PMA-SiO 2-Mediated MCR in PEG-400: A Greener aza-Friedel-Crafts Reaction Leading to 3-Arylmethyl/Diarylmethyl Indoles

Article abstract of DOI:10.1080/00397911.2014.966392

A greener approach for the synthesis of 3-arylmethyl/diarylmethyl indoles has been achieved via a PMA-SiO₂-mediated three-component reaction (the aza-Friedel-Crafts reaction) involving indoles, aldehydes, and N,N-disubstituted anilines in PEG-4

Full text of DOI:10.1080/00397911.2014.966392

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PMA-SiO2 Mediated MCR in PEG-400: A Greener Aza-
Friedel-Crafts Reaction Leading to 3-Arylmethyl/
diarylmethyl Indoles
Dinne Naresh Kumar Reddyab, Kothapalli Bannoth Chandrasekharb, Yaddanapudi Sesha Siva
Ganesha, Srikanth Sharathchandra Gorantlaa, Siddabathuni Ramanjaneyulua, K. Shiva Kumarc
& Manojit Pald
a Custom Pharmaceuticals Services and Dr. Reddy's Laboratories Ltd, Hyderabad, India
b College of Engineering, JNTU, Anantapur, Andhra Pradesh, India
c Department of Chemistry, Osmania University, Hytderabad, India
d Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, India
Accepted author version posted online: 03 Nov 2014.
To cite this article: Dinne Naresh Kumar Reddy, Kothapalli Bannoth Chandrasekhar, Yaddanapudi Sesha Siva Ganesh, Srikanth
Sharathchandra Gorantla, Siddabathuni Ramanjaneyulu, K. Shiva Kumar & Manojit Pal (2014): PMA-SiO2 Mediated MCR in
PEG-400: A Greener Aza-Friedel-Crafts Reaction Leading to 3-Arylmethyl/diarylmethyl Indoles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.966392
To link to this article: http://dx.doi.org/10.1080/00397911.2014.966392
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PMA-SiO2 mediated MCR in PEG-400: A greener aza-Friedel-Crafts reaction
leading to 3-arylmethyl/diarylmethyl indoles
Dinne Naresh Kumar Reddy1,2, Kothapalli Bannoth Chandrasekhar2, Yaddanapudi Sesha
Siva Ganesh1, Srikanth Sharathchandra Gorantla1, Siddabathuni Ramanjaneyulu1, K.
Shiva Kumar3, Manojit Pal4
1Custom Pharmaceuticals Services and Dr. Reddy’s Laboratories Ltd, Hyderabad, India,
2College of Engineering, JNTU, Anantapur, Andhra Pradesh, India, 3Department of
Chemistry, Osmania University, Hytderabad, India, 4Dr. Reddy’s Institute of Life
Sciences, University of Hyderabad Campus, Hyderabad, India
Address correspondence to Manojit Pal, Dr. Reddy’s Institute of Life Sciences,
University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh,
India. Email: manojitpal@rediffmail.com
Abstract
A greener approach for the synthesis of 3-arylmethyl/diarylmethyl indoles has been
achieved via a PMA-SiO2 mediated three-component reaction (the aza-Friedel-Crafts
reaction) involving indoles, aldehydes and N,N-disubstituted anilines in PEG-400. A
variety of indole derivatives were prepared by using this operationally simple and straight
forward methodology in acceptable yields.
KEYWORDS: indole, aldehyde, aniline, MCR, PMA-SiO2, PEG-400.
1

