Synthesis of indanones by sequential Heck-reduction-cyclization-alkylation (HRCA) reactions

Article abstract of DOI:10.1016/j.tetlet.2011.11.042

A simple and efficient synthesis of indanones, bearing a quaternary carbon centre, has been developed. The method features, in a one-pot process, the use of a multi-task palladium catalyst for the sequential Heck-reduction reactions, followed by a base-me

Full text of DOI:10.1016/j.tetlet.2011.11.042

Tetrahedron Letters 53 (2012) 338–341
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Tetrahedron Letters
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Synthesis of indanones by sequential Heck-reduction–cyclization–alkylation
(HRCA) reactions
Luma Nassar-Hardy a, Sandy Fabre a, Atef M. Amer b, Eric Fouquet a, François-Xavier Felpin a,c,
⇑
a Université de Bordeaux, CNRS-UMR 5255, Institut des Sciences Moléculaires (ISM), 351 Cours de la Libération, Talence 33405, France
b Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
c Université de Nantes, UFR Sciences et Techniques, CNRS-UMR 6230, CEISAM, 2 Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of indanones, bearing a quaternary carbon centre, has been developed.
The method features, in a one-pot process, the use of a multi-task palladium catalyst for the sequential
Heck-reduction reactions, followed by a base-mediated cyclization–alkylation sequence. This methodol-
ogy, called Heck-reduction–cyclization–alkylation (HRCA), is carried out under mild and simple experi-
mental conditions with the use of inexpensive reagents. The mild conditions have been made possible
by the use of diazonium salts that allow Heck couplings at moderate temperature (40 °C) under
ligand-free conditions.
Received 24 October 2011
Revised 6 November 2011
Accepted 9 November 2011
Available online 15 November 2011
Keywords:
Aryl diazonium salt
Palladium
Ó 2011 Elsevier Ltd. All rights reserved.
Heck reaction
Indanone
One-pot reaction
The indanone skeleton is an important structure in medicinal
chemistry that has been incorporated in many biologically active
compounds having anti-cancer1 (Indanocine 1) or anti-neurode-
generative activities.
For instance, the marketed drug Donepezil 2 is a potent acetyl-
choline esterase inhibitor prescribed for the treatment of Alzhei-
mer’s disease (Scheme 1).2 Indanone moieties are also frequently
encountered in biologically active natural products such as Paucifl-
oral F 33 and Pterosin K 4.4
the synthesis of indanones bearing a quaternary carbon centre
(Scheme 2, Eq. 5).
The general approach for the synthesis of indanones was related
to our recently reported HRC sequences and was based on Heck
cross-coupling of a 2-carboxymethyl aryl diazonium tetrafluorobo-
rate A with the methyl vinyl ketone 5 (Scheme 3).8,9 A subsequent
Pd-catalysed hydrogenation of the olefin B would give the corre-
sponding ketoester C, which should cyclize under base-mediated
conditions. The generated diketo-anion D could be then trapped
We have recently reported the use of a palladium multi-task
catalyst for the synthesis of various heterocycles including oxin-
dole,5 2-quinolone6 and 1,2-dihydroisoquinolin-3-ones7 through
Heck-reduction–cyclization (HRC) sequences (Scheme 2, Eqs. 1–
4). Our concept allowed four transformations in the same pot with
one C–C bond formation, two reductions and one cyclization. The
use of aryl diazonium salts as ‘super-electrophiles’ was a key to
the success of our strategy. Indeed, due to their high reactivity
we were able to work with simple and mild experimental condi-
tions.5–7 Moreover, aryl diazonium salts were easily accessed by
diazotation of inexpensive anilines with sodium nitrite or t-buty-
lnitrite and can be stored at À20 °C for several years. In this Letter
we wish to extend this concept to non-heterocyclic substrates with
NH2
O
O
MeO
MeO
MeO
MeO
Me
OH
N
Me
2
Donepezil :
1
Indanocine :
O
HO
Cl
OH
Me
O
Me
OH
Me
OH
HO
Pterosin K : 4
HO
Paucifloral F :
⇑
Corresponding author at present adress: Université de Nantes, UFR Sciences et
Techniques, CNRS-UMR 6230, CEISAM, 2 Rue de la Houssinière, BP 92208, 44322
Nantes Cedex 3, France. Tel.: +33 251 125 422; fax: +33 251 125 402.
E-mail address: fx.felpin@univ-nantes.fr (F.-X. Felpin).
3
Scheme 1. Structure of Indanicine 1, Donepezil 2, Paucifloral F 3 and Pterosin K 4.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.042

