New Heck coupling strategies for the synthesis of paullone and dimethyl paullone

Article abstract of DOI:10.1016/j.tetlet.2006.08.118

The short total synthesis of paullone (1) and dimethyl paullone (2) via a novel palladium-catalyzed intramolecular coupling using the o-bromo- and o-iodo anilides of indoles (3 and 3a) and N-methyl indole 4 is described.

Full text of DOI:10.1016/j.tetlet.2006.08.118

Tetrahedron Letters 47 (2006) 7987–7989
New Heck coupling strategies for the synthesis
of paullone and dimethyl paullone
a,
a
*
´
´
Jose Gustavo Avila-Zarraga, Armando Lujan-Montelongo,
b
c
´
´
´
Adrian Covarrubias-Zuniga and Moises Romero-Ortega
˜
aFacultad de Quı´mica, Universidad Nacional Auto´noma de Me´xico, Me´xico, D.F. 04510, Mexico
bInstituto de Quı´mica, Universidad Nacional Auto´noma de Me´xico, Me´xico, D.F. 04510, Mexico
cFacultad de Quı´mica, Universidad Auto´noma del Estado de Me´xico, Toluca, Edo. de Me´xico, Mexico
Received 10 July 2006; revised 22 August 2006; accepted 25 August 2006
Available online 26 September 2006
Abstract—The short total synthesis of paullone (1) and dimethyl paullone (2) via a novel palladium-catalyzed intramolecular
coupling using the o-bromo- and o-iodo anilides of indoles (3 and 3a) and N-methyl indole 4 is described.
Ó 2006 Elsevier Ltd. All rights reserved.
Paullones1 are a series of structures from 7,12-dihydro-
indolo[3,2-d]benzazepin-6(5H)-ones,2 which constitute
a class of CDK inhibitors.3 These cyclin-dependent
kinases2 (CDKs) are a family of serine–threonine
kinases that play a major role in cell cycle division. In
a wide variety of human tumors and tumor cell lines,
CDK-related mechanisms are deregulated.4 Synthetic
CDK-inhibitors have been studied as potential candi-
dates for treating neoplastic diseases.5 In addition,
paullones are potent inhibitors of glycogen synthase
kinase-3B (GSK-3B) and neuronal CDK5/p25.5 These
latter two enzymes cause hyperphosphorylation of the
microtubule-binding protein tau, a feature observed in
the brains of patients with Alzheimer’s disease.3 The
dual specificity of paullones makes them potentially very
useful agents for the treatment of neurodegenerative and
proliferative disorders.
thetic strategy involving a palladium-catalyzed boryl-
ation–Suzuki coupling reaction sequence.7
Here, we describe a short route for constructing paul-
lone (1) and dimethyl paullone (2) via a novel intra-
molecular cyclization of the indole derivatives 3, 3a
and 4, respectively (Scheme 1).
The indole derivative 3 and 3a8 were easily obtained by
treating 3-indolylacetic acid and o-bromo or o-iodo-
aniline with a solution of DCC in CH2Cl2. Based on
the precedent that one generalized intramolecular
O
O
R
R
N
N
X
N
R
N
R
Paullone (1) has been synthesized by the reaction of
anthranilic acid ethyl ester with ethyl succinoyl chloride
to yield an amide, on which Dieckmann condensation
was performed followed by a Fischer indole synthesis.1a
In addition, 1 can be obtained from 1,4-naphthoquinone
by the Schmidt reaction followed by catalytic reduction
and indolization.6 1 has also been prepared by a syn-
R= H, X=Br, 3
R= H, X=I, 3a
R= Me, X=Br, 4
R= H, 1, Paullone
R=Me, 2, Dimethyl paullone
O
NH2
OH
X
+
Keywords: Indole; Cyclization; Free radical; Palladium; Intramolecu-
lar; Paullones.
N
H
X=Br, I
*
Corresponding author. Tel./fax: +525 5622 3784; e-mail: gavila@
correo.unam.mx
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.118

