Efficient palladium-catalyzed oxidative indolation of allylic compounds with DDQ via sp3 C-H bond activation and carbon-carbon bond formation under mild conditions

Article abstract of DOI:10.1002/adsc.200900561

An efficient oxidative cross-coupling reaction between 1,3-diarylpropenes and indoles in the presence of palladium chloride was achieved with 2,3-dichloro-5,6-dicyanoquinone (DDQ) as oxidant. The reaction afforded 1,3-diphenylallylindoles in moderate to h

Full text of DOI:10.1002/adsc.200900561

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DOI: 10.1002/adsc.200900561
Efficient Palladium-Catalyzed Oxidative Indolation of Allylic
3
À
Compounds with DDQ via sp C H Bond Activation and
Carbon-Carbon Bond Formation Under Mild Conditions
Hanjie Moa and Weiliang Baoa,*
a
Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; phone: (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
Received: August 10, 2009; Published online: November 18, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900561.
Abstract: An efficient oxidative cross-coupling re-
action between 1,3-diarylpropenes and indoles in
the presence of palladium chloride was achieved
with 2,3-dichloro-5,6-dicyanoquinone (DDQ) as ox-
idant. The reaction afforded 1,3-diphenylallylin-
doles in moderate to high yields under mild condi-
tions, thus providing a novel methodology to syn-
thesize the respective products.
1970s.[11] Recently, Liꢀs group has reported a first cata-
lytic allylic alkylation reaction directly from allylic sp3
3
À
À
C H and methylenic sp C H bonds using Cu(I)/
Co(II) and t-BuOOH as the catalyst-system.[6e] Our
group has reported a metal-free allylic alkylation re-
3
[6a]
À
action by using the allylic sp C H bond. Herein,
we report the first Pd(II)-catalyzed CDC reactions of
allylic indolation directly using allylic sp C H bond
and indoles with 2,3-dichloro-5,6-dicyanoquinone
(DDQ) as the oxidant under mild conditions.
3
À
À
À
Keywords: C C bond formation; C H bond activa-
tion; cross-dehydrogenative-coupling (CDC) reac-
tion; indolation; palladium catalysis
To begin our study, we chose 1,3-diphenylpropene
1a and indole 2a as the standard substrates to search
for suitable reaction conditions. DDQ is a well-known
oxidation reagent for organic synthesis.[12] The cou-
pling reactions between some nucleophiles and ben-
zylic substrates bearing a heteroatom at the a-posi-
Indoles are key structural units in many natural prod- tion were reported in the presence of DDQ.[13]
ucts and important pharmaceuticals.[1] The develop-
We also applied a stoichiometric amount of DDQ
ment of new, efficient and selective synthetic methods as an oxidant in our allylic indolation reaction. How-
for the functionalization of indoles continues to re- ever, the desired product was obtained only in less
ceive considerable attention.[2] With the emergence of than 5% yield without catalyst (Table 1, entry 1).
the concepts of “atom economy”[3] and “green From the literature we found that CuBr may be an ef-
chemistry”[4] transition metal-catalyzed C H bond ac- ficient catalyst in the indolation reaction.[8a] To im-
tivation directly to form C C bond has attracted prove the reaction yield, CuBr was used as a catalyst.
À
À
great attention recently and a number of excellent re- The yield of the desired product was raised to 19%
sults have been obtained.[5] Various oxidative intermo- (Table 1, entry 2). After various transition metal cata-
lecular cross-dehydrogenative-coupling (CDC) reac- lysts were surveyed to optimize the reaction results
tions by using two different C H bonds have also (Table 1, entries 3, 4 and 5), PdCl2 was found to be
been developed, such as (i) sp C H with sp C H,
À
3
3
[6]
À
À
the most efficient catalyst and the yield of the product
was far improved. Allylation had taken place at the 3-
position of indoles and no N-allylation product was
2
2
[7]
3
2
À
À
À
À
(ii) sp C H with sp C H, (iii) sp C H with sp C
H,[8] and (iv) sp C H with sp C-H.
3
[9]
À
The palladium-catalyzed allylic alkylation (Tsuji– detected (Table 1, entry 6). In addition, we tried other
Trost coupling reaction), usually employing an allylic oxidants such as tert-butyl hydroperoxide (TBHP),
acetate or its derivatives, and later using allylic alco- tert-butyl peroxide and benzoquinone (BQ), since
hols directly as the starting material, represents one they acted well as the oxidants in recent reports of
À
À
À
of the most common C C bond formation methodol- C C bond formation reactions via the C H bond ac-
ogies in organic synthesis.[10] In fact, Trostꢀs group tivation. Unfortunately, all these oxidants were not
tried to make an allylic alkylation directly from an al- suitable for this CDC reaction (Table 1, entries 7–9).
lylic sp3 C H by palladating an olefin in the late Then a number of solvents were screened and the re-
À
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Oxidant
Solvent
Temp. [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
None
CuBr
FeCl3
NiCl2
ZrCl4
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
TBHP
tert-butyl peroxide
BQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3NO2
THF
0
0
0
0
0
0
0
0
50
0
0
0
0
0
0
-10
r.t