L. Nassar-Hardy et al. / Tetrahedron Letters 53 (2012) 338–341
339
Table 1
N2BF4
Optimization studies for the HRC sequence
HRC
CO2Me
O
O
R2
+
+
1. Pd(OAc)2 (5 mol%)
THF, 40°C, 12 h
R1
O
Ref. 5
O
NO2
OCH3
N
H
R1
R2
+
O
5
2. H2, 25°C, 5 h
3. NaOEt, 35°C, 15 h
N2BF4
Eq. 1
7a
6a
R2
"Standard" conditions
N2BF4
Entrya
Variation from the ‘standard’ conditions
Yieldb (%)
HRC
R1
CO2Me
NO2
Ref. 6
1
2
3
4
5
6
None
56
0
42
25
0
R2
N
H
MeOH instead of THF
12 h instead of 5 h for step 2
NaH instead of NaOEt
NaOMe instead of NaOEt
t-BuOK instead of NaOEt
O
R1
Eq. 2
N2BF4
NO2
R2
R2
45
HRC
R1
+
a
Ref. 6
Reaction conditions: methyl vinyl ketone (2 mmol), diazonium salt (1 mmol),
Pd(OAc)2 (5 mol %) in THF at 40 °C for 12 h, then H2 for 5 h at 25 °C, then NaOEt
(10 mmol) for 15 h at 35 °C.
CO2CH3
N
H
O
Eq. 3
R1
b
Yields of isolated products.
R2
N2BF4
HRC
CO2Me
O
+
Ref. 7
sequence worked well, the cyclization did not proceed whatever
the base used (entry 2). The hydrogenation time also proved to
be crucial for the success of the sequence (entry 3). Indeed, under
a prolonged reaction time, a significant amount of methyl-2-buty-
lbenzoate, resulting from the over reduction of the ketone function,
was observed, likely due to the presence of HBF4 in the solution.
After extensive experimentations we found that the reduction
was best achieved in 5 h, limiting the formation of methyl-2-buty-
lbenzoate (<10%) and achieving full conversion of the coupling
product. Surprisingly, the cyclization step was strongly dependant
on the structure and the quality of the base (entries 4–6). With old
batches of bases, we observed significant diminished yields, likely
due to the presence of hydroxide ions. For some reason we were
unable to achieve the cyclization with NaOMe as a base. While this
result remains unclear at this time, we believe that the high
hygroscopy of NaOMe could prevent sodium hydroxide-free
conditions.
Having optimized the reaction conditions for the first three
steps, we explored the opportunity of telescoping the diketo-anion
D with an electrophile to get highly functionalized indanones bear-
ing a quaternary carbon centre. Towards this end, we screened a
variety of alkyl, allyl, propargyl and benzyl halides as depicted in
the Table 2. We obtained indanones with very practical yields, typ-
ically in the range of 40–50%.12 While these yields could be consid-
ered as rather modest, as it should be kept in mind that four
different steps are carried out in the same flask. Thereby, a better
indicator of the efficiency of the methodology can be found with
the average yield per step over the whole process. As reported in
Table 2 (see yields in brackets), calculated yields per step are in
the range of 75–85%. For such simple experimental conditions, this
efficiency is quite relevant. The introduction of allyl (entries 2 and
8) or propargyl (entries 3 and 9) functions as well as halogenated
aryls (entries 5 and 6) opened the way for further transformations
by standard synthetic chemistry of metal-mediated cross-
couplings.
CN
NH
R1
R2
Eq. 4
R1
O
O
R2
HRCA
OCH3
+
R1
This work
O
N2BF4
R1
O
Eq. 5
Scheme 2. Variations in the HRC strategy.
O
O
[Pd]
OCH3
OCH3
R1
+
R1
Heck
O
N2BF4
B
A
5
O
O
O
O
H2, [Pd]
Reduction
Base
Cyclization
OCH3
O
R1
R1
D
C
O
> Use of dual properties of palladium
> Creation of a quaternary carbon
> Four steps in a one-flask sequence
R
R
X
O
R1
Alkylation
E
Scheme 3. General strategy for accessing indanones E.
with an electrophile to give the corresponding indanones E. This
sequence allows four different steps in the same flask with a Heck
reaction, a hydrogenation, a base-mediated cyclization and an
alkylation (HRCA). Our HRCA method aims to exploit, in a one flask
sequence, the dual properties of a palladium catalyst (C–C bond
formation and hydrogenation) which have been mostly overlooked
for the preparation of elaborated compounds.10
We started our studies with the optimization of the Heck-
reduction–cyclization sequence on a model reaction involving the
coupling of 2-carboxymethyl diazonium tetrafluoroborate 6a11
with methyl vinyl ketone 5 (Table 1). We found that the corre-
sponding indanone 7a could be obtained when THF was selected
as the reaction solvent and NaOEt as a base in a promising yield
over the three steps (56%). In MeOH, while the Heck-reduction
The reaction time of the alkylation step has been carefully opti-
mized through in situ 1H NMR analyses on a model reaction
(Scheme 4). Indeed, the alkylation step proved to be a rather slow
process, requiring usually 20–24 h of stirring for a complete con-
version. However, under prolonged reaction time (48 h), we ob-
served the formation of a substantial amount of the unexpected
product 10 arising from a double alkylation at carbon 2 (Scheme
4). This by-product was likely formed through alkylation of enolate
12 arising from a retro-type claisen fragmentation of 11.

