Palladium catalyzed alkylation of indole via aliphatic C-H bond activation of tertiary amine

Article abstract of DOI:10.1016/j.tetlet.2011.04.110

Alkylation of indoles has been achieved via Pd-catalyzed aliphatic C-H bond activation of tertiary amine coupling with indole followed by C-N bond cleavage and subsequent addition of indole. This method involves the migration of alkane chain from tertiary amine to indole.

Full text of DOI:10.1016/j.tetlet.2011.04.110

Tetrahedron Letters 52 (2011) 3579–3583
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Tetrahedron Letters
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Palladium catalyzed alkylation of indole via aliphatic C–H bond activation
of tertiary amine
⇑
K. Ramachandiran, D. Muralidharan, P. T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkylation of indoles has been achieved via Pd-catalyzed aliphatic C–H bond activation of tertiary amine
coupling with indole followed by C–N bond cleavage and subsequent addition of indole. This method
involves the migration of alkane chain from tertiary amine to indole.
Received 18 February 2011
Revised 26 April 2011
Accepted 28 April 2011
Available online 10 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
C–H activation
1,1-Bis-indolymethane
C–C coupling
Alkylation of indole
Selective functionalization of C–H bonds adjacent to a nitrogen
atom in simple amines and amides is of great importance for the
synthesis of nitrogen-containing compounds and understanding
enzymatic oxidations.1 Murahashi’s pioneering work on the oxida-
tion of tertiary amines using Pd0 and RuII catalysts mimics amine
oxidase type (Eq. 1) and cytochrome P-450 type (Eq. 2) reactivity.2
Transition metal catalyzed oxidation of N,N-dialkylanilines to
iminium ions (Eq. 3) followed by nucleophilic capture has been uti-
lized by Murahashi and Li to form C–C bonds with selected
substrates.3,4
Development of synthetic methodologies for direct activation of
C–H bonds is of great significance, from both scientific and envi-
ronmental points of view. Metal-catalyzed carbon–carbon and car-
bon–heteroatom bond formation has attracted much attention
currently.8–10 The challenges of direct functionalization of indoles
stimulated us to investigate the present oxidative coupling reac-
tions. Pd-catalyzed oxidative coupling reaction of the sp3 C–H bond
adjacent to a nitrogen atom with the sp2 C–H bond has virtually
been untouched.1,6,10 1,1-Bis-indolylmethane derivatives11a are
found in bioactive metabolites of terrestrial and marine natural
sources.11b–d The condensation of carbonyl compounds with in-
doles is the most practical method of synthesizing symmetric
1,1-bis-indolylmethane compounds. However, a multistep meth-
odology had to be followed for the synthesis of unsymmetric 1,
1-bis-indolylmethanes.12 Herein, we report a novel and simple
method to construct both symmetric and unsymmetric 1,1-bis-
indolylmethanes using palladium catalyst in a single step which
is the formal oxidative coupling reaction of the sp2 C–H bond with
Pd0
R1R2NCH-R3R4
ð1Þ
R1R2N=CR3R4
R1R2N=CR3R4
PdH
RuIII(OH)
RuV=O
ð2Þ
ð3Þ
R1R2NCH-R3R4
ArR1NCH-R2R3
Cu(I), Ru(II)
Peroxides
ArR1N=CR2R3
Recently, Doyle described an efficient alkylation of C–H bond
adjacent to nitrogen atom with a wide range of N,N-dialkylanilines
using dirhodium caprolactamate.5 Benzylic addition of 2-methyl
azaarenes to N-sulfonyl aldimines via C–H bond activation result-
ing in an amine was reported by Huang recently.6 A novel method
of generating 1,1-bis-indolylmethanes via tandem iron-catalyzed
functionalization of C–H bond adjacent to an oxygen atom was also
reported.7
an inactivated a
-sp3 C–H bond of tertiary amine followed by C–N
bond cleavage and subsequent addition of indole. We could syn-
thesize and/or introduce the indole unit into simple or complex
molecules with potential biological applications by this method
which represents
methodologies.
a
significant contribution to synthetic
We have attempted to synthesize the indole aryl ketone in the
presence of palladium(II) acetate as a catalyst and triethyl amine as
a base under neat condition, but unfortunately we obtained 1,1-
bis-indole methane. We examined the reaction conditions by vary-
ing the substrates to find out the optimal condition. When the
⇑
Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.110

