Sequential amino-Claisen rearrangement/intramolecular 1,3-dipolar cycloaddition/reductive cleavage approach to the stereoselective synthesis of cis-4-hydroxy-2-aryl-2,3,4,5-tetrahydro-1(1H)-benzazepines

Article abstract of DOI:10.1055/s-2006-949654

A novel stereoselective synthesis of cis-2-aryl-4-hydroxy-2,3,4,5- tetrahydro-1-benzazepines from N-allylanilines utilizing aromatic amino-Claisen rearrangement and intramolecular 1,3-dipolar cycloaddition methodologies is described. This sequence involve

Full text of DOI:10.1055/s-2006-949654

LETTER
2275
Sequential Amino-Claisen Rearrangement/Intramolecular 1,3-Dipolar
Cycloaddition/Reductive Cleavage Approach to the Stereoselective Synthesis
of cis-4-Hydroxy-2-aryl-2,3,4,5-tetrahydro-1(1H)-benzazepines
Stereoselectiv
a
S
ynthesis
n
of cis-4-Hyd
d
roxy-2-aryl-
r
2,3,4, 5-t
a
etrahydro-1(
1
H)-L
a
Laboratorio de Síntesis Orgánica, Centro de Investigación en Biomoléculas, Escuela de Química, Universidad Industrial de Santander,
A.A., 678 Bucaramanga, Colombia
Fax +57(76)349069; E-mail: apalma@uis.edu.co
b
Laboratorio de RMN, Grupo de Productos Naturales, Departamento de Química, Universidad de Los Andes, Mérida 5101, Venezuela
Received 18 May 2006
The synthetic route to the novel compounds is outlined in
Scheme 1. The starting materials, anilines 1a–g, obtained
by direct reductive amination of the corresponding benz-
aldehydes with sodium cyanoborohydride (NaBH3CN),13
Abstract: A novel stereoselective synthesis of cis-2-aryl-4-hy-
droxy-2,3,4,5-tetrahydro-1-benzazepines from N-allylanilines uti-
lizing aromatic amino-Claisen rearrangement and intramolecular
1,3-dipolar cycloaddition methodologies is described. This se-
quence involves N-allylation of corresponding N-benzylanilines were alkylated by treatment with an excess (2 equiv) of
followed by amino-Claisen rearrangement, subsequent oxidation
allyl bromide in the presence of potassium carbonate in
with in situ 1,3-dipolar cycloaddition affording isoxazolidines, and
finally reductive cleavage of the isoxazolidinic N–O bond.
acetone at reflux for 6–8 hours affording the correspond-
ing N-allylanilines 2a–g in good yield (65–95%). Intro-
duction of an allyl moiety at the ortho-position of the
Key words: amino-Claisen rearrangement, intramolecular 1,3-di-
polar cycloaddition, tetrahydro-1-benzazepines, ortho-allylanilines,
reductive cleavage
aniline amino group was achieved by the aromatic amino-
Claisen rearrangement14 of the N-allyl derivatives 2a–g.
Thus, rearrangement of these derivatives by heating in the
presence of 1.5 equivalents of boron trifluoride–diethyl
Tetrahydro-1-benzazepine derivatives have been exten-
ether complex (BF3·OEt2), as acid catalyst, at 140–150 °C
sively investigated synthetically and pharmacologically.
The diverse biological activities of these derivatives are
well known as highly potent and orally active non-peptide
for 2–5 hours (monitored by TLC) gave the expected
rearranged products 3a–g in moderate to good yields
(55–75%).
arginine vasopressin antagonists for both V1A and V2
In the past three decades, much attention has been focused
receptors,1 potent inhibitors of cyclin-dependent kinases,2
on the 1,3-dipolar cycloaddition of nitrone to olefin. This
potent and orally bioavailable growth hormone
type of reaction has proven to be a very powerful method
for the synthesis of five- and six-membered nitrogen-con-
secretagogue,3 antagonists of N-methyl-D-aspartate and
a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
taining heterocycles.15 However, to the best of our knowl-
(AMPA) receptors,4 antagonists of platelet-activating fac-
edge the intramolecular 1,3-dipolar cycloaddition using
tor,5 and promising agents against HIV-1 infection.6 The
N-benzyl-ortho-allylanilines as appropriate building
interesting biological activity of tetrahydro-1-benz-
blocks in the construction of tetrahydro-1-benzazepine
azepines make them attractive targets in organic synthe-
ring has not been explored yet. For this reason we exam-
sis, consequently several synthetic strategies for their
ined its applicability to the synthesis of 4-hydroxy-2-aryl-
2,3,4,5-tetrahydro-1-benzazepines.
synthesis have already been developed. This heterocyclic
system can be synthesized by the intramolecular Claisen-
type reaction,7 transition-metal-catalyzed oxidative N-
heterocyclization of amino alcohols,8 palladium- and
nickel-catalyzed intramolecular amination of aryl
bromides9 and aryl chlorides.10 Recently, the ring-closing
metathesis (RCM) methodology was also conveniently
applied for the synthesis of tetrahydro-1-benzazepines.11
Our continuing interest in ortho-allylaniline chemistry12
led us to explore a new and efficient synthetic approach
for the stereoselective synthesis of cis-2-aryl-4-hydroxy-
tetrahydro-1-benzazepines applying intramolecular 1,3-
dipolar cycloaddition as the key reaction.
Thus, ortho-allyl-N-benzylanilines 3a–g were subjected
to oxidation with 30% H2O2 in the presence of catalytic
amounts of sodium tungstate (Na2WO4) according to a
methodology described by Murahashi to obtain the corre-
sponding nitrones.16 Under the conditions employed, not
only the amino group was transformed to a nitrone, but
surprisingly an in situ intramolecular 1,3-dipolar cycload-
dition of nitrone to olefin also took place affording the
corresponding isoxazolidines 4a–g in low yield (20–
30%), and the starting ortho-allylanilines were recovered
in 40–50%. To increase the yield of cycloadducts, the or-
ganic residue obtained after removing the solvent (ace-
tone–H2O) and the catalyst was dissolved in toluene and
heated under reflux for 3–4 hours. In this thermal condi-
tion, cycloadducts were obtained in 40–60%, after column
SYNLETT 2006, No. 14, pp 2275–2277
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949654; Art ID: S11206ST
© Georg Thieme Verlag Stuttgart · New York

