Palladium-catalyzed direct C-2 arylation of indoles with aryl halides in aqueous medium

Article abstract of DOI:10.1055/s-0032-1317702

A newly developed, efficient catalytic system for direct C2-arylation of indoles with aryl halides in aqueous medium under mild conditions (80 °C) is reported. These procedures are free of toxic solvents, and exhibit improved yields and high chemo- and regioselectivity. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317702

2992▌
LETTER
letter
Palladium-Catalyzed Direct C-2 Arylation of Indoles with Aryl Halides in
Aqueous Medium
Synthesis of 2-Arylindoles through C–H Activation of Indoles
Guo-ping Lu, Chun Cai*
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu 210094, P. R. of China
Fax +86(25)84315030; E-mail: c.cai@mail.njust.edu.cn
Received: 13.10.2012; Accepted after revision: 05.11.2012
couplings in water could be promoted by adding appropri-
Abstract: A newly developed, efficient catalytic system for direct
ate surfactants.10 Thus, we hypothesized that use of car-
C2-arylation of indoles with aryl halides in aqueous medium under
boxylate salts formed in situ from bases and carboxylic
acids (or carboxylic acid anhydrides) and surfactants
could accelerate the direct arylation of indoles in water.
mild conditions (80 °C) is reported. These procedures are free of
toxic solvents, and exhibit improved yields and high chemo- and
regioselectivity.
Key words: arylation, indole, aqueous medium, green chemistry,
synthetic method
Ar1
Ar1
Pd0Ln
+
Ar1I
Ar2–H
Ar1–Ar2
PdLn
PdLn
– Pd0Ln
slow
Ar2
I
I
path a
II
2-Arylindoles are a class of important synthetic inter-
mediates of various biologically and medicinally active
molecules.1 Many traditional approaches to these com-
pounds often require pre-functionalization of indoles in-
cluding multistep synthesis processes,1e,2 so recent work
has mainly focused on the development of transition-metal-
catalyzed methods for the direct C–H arylation of in-
doles.3 Typically, such arylations involve a coupling be-
tween an aryl halide or pseudohalide and an indole
derivative catalyzed by palladium complexes at high tem-
perature (120–160 °C).4 Although several attempts have
been made to perform these reactions under thermally
mild conditions (room temperature to 80 °C),5 use of (po-
tentially toxic) organic solvents is always the norm, which
by definition fails to meet the 12 principles of green chem-
istry.6
Ar2-H
– RCOOH
MOCOR
– MI
path b
fast
M: metal ion
Ar1
LnPd-Ar1
PdLn
O COR
OCH2OR
III
IV
Scheme 1 Working hypothesis: an activated palladium(II) species for
C–H arylation
As a starting point, we performed a test reaction of iodo-
benzene and indole in 2 wt.% PTS 600 aqueous micelles
catalyzed by bis[di-tert-butyl(4-dimethylaminophenyl)-
phosphino]dichloropalladium(II) [Pd(Amphos)2Cl2,
2
mol%] using NaOH and o-nitrobenzoic acid (A) as the ad-
ditives at 60 °C for 24 hours. A low yield (19%) of 2-phe-
nyl-1H-indole (2a) was obtained (Table 1, entry 1). After
screening several bases and carboxylic acids (or carboxyl-
ic acid anhydrides; entries 1–8), the combination of
NaOH and tetrachlorophthalic anhydride (TCPA, B; Fig-
ure 1) was found to be the best selection for the reaction
(entry 3). To further improve these modest results, differ-
ent surfactants and catalysts were employed in the system
(entries 3 and 9–16), but limited success was found. Sur-
prisingly, the reaction in aqueous micelles was more slug-
gish than ‘on water’ (entry 12),11 suggesting that the
aqueous micelle system may inhibit the ion exchange be-
tween substrates and additives, and thereby decrease the
reaction rate.12
To solve these problems, scattered reports have men-
tioned the direct arylation of (hetero)arenes in aqueous
medium.7 Recently, Joucla et al. have carried out the
direct C–H arylation of indoles ‘on water’.8 However,
high temperatures (110 °C) are required, and the yields
and selectivity are also unsatisfactory. As a part of our in-
terest in designing cross-coupling reactions in water, we
describe here a novel and facile protocol for the direct C-
2 arylation of indoles in aqueous medium under mild con-
ditions (80 °C), with improved yields and high regioselec-
tivity.
Silver(I) carboxylates, which can be generated in situ
through a procedure from Ag2O and the corresponding
carboxylic acids, have proved to be efficient additives for
the direct C-2 arylation of indoles, which could increase
the rate of the palladation step (path b) and enhance the
electrophilicity of a cationic palladium species (IV;
Scheme 1).5b,9 Furthermore, many Pd-catalyzed cross-
Cl
O
COOH
NO2
Cl
Cl
O
O
O
O
O
Cl
B (TCPA)
A
C
Figure 1 The chemical structures of A–C
SYNLETT 2012, 23, 2992–2996
Advanced online publication: 28.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317702; Art ID: ST-2012-W0882-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Arylindoles through C–H Activation of Indoles
2993
Additionally, a series of organic solvents was selected as ed amounts of co-solvent to water sufficiently maintains
the co-solvents to improve the poor solubility of sub- the hydrophilicity and hydrogen bonding effects of water,
strates in water,13 and only EtOH–H2O (1:1) provided a which may accelerate formation of palladium intermedi-
trace of product (entries 18–20). Remarkably, the extent ates III and IV, and raise the electrophilicity of cationic
of reaction could be increased by reducing the ratio of palladium species IV.14
EtOH to water (entries 20–23). Presumably, adding limit-
Table 1 Optimization of Reaction Conditionsa
I
cat. Pd
+
N
60 °C, 24 h
N
H
H
1a
2a
Entry
Solvent (v/v)
Acid
Base
Catalyst
Yield (%)b
1
2
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% PTS 600c–H2O
2 wt% SDS–H2O
2 wt% CTAB–H2O
2 wt% TX 100d–H2O
H2O
A
AcOH
B
NaOH
NaOH
NaOH
NaOH
NaOH
Ag2O
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(OAc)2 (2 mol%)
19
5
3
35
3
4
C
–
5
nr
6
B
nr
7
B
NaOt-Bu
DABCO
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
26
10
nr
8
B
9
B
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25h
B
nr
B
9
B
48
14
22
7
H2O
B
H2O
B
Pd(dppf)Cl2 (2 mol%)
H2O
B
Pd(PPh3)2Cl2 (2 mol%)
H2O
B
Pd(BF4)2(MeCN)4 (2 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
Pd(Amphos)2Cl2 (20 mol%)
15
nr
H2Oe
B
PEG 200–H2O (1:1)
AcOH–H2O (1:1)
EtOH–H2O (1:1)
H2O–EtOH (2:1)
H2O–EtOH (5:1)
H2O–EtOH (10:1)
H2O–DMAc (5:1)
H2O–EtOH (5:1)
B
nr
B
nr
B
4
B
24
63, 80f,g
66, 76f,g
19
72f,g
B
B
B
B
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2992–2996

