A short synthesis of lennoxamine via ynamides

Article abstract of DOI:10.1016/j.tetlet.2005.11.093

Lennoxamine was synthesized in eight steps from 2,3-dimethoxybenzoic acid via an intermediate ynamide by using palladium-catalyzed Heck-Suzuki-Miyaura domino reactions.

Full text of DOI:10.1016/j.tetlet.2005.11.093

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 767–769
A short synthesis of lennoxamine via ynamides
Sylvain Couty, Christophe Meyer and Janine Cossy*
Laboratoire de Chimie Organique, associ e´ au CNRS, ESPCI, 10 rue Vauquelin 75231 Paris Cedex 05, France
Received 14 October 2005; revised 15 November 2005; accepted 18 November 2005
Abstract—Lennoxamine was synthesized in eight steps from 2,3-dimethoxybenzoic acid via an intermediate ynamide by using pal-
ladium-catalyzed Heck–Suzuki–Miyaura domino reactions.
Ó 2005 Elsevier Ltd. All rights reserved.
Polycyclic nitrogen containing heterocycles are encoun-
tered in naturally occurring alkaloids and numerous
physiologically active drugs. Lennoxamine, an iso-
O
X
ArB(OH)2
O
R1
cat. Pd(0), base
1
R2
N
R2
N R1
indolobenzazepine alkaloid, belongs to the aporhoedane
series and was extracted from the Chilean plant Berberis
THF, reflux
A
B
H
2
Ar
S
darwinii (Fig. 1). Although this compound has no
important biological activity, its unique structural fea-
ture, five- and seven-membered rings fused with an aro-
matic moiety, has rendered this molecule attractive as a
synthetically challenging target. Several total syntheses
of lennoxamine have been reported relying on the
Scheme 1. Synthesis of 3-(arylmethylene)isoindolin-1-ones by Heck–
Suzuki–Miyaura domino reactions.
As lennoxamine can arise from the cyclization of an iso-
3
construction of ring B or/and ring C as the key steps.
indolinone of type C under acidic conditions followed
3
i,p
by catalytic hydrogenation, it was envisaged to apply
the Heck–Suzuki–Miyaura reactions to an ynamide of
type D. The latter compound should be prepared from
Recently, we have shown that 3-(arylmethylene)isoindo-
lin-1-ones of type B could be obtained from ynamides of
type A by using palladium-catalyzed Heck–Suzuki–
Miyaura domino reactions in the presence of an aryl-
2,3-dimethoxybenzoic acid 1 (Scheme 2).
4
boronic acid (Scheme 1).
OMe
A
OMe
O
RO
O
MeO
MeO
OR
O
OMe
O
B N
N
MeO
C
A
B N
lennoxamine
C
C
D
O
(HO)2B
E
D
O
O
Pd(0)
O
O
E
lennoxamine
Figure 1. Structure of lennoxamine.
O
O
OMe O
OMe O
MeO
MeO
OR
OH
N
Keywords: Lennoxamine; Isoindolinones; Isoindolobenzazepines;
Suzuki–Miyaura coupling; Palladium-catalyzed reactions.
OR
Br
1
D
*
Corresponding author. Tel.: +33 1 40 79 44 29; fax: +33 1 40 79 46
0; e-mail: janine.cossy@espci.fr
6
Scheme 2. Retrosynthetic analysis of lennoxamine.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.093

