Stereoselective palladium-catalyzed carboaminoxylations of indoles with arylboronic acids and TEMPO

Full text of DOI:10.1002/anie.200901072

Angewandte
Chemie
DOI: 10.1002/anie.200901072
Synthetic Methods
Stereoselective Palladium-Catalyzed Carboaminoxylations of Indoles
with Arylboronic Acids and TEMPO**
Sylvia Kirchberg, Roland Frꢀhlich, and Armido Studer*
Table 1: Direct arylation of indole (R=H) with various arylboronic acids
Indoles and their derivatives belong to an important sub-
[
a]
[see Eq. (1)].
stance class which is often found in natural products and in
[
1]
[b]
[c]
many pharmaceuticals. Great efforts have recently been
devoted to transition-metal-catalyzed chemical modifications
of indoles, in particular direct C(2)ꢀH or C(3)ꢀH arylations.
Entry Solvent
Catalyst
Ar
Product Yield [%]
1
2
3
4
5
6
7
8
9
0
EtCO H
Pd(OAc)2
C6H5
C6H5
C6H5
1a
1a
1a
1a
1a
1b
1c
1d
1e
81 (10)
2
MeCO H Pd(OAc)2
<2 (n.d.)
64 (n.d.)
75 (n.d.)
62 (n.d.)
73 (10)
78 (9)
71 (10)
67 (2)
68 (9)
2
[2–7]
Palladium has been heavily used in that regard.
Herein we
nPrCO H Pd(OAc)2
2
present our first results on direct CꢀH arylations of indoles
EtCO
H
Pd(O
CCF
)
2
C H
6
2
2
3
5
EtCO H
[Pd(acac)2]
C6H
with arylboronic acids and the 2,2,6,6-tetramethylpiperidine
2
5
[
8]
EtCO H
Pd(OAc)2
4-CH C H
2
3
6
4
N-oxyl radical (TEMPO) as an external mild oxidant (!
EtCO H
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4-FC H
2
6
4
1
a–f) [Eq. (1)]. More importantly, we will show that upon
EtCO H
3-CH C H
3-ClC H
C6H5
2
3 6
4
installing a protecting group (PG) on the indole nitrogen
atom, the reaction outcome changes and the product formed
is that of a highly stereoselective oxidative arylcarboaminox-
EtCO H
2
6
4
[
d]
[e]
1
EtCO H
1 f
2
[
a] Conditions: ArB(OH) (4 equiv), TEMPO (4 equiv), KF (4 equiv) in
[9]
2
ylation reaction (!2a–c). To our knowledge metal-cata-
RCOOH at room temperature for 1 h (n.d.=not determined).
b] 10 mol%. [c] In parenthesis yield of the isolated 3-arylated indole.
lyzed arylation of indoles by oxidatively intercepting putative
[
[
10]
cationic intermediates is unknown.
[d] With N-methylindole. [e] 1-Methyl-2-phenyl-1H-indole (R=Me).
in butyric acid afforded 1a in 64% yield (Table 1; entry 3).
Pd(O CCF ) and [Pd(acac) ] (acac = acetylacetonate) turned
2
3
2
2
out to be slightly less efficient precatalysts (Table 1; entries 4,
). The aryl group could readily be varied upon changing the
5
arylboronic acid component (Table 1; entries 6–9). For all
acids tested, the 3-arylated indole was formed as a side
product. Note that many arylboronic acids are commercially
available. Moreover, N-alkyl groups were tolerated as shown
for the transformation of N-methylindole to 1-methyl-2-
phenylindole (1 f; 68%, Table 1; entry 10).
We have recently shown that TEMPO can be used as an
external oxidant in palladium-catalyzed direct CꢀH aryla-
[11]
tions of arenes by using arylboronic acids as aryl sources.
We next tested N-acylated and N-carbamoylated indoles
in the direct CꢀH arylation reaction. Surprisingly, treatment
We decided to further extend that chemistry to indoles.
Pleasingly, we found that indole underwent direct C(2)
arylation with phenylboronic acid in the presence of
of N-acetylindole in acetic acid with phenylboronic acid, KF,
and TEMPO in the presence of Pd(OAc) (10 mol%) at room
2
Pd(OAc) (10 mol%), KF (4 equiv), and TEMPO (4 equiv)
in propionic acid under very mild conditions (room temper-
ature, 1 h) in 81% yield (Table 1, entry 1). As a side product,
temperature for 1 h afforded the arylcarboaminoxylation
product 2a (Ar= Ph) in a moderate yield (55%, Table 2,
entry 1). Importantly, 2a was formed highly diastereoselec-
tively (d.r. > 99:1; HPLC analysis). The relative trans-config-
uration was unambiguously assigned by single-crystal X-ray
2
3
-phenylindole was formed in 10% yield. Surprisingly, in
acetic acid only traces of 1a were formed (thin-layer
chromatography (TLC), Table 1; entry 2). The same reaction
[12]
analysis (Figure 1). In CF CO H, under otherwise identical
3 2
conditions, 2a was not formed (Table 2; entry 2). An
improved yield was observed upon switching to propionic
acid as the solvent (85%, Table 2; entry 3). Butyric acid and
valeric acid provided lower yields (Table 2; entries 4, 5).