INTRODUCTION
Multicomponent reactions (MCRs) due to their well-known ability of creating
diversity around a particular scaffold have attracted continuing interest in organic
synthesis and medicinal / pharmaceutical chemistry.[1–3] In fact MCRs can deliver
library of molecules for various uses by saving time, energy and cost and are
considered as preferred techniques not only in green chemistry but also for drug
discovery efforts. However, all MCRs are not green and therefore improving the
greenness of existing MCRs has become a major goal of both academic and industrial
R&Ds.
While some limited pharmacological properties of 3-diarylmethyl indoles were
studied[4] way back in 1974 by Whitehead and Whitesitt, not much progress has been
made thereafter to evaluate this class of compounds further. In 2004, 3-[(4-
fluorophenyl)(1H-imidazol-1-yl)methyl]-1-ethyl-2-methyl-1H-indole that is related to
this class of indoles has been reported by Borgne et al as a potent, selective and non-
steroidal inhibitor of enzyme aromatase.[5] The selective inhibition of COX-2
(cyclooxygenase-2) by 3-arylmethyl indoles have been reported by Campbell et al in
the same year.[6] One of the possible reasons for the lack of further pharmacological
studies on this class of indoles is perhaps their limited access. Indeed, the synthesis of
3-arylmethyl/diarylmethyl indole from indole and aldehyde/ketone was not
straightforward due to the high nucleophilicity of indole towards azafulven
intermediate formed during the reaction leading to the formation of
2

bis(indolyl)methane.[7] To overcome this difficulty Et3SiH /TFA (trifluoroacetic acid)
was utilized by Steele et al in 2004 for a rapid donation of hydride ion to the
azafulven intermediate to form 3-arylmethyl indole.[7] Similarly, TMSOTf/Et3SiH was
used to synthesize 3-arylmethyl indoles.[6] In 2006, the reaction of indole, N,N-
dimethylanilne and aromatic aldehyde (or its equivalent) termed as aza-Friedel-Crafts
reaction was performed in the presence of copper(II)bis(trifluoromethanesulfonate) /
2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl to give the 3-diarylmethyl indole
derivative.[8] Recently, TFA,[9] HClO4-SiO2 (in MeOH),[10] FeCl3,[11] binuclear
complex of bis(ethylcyclopentadienyl)zirconium perfluorooctanesulfonate (in 1,2-
dichloroethane)[12] and ZnCl2[13] have been utilized for aza-Friedel-Crafts reaction
leading to the synthesis of 3-arylmethyl/diarylmethyl indoles. While many of these
methods are efficient and useful, most of them however involved the use of non-
environmental friendly catalyst or solvent. In some cases, in addition to their
cumbersome preparation, catalysts are either air- or moisture-sensitive (thereby
required strictly anhydrous reaction conditions) and cannot be recycled. Thus,
development of more environmental friendly method for aza-Friedel-Crafts reaction
leading to the synthesis of 3-arylmethyl/diarylmethyl indoles is highly desirable.
Recently the use of phosphomolybdic acid (PMA or H3PMo12O40) that belongs to the
class of heteropolyacids (HPA) has been explored as a reagent/catalyst in various
organic transformations. Being several times stronger than the common acids such as
H2SO4, TsOH, BF3·Et2O and ZnCl2, heteropolyacids can facilitate the reaction at
lower concentration and temperature[14] and therefore became key catalysts in the
3

development and commercialization of several synthetic methods.[15-19] The use of
PMA in combination with SiO2 (e.g. silica supported phospomolybdic acid or PMA-
SiO2) in a MCR involving the reaction of arylaldehyde, N-methyl aniline and indole
leading to 3-substituted indole derivatives i.e. N-((1H-indol-3-yl)arylmethyl)aniline
(Scheme 1) has been reported earlier.[20] We have observed that the use of N,N-
disubstituted anilines (3) in place of N-methyl aniline in a similar MCR afforded the
aza-Friedel-Crafts reaction products (4) in good yields (Scheme 1). It is evident that
the N-monosubstituted aniline reacted though its amine nitrogen in the previously
reported catalytic process whereas the N,N-disubstituted aniline reacted through its C-
4 atom in the present reaction. Herein we report the preliminary results of this green
synthesis.
RESULTS AND DISCUSSION
At first the MCR of indole (1a), benzaldehyde (2a) and N,N-dimethyl aniline (3a) was
carried out using a range of catalysts, and solvents at various temperatures and the
results are summarized in Table 1. When the reaction was carried out in the absence
of any catalyst in PEG-400 at 120 °C, the product 4a was isolated in 15% yield (entry
1, Table 1). However, the yield of 4a was increased to 30% when Amberlite was used
as a catalyst (entry 2, Table 1). A further increase in product yield was observed when
Amberlite was replaced by PMA-SiO2 (entry 3, Table 1). We were delighted with this
observation as both PMA-SiO2 and PEG-400 are considered as environmental
friendly catalyst and solvent, respectively. This encouraged us to continue our study
further. In the quest of improving the product yield further we examined the use of
4