340
L. Nassar-Hardy et al. / Tetrahedron Letters 53 (2012) 338–341
Table 2
Scope of the HRCA process
O
1. Pd(OAc)2 (5 mol%)
THF, 40°C, 12 h
O
R2
OCH3
O
+
N2BF4
6a-b
2. H2, 25°C, 5 h
R1
R1
O
5
9a-j
3. NaOEt, 35°C, 15 h
4. R2-X, 35°C, 24 h
Entrya
Diazonium
R2–X
Indanone
Yieldb (%)
52 (85)
O
Me
I
O
8a
Me
OMe
1
N2BF4
O
6a
6a
6a
9a
9b
O
Br
O
O
8b
OMe
N2BF4
O
2
3
43 (81)
47 (83)
O
O
Br
8c
OMe
N2BF4
9c
O
Br
O
O
OMe
N2BF4
8d
4
5
56 (86)
31 (75)
6a
6a
6a
9d
O
O
O
Br
OMe
N2BF4
Br
8e
Br
9e
O
I
Br
OMe
N2BF4
I
8f
O
6
50 (84)
9f
O
O
Me
I
O
O
8a
MeO
MeO
MeO
MeO
Me
OMe
7
8
40 (80)
33 (76)
N2BF4
O
6b
6b
6b
9g
O
Br
8b
8c
MeO
MeO
MeO
MeO
OMe
N2BF4
9h
9i
O
O
O
Br
O
O
MeO
MeO
MeO
MeO
OMe
N2BF4
9
31 (75)
47 (83)
O
Br
MeO
MeO
OMe
N2BF4
8d
MeO
MeO
10
6b
O
9j
a
Reagents and conditions: methyl vinyl ketone (2 mmol), diazonium salt (1 mmol), Pd(OAc)2 (5 mol %) in THF at 40 °C for 12 h, then H2 for 5 h at 25 °C, then NaOEt
(10 mmol) for 15 h at 35 °C, then R2–X (3 mmol) at 35 °C for 24 h.
b
Yields of isolated product. Yields in bracket are the average yields per step. All compounds gave satisfactory spectroscopic data.

L. Nassar-Hardy et al. / Tetrahedron Letters 53 (2012) 338–341
341
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O
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11. Diazonium salts 6a and 6b were prepared following a published procedure: (a)
Hanson, P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,
Perkin Trans. 2 2002, 1126–1134; (b) Hanson, P.; Jones, J. R.; Taylor, A. B.;
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MeO
MeO
Bn-Br
+
35°C, 48 h
MeO
MeO
9j,
O
10
, 35% yield
~15% yield
O
O
MeO
MeO
Bn-Br
-CH3CO2Et
MeO
MeO
EtO
12
O
11
Scheme 4. Formation of a dialkylated by-product.
In summary, we have disclosed a novel approach for the synthe-
sis of indanones bearing a quaternary carbon centre by the mean of
a HRCA sequence. We exploited the high reactivity of diazonium
salts under palladium catalysis for developing simple experimental
conditions compatible with the four different steps carried out in
the same flask. We anticipate that such an approach could be use-
ful for synthetic and medicinal chemists involved in the prepara-
tion of indanone-based targets. Alternatively, we believe that this
concept could also be extended to other elaborated structures of
interest. We are currently working on an asymmetric version of
the HRCA strategy. These new exciting developments will be re-
ported in due course.
Acknowledgments
We gratefully acknowledge the ‘Université de Bordeaux’, the
‘Centre National de la Recherche Scientifique’ (CNRS), and the
‘Agence Nationale de la Recherche’ (ANR JCJC 7141) for the finan-
cial support of this project. A.M.A. thanks the European Commis-
sion for a FFEEBB mobility scholarship.
12. For a representative procedure: To a solution of methyl vinyl ketone 5 (166 lL,
2 mmol) in dry THF (8 mL) was added the diazonium salt 6a (250 mg, 1 mmol)
and Pd(OAc)2 (5 mol %) and stirred for 12 h at 40 °C. The resulting mixture was
then cooled to 25 °C and stirred under an atmosphere of H2 for 5 h. Then, a
solution of EtONa (680 mg, 10 mmol) in THF (8 mL) was added to the reaction
References and notes
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quenched with water, extracted with CH2Cl2 (three times), dried over MgSO4,
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(10% EtOAc–petroleum ether) gave the desired indanone 9a (52% yield) as a
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m .
1589, 1607, 1699, 1723, 2931, 2974, 3035 cmÀ1 1H NMR
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3.82 (d, 1H, J = 17.6 Hz), 7.35–7.40 (m, 1H), 7.47 (dt, 1H, J = 7.6 Hz), 7.58–7.64
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