Mechanochemical Pd(II)-Catalyzed Direct and C-2-Selective Arylation of Indoles

Article abstract of DOI:10.1021/acs.joc.9b01280

A mechanochemical method for the preparation of synthetically useful 2-arylindoles is developed using Pd(II) as the catalyst in the absence of phosphine ligands in a ball-mill. The developed protocol is highly C-2 selective and tolerant of structural variations with electron-rich and electron-deficient substituents both in indoles and iodoarenes. Arylation is possible in both unprotected indoles and N-protected indoles with the electron-donating group with the former substrate being relatively slower to react and little less yielding. Indoles with a deactivated five-membered ring could also take part in the reaction with ease. The scalability of the reaction was demonstrated by conducting the reaction in the gram scale. In general, the reactions were achieved in a shorter time than the conventional methods.

Full text of DOI:10.1021/acs.joc.9b01280

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Article
Mechanochemical Pd(II)-Catalyzed Direct
and C2-Selective Arylation of Indoles
Dharmendra Das, Zigmee T. Bhutia, Amrita Chatterjee, and Mainak Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01280 • Publication Date (Web): 02 Aug 2019
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Mechanochemical Pd(II)-Catalyzed Direct and C2-Selective Arylation of Indoles
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Dharmendra Das, Zigmee T. Bhutia, Amrita Chatterjee* and Mainak Banerjee*
Department of Chemistry, BITS Pilani, K. K. Birla Goa Campus, Goa 403 726, India.
Abstract
A mechanochemical method for the preparation of synthetically useful 2-arylindoles is
developed using Pd(II) as catalyst in the absence of phosphine ligands in a ball-mill. The
developed protocol is highly C-2 selective and tolerant of structural variations with electron-
rich and electron-deficient substituents both in the indoles and in the iodoarenes. Arylation is
possible in both unprotected indoles and N-protected indoles with electron donating group
with former substrate being relatively slower to react and little less yielding. Indoles with
deactivated five-membered ring could also take part in the reaction with ease. The scalability
of the reaction was demonstrated by conducting the reaction in gram scale. In general, the
reactions were achieved in shorter time than the conventional methods.
Introduction
2-Arylindole substructure is ubiquitous among a large variety of biologically active
molecules that are found in many natural products and pharmaceuticals (Fig. 1).1 Traditional
approaches for the synthesis of these compounds involve cross-coupling between a C2-
prefunctionalized indole and a functionalized arene derivative, which is not cost effective
because of the requirement of pre-activation step.1a,2 Conversely, focus has been given on the
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development of atom economic approaches involving transition metal-catalyzed methods for
the direct arylation of indoles via C-H bond functionalization.3 Typically, several of such
arylations involve coupling between an aryl halide and an electron rich indole derivative via a
PdII/0 catalytic cycle in the presence of phosphine based ligands.3a-c However, the reported
methods suffered from one or more disadvantages including low regioselectivity (C2 over
C3), high reaction temperatures (>100 °C), toxic organic solvents, long reaction time, N-
protection of indoles, moderate substrate scope and functional group tolerance. On the other
hand, Sanford4 and Larrosa5 separately demonstrated phosphine ligands free regioselective C-
2 arylation of indoles in the presence of an acid, the chemistry introduced by Gaunt,6 at much
milder condition. Inspired by these works several other groups developed protocols for C-2
arylation,7-9 in particular, on heterogeneous supports8 or in green media.9 However, every
protocol has its own scopes and limitations, which indulge researchers to develop new and
contemporary methods.
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Figure 1. Representative Examples of Biologically Active Molecules and Drug Candidates
having 2-Arylindole Substructure.
H
O2N
N
O
N
MeO
O
MeO2S
N
H
N
N
H
H
INF55
N
Anticancer
Nor A efflux pump inhibitor
cytochrome inhibitor
HN
N
Cl
Cl
O
O
OH
N
CN
O
N
Et
NSC-370875
Mammary tumor inhibitor
HO
O
N
Et
Zindoxifene
Anticancer
Cl
O
X receptor agonist
In recent times, “mechanochemistry” has emerged as one of the better alternatives to
conventional solution based reactions in the paradigm of synthetic organic chemistry.10 Apart
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from providing high mechanical force to overcome activation energy barriers to make various
chemical transformations possible at ambient temperatures, attributes like solvent-free or
solvent-less conditions, time efficiency, cleaner and safer reaction profile, easy handling,
easy work-up or absence of a work-up step make this technique highly sustainable for future
directions. In last few years, the positive effects of mechanochemical conditions have also
been well-explored in transition metal-catalysed C-H bond functionalization.11 For example,
Bolm12 and Stolle13 developed methods for the syntheses of indoles by cyclo-annulation via
C-H bond activation. The directing group assisted allylation,14 alkynylation15 at C-2 and
asymmetric alkylation16 or oxidative coupling17 at C-3 of indole are also reported in recent
times. However, the great potential of mechanochemistry demands its further exploration in
this area. With our keen interest in mechanochemical reactions,18 we envisaged, development
of a mechanochemical method for synthetically useful 2-arylindoles by Pd(II)-catalysed
regioselective direct C-2 arylation. The arylation was achieved by cross-coupling of both N-
protected and unprotected indoles with iodoarenes under mechanochemical condition in the
presence of Pd(OAc)2 as catalyst and PEG-400 as grinding auxiliary (Scheme 1).
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Scheme 1: Mechanochemical C-H Bond Arylation of Indoles.
I
Pd(OAc)2 (5 mol%),
AgOAc (1.2 equiv)
R3
H
+
N
R1
N
CH3CO2H (0.5 equiv),
PEG-400
R2
R2
R3
R1
3a-z, aa-ak
Ball-Milling, 30 Hz, 2 h (or 4 h)
1
2
R1 = Me (1a), Bn (1b), H (1c), Boc (1d).
R2 = 5-CN (1e), 5-Br (1f), 5-OMe (1g).
R3 = H (2a), 4-CN (2b), 4-CF3 (2c), 3-CF3 (2d), 4-Br (2e), 4-OMe (2f),
2-OMe (2g), 4-OH (2h), 2-Me (2i), 3-Me (2j), 4-Me (2k), 4-t-Bu (2l), 2-CF3 (2m).
At the outset, we started our investigation by selecting N-methylindole (1a), an N-protected
indole derivative with activated ring and iodobenzene (2a) as the basic substrates and a model
reaction was carried out with 5 mol% of Pd(OAc)2 as the catalyst under milling conditions in
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RETSCH mixer mill (MM 400) at 30 Hz. As a silver salt and acidic media usually assist this
type of reaction, AgOAc was chosen as the oxidant and the reaction was considered to carry
out in the presence of small amount of glacial acetic acid. We first paid our attention in
selecting a suitable milling auxiliary and silica gel was chosen for the same. To our delight,
TLC revealed complete conversion of the starting materials to product 3a within 1 h but
isolated yield was unexpectedly less (72%, Table 1, entry 1). It is presumed that a part of the
product gets adhered in the solid matrix and does not come out even after using polar eluent.
The problem was more severe for the C-2 arylation of unprotected indole (1c) with
iodobenzene (2a) to form corresponding product, 3b as the free base adhere more in acidic
silica to drop the yield down to 53%. Whereas, the same reaction between 1a and 2a under
neat condition did not go to completion even after prolonged milling (4 h) and a lower yield
of 3a was obtained (Table 1, entry 2). This necessitates the requirement of a milling auxiliary
for faster reaction. Keeping other condition same, neutral Al2O3 was tried in place of silica
gel as the milling auxiliary but it was found not useful for the purpose (Table 1, entry 3).
Other water soluble salts like Na2SO4, NaCl, KCl were also used as milling auxiliaries with a
consideration that the matrix can be dissolved in water and the product can be easily
extracted in good yield but to our dismay, the reactions became sluggish in the solid ionic
media (Table 1, entries 4-6). Considering there are isolation issues with silica or other solid
milling auxiliary we chose water soluble PEG-400 as the media for mixing or kneeding
purpose. PEG is considered as a useful “green” media for mechanochemical milling because
of its biodegradability.19 The reaction between 1a and 2a went well in the presence of 0.3 mL
of PEG per mmol of indole derivative to produce 2-phenyl-N-methylindole (3a) in 91% yield
with exclusive C-2 selectivity within 1 h and no trace of 3-phenyl-N-methylindole was seen
(Table 1, entry 7). With the success in finding suitable milling auxiliary a thorough screening
of type and quantity of the catalysts and additives were performed (Table 1, entries 8-27).
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The focus was to reduce the cost and toxicity of chemicals that were used for the reaction.
The cheaper alternative to Pd(OAc)2, the first row transition metal catalyst, Co(OAc)2 was
used for the reaction keeping other conditions same but only a faint product spot was visible
in the TLC after milling the reaction mixture for 4 h (Table 1, entry 8). Similar results were
observed in case of ruthenium and rhodium based catalysts (Table 1, entries 9 and 10).
