Synthesis of a [2]benzazepine analogue of clavizepine

Article abstract of DOI:10.1016/S0040-4039(00)02100-6

The synthesis of N-tosylbenzopyran[2]benzazepinone 2 using a simple protocol for assembly of an azepine ring on the xanthene skeleton is described. Formation of the C-C bond between C9 of the xanthen-9-ol 7 and the β-C of N-tosyl aminoacetaldehyde dimethyl acetal leads to 10, which upon treatment with formaldehyde undergoes ring closure.

Full text of DOI:10.1016/S0040-4039(00)02100-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 665–667
Synthesis of a [2]benzazepine analogue of clavizepine
Alberto Garc´ıa, Sonia Paz and Domingo Dom´ınguez*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received 23 October 2000; accepted 16 November 2000
Abstract—The synthesis of N-tosylbenzopyran[2]benzazepinone 2 using a simple protocol for assembly of an azepine ring on the
xanthene skeleton is described. Formation of the CꢀC bond between C9 of the xanthen-9-ol 7 and the b-C of N-tosyl
aminoacetaldehyde dimethyl acetal leads to 10, which upon treatment with formaldehyde undergoes ring closure. © 2001 Elsevier
Science Ltd. All rights reserved.
Clavizepine (1), first isolated from the plant Corydalis
claviculata (L.) DC.,1 is the sole member of the ben-
zopyran[3]benzazepine class of alkaloids. Its total syn-
thesis has been achieved by Ikeda and co-workers2a,b
and in our own laboratory.2c,d In the course of pharma-
cological evaluation of some clavizepine analogues we
discovered that certain N-tosylated clavizepine precur-
sors have interesting biological properties. In view of
these findings, we decided to investigate modified ana-
logues with the structure of N-tosylbenzazepines, start-
ing with the [2]benzazepine 2.
Initially, we designed a synthetic strategy based on
acylation of a 9-xanthenyllithium with an appropriate
amino acid derivative as the source for the C2N unit,
which could then be cyclised to the required azepine
(Scheme 1).
To this end we prepared the N-tosyloxazolidinone
derivatives of glycine and -valine 5a and 5b by N-tosy-
L
lation of the corresponding amino acids (1 M NaOH,
TsCl, rt, 4.5 h) followed by treatment with excess
paraformaldehyde and catalytic p-toluenesulfonic acid
in refluxing benzene, with azeotropic removal of water.
However, addition of a THF solution of either of these
oxazolidinones to 9-xanthenyllithium (4) at −100, −78
or 0°C failed to afford the corresponding acylated
products (6a or 6b). Instead, the main product was the
xanthene 3, which was probably the result of protona-
tion of 4 by the acidic a-hydrogens of the starting
oxazolidinones. To avoid this undesired process we
tried replacing the N-protecting group with the more
Ts
N
N Me
HO
MeO
O
O
O
OMe
OMe
Clavizepine (1)
2
R2
O
R1
HN
R1
O
R
a, R1=H, R2=Ts
b, R1=iPr, R2=Ts
N
R2
5
O
O
O
c, R1=Me, R2=Pf
6
3, R=H
4, R=Li
n-BuLi
THF/rt, 1h
Scheme 1.
Keywords: xanthenes; acetals; amino aldehydes; benzazepines; polycyclic heterocyclic compounds.
* Corresponding author. Fax: +34-981-595012; e-mail: qomingos@usc.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02100-6