768
S. Couty et al. / Tetrahedron Letters 47 (2006) 767–769
O
Br
Br
1) SOCl , reflux
2
N
N
OMe O
OMe O
OMe O
OMe
2
) H N
2
MeO
MeO
OMe
MeO
O
OH
N
H
OH
2
4 OMe
OMe
aq. NaOH, rt
Br
Et N, cat. DMAP
Br
3
1
3
5
1
00%
CH Cl , rt
2
2
1
) KHMDS, toluene
6
7%
0
I
°C to rt
TfO
Ph
B(OH)2
2)
SiMe3
O
O
6
47%
OMe
O MeO
N
9
MeO
OMe
OMe O
OMe O
Pd(OAc) (5 mol%)
2
MeO
OMe
OMe
MeO
OMe
OMe
PPh3 (10 mol%)
n-Bu NF
N
4
N
O
O
aq. NaOH, THF, reflux
77%
THF, 0 ˚C
90%
Br
Br
1
0
8
7
SiMe3
(
E)/(Z) = 85/15
H , cat. Pd(10%)/C
2
MeOH, rt
8
0%
OMe
OMe
OMe
O
N
O MeO
N
O
H2
MeO
OMe
MeO
MeO
H SO
2
cat. Pd(10%)/C
4
N
AcOH, rt
60%
AcOH, rt
65%
1
1
12
lennoxamine
O
O
O
O
O
O
Scheme 3. Synthesis of lennoxamine.
The synthesis of lennoxamine (Scheme 3) began with
the bromination of 2,3-dimethoxybenzoic acid 1 with
[(E):(Z) = 85:15].8,9 The latter result was in sharp con-
trast with our initial observation that 3-(arylmethyl-
ene)isoindolin-1-ones of type B were obtained with
high (E) stereoselectivity by Heck–Suzuki–Miyaura
1
,3-dibromo-5,5-dimethylhydantoin 2 (aqueous NaOH,
5
rt), which led to 2,3-dimethoxy-6-bromobenzoic acid
in quantitative yield. Carboxylic acid 3 was converted
4
3
domino reactions from ynamides of type A. Carbopal-
to the corresponding acyl chloride (SOCl , reflux) and
the latter was coupled with aminoacetaldehyde dimethyl
ladations of alkynes are known to involve a syn-addition
process but isomerization of the initially formed r-vinyl-
palladium complex has been observed in some cases,
presumably through a zwiterrionic palladium–carbene
2
acetal 4 (Et N, cat. DMAP, CH Cl , rt) to afford the
3
2
2
secondary amide 5 in 67% overall yield (one-pot pro-
cess). After the formation of the potassium amide
1
0
complex. Although such a scenario cannot be ruled
out in the carbopalladation of the triple bond of yna-
mide 8, the particular structure of 3-(arylmethylene)iso-
indolin-1-one 10, which possesses a rather electron-rich
enamide moiety, may be responsible for the observed
isomerization. The latter could occur through a revers-
ible protonation of the double bond or a hydration–
(
KHMDS, toluene, 0 °C to rt) and condensation with
6
the alkynyliodonium salt 6, ynamide 7 was obtained
in modest yield (47%). Alternative alkynylation proce-
dures did not provide satisfactory results in the case of
7
amide 5. The trimethylsilyl group was then removed
by treatment of 7 with tetrabutylammonium fluoride
in THF to afford the terminal ynamide 8 (90%). The
next task, that constitutes the key step of our synthetic
plan, was to construct ring B and hence elaborate the
isoindolone core of lennoxamine by the palladium-catal-
1
1–13
dehydration pathway.
A photochemical process
could also be involved due to the light sensitivity of
compound 10.
4
yzed Heck–Suzuki–Miyaura domino reactions. Thus,
However, this lack of stereoselectivity in the synthesis of
compound 10 had no consequence for the total synthesis
of lennoxamine since the mixture of geometric isomers
was subsequently subjected to a catalytic hydrogenation
the terminal ynamide 8 was treated with a catalytic
amount of Pd(OAc) (5 mol %), PPh (10 mol %) and
2
3
a base (aqueous NaOH) in the presence of the commer-
cially available boronic acid 9 that incorporates both the
D and E rings of the natural product (THF, reflux).
Under these conditions, the Heck–Suzuki–Miyaura
domino reactions proceeded smoothly and the resulting
(cat. Pd (10%)/C, 1 atm H , MeOH, rt) that led to
2
3-(arylmethyl)isoindolin-1-one 11 in 60% yield. Comple-
tion of the total synthesis could be achieved from com-
3
i,3p
pound 11, as previously reported,
by treatment
3
7
-(arylmethylene)isoindolin-1-one 10 was isolated in
7% yield but as a mixture of two geometric isomers
under acidic conditions (H SO in AcOH, rt) that served
to elaborate the seven-membered ring (ring C) and the
2
4
3
i

S. Couty et al. / Tetrahedron Letters 47 (2006) 767–769
769
resulting dehydrolennoxamine 12 (60%) was finally
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spectroscopic and analytical data of this compound
were in perfect agreement with those reported in the
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A concise route to lennoxamine has been developed
from 2,3-dimethoxybenzoic acid (8 steps, 7% overall
yield) using a strategy complementary to the previously
reported approaches for the construction of the isoindo-
lone core of this isoindolobenzazepine alkaloid, that
relies on palladium-catalyzed Heck–Suzuki–Miyaura
domino reactions from an intermediate ynamide.
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Acknowledgements
We thank Johnson and Johnson for financial support
. The ratio of the two geometric isomers was determined by
(
(
Focus Giving Award to J.C.) and Dr. Axel Couture
Universit e´ des Sciences et Technologies de Lille) for
1
H NMR and their configuration was readily assigned by
3i
comparison with the data reported for the (E)-isomer. It
providing us with a detailed experimental procedure
for the cyclization of compound 11.
was checked that purification of compound 10 by chro-
matography on silica gel did not lead to any isomerization
since the crude product was already an 85/15 isomeric
mixture.
9
. As alkynylsilanes are known to be deprotected under
alkaline conditions, the preparation of 10 could also be
directly achieved from trimethylsilylynamide 7 by initial
treatment with the base (aq NaOH, THF, reflux) followed
by addition of the palladium catalyst and arylboronic acid
9 although the overall yield of compound 10 was not
improved by this one-pot procedure.
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3
9
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