Although PdCl2 can catalyze the reaction with good efficacy a small amount (~5%) of 3-
phenylindole was also isolated reducing the final yield of the desired product, 3a (Table 1,
entry 11). The ideal mol% of most suitable catalyst, Pd(OAc)2 was determined by varying the
catalyst loading and checking the time and % of yields. As mentioned in table 1, entry 12, 2
mol% of Pd(OAc)2 is capable of converting 1a and 2a to 3a but the reaction becomes slower
and the yield drops marginally. The increase in loading of Pd(OAc)2 does not make any
difference in terms of yield and time (Table 1, entry 13). A screening of oxidants was done
by replacing AgOAc with cheaper variation Cu(OAc)2 or mild bases like K2CO3 in place of
acid but the yield of 3a was not promising enough in each case (Table 1, entries 14-16).
However, both CsOAc and Cs2CO3 as additive produced comparatively better results but in
both cases reaction took longer time and yields were not highly satisfactory (Table 1, entries
17,18). Replacement of AgOAc by Ag2CO3 slower down the reaction a bit and marginally
reduce the yield of the desired product (3a) (Table 1, entries 19, 20). The ideal proportion of
AgOAc was set as 1.2 equiv only as there is a drop in yield from 91% to 83% as well as the
rate of the reaction when 1.0 equiv of AgOAc was used (Table 1, entry 21). However, the
reaction gets slower when AcOH is not added (Table 1, entry 22) and the reaction becomes
very sluggish in the absence of a silver salt (Table 1, entry 23). An attempt to reduce the
amount of costly AgOAc by a combination of 10 mol% of AgOAc and 1 equiv of Cu(OAc)2
did not work well in terms of the yield of the desired product (Table 1, entry 24). It was also
observed that the reaction does not provide the best results when mineral acid (conc. HCl) is
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used in place of AcOH (Table 1, entries 26,27). Based on above observations, a combination
of 5 mol% Pd(OAc)2, AgOAc (1.2 equiv), AcOH (0.5 equiv) in PEG-400 (0.3 mL per mmol
of substrate) was set as optimum condition to carry out C-2 arylation of indoles. At the
optimized condition, attempted coupling of 1a with other aromatic substrates (viz. PhBr or
PhOTs) did not produce any noticeable amount of product (3a) after 4 h of milling at 30 Hz
making this method selective for iodoarenes. Next, few reactions were conducted in the
solution phase to assess the advantage of milling condition over conventional condition. It
was observed that the reaction takes prolonged time with some drop in the yield of the final
product (3a) when a mixture of 1a and 2a is stirred in variable volume of PEG-400 and
DMF5 at room temperature (Table S1). The same reaction in the absence of “milling” in
otherwise similar condition took 10 folds more time for completion with 21% drop in the
yield of 3a. However, the solution phase reaction between free indole (1c) and iodobenzene
(2a) produced only negligible amount of product (3b) after 24 h of stirring at room
temperature. The results clearly explicate the advantage of mechanochemical milling in faster
and smoother arylation at C-2 of indole with a broader substrate scope. Notably, the rate of
the reaction was much faster for 3a in PEG-400 than in DMF. Presumably, polar PEG-400
acts as a better medium for both organic substrates and inorganic catalysts and additives to
bring all reacting components in contact with each other with ease to afford the product in
shorter time. In a separate study, the milling conditions were optimized by changing the
milling frequency, the number of balls, the size of the balls and the amount of the reaction
mixture (Table 2). All the reactions were carried out in 5 mL stainless steel jars. The best
results were obtained by carrying out reactions in 1 mmol quantity of 1a and with one 10 mm
ball. There was not much change in terms of yield of the final product (3a) by reducing the
milling frequency to 25 Hz but the reaction became really slower at 20 Hz or lower
frequency. Thus, the milling frequency was set at 30 Hz for remaining reactions.
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Table 1: Optimization of the Reaction Conditionsa
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catalyst, oxidant
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N
Me
3a
N
acid, milling auxiliary
milling at 30 Hz
Me
2a
1a
Entr Catalyst
Oxidant
(equiv)
Additive
(equiv)
Milling
Time for
Isolated
y
loading
(mol%)
auxiliaryb formation yield of 3a
of 3a (h)
(%)
72
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) AgOAc (1.2)
Co(OAc)2 (10) AgOAc (1.2)
AcOH (0.5) SiO2
1
AcOH (0.5) Neat
AcOH (0.5) Al2O3
AcOH (0.5) Na2SO4
AcOH (0.5) KCl
4
4
4
4
4
1
4
6
52c
56c
54c
25c
32c
91
AcOH (0.5) NaCl
AcOH (0.5) PEG-400
AcOH (0.5) PEG-400
AcOH (0.5) PEG-400
n.d.
n.d.
[RuCl2(p-
AgOAc (1.2)
cymene)]2 (5)
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13
14
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16
17
18
19
20
21
22
23
24
[CpRhCl2]2 (2)AgOAc (1.2)
AcOH (0.5) PEG-400
AcOH (0.5) PEG-400
AcOH (0.5) PEG-400
AcOH (0.5) PEG-400
4
n.d.
81d
86
PdCl2 (5) AgOAc (1.2)
1.5
3
Pd(OAc)2 (2) AgOAc (1.2)
Pd(OAc)2 (10) AgOAc (1.2)
1
88
Pd(OAc)2 (5) Cu(OAc)2 (1.2) AcOH (0.5) PEG-400
4
46c
25c
22c
68
Pd(OAc)2 (5) Na2CO3 (2)
Pd(OAc)2 (5) K2CO3 (2)
Pd(OAc)2 (5) CsOAc (1.2)
Pd(OAc)2 (5) Cs2CO3 (2)
Pd(OAc)2 (5) Ag2CO3 (1.2)
Pd(OAc)2 (5) Ag2CO3 (1.2)
Pd(OAc)2 (5) AgOAc (1.0)
Pd(OAc)2 (5) AgOAc (1.2)
Pd(OAc)2 (5) -
-
-
PEG-400
PEG-400
4
4
AcOH (0.5) PEG-400
PEG-400
AcOH (0.5) PEG-400
PEG-400
AcOH (0.5) PEG-400
PEG-400
3
-
4
61
2
82
-
4
76
1.5
3
83
-
81
AcOH (0.5) PEG-400
AcOH (0.5) PEG-400
4
24b
29c
Pd(OAc)2 (5) AgOAc (0.1)-
Cu(OAc)2 (1.0)
Pd(OAc)2 (5) AgOAc (1.0)
4
25
26
AcOH
(0.5 mL)
HCl (0.1
mL)
--
2
1
57c
78
Pd(OAc)2 (5) AgOAc (1.2)
PEG-400
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27
PdCl2 (5)
AgOAc (1.2)
HCl (0.1
mL)
PEG-400
1.5
71d
a1 mmol of 1a and 1.1 mmol of 2a were milled together in a RETSCH mixer mill (MM 400) with one 10 mm
ball in a 5 ml stainless steel jar at 30 Hz frequency; bauxiliary taken was 2-3 times of the weight of 1a; cin each
case little to significant amounts of starting materials were recovered; d5% of C-3 arylated product was isolated;
n.d. not determined.
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Table 2. Optimization of the Milling Parametersa
Entry Ball size
(& No.)
Operating Amount Time Isolated
frequency of 1a (in (h)
yield of
3a (%)
91
(Hz)
mmol)
1.0
1
10 mm (1) 30
1
2
1
1
1
2
2
2
2
1
1
2
10 mm (1) 30
1.0
2.0
0.5
1.0
1.0
1.0
1.0
1.0
1
92
3
10 mm (1) 30
10 mm (1) 30
10 mm (1) 25
10 mm (1) 20
10 mm (1) 15
88
4
86
5
75
6
54b
46b
73b
68b
67b
52b
7
8
7 mm (1)
7 mm (2)
5 mm (2)
5 mm (4)
30
25
30
25
9
10
11
1
a jars and balls are made of stainless steel and all reactions were carried out in 5 mL jars; bin each case little to
significant amounts of starting materials were recovered.
To test the generality of this method, a series of iodoareanes (2a-m) was coupled with a
variety of indole derivatives at the optimum mechanochemical condition set above to afford
C-2 arylated indoles (3) in excellent yields (Table 3). Notably, N-protected indoles with both
electron donating (Me or Bn) and electron withdrawing (viz. Boc) groups were used for this
C-H activation reaction along with free indole as the substrate. All the 2-arylindole
derivatives were characterized by 1H NMR, 13C NMR, IR and HRMS analysis. The spectra of
known compounds were in good agreement with the reported values.4-9 In all cases the
characteristic peak of C-3 H was observed between  6.50-6.75 ppm,4,5 which clearly
indicates complete regioselectivity for C-2. In general, the method worked well with a variety
of substituents in the iodoarenes. Initially, N-methyl and N-benzyl indoles (1a and 1b) were
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treated with a series of iodoarenes with both electron withdrawing groups (EWG), 2b-e,m
and electron donating groups (EDG), 2f-l to obtain 2-arylindoles, 3(a,c-y). Although in few
cases the reactions were completed within 1 h, in several other cases it took 2 h for complete
conversion. Therefore, the reactions were generally milled for 2 h to afford 3 in high yields.