2276
S. L. Gómez Ayala et al.
LETTER
R
R
R
ii
R2
R1
R2
R1
R2
R1
i
N
H
N
N
H
2a–g
3a–g
1a–g
H
OH
R
R
R
O
+
N
v
iii, iv
N
N
–O
H
R1
R1
R1
R2
R2
R2
5a–g
4a–g
a: R = R1 = R2 = H; b: R = CH3, R1 = R2 = H; c: R = Cl, R1 = R2 = H; d: R = F, R1 = R2 = H;
e: R = OCF3, R1 = R2 = H; f: R = R2 = H, R1 = Cl; g: R = R1 = H, R2 = CH3
Scheme 1 Reagents and conditions: (i) BrCH2CH=CH2 (2 equiv), acetone, K2CO3, reflux, 6–8 h; (ii) BF3·OEt2 (1.5 equiv), 140–155 °C,
2–5 h, 25 °C then sat. Na2CO3 solution and extraction with CH2Cl2; (iii) 30% H2O2 (3–4 mol), Na2WO4·2H2O (4–6 mol%), acetone–H2O (9:1
v/v), 25 °C to –5 °C, 40–50 h, then H2O and extraction with CH2Cl2; (iv) toluene, reflux, 3–4 h; (v) Zn (6 mol), 80% AcOH (excess),
80–85 °C, 2–5 h, 25 °C then 5% NH4OH solution and extraction with EtOAc.
chromatographic purification on silica gel, together with a 5-Heq).18 The exclusive formation of cis-diastereomers
considerable amount of polymeric material.
may be explained by the stereospecific ring-opening of
exo-cycloadducts during the reductive cleavage of N–O
bond.
In all cases only one of the two possible diastereomers
was isolated. Cycloadducts 4a–g were shown to be exo-
cycloadducts as evidenced by NOESY experiments.17
In summary, the stereoselective synthesis of cis-2-aryl-4-
hydroxytetrahydro-1-benzazepines, based on one-pot ox-
idation–intramolecular 1,3-dipolar cycloadditon of ortho-
allylanilines followed by reductive cleavage of the isox-
azolidinic cycloadducts has been achieved. The method is
flexible enough to allow the synthesis of many cis-tet-
rahydro-1-benzoazepine derivatives, by simply varying
the substituents on both benzene nuclei. Furthermore, this
method could be potentially extended to the synthesis of
important bioactive molecules analogues.
Even though oxidation of ortho-allylanilines 3a–g afford-
ed in one-pot the desired cycloadducts 4a–g with high re-
gio- and stereocontrol, the relative poor yield of this
interesting transformation was a cause for concern. How-
ever, our attempts to improve the yields of cycloadducts
by changing the reaction temperature or by increasing the
relative quantity of the reagents and the reaction time
were unsuccessful. The scope and mechanistic details of
this one-pot transformation are under investigation and
will be described in a forthcoming publication.
Acknowledgment
Finally, when exo-cycloadducts 4a–g were subjected to
reductive cleavage of N–O bond using Zn in excess of
80% acetic acid at 80–85 °C for 2–5 hours, as expected,
the exclusive cis-2-aryl-4-hydroxytetrahydro-1-benzaze-
pines 5a–g were obtained in nearly quantitative yield after
