N-(2-Aminobenzylidene)-4-methylanilines - stable and cheap alternate for 2-aminobenzaldehydes: concise synthesis of 3-unsubstituted-2-aroylindoles

Article abstract of DOI:10.1016/j.tetlet.2015.07.073

Abstract Synthesis of 3-unsubstituted-2-aroylindoles starting from readily available N-(2-aminobenzylidene)-4-methylanilines, cheap and stable alternative to 2-aminobenzaldehydes, and α-bromoketones was achieved in moderate to good yields under basic cond

Full text of DOI:10.1016/j.tetlet.2015.07.073

Accepted Manuscript
N-(2-Aminobenzylidene)-4-methylanilines - stable and cheap alternate for 2-
aminobenzaldehydes: concise synthesis of 3-unsubstituted-2-aroylindoles
Thavaraj Vivekanand, Thiruvalluvan Sandhya, Perumal Vinoth, Subbiah
Nagarajan, C. Uma Maheswari, Vellaisamy Sridharan
PII:
S0040-4039(15)01237-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.073
TETL 46562
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 July 2015
20 July 2015
24 July 2015
Please cite this article as: Vivekanand, T., Sandhya, T., Vinoth, P., Nagarajan, S., Uma Maheswari, C., Sridharan,
V., N-(2-Aminobenzylidene)-4-methylanilines - stable and cheap alternate for 2-aminobenzaldehydes: concise
synthesis of 3-unsubstituted-2-aroylindoles, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2
015.07.073
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Graphical Abstract
N-(2-Aminobenzylidene)-4-methylanilines - stable
and cheap alternate for 2-aminobenzaldehydes:
concise synthesis of 3-unsubstituted-2-aroylindoles
Leave this area blank for abstract info.
Thavaraj Vivekanand, Thiruvalluvan Sandhya, Perumal Vinoth, Subbiah Nagarajan, C. Uma Maheswari
and Vellaisamy Sridharan*

Tetrahedron Letters
1
Tetrahedron Letters
N-(2-Aminobenzylidene)-4-methylanilines - stable and cheap alternate for 2-
aminobenzaldehydes: concise synthesis of 3-unsubstituted-2-aroylindoles
Thavaraj Vivekanand, Thiruvalluvan Sandhya, Perumal Vinoth, Subbiah Nagarajan, C. Uma
Maheswari and Vellaisamy Sridharan*
Organic Synthesis Group, Department of Chemistry & Centre for Research on Infectious Diseases (CRID), School of Chemical and Biotechnology, SASTRA
University, Thanjavur 613401, Tamil Nadu, India. E-mail: vsridharan@scbt.sastra.edu, vesridharan@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of 3-unsubstituted-2-aroylindoles starting from readily available N-(2-
aminobenzylidene)-4-methylanilines, cheap and stable alternate to 2-aminobenzaldehydes, and
-bromoketones was achieved in moderate to good yields under basic conditions. The reaction
proceeded via sequential N-alkylation-intramolecular nucleophilic cyclization-elimination steps
in a single operation.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Indole synthesis
2
-Aroylindoles
N-(2-Aminobenzylidene)-4-methylanilines
N-Alkylation
Intramolecular cyclization
Nitrogen heterocycles are common structural fragments of
countless pharmaceuticals and agrochemicals, indeed, 59% of US
FDA approved small molecule drugs contain at least one nitrogen
aminobenzaldehyde is known to undergo trimerization in
11
nucleophilic solvents or in the presence of moisture. Moreover,
2-aminobenzaldehyde is rather expensive, for instance, one gram
of unsubstituted 2-aminobenzaldehde costs 180 USD. Hence it is
highly essential to find out a cheap and stable alternate for 2-
aminobenzaldehydes to access 3-unsubstituted-2-aroylindoles.
Jones and Suárez reported the synthesis of 2-aroylindoles 2
starting from amino acetal 1 and phenacyl bromide in moderate
1
heterocycle. Especially indoles occupy a position in the top-ten
most frequent nitrogen ring system present in drug molecules.