It is worth noting that the substitution with electron-rich groups such as Me, OMe at o-, m- or
p-positions and electron-poor groups, such as CN, CF3, Br at p- or m-positions of the benzene
rings tolerated the mechanochemical reaction condition and these substituents do not pose
any significant effect either on the reaction rate or the yields. However, it was observed that
the presence of strong EWG (such as –CN) in iodoarene ensures completion of the reaction
within 1 h (3c, n, Table 3); same as in the case iodobenzene (3a, Table 3). The rest of the
reactions with N-alkyl indoles took 2 h for completion. The yield in each case is generally
very high for both EWG and EDG but a finer analysis revealed above 90% yields for 2-
arlyindoles derived from iodoarenes with EWG (compounds 3c-f, 3n-q, Table 3) and just
below 90% mark for 2-arlyindoles derived from iodoarenes with EDG (compounds 3g-m, 3s-
y, Table 3). Only in one case, for the reaction between N-methylindole (1a) and iodoarene
having a phenolic–OH group at para-position (2h), the yield drops below 80% (3i, Table 3).
Notably, the steric effect does not play any major role in the reaction as bulky 4-tert-
butyliodobenzene (2l) participated in the reaction to afford corresponding product in about
90% yield in 2 h (3m, 3y, Table 3). Next, a short series of products was synthesized from
unprotected indole (1c) and N-Boc protected indoles (1d) to explore the broader substituent
scope (compounds 3b, 3z, 3aa-ac, Table 3). It was observed that the course of the reaction
was to some extent influenced by N-substitution in the indole ring. While an EDG at the
nitrogen atom (Me or Bn) helped to carry out the reaction at a faster rate and in high yields of
the desired products (3a, 3c–y, Table 3), an EWG (viz. Boc) at the N-atom reduced the rate of
the reaction (4 h for complete conversion) as well as the isolated yields were relatively less
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than the cases with N-alkyl protections (76% yield for 3ac, Table 3). Also, to our delight,
reactions of unprotected indoles were efficiently conducted with some iodoarenes to afford
the desired products in good yields (3b,3z,3aa, Table 3). However, as expected, these
reactions took little longer time (4 h) than N-alkylated indoles because of the reduced electron
density in the ring. However, as a whole, the final products involving a deactivated or
unprotected indole ring were obtained in shorter time and the yields were good enough to
establish a wide substrate scope for this mechanochemical protocol. It is noteworthy to
mention that the presence of another halogen atom (such as Br) does not disturb the
chemoselectivity as the products 3f and 3q were formed as the sole products of the
corresponding reactions (Table 3). The same statement holds good for a Br-substituent in the
indole ring as well (3af and 3ag, Table 3). Therefore, it can be said that the
mechanochemimcal condition is halogen-atom tolerant and transmetalation takes place only
at Ar-I bond during the reaction.
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Table 3. Substrate Scope of the Mechanochemical Pd(II)-catalyzed C-H Arylationa
I
Pd(OAc)2 (5 mol%),
AgOAc (1.2 equiv)
R3
H
N
CH3CO2H (0.5 equiv),
PEG-400
N
R2
R3
R2
R1
Ball-Milling, 30 Hz, 2 h (or 4 h)
R1
2
3
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R3
R3
N
Me
3a:4 91%b
N
Me
N
Me
N
H
3b:4 78%c
3c:8d R3 = 4-CN, 91%b
3d:7d R3 = 4-CF3, 97%
3e:4 R3 = 3-CF3, 99%
3f:5 R3 = 4-Br, 95%b
3g:4 R3 = 4-OMe, 82%
3h:5 R3 = 2-OMe, 83%
3i:5 R3 = 4-OH, 72%
3j:4 R3 = 2-Me, 85%
3k:5 R3 = 3-Me, 88%
3l:4 R3 = 4-Me, 84%
3m:7d R3 = 4-t-Bu, 87%
R3
N
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N
Bn
R3
Bn
3r:8a R3 = H, 93%b
3n: R3 = 4-CN, 95%b
3o: R3 = 4-CF3, 96%
3p: R3 = 3-CF3, 96%
3q: R3 = 4-Br, 97%
3s: R3 = 4-OMe, 81%
3t: R3 = 2-OMe, 85%
3u: R3 = 4-OH, 82%
3v: R3 = 2-Me, 85%
3w: R3 = 3-Me, 91%
3x:7e R3 = 4-Me, 92%
3y: R3 = 4-t-Bu, 91%
R3
N
H
3z:9e R3 = 4-CN, 75%c
R3
N
3aa:9e R3 = 2-CF3, 77%c
Boc
3ab:8b R3 = H, 85%c
3ac: R3 = 4-CN, 76%c
Br
Br
NC
NC
CN
CN
N
Me
N
Me
N
Me
N
Me
3ae: 81%c
3ag: 97%
3af:5 98%
3ad:8a 93%c
MeO
MeO
MeO
OMe
Br
OMe
CN
N
N
N
Me
N
Me
Me
Me
3ak: 90%
3aj: 91%
3ai:7e 96%
3ah: 95%
aIn each case 1 mmol of indole (1) and 1.1 mmol of iodoarene (2) were milled together for 2 h (unless otherwise
stated) in a RETSCH mixer mill (MM 400) with one 10 mm ball in a 5 mL stainless steel jar at 30 Hz
frequency; bcomplete conversion took just 1 h; c the reaction mixture was milled for 4 h.
In our next study, a series of indole derivatives with substitution at the C-5 position was used
as substrates for the reaction to elaborate the scope of this reaction methodology and
corresponding electronic effect on the reaction time and on the yield of the final product were
also investigated. As shown in last few entries of table 3, the results showed that the
substituent at a distant place does not have any significant role to play in terms of the yield of
2-arylindole (3ad-ak, Table 3). In all the cases except one the yield was 90% or above.
Notably, unlike previous reports7c,8a the strong mechanochemical condition enforce indoles
with strong electron-withdrawing substituent, –CN at C-5 to take part in the reaction with
good efficiency. However, the electronic effect does reduce the rate of the reaction to some
extent (reactions require 4 h for complete conversion) as well as the yield drops below 90% at
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times (3ae, Table 3). The present method was compared with available methods for ligand-
free C2-selective arylation of indoles in terms of yields, reaction time, substrate scope etc.
and a clear edge on many aspects for the current method has been realized over others
conventional methods and several “green” methods (Table S2, SI).
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To get a better insight about the substituent effect on the rate of the reaction and product
formation couple of kinetic experiments were performed by challenging a strong electron-
donating group, -OMe with a strong electro-withdrawing group, -CN both in indole and
iodoarenes (Scheme 2). The competing substrates were taken in stoichiometric amounts and
the reaction mixtures were subjected to milling at standard condition for 2 h. The desired
products and unreacted starting materials were separated by flash chromatography and
analysed. TLC revealed complete conversion of the limiting substrates. From the isolated
yields of products as shown in scheme 2, it can be understood that the substituent effect is not
very significant for iodoarenes as a nominal product selectivity was obtained in favour of –
CN derivative (isolated yields are 50% for 3c and 34% for 3g). In contrary, electronic effect
is quite significant for the substituents present in the benzene ring of indole as the isolated
yields were 17% and 69% for 3ad and 3ai, respectively.
Scheme 2. Competition Experiments to Study Substituent Effect
I
Pd(OAc)2 (5 mol%),
AgOAc (1.2 equiv)
A)
H
OMe/CN
+
N
N
CH3CO2H (0.5 equiv),
PEG-400
Me
Me
Ball-Milling, 30 Hz, 2 h
OMe/CN
1a
(1.0 mmol )
Product selectivity: 3c:3g::3:2
2b and 2f
(1.0 mmol each)
B)
I
Pd(OAc)2 (5 mol%),
AgOAc (1.2 equiv)
MeO/NC
MeO/NC
+
H
N
CH3CO2H (0.5 equiv),
Ball-Milling, 30 Hz, 2 h
PEG-400
N
Me
1e and 1g
Me
Product selectivity: 3ad:3ai::1:4
2a
(1.0 mmol)
(1.0 mmol each)
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On the basis of literature reports of similar kinds of ligand free C-2 arylation reactions of
indoles5,7c,d a plausible mechanism of a PdII/0 cycle is proposed. The general reaction pathway
is represented by the formation of 3a (Scheme 3). First, the Pd(II) catalyst may get inserted in
the Ar-I bond to form an Ar-Pd(II)-X (where X = OAc) complex which undergoes C-H bond
insertion at C-3 (intermediate A). The palladium from the temporary intermediate, A may
eventually migrate to the C-2 position to form an intermediate B. The intermediate B may
subsequently undergo an oxidative H-elimination to regain aromaticity (intermediate C),
which finally release the product and the catalyst at Pd(0) state. The oxidant (here AgOAc)
converts Pd(0) to Pd(II) state, which can take part in the next cycle. The presumed
mechanistic pathway was further supported by the observation based on a reaction between
1a and 2a in the presence of stoichiometric amount of Pd(OAc)2 instead of catalytic amount
(5 mol%) without the addition of an oxidant (viz. AgOAc). Although the reaction was not
very fair, it produced 2-arylated product (3a) as the major product (53%) along with some
amount of 3-arylated product (12%) and inseparable polar side products with complete
consumption of the starting materials after just 15 min of milling indicating the migration of
palladium from metal-complex A to B.
