"on water" direct and site-selective Pd-catalysed C-H arylation of (NH)-indoles

Article abstract of DOI:10.1002/adsc.201000512

This communication describes the development of a versatile catalytic system based on palladium(II) acetate/bis(diphenylphosphino)methane [Pd(OAc)₂/dppm] that works "on water" giving site-selective C-H arylation of (NH)-indoles without protecting or directing groups. Remarkably, the control of regioselectivity was achieved by small changes in the "extra-catalytic" base/halide partners. These innovative methodologies allow a high-yielding access to both C2 and C3-arylindoles, as well as 2,3-diarylindoles, and display high chemo/regioselectivities and structural versatility with regard to either indole or aryl moieties. Copyright

Full text of DOI:10.1002/adsc.201000512

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DOI: 10.1002/adsc.201000512
ꢀ
“On Water” Direct and Site-Selective Pd-Catalysed C H
Arylation of (NH)-Indoles
Lionel Joucla,a Nelly Batail,a and Laurent Djakovitcha,*
a
Universitꢀ de Lyon, CNRS, UMR 5256, IRCELYON, Institut de recherches sur la catalyse et l’environnement de Lyon, 2
avenue Albert Einstein, F-69626 Villeurbanne, France
Fax : (+33)-4-7244-5399; phone: (+33)-4-7244-5381; e-mail: Laurent.Djakovitch@ircelyon.univ-lyon1.fr
Received: June 30, 2010; Revised: September 22, 2010; Published online: November 17, 2010
Dedicated to the memory of Professor Keith Fagnou.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000512.
Abstract: This communication describes the devel-
opment of a versatile catalytic system based on pal-
ladium(II) acetate/bis(diphenylphosphino)methane
rials science, pharmaceutical and natural products,[3]
major improvements have been achieved in the direct
and site-selective arylation of (NH)-indoles through
either Pd-, Rh- or Cu-catalyzed methodologies.[4] Nev-
ertheless, to the best of our knowledge no report fo-
cuses on complementary C2-[5] and C3-arylation[6] pro-
cedures by means of a unique catalytic system.[7]
Moreover, several drawbacks remain associated with
these methodologies such as the often required nitro-
gen protecting groups or the need of high-boiling,
toxic solvents. Recently, substantial “green-oriented”
[PdACHTUNGTRENNUNG(OAc)2/dppm] that works “on water” giving
ꢀ
site-selective C H arylation of (NH)-indoles with-
out protecting or directing groups. Remarkably, the
control of regioselectivity was achieved by small
changes in the “extra-catalytic” base/halide part-
ners. These innovative methodologies allow a high-
yielding access to both C2 and C3-arylindoles, as
well as 2,3-diarylindoles, and display high chemo/re-
gioselectivities and structural versatility with regard
to either indole or aryl moieties.
ꢀ
efforts have been achieved in the field of C H activa-
tion[8] through the development of “on water” transi-
tion metal-catalyzed reactions[9] which afford econom-
ical, environmental and safety advantages. Unfortu-
ꢀ
Keywords: C H arylation; indoles; palladium; re-
ꢀ
gioselectivity; water
nately, accounts dealing with direct C H arylation of
heterocycles on water are scarce. Greaney et al. dis-
closed an arylation reaction of five-membered hetero-
cycles under mild reaction conditions,[10] but a bimet-
allic system was needed including the expensive
“Direct arylation”[1] has emerged over the past few Ag2CO3 base. Herein, we describe an innovative “on
ꢀ
years as an outstanding alternative to traditional water” palladium-catalyzed C H arylation of (NH)-
cross-coupling reactions[2] in the preparation of biaryl indoles that is site-selective and base/halide-con-
molecules because this strategy partially avoids the trolled using cheap reagents.[11] This methodology
need of stoichiometric organometallic activating allows the preparation of either C2- or C3-arylindoles
groups. Since the indole nucleus is ubiquitous in mate- (Scheme 1).