Furthermore, indoles are one of the most significant scaffold
2
present in large number of natural products and bioactive
3
,4
molecules. Consequently, much effort has been devoted to the
synthesis of indole derivatives despite the available traditional
methods including Fischer, Bischler, Bartoli, Reissert and
1
2
yield (Scheme 1b). Alternatively, the relatively stable N-
1
3
trifluoroacetyl or N-phenylsulfonyl-2-aminobenzaldehydes (3
5
14
Nenitzescu reactions.
and 4 ) were used as 2-aminobenzaldehyde equivalents to obtain
the products 2 and 5, respectively, in good to moderate yields
2
-Aroylindoles are particularly important owing to their
(Scheme 1c). However, compound 3 was prepared from the
specific pharmacological properties. For instance, these
6
corresponding 2-aminobenzaldehydes, again with the difficulties
associated with handling of 2-aminobenzaldehydes, on the other
hand, compound 4 was prepared from 2-aminobenzyl alcohol in
two steps. Notwithstanding these protocols, it would be
convenient if we could protect the aldehyde group instead of the
amino functionality of 2-aminobenzaldehyde to obtain N-
unsubstituted indoles. With this background, we envisioned to
utilize the readily available and stable N-(2-aminobenzylidene)-
4-methylanilines 6 as alternate to 2-aminobenzaldehydes to
compounds act as tubulin polymerization inhibitors and
autophosphorylation of platelet-derived growth factor (PDGF)
7
receptor tyrosine kinase inhibitors. Besides, 2-aroylindoles are
potential histone deacetylase (HDAC) class I/II inhibitors with
8
broad cytotoxicity superior to that of the approved drug SAHA
9
and posses antimitotic activity in human cancer cells. Despite
the biological significance of these class of compounds, only a
limited number of straightforward procedures have been
1
0
developed for their synthesis.
synthesize 3-unsubstituted-2-aroylindoles
8
(Scheme 1d).
One of the simplest routes to access 2-aroylindoles includes
the reaction between 2-aminobenzaldehydes and -bromoketones
under basic conditions involving N-substitution-intramolecular
aldol condensation steps (Scheme 1a). Nonetheless, 2-
aminobenzaldehyde is highly unstable; it undergoes
polymerization rapidly under ambient conditions due to the
intermolecular condensation between the reactive amino and
Importantly, compound 6 could be derived from the stable and
economical 2-nitrobenzaldehydes (25 g = 51 USD) in two simple
steps involving imine formation and sodium sulfide-mediated
1
5
reduction.
Our initial optimization study began with the reaction of N-(2-
aminobenzylidene)-4-methylaniline 6a and p-chlorophenacyl
o
bromide 7a. The reaction was carried out at 25 C in a variety of
aldehyde
functionalities.
Besides
polymerization,
2-

2
Tetrahedron Letters
-bromoketone improved the yield significantly. A green
alternate, water, was also tested for the reaction and merely 24%
of product was isolated (entry 8). When other bases including
Cs CO , triethylamine, pyrrolidine and piperidine were tested in
2
3
acetonitrile, the yields were decreased considerably, in fact, only
traces of the product was observed in the presence of Cs CO
2
3
(
entries 9-12). Ultimately, we reserved the combination of
o
acetonitrile and potassium carbonate at 80 C for further studies.