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Scheme 3. Proposed Mechanism
I
HOAc, HI
OAc
OAc
Ar
I
Pd
Ar
Pd(OAc)2
AgOAc
OAc
H
Ar Pd
[O]
N
Me
Pd(0)
Pd Ar
Ar
N
N
Me
product
A
H
Me
H
Pd Ar
H
N
Pd Ar
C
Me
N
B
Me
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Next, a gram scale experiment was conducted to test the scalability of this mechanochemical
procedure. The reaction was carried out with N-methylindole (10 mmol), iodobenzene (11
mmol) and 5 mol% Pd(OAc)2 in the presence of AgOAc and AcOH as per the optimum
reaction condition. For this purpose 25 mL of SS jar was used with one 15 mm ball. Although
the reaction took slightly longer reaction time (1.5 h instead of 1 h), a satisfactory yield of
87% of 3a was achieved. Therefore, the method can be scaled up by taking the reaction
mixture in a bigger jar of adequate volume.
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In conclusion, we have developed an efficient mechanochemical method for the direct C-2
selective arylation of indoles with aryl iodides at ambient temperature without the
requirement of phosphines or other ligands. Pd(OAc)2 was used as the catalyst and AgOAc as
oxidant and the reactions were conducted at mild acidic condition. These mechanochemical
conditions permit a broad set of functionalities both in the indole and in the aryl iodide units,
and the corresponding 2-arylindoles were obtained up to 99% yields. Arylation is possible in
both unprotected indoles and N-alkyl indoles with former substrate being relatively slower to
react and little less yielding. In addition, indoles with deactivated five-membered ring took
part in the reaction to afford high yields of 2-arylindoles. The scalability of the reaction was
demonstrated by conducting the reaction in gram scale. The simplicity of this synthetic
process, high yields, broad substrate scope, shorter reaction time and environmentally benign
reaction conditions make this mechanochemical protocol a more efficient method than
several existing methods for direct C-2 selective arylation of indoles.
EXPERIMENTAL SECTION:
General information: All the chemicals were used without further purification as obtained
from commercial suppliers unless otherwise mentioned. N-Protection of indole derivatives
1
was done by adopting the methods reported in the literature,20-22 characterized by H NMR
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and used for the arylation reaction. All the mechanochemical reactions were carried out in 5
mL SS grinding jars with a single 10 mm ball in RETSCH MM 400. Isolation and
purification of all the compounds were done by flash chromatography or conventional
column chromatography (silica gel, 100–200 mesh) using ethyl acetate-petroleum ether as
eluent. NMR spectra were recorded on Bruker Avance (400 MHz) NMR spectrometer and
chemical shifts are reported downfield from TMS (= 0) in parts per million (δ) units. HRMS
spectra were recorded on Agilent Technologies 6545 Q-TOF LC/MS mass spectrometer with
ESI as the ion source. IR Affinity 1, Shimadzu was used to record IR spectra on KBr pellets.
Heidolph Hei-Tec stirrer-cum-hot plate was used at 600 rom for N-protection of indole
derivatives.
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Synthetic procedures for N-protection of indole.
Preparation of 1-methyl-1H-indole (1a):20 Indole (5 g, 42 mmol) and K2CO3 (5.8 g, 42
mmol) were taken in 35 mL of DMF, and 5.5 mL of dimethyl carbonate (65 mmol) was
mixed together and the reaction mixture was heated at 130 °C for 2 h in heat-on blocks. At
this point TLC showed starting material largely unchanged. The reaction mixture was cooled
to about 50 °C and another 5.5 mL of dimethyl carbonate (65 mmol) was added at one
portion. The mixture was again heated for another 7 h. The reaction mixture was cooled to
room temperature and 150 mL of water was added. The resulting mixture was extracted with
EtOAc (2 x 30 mL). The organic layer was washed with water, dried over anhydrous Na2SO4
and evaporated under vacuum to get sufficiently pure 1-methylindole (1a) as light-yellow oil
1
in 98% yield. H NMR (400 MHz, CDCl3):  (ppm) 7.71 (dt, J1 = 0.8 Hz, J2 = 6.8 Hz, 1H),
7.39 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H), 7.30 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 7.18 (td, J1 =
0.8 Hz, J2 = 6.8 Hz, 1H), 7.11 (d, J = 2.8 Hz, 1H), 6.56 (dd, J1 = 1.2 Hz, J2 = 3.2 Hz, 1H),
3.84 (s, 3H).
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Preparation of 1-benzyl-1H-indole (1b):21 A 100 mL round-bottom flask equipped with a
magnetic stirring bar was charged with 25 mL of dimethyl sulfoxide and 4.7 g (0.084 mol) of
potassium hydroxide. The mixture was stirred at room temperature for 5 min before indole (2
g, 17 mmol) was added. Stirring was continued for 45 min and then benzyl bromide (4.3 g,
34 mmol) was added to the reaction mixture. The reaction mixture was stirred for another 45
min and then diluted with 35 mL of water. The reaction mixture was extracted with diethyl
ether (3 x 15 mL), the combined ether layer was washed with brine water, dried over
anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by column
chromatography to obtain pure product 1b as colourless oil (3.5 g, 97%).1H NMR (400 MHz,
CDCl3):  (ppm) 7.72 (dt, J1 = 0.8 Hz, J2 = 7.2 Hz, 1H), 7.46-7.43 (m, 2H), 7.36-7.30 (m,
3H), 7.23 (td, J1 = 1.2 Hz, J2 = 6.8 Hz, 1H), 7.19-7.14 (m, 3H), 6.62 (dd, J1 = 1.2 Hz, J2 = 3.4
Hz, 1H), 5.37 (s, 2H).
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Preparation of tert-butyl 1H-indole-1-carboxylate (1d):22 To a stirred solution of indole (1
g, 8.55 mmol) in CH3CN (12 mL) and DMAP (0.104 g, 0.85 mmol) in a round-bottom flask
was added Boc2O (2.79 g, 12.82 mmol) and the reaction mixture was stirred at room
temperature for 2 h. The solvent was evaporated, diluted with 10 mL EtOAc, washed with
H2O (50 mL), aq sat. NaHCO3 (25 mL), brine (25 mL), and dried over anhydrous Na2SO4.
The solvent was removed under vacuum and the residue was purified by column
1
chromatography to obtain pure N-Boc indole, 1d as colourless oil (1.8 g, 97%). H NMR
(400 MHz, CDCl3):  (ppm) 8.20 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 3.6 Hz, 1H), 7.60 (dt, J1 =
0.8 Hz, J2 = 6.8 Hz, 1H), 7.34 (td, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H), 7.26 (td, J1 = 1.2 Hz, J2 =
7.6 Hz, 1H), 6.60 (dd, J1 = 0.8 Hz, J2 = 3.6 Hz, 1H), 1.71 (s, 9H).
General Procedure for the Synthesis of Compound 3.
Indole derivative, 1 (1 mmol), iodoarene 2 (1.1 mmol), Pd(OAc)2 (0.05 mmol, 5 mol%),
AgOAc (1.2 mmol) and CH3COOH (0.5 mmol) were taken in a 5 mL stainless steel milling
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jar containing PEG-400 (0.3 mL) and a stainless steel ball (10 mm diameter). The jar was
capped properly and the reaction mixture was subjected to milling in MM 400 for 2 h (or 4 h)
at 30 Hz. After completion of reaction, the crude mixture was transferred to a beaker and
stirred in the presence of 5 mL of EtOAc and 10 mL of water to take up the product in the
organic layer and PEG-400 in water. After separating the organic layer, the aqueous layer
was extracted with EtOAc (1 × 5 mL); organic fractions were combined, filtered through a
celite bed, washed with brine and then dried over anhydrous Na2SO4. The solvent was
evaporated in vacuum and the crude product was purified by flash chromatography or
conventional column chromatography (silica gel, 100–200 mesh) to afford 72-99% of
respective pure product (3).
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1-Methyl-2-phenyl-1H-indole (3a):4 White solid, 189 mg (91%), m.p. 95-97 °C (lit. m.p.
