Palladium-catalyzed direct denitrogenative C-3-arylation of 1H-indoles with arylhydrazines using air as the oxidant

Article abstract of DOI:10.1002/adsc.201200997

A novel palladium-catalyzed approach to direct C-3-arylation of 1H-indoles with arylhydrazines using air as the oxidant via C-N bond cleavage has been developed. Various substituents are tolerated in this system in moderate to good yields. This reaction could also be compatible with a larger scale. Thus, this strategy using arylhydrazines as arylating reagents provides a powerful method for constructing substituted 3-aryl-1H-indoles. Copyright

Full text of DOI:10.1002/adsc.201200997

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DOI: 10.1002/adsc.201200997
Palladium-Catalyzed Direct Denitrogenative C-3-Arylation of
1H-Indoles with Arylhydrazines using Air as the Oxidant
Yongxin Chen,a Shuaibo Guo,a Kangning Li,a Jinpeng Qu,a Hua Yuan,a
Qiuru Hua,a and Baohua Chena,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu Lanzhou, 730000, People’s Republic of
China and Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou
730000, Peopleꢀs Republic of China
Fax : +(86)-931-891-2582; e-mail: chbh@lzu.edu.cn
Received: November 13, 2012; Revised: December 24, 2012; Published online: February 25, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200997.
Abstract: A novel palladium-catalyzed approach to
direct C-3-arylation of 1H-indoles with arylhydra-
zines using air as the oxidant via C N bond cleav-
age has been developed. Various substituents are
tolerated in this system in moderate to good yields.
This reaction could also be compatible with a larger
scale. Thus, this strategy using arylhydrazines as ar-
ylating reagents provides a powerful method for
constructing substituted 3-aryl-1H-indoles.
been focused on the direct and site-selective arylation
of indoles with various arylating reagents.[9] Su and
Larrosa independently synthesized arylindoles with
benzoic acids as arylating reagents,[10] but the ortho-
substituted benzoic acids were required for the trans-
formations. Deng and co-workers developed a palladi-
um-catalyzed cascade for the direct desulfitative C-2-
arylation of indoles with sodium sulfinates.[11] How-
À
AHCTUNGTREGeNNUN ver, most of them required N-protecting groups, high
loading of metal oxidants, or harsh reaction condi-
tions. Notably, apart from aryl halides,[12] only a few
approaches to the direct C-3-arylation of 1H-indoles
with arylating reagents have been reported.[13] Consid-
ering economical and environmental viewpoints, air
serves as the ideal oxidant because of its abundance,
lack of toxic by-products and is more applicable to in-
dustry.[14] Herein, as part of our ongoing study on the
À
Keywords: arylhydrazines; 3-aryl-1H-indoles; C H
activation; denitrogenative process; palladium-cata-
lyzed reaction
Transition metal-catalyzed C C bond-forming reac- functionalization of heterocycles,[15] we report a facile
tions represent important and useful synthetic meth- and efficient method to synthesize 3-aryl-1H-indoles
ods in organic synthesis,[1] which have widespread ap- with arylhydrazines by using air as the oxidant.
À
plications in medicinal chemistry and materials sci-
To begin this study, 1H-indole (1a) and phenylhy-
ence.[2] Among them, using arylating reagents such as drazine (2a) were chosen as model substrates to opti-
aryl halides, ArC(O)OH, and ArSO2X (X=H, Na, mize the reaction conditions (Table 1). The desired
and NHNH2) for direct arylation is one of the most product 3aa was obtained in 78% yield in the pres-
[3]
À
powerful methods in the construction of C C bonds.
Arylhydrazines as active compounds are used for pre-
ence of 10 mol% of Pd
ACHTUNGRTEN(NUNG OAc)2, 20 mol% of 1,10-phen-
AHCTUNGTRENNUNG
paring nitrogen-containing compounds[4] and generate at 1008C (Table 1, entry1). To improve the reaction
radical species via oxidation.[5] Even so, little atten- efficiency, various oxidants were then investigated,
tion has been paid to utilize them as arylating re- but only inferior results were obtained (Table 1, en-
