Potassium iodide catalyzed simultaneous C3-formylation and N-aminomethylation of indoles with 4-substituted-N,N-dimethylanilines

Article abstract of DOI:10.1039/c2ob26636a

A one-pot dual functionalization of indoles has been developed. The simultaneous C3-formylation and N-aminomethylation of indoles can be achieved using readily available potassium iodide as a catalyst and tert-butyl peroxybenzoate as a co-oxidant. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26636a

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Organic &
Biomolecular
Chemistry
COMMUNICATION
Potassium iodide catalyzed simultaneous
C3-formylation and N-aminomethylation of indoles
with 4-substituted-N,N-dimethylanilines†
Cite this: Org. Biomol. Chem., 2012, 10,
9519
Received 17th August 2012,
Accepted 1st November 2012
Lan-Tao Li, Hong-Ying Li, Li-Juan Xing, Li-Juan Wen, Peng Wang* and Bin Wang*
DOI: 10.1039/c2ob26636a
www.rsc.org/obc
A one-pot dual functionalization of indoles has been developed. to traditional methods, these newly developed strategies for
The simultaneous C3-formylation and N-aminomethylation of C3-formylation and N-alkylation of indoles avoid the use of
indoles can be achieved using readily available potassium iodide toxic POCl3, alkyl halide and stoichiometric amounts of base.
as a catalyst and tert-butyl peroxybenzoate as a co-oxidant.
Notably, Che and Huang independently demonstrated that ter-
tiary amines can be employed for selective C3-alkylation of
indoles in the presence of ruthenium or copper species.2c,4b In
their studies, the C3-alkylation of indoles with N,N-dimethyl-
anilines was extensively investigated. However, the N-alkylation
of free NH-indoles was not involved in their transformations.
To our knowledge, the simultaneous C3-formylation and
N-alkylation of indoles in a one-step process has not been
achieved. In our continuous efforts toward the iodide ion cata-
lyzed oxidative coupling reactions of N-methylanilines,9l we
report herein the potassium iodide catalyzed simultaneous C3-
formylation and N-aminomethylation of indoles with 4-substi-
tuted N,N-dimethylanilines.
We began our investigation by using indole 1a (0.5 mmol)
and 4-methyl-N,N-dimethylaniline 2a (1.0 mmol) as the model
substrates in the presence of H2O2 (2 mmol) and nBu4NI
(20 mmol%). Pivalic acid was employed to inhibit the
decomposition of indole 1a under oxidative conditions
(Table 1, entry 1).11 The reaction was carried out at 80 °C in
DMSO, yielding 5% of dialkylated product 4 (Table 1, entry 1).
The same results were obtained by using tert-butyl hydroper-
oxide (TBHP) as an oxidant (Table 1, entry 2). When tert-butyl
peroxybenzoate (TBPB) was used, 36% of the C3-formylation
and N-alkylation product 3a, 30% of product 4, and 20% of
C3-formylation product 5 were obtained. The reaction afforded
an excellent total yield (86%), albeit in low selectivity (Table 1,
entry 3). Subsequent optimization revealed that a slightly
higher selectivity was observed by addition of 3.0 equiv. of 2a
and use of a lower reaction temperature (60 °C) (Table 1, entry
4). When the amounts of 2a and TBPB were increased to 4.0
and 6.0 equiv., respectively, further improvements were rea-
lized by using KI as the catalyst after a prolonged reaction time
(16 h), and both yield and selectivity were sharply increased
(Table 1, entry 5). In contrast, sodium iodide and elemental
iodine gave poor selectivities and low yields under the same
conditions as entry 5 (Table 1, entries 6, 7). The metal catalysts
In recent years, the sp3 C–H functionalization reactions have
emerged as an attractive and challenging goal in organic
chemistry. Most studies in this area focus on some special sub-
strates that contain heteroatoms or directed groups adjacent to
the sp3 carbon atom.1 A variety of tertiary amine derivatives are
particularly attractive starting materials for the reason that the
sp3 C–H bond α to nitrogen can be readily activated to generate
iminium ions under oxidative conditions. These iminium ions
then undergo nucleophilic addition to form C–C bonds or C–
heteroatom bonds. The oxidative coupling of tertiary amines is
currently being actively investigated using the transition-metal
catalysts such as Cu,1a,2 Fe,3 Ru,4 Rh,5 Au,6 and V.7 In contrast,
the environmentally benign, inexpensive reagents and tran-
sition-metal-free catalysts for the functionalization of tertiary
amines are highly desirable.8 Recently, the combination of the
iodide ion (I−) and peroxide has frequently been employed for
various oxidative C–H functionalizations.9 The use of readily
available inorganic iodides, environmentally friendly co-oxi-
dants (H2O2 or tBuOOH), and mild conditions makes these
reactions particularly attractive.
The prevalence of indoles in many bioactive molecules has
prompted the development of synthetically useful methods for
their C3- and N-functionalization. More recently, Su and co-
workers revealed an elegant Ru-catalyzed C3-formylation of
indoles using N-methylaniline as the carbonyl source.4a For
the preparation of various N-alkylated indoles, Ru- and Hf
(OTf)4-catalyzed N-alkylations have been achieved using alco-
hols and N,O-acetals as benign alkylating agents.10 In contrast
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai
University, 94 Weijin Road, Tianjin 300071, China. E-mail: wangbin@nankai.edu.