70
trace
19
trace
28
39
67
N.D.
N.D.
trace
75
36
66
52
81
51
79
38
20
9
10
11
12
13
14
15
16
17
18
DMF
CH3CN
CHCl3
CH3CN
CH3CN
CH3CN
DDQ
[a]
0.5 mmol of 1a, 0.6 mmol of 2a, 1.5 mL of solvent, 0.6 mmol of oxidant.
Isolated yield
[b]
action could proceed in CH2Cl2, toluene, CH3NO2, tries 9–13). Interestingly, no isomers were detected
THF, DMF, CH3CN and CHCl3. However, considera- when 1g reacted with indole (Table 2, entry 14), while
ble amounts of undesired products were formed in a- and g-indolated isomers were detected when the
CH3NO2, DMF and CHCl3 (Table 1, entries 11, 13 mono- or asymmetrically disubstituted 1,3-diarylpro-
and 15). And the reaction performed best in CH3CN penes reacted with indole (Table 2, entries 9, 12 and
(Table 1, entry 14). Further investigation showed that 13). The steric effect caused the yield of the coupling
this CDC reaction was very sensitive to the tempera- product to decrease (Table 2, entries 4 and 15).
ture. The yield of the coupling product rapidly de-
Interestingly, when the 3-position of indole was sub-
creased when we increased the reaction temperature stituted, the C-2 alkylation product was also obtained
(Table 1, entries 17 and 18). Lower reaction tempera- (Table 2, entry 16).
tures also caused the yield of the desired product to
go down slightly (Table 1, entry 16).
On the basis of these observations, a tentative
mechanism is proposed in Scheme 1. Firstly, DDQ ab-
With the optimized reaction conditions established, stracted a hydride from 1a to form the conjugated in-
various substrates were subjected to the CDC reac- termediate A.[6a] Then A would undergo carbometala-
tions and representative results are summarized in tion with palladium chloride and indole to form p-
Table 2. Indoles with electron-withdrawing groups re- allyl palladium intermediate B.[14] Subsequent elimina-
acted well with the diarylpropenes under the standard tion would produce intermediate C, which finally af-
reaction conditions (Table 2, entries 2 and 3). How- forded the product 3a after a proton was abstracted
ACHTUNGTRENNUNGever, PPh3 was required to achieve a moderate yield by the phenolic anion. The fact that isomers were de-
when indoles bearing electron-donating group were tected when indole reacted with mono- or asymmetri-
used (Table 2, entries 5–7). To expand the scope of cally disubstituted 1,3-diarylpropenes implies the in-
the reaction, we further examined mono- and disub- volvement of the p-allyl palladium intermediate B
stituted 1,3-diarylpropenes. High yields in the cou- during the catalytic cycle.
pling products were obtained with electron-donating
In summary, we have developed an efficient catalyt-
groups on the aromatic ring of the 1,3-diarylpropenes, ic allylic indolation via a CDC reaction between allyl-
3
À
while moderate yields were found with electron-with- ic sp C H and the C-3 and/or C-2 position of indole
drawing-groups on the aromatic ring (Table 2, en- catalyzed by palladium chloride under mild condi-
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Efficient Palladium-Catalyzed Oxidative Indolation of Allylic Compounds
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Table 2. CDC reaction of indoles with diarylpropenes.[a]
Entry
R1, R2, R3, R4, R5
X, R6
Product
Yield [%][b]
1
H, H, H, H, H 1a
H, H 2a
3a
81
2
1a
5-Br, H 2b
3b
71
3
1a
5-CN, H 2c
3c
83
4
5
6
7
1a
1a
1a
1a
4-CO2CH3, H 2d
5-CH3, H 2e
5-OMe, H 2f
7-CH3, H 2g
3d
3e
3f
3g
46
53[c]
48[c]
51[c]
77
8
1a
H, CH3 2h
3h
9
H, Cl, H, H, H 1b
Cl, Cl, H, H, H 1c
H, H, Br, Br, H 1d
CH3, H, H, H, H 1e
H, CH3, H, H, H 1f
OMe, Cl, H, H, H 1g
H, H, H, H, CH3 1h
2a
2a
2a
2a
2a
2a
2a
3i, 3j
3k
3l
3m, 3n
3m, 3n
3o
71
60
49
94
90
91
40
10
11
12
13
14
15
3p
16
1a
55
[a]
0.5 mmol of diarylpropenes, 0.6 mmol of indole, 1.5 mL of CH3CN, 0.6 mmol of DDQ, 5 mol% PdCl2, 08C, 2 h.
Isolated yield based on diarylpropene.
10 mol% PPh3 were added.
[b]
[c]
Scheme 1. Possible mechanism.
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Hanjie Mo and Weiliang Bao
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Experimental Section
General Procedure for Products 3
To a mixture of PdCl2 (0.025 mmol), 1,3-diarylpropene
(0.5 mmol) and 1.5 mL of CH3CN, DDQ (0.6 mmol) was
added at 08C. After stirring for 5 min, indole (0.6 mmol)
was added to the mixture dropwise. Then the reaction vessel
was capped and the mixture stirred for 2 h. The resulting
mixture was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate=10/1), and the
fraction with an Rf =0.3 was collected to give the desired
product (E)-3-(1,3-diphenylallyl)-1H-indole (3a) as a light
yellow oil. 1H NMR (400 MHz, CDCl3): d=8.03 (s, 1H),
7.50–7.17 (m, 14H), 7.09–7.03 (m, 1H), 6.92 (s, 1H), 6.81–
6.73 (dd, J=7.2, 15.6 Hz, 1H), 6.48 (d, J=15.6 Hz, 1H),
5.16 (d, J=6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
46.1, 111.0, 118.7, 119.4, 119.8, 122.0, 122.5, 126.2, 126.3,
126.8, 127.1, 128.3, 128.4, 130.5, 132.5, 136.6, 137.4, 143.3;
MS (70 eV, EI) m/z=309.
Acknowledgements
This work was financially supported by the Specialized Re-
search Fund for the Doctoral Program of Higher Education
of China (20060335036).
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