Csp2-Csp2 bond formation via Lewis acid/ammonium salt cocatalyzed tandem addition and oxidative dehydrogenation strategy: Alkenylation of indoles with α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2012.05.053

The alkenylation of indoles with α,β-unsaturated ketones through a tandem addition and oxidative dehydrogenation strategy has been developed. This method provides an alternative approach for C3 alkenylation of indoles with α,β-unsaturated ketones. Using inexpensive and readily available BF₃·Et₂O and an ammonium salt as the efficient cocatalyst constitutes the attractive advantage of this reaction.

Full text of DOI:10.1016/j.tetlet.2012.05.053

Tetrahedron Letters 53 (2012) 3802–3804
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Tetrahedron Letters
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Csp2–Csp2 bond formation via Lewis acid/ammonium salt cocatalyzed
tandem addition and oxidative dehydrogenation strategy: alkenylation of
indoles with a,b-unsaturated ketones
Shi-Kai Xiang a, Guolin Wu b, Bo Zhang b, Yuxin Cui b, , Ning Jiao b,c,
⇑
⇑
a College of Chemistry and Materials Science, Sichuan Normal University, Chengdu, Sichuan 610066, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Perking University, XueYuan Rd. 38, Beijing 100191, China
c Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The alkenylation of indoles with
dehydrogenation strategy has been developed. This method provides an alternative approach for C3 alk-
a,b-unsaturated ketones through a tandem addition and oxidative
Received 7 March 2012
Revised 3 May 2012
Accepted 11 May 2012
Available online 17 May 2012
enylation of indoles with
an ammonium salt as the efficient cocatalyst constitutes the attractive advantage of this reaction.
a
,b-unsaturated ketones. Using inexpensive and readily available BF3ÁEt2O and
Ó 2012 Published by Elsevier Ltd.
Keywords:
Alkenylation
Indoles
a,b-Unsaturated ketones
Tandem reaction
Lewis acids
Organocatalyst
The indole nucleus is embedded in many pharmaceuticals and
biologically active alkaloids.1 For a long time, the modification of
the indole unit arouses great interest of organic chemists.2–5 Me-
tal-catalyzed C–H functionalization of indoles represented an
important approach of modifying the indole unit. Although, C–H
arylation of indoles has been extensively investigated,2 it was only
in recent years that metal-catalyzed alkenylation reaction of in-
doles was explored widely.3–5,7 In 2005, Gaunt and co-workers de-
used as substrates under that conditions. After some effort, the
scope of substrates was expanded successfully to ,b-unsaturated
ketones by altering the catalytic conditions. Herein, we report the
alkenylation of indoles with ,b-unsaturated ketones via a Lewis
acid/ammonium salt cocatalyzed tandem addition and oxidative
dehydrogenation strategy (Eq. (2)).
a
a
O
H
O
scribed
a Pd-catalyzed alkenylation reaction in which the
O
N
(20%)
H•TFA
regioselectivity of C2 or C3 can be controlled by varying the reaction
media and the oxidant.3 Directing group strategy was also utilized
to achieve the regioselective C2 allenylation of indoles by Brown
and co-workers,4a Arrayas, and Carrretero et al.4b,c In 2006, Vander-
wal and co-workers reported a novel method for the synthesis of
vinylated indoles by the ring-opening reaction of pyridinium salts.6
More recently, we developed a novel organocatalytic direct C3 alk-
+
R1
(1)
H
R1
DDQ, THF
N
N
R2
previous work
R2
R3
O
BF3•Et2O(10 %),
i-PrNHBn•TFA (20 %)
enylation of indoles with a
,b-unsaturated aldehydes (Eq. (1)).7 Sim-
ple and readily available morpholine trifluoroacetic acid salt was
employed as the efficient catalyst in this reaction. Various C3 alke-
nylated indoles with
O
R1
(2)
+
R3
R1
DDQ, THF
N
R3 ≠ H
N
R2
this work
R2
a,b-unsaturated aldehydes as substituents
could be easily synthesized by this approach. However, this trans-
formation became ineffective when a,b-unsaturated ketones were
Initially, we investigated the reaction of indole (1a) with ethyl
vinyl ketone (2a) in THF using BF3ÁEt2O as the cocatalyst. After
⇑
Corresponding authors. Tel./fax: +86 010 8280 5297.
E-mail addresses: yxcui@bjmu.edu.cn (Y. Cui), jiaoning@bjmu.edu.cn (N. Jiao).
screening various oxidants, we found that DDQ can give the best
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.05.053