3580
K. Ramachandiran et al. / Tetrahedron Letters 52 (2011) 3579–3583
NH
reaction was carried out without benzoyl chloride, the same
vibrindole A was obtained (Scheme 1). In order to comprehend
whether the ethyl group is transferred from triethyl amine or
Pd(OAc)2, the same reaction was repeated in the presence of Pd(O-
COCF3)2, which resulted in vibrindole A and hence it was confirmed
that the ethyl group was transferred from triethyl amine. The spec-
tral data14 were in excellent agreement with the literature report.7
Indole was chosen as a model substrate for the reaction with
different tertiary amines to test the viability of our hypothesis
(Scheme 2). To our delight, the desired coupling reaction pro-
ceeded smoothly by the use of 10 mol % of palladium catalyst to
give 1,1-bis-indolylmethane in 67% yield in presence of 1.2 equiv
of Cu(OAc)2 under neat at 70 °C for 12 h (Table 1, entry 1). Screen-
ing of palladium and other metal sources revealed that Pd(OAc)2
was the most efficient catalyst while other palladium catalysts
did not produce the desired results (Table 1, entries 11 and 12).
A control experiment showed that other than Pd(OAc)2 the reac-
tion with Ag(OAc)2 as catalyst yielded only 15% (Table 1, entry
13) of the product. With Pd(OAc)2 as the catalyst, we proceeded
further to screen other reaction parameters. The effect of different
solvents and temperature on the reaction was studied. The reaction
was found to proceed more efficiently under neat condition at
70 °C than in solvent (Table 1). The reaction yield was reduced
when the reaction was performed using solvents for prolonged
reaction times. It was observed that the reaction temperature
had a significant effect on the reaction. Only a very low amount
of the desired product could be detected at 40 °C and an increase
in temperature from 40 to 70 °C led to an increase in yield (Table 1,
entries 1, 2 and 3), but further increase in temperature to 110 °C
led to very low yield and at higher temperature no product was
observed.
10 mol % Pd(OAc)2
1.2 equiv Cu(OAc)2
2
N
neat, 12 h, 70 o
C
N
H
N
3a
H
1a
2a
Scheme 2. Synthesis of 1,1-bis-indolylmethane.
Table 1
Screening of reaction conditions
Entry
Catalyst
Oxidative
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
None
Ag2CO3
PhI(OAc)2
CuO
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
70
40
110
70
70
70
70
70
70
70
70
70
70
70
70
40
rt
67
21
9
30
12
28
Trace
13b
26c
20d
—
9
10
11
12
13
14
15
16
17
18
PdBr2
—
15
—
16
Ag(OAc)2
Rh(OAc)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
11
Trace
28
70
a
b
c
Isolated yield based on indole.
The reactions were carried out in DMSO.
The reactions were carried out in DMF.
The reactions were carried out in THF as solvent.
d
Scope of indole was also examined (Scheme 3) and it was ob-
served that the reaction was significantly affected by electronic ef-
fect of the substituents on the indole substrate.
NH
R1
R1
10 mol % Pd(OAc)2
R2
R2
1.2 equiv Cu(OAc)2
The reaction of indole with electron-donating substituents on
the benzene ring of indole substrate proceeded efficiently (Table
2). On the other hand the yield of the product 5-cyanoindole was
low. The presence of bromine in indole did not alter the reaction
pathway and moderate yields were obtained for these moderately
electron-deficient indoles (Table 2). N-Methyl indole and N-benzyl
indole were incompatible with the reaction, and no desired 1,1-
bis-indolylmethane compound was isolated. Treatment of triethyl
amine with 5-methoxy and 5-methyl indole in presence of Pd-cat-
alyst under neat condition resulted in the formation of both sym-
metric and unsymmetric 1,1-bis-indolylmethanes (Scheme 5).
Encouraged by the successful 1,1-bis-indolylmethane formation,
we next examined benzofuran by treating with triethyl amine,
unfortunately, benzofuran failed to couple with triethyl amine
under the above optimal reaction conditions.
2
R1
R3
neat, 12h, 70 o
C
N
R3
R3
N
H
N
H
R2
2
1a-i
3a-l
Scheme 3. Reaction of trimethyl amine with different indole.
Table 2
Substrate scope of indole
Entry
Indole
Amine
Product
Time
Yielda,b
R1
R2
R3
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
Cl
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
12
12
12
12
24
12
12
12
12
12
12
12
65
59
57
52
40
68
62
63
68
65
60
62
Br
CN
OMe
H
OMe
OMe
H
H
H
Me
Cl
Br
OMe
H
9
10
11
12
H
H
H
H
H
H
3j
O
3k
3l
Pd(OAc)2
X
a
Et3N, Neat, 70 o
C
Isolated yields.
All the compounds were characterized by 1H and 13C NMR and mass spectro-
N
b
H
O
scopic techniques.
Cl
NH
N
H
1
Pd(OAc)2
Et3N, Neat, 70 o
With the optimized reaction condition,13 the scope of this reac-
tion with various tertiary amines was explored (Table 3).The reac-
tion did not occur when the primary or secondary amine is used.
The reaction of triethylamine with 5-methoxy indole proceeded
smoothly to provide the corresponding product 4a in 67% yield
C
N
H
Vibrindole A
Scheme 1. Formation of vibrindole A.