column chromatographic purification on silica gel. The
relative configurations at the stereocenters of new com-
pounds 5a–g were assigned on the basis of NOESY exper-
iments, in which the methynic protons 4-H and 2-H gave
unambiguous cross signal. The 2-aryl groups are in equa-
torial positions, according to the geminal methine protons
2-Hax showing one large coupling about 11.1 Hz and one
small coupling about 2.1 Hz and therefore having exactly
one trans-axial and one cis-equatorial coupling partners,
namely 3-Hax and 3-Heq. The 4-hydroxy groups are also
positioned equatorially, according to the geminal methine
proton 4-Hax showing one large coupling about 10.1 Hz
and two small couplings about 3.7 and 1.6 Hz and there-
fore having two trans-axial coupling partners (3-Hax and
5-Hax) and two cis-equatorial coupling partners (3-Heq and
This work was supported by a Grant from the Colombian Institute
for Science and Research (Colciencias, No. 1102-05-13567).
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Synlett 2006, No. 14, 2275–2277 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of cis-4-Hydroxy-2-aryl-2,3,4,5-tetrahydro-1(1H)-benzazepines
2277
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(17) NMR data for exo-cycloadduct 4a: 1H NMR (400 MHz,
CDCl3): d = 2.58 (1 H, d, J = 16.5 Hz, 5-HA), 2.61–2.69 (2
H, m, 3-HAHB), 3.45 (1 H, dd, J = 16.6, 5.4 Hz, 5-HB), 4.62
(1 H, dd, J = 11.2, 4.4 Hz, 2-H), 4.97 (1 H, m, 4-H), 7.12 (1
H, dd, J = 6.6, 2.1 Hz, 9-H), 7.15–7.24 (3 H, m, 6-H, 7-H, 8-
H), 7.30 (1 H, t, J = 7.6 Hz, 4¢-H), 7.39 (2 H, t, J = 7.6 Hz,
3¢-H, 5¢-H), 7.50 (2 H, d, J = 7.2 Hz, 2¢-H, 6¢-H). 13C NMR
(100 MHz, CDCl3): d = 34.6 (5-C), 42.7 (3-C), 75.1 (4-C),
75.3 (2-C), 121.9 (9-C), 125.2 (5a-C), 125.9 (7-C), 126.4 (2¢-
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CDCl3): d = 2.14 (1 H, ddd, J = 11.0, 10.7, 10.5 Hz, 3-Hax),
2.22 (1 H, ddt, J = 11.0, 2.9, 1.9 Hz, 3-Heq), 3.03 (1 H, dt,
J = 13.6, 1.9 Hz, 5-Heq), 3.13 (1 H, dd, J = 13.6, 10.5 Hz, 5-
Hax), 3.88 (1 H, tdd, J = 10.5, 2.9, 1.9 Hz, 4-Hax), 3.98 (1 H,
dd, J = 11.0, 1.9 Hz, 2-Hax), 6.70 (1 H, d, J = 7.6 Hz, 9-H),
6.92 (1 H, t, J = 7.6 Hz, 7-H), 7.10 (1 H, t, J = 7.6 Hz, 8-H),
7.18 (1 H, d, J = 7.6 Hz, 6-H), 7.35 (1 H, t, J = 6.9 Hz, 4¢-H),
7.39 (2 H, d, J = 6.9 Hz, 2¢-H, 6¢-H), 7.43 (2 H, t, J = 6.9 Hz,
3¢-H, 5¢-H). 13C NMR (100 MHz, CDCl3): d = 44.7 (5-C),
48.5 (3-C), 61.3 (2-C), 70.0 (4-C), 120.1 (9-C), 121.8 (7-C),
126.6 (2¢-C, 6¢-C), 127.4 (8-C), 127.8 (4¢-C), 128.0 (5a-C),
128.9 (3¢-C, 5¢-C), 131.6 (6-C), 145.1 (1¢-C), 149.4 (9a-C).
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Synlett 2006, No. 14, 2275–2277 © Thieme Stuttgart · New York