S.-K. Xiang et al. / Tetrahedron Letters 53 (2012) 3802–3804
3803
Table 1
Table 2
Alkenylation of indole 1a with ethyl vinyl ketone 2a in different conditionsa
Alkenylations of substituted indoles 1 with various of
a
,b-unsaturated ketone 2a
R3
O
O
BF3•Et2O(10 %),
O
O
i-PrNHBn⋅TFA (20 %)
catalyst
R1
+
+
R3
R1
DDQ(1.3 eq.) THF, 40°C
N
oxidant, THF, 40°C
N
N
H
R2
N
H
3aa
R2
1a
2a
1
2
3
Entry Catalyst (mmol %)
Solvent
Oxidant
(1.3 equiv)
Yieldb
(%)
O
O
O
1
2
3
4
5
6
7
8
9
BF3ÁEt2O (10)
BF3ÁEt2O (10)
BF3ÁEt2O (10)
BF3ÁEt2O (10)
BF3ÁEt2O (10)
BF3ÁEt2O (10)
BF3ÁEt2O (10)
BF3ÁEt2O (10)
THF
THF
THF
THF
THF
THF
MeCN
DDQ
CAN
PCC
o-Chlororanil
p-Chlororanil
IBX
36
NDc
Trace
Trace
20
Me
N
N
Me
N
H
H
NDc
30
Trace
52
3aa
(60%)
3ca
(73%)
3ba
(67%)
DDQ
Toluene DDQ
BF3ÁEt2O (10); pyrilidine (20); THF
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
O
O
O
TFA (20)
10
11
12
13
14
15
16
BF3ÁEt2O (10); morpholineÁTFA THF
51d
50
Me
F
MeO
(20)
BF3ÁEt2O (10); proline (20),
THF
THF
THF
N
H
N
H
N
H
TFA (20)
BF3ÁEt2O (10); i-Pr2NH (20),
TFA (20)
56
3da
(45%)
3fa
3ea
(49%)
(42%)
BF3ÁEt2O (10); i-PrNHBnÁTFA
60d
45
Ph
O
(20)
O
O
BF3ÁEt2O (10); Et2NH (20), TFA THF
(20)
BF3ÁEt2O (10); i-PrNH2 (20),
THF
THF
53
Ph
N
H
TFA (20)
N
H
N
BF3ÁEt2O (10); BnNH2 (20),
TFA (20)
45
H
OMe
3ab
(33%)
3ga
(56%)
3ha
(55%)
a
Reaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), catalyst, DDQ (0.52 mmol),
solvent (3 mL), 40 °C, 26 h. Amine TFA salt catalyst and DDQ were added after 24 h.
a
Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), catalyst, DDQ (0.52 mmol),
TFA = trifluoroacetic acid.
solvent (3 mL), 40 °C, appointed reaction time. i-PrNHBnÁTFA and DDQ were added
after appointed time. For the detail, see experimental section. TFA = trifluoroacetic
acid. The yield was isolated yields.
b
Isolated yields.
ND = not detected.
MorpholineÁTFA and i-PrNHBnÁTFA were added as salts.
c
d
result of 36% yield (Table 1, entries 1–6). Although this reaction can
undergo in MeCN and get the product in 30% yield (Table 1, entry 7),
the best solvent was THF (Table 1, entries 1, 7, and 8). Inspired by
our previous work,7 we decided to utilize ammonium salt as an
organocatalyst8 to promote the oxidation step. After screening var-
ious ammonium salts, it was found that all the ammonium salt pre-
sents positive effects on the transformation. Among them,
i-PrNHBnÁTFA salt gave the best efficiency with 60% yield of 3aa
(Table 1, entries 9–16).
O
R1
ꢀ
R3
N
R2
1
2
BF3•Et2O
R3
O
R
R3
The scope of alkenylation reaction of indoles was expanded to a
N
R'
variety of indole derivatives 1 and
a,b-unsaturated ketones 2
4
R1
(Table 2). Indoles 1 with both electron-donating groups and elec-
tron-withdrawing groups smoothly underwent this kind of trans-
formation generating alkenylation products 3 in moderate yields
(33–73%) (Table 2). It is noteworthy that the efficiency is not
affected by the steric hindrance of the substitutes at the 2-position
of indoles (see products 3ca, 3ga, and 3ha, Table 2). Interestingly,
the reactions executed with high stereoselectivity giving only the
(E)-isomer as the solo product. Besides alkyl vinyl ketone, aryl
vinyl ketone could also undergo this transformation generating
the desired C3 vinylated product 3ab.
A
N
R1
R2
N
R3
R2
DDQ
B
R
R'
R1
N
H2
X
N
R2
R3
O
R
N
X
R
N
R3
R3
R'
DDQ
R'
R1
The probable catalytic mechanism for this transformation is
N
X
illustrated in Scheme 1. Initially, indoles 1 and
a
,b-unsaturated ke-
R2
3
tones 2 can undergo Michael addition reaction to generate the satu-
rated ketones 4. The saturated ketones 4 react with amine catalysts
to generate activated enamine species B through iminium species A.
The activated enamine species B are oxidized by DDQ to give inter-
N
R1
N
R1
R2
R2
C
Scheme 1. Probable mechanism for this transformation.

3804
S.-K. Xiang et al. / Tetrahedron Letters 53 (2012) 3802–3804
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,b-unsaturated ketones through tandem addition and oxidative
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Acknowledgments
Financial support from the National Basic Research Program of
China (973 Program) (Grant No. 2009CB825300), the National Sci-
ence Foundation of China (Nos. 20872003, 21172006), and Peking
University are greatly appreciated.
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Supplementary data associated with this article can be found, in
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053.
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