ꢀ
Scheme 1. Tunable functionalization of (NH)-indoles through [base/halide]-controlled regioselective Pd-catalyzed C H ary-
lation.
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Initially, we examined the coupling between indole rich phosphines such as PCy3 and PACTHUNTRGNENG(U OEt)3 (entries 4
(1a) and iodobenzene (Table 1) using 5 mol% of Pd- and 5) or hydrosoluble ones like TPPTS and TPPMS
(OAc)2 and AcOK as base, a catalytic system inspired (entries 7 and 8) were found unsuitable to perform
by the work of Sames. Under these conditions, 2-phe- such arylation. Remarkably, PdCl2A(dppm)·CH2Cl2
nylindole (2a) was obtained as the major regioisomer (entry 10) and especially Pd(OAc)2/dppm (entry 13)
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
albeit with a low 20% yield (entry 1). Further optimi- exhibited both higher activities (75% yield within
zation toward a selective C2-arylation protocol fea- 18 h) and selectivities (>20/1) toward 2-phenylindole.
tured the crucial role of arylphosphine ligands in
The scope of the reaction was then examined for
order to achieve a better catalytic performance. As several aryl iodides and indole derivatives (Table 2).
shown in Table 1, such easy-to-handle mono- or bi- This methodology was found to be general, providing
dentate phosphines (i.e., PPh3, BINAP) with a [Pd]/ the desired C2-arylindoles in useful to good yields
phosphine ratio of 1/2 (see Supporting Information, (48–79%); disappointingly, the use of 7-azaindole
Figure S1), as well as commonly employed complexes (2k) resulted in no arylation. High regioselectivities
[e.g., Herrmann-Bellerꢂs palladacycle, PdCl2ACHTNUTRGNEUNG(PPh3)2], (ca. 20:1) were generally obtained except when ortho-
allowed enhanced conversions (50–60%) and selectiv- substituted derivatives were used. Furthermore, these
ities (up to 20:1). On the other hand, either electron reaction conditions featured a full chemoselectivity
with either 5-bromoindole (2j) or 4-bromoiodoben-
zene (2f), the arylation occurring selectively on the
ꢀ
C I bond. The procedure is tolerant for both elec-
Table 1. Optimization studies for indole C2-arylation: phos-
phine screening.[a]
tron-donating and electron-withdrawing groups in-
cluding OMe (2d, 2i), Ac (2c), naphthyl (2g) and
CO2Me (2l). Especially noteworthy are substrates
bearing a Cl (2b, 2e, 2h) or a Br (2f, 2j) substituent,
which allow further functionalization through cross-
coupling reactions.[12] Comparatively, the use of Lar-
rosaꢂs conditions[5m] [i.e., 5 mol% Pd
ACHTNUTRGNE(UNG OAc)2, 1.5 equiv.
o-nitrobenzoic acid, 0.75 equiv. Ag2O, H2O, 1108C]
furnished 2j in a slightly improved 59% yield and 2l
in a poor 12% yield despite full conversions, which
suggests a high rate of degradation of the starting ma-
terial when silver salts are used.[13]
We next turned our attention to the development
of a selective C3-arylation procedure since a profound
base effect was uncovered during optimization of the
C2 protocol. Remarkably, extensive screening[14] re-
vealed that LiOH·H2O resulted in a 3.6:1 ratio of
3a:2a and a full conversion within 18 h. To our de-
light, when iodobenzene was replaced by bromoben-
zene, an enhanced and synthetically useful 6.5:1 regio-
selectivity (Table 3, entry 1) was achieved. By these
means, 3a was obtained in 74% yield together with a
small amount of 2a (13%).
The scope of the reaction with aryl bromides is out-
lined in Table 3. Gratifyingly, good to high yields (69–
91%) were achieved independent of the electron do-
nating or withdrawing nature of substituents (OMe,
Cl, CF3 groups, entries 4–6) and the substitution pat-
tern of both indole (4-, 5- and 6-positions) and aryl
moieties, including ortho-substituted bromoarenes.