1
99-102 °C); H NMR (400 MHz, CDCl3):  (ppm) 7.63 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m,
4H), 7.39 (dt, J1 = 1.2 Hz, J2 = 4.8 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.24 (td, J1 = 0.8 Hz, J2
13
= 6.8 Hz, 1H), 7.14 (td, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 6.56 (s, 1H), 3.72 (s, 3H); C {1H}
NMR (100 MHz, CDCl3):  (ppm) 141.6, 138.4, 132.9, 129.4, 128.5, 128.0, 127.9, 121.7,
120.5, 119.9, 109.7, 101.7, 31.2; IR (KBr): ṽ 3055, 2935, 1600, 1465, 766 cm-1; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H13N 208.1121; Found 208.1099.
2-Phenyl-1H-indole (3b):4 White solid, 151 mg (78%), m.p. 185-186 °C (lit. m.p. 188-189
°C); 1H NMR (400 MHz, CDCl3):  (ppm) 8.24 (br s, 1H), 7.60-7.55 (m, 3H), 7.38-7.33 (m,
3H), 7.25 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.76 (s, 1H);
13C {1H} NMR (100 MHz, CDCl3):  (ppm) 137.9, 136.8, 132.4, 129.3, 129.1, 127.7, 125.2,
122.4, 120.7, 120.3, 110.9, 100.0; IR (KBr): ṽ 3446, 3049, 2922, 1647, 1458, 742 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H11N 194.0964; Found 194.0942.
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4-(1-Methyl-1H-indol-2-yl)benzonitrile (3c):8d Light brown solid, 212 mg (91%), m.p. 156-
158 °C (lit. m.p. 161-162 °C); 1H NMR (400 MHz, CDCl3):  (ppm) 7.76-7.73 (m, 2H), 7.66-
7.60 (m, 3H), 7.38 (d, J1 = 8.4 Hz, 1H), 7.30 (td, J1 = 1.2 Hz, J2 = 6.8 Hz, 1H), 7.17 (td, J1 =
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1.2 Hz, J2 = 6.8 Hz, 1H), 6.65 (s, 1H), 3.76 (s, 3H); C {1H} NMR (100 MHz, CDCl3): 
(ppm) 139.3, 139.1, 137.4, 132.3, 129.5, 127.8, 122.8, 121.0, 120.4, 118.7, 111.3, 109.9,
103.6, 31.5; IR (KBr): ṽ 3070, 2939, 2221, 1928, 1602, 1465, 844, 796, 754 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H12N2 233.1073; Found 233.1061.
1-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-indole (3d):7d White solid, 267 mg (97%), m.p.
56-59 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.73 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 8.8 Hz,
3H), 7.38 (d, J = 8.4 Hz, 1H), 7.28 (td, J1 = 1.2 Hz, J2 = 6.8 Hz, 1H), 7.17 (td, J1 = 1.2 Hz, J2
= 7.2 Hz, 1H), 6.63 (s, 1H), 3.76 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3):  (ppm) 139.9,
138.8, 136.4, 129.8 (q, 2JC-F = 32.4 Hz), 129.4, 128.2, 127.8, 125.5 (q, 3JC-F = 3.8 Hz), 123.9
(q, 1JC-F = 272.0 Hz), 122.4, 120.8, 120.2, 109.8, 102.9, 31.3; IR (KBr): ṽ 3059, 2945, 1614,
1465, 1323, 748 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H12F3N 276.0995;
Found 276.0965.
1-Methyl-2-(3-(trifluoromethyl)phenyl)-1H-indole (3e):4 Pale yellow solid, 273 mg (99%),
m.p. 55-57 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.77 (s, 1H), 7.70-7.57 (m, 4H), 7.38
(d, J = 8.4 Hz, 1H), 7.28 (td, J1 = 1.2 Hz, J2 = 6.8 Hz, 1H), 7.16 (td, J1 = 1.2 Hz, J2 = 7.2 Hz,
1H), 6.62 (s, 1H), 3.75 (s, 3H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 139.8, 138.6,
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133.7, 132.5 (q, JC-F = 1.2 Hz), 131.2 (q, JC-F = 32 Hz), 129.1, 127.8, 126.0 (q, JC-F = 3.7
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1
Hz), 124.51 (q, JC-F = 3.7 Hz), 124.49 (q, JC-F = 273.0 Hz), 122.3, 120.8, 120.2, 109.8,
102.6, 31.3; IR (KBr): ṽ 3062, 2949, 1606, 1325, 752 cm-1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C16H12F3N 276.0995; Found 276.0968.
2-(4-Bromophenyl)-1-methyl-1H-indole (3f):5 White solid, 271 mg (95%), m.p. 99-102 °C
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(lit. m.p. 113–114 °C); H NMR (400 MHz, CDCl3):  (ppm) 7.63 (d, J = 7.6 Hz, 1H), 7.59
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(dt, J1 = 2.4 Hz, J2 = 6.4 Hz, 2H), 7.38-7.34 (m, 3H), 7.26 (td, J1 = 1.2 Hz, J2 = 6.8 Hz, 1H),
7.15 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 6.56 (d, J = 0.8 Hz, 1H), 3.73 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3):  (ppm) 140.3, 138.5, 131.7, 130.8, 127.9, 122.2, 122.0, 120.6, 120.1,
109.7, 102.0, 31.2; IR (KBr): ṽ 3047, 2945, 1527, 1465, 1315, 779 cm-1; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H12BrN 286.0226 (for 79Br) and 288.0207 (for 81Br); Found
286.0233 (for 79Br) and 288.0214 (for 81Br).
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2-(4-Methoxyphenyl)-1-methyl-1H-indole (3g):4 Off-white solid, 195 mg (82%), m.p. 115-
117 °C (lit. m.p. 117-120 °C); 1H NMR (400 MHz, CDCl3):  (ppm) 7.62 (d, J = 8.0 Hz, 1H),
7.43 (dt, J1 = 3.2 Hz, J2 = 6.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.23 (td, J1 = 1.2 Hz, J2 = 7.2
Hz, 1H), 7.13 (td, J1 = 0.8 Hz, J2 = 8.0 Hz, 1H), 7.00 (dt, J1 = 2.8 Hz, J2 = 6.8 Hz, 2H), 6.50
(s, 1H), 3.86 (s, 3H), 3.71 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3):  (ppm) 159.5, 141.5,
138.2, 130.7, 128.0, 125.3, 121.4, 120.3, 119.8, 114.0, 109.6, 101.0, 55.4, 31.1; IR (KBr): ṽ
3051, 2937, 1919, 1610, 1496, 1246, 842 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H15NO 238.1226; Found 238.1222.
2-(2-Methoxyphenyl)-1-methyl-1H-indole (3h):5 Pale yellow solid, 196 mg (83%), m.p. 75-
77 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.63 (d, J = 8.0 Hz, 1H), 7.42 (td, J1 = 1.6 Hz,
J2 = 7.2 Hz, 1H), 7.35 (td, J1 = 2.0 Hz, J2 = 7.6 Hz, 2H), 7.22 (td, J1 = 1.2 Hz, J2 = 6.8 Hz,
1H), 7.11 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 7.05 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 7.00 (d, J
= 8.4 Hz, 1H), 6.49 (s, 1H), 3.80 (s, 3H), 3.58 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): 
(ppm) 157.5, 138.6, 137.7, 132.6, 130.1, 128.0, 122.1, 121.3, 120.7, 120.5, 119.4, 110.9,
109.3, 101.7, 55.5, 30.7; IR (KBr): ṽ 3050, 2950, 1609, 1470, 1255, 1106, 785 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H15NO 238.1226; Found 238.1204.
4-(1-Methyl-1H-indol-2-yl)phenol (3i):5 Brown solid, 160 mg (72%), m.p. 98-100 °C (lit.
m.p. 106–107 °C); 1H NMR (400 MHz, CDCl3):  (ppm) 7.62 (d, J = 8.0 Hz, 1H), 7.39-7.33
(m, 3H), 7.25-7.21 (m, 1H), 7.13 (td, J1 = 0.8 Hz, J2 = 6.8 Hz, 1H), 6.92 (dt, J1 = 2.4 Hz, J2 =
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6.4 Hz, 2H), 6.49 (s, 1H), 3.71 (s, 3H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 155.5,
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141.4, 138.2, 130.9, 128.0, 125.5, 121.4, 120.3, 119.8, 115.4, 109.5, 101.0, 31.1; IR (KBr): ṽ
3447, 3065, 2936, 1750, 1603, 1069, 740 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H13NO 224.107; Found 224.1066.
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1-Methyl-2-o-tolyl-1H-indole (3j):4 White solid, 188 mg (85%), m.p. 88-90 °C (lit. m.p. 90-
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92 °C); H NMR (400 MHz, CDCl3):  (ppm) 7.64 (d, J = 8.0 Hz, 1H), 7.36-7.24 (m, 6H),
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7.14 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 6.43 (s, 1H), 3.50 (s, 3H), 2.20 (s, 3H); C {1H}
NMR (100 MHz, CDCl3):  (ppm) 140.5, 138.1, 137.3, 132.6, 131.2, 130.1, 128.7, 128.1,
125.6, 121.3, 120.4, 119.7, 109.4, 101.6, 30.4, 20.1; IR (KBr): ṽ 3053, 2951, 1913, 1465,
1336, 767 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15N 222.1277; Found
222.1283.