666
A. Garc´ıa et al. / Tetrahedron Letters 42 (2001) 665–667
OMe
OMe
H
R
N
O
OMe
HBr/AcOH
H
OMe
OH
N
MeO
R
MeO
NHR
MeO
O
O
O
8a, R=H
8b, R=Ts
8c, R=Ac
7
[9b, R=Ts]
9c, R=Ac
Ac2O
Ts
O
Ts
O
OMe
OMe
HN
N
TsHN
CH2O
MeO
MeO
O
.
O
BF3 OEt2
HBr/AcOH
10
2
Scheme 2.
sterically hindered and less electron withdrawing 9-
phenylfluoren-9-yl group (Pf), first used by Rapoport to
protect a-amino carbonyl compounds against enolisa-
tion.3,4 When a THF solution of the oxazolidinone 5c,
from readily available materials. Further application of
this methodology to related systems is currently being
investigated.
prepared from
L-alanine following a reported proce-
dure,4b was cooled to −78°C and treated with xan-
thenyllithium 4, a 43% yield of the expected acylation
product 6c was obtained.
Acknowledgements
Support of this work by grants from the Spanish Min-
istry of Education (project PB98-0606) and from
Janssen-Cilag S.A. is gratefully acknowledged.
However, at this point, while working on a parallel
project, we discovered an alternative, much simpler and
more direct route to the desired methoxy substituted
amino ketone 10 (Scheme 2). Specifically, we found that
the N-tosyl derivative 8b,5 which is readily prepared
from 4-methoxyxanthen-9-ol (7),6 afforded compound
10 directly in 50% yield when treated with HBr in acetic
acid at rt.7 A plausible mechanism consists of attack by
the enolic form of the hydrolysed acetal derivative of 8
on the doubly benzylic, highly activated position 9 of
the xanthene to give the amino acetaldehyde 9b, which
in the reaction conditions used might undergo a 1,2-
(xanthen-9-yl) shift followed by a 1,2-hydrogen shift to
give 10 according with an unusual rearrangement
already described.8 In support of this mechanism, the
N-acetyl analogue 8c9 was converted to the amino
aldehyde 9c; this compound, however, unexpectedly
failed to rearrange to the corresponding amino ketone,
being stable under the HBr/AcOH conditions
employed.
References
1. Boente, J. M.; Castedo, L.; Dom´ınguez, D.; Ferro, M. C.
Tetrahedron Lett. 1986, 27, 4077–4078.
2. (a) Ishibashi, H.; Takagaki, K.; Imada, N.; Ikeda, M.
Synlett 1994, 49–50; (b) Ishibashi, H.; Takagaki, K.;
Imada, N.; Ikeda, M. Tetrahedron 1994, 50, 10215–10224;
(c) Va´zquez, R.; de la Fuente, M. C.; Castedo, L.;
Dom´ınguez, D. Synlett 1994, 433–434; (d) De la Fuente,
M. C.; Castedo, L.; Dom´ınguez, D. J. Org. Chem. 1996,
61, 5818–5822.
3. Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987,
109, 236–239.
4. (a) N-Pf-oxazolidinones derived from amino acids have
previously been used in our laboratory for the
intramolecular acylation of aryllithium derivatives: Paleo,
M. R.; Castedo, L.; Dom´ınguez, D. J. Org. Chem. 1993,
58, 2763–2767; (b) More recently, intermolecular reac-
tions with Li and Mg organometallics have been
described: Paleo, M. R.; Calaza, M. I.; Sardina, F. J. J.
Org. Chem. 1997, 62, 6862–6869.
5. Solid 7 (1.0 g, 4.38 mmol) was added in small portions,
with stirring at rt, to a solution of thionyl chloride (0.40
ml, 5.48 mmol) in 15 ml of dry hexane and the mixture
was refluxed under anhydrous conditions (CaCl2 tube)
for 30 min. After cooling in an ice-bath, the solvent was
decanted off and the solid residue was washed twice with
dry hexane, dried under vacuum, and dissolved in 10 ml
of dry THF. This solution was added through a cannula
to a solution of the sodium salt of N-tosyl amino-
The above mechanistic hypothesis suggested an even
more direct way of getting the required amino ketone
10, namely by intermolecular reaction of xanthen-9-ol 7
with N-tosyl aminoacetaldehyde dimethyl acetal under
the same acidic conditions as in the intramolecular case.
This procedure led to an improved 64% yield of 10 after
chromatographic purification.7,10
Finally, reaction of 10 in chloroform with 37% aq.
formaldehyde in the presence of boron trifluoride di-
ethyl etherate afforded a 90% yield of [2]benzazepinone
2.7,11 In this way, we constructed the N-tosyl-
[2]benzazepinone analogue of clavizepine in two steps

