1,2,3-trisubstituted indanes by highly diastereoselective palladium-catalyzed oxyarylation of indenes with arylboronic acids and nitroxides

Article abstract of DOI:10.1002/anie.201002214

Chemecal quation presented Excellent stereoselectivity is obtained in the synthesis of biologically interesting 1,2,3-trisubstituted indanes B by the reaction of readily prepared 3-substituted indenes A with commercially available arylboronic acids by using various TEMPO derivatives as external oxidants and Pd(OAc)₂ as a catalyst. The anti,anti isomers are formed and reactions occur stereospecifically under mild conditions.

Full text of DOI:10.1002/anie.201002214

Angewandte
Chemie
DOI: 10.1002/anie.201002214
Oxyarylation
1,2,3-Trisubstituted Indanes by Highly Diastereoselective Palladium-
Catalyzed Oxyarylation of Indenes with Arylboronic Acids and
Nitroxides**
Sylvia Kirchberg, Roland Frꢀhlich, and Armido Studer*
Palladium-catalyzed oxidative difunctionalization of olefins is
a heavily investigated field of research [Eq. (1)].[1] Dioxyge-
nations,[2] diamidations,[3] and oxyamidations[4] have been
realized. However, compared to difunctionalization, in which
two heteroatom-containing groups are added to the olefin,
and even when considering metals other than palladium,
there are only very few reports on intermolecular metal-
mediated oxidative carbofunctionalization of olefins
[Eq. (2)].[5–7] Herein we present highly stereoselective inter-
molecular palladium-catalyzed oxyarylation of indenes with
various aryl boronic acids and the 2,2,6,6-tetramethylpiper-
idine-N-oxyl radical[8] (TEMPO) as an oxidant and trapping
reagent to provide 1,2,3-trisubstituted indanes [Eq. (3)].
Indenes[9] and indanes[10] have found widespread application
as biologically important substructures in medicinal chemis-
try. Therefore, development of novel methods for their
preparation is highly important.
Recently we reported the successful use of TEMPO as an
environmentally benign organic oxidant in rhodium- and
palladium-catalyzed C C bond forming reactions.[8b,11] More-
À
over, we have shown that indoles undergo highly diastereo-
selective palladium-catalyzed TEMPO-mediated carbo-
aminoxylations.[12] During our ongoing studies in that area
we found that the double bond of indene can be highly
regioselectively carbofunctionalized under oxidative palla-
dium catalysis using aryl boronic acids with excellent stereo-
control. Treatment of indene with Pd(OAc)2 in the presence
of TEMPO, PhB(OH)2, and KF (4 equiv each) in propionic
acid at room temperature provided carboaminoxylation
product 1 (R = H, Ar= Ph) as a single diastereoisomer in
79% yield [Eq. (3)].[13] Based on this highly promising initial
result, we decided to further investigate that reaction and to
extend the studies to 3-substituted indenes for the synthesis of
1,2,3-trisubstituted indanes. Along with the simple diastereo-
control of the carboaminoxylation reaction, the induced
stereoselectivity exerted by the indene substituent posed an
additional challenge. Moreover, also the regioselectivity
needed to be controlled.
As a test substrate, we chose racemic indene 2, which was
readily obtained as a single diastereoisomer by lithiation of
indene (Et2O, nBuLi, tetramethylethylenediamine) and sub-
sequent trapping with pivaldehyde.[14] Indene 2 was then
reacted under different conditions with various commercially
available aryl boronic acids under oxidative palladium
catalysis (Scheme 1, Table 1).
Scheme 1. Carboaminoxylation of indene 2.
[*] S. Kirchberg, Dr. R. Frꢀhlich, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfꢁlische Wilhelms-Universitꢁt
Corrensstrasse 40, 48149 Mꢂnster (Germany)
Fax: (+49)281-833-6523
We were very pleased to observe that with Pd(OAc)2
(10 mol%) as a catalyst in EtCO2H at RT for 1 h by using
4 equiv of PhB(OH)2, KF, and TEMPO the highly substituted
indane 3a bearing four contiguous stereogenic centers was
formed as a single isomer in 73% yield (Table 1, entry 1). The
assignment of the relative configuration was based on the X-
ray structure of 3a (Figure 1).[15] This structure furthermore
E-mail: studer@uni-muenster.de
[**] We thank the International Research Training Group Mꢂnster/
Nagoya for funding. A.S. thanks Novartis Pharma AG for financial
support (Novartis Young Investigator Award).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002214.