Having established the optimal reactions conditions, we then
studied the scope and limitations of the methodology involving a
couple of N-(2-aminobenzylidene)-4-methylanilines 6 and a large
number of -bromoketones 7 to access 3-unsubstituted-2-
1
6
aroylindoles 8 and the results are summarized in Table 2. The
reaction showed high functional group tolerance in both the
reactants. -Bromoketones bearing electron-donating group (Me,
entry 4), moderately electron-withdrawing groups (Cl, Br entries
2
, 3, 6 and 11) and strongly electron-withdrawing group (NO2,
entries 5 and 10) afforded the corresponding 3-unsubstituted-2-
aroylindoles 8 in moderate to good yields. 2-Acetylnaphthalene
derived -bromoketone (entries 7 and 12) and 2-furfuryl
derivative (entry 8) were also effective to afford the
corresponding 2-aroylindoles in good yields. Furthermore, 2,4-
dichlorophenacyl bromide was also reacted with compound 7 to
yield 76% of the product (entry 6). To our delight, N-(2-
aminobenzylidene)-4-methylaniline also tolerated bromo-
substituent with no significant change in the reactivity (entries 9-
Scheme 1 Synthesis of 2-aroylindoles from 2-aminobenzaldehyde
equivalents and -bromoketones.
1
2).
solvents including ethanol, DCM, DCE, dioxane, toluene, DMF,
acetonitrile and water in the presence of two equivalents of
potassium carbonate. Virtually, in all these solvents no product
formation was observed and in few cases the intermediate N-
alkylation product was noticed in small quantities. Increase of
the reaction temperature led to the product formation albeit in
low yields in most of the tested solvents. Although the starting
materials were completely consumed within four hours in
ethanol, DCM, DCE and dioxane only 15-30% product was
isolated (Table 1, entries 1 to 4). Toluene was completely
ineffective and DMF furnished only 36% of isolated product
The proposed mechanism for the formation of 2-aroylindoles is
depicted in Scheme 2. A base mediated initial N-alkylation of
imines 6 with -bromoketones 7 affords N-phenacylanilines 9.
Subsequently, intermediate 9 undergoes an intramolecular
nucleophilic cyclization via its enolic form A to generate the 3-
aminoindoline species B. Final elimination of p-toluidine from
intermediate B at elevated temperature furnishes the products
1
7
1
1b,12
8
.
High temperature is essential for the intramolecular
cyclization and the subsequent elimination steps. Among the
tested solvents, acetonitrile was the best presumably due to its
polar aprotic nature to facilitate the initial S 2 reaction and the
subsequent intramolecular nucleophilic cyclization. Potassium
carbonate, a weak base, promotes the initial N-alkylation in a
controlled manner and facilitates the subsequent cyclization via
enolization.
(entries 5 and 6). Eventually, we found that acetonitrile was
N
effective to afford 71% of indole 8a in three hours reaction time
o
at 80 C (entry 7). Neither increase of the amount of base nor the
a
Table 1 Optimization of reaction conditions.
Entry
Base
2 equiv)
Solvent
Temp. Time
Yield
(%)
o
b
c
(
( C)
(h)
1
2
3
4
5
6
K CO
EtOH
DCM
DCE
Dioxane
Toluene
DMF
80
40
45
100
100
100
80
4
15
13
24 (29)
30
trace
36
2
3
3
3
3
3
3
K CO
2.5
2.5
3
15
3
2
e
K CO
2
K CO
2
K CO
2
K CO
2
d
f
7
K CO
2
MeCN
3
71 (70,
3
g
7
4 )
8
9
1
1
1
K CO
Water
MeCN
MeCN
80
80
80
80
80
3
3
2
3.5
3.5
24
trace
18
15
23
2
3
Cs CO
2
3
0
1
2
Et N
3
Pyrrolidine MeCN
Piperidine MeCN
a
Unless otherwise noted, all reactions were carried out with 6a (1 mmol), 7a
1 mmol) and base (2 mmol) in 5 mL solvent. No product formation was
observed for reactions 1 to 8 at 25 C. Isolated yield. Use of 3 equiv of base
did not improve the yield. Reaction was carried out at 80 C. 1.3 equiv of
b
(
o
c
d
e
o
f
g
7
a was used. 1.5 equiv of 7a was used.
Scheme 2 Plausible mechanism.