Furthermore, 2-phenylindole 2a was fully converted
under such conditions and furnished 2,3-diphenylin-
dole 3j [Scheme 2, Eq. (1)] in a nearly quantitative
yield. Thus, the synthesis of 2,3-diarylindoles can be
envisioned via the sequential C2- then C3-arylation of
the parent indole core in two steps.[5h,15] Ester groups
resulted in a complete degradation of the starting ma-
terial as hydrolysis might be expected in the presence
Entry Phosphine (mol%)
Selectivity[b] Yield [%][c]
1
–
11:1
14:1
17:1
–
20
54
60
28
2
3
4
PPh3 (5)
PPh3 (10)
PCy3 (10)
5
6
P
P
N
–
9
E
16:1
–
31
20
7
8
9
TPPTS (10)
TPPMS (10)
HBP (1.0)
–
31
7.5:1
57
10
11
12
13
14
15
PdCl
G
68 (82)[d]
PdCl
2A(PPh3)2 (5)
19:1
48
BINAP (5)
dppm (5)
dppm (10)
dppm (5)
>20:1
>20:1
>20:1
–
54
75 (90)[d]
58
34[e]
[a]
Reaction conditions: 1a (1.0 mmol), iodobenzene
(1.2 mmol), AcOK (3.0 mmol), [Pd] (5 mol%), H2O
(2 mL), 1108C, 18 h. TPPTS=tris(3-sulfonatophenyl)-
phosphine sodium salt; TPPMS=diphenylphosphinoben-
zenesulfonic acid sodium salt; dppm=bis(diphenylphos-
phino)methane; HBP=Herrmann–Beller palladacycle.
2a:3a selectivity determined by GC.
The yield was determined by GC.
48 h at 1108C.
PdCl2 (5 mol%) was used as palladium source.
[b]
[c]
[d]
[e]
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“On Water” Direct and Site-Selective Pd-Catalysed C H Arylation of (NH)-Indoles
Table 2. Regioselective C2-arylation of indoles.[a]
[a]
Reaction conditions: 1 (1.0 mmol), aryl iodide (1.2 mmol), AcOK (3.0 mmol), Pd-
AHCTUNTGREG(NNUN OAc)2 (5 mol%), dppm (5 mol%), H2O (2 mL), 1108C, 24 h. Isolated yields of pure
C2-isomers after flash column chromatography over silica are reported. Values in
brackets refer to 2:3 selectivity of crude material determined by GC.
24% of starting material recovered.
40% of starting material recovered.
Traces of 2-phenyl-7-azaindole detected by GC/MS.
53% of starting material recovered.
[b]
[c]
[d]
[e]
Scheme 2. Sequential synthesis of 2,3-diphenylindole [Eq. (1)] and special behaviour of methyl ester derivative [Eq. (2)].
Adv. Synth. Catal. 2010, 352, 2929 – 2936
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Table 3. Regioselective C3-arylation of indoles.[a]
[a]
Reaction conditions: 1 (1.0 mmol), aryl bromide (1.2 mmol), LiOH·H2O (3.0 mmol), Pd-
(OAc)2 (5 mol%), dppm (5 mol%), H2O (2 mL), 1108C, 18 h. 3:2 selectivity of crude materi-
ACHTUNGTRENNUNG
al determined by GC in brackets. In some cases, small amounts (<5%) of 2,3-diarylindoles
were also detected. Isolated yield of pure C3-isomer (C2-isomer in square brackets) after
flash column chromatography over silica.