other catalysts such as indian resin, clay (montmorillonite k10) and SiO2. However,
none of them were found to be effective (entries 4-6, Table 1). We also examined the
use of other solvents like MeOH, i-PrOH, MeCN and water but were found to be less
effective (entries 7-10, Table 1). We then examined the effect of variation of reaction
temperature and the amount of catalyst used. After carrying out the reaction at various
temperatures (entries 11- 14, Table 1), the range 90-95 °C (entry 3, Table 1) was
found to be optimum though a slight increase of product yield was observed at 110-
115 °C (entry 13, Table 1). Similarly, the use of 15 mol% (15 mg of catalyst for 100
mmol of indole 1a) of catalyst was found to be optimum (entry 3, Table 1) as the
decrease or increase in catalyst amount did not afford better yields (entries 15-18 and
3, Table 1). It is mention worthy that 3,3'-(phenylmethylene)bis(1H-indole) was
obtained as a side product in these cases. To test the recyclability of the catalyst
used, PMA-SiO2 was recovered by simple filtration and reused in the same reaction
when 4a was isolated without significant loss of its yield (entry 3, Table 1). Overall, a
combination of PMA-SiO2 (15 mol%) and PEG-400 was appeared to be optimal for
the preparation of 4a and was used further to expand the scope and generality of this
methodology.
A range of indoles (1), aldehydes (2) and N,N-disubstituted anilines (3) were
employed under the optimized reaction conditions and results are summarized in
Table 2. While groups like Br or Me were tolerated on the indole ring (1), various
electron-donating / withdrawing groups e.g. Cl, Br, OMe, NO2 and CN present on the
5

benzene ring of the reactant aldehyde 2 were found to remain unaffected under the
condition employed (entries 2-8, Table 2). The use of heteroaromatic (entries 9, 10
and 19, Table 2) and aliphatic aldehydes (entry 20, Table 2) as well as formaldehyde
(entries 11 and 15, Table 2) were also successful and afforded the desired indole
derivatives (4) in acceptable yields. Notably, the corresponding bis(indolyl)methane
derivative was isolated in 7-10% yield in all these cases.
Based on the previous findings[13] a plausible mechanism for the present PMA-SiO2
mediated MCR leading to the 3-arylmethyl/diarylmethyl indoles is shown in Scheme
2. The initial step involved the reaction of aldehyde 2 with indole 1 in the presence of
PMA-SiO2 leading to the formation of the azafulven intermediate E-2 via E-1 (in
general, indole is known to reacts through its C-3 carbon due to the higher
nucleophilicity of C-3 over C-2 caused by resonance). Subsequent reaction of E-2
with the aniline 3 afforded E-3 which on deprotonation yielded the desired product 4
with the regeneration of the catalyst. It is evident from this proposed reaction
mechanism that the proton released from PMA-SiO2 is the actual catalytic species in
the present reaction. While the N,N-disubstituted amine moiety of 3 facilitated the
attack through its C-4 atom (via positive mesomeric effect) in the present case, the N-
monosubstituted aniline however reacted though its amine nitrogen leading to a
different type of indole derivatives.[20]
6

