Synthesis of 1-arylidene-2,3-dihydro-1H-inden-2-ols through a tandem carbopalladation/Suzuki-Miyaura sequence

Article abstract of DOI:10.1016/j.tetlet.2008.04.042

A regio- and stereoselective synthesis of arylidene indenols has been developed. The key step involves a palladium-catalyzed tandem carbocyclization/Suzuki-Miyaura sequence.

Full text of DOI:10.1016/j.tetlet.2008.04.042

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3713–3715
Synthesis of 1-arylidene-2,3-dihydro-1H-inden-2-ols through
a tandem carbopalladation/Suzuki–Miyaura sequence
Estelle Marchal, Jean-Franßcois Cupif, Philippe Uriac, Pierre van de Weghe *
Laboratoire des Substances Liche´niques et Photoprotection, Faculte´ des Sciences Biologiques et Pharmaceutiques Universite´ de Rennes 1,
Avenue du Prof. L. Bernard, F-35043 Rennes Cedex, France
Received 14 March 2008; revised 2 April 2008; accepted 7 April 2008
Available online 10 April 2008
Abstract
A regio- and stereoselective synthesis of arylidene indenols has been developed. The key step involves a palladium-catalyzed tandem
carbocyclization/Suzuki–Miyaura sequence.
Ó 2008 Elsevier Ltd. All rights reserved.
Metal-catalyzed carbocyclization/cross-coupling reac-
tion has emerged as one of the most versatile and powerful
methods for the construction of polycyclic molecules from
acyclic precursors.1 Recently 3-alkylidene oxindoles, an
important class of natural alkaloids, were prepared by
intramolecular Heck reaction of arylbromides or iodides
to alkynes involving terminations of insertion cascades
as Sonogashira, Suzuki–Miyaura, or Heck cross-coupling
reactions.2 Zhu and co-workers achieved the synthesis of
3-arylidene oxindoles via a novel approach based on the
multicomponent reaction concept using a palladium-
catalyzed domino Songashira/carbopalladation/C–H activa-
tion/C–C bond forming sequence.3 Cyclocarbopalladation
of alkynes following a Suzuki–Miyaura cross-coupling ter-
mination was also employed for the synthesis of dibenzoxa-
pines.4 One example reported in the literature described
the preparation of alkylidene indenols by an intramolecu-
lar domino Heck double cyclization.5
Ar
R1
OR2
I
I
ArB(OH)2
[Pd]
steps
1
A
C
B
CO2Me
R2O
ArB(OH)2
R1
[Pd]
R1
[Pd]
OR2
Scheme 1. General approach.
tandem cyclocarbopalladation/Suzuki–Miyaura coupling
sequence. In this Letter, we describe a cascade bond forma-
tion proceeding smoothly by the use of palladium diace-
tate–triphenylphosphine as catalyst’s system in the
presence of CsF as base.
Substrates 3–6 for the tandem reaction were synthesized
in correct yields in few steps from the methyl 2-(2-iodo-
phenyl)acetate 1 (Scheme 2).
In an initial investigation, 3 was employed as the model
substrate in combination with PhB(OH)2 to examine the
best reaction conditions. Various palladium sources, bases,
and solvents were tested but no satisfactory and reproduc-
ible result was observed. Probably the presence of the free
As a continuation of our ongoing work on the prepara-
tion of potent photoprotective compounds,6 we report
herein our preliminary studies on the preparation of arylid-
ene indenols. The general approach we have employed is
outlined in Scheme 1. The key step was the projected
*
Corresponding author. Tel.: +33 2 23 23 38 03; fax: +33 2 23 23 47 90.
E-mail address: pierre.van-de-weghe@univ-rennes1.fr (P. van de
Weghe).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.042