Worse results were achieved in non-acidic solvents such as
dichloromethane or dichloroethane (Table 2; entries 6, 7). As
for the direct CꢀH arylation discussed above, Pd(O CCF )
[
*] S. Kirchberg, Dr. R. Frꢀhlich, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfꢁlische Wilhelms-Universitꢁt
Corrensstrasse 40, 48149 Mꢂnster (Germany)
Fax: (+49)251-83-36523
E-mail: studer@uni-muenster.de
2
3 2
[
**] We thank the International Research Training Group Mꢂnster/
Nagoya for funding. A.S. thanks the Novartis Pharma AG for
financial support (Novartis Young Investigator Award).
TEMPO=2,2,6,6-tetramethylpiperidine N-oxyl radical.
and [Pd(acac) ] turned out to be slightly less efficient
2
precatalysts (Table 2; entries 8, 9). Reducing catalyst loading
to 5 mol% did not affect the yield to a great extent (Table 2;
entry 10). However, with 2 mol% Pd(OAc) the yield drop-
ped significantly (Table 2; entry 11). Reducing the amount of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901072.
2
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
[
a]
Table 2: Arylcarboaminoxylation of indoles (Ar=Ph) [see Eq. (1)].
Entry
Solvent
Catalyst
PG
Product
Yield [%]
1
2
3
4
5
6
7
8
9
MeCO H
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(O CCF )
[Pd(acac)2]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Bz
Boc
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
55
–
2
CF CO H
3
2
EtCO H
85
72
41
20
18
76
73
83
61
52
61
91
82
2
nPrCO H
2
nBuCO H
2
CH Cl2
2
ClCH CH Cl
2
2
EtCO H
2
2
3 2
EtCO H
2
[
[
[
[
c]
d]
e]
f]
Figure 1. Molecular structure of 2a (left) and 2b (right).
10
11
12
13
14
15
EtCO H
2
EtCO H
2
EtCO H
2
EtCO H
2
EtCO H
Pd(OAc)2
2
arylboronic acids (Table 3; entries 8, 12, 13). However, with
ortho-methylphenylboronic acid significantly lower yields
were obtained, probably for steric reasons (Table 3; entries 4,
14). Note that arylbromides, which can readily be further
manipulated by using transition-metal-based methods, were
tolerated under the reaction conditions.
EtCO
2
H
Pd(OAc)
2
[
a] Conditions: PhB(OH) (4 equiv), TEMPO (4 equiv) and KF (4 equiv)
at room temperature for 1 h. [b] 10 mol%. [c] With 5 mol% Pd(OAc)2.
d] With 2 mol% Pd(OAc) . [e] With 1 equivalent PhB(OH) and 1 equiv-
2
[
2
2
alent KF. [f] With 2 equivalents TEMPO.
PhB(OH) (Table 2; entry 12) or TEMPO (Table 2; entry 13)
2
led to lower yields.
The N-protecting group was varied next. Indole with a
benzoyl (Bz) protecting group afforded the highest yield (!
2
b, Ar= Ph, 91%, Table 2; entry 14) and a good yield was
also achieved with the tert-butoxycarbonyl (Boc) protected
indole (! 2c, Ar= Ph, 82%, Table 2; entry 15). In both
reactions only the trans-isomer was formed (HPLC analysis).
For 2b the trans configuration was
assigned by single-crystal X-ray
[
a]
Table 3: Arylcarboaminoxylation of N-protected indoles with various arylboronic acids.
analysis (see Figure 1) and for 2c
the relative configuration was
assigned in analogy to 2a and 2b.
Biphenyl deriving from oxidative
homocoupling of phenylboronic
acid was always formed as side
product in these arylcarboaminox-
1
2
3
4
Entry
R
R
R
R
Ar
PG
Yield [%]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Br
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
4-CH C H
4-CH
4-FC H
2-CH C H
4-CH C H
4-FC H
4
4-BrC H
3-CH C H
4-CH C H
4-BrC
4-FC H
3-CH C H
3-ClC H
2-CH C H
C6H5
C6H5
C6H5
Ac
Ac
Ac
Ac
Bz
Bz
Bz
Bz
Boc
Boc
Boc
Boc
Boc
Boc
Ac
Ac
Ac
Bz
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
3a
73
59
80
35
69
91
52
76
80
72
78
79
77
31
78
68
48
91
97
99
85
92
99
96
94
93
3
6
4
OC
3
H
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
6
4
6
4
3
6
4
3
6
4
[
13]
6
ylations.