CONCLUSIONS
In conclusion, we have described the first use of PMA-SiO2 in the synthesis of 3-
arylmethyl/diarylmethyl indoles via a three-component reaction (the aza-Friedel-
Crafts reaction) involving indoles, aldehydes and N,N-disubstituted anilines in PEG-
400. The methodology does not require the use of any expensive catalyst, reagent or
solvent. The catalyst PMA-SiO2 can be recovered and reused. A variety of indole
derivatives were prepared by using this operationally simple and straight forward
methodology in acceptable yields. The curent methodology represents a greener and
safer alternative to the existing methods leading to 3-arylmethyl/diarylmethyl indoles
and may find usage towards the synthesis of more complex indole derivatives of
chemical / pharmacutical interest.
EXPERIMENTAL
Preparation21 Of PMA-Sio2
To a solution of H3PMo12O40 (1.0 g, 0.1 equiv by wt) in Methanol (50 mL) was added
silica gel (9.0 g, 0.9 equiv by wt, 60-120 mesh), and the mixture was stirred at room
temperature for 4-5 hr. Evaporation of methanol under reduced pressure gave a dry
yellowish powder which contained 10% w/w of PMA.
General Procedure For The Preparation Of 3-Arylmethyl/Diarylmethyl Indoles (4)
A mixture of indole (1) (1.0 equiv), aldehyde (2) (1.2 equiv), N,N-dimethyl aniline (3)
(1.3 equiv) and PMA-SiO2 (15 mol%) in PEG-400 (4 mL) was stirred at 90-95 °C for
time indicated in Table 2. After completion of the reaction, the mixture was cooled to
7

room temperature, diluted with EtOAc (5 mL) and filtered. The filtrate was washed with
water (10 mL) and the aqueous layer was extracted with EtOAc (2 x 5 mL). The organic
layers were collected, combined, dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by column chromatography on silica
gel using ethyl acetate-hexane to give the desired product.
ACKNOWLEDGEMENTS
D. N. K. Reddy thanks Mr. A. Sanjay Reddy, Dr. Upadhya Thimanna, Dr. Vilas
Dhanukar and the management of CPS, DRL, Hyderabad, India for support and
encouragements.
SUPPORTING INFORMATION
Full experimental detail and spectral data for this article can be accessed on the
publisher’s website.
REFERENCES
[1]Ugi, I.; Wernwer, B.; Domling, A. Molecules 2003, 8, 53-66;
[2]Domling, A. Curr. Opin. Chem. Biol. 2000, 4, 318-323;
[3]Weber, L. Drug Disc. Today 2002, 7, 143-147.
[4]Whitehead, C. W.; Whitesitt, C. A. J. Med. Chem. 1974, 17, 1298-1304.
[5]Lézé, M. P.; Le Borgne, M.; Marchand, P.; Loquet, D.; Kogler, M.; Le Baut, G.;
Palusczak, A.; Hartmann, R. W. J. Enzyme Inhib. Med. Chem. 2004, 19, 549-547.
8

[6]Campbell, J. A.; Bordunov, V.; Broka, C. A.; Dankwardt, J.; Hendricks, R. T.; Kress,
J. M.; Walker, K. A. M.; Wang, J.-H. Tetrahedron Lett. 2004, 45, 3793-3796.
[7]
Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele, J. Tetrahedron Lett. 1993, 34,
1529-1532.
[8]Esquivias, J.; Gomez Arrayas, R.; Carretero, J. C. Angew. Chem. Int. Ed. 2006, 45,
629-633.
[9]Robertson, F. J.; Kenimer, B. D.; Wu, J. Tetrahedron 2011, 67, 4327-4332.
[10]
[11]
[12]
Kumar, A.; Sharma, S.; Maurya, R. A. Tetrahedron Lett. 2009, 50, 5937-5940.
Liu, J.; He, T.; Wang, L. Tetrahedron 2011, 67, 3420-3426.
Zhang, X.; Zhang, X.; Li, N.; Xu, X.; Qiu, R.; Yin, S. Tetrahedron Lett. 2014,
55, 120-123.
[13]
[14]
[15]
[16]
S. S. Ganesan, and A. Ganesan, Tetrahedron Lett. 2014, 55, 694-698.
Kozhevnikov, I. V. Russ. Chem. Rev. 1987, 56, 811-825
Firouzabadi, H.; Iranpoor, N.; Amani, K. Synthesis 2003, 408-412;
Kozhevnikova, E. F.; Derouane, E. G.; Kozhevniko, I. V. Chem. Commun. 2002,
1178-1179;
[17]
[18]
Kumar, G. D. K.; Baskaran, S. Synlett 2004, 1719-1722;
Yadav, J. S.; Raghavendra, S.; Satyanarayana, M;. Balanarasaiah, E. Synlett
2005, 2461-2464;
[19]
[20]
Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520-4523.
Shrihari, P.; Singh, V. K.; Bhunia, D. C.; Yadav, J. S. Tetrahedron Lett. 2009,
50, 3763-3766.
[21] Murugan, K.; Srimurugan, S.; Chen, C. Chem. Commun. 2010, 46, 1127-1129.
9