1-Methyl-2-m-tolyl-1H-indole (3k):5 White solid, 194 mg (88%), m.p. 35-37 °C (lit.
colourless oil); 1H NMR (400 MHz, CDCl3):  (ppm) 7.63 (d, J = 8.0 Hz, 1H), 7.37-7.29 (m,
4H), 7.26-7.20 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 3.73 (s, 3H), 2.42 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3):  (ppm) 141.8, 138.4, 138.2, 132.8, 130.1, 128.7, 128.4,
128.1, 126.5, 121.6, 120.5, 119.8, 109.6, 101.6, 31.2, 21.5; IR (KBr): ṽ 3049, 2914, 1604,
1465, 1340, 750 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15N 222.1277; Found
222.1272.
1-Methyl-2-p-tolyl-1H-indole (3l):4 White solid, 186 mg (84%), m.p. 95-97 °C (lit. m.p. 96-
1
98 °C); H NMR (400 MHz, CDCl3):  (ppm) 7.62 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
2H), 7.35 (d, J = 8.0 Hz, 1H), 7.28-7.21 m, 3H), 7.13 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 6.53
(s, 1H), 3.73 (s, 3H), 2.42 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3):  (ppm) 141.7, 138.3,
137.8, 130.0, 129.3, 129.2, 128.1, 121.5, 120.4, 119.8, 109.6, 101.4, 31.1, 21.3; IR (KBr): ṽ
3024, 2914, 1604, 1462, 1338, 775 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15N
222.1277; Found 222.1270.
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2-(4-tert-Butylphenyl)-1-methyl-1H-indole (3m):7d White solid, 229 mg (87%), m.p. 55-60
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°C; H NMR (400 MHz, CDCl3):  (ppm) 7.63 (d, J = 8.0 Hz, 1H), 7.50-7.44 (m, 4H), 7.35
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(d, J = 7.6 Hz, 1H), 7.23 (td, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.13 (td, J1 = 1.2 Hz, J2 = 7.2 Hz,
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1H), 6.54 (s, 1H), 3.75 (s, 3H), 1.38 (s, 9H); C {1H} NMR (100 MHz, CDCl3):  (ppm)
150.9, 141.7, 138.3, 129.9, 129.1, 128.0, 125.4, 121.5, 120.4, 119.8, 109.5, 101.4, 34.7, 31.4,
31.2; IR (KBr): ṽ 3047, 2964, 1498, 1465, 736 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C19H21N 264.1747; Found 264.1724.
4-(1-Benzyl-1H-indol-2-yl)benzonitrile (3n): White solid, 293 mg (95%), m.p. 155-156 °C;
1H NMR (400 MHz, CDCl3):  (ppm) 7.69 (dt, J1 = 1.2 Hz, J2 = 6.4 Hz, 1H), 7.64 (dt, J1 =
2.0 Hz, J2 = 6.4 Hz, 2H), 7.51 (dt, J1 = 1.6 Hz, J2 = 6.4 Hz, 2H), 7.31-7.25 (m, 3H), 7.22-7.15
(m, 3H), 7.01 (d, J = 6.8 Hz, 2H), 6.72 (s, 1H), 5.36 (s, 2H); C {1H} NMR (100 MHz,
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CDCl3):  (ppm) 139.6, 138.8, 137.6, 137.3, 132.4, 129.4, 129.0, 128.1, 127.5, 125.8, 123.0,
121.1, 120.7, 118.7, 111.4, 110.7, 104.2, 48.0; IR (KBr): ṽ 3055, 2223, 1932, 1604, 1458,
1348, 856, 798, 725 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H16N2 309.1386;
Found 309.1395.
1-Benzyl-2-(4-(trifluoromethyl)phenyl)-1H-indole (3o): White solid, 337 mg (96%), m.p.
65-68 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.70-7.68 (m, 1H), 7.63 (d, J = 8.4 Hz, 2H),
7.53 (d, J= 8.4 Hz, 2H), 7.29-7.26 (m, 3H), 7.21-7.16 (m, 3H), 7.02 (dd, J1 = 1.6 Hz, J2 = 7.6
Hz, 2H), 6.72 (s, 1H), 5.36 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3):  (ppm) 140.1, 138.5,
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3
137.8, 136.3, 129.9 (q, JC-F = 32.6 Hz), 129.3, 128.9, 128.1, 127.4, 125.8, 125.5 (q, JC-F
=
1
3.7 Hz), 124.1 (q, JC-F = 270.0 Hz), 122.6, 120.9, 120.5, 110.6, 103.5, 47.9; IR (KBr): ṽ
3057, 2933, 1616, 1458, 1325, 1068, 786 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H16F3N 352.1308; Found 352.1278.
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1-Benzyl-2-(3-(trifluoromethyl)phenyl)-1H-indole (3p): Colourless oil, 336 mg (96%), H
NMR (400 MHz, CDCl3):  (ppm) 7.62-7.59 (m, 2H), 7.50 (t, J = 8.8 Hz, 2H), 7.39 (t, J = 7.6
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Hz, 1H), 7.22-7.07 (m, 6H), 6.92 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 2H), 6.63 (s, 1H) 5.26 (s, 2H);
13C {1H} NMR (100 MHz, CDCl3):  (ppm) 140.0, 138.4, 137.9, 133.5, 132.2, 131.0 (q, 2JC-F
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= 32.2 Hz), 129.1, 128.9, 128.1, 127.4, 126.0 (q, JC-F = 3.9 Hz), 125.9, 124.7 (q, JC-F = 3.7
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Hz), 123.9 (q, JC-F = 271.0 Hz), 122.6, 120.9, 120.5, 110.6, 103.3, 47.8; IR (KBr): ṽ 3061,
2927, 1496, 1452, 1325, 1124, 700 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H16F3N 352.1308; Found 352.1278.
1-benzyl-2-(4-bromophenyl)-1H-indole (3q): White solid, 349 mg (97%), m.p. 103-105 °C;
1H NMR (400 MHz, CDCl3):  (ppm) 7.67-7.65 (m, 1H), 7.48 (dt, J1 = 2.8 Hz, J2 = 6.4 Hz,
2H), 7.28-7.23 (m, 5H), 7.18-7.13 (m, 3H), 6.99 (d, J = 6.8 Hz, 2H), 6.64 (s, 1H), 5.32 (s,
2H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 140.5, 138.2, 138.0, 131.8, 131.7, 130.7,
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128.9, 128.3, 127.3, 125.9, 122.4, 122.3, 120.7, 120.4, 110.6, 102.8, 47.8; IR (KBr): ṽ 3028,
2916, 1602, 1460, 1344, 754 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H16BrN
79
81
79
362.0539 (for Br) and 364.0521 (for Br); Found 362.0552 (for Br) and 364.0531 (for
81Br).
1-Benzyl-2-phenyl-1H-indole (3r):8a Off white solid, 263 mg (93%), m.p. 35-40 °C; H
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NMR (400 MHz, CDCl3):  (ppm) 7.68-7.65 (m, 1H), 7.44-7.42 (m, 2H), 7.39-7.34 (m, 3H),
7.28-7.23 (m, 3H), 7.18-7.12 (m, 3H), 7.02 (d, J = 6.8 Hz, 2H), 6.65 (s, 1H), 5.35 (s, 2H); 13C
{1H} NMR (100 MHz, CDCl3):  (ppm) 141.9, 138.3, 138.0, 132.7, 129.3, 128.85, 128.79,
128.6, 128.3, 128.1, 126.0, 122.0, 120.6, 120.2, 110.6, 102.4, 47.8; IR (KBr): ṽ 3043, 3015,
1780, 1602, 1462, 1344, 748 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H17N
284.1434; Found 284.1441.
1-Benzyl-2-(4-methoxyphenyl)-1H-indole (3s): White solid, 255 mg (81%), m.p. 99-100
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°C; H NMR (400 MHz, CDCl3):  (ppm) 7.66-7.64 (m, 1H), 7.34 (dt, J1 = 2.8 Hz, J2 = 6.4
Hz, 2H), 7.29-7.22 (m, 3H), 7.16-7.11 (m, 3H), 7.02 (d, J = 6.8 Hz, 2H), 6.90 (dt, J1 = 2.8
Hz, J2 = 6.8 Hz, 2H), 6.59 (s, 1H), 5.32 (s, 2H), 3.81 (s, 3H); C {1H} NMR (100 MHz,
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CDCl3):  (ppm) 159.6, 141.7, 138.3, 137.8, 130.5, 128.8, 128.4, 127.2, 126.0, 125.1, 121.7,
120.4, 120.1, 114.0, 110.5, 101.7, 55.4, 47.7; IR (KBr): ṽ 3026, 2958, 2345, 1610, 1498,
1253, 788, 725 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H19NO 314.1539; Found
314.1550.