agents via denitrogenation. Recently, Loh and co- tries 2–5). When O2 was employed as the oxidant,
À
workers first reported the palladium-catalyzed C C 76% of 3aa was isolated (Table 1, entry 6). To our de-
bond formation of arylhydrazines with olefins via light, increasing the amount of 1,10-phenanthroline to
[6]
À
C N bond cleavage.
30 mol%, the yield of 3aa resulted in 89%, while 2,2-
Arylindole skeletons are ubiquitous in many biolog- bipy showed no better effect on the promotion of this
ically active natural products and pharmaceuticals.[7] reaction (Table 1, entries 7 and 8). Other palladium
They also exhibit a wide range of biological proper- species such as PdCl2, PdCl
ties, such as antiprotozoal agents, h5-HT2A receptor were substantially less effective (Table 1, entries 9–
antagonist, etc.[8] Therefore, considerable efforts have 11). Reducing the amount of Pd
(OAc)2 to 5 mol% led
2ACHTUNGTNERNUG(PPh3)2, and PdACHTUNGTRENNUNG(dba)2
AHCTUNGTRENNUNG
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Ligand
Oxidant
air
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
N
1,10-Phen (20%)
1,10-Phen (20%)
1,10-Phen (20%)
1,10-Phen (20%)
1,10-Phen (20%)
1,10-Phen (20%)
1,10-Phen (30%)
2,2’-bipy (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
1,10-Phen (30%)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhMe
DMF
DCE
1,2-dichlorobenzene
PhCl
78
0
15
trace
62
76
89
18
37
Cu
N
AgOAc
BQ
K2S2O8
O2
air
air
air
air
air
air
Pd
Pd
N
U
9
10
11
12
13
14
15
16
17
E
20
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
65
67[c]
68
air
air
air
air
0
trace
60
air
30[d]/79[e]
[a]
Conditions: 1a (0.20 mmol), 2a (0.40 mmol), catalyst (10 mol%), oxidant (2 equiv.), CF3COOH (1.5 equiv.), solvent
(1 mL), 12 h, 1008C.
Isolated yields after column chromatography.
With 5 mol% PdACTHUNRGTNEUNG(OAc)2.
At 808C.
[b]
[c]
[d]
[e]
At 1208C.
to a lower yield (Table 1, entry 12). Different solvents in the corresponding product 3ka in 65% yield
were also evaluated, and they showed disappointing (Table 2, entry 11). Unfortunately, no desired prod-
results (Table 1, entries 13–16). The yield was found ucts were observed when N-protected indoles were
to decrease with the temperature changed to 80 or subjected to the optimized conditions.
1208C (Table 1, entry 17). Additionally, the reaction
The reaction scope was further expanded to substi-
(OAc)2 or tuted arylhydrazines 2 (Table 3). It was found that
most arylhydrazines bearing ortho-, meta-, and para-
was inefficient in the absence of Pd
CF3COOH.
ACHTUNGTRENNUNG
Under the optimized reaction conditions, a wide substitutions provided moderate to good yields, and
range of 1H-indoles were examined to establish the showed good functional group tolerance. Higher
scope of this reaction (Table 2). Generally, various yields were obtained with electron-withdrawing sub-
1H-indoles with substituted groups such as methyl, stituents, and the yields were reduced significantly
methoxy, chloro, and 7-azaindole were compatible with methoxy groups (Table 3, entry 10). More impor-
with the reaction conditions, affording the desired tantly, halogen substituents in the substrate can also
products in moderate to good yields. With indoles be well tolerated, allowing further coupling reactions
substituted at the 5-position, the electron-rich sub- for the synthesis of more complex molecules (Table 3,
stituents showed better reactivities and gave higher entries 1–3, 5, 11–14). More bulky substrates such as
yields than electron-deficient ones (Table 2, entries 2– 1-naphthylhydrazine (2m) also could be transformed
6). Strongly electron-deficient nitro or cyano groups smoothly and afforded 3-(naphthalen-1-yl)-1H-indole
lowered the yield significantly even after a prolonged in 63% yield (Table 3, entry 16).
reaction time (Table 2, entries 7 and 8). Indoles with
a methyl on the 6- or 7-position were also examined,
This coupling reaction was also compatible with
larger scale under the optimized condition
a
and high yields were obtained (Table 2, entries 9 and (Scheme 1). A mixture of 1H-indole (1 mmol), phe-