Tetrahedron Letters
3
a
Table 2 Synthesis of 3-unsubstituted-2-aroylindole.
b
b
Entry
1
Product 8
Yield (%)
Entry
7
Product 8
Yield (%)
67
74
71
74
70
2
3
4
8
69
65
60
9
10
5
6
68
76
11
12
57
66
a
2 3
Reaction conditions: unless otherwise noted all reactions were carried out with 6 (1 mmol), 7 (1 mmol) and K CO (2 mmol) in 5 mL acetonitrile at
0 C for 3 h. Isolated yield
o
b
8
0
2(0219)/14/EMR-II) is gratefully acknowledged. TV
thanks SASTRA University for research fellowship.
In summary, we have developed a facile synthetic procedure
for the synthesis of 3-unsubstituted-2-aroylindoles starting from
readily available N-(2-aminobenzylidene)-4-methylanilines and
Supplementary data

-bromoketones under basic conditions. The base-mediated
Supplementary data
associated
with
this
article
sequential N-alkylation-intramolecular nucleophilic cyclization-
elimination reactions afforded the products in moderate to good
yields in a single operation. The reaction tolerated a variety of
substituents on both the reactants. We believe that this method
would be a good addition to the existing methods to access 3-
unsubstituted-2-aroylindoles. This protocol demonstrated that N-
(characterization data and copies of NMR spectra) can be found,
in the online version at http://dx.doi.org/10.1016/j.tetlet.2015
References and notes
1. For a miniperspective, see: Vitaku, E.; Smith, D. T.; Njardarson, J.
T. J. Med. Chem. 2014, 57, 10257.
(2-aminobenzylidene)-4-methylanilines derived from easily
2
.
For selected reviews of indole natural products, see: (a) Xu, W.;
Gavia, D. J.; Tang, Y. Nat. Prod. Rep. 2014, 31, 1474; (b) Marcos,
I. S.; Moro, R. F.; Costales, I.; Basabe, P.; Díez, D. Nat. Prod.
Rep. 2013, 30, 1509; (c) Ishikura, M.; Abe, T.; Choshi, T.; Hibino,
S. Nat. Prod. Rep. 2013, 30, 694; (d) Kochanowska-Karamyan, A.
J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489; (e) Walker, S. R.;
Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev. 2009, 109,
3080.
accessible 2-nitrobenzaldehydes, remain the stable and cheap
alternate to 2-aminobenzaldehydes.
Acknowledgements
Financial support from the Department of Science and
Technology, DST (No. SB/FT/CS-006/2013) and the
Council of Scientific and Industrial Research, CSIR (No.
3. For selected reviews of biological importance of indoles, see: (a)
Sidhu, J. S.; Singla, R.; Mayank, E. Y.; Jaitak, V. Anticancer Med.

4
Tetrahedron Letters
Chem. 2015, DOI: 10.2174/1871520615666150520144217; (b)
11. (a) Richers, M. T.; Deb, I.; Platonova, A. Y.; Zhang, C.; Seidel, D.
Synthesis 2013, 1730; (b) Sridharan, V.; Ribelles, P.; Ramos, M.
T.; Menéndez, J. C. J. Org. Chem. 2009, 74, 5715; (c) Xiao, X. S.;
Fanwick, P. E.; Cushman, M. Synth. Commun. 2004, 34, 3901.
12. Jones, C. D.; Suárez, T. J. Org. Chem. 1972, 23, 3622.
13. Zhao, Y.; Li, D.; Zhao, L.; Zhang, J. Synthesis 2011, 873.
14. Dhayalan, V.; Panchapakesan, G.; Mohanakrishnan, A. K. Synth.
Commun. 2012, 42, 402.
15. (a) Leleu, S.; Papamicaël, C.; Marsais, F.; Dupas, G.; Lavacher,
Tetrahedron: Asymmetry 2004, 15, 3919.
16. General procedure for the synthesis of 3-unsubstituted-2-
aroylindoles 8: To a solution of (E)-N-(2-aminobenzylidene)-4-
methylbenzenamines 6 (1 mmol) and -bromoketones 7 (1 mmol)
in dry acetonitrile (5 mL) was added potassium carbonate (2
Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620; (c) Olgen, S.
