alkyla-
1
verified by LC–MS and H NMR. Cleavage of 8 from
the resin was achieved using 5% TFA in DCM at room
temperature for 30 min to give 9. The product was
isolated in 64% yield based on the original resin loading
and was approximately 80% pure by HPLC (ELS
detection).8 It was envisaged that nitro reduction and
derivatization of the resulting aniline would offer a
third point of diversity. However, this reduction could
not be adequately accomplished under a variety of
conditions.
Consequently an alternative route which incorporated a
third point of diversity was sought, and this involved
initial construction of three dibenzoxazepinone tem-
plates in solution (Scheme 2). 3-Amino-4-hydroxyben-
zoic acid 10 was treated with methanolic HCl to give
the methyl ester 11 which was reductively alkylated
with 2,4,6-trimethoxybenzaldehyde to give the sec-
ondary amine 12. This amine was acylated with 2-
fluoro-5-nitrobenzoic acid using EDC and HOBt and
although the product 13 required chromatography for
* Corresponding author.
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doi:10.1016/j.tetlet.2003.09.037

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N. D. Hone et al. / Tetrahedron Letters 44 (2003) 8169–8172
Scheme 1. Reagents and conditions: i, n-propylamine (5 equiv.), 1% AcOH in DMF, rt, 2 h then Na(OAc)3BH (3 equiv.), rt, 18
h; ii, 4-fluoro-3-nitrobenzoic acid (4 equiv.), DIC, DCM, rt, 2 h; iii, AcOH (10 equiv.), Cs2CO3 (10 equiv.), DMF, 70°C, 2 h; iv,
SnCl2 (5 equiv.), 2,6-lutidine (5 equiv.), DMF, rt, 3 h; v, 4-chlorobenzaldehyde (5 equiv.), 1% AcOH in DMF, NaCNBH3 (5
equiv.), rt, 3 h; vi, 2-fluoro-5-nitrobenzoic acid (5 equiv.), HOBt, DIC, rt, 2 h, repeat, then K2CO3 (5 equiv.), DMF, rt, 2 h; vii,
5% DBU in DMF, rt, 18 h; viii, 5% TFA in DCM, rt, 30 min.
purification, it was found that it could instead be taken
on in a crude state for cyclisation with DBU. This
gave the hydrophobic tricyclic product 14 which was
readily separable from impurities through chromato-
graphy.
50% TFA in DCM at room temperature for 1 h to give
secondary amides 20. These were alkylated on a 2 g
scale using activated alkyl halides12 and DBU to give
21. Alkylations under these conditions were extremely
fast, exothermic and led to product loss from the resin
on prolonged treatment. Optimal conditions involved
cooling prior to exposure to the alkylating mixture and
terminating the reaction after 5 min. Each resin combi-
nation was then cleaved with amine13 solutions in DCM
on a 100 mg scale to provide 1152 individual com-
pounds 22.14 Excess amine was scavenged from solution
using a macroporous anhydride resin.15 The average
crude yield was 43% based on the original resin loading
with 72% of the products exhibiting greater than 70%
purity by HPLC (ELS detection).
The overall yield of 14 from 10 was 63%. Hydrogena-
tion of 14 over Pd provided the aniline 16 which was
diazotized in the presence of copper(II) chloride9 to
give chloroarene 17. Compound 16 was also diazotised
in the presence of hypophosphorous acid10 to give the
des-aminoarene 18. The three dibenzoxazepinones were
saponified and the acids (15 and analogues) loaded
onto oxime resin11 using DIC-DMAP on a 40 g scale.
The trimethoxybenzyl group of 19 was removed using