3714
E. Marchal et al. / Tetrahedron Letters 49 (2008) 3713–3715
Table 1
I
I
I
I
a
b
c
Palladium-catalyzed tandem reactions
Ar
R1
OTBS
CO2Me
CHO
Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)
1
2
HO
R1 = Ph, 42%
TBSO
R1
R1
R1 = Ph, 74%
4 or 6
+ ArB(OH)2
3
5
4
CsF (2 equiv)
THF, 65 °C
R
1 = C3H7, 52%
6
R
1 = C3H7, 50%
7a-f : R1 = Ph
8a-b : R1 = C3H7
Scheme 2. Synthesis of substrates 3–6 for the tandem reaction. Reagents
and conditions: (a) DIBAH, Tol, ꢀ78 °C, 4 h (82%); (b) R1–C„CH,
BuLi, THF, 0 °C then 2, THF, rt, 12 h; (c) TBSCl, Im, CH2Cl2, rt, 12 h.
Entry Substrate Ar
Time (h) Product Yielda (%)
1
2
3
4
5
6
7
8
4
4
4
4
4
4
6
6
C6H5
5
7a
7b
7c
7d
7e
7f
75
71
58
70
72
77b
86
75
3,4-(MeO)2C6H3 20
3-Thienyl
4-NHBoc–C H4
20
3
hydroxyl group raises problem. Compound 4, prepared
after protection of the hydroxyl group of 3 as silylether,
was then submitted to various condition reactions. Best
conversions and yields were obtained by the use of
10 mol % Pd(OAc)2, 20 mol % PPh3, CsF as the base upon
THF at 65 °C (Eq. 1). We subsequently discovered that the
reaction is dependent on the base and solvent employed.
For example, in toluene instead THF or with K3PO4 as
the base, the starting material 4 was partially recov-
ered after 12 h (50–85% conversion following the reaction
conditions).
6
2-F–C6H4
2-Me–C6H4
C6H5
20
24
20
8a
8b
3,4-(MeO)2C6H3 20
a
Isolated yield (average of two or three runs).
2 equiv arylboronic acid and 2.5 equiv CsF.
b
Ar
Ar
R1
R1
OH
TBAF
OTBS
ð2Þ
THF, 0 °C to rt
7a-f : R1 = Ph
12 h
62 - 96%
9a-f : R1 = Ph
Ph
Ph
OTBS
Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)
8a-b : R1 = C3H7
10a-b : R1 = C3H7
I
+
PhB(OH)2
Ph
ð1Þ
Desilylation of indenols 7 and 8 with TBAF in THF led to
indenols 9 and 10 in good yields (Eq. 2). A careful analysis
of the 1H and 13C NMR spectra of the silylated indenols 7e
and 7f and deprotected indenols 9e and 9f showed that these
derivatives were isolated as inseparable mixtures of two
isomers in a 1/1 ratio. At first we thought that products
were obtained as a mixture of E and Z isomers resulting
from an isomerization in the course of the reaction. How-
ever, this hypothesis was quickly abandoned. Indeed oxida-
tion of 9e and 9f with the Dess–Martin periodinane gave
indenones 11e and 11f isolated as single compounds in
quantitative yields (Eq. 3). We suppose that there is an
absence of free rotation of the carbon–carbon bond bearing
the ortho-substituted aromatic ring. Consequently, deri-
vatives 7e, 7f, 9e, and 9f possess two sources of chirality;
a stereogenic center disappearing during the oxidation step
and a conformational chirality because of the hindrance of
the free rotation of the C–C bond (Fig. 2).9 The silylated
indenols 7e and 7f and indenols 9e and 9f are thus obtained
as mixtures of atropoisomers.
CsF (2 equiv)
THF, 65 °C, 5 h
75%
4
7a
TBSO
Only regioisomer 7a was isolated resulting from the for-
mation of organopalladium B (Fig. 1). Based on the previ-
ous observations of Overman et al. with alkenes, the
preferential formation of exo-arylidene organopalladium
intermediate B could be explained by the preference for
eclipsed alignment of the Pd–C r and alkyne p bonds (as
opposed to twisted leading the endo intermediate D) in
the carbopalladation step.7
Under these optimized conditions, various arylboronic
acids can be used to afford the products uniformly in high
yields (Table 1).8 The nature of the arylboronic acid does
not seem to have influence on the result of the reaction.
As expected, this tandem reaction is regio- and stereoselec-
tive, only the E isomer was obtained.
Ar
Ar
Ph
OH
Ph
O
[Pd]
R1
R1
DMP
R1
OR2
[Pd]
[Pd]
ð3Þ
[Pd]
OR2
exo-
R1
endo-
CH2Cl2, 0 °C to rt
9e : Ar = 2-F-C6H4
9f : Ar = 2-Me-C6H4
6 h
91 - 99%
11e : Ar = 2-F-C6H4
11f : Ar = 2-Me-C6H4
OR2
R1
B
D
[Pd]
OR2
With the optimized palladium-catalyzed process in hand,
we turned our attention to the preparation of 2H-indeno
[2,1-b] furan-2-one 15 (Scheme 3). The transformation of
aldehyde 2 into the precursor of cyclization 13 was readily
OR2
eclipsed
twisted
Fig. 1. Eclipsed versus twisted alignment.