Mini-Rev. Med. Chem. 2013, 13, 1700; (d) Biersack, B.; Schobert,
R. Curr. Drug Targets 2012, 13, 1705; (e) Lal, S.; Snape, T. J.
Curr. Med. Chem. 2012, 19, 4828; (f) Ahmad, A.; Sakr, W. A.;
Rahman, K. M. Curr. Drug Targets 2010, 11, 652; (g) Xu, H.; Lv,
M. Curr. Pharm. Des. 2009, 15, 2120; (h) Patil, S. A.; Patil, R.;
Miller, D. D. Curr. Med. Chem. 2009, 16, 2531.
For selected, recent examples, see: (a) Revenga, M. F.; Fernández-
Sáez, N.; Herrera-Arozamena, C.; Morales-García, J. A.; Alonso-
Gil, S.; Pérez-Castillo, A.; Caignard, D.-H.; Rivara, S.; Rodríguez-
Franco, M. I. J. Med. Chem. 2015, 58,
DOI: 10.1021/acs.jmedchem.5b00245; (b) Boyd, S.; Brookfield,
J. L.; Critchlow, S. F.; Cumming, I. A.; Curtis, N. J.; Debreczeni,
J.; Degorce, S. J.; Donald, C.; Evans, N. J.; Groombridge, S.;
Hopcroft, P.; Jones, N. P.; Kettle, J. G.; Lamont, S.; Lewis, H. J.;
MacFaull, P.; McLoughlin, S. B.; Rigoreau, L. J. M.; Smith, J. M.;
St-Gallay, S.; Stock, J. K.; Turnbull, A. P.; Wheatley, E. R.;
Winter, J.; Wingfield, J. J. Med. Chem. 2015, 58, 3611; (c)
Aksenov, A. V.; Smirnov, A. N.; Magedov, I. V.; Reisenauer, M.
R.; Aksenov, N. A.; Aksenova, I. V.; Pendleton, A. L.; Nguyen,
G.; Johnston, R. K.; Rubin, M.; De Carvalho, A.; Kiss, R.;
Mathieu, V.; Lefranc, F.; Correa, J.; Cavazos, D. A.; Brenner, A.
J.; Bryan, B. A.; Rogelj, S.; Kornienko, A.; Frolova, L. V. J. Med.
Chem. 2015, 58, 2206.
4
.
o
mmol) and the mixture was stirred at 80 C for 3 h. After
completion of the reaction, as indicated by TLC, the mixture was
diluted with water and extracted with CH Cl (4 x 10 mL). The
2
2
combined organic layer was washed with water followed by brine
solution, dried over anhydrous Na SO and the solvent was
2
4
evaporated under reduced pressure. The crude mixture was
purified through silica column chromatography eluting with
petroleum ether and ethyl acetate mixture (98:2 v/v).
Characterization data for representative compounds. 8a: Off-white
o
o
12
solid, mp. 146-147 C (147-148 C); Yield: 74%; IR (KBr)
3313.6, 3057.2, 2924.9, 1619.7, 1516.0, 1259.6, 1126.0, 1011.4
cm ; H NMR (CDCl , 300 MHz): δ 7.15-7.20 (m, 2H), 7.39 (td, J
-
1 1
3
5
.
For selected reviews on indole synthesis, see: (a) Guo, T.; Huang,
F.; Yu, L.; Yu, Z. Tetrahedron Lett. 2015, 56, 296; (b) Shiri, M.
Chem. Rev. 2012, 112, 3508; (c) Platon, M.; Amardeil, R.;
Djakovitch, L.; Hierso, J. C. Chem. Soc. Rev. 2012, 41, 3929; (d)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215; (e) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873.
Brancale, A.; Silvestri, R. Med. Chem. Rev. 2007, 27, 209.
Mahboobi, S.; Teller, S.; Pongratz, H.; Hufsky, H.; Sellmer, A.;
Botzki, A.; Uecker, A.; Beckers, T.; Baasner, S.; Schächtele, C.;
Überall, F.; Kassack, M. U.; Dove, S.; Böhmer, F.-D. J. Med.