Table 1. Effect of reaction conditions on the MCR of 1a, 2a and
N
Ph
CHO
N
Catalyst
+
+
N
Solvent
N
H
H
heat, 14h
3a.a
1a
2a
3a
4a
Entry Catalyst
Solvent
Temp (°C)
90-95
90-95
90-95
90-95
90-95
90-95
65
Yield (%)b
1
No catalyst
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
15
2
Amberlite (15 mol%)
PMA-SiO2 (15 mol%)
Indion resin (15 mol%)
SiO2 (15 mol%)
30
3
65 (64, 65, 63, 64 62)c
4
32
15
17
20
30
15
40
30
42
67
65
48
55
5
6
Montmorillonite k10 (15 mol%) PEG-400
7
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (15 mol%)
PMA-SiO2 (5 mol%)
PMA-SiO2 (10 mol%)
MeOH
8
i-PrOH
80-85
80-85
90-95
65
9
MeCN
10
11
12
13
14
15
16
H2O
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
80-85
110-115
130-135
90-95
90-95
10

17
18
PMA-SiO2 (20 mol%)
PMA-SiO2 (30 mol%)
PEG-400
PEG-400
90-95
90-95
67
68
aAll the reactions were carried out using 1a (1.0 equiv), 2a (1.2 equiv) and 3a (1.3 equiv)
in a solvent.
bIsolated yield.
cThe catalyst was recovered and reused for an additional five runs and the figures within
parentheses indicate the corresponding yield for each run.
11

Table 2. Synthesis of 3-arylmethyl/diarylmethyl indoles
R3
N
R
R3
PMA-SiO2
(15 mol%)
R3
R1
R1
N
+
RCHO +
N
R3
N
PEG-400
110-115 oC
10-14 h
R2
R2
3
4
2
1
(4).a
Entry
Indole (1)
Aldehyde (2)
Dialkyl aniline (3)
Product (4)
Yield (%)
1
65
2
68
1a
3a
12

3
63
1a
2b
4
66
1a
3a
5
62
1a
3a
13

6
65
1a
3a
7
65
1a
3a
8
60
1a
3b
14

9
63
1a
3a
10
62
1a
3a
HCHO
11
70c
1a
3a
2j
15

12
60
2a
3a
13
66
1b
2f
3a
14
61
1b
2c
3a
16

15
67c
1b
2j
3a
16
60
1c
2a
3a
17
61
1c
2g
3a
17

18
67
1d
2e
3b
19
65
1d
2h
3a
Me₂CHCH₂CHO
20
62d
1d
3a
2k
aAll the reactions were carried out using indole 1 (1.0 eq), aldehyde 2 (1.2 eq) and dialkyl aniline 3 (1.3 eq) and PMA-SiO2 (15
mol%) in PEG-400 at 90-95 °C.
18

bIsolated yield.
cThe reaction was carried out at 40–60 °C for 11h.
dThe reaction was carried out at 60–70 °C for 11h.
19

Scheme 1. PMA-SiO2 catalyzed MCR of indole, arylaldehyde, and aniline derivative.
20

Scheme 2. Proposed reaction mechanism
21