2994
G.-p. Lu, C. Cai
LETTER
Table 1 Optimization of Reaction Conditionsa
I
cat. Pd
+
N
60 °C, 24 h
H
N
H
1a
2a
Entry
Solvent (v/v)
Acid
Base
Catalyst
Yield (%)b
a Reaction conditions: iodobenzene (0.375 mmol), 1a (0.250 mmol), catalyst, NaOH (0.375 mmol), acid (0.375 mmol), solvent (0.6 mL), 60
°C, 24 h.
b Yield was determined by GC–MS.
c PTS 600 = Polyoxyethanyl α-tocopheryl sebacate 600.
d TX 100 = t-Octylphenoxypolyethoxyethanol.
e TBAB (20 mol%) was used.
f The reaction was carried out at 80 °C.
g Isolated yield.
h Amount of NaOH (as the base) used was 3 equiv.
Although H2O–EtOH (10:1) resulted in the highest yield
I
Pd(OAc)2/dppm (5 mol%)
AcOK, H2O, 110 °C, 24 h
at 60 °C (entry 23), H2O–EtOH (5:1) emerged as the bet-
ter choice along with an increase in reaction temperature
to 80 °C (entry 22). A solvent switch to DMAc led to a
much lower yield of the desired product (entry 24), and in-
creasing the amount of NaOH also proved to be harmful
for the reaction (entry 25). To compare and contrast these
couplings with the previous work,8 a direct comparison of
the coupling between indole and iodobenzene was per-
formed. As shown in Scheme 2, our protocol could afford
higher yield and regioselectivity by using less catalyst un-
der milder conditions (Scheme 2).
75%, 2a/3a = 22:18
+
Pd(Amphos)2Cl2 (2 mol%)
TCPA, NaOH
N
H
80%, only 2a
H2O–EtOH, 80 °C, 24 h
N
H
Scheme 2 The coupling of indole and iodobenzene
Encouraged by these preliminary results, various aryl ha-
lides were chosen to establish the scope and generality of
the protocol (Scheme 3). Aryl iodides containing electron-
withdrawing or electron-donating groups reacted well to
yield the corresponding 2-arylindoles. However, aryl
iodides with strong electron-withdrawing groups (such as
R
X
Pd(Amphos)2Cl2, TCPA
R
+
+
R
N
N
NaOH, 80 °C, 24 h
H2O–EtOH (5:1)
H
H
1a
2
N
H
3
CF3
F
N
N
N
N
H
H
H
H
2b: X = I, 74%
2c: X = I, 80%
2d: X = I, 85%
2a: X = I, 80%
X = Br, 19%a (19:1)a,b
CF3
Br
N
H
N
H
N
H
N
H
CF3
2e: X = I, 87%
2f: X = I, 48%
2g: X = I, 69%
2h: X = I, 70%
F3C
NO2
CN
N
N
H
N
H
H
2j: X = Br, 12%a (6:1)a,b
2i: X = I, trace
2k: X = Br, trace
Scheme 3 The couplings of various aryl halides with indole in aqueous medium, with isolated yields of the 2-arylindole products. Reagents and
conditions: aryl halide (0.375 mmol), 1a (0.250 mmol), Pd(Amphos)2Cl2 (0.050 mmol), NaOH (0.375 mmol), TCPA (0.375 mmol), H2O–EtOH
(5:1; 0.6 mL), 80 °C, 24 h. a The yield of 2 and the ratio of 2/3 were determined by GC–MS. b Values in brackets refer to the ratio of 2/3.
Synlett 2012, 23, 2992–2996
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Arylindoles through C–H Activation of Indoles
2995
R1
R1
R2
R2
I
Pd(Amphos)2Cl2, TCPA
R1
R2
+
+
N
N
NaOH, 80 °C, 24 h
H2O–EtOH (5:1)
H
H
1
2
N
H
3
F
N
N
N
H
Cl
Cl
N
H
Cl
Me
H
2l: 71%
2m: 55%
2n: 72%
2o: 52%
MeO
MeO
F
Cl
N
N
N
H
N
H
Me
Me
2p: 39%
2q: 36%
2r: 73%
2s: 70%
O2N
MeO
N
H
N
H
N
N
H
N
H
2t: 67%
2u: 9%a
2w: nrb
2v: trace
Scheme 4 The couplings of aryl iodides with various indoles in aqueous medium, with isolated yields of the 2-arylindole products. Reagents
and conditions: aryl halide (0.375 mmol), 1 (0.250 mmol), Pd(Amphos)2Cl2 (0.050 mmol), NaOH (0.375 mmol), TCPA (0.375 mmol), H2O–