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Table 1: Arylcarboaminoxylation of 2 with various arylboronic acids
(4 equiv each of ArB(OH)2, TEMPO, and KF).
boronic acid a poor yield resulted, probably for steric reasons
(entry 14).
We then varied the substituent R at the indene moiety.
(Experimental details on the synthesis of indenes 4a,b,f–i can
be found in the Supporting Information.) Palladium-cata-
lyzed carboaminoxylations to provide 5a–i were performed
under the optimized conditions by using phenylboronic acid
(Scheme 2).
Entry Solvent
Catalyst
(10 mol%)
Ar
Product
Yield
[%][a]
1
2
3
4
5
EtCO2H Pd(OAc)2
MeCO2H Pd(OAc)2
nPrCO2H Pd(OAc)2
EtCO2H Pd(O2CCF3)2
EtCO2H [Pd(acac)2]
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
4-FC6H4
4-BrC6H4
4-
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
73
30
54
72
53
45
25
66
69
43
45
6[b] EtCO2H Pd(OAc)2
7[c] EtCO2H Pd(OAc)2
8
9
10
11
EtCO2H Pd(OAc)2
EtCO2H Pd(OAc)2
EtCO2H Pd(OAc)2
EtCO2H Pd(OAc)2
CH3OC6H4
3-CH3C6H4
3-ClC6H4
2-CH3C6H4
12
13
14
EtCO2H Pd(OAc)2
EtCO2H Pd(OAc)2
EtCO2H Pd(OAc)2
3 f
3g
3h
73
57
20
Scheme 2. Carboaminoxylation of various indenes 2 and 4a,b,f–j.
[a] Yield of isolated product. [b] With 5 mol% Pd(OAc)2. [c] With 2 mol%
Pd(OAc)2.
Reaction of indene 4a with TEMPO as an oxidant/
trapping reagent gave 5a in 65% yield of isolated product as a
single isomer (Table 2, entry 1). A slightly lower yield (58%)
was noted in the reaction with the acetone adduct of indene
(4b), where we observed the formation of the 2,3-bispheny-
Table 2: Phenylcarboaminoxylation of the 3-substituted indenes 2 and
4a,b,f–j (4 equiv each of PhB(OH)2, X-TEMPO, and KF).
Entry
R1
R2
X
Product
Yield [%]
1
2[a]
3
4
5
6
7
8
9
CH(OH)Ph
COH(CH3)2
CH(OH)C(CH3)3
CH(OH)C(CH3)3
CH(OH)C(CH3)3
Me
iPr
cyclohexyl
benzyl
CH(OH)C(CH3)3
H
H
H
H
H
H
H
H
H
Br
H
H
OH
NHAc
NH-Ala-Boc
NHAc
NHAc
NHAc
NHAc
H
5a
5b
5c
5d
5e
5 f
5g
5h
5i
65
58
50
54
80
76
65
70
68
34
10
5j
Figure 1. Structure of 3a in the solid state.
[a] The 2,3-bisphenylated indene was formed as a side product (see the
Supporting Information).
allowed us to unambiguously assign the relative stereochem-
istry obtained for the initial hydroxyalkylation of indene 2 and
also for the subsequent carboaminoxylation. All further
compounds prepared were assigned in analogy. Reactions in
acetic or butyric acid were lower-yielding (entries 2 and 3).
Replacing Pd(OAc)2 by Pd(O2CCF3)2 did not influence
reaction outcome, whereas with [Pd(acac)2] a significantly
lower yield was obtained under otherwise identical conditions
(entries 4 and 5). Reducing catalyst loading to 5 and 2 mol%,
respectively, led to a decrease of the yield (entries 6 and 7).
Under the optimized conditions, other arylboronic acids
were tested. No trends on electronic effects exerted by the 4-
substituent of the arylboronic acids could be extracted from
the experimental results. Good yields were achieved with 4-
methyl and 4-F-substituted phenylboronic acids, whereas the
methoxy and bromo congeners delivered slightly lower yields
(entries 8–11). Substituents at the meta position were toler-
ated (entries 12 and 13); however, with ortho-methylphenyl-
lated indene as a side product (entry 2). TEMPO could be
replaced by the cheaper HO-TEMPO (5c, entry 3) or AcNH-
TEMPO (5d, entry 4). Importantly, the oxidation/trapping
reagent can also be successfully used for the installation of
interesting functionalities at the 1-position of the indane core.