K. Ramachandiran et al. / Tetrahedron Letters 52 (2011) 3579–3583
3581
Table 3
Substrate scope of sp3 C–H bonds of tertiary amine
Entry
Amine (a–g)
Indole
Product
Time
12
Yielda,b
H
N
MeO
Triethylamine
2a
1
1h
67
68
65
N
H
4a
OMe
H
N
C2H5
MeO
Tributylamine
2b
2
1h
12
N
H
OMe
H
4b
N
MeO
N,N-Diethylaniline
2c
3
1h
12
N
H
OMe
H
4c
N
MeO
Tribenzylamine
4d
4
1h
24
55
N
H
OMe
4d
H
N
TMEDA
2e
5
1a
12
62
N
H
4e
MeO
C6H13
OMe
N
H
Trioctylamine
2f
6
1h
12
62
N
H
4f
H
N
MeO
N,N-Diisopropylethylamine
2g
7
1h
12
63
N
H
OMe
4g
Typical reaction condition: Mixture of indole (2 mmol), Cu(OAc)2 (1.2 mmol), Pd(OAc)2 (0.1 mmol) and triethyl amine (0.32 mL, 1.3 mmol) was stirred at 70 °C under neat for
12 h.
a
Isolated yields.
b
All the compounds were characterized by 1H and 13C NMR and mass spectroscopic techniques.
(Table 3, entry 1). The reaction of amine containing benzyl group
NH
R
with indole resulted in low yield due to steric effect of the benzyl
group. Treatment of n-trioctylamine with 1h resulted in 62% yield
which shows that increasing alkyl chain length decreases the yield
(Scheme 4). These observations reveal that electronic effect of the
substituent groups in amine has only a marginal effect on Pd-cat-
alyzed reaction.
10 mol % Pd(OAc)2
1.2 equiv Cu(OAc)2
MeO
MeO
2a-g
neat, 12 h, 70 o
C
N
H
N
H
1h
OMe
4a-g
Scheme 4. Reaction of indole with different tertiary amines.

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K. Ramachandiran et al. / Tetrahedron Letters 52 (2011) 3579–3583
NH
MeO
Me
N
NH
Me
H
1h
2
N
Me
10 mol % catalyst
1.2 equiv of oxidant
Neat, 70 oC
H
MeO
3b
17%
N
N
NH
H
5
Me
MeO
21%
N
N
H
OMe
1d
H
3f
27%
Scheme 5. Synthesis of symmetric and unsymmetric 1,1-bis-indolylmethanes.
H
H
N
H
O
O
H
N
N
Pd
OAc
N
PdOAc
N
Pd(OAc)2
AcO Pd
N
Ph
8
7
2c
6
O
PdHOAc
Pd
H
N
H
N
..
..
H
N
H
N
N
N
Et3NH
H
9
10
N
H
3a
Scheme 6. Plausible mechanism.
Huang et al. have reported the sp3 C–H bond activation of 2,6-
lutidine by Pd(II) acetate which prompted us to propose the mech-
anism intermediate 6 (Scheme 6). Although the mechanistic details
of this transformation are not clear at the moment, on the basis of
the experimental results, a plausible reaction pathway is outlined.
Compound 2c is coordinated to Pd(OAc)2 to form complex 6,6 after
which C–H bond cleavage might proceed via agnostic three–cen-
ter–two-electron interaction to form the intermediate 7 at elevated
temperature, in which the acetate (OAcꢀ) serves as an internal
base. Intermediate 7 might be coordinated with indole 1 giving
the intermediate 8, which would undergo coupling to produce
the adduct 9. Subsequent protonolysis would form 10 of which fur-
ther undergo C–N bond cleavage and subsequent addition of indole
results in the formation of product 3a. We found ethyl aniline as
byproduct in the reaction mixture by using NMR spectrum.
In conclusion, we have developed a novel method of alkylation
of indole via Pd-catalyzed oxidative coupling of aliphatic sp3 C–H
bond of tertiary amines with indole followed by C–N bond cleavage
and subsequent addition of indole to form 1,1-bisindolylmethanes.
This new protocol involves the migration of alkane chain from ter-
tiary amine to indole and provides a facile route to 1,1-bis-
indolylmethanes under neat condition. Current work is aimed at
elucidating the scope of potential substrates as well as gaining fur-
ther insights into the mechanism of these transformations.
References and notes
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Acknowledgment
One of the authors, K.R. thanks the Council of Scientific and
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.110.