E. Marchal et al. / Tetrahedron Letters 49 (2008) 3713–3715
3715
Acknowledgments
We gratefully acknowledge the CRMPO for mass mea-
stereogenic center
´
surements. We thank the Region Bretagne for the fellow-
ship to E.M. Financial support of this project by the
´
´
Universite de Rennes 1 and Rennes Metropole is gratefully
axial chirality
acknowledged.
(no C-C bond rotation)
Supplementary data
Fig. 2. Chem3D view of 9f.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.04.042.
I
I
I
a, b
c
References and notes
2
12
TBSO
13
TBSO
CHO
´
H
CO2Me
O
1. Negishi, E.-I.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev.
1996, 96, 365–393.
Ph
Ph
CO2Me
OTBS
2. (a) D’Souza, D. M.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem., Int.
Ed. 2005, 44, 153–158; (b) Cheung, W. S.; Patch, R. J.; Player, M. R. J.
Org. Chem. 2005, 70, 3741–3744; (c) Yanada, R.; Obika, S.; Inokuma,
T.; Yanada, K.; Yamashita, M.; Ohta, S.; Takemoto, Y. J. Org. Chem.
2005, 70, 6972–6975; (d) Arthuis, M.; Pontikis, R.; Florent, J.-C.
Tetrahedron Lett. 2007, 48, 6397–6400.
d
e
O
14
15
Scheme 3. Synthesis of indenofuranone 15. Reagents and conditions: (a)
HC„C–TMS, i-PrMgCl, THF, 0 °C then 2, 0 °C to rt, 3 h (80%); (b) (i)
TBSCl, Im, CH2Cl2, rt, 6 h; (ii) K2CO3 cat, MeOH, 10 h (85%); (c) 12, i-
PrMgCl, THF, 0 °C then ClCO2Me, 0 °C to rt, 3.5 h (64%); (d) PhB(OH)2,
10 mol % Pd(OAc)2, 20 mol % PPh3, CsF, THF, 65 °C, 6 h (84%); (e)
CF3CO2H (excess), THF/H2O (1:1), 12 h (86%).
3. (a) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8,
4927–4930; (b) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed.
2007, 46, 3291–3295.
4. (a) Yu, H.; Richey, R. N.; Carson, M. W.; Coghlan, M. J. Org. Lett.
2006, 8, 1685–1688; (b) Yu, H.; Richey, R. N.; Mendiola, J.; Adeva,
M.; Somoza, C.; May, S. A.; Carson, M. W.; Coghla, M. J.
Tetrahedron Lett. 2008, 49, 1915–1918.
5. Tietze, L. F.; Kahle, K.; Raschke, T. Chem. Eur. J. 2002, 8, 401–407;
Other closely related work: (a) Min, S.-H.; Pang, S. J.; Cho, C. G.
Tetrahedron Lett. 2003, 44, 4439–4442; (b) Oh, C. H.; Lim, Y. M.
Tetrahedron Lett. 2003, 44, 267–270; (c) Salem, B.; Delort, E.; Klotz,
P.; Suffert, J. Org. Lett. 2003, 5, 2307–2310.
6. (a) Murphy, G. M. Photodermatol. Photoimmunol. Photomed. 2002, 18,
1–4; (b) Unpublished results.
7. Overman, L. E.; Abelman, M. M.; Kucera, D. J.; Tran, V. D.; Ricca,
D. J. Pure Appl. Chem. 1992, 64, 1813–1819.
8. General procedure for tandem cyclization/cross-coupling reaction: Under
Ar to a solution of 4 or 6 (0.11 mmol) in 1 mL of anhydrous THF were
added PPh3 (0.022 mmol), arylboronic acid (0.17 mmol), CsF
(0.22 mmol) and Pd(OAc)2 (0.011 mmol). The reaction mixture was
stirred at 60 °C. After the disappearance of the starting material, the
reaction mixture was partitioned between water and ethyl acetate, the
organic layers were extracted twice with ethyl acetate, washed with
brine, and dried (Na2SO4). The solvents were removed under reduced
pressure and the crude product was chromatographed on silica gel
(eluent: cyclohexane/CH2Cl2 = 9/1).
achieved in three steps. Reaction of 13 with PhB(OH)2 in
the presence of Pd(OAc)2 (10 mol %), PPh3 (20 mol %)
and CsF (2 equiv) in THF promoted the carbocycliza-
tion/cross-coupling sequence to give 14 in a high yield
(84%). The desilylation–lactonization step was effected in
good yield by the use of an excess of trifluoroacetic acid
in THF-water at room temperature. The formation of this
lactone confirms also the stereospecificity of the palladium-
catalyzed cyclization/cross coupling reaction.
In summary, we have developed an efficient palla-
dium-catalyzed tandem carbopalladation/Suzuki–Miyaura
sequence for the synthesis of a series of arylidene indenols.
By varying arylboronic acids we have in hand a procedure
which allows to reach indenols with a wide diversity. This
approach provides a straightforward tool for further syn-
thetic applications. A study of photoprotective properties
of these arylidene indenols is undertaken and the results
will be reported in due course.
9. This representation is freely inspired from X-ray structures published:
see 3a and Kapoor, M.; Dhawan, S. N.; Mor, S.; Bhatia, S. C.; Gupta,
S. C.; Hundal, M. S. Tetrahedron 2003, 59, 5027–5031.