10). In addition, a heterocyclic indole, such as 7-azain- nylhydrazine (2 mmol), Pd(OAc)2 (10%, 22.5 mg),
dole (1k), could also be used in the reaction, resulting 1,10-phen (30%, 59.5 mg), CF3COOH (1.5 equiv.,
AHCTUNGTRENNUNG
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Palladium-Catalyzed Direct Denitrogenative C-3-Arylation of 1H-Indoles with Arylhydrazines
Table 2. Reactions of various 1H-indoles (1) with phenylhy-
drazine (2a).[a]
Table 3. Reactions of 1H-indole (1a) with various arylhydra-
zines (2).[a]
Entry
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
4-FC6H4 (2b)
4-ClC6H4 (2c)
4-BrC6H4 (2d)
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
81[c]
92[c]
95[c]
90[c]
78[c]
0
Entry
R1
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
H (1a)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
89
91
82
81
70
78
4-CF3C6H4 (2e)
3-Cl-4-CH3C6H3 (2f)
4-NO2C6H4 (2g)
4-CH3C6H4 (2h)
4-t-BuC6H4 (2i)
2-CH3C6H4 (2j)
2-CH3OC6H4 (2k)
2-CH3-5-Cl-C6H3 (2l)
2-ClC6H4 (2m)
3-ClC6H4 (2n)
5-Me (1b)
5-OMe (1c)
5-F (1d)
5-Cl (1e)
5-Br (1f)
5-CN (1g)
5-NO2 (1h)
6-Me (1i)
7-Me (1j)
74
74
85
23
9
trace
10
11
12
13
14
15
16
trace[a]/18[c]
72[c]
76[c]
83[c]
89[c]
73
79
84
10
3ja
3-BrC6H4 (2o)
3-CH3C6H4 (2p)
1-naphthyl (2q)
11
3ka
65[c]
63
[a]
Conditions: 1 (0.20 mmol), 2a (0.40 mmol), Pd
ACHTUNGERTN(NUNG OAc)2
[a]
Conditions: 1a (0.20 mmol), 2 (0.40 mmol), Pd
(10 mol%), 1,10-phen (30 mol%), CF3COOH
(1.5 equiv.), PhCl (1 mL), 12 h, 1008C.
Isolated yields after column chromatography.
17 h.
ACHTUNGTRENNUNG(OAc)2
(10 mol%), 1,10-phen (30 mol%), CF3COOH
(1.5 equiv.), PhCl (1 mL), 12 h, 1008C.
Isolated yields after column chromatography.
24 h.
[b]
[c]
[b]
[c]
decomposed into Pd(0)L2, N2, and H2O by air. Finally,
the Pd(0) species is reoxidized to Pd(II) by air with
the assistance of a ligand.
In summary, we have demonstrated a novel Pd-cat-
alyzed direct denitrogenative C-3-arylation of indoles
with arylhydrazines. The procedure, using air as the
oxidant, is a simple, economical, and environmentally
friendly protocol, which could be applied to various
available substrates in moderate to good yields. This
approach is a useful strategy to develop new arylating
Scheme 1. Coupling of 1H-indole with phenylhydrazine on
a larger scale.
112.5 mL), and PhCl (5 mL) was stirred at 1008C for reagents for the preparation of 3-aryl-1H-indoles.
12 h and afforded the desired product in 73% yield.
Based on the above results and research from other
groups,[3i,6,10,11] a tentative reaction mechanism is illus- Experimental Section
trated in Scheme 2. Initially, the metathesis of sub-
CAUTION: Arylhydrazines should be handled with care
due to possible toxicity and carcinogenicity.
strate 2a and Pd(II)2L2 affords palladiaziridine com-
plex A that has been established by MuÇiz,[16] and
then oxidative addition of complex A with Pd(0)L2
forms the two palladium(II) centered complex B via
C N bond cleavage, which was proposed by Loh.
Subsequent protonolysis of B gives the aryl palladium
Typical Procedure for the Preparation of 3-Aryl-1H-
indoles 3
[6]
À
1H-Indole
1 (0.20 mmol), arylhydrazine 2 (0.40 mmol),
complex C and the palladiaziridine complex D. Next,
Pd(OAc)2 (4.5 mg, 10 mmol%), 1,10-phen (11.9 mg,
AHCTUNGTRENNUNG
À
C is attacked by 1H-indole 1a via C H activation to
30 mmol%), CF3COOH (22.5 mL, 1.5 equiv.), and PhCl
(1 mL) were added to a flask with a magnetic stirring bar.
The resulting mixture was stirred at 1008C for 12 h. After
generate a palladium(II) aryl heteroaryl intermediate
À
(E), which would undergo C C reductive elimination
to produce the target product 3aa and Pd(0)L2. D is cooling to room temperature, the mixture was diluted with
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713

Yongxin Chen et al.
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Scheme 2. A tentative reaction mechanism.
ethyl acetate and filtered. The filtrate was evaporated under
reduced pressure to get the crude product, which was fur-
ther purified by silica gel chromatography to give product 3.
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