This is documented by the reaction of 2 with the amino acid
conjugated nitroxide (Boc-Ala-NH-TEMPO) to afford the
carboaminoxylation product 5e in a very good yield with
perfect diastereocontrol (entry 5). Moreover, with smaller
unbranched R1-substituents, such as methyl and benzyl
groups, diastereoselectivity remained excellent (entries 6
and 9). A similar result was achieved for reaction of indenes
4g and 4h bearing secondary alkyl substitutents as stereodi-
recting groups (entries 7,8). Decreasing electron density in
the arene moiety (see 4j) led to a significantly reduced
reactivity of the indene substrate (entry 10).
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We propose the mechanism depicted in Scheme 3 for our
highly diastereoselective carboaminoxylation. Reaction of
PdX2 with K[ArBF(OH)2] by transmetalation from boron to
palladium affords X-Pd-Ar which undergoes electrophilic
Scheme 4. Transformation of styrene, trans-stilbene, trans-b-methylstyr-
ene, and benzofuran.
systems, deprotonation of the cationic intermediate of type A
is faster than cation interception giving compounds of type B.
Along this line, carboaminoxylation of benzofuran provided 8
in 91% yield.
To document the potential of our approach for the
synthesis of enantiomerically pure trisubstituted indanes, we
had to make sure that the stereocenter of the starting indene
is configurationally stable under the applied conditions. We
therefore prepared enantioenriched indene 2 (65% ee) by
using the Hoppe approach with (À)-sparteine as an additive
for indene lithiation.[14c] Palladium-mediated phenylamin-
oxylation afforded 3a with 65% ee (see the Supporting
Information).
Scheme 3. Proposed mechanism.
addition at the 2-position of the indene trans to the steering
R substitutent to generate the benzylic cationic intermediate
A. The counteranion XÀ can either be EtCO2À or TEMPOÀ.
The fact that a lower yield was achieved with the brominated
indene 4j supports the suggested electrophilic process.
Stereoselective trans trapping of A with TEMPOH provides
B, which upon reductive elimination gives the 1,2,3-trisub-
stituted indane with an anti,anti relative configuration along
with palladium(0). We believe that TEMPO or TEMPOH
helps stabilize the palladium(0) species, as no palladium black
was observed during the reaction. Oxidation of palladium(0)
with 2 equiv of TEMPO eventually regenerates the palladi-
um(II) salt. We currently disfavour a mechanism comprising
regio and trans-selective (with respect to the substituent R)
Heck-type addition of TEMPO-Pd-Aryl to the indene double
bond followed by oxidation of the thus formed benzylic
palladium species to the corresponding palladium(IV) species
and subsequent reductive elimination. For that mechanism to
be operative, TEMPO and the aryl group would have to be
syn-orientated in the final product.[1c] However, the benzylic
palladium(IV) species might also act as an electrophile in a
SN2-type substitution with TEMPOÀ to give the isolated anti
product.[1c] This pathway can not be excluded based on the
stereoselectivity observed.
Finally, we ran a sequence on 2 comprising a phenyl-
À
aminoxylation with subsequent reductive N O bond cleavage
with zinc in AcOH/H2O (3:1) to provide benzylic alcohol 9
(Scheme 5). The TEMPO moiety can therefore be regarded
À
Scheme 5. Carboaminoxylation and reductive N O bond cleavage.
as a protected hydroxy group. Recrystallization of 9 afforded
crystals suitable for X-ray analysis, which confirmed the
relative configuration of all four stereogenic centers and
À
showed that N O bond cleavage in the last step occurred
stereospecifically (Figure 2).[15]
In conclusion, we introduced palladium-catalyzed highly
stereoselective carboaminoxylation of readily available
3-substituted indenes with commercially available aryl-
boronic acids and nitroxides to give biologically interesting
1,2,3-trisubstituted indanes. The reactions occur under mild
conditions (room temperature) in a short time (1 h). The
palladium-mediated oxyarylation occurs stereospecifically,
and the alkoxyamine moiety can readily be converted into
We then tested whether our carboaminoxylation works
also on other alkenes. trans-Stilbene reacted with PhB(OH)2
to triphenylethene 6 (95%), and the same product was also
isolated in the reaction with styrene (83%, Scheme 4; see also
the Supporting Information). b-Methylstyrene provided
methylstilbene 7 in 45% yield. It seems that for noncyclic
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Figure 2. Structure of 9 in the solid state.
À
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We are currently working on the development of a general
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indenes.
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obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: April 14, 2010
Published online: August 4, 2010
Keywords: homogeneous catalysis · nitroxides · palladium ·
.
stereoselective reactions · synthetic methods
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