of such a strong base [Scheme 2, Eq. (2)]. K2CO3 fur- found bromide effect supported by a weakened reac-
nished the targeted arylindoles in 17% overall yield tivity of AcOK/I partners toward C2-arylation when
despite a full conversion. To our delight, the use of LiBr is added to the reaction mixture (entry 9 versus
the weaker base KHCO3 prevented saponification 7). Nevertheless, almost full conversions and good
and successfully provided the C3-regioisomer (4b) in C3-selectivities were achieved with NaOH or KOH
a useful 55% yield (72% with combined C2- and C3- whether aryl bromides or iodides are used (en-
regioisomers).[16]
tries 10–13). These results support an electrophilic
Obviously, the use of the appropriate base/halide palladation at the C3 position of the indole nucleus[6a]
partners is the key element in the catalyst design to and suggest that two kinds of active palladium species
control C2- versus C3-arylation. Particularly, the pres- are involved (Scheme 3). Indeed, the highly electro-
ence of bromide anions significantly controls the out- philic cationic Pd complex A[18] is expected to easily
ꢀ
come of this palladium-catalyzed C H arylation, both undergo a C3-palladation while the activation of the
in terms of selectivity and activity (Table 4).[17] Ac- neutral complex B requires the action of a stronger
cordingly, superior selectivities and/or catalytic activi- base than AcOK, probably through in situ deprotona-
ties were observed with respect to LiOH/ArBr part- tion of the indole nitrogen. Therefore, the key inter-
ners (entries 3/5 versus 2/4). Itꢂs noteworthy that the mediate C is expected to follow two pathways: a) a
addition of LiBr featured an improved C3-selectivity C3!C2 migration of the palladium center favored in
when LiOH/PhI partners are used (entry 8 versus 2). the presence of the weak base AcOK, affording the
In contrast, AcOK/Br association suppressed either complex D which leads to the C2-regioisomer; b) a
C2- or C3-arylation (entry 7 versus entries 6/1), a pro- rearomatization privileged with stronger bases such as
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“On Water” Direct and Site-Selective Pd-Catalysed C H Arylation of (NH)-Indoles
Table 4. Connecting base and halide effects to regioselectivity.[a]
Entry
R
R’
Additive
Base/Halide
Selectivity
Conversion [%]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
4-OMe
–
–
–
–
–
–
–
AcOK/I
LiOH/I
LiOH/Br
LiOH/I
LiOH/Br
AcOK/I
AcOK/Br
LiOH/I
AcOK/I
NaOH/Br
NaOH/I
KOH/Br
KOH/I
>20:1
1:3.6
1:6.5
1.3:1
1:5
13:1
–
1:4.5
3:1
1:5.9
1:5.5
1:6.5
1:5.7
>95
100
100
60
100
60
0
100
20
100
100
100
100
H
4-OMe
Br
H or Br
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
LiBr
LiBr
–
–
–
–
9
10
11
12
13
[a]
Reaction conditions: indole (1.0 mmol), aryl halide (1.2 mmol), base (3.0 mmol), PdACTHNUTRGNEUNG(OAc)2 (5 mol%), dppm (5 mol%),
H2O (2 mL), 1108C, 18-24 h. LiBr (1.0 mmol) was added when indicated. Conversions and 2:3 selectivities were deter-
mined by GC.
CO3 or OHꢀ affording the s-Pd complex E, precur- Experimental Section
2ꢀ
sor of the C3-regioisomer after reductive elimination
of Pd(0). Notably, such a rearomatization could be General Procedures for the Direct Arylation of
elsewhere promoted by the presence of the more nu- (NH)-Indoles
cleophilic bromide anions compared to the iodide
ones. Thus, such mechanisms rationalize the reversed
General procedure for C2 arylation: In a screw-cap vial
under air, a mixture of PdACHTNUTRGNENG(U OAc)2 (11.3 mg, 0.05 mmol,
C3/C2 selectivity obtained with LiOH/PhI partners
and the C3-selectivity enhancement when either bro-
mides are added in the reaction media – via a A!B
Pd species displacement – or a more nucleophilic
base (i.e., NaOH or KOH) is employed. However, we
cannot rule out the co-existence of the so-called “con-
certed metallation-deprotonation” pathway when
AcOK/ArI partners are used.[19]
5 mol%), dppm (19.2 mg, 0.05 mmol, 5 mol%), AcOK
(294 mg, 3.00 mmol, 3.0 equiv.), iodobenzene (244 mg,
1.20 mmol, 1.2 equiv.), and indole 1a (117 mg, 1.0 mmol,
1.0 equiv.) in degassed H2O (2 mL) was vigorously stirred at
1108C. After 24 h the reaction mixture was cooled to room
temperature and partitioned between 1N HCl (5 mL) and
ethyl acetate (10 mL). The layers were separated and the
aqueous layer was further extracted with 2ꢃ10 mL ethyl
acetate. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure.