Chem. 2002, 45, 1002.
= 8.4, 1. 2 Hz, 1H), 7.49 (dd, J = 8.4, 0.9 Hz, 1H), 7.54 (t, J = 7.5
Hz, 2H), 7.63 (tt, J = 7.5, 1.2 Hz, 1H), 7.73 (dd, J = 8.1, 0.6 Hz,
13
1H), 8.00 (dd, J = 8.4, 1.2 Hz, 2H), 9.32 (s, 1H); C NMR
(CDCl3, 75 MHz): δ 112.2, 112.9, 121.1, 123.3, 126.6, 127.8,
128.5, 129.2, 132.4, 134.4, 137.6, 138.3, 187.3; 8c: Pale yellow
o
solid, mp. 202-204 C; Yield: 74%; IR (KBr) 3309.1, 3051.5,
-
1 1
6
7
.
.
2924.9, 1619.9, 1514.5, 1259.9, 1126.3, 1067.2 cm ; H NMR
(CDCl , 300 MHz): δ 7.14 (d, J = 1.2 Hz, 1H), 7.17 (td, J = 7.2,
3
0.9 Hz, 1H), 7.39 (td, J = 8.1, 0.9 Hz, 1H), 7.48 (d, J = 8.4 Hz,
1H), 7.69 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.87 (d, J =
13
8.7 Hz, 2H), 9.36 (s, 1H); C NMR (CDCl , 75 MHz): δ 112.6,
3
8
9
.
.
Mahboobi, S.; Sellmer, A.; Höcher, H.; Garhammer, C.; Pongratz,
H.; Maier, T.; Ciossek, T.; Beckers, T. J. Med. Chem. 2007, 50,
112.8, 121.0, 123.1, 126.5, 127.1, 127.5, 130.7, 131.7, 134.1,
137.0, 138.1, 186.1; 8f: Pale yellow solid, mp. 176-178 C; Yield:
o
4
405.
76%; IR (KBr) 3313.0, 3079.5, 2925.4, 1621.1, 1514.2, 1254.1,
-
1 1
Mahboobi, S.; Pongratz, H.; Hufsky, H.; Hockemeyer, J.; Frieser,
M.; Lyssenko, A.; Paper, D. H.; Bürgermeister, J.; Böhmer, F.-D.;
Fiebig, H.-H.; Burger, A. M.; Baasner, S.; Beckers, T. J. Med.
Chem. 2001, 44, 4535.
1128.2, 1103.0 cm ; H NMR (CDCl , 300 MHz): δ 6.89 (d, J =
3
1.2 Hz, 1H), 7.16 (td, J = 7.2, 0.9 HZ, 1H), 7.37-7.43 (m, 2H),
7.47-7.52 (m, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.1 Hz,
13
1H), 9.33 (s, 1H); C NMR (CDCl , 75 MHz): δ 112.6, 114.6,
3
1
0. For methods to access 2-aroylindoles, see: (a) Goriya, Y.;
Ramana, C. V. Chem. Commun. 2014, 50, 7790; (b) Pan, C.; Jin,
H.; Liu, X.; Cheng, Y.; Zhu, C. Chem. Commun. 2013, 49, 2933;
121.4, 123.4, 126.8, 127.4, 127.5, 130.4, 130.5, 132.9, 134.5,
1
36.1, 136.9, 138.5, 185.2.
1
7. Sridharan, V.; Avendaño, C.; Menéndez, J. C. Synlett 2006, 91.
(c) Reddy, B. V. S.; Reddy, M. R.; Rao, Y. G.; Yadav, J. S.;
Sridhar, B. Org. Lett. 2013, 15, 464; (d) Gao, W.-C.; Jiang, S.;
Wang, R.-L.; Zhang, C. Chem. Commun. 2013, 49, 4890; (e)
Arthuis, M.; Pontikis, R.; Florent, J.-C. Org. Lett. 2009, 11, 4608.