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filtered and concentrated. The residue was purified by column
chromatography with ethyl acetate (EA) and petroleum ether (Pet) as eluent
to afford the corresponding products and appropriate yield is shown in Table 2
and 3.
14. Spectral data of compound 3f: 5-methoxy-3-(1-(5-methoxy-1H-indol-3-
yl)ethyl)-1H-indole Yellow oil; Rf 0.24 (25% AcOEt/petroleum ether); IR
(cmꢀ1): 3403, 2960, 1578, 1478; 1H NMR (500 MHz, CDCl3): d 1.82 (d, 3H,
J = 6.9 Hz), 3.80 (s, 6H), 4.61 (q, 1H, J = 6.8 Hz), 6.85–6.88 (m, 4H), 7.07 (s, 2H),
7.20 (d, 2H, J = 8.4 Hz), 7.79 (s, 2H). 13C NMR (125 MHz, CDCl3) d 21.7, 28.3,
56.1, 101.9, 111.8, 111.9, 121.3, 122.4, 127.4, 132.1, 153.6.; MS (EI): m/z 321.28
[M+H]+; Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74; O, 9.99; Found:
C, 74.84; H, 6.35; N, 8.68; O, 9.92.
Spectral data of compound 4b: 5-methoxy-3-(1-(5-methoxy-1H-indol-3-
yl)butyl)-1H-indole; Yellow oil; Rf 0.21 (25% AcOEt/petroleum ether); IR
(cmꢀ1): 3412, 2936, 1581, 1477, 1212; 1H NMR (500 MHz, CDCl3): d 0.99 (t, 3H,
J = 7.6 Hz), 1.43–1.48 (m, 2H), 2.17–2.21 (m, 2H), 3.8 (s, 6H), 4.40 (t, 1H,
J = 7.6 Hz), 6.84 (dd, 2H, J = 8.4, 2.2 Hz), 6.92 (d, 2H, J = 2.3 Hz), 7.08 (d, 2H,
J = 2.3 Hz), 7.17 (d, 2H, J = 9.1 Hz), 7.80 (s, 2H). 13C NMR (125 MHz, CDCl3) d
14.3, 21.5, 33.7, 37.9, 56.1, 102.1, 111.5, 111.8, 120.2, 122.5, 127.7, 131.9,
153.6; MS (EI): m/z 349.23 [M+H]+; Anal. Calcd for C22H24N2O2: C, 75.83; H,
6.94; N, 8.04; O, 9.18; Found: C, 75.92; H, 6.84; N, 8.15.
13. General procedure for the synthesis of compound
3 and 4: A mixture of
substituted indoles (2 mmol), Cu(OAc)2 (1.2 mmol), Pd(OAc)2 (0.1 mmol) and
tertiary amines (1.3 mmol) was stirred at 70 °C for 12 h under neat condition.
The reaction mixture was dissolved in ethyl acetate and filtered through a plug
of Celite. The residue was washed with ethyl acetate (2 ꢁ 20 mL). The filtrate
was washed with 100 mL of water and 10 mL of 0.5 N HCl and the organic layer
was collected. The aqueous phase was extracted with ethyl acetate
(3 ꢁ 20 mL). The combined organic phase was washed with saturated
sodium chloride solution (50 mL), dried over anhydrous sodium sulfate,