7988
J. G. Avila-Za´rraga et al. / Tetrahedron Letters 47 (2006) 7987–7989
total synthesis of 1 in eight steps (1.27% yield) using as
O
O
R
R
key step a free radical cyclization of an iodoacetamide
derivative.12 Given the fact that there are two NH
groups in the starting material, it is noteworthy that
no N-arylation products were detected in the reaction
mixture. Furthermore, the starting material which had
not been consumed could be recovered in high yield,
and thus in principle is recyclable. We then decided to
test both the radical and the palladium based methods
for the intramolecular cyclization of the bis-N-methyl-
ated compound 4. After some optimization (base, sol-
vent, temperature), 413 was prepared from 3 in 82%
yield with powdered KOH and methyl iodide in
DMSO14 solution. The best result for the cyclization
via free radicals15 was obtained with n-Bu3SnH in the
presence of AIBN at 80 °C for 4 h, which yielded the
desired compound 2 (12%) in three steps and the
reduced compound 6 (60%, entry 5).
N
N
X
N
R
N
R
R= H, X=Br, 3
R= H, X=I, 3a
R= Me, X=Br, 4
R= H, 1
R= Me, 2
+
O
R
N
N
R
R= H, 5
R= Me, 6
Scheme 2.
For the palladium catalyzed cyclization16 with the com-
mon base K3PO4, we also found the two competitive
processes: the desired cross-coupling and the reduced
compound formation (entries 6 and 7). However, using
Cs2CO3 as a base17 in simple conditions we improve
the intramolecular palladium-catalyzed C2-arylation,
obtaining an excellent yield (86%) in three steps of the
desired dimethyl paullone (2), with low catalyst loading
in DMF as a solvent and 13% yield of the reduced
compound 6 (entry 8). The synthesis of 2 using the
iododerivatives, Pd(OAc)2, PPh3 and AgCO3, was
accomplished under similar conditions by Benoit and
co-workers.18
reaction had been used to synthesize heterocyclic com-
pounds on treatment with tributyltin hydride in the
presence of lauroyl peroxide (LP) or AIBN,9 we decided
to perform the cyclization via these conditions. Only the
reductive dehalogenation product 510 was obtained
under these and related conditions rather than the
desired product 1 (Scheme 2).
These negative results led us to explore an intramolecu-
lar palladium-catalyzed C-arylation of the aryl halide 3
and 3a in the presence of a base. Whereas the use of
the standard alkali metal base K3PO4 produced only
the reduced compound 5 (Table 1, entry 1), MgO, which
is reported to be the optimum base for the arylation of
indole and other (NH)-heteroarenes,11 gave paullone
(1) in two steps as the only product, albeit only in ca
9, 10% yield and the main product in 70% yield (Table
1, entries 2–4). Bremner and Sengpracha achieved a
In conclusion, this investigation presents a new, short,
practical method by which (NH 3, 3a and NMe 4)-
indoles may be intramolecularly cyclized to paullone 1
and dimethyl paullone 2 with low catalyst loading,
under Heck reaction conditions. Using free radicals we
get 2 and the reduced compounds 510 and 619 were the
major products. The application of the present method
carries the potential of also being extended to several
other products syntheses.
Table 1. Cyclization reactions with Palladium
Entry
1
Substrate
Conditionsa (mol)
Products (%)
3
K3PO4 (1.4)
5 (60)
3 (28)
Acknowledgments
2
3
4
5
6
7
8
3
MgO (1.4)
MgO (2.8)
MgO (2.8)
1 (9)
3 (88)
This research was supported by Facultad de Quimica
UNAM. Mexico. We thank Dr. J. Muchowski for help-
ful suggestion concerning this manuscript. We are also
grateful to Georgina Duarte, Margarita Guzman, Rosa
I. Del Villar, Victor Arrollo and Mericela Gutierrez for
their assistance in acquiring spectral data.
3
1 (10)
3 (78)
´
3a
4
1 (70)
5 (18)
´
n-BuSnH (1)
AIBN (1)
2 (12)
6 (60)
4
K3PO4 (1.4)
K3PO4 (1.2)
Cs2CO3 (1.4)
2 (46)
6 (36)
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.08.118.
4
2 (33)
6 (20)
4
2 (86)
6 (13)
a All yields were determined by GC–MS. Pd(OAc)2 was used in
0.1 mol. Solvents used: DMF (1–4, 6 and 8), DMA (7) and C6H6 (5);
temperature: 130 °C except 5 80 °C. Time: 4 h (5); 24 h (1–4); 30 h
(6–8).
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´
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