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1-Benzyl-2-(2-methoxyphenyl)-1H-indole (3t): Colourless thick oil, 267 mg (85%); H
NMR (400 MHz, CDCl3):  (ppm) 7.66-7.64 (m, 1H), 7.38-7.31 (m, 3H), 7.20-7.15 (m, 3H),
7.12-7.09 (m, 2H), 7.00-6.92 (m, 4H), 6.56 (s, 1H), 5.18 (s, 2H), 3.60 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3):  (ppm) 157.5, 138.6, 138.3, 137.2, 132.8, 130.2, 128.4, 128.3, 127.8,
127.7, 126.8, 126.4, 121.8, 121.5, 120.6, 120.5, 119.6, 110.7, 110.5, 102.6, 55.1, 48.0; IR
(KBr): ṽ 3049, 2941, 1606, 1458, 1246, 736 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H19NO 314.1539; Found 314.1516.
4-(1-Benzyl-1H-indol-2-yl)phenol (3u): Light brown solid, 264 mg (82%), m.p. 80-82 °C;
1H NMR (400 MHz, CDCl3):  (ppm) 7.66-7.63 (m, 1H), 7.29-7.21 (m, 5H), 7.12-7.11 (m,
3H), 7.01 (d, J = 6.8 Hz, 2H), 6.81 (dt, J1 = 3.2 Hz, J2 = 6.4 Hz, 2H), 6.57 (s, 1H), 5.32 (s,
2H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 155.6, 141.6, 138.3, 137.8, 130.7, 128.8,
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128.3, 127.2, 126.0, 125.3, 121.7, 120.4, 120.1, 110.5, 101.8, 47.6; IR (KBr): ṽ 3491, 3028,
2933, 1610, 1166, 754 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H17NO 300.1383;
Found 300.1390.
1-Benzyl-2-o-tolyl-1H-indole (3v): Colourless thick oil, 252 mg (85%), 1H NMR (400 MHz,
CDCl3):  (ppm) 7.67-7.65 (m, 1H), 7.30-7.22 (m, 4H), 7.19-7.13 (m, 6H), 6.87-6.84 (m,
2H), 6.50 (s, 1H), 5.13 (s, 2H), 2.12 (s, 3H); C {1H} NMR (100 MHz, CDCl3):  (ppm)
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140.3, 138.2, 137.9, 136.9, 132.3, 131.1, 130.2, 128.7, 128.5, 128.4, 127.1, 126.4, 125.5,
121.5, 120.5, 119.9, 110.5, 102.5, 47.3, 20.1; IR (KBr): ṽ 3024, 2908, 1602, 1460, 723 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H19N 298.159; Found 298.1599.
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1-Benzyl-2-m-tolyl-1H-indole (3w): White solid, 271 mg (91%), m.p. 75-76 °C; H NMR
(400 MHz, CDCl3):  (ppm) 7.67-7.65 (m, 1H), 7.28-7.22 (m, 6H), 7.19-7.12 (m, 4H), 7.02
(d, J = 6.8 Hz, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 2.32 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3):  (ppm) 142.1, 138.4, 138.2, 138.0, 132.7, 130.1, 128.8, 128.7, 128.4, 127.1, 126.3,
126.1, 121.8, 120.5, 120.1, 110.5, 102.2, 47.8, 21.4; IR (KBr): ṽ 3024, 2918, 1604, 1462,
1354, 727 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H19N 298.159; Found
298.1604.
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1-Benzyl-2-p-tolyl-1H-indole (3x):7e White solid, 273 mg (92%), m.p. 79-82 °C; H NMR
(400 MHz, CDCl3):  (ppm) 7.66-7.64 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.28-7.21 (m, 3H),
7.19-7.11 (m, 5H), 7.02 (d, J = 6.8 Hz, 2H), 6.62 (s, 1H), 5.35 (s, 2H), 2.37 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3):  (ppm) 142.0, 138.3, 138.0, 137.9, 129.8, 129.3, 129.2, 128.8,
128.4, 127.1, 126.0, 121.8, 120.5, 120.1, 110.5, 102.0, 47.7, 21.3; IR (KBr): ṽ 3028, 2914,
1602, 1460, 752 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H19N 298.159; Found
298.1604
1-Benzyl-2-(4-tert-butylphenyl)-1H-indole (3y): White solid, 310 mg (91%), m.p. 120-125
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°C; H NMR (400 MHz, CDCl3):  (ppm) 7.67-7.64 (m, 1H), 7.41-7.36 (m, 4H), 7.30-7.23
(m, 3H), 7.15-7.11 (m, 3H), 7.04 (d, J = 7.2 Hz, 2H), 6.63 (s, 1H), 5.34 (s, 2H), 1.33 (s, 9H);
13C {1H} NMR (100 MHz, CDCl3):  (ppm) 151.1, 141.9, 138.4, 137.9, 129.7, 128.8, 128.7,
128.4, 127.1, 126.0, 125.5, 121.7, 120.4, 120.1, 110.5, 102.0, 47.8, 34.7, 31.3; IR (KBr): ṽ
3055, 2964, 1496, 1460, 1348, 727 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H25N
340.206; Found 340.2031.
4-(1H-Indol-2-yl)benzonitrile (3z):9e Pale green solid, 163 mg (75%), m.p. 170-174 °C; H
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NMR (400 MHz, CDCl3):  (ppm) 8.38 (br s, 1H), 7.67-7.57 (m, 5H), 7.35 (dd, J1 = 0.8 Hz,
J2 = 8.0 Hz, 1H), 7.18 (td, J1 = 1.2 Hz, J2 = 6.8 Hz, 1H), 7.08 (td, J1 = 1.2 Hz, J2 = 7.0 Hz,
1H), 6.88 (dd, J1 = 0.8 Hz, J2 = 2.0 Hz, 1H); C {1H} NMR (100 MHz, CDCl3):  (ppm)
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137.4, 136.6, 135.5, 132.9, 128.9, 125.3, 123.7, 121.2, 120.8, 118.9, 111.2, 110.6, 102.7; IR
(KBr): ṽ 3408, 3055, 2922, 2221, 1425, 804, 754 cm-1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C15H10N2 219.0917; Found 219.0899.
2-(2-(Trifluoromethyl)phenyl)-1H-indole (3aa):9e White solid, 191 mg (77%), m.p. 88-90
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°C; H NMR (400 MHz, CDCl3):  (ppm) 8.27 (br s, 1H), 7.81-7.80 (m, 1H), 7.75-7.72 (m,
1H), 7.57 (dd, J1 = 0.8 Hz, J2 = 7.6 Hz, 1H), 7.49-7.47 (m, 2H), 7.34 (dd, J1 = 1.2 Hz, J2 =
8.4 Hz, 1H), 7.16 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 7.07 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H),
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6.82 (dd, J1 = 1.2 Hz, J2 = 2.4 Hz, 1H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 137.1,
136.2, 133.2, 131.4 (q, 2JC-F = 32.2 Hz), 129.6, 129.1, 128.3, 124.2 (q, 3JC-F = 3.8 Hz), 124.0
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(q, JC-F = 273 Hz), 123.1, 121.7 (q, JC-F = 3.8 Hz), 121.0, 120.6, 111.1, 101.3; IR (KBr): ṽ
3442, 3045, 2920, 1602, 1455, 1350, 735 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H10F3N 262.0838; Found 262.0802.
tert-Butyl-2-phenyl-1H-indole-1-carboxylate (3ab):8b White solid, 250 mg (85%), m.p. 73-
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75 °C (lit. m.p. 75-76 °C); H NMR (400 MHz, CDCl3):  (ppm) 8.14 (d, J = 8.0 Hz, 1H),
7.48 (d, J = 7.2 Hz, 1H), 7.35-7.24 (m, 6H), 7.18 (td, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 6.48 (s,
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1H), 1.23 (s, 9H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 150.2, 140.5, 137.4, 135.0,
129.2, 128.7, 127.8, 127.6, 124.3, 122.9, 120.5, 115.2, 109.9, 83.4, 27.6; IR (KBr): ṽ 3053,
2980, 1730, 1540, 1338, 752 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H19NO2
294.1489; Found 294.1484.
tert-Butyl-2-(4-cyanophenyl)-1H-indole-1-carboxylate (3ac): White solid, 241 mg (76%),
m.p. 73-75 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 8.12 (d, J = 9.2 Hz, 1H), 7.62 (dt, J1 =
1.6 Hz, J2 = 6.8 Hz, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.46 (dt, J1 = 2.0 Hz, J2 = 6.4 Hz, 2H),
7.30 (td, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 7.21 (td, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 6.57 (s, 1H),
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1.30 (s, 9H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 149.9, 139.5, 138.3, 137.7, 131.6,
129.3, 128.9, 125.2, 123.4, 120.9, 118.9, 115.5, 111.7, 111.1, 84.3, 27.7; IR (KBr): ṽ 3053,
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2983, 2227, 1728, 1452, 1340, 752 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H18N2O2 319.1441; Found 319.1458.