6
4
Under optimized conditions
various protected indoles were
arylcarboaminoxylated with differ-
ent arylboronic acids [Eq. (2)]. All
the reactions conducted delivered
only one diastereoisomer (HPLC
analysis). The relative trans config-
uration was assigned in analogy to
3
6
4
3
6
4
10
H
6
4
1
1
1
1
1
1
1
2
3
4
5
6
6
4
3
6
4
6
4
3
6
4
2
a,b. para-Substituted arylboronic
acids bearing electron-donating or
withdrawing groups afforded the
17
18
C H
6
5
1
2
2
2
2
9
0
1
2
3
CH3
C6H
3s
3t
-
5
OMe
C6H5
C6H5
C6H5
C6H5
C6H5
carboaminoxylation product in a
good yield (Table 3). This is true
Br
H
H
H
H
H
3u
3v
3w
3x
3y
3z
for
N-acetylated
(Table 3;
CO Me
2
entries 1–3),
N-benzoylated
24
25
H
H
H
(
Table 3; entries 5–7), and N-Boc-
C H
6
5
2
6
C6H
protected indoles (Table 3;
5
entries 9–11). Similar results were
[a] Conditions: ArB(OH)2 (4 equiv), TEMPO (4 equiv), KF (4 equiv), and Pd(OAc)2 (10 mol%) in
achieved with meta-substituted
propionic acid at room temperature for 1 h.
4
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Chemie
To further study scope and limitations, various N-pro-
tected substituted indole derivatives were treated with
phenylboronic acid under optimized conditions. Electron-
donating and also electron-withdrawing substituents were
tolerated in positions 4–7 of the indole core (Table 3;
entries 15–26) and good to excellent yields were achieved
reaction we believe that TEMPO or TEMPOH helps to
0
0
stabilize the Pd species. Oxidation of Pd with 2 equivalents
II
of TEMPO eventually regenerates the Pd salt. We exclude
Heck-type addition of TEMPO-Pd-aryl to indole followed by
IV
oxidation to the corresponding Pd species and subsequent
reductive elimination since TEMPO and the aryl group would
have to be syn-oriented. Moreover, possible reaction through
coordination of the X-Pd-Ar intermediate to the protected
indole followed by anti-oxypalladation to generate directly
intermediate D is unlikely, because the polarization of the
indole alkene moiety and the electrophilic nature of the X-
Pd-Ar species should lead to the opposite regioisomer.
The TEMPO substituent, which is biologically probably
not so relevant, can be regarded as a protected hydroxy group.
(
48–99%). For substituted indoles, systems bearing the Boc
group afforded the highest yields (85–99%, Table 3;
entries 19–26). We could further show that for Boc-protected
6
-(methoxycarbonyl)indole, for which 3w was obtained in a
quantitative yield under standard conditions (see Table 3;
entry 23), the arylcarboaminoxylation could be conducted in
good yield (90%) by using only 5 mol% Pd(OAc)2 with
1
.5 equivalents of PhB(OH) , 1.5 equivalents KF, and 3 equiv-
2
alents TEMPO.
Hence, treatment of 2a with Zn in H O/AcOH (3:1) at room
2
We suggest the following mechanism to explain the
observed chemodivergent reaction outcome (Scheme 1).
temperature for 1 h afforded the 3-hydroxydehydroindole 4
stereospecifically in a quantitative yield [Eq. (3)].
[
14]
In conclusion, we presented palladium-catalyzed chemo-
divergent chemical modifications of various indoles with
commercially available arylboronic acids and TEMPO as a
commercially available mild oxidant. Depending on the
substituent on the indole N atom, either direct C(2) arylation
(R = H, Me) or a highly diastereoselective arylcarboaminox-
ylation (R = Ac, Bz, Boc) occurs. To our knowledge the latter
process is unprecedented and delivers biologically interesting
structures. Importantly, the reactions occurred under mild
conditions (room temperature) in a short time (1 h).
Received: February 24, 2009
Published online: May 4, 2009
Scheme 1. Suggested mechanism for the chemodivergent reactions.
Keywords: CꢀH activation · chemodivergent reactions ·
.
homogeneous catalysis · asymmetric synthesis ·
transition metals
Transmetalation from boron to palladium by reaction of
PdX2 with [ArBF(OH) ]K provides an X-Pd-Ar species
2
which adds at the 3-position of the indole to give intermediate
[
3b,4b,6c,7a]
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Angew. Chem. Int. Ed. 2009, 48, 4235 –4238
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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