Purification of the residue by flash chromatography (SiO2,
petroleum ether/EtOAc 9/1) afforded 2-phenylindole 2a as a
white solid; yield: 145 mg (0.75 mmol, 75%).
In summary, we have developed a versatile catalytic
system allowing an innovative “on water” direct and
site-selective arylation of (NH)-indoles. This palladi-
ꢀ
um-catalyzed C H functionalization reaction high-
lighted a [base/halide]-controlled regioselectivity, so
General procedure for C3 arylation: In a screw-cap vial
that the arylation can be directed to either the 2- or under air, a mixture of Pd
ACHTUNGETRN(NUNG OAc)2 (11.3 mg, 0.05 mmol,
5 mol%), dppm (19.2 mg, 0.05 mmol, 5 mol%), LiOH·H2O
(126 mg, 3.00 mmol, 3.0 equiv.), bromobenzene (188 mg,
1.20 mmol, 1.2 equiv.), and indole 1a (117 mg, 1.0 mmol,
1 equiv.) in degassed H2O (2 mL) was vigorously stirred at
1108C. After 18 h the reaction mixture was cooled to room
temperature and partitioned between 1N HCl (5 mL) and
ethyl acetate (10 mL). The layers were separated and the
aqueous layer was further extracted with 2ꢃ10 mL ethyl
acetate. The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure.
Purification of the residue by flash chromatography (SiO2,
the 3-position of (NH)-indoles. By these means, a
straightforward two-step synthesis of 2,3-diarylindoles
can be envisioned. These procedures exhibit good to
high regio- and chemoselectivity, displaying high
structural versatility with regard to both indole and
aryl moieties. Current studies are directed towards
mechanistic investigations and application of these
methodologies to other heterocyclic scaffolds.
Adv. Synth. Catal. 2010, 352, 2929 – 2936
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ꢀ
“On Water” Direct and Site-Selective Pd-Catalysed C H Arylation of (NH)-Indoles
petroleum ether/EtOAc 9/1) afforded 3-phenylindole 3a as a
pale yellow solid; yield: 143 mg (0.74 mmol, 74%) and 2-
phenylindole 2a; yield: 25 mg (0.13 mmol, 13%).
Cauteruccio, R. Rossi, Tetrahedron 2007, 63, 1970;
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Acknowledgements
The authors thank Prof. Piet W. N M. van Leeuwen for
proof-reading and correction of the manuscript. We gratefully
acknowledge the Rꢀgion Rhꢁne-Alpes Programme CIBLE-
2007 (Contract number 07 016376 01/02/03) and the National
Agency of Research (No. ANR-07-BLAN-0167-01/02) for
funding.
[6] For a new C3-selective arylation of indoles through a
decarboxylative cross-coupling, see: J. Cornella, P. Lu,
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2935

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[11] During the preparation of this manuscript, Lavilla and
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tophan derivatives [i.e., C3-substituted (NH)-indoles]
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[16] A 3:1 (4b:4a) GC-selectivity was observed with either
K2CO3 or KHCO3. This result might explain the
modest activity of K2CO3 through in situ formation of
KHCO3.
[17] Such halide effects in direct arylation reactions have al-
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[13] The use of Ag2CO3 as well as AcOAg in the presence
of dppm led to a complete degradation of (NH)-in-
doles.
[14] M2CO3, AcOM, M(OH)n (M=Li, Na, K, Cs, Ca or
Mg; n=1 or 2), tertiary amines and phosphate bases
were evaluated.
[15] For an amazing synthesis of 2,3-diarylindoles from
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2936
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2929 – 2936