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1-Methyl-2-phenyl-1H-indole-5-carbonitrile (3ad):8a White solid, 216 mg (93%), m.p.
166-170 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.88 (s, 1H), 7.45-7.40 (m, 4H), 7.39-7.36
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(m, 2H), 7.31 (dt, J1 = 0.8 Hz, J2 = 8.0 Hz, 1H), 6.54 (s, 1H), 3.69 (s, 3H); C {1H} NMR
(100 MHz, CDCl3):  (ppm) 143.9, 139.7, 131.6, 129.4, 128.75, 128.68, 127.7, 125.9, 124.6,
120.9, 110.5, 102.8, 102.3, 31.5; IR (KBr): ṽ 2925, 2217, 1610, 1330, 770 cm-1; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C16H12N2 233.1073; Found 233.1067.
2-(4-Cyanophenyl)-1-methyl-1H-indole-5-carbonitrile (3ae): White solid, 208 mg (81%),
m.p. 206-211 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 8.00 (s, 1H), 7.82 (dt, J1 = 1.6 Hz, J2
= 6.8 Hz, 2H), 7.66 (dt, J1 = 2.0 Hz, J2 = 6.4 Hz, 2H), 7.52 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H),
7.46 (dt, J1 = 0.8 Hz, J2 = 7.6 Hz, 1H), 6.74 (s, 1H), 3.83 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3):  (ppm) 141.6, 140.2, 136.1, 132.5, 129.8, 127.4, 126.4, 125.4, 120.5, 118.5, 112.2,
110.8, 104.0, 103.4, 31.7; IR (KBr): ṽ 3076, 2957, 2230, 2217, 1608, 1472, 798 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H11N3 258.1026; Found 258.1022.
5-Bromo-1-methyl-2-phenyl-1H-indole (3af):5 White solid, 280 mg (98%), m.p. 108-110
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°C; H NMR (400 MHz, CDCl3):  (ppm) 7.79 (d, J = 2.0 Hz, 1H), 7.55-7.44 (m, 5H), 7.35
(dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.26 (dt, J1 = 0.8 Hz, J2 = 8.0 Hz, 1H), 6.53 (s, 1H), 3.76
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3):  (ppm) 142.7, 137.0, 132.3, 129.6, 129.4, 128.6,
128.2, 124.4, 122.9, 113.1, 111.1, 101.1, 31.3; IR (KBr): ṽ 3076, 2968, 1602, 1467, 1329,
758, 659 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H12BrN 286.0226 (for 79Br)
and 288.0207 (for 81Br); Found 286.022 (for 79Br) and 288.0201 (for 81Br).
4-(5-Bromo-1-methyl-1H-indol-2-yl)benzonitrile (3ag): White solid, 300 mg (97%), m.p.
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158-160 °C; H NMR (400 MHz, CDCl3):  (ppm) 7.80-7.77 (m, 3H), 7.64 (dt, J1 = 2.0 Hz,
J2 = 6.4 Hz, 2H), 7.38 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.27 (dt, J1 = 0.8 Hz, J2 = 8.4 Hz,
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1H), 6.61 (s, 1H), 3.77 (s, 3H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 140.4, 137.6,
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136.8, 132.4, 129.6, 129.3, 125.5, 123.3, 118.6, 113.6, 111.6, 111.3, 102.9, 31.6; IR (KBr): ṽ
3080, 2927, 2225, 1610, 1470, 789 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H11BrN2 311.0178 (for 79Br) and 313.0163 (for 81Br); Found 311.0174 (for 79Br) and
313.0158 (for 81Br).
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5-Bromo-2-(4-methoxyphenyl)-1-methyl-1H-indole (3ah): Yellowish solid, 301 mg (95%),
m.p. 98-100 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.76 (d, J = 1.6, 1H), 7.44 (dt, J1 = 2.8
Hz, J2 = 6.4 Hz, 2H), 7.33 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.23 (dt, J1 = 0.8 Hz, J2 = 8.0
Hz, 1H), 7.04 (dt, J1 = 2.8 Hz, J2 = 6.8 Hz, 2H), 6.46 (s, 1H), 3.90 (s, 3H), 3.73 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3):  (ppm) 159.7, 142.6, 136.8, 130.6, 129.6, 124.7, 124.1,
122.7, 114.1, 113.0, 111.0, 100.5, 55.4, 31.2; IR (KBr): ṽ 3074, 2958, 2836, 1609, 1468,
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1244 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14BrNO 316.0332 (for Br) and
318.0312 (for 81Br); Found 316.0326 (for 79Br) and 318.0307 (for 81Br).
5-Methoxy-1-methyl-2-phenyl-1H-indole (3ai):7e Yellowish solid, 228 mg (96%), m.p. 90-
96 °C; 1H NMR (400 MHz, CDCl3):  (ppm) 7.43-7.35 (m, 4H), 7.33-7.29 (m, 1H), 7.17 (d, J
= 8.8 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.83 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 6.41 (s, 1H),
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3.78 (s, 3H), 3.63 (s, 3H); C {1H} NMR (100 MHz, CDCl3):  (ppm) 154.4, 142.2, 133.8,
132.9, 129.3, 128.5, 128.3, 127.8, 111.9, 110.4, 102.2, 101.3, 56.0, 31.3; IR (KBr): ṽ 3074,
2986, 1854, 1616, 1475, 1220, 801 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H15NO 238.1226; Found 238.1222.
4-(5-Methoxy-1-methyl-1H-indol-2-yl)benzonitrile (3aj): Light pink solid, 238 mg (91%),
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m.p. 118-120 °C; H NMR (400 MHz, CDCl3):  (ppm) 7.77 (dt, J1 = 1.6 Hz, J2 = 6.8 Hz,
2H), 7.63 (dt, J1 = 1.6 Hz, J2 = 6.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H),
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6.99 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 6.61 (s, 1H), 3.90 (s, 3H), 3.77 (s, 3H); C {1H}
NMR (100 MHz, CDCl3):  (ppm) 154.6, 139.8, 137.4, 134.5, 132.3, 129.4, 128.1, 118.8,
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113.3, 111.1, 110.7, 103.2, 102.2, 55.9, 31.7; IR (KBr): ṽ 3057, 2924, 2834, 2232, 1607,
1474, 1221, 840, 574 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H14N2O 263.1179;
Found 263.1175.
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5-Methoxy-2-(4-methoxyphenyl)-1-methyl-1H-indole (3ak): Yellowish solid, 241 mg
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(90%), m.p. 78-80 °C; H NMR (400 MHz, CDCl3):  (ppm) 7.34 (dt, J1 = 3.0 Hz, J2 = 6.4
Hz, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.91 (dt, J1 = 2.0 Hz, J2 = 6.8 Hz,
2H), 6.81 (dd, J1 = 2.8 Hz, J2 = 9.2 Hz, 1H), 6.35 (s, 1H), 3.78 (s, 6H), 3.61 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3):  (ppm) 159.4, 154.3, 142.0, 133.6, 130.6, 128.3, 125.4, 114.0,
111.6, 110.3, 102.1, 100.7, 56.0, 55.4, 31.2; IR (KBr): ṽ 2957, 1613, 1476, 1216, 1173 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H17NO2 268.1332; Found 268.1324.
Scale-up synthesis of compound 3a
For scale-up synthesis of 3a all the substrates, reagents and catalyst were taken 10 times of
the usual quantity (i.e. 10 mmol of 1a and rest in appropriate proportions) and the reaction
was conducted in a 25 mL SS jar with one 15 mm ball and reaction was milled for 1.5 h for
complete conversion. The rest of the procedure remained same. After purification by flash
chromatography 1.81 g (87%) of 3a was obtained.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
1
Information on solution phase reactions, a comparative table, copies of H NMR and 13C
NMR spectra.
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AUTHOR INFORMATION
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E-mail addresses: dharmendradas0@gmail.com (D.D.); eemgiz@gmail.com (Z.T.B.);
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amrita@goa.bits-pilani.ac.in (A.C.); mainak@goa.bits-pilani.ac.in (M.B.)
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*Corresponding authors:
Dr. Mainak Banerjee
Department of Chemistry
BITS Pilani, K. K. Birla Goa Campus,
Goa 403 726, India
Tel.: +91-832-2580-347; fax: +91-832-255-7031
and
Dr. Amrita Chatterjee
Department of Chemistry
BITS Pilani, K. K. Birla Goa Campus,
Goa 403 726, India
Tel.: +91-832-2580-320; fax: +91-832-255-7031
ACKNOWLEDGEMENTS
M. B. thanks DST-SERB (project No. EMR/2016/002253) for financial support and
D. D. is indebted to SERB for JRFship. Z. T. B thanks DST-INSPIRE for INSPIRE
Fellowship. We acknowledge central instrumentation facility of BITS-Pilani, Pilani
campus for NMR and HRMS analysis.
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