N. D. Hone et al. / Tetrahedron Letters 44 (2003) 8169–8172
8171
Scheme 2. Reagents and conditions: i, MeOH–HCl, rt, 18 h; ii, 2,4,6-trimethoxybenzaldehyde, NaCNBH3, EtOH, rt, 2 h; iii,
2-fluoro-5-nitrobenzoic acid, EDC, HOBt, DMF, rt, 18 h; iv DBU, DCM, rt, 1 h; v, LiOH(aq), THF, MeOH, rt, 2 h; vi, H2, Pd,
THF, rt, 1 atm., 48 h; vii, t-butyl nitrite, CuCl2, MeCN, rt, 2 h; viii, sodium nitrite, hypophosphorous acid, THF, 0°C, 30 min.
then rt, 2 h, ix, oxime resin, DIC, DMAP (10%), DMF/DCM, rt, 18 h; x, 50% TFA in DCM, rt, 1 h; xi, alkyl halide (R2X),12
(5 equiv.), DBU (5 equiv.), DMF, 0°C to rt, 5 min; xii, amine (R3R4NH),13 (5 equiv.), DCM, rt, 72 h.
3. Nagarajan, K.; David, J.; Bhat, G. A. Ind. J. Chem. Sec.
B 1985, 24B, 840–844.
References
1. Nagarajan, K.; David, J.; Kaul, C.; Maller, R. K.; Rao,
R. R.; Grewal, R. S. Ind. J. Phys. Pharm. 1975, 19,
39–42.
2. Klunder, J. M.; Hargrave, K. D.; West, M.; Cullen, E.;
Pal, K.; Behnke, M. L.; Kapadia, S. R.; McNeil, D. W.;
Wu, J. C.; Chow, G. C. J. Med. Chem. 1992, 35, 1887–
1897.
4. Albright, J. D.; Venkatesan, A. M.; Delos Santos, E. G.
US Pat. 5,849,735, A 19981215.
5. Power, P. L.; Rakhit, S. US Pat. 5,703,072, A 19971230.
6. Ouyang, X.; Tamayo, N.; Kiselyov, A. S. Tetrahedron
1999, 55, 2827–2834.
7. (a) Estep, K. G. J. Org. Chem. 1998, 63, 5300–5301; (b)
Yan, B. J. Comb. Chem. 2000, 2, 66–74; (c) Novabiochem

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N. D. Hone et al. / Tetrahedron Letters 44 (2003) 8169–8172
(3-formylindolyl)acetamidomethyl 1% DVB polystyrene,
1 mmol/g.
mide, 3-cyanobenzyl bromide, 4-cyanobenzyl bromide,
benzyl bromide, 2,3-difluorobenzyl bromide and 2,4-
difluorobenzyl bromide. The free NH resin (20) was also
used in step xii.
8. 1H NMR (400 MHz, CDCl3) 8.72 (1H, d, J=2.5 Hz), 8.26
(1H, dd, J=8.9, 2.7 Hz), 7.70 (1H, s), 7.40–7.15 (7H, m),
5.85 (1H, br s), 5.27 (2H, s), 3.34–3.23 (2H, m),
1.59–1.46 (2H, m), 0.87 (3H, t, J=7.3 Hz). m/z (ES+) 466
(MH+).
13. Amines used were ammonia, methylamine, ethanolamine,
1-amino-2-propanol, N-methylethylenediamine, N,N-
dimethylethylenediamine, 2-methoxyethylamine, cyclo-
9. Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. J. Org.
Chem. 1977, 42, 2426–2430.
10. Kornblum, N.; Iffland, D. C. J. Am. Chem. Soc. 1949, 71,
2137–2143.
propylamine,
3-amino-1,2-propanediol,
morpholine,
N-methylpiperazine, tetrahydrofurfurylamine, n-propyl-
amine, pyrrolidine, 2,2,2-trifluoroethylamine and 3-pyrro-
lidinol.
11. Novabiochem 1% DVB polystyrene, 1.3 mmol/g.
12. Alkyl halides used were methyl iodide, iodoacetonitrile,
allyl bromide, bromoacetamide, methyl bromoacetate, 2-
chlorobenzyl bromide, 3-chlorobenzyl bromide, 4-
chlorobenzyl bromide, 2-methoxybenzyl bromide,
3-methoxybenzyl bromide, 4-methoxybenzyl bromide, 2-
methylbenzyl bromide, 3-methylbenzylbromide, 4-methyl-
benzyl bromide, 2-fluorobenzyl bromide, 3-fluorobenzyl
bromide, 4-fluorobenzyl bromide, 2-cyanobenzyl bro-
14. Where R1=NO2, R2=CH3, R3=n-propyl, R4=H, 1H
NMR (400 MHz, CDCl3) 8.71 (1H, d, J=2.8 Hz), 8.25
(1H, dd, J=8.9, 2.6 Hz), 7.71 (1H, d, J=1.9 Hz), 7.40
(1H, dd, J=8.3, 1.8 Hz), 7.27 (1H, d, J=8.9 Hz), 7.24
(1H, d, J=8.3 Hz), 5.97 (1H, br s), 3.55 (3H, s), 3.39–3.29
(2H, m), 1.60–1.47 (2H, m), 0.92 (3H, t, J=7.3 Hz). m/z
(ES+) 356 (MH+).
15. Novabiochem MP-polystyrene anhydride resin, 6 mmol/g.