cn, pwang@nankai.edu.cn; Fax: (+86)-22-23507760; Tel: (+86)-22-23506290
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c2ob26636a
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Table 1 Oxidative coupling of 4-methyl-N,N-dimethylaniline with indolea
1a
2a
Yield (%)
Entry
(mmol)
[O] (mmol)
Cat. (20 mol%)
T (°C)
t (h)
3a
4
5
1
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.5
2
2
2
H2O2 (2)
TBHP (2)
TBPB (2)
TBPB (2)
TBPB (3)
TBPB (3)
TBPB (3)
TBPB (3)
TBPB (3)
Bu4NI
Bu4NI
Bu4NI
Bu4NI
KI
NaI
I2
80
80
80
60
60
60
60
60
60
8
8
8
0
0
36
47
91
74
9
5
5
30
31
4
6
8
0
0
20
8
2
4
15
20
10
8
16
16
16
16
16
2
2
RuCl3
FeCl2
42
9
7
9
a Reaction conditions: indole (0.5 mmol), PivOH (2.5 mmol, 5 equiv.), catalyst (0.1 mmol, 20 mol%), DMSO (1 mL), under air, isolated yields.
Table 2 Potassium iodide catalyzed oxidative coupling of N,N-dimethylaniline with indolea
Entry
R1
R2
Yield (%)
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
H
5-F
5-Cl
5-Br
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
91, 3a
73, 3b
75, 3c
64, 3d
67, 3e
76, 3f
83, 3g
68, 3h
49, 3i
88, 3a
11
12
13
14
15
16
17
18
19
20
H
H
H
H
F
Cl
Br
OCH3
C(CH3)3
CH3
CH3
CH3
CH3
CH3
47, 3j
51, 3k
32, 3l
77, 3m
69, 3n
81, 3o
79, 3p
65, 3q
84, 3r
70, 3s
5-I
H
4-Br
4-OCH3
4-COOCH3
4-OBn
6-CH3
6-COOCH3
5-OCH3
6-CN
5-NO2
3-CHO
9
10b
a Reaction conditions: indole (0.5 mmol), N,N-dimethylaniline (2 mmol, 4 equiv.), PivOH (2.5 mmol, 5 equiv.), KI (0.1 mmol, 20 mol%), TBPB
(3 mmol, 6 equiv.), DMSO (1 mL), under air, 60 °C, 16 h, isolated yield. b 4-Methyl-N,N-dimethylaniline (1 mmol, 2 equiv.), TBPB (1.5 mmol,
3 equiv.).
examined such as RuCl3 and FeCl2 were less effective than KI when 3-formylindole was subjected to the optimized con-
with respect to both the yield and selectivity (Table 1, entries ditions, the desired N-alkylation product 3a was isolated in
8, 9).
88% yield (Table 2, entry 10). Unfortunately, application of this
With these optimized conditions in hand (Table 1, entry 5), methodology to 7-methyl, 7-ethyl, and 7-benzyloxy-indole
we next investigated the general applicability of the KI/TBPB failed to give the desirable products even after a prolonged
system for this process. The scope of the indole and N,N- reaction time, presumably due to steric hindrance. The scope
dimethylaniline substrates was extensively surveyed. Indoles of 4-substituted N,N-dimethylaniline was also examined. The
containing both electron-donating and -withdrawing groups reaction proceeded well with 4-methoxy, 4-fluoro, 4-chloro,
were formylated and alkylated simultaneously in moderate to 4-bromo, and 4-tert-butyl-N,N-dimethylaniline, giving the
good yields (Table 2, 3a–i). The reaction conditions were com- desirable products in good to moderate yields (Table 2, 3j–n).
patible with a wide range of functionalities, such as halide,
Some control experiments were carried out to investigate
ester, ether, nitro, and cyano functional groups. Furthermore, the reaction mechanism. It has been proposed that the in situ
9520 | Org. Biomol. Chem., 2012, 10, 9519–9522
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Scheme 2 A plausible reaction mechanism.
conditions with a combination of KI and TBPB. Further
studies to extend the scope of synthetic utility are ongoing in
our laboratory.
Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (No. 21172120, 20902050) is greatly
appreciated.
Scheme 1 Control experiments for investigation of the mechanism.
generated hypoiodite ([IO]−) and iodite ([IO2]−) might be active
species for iodide ion (I−) catalyzed C–H functional-
ization.9c,g,h,k,12 In this case, neither formylation nor alkylation
product was observed in the presence of stoichiometric
amounts of Bu4NOH and iodine ([IO]− generated in situ)
(Scheme 1, eqn (1)).9i When PhI(OAc)2 was employed as an
oxidant under optimized conditions without catalysts, only
traces of 3a were detected (Scheme 1, eqn (2)). These results
indicate that in situ generated I(I) or I(III) species are ineffective
for this transformation. When a radical inhibitor, 2,2,6,6-tetra-
methylpiperidine-N-oxyl (TEMPO), was utilized under the opti-
mized conditions, the reaction of 1a and 2a did not occur
(Scheme 1, eqn (3)), suggesting that this transformation is
probably a radical process.3a,4a,13 In addition, when dialkyla-
tion product 4 was subjected to the standard reaction con-
ditions, the desirable product 3a was obtained in 50% yield
(Scheme 1, eqn (4)). This finding seems to indicate that com-
pound 4 is an intermediate for this transformation. On the
basis of these investigations, a plausible mechanism for the
reaction is shown in Scheme 2. First, decomposition of TBPB
with the iodine ion (I−) can occur to give either the tert-buty-
loxy or benzoyloxy radical, which abstracts an α-hydrogen of N,
N-dimethylaniline and forms the intermediate A. The radical A
is further oxidized to iminium ion B, which then undergoes
nucleophilic attack by an indole derivative, affording dialky-
lated intermediate C. Subsequently, a similar oxidation of
intermediate C occurs to provide the second iminium ion E,
followed by hydrolysis to produce the final products 3a–n.
In conclusion, we present the first example of a simul-
taneous C3-formylation and N-aminomethylation of indoles in
a one-step process. These transformations proceed under mild
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