A. Garc´ıa et al. / Tetrahedron Letters 42 (2001) 665–667
667
acetaldehyde dimethyl acetal in 10 ml of THF, and the
resulting mixture was refluxed for 3 h. The solvent was
then evaporated and the residue partitioned between
EtOAc and water. After evaporation of EtOAc the
residue was crystallised from Et2O–hexane affording 0.62
resulting mixture was stirred for 0.5 h and then poured
onto water and extracted with EtOAc. After evaporation
of the organic solvent the residue was chromatographed
on an SiO2 column (30/70, EtOAc/hexane), affording
1
0.60 g (64%) of 10 as an oil. H NMR l 7.48 (d, J=8.5,
1
g (30%) of 8b. Mp 114–117°C. H NMR l 7.91 (d, J=8,
2H), 7.31–6.89 (m, 8H), 6.58 (dd, J=7.5 and 2, 1H), 5.11
(t, J=5.5, 1H), 4.90 (s, 1H), 3.96 (s, 3H), 3.69 (d, J=5.5,
2H), 2.39 (s, 3H).
2H), 7.39 (d, J=8, 2H), 7.28–7.14 (m, 3H), 7.03–6.84 (m,
3H), 6.66 (dd, J=7.5 and 1.5, 1H), 6.43 (1H, s), 3.92 (s,
3H), 3.67 (t, J=5.0, 1H), 3.04–2.98 (m, 2H), 2.92 (s, 3H),
2.89 (s, 3H), 2.49 (s, 3H).
11. To a solution of 10 (1.0 g, 2.36 mmol) in 35 ml of dry
chloroform at 0°C under Ar were added 37% aq. formal-
dehyde (0.26 ml) and BF3·OEt2 (1.26 ml, 7.50 mmol).
After stirring for 90 min, the reaction mixture was poured
onto water and basified with 10% NH4OH. The organic
phase was concentrated and purified on a silica gel
column eluted with methylene chloride, affording 0.91 g
(90%) of 2 as a white solid. Mp 205°C (decomp.). 1H
NMR l 7.79 (d, J=8, 2H), 7.41 (d, J=8, 2H), 7.29 (td,
J=8.3 and 1.2, 1H), 7.17 (dd, J=8.5 and 1.2, 1H), 7.07
(td, J=7.5 and 1.5, 1H), 6.87 (d, J=8.5, 1H), 6.81 (d,
J=8.5, 1H), 6.68 (dd, J=7.5 and 1, 1H), 5.15 (s, 1H),
5.11 (d, J=14.5, 1H), 4.44 (d, J=18.5, 1H), 4.40 (d,
J=14.5, 1H), 3.90 (s, 3H), 3.73 (d, J=18.5, 1H), 2.49 (s,
3H). 13C NMR l 201.9 (CO), 150.8, 148.6, 144.7, 141.1,
135.4, 130.6 (3×CH), 129.6 (CH), 127.6 (2×CH), 124.0,
123.7 (CH), 123.6 (CH), 117.0 (CH), 116.4, 115.4, 111.6
(CH), 56.6 (OCH3), 53.4 (CH2), 51.6 (CH2), 46.9 (CH),
21.9 (CH3). IR (KBr): 1734 cm−1. MS FAB 436 (M+1,
8%), 435 (7%), 404 (2%), 348 (6%). HRMS (FAB): calcd:
436.1219; found: 436.1215.
6. Filippatos, E.; Papadaki-Valiraki, A.; Roussakis, C.; Ver-
bist, J. F. Arch. Pharm. (Weinheim Ger.) 1993, 326,
451–456.
7. All new compounds were fully characterised spectroscop-
ically and had satisfactory elemental analyses or HRMS
data.
8. A similar acid catalysed rearrangement of N,N-dibenzyl-
2-aminopropanal to N,N-dibenzyl-1-aminopropanone
has recently been described: Adia, M. H.; Whiting, A.
Tetrahedron Lett. 1997, 38, 3101–3102.
9. Acetal 8c was prepared by acetylation of 8a (Ac2O, THF,
K2CO3, −20°C, 12 h), which was obtained from xanthen-
9-ol 7 by condensation with aminoacetaldehyde dimethyl
acetal (100 mol%) in refluxing toluene containing AcOH
(30 mol%).
10. Commercial 33% HBr in AcOH (3ml) was added drop-
wise at rt to a solution of xanthen-9-ol 7 (0.5 g, 2.19
mmol) and N-tosyl aminoacetaldehyde dimethyl acetal
(0.75 g, 2.80 mmol) in 1.5 ml of glacial acetic acid. The
.
.