EtOH (5:1, 0.6 mL), 80 °C, 24 h. a The yield of 2u was determined by GC–MS. b No reaction was observed.
Br
Pd(Amphos)2Cl2 (2 mol%)
N
H
H2O–EtOH (5:1)
N
H
+
NaOH (1.5 equiv)
TCPA (1.5 equiv), 80 °C, 24 h
I
2x: 86%
O
Br
NH
H
N
N
8-desbromohinckdentine A1
Scheme 5 A potential application of direct C-2 arylation of indoles to total synthesis
4-nitro-1-iodobenzene) afforded only traces of the final (2u, 9%). Disappointingly, the use of 7-azaindole (2w) re-
product (2i). The coupling appeared to be unaffected by sulted in no arylation. It should be noted that the coupling
steric effects (2h). In all cases, only 2-arylindoles (2/3 of 3-methylindole with iodobenzene only afforded trace
>50:1) were formed when aryl iodides were employed. 2v, indicating that a C-3-to-C-2 migration (1,2-migration)
Initial attempts were also made to couple aryl bromides of palladium may take place during the reaction,4b which
with indole under identical conditions. As expected, the would be inhibited due to a methyl group on the C-3 in-
reactions were more sluggish (2a, 2j and 2k), likely due to dole ring. Alternately, a steric effect in 3-methylindole
the rate of oxidative insertion. Moreover, the reaction re- may be operative.
gioselectivity was also unsatisfactory (2a and 2j).
To further demonstrate the potential of this methodology,
Likewise, a variety of indoles could also be coupled with 2-arylindole 2x, a crucial intermediate en route to 8-des-
aryl iodides efficiently in an aqueous medium (Scheme 4). bromohinckdentine A1, was smoothly generated by the
Unlike previous reports,4e,f,5b N-methylindole was found coupling of indole with 2-bromo-1-iodobenzene in this
to be less active than indole itself under these conditions aqueous medium (Scheme 5), avoiding the harsh reaction
(2o–q). Presumably, the free (NH)-indoles could form a conditions described in a previous report.1a
more electron-rich intermediate in strong basic aqueous
In conclusion, the direct C-2 arylation of indoles can be
medium. Indoles bearing a strong electron-withdrawing
performed in aqueous media under mild conditions (80
group (e.g., 5-nitroindole) gave a poor yield of the product
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2992–2996

2996
G.-p. Lu, C. Cai
LETTER
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m
iotSrat
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(15) General Procedure for Direct C-2 Arylation of Indoles in
Aqueous Medium: Pd(Amphos)2Cl2 (0.005 mmol), NaOH
(0.375 mmol), tetrachlorophthalic anhydride (TCPA; 0.375
mmol) and indole 1 (0.250 mmol) were weighed into a
microwave vial at r.t. Aryl halide (0.375 mmol), EtOH (0.10
mL) and H2O (0.50 mL) were then added by syringe. The
resulting solution was allowed to stir at 80 °C for 24 h. Upon
completion, the reaction mixture was diluted with EtOAc
(4.0 mL), filtered through a bed of silica gel layered over
Celite, The volatiles were removed in vacuo to afford the
crude product. The extent of conversion was determined by
GC–MS. Further column chromatography on silica gel
afforded the pure desired product 2.
Synlett 2012, 23, 2992–2996
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