InCl3 catalyzed three-component synthesis of α-benzylamino coumarins and diketones

Article abstract of DOI:10.1016/j.tetlet.2012.07.098

A convenient and practical InCl₃ catalyzed three-component reaction of 4-hydroxy coumarin/1,3 diones, aromatic aldehyde, and secondary amine for the synthesis of α-benzylamino coumarins and diketones in good yields has been reported.

Full text of DOI:10.1016/j.tetlet.2012.07.098

Tetrahedron Letters 53 (2012) 5314–5317
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Tetrahedron Letters
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InCl3 catalyzed three-component synthesis of
and diketones
a-benzylamino coumarins
Pallavi Rao b, , Saidulu Konda a, Javed Iqbal a, Srinivas Oruganti b
⇑
a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
b Cosmic Discoveries, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and practical InCl3 catalyzed three-component reaction of 4-hydroxy coumarin/1,3 diones,
Received 22 June 2012
Revised 17 July 2012
Accepted 21 July 2012
Available online 28 July 2012
aromatic aldehyde, and secondary amine for the synthesis of
good yields has been reported.
a
-benzylamino coumarins and diketones in
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
a
a
-Benzylamino coumarins
-Benzylamino diketones
InCl3
4-Hydroxy coumarin
1,3-Diones
Multicomponent reactions (MCRs) typically involve more than
two reactants to combine in a sequential manner giving highly
selective products while retaining majority of the atoms of the
starting material. MCRs have received considerable attention be-
cause of their wide range of applications in pharmaceutical chem-
istry for the creation of structural diversity and combinatorial
libraries for drug discovery.1
Synthesis of a-benzylamino coumarin has been recently reported
by Kumar et al.7 using triton X-100 catalyst and by Ghosh et al.8
using nano crystalline ZnO via a Mannich type reaction in aqueous
media.
We initially attempted a three-component reaction of 4-hydro-
xy coumarin, aryl aldehyde, and secondary amines in the presence
.
of various catalysts such as FeCl3, BF3 OEt2, AlCl3, InCl3, amberlite
Coumarin and its derivatives are an important class of heterocy-
clic compounds, which constitute the key core of various natural
products.2 They exhibit a wide range of biological activities such
as anti-HIV, antimalarial, insecticidal, and antioxidant properties.3
Most significant are 3-substituted-4-hydroxy coumarin derivatives
which have important clinical applications (Fig. 1).4
IR-120 resin, and I2. Among these, InCl3 was found to be an effec-
tive catalyst wherein the
a-benzylamino coumarin was obtained
in good yields under mild conditions with no traces of bis-couma-
rin product (Scheme 1). Except BF3ÁOEt2, all other Lewis acids stud-
ied furnished the desired product, albeit in low yields (20–50% over
We were interested in the development of one-pot MCR route
to 3-substituted coumarin derivatives catalyzed by mild Lewis
acids. Recently, indium(III)chloride has evolved as a mild and
water tolerant Lewis acid imparting high regio-, chemo- and dia-
stereoselectivities in various organic transformations.5 Compared
to conventional Lewis acids, indium(III)chloride in particular has
advantages of low catalyst loading, moisture stability, and catalyst
recycling.
OH
O
OH
O
O
O
Phenprocoumon 1
Coumatetralyl 2
O
In continuation of our interest in exploring the synthetic utility
of indium(III)chloride,6 we report a three-component reaction for
OH
OH
the direct synthesis of
a-benzylamino coumarin derivatives from
4-hydroxy coumarin, aromatic aldehyde, and secondary amines.
O
O
O
O
Warfarin 3
Difenacoum 4
⇑
Corresponding author. Tel.: +91 40 665 71500; fax: +91 40 665 71581.
E-mail address: pallavir@ilsresearch.org (P. Rao).
Figure 1. Biologically active coumarins.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.098

P. Rao et al. / Tetrahedron Letters 53 (2012) 5314–5317
5315
O
O
O
O
N
CHO
InCl3 10 mol%
Toluene, rt, 3h
CHO
InCl3 10 mol%,
O
O
O
O
R
Toluene,
n
reflux, 3h
N
H
R
OH
80-90%
N
H
70-80%
OH
R
OH
R
OH
HN
5
10
n
9
7
5
7
6
8
Scheme 2. InCl3 catalyzed synthesis of aryl indole coumarins.
n = 1,2
Scheme 1. InCl3 catalyzed three-component reaction to synthesize a-benzylamino
coumarins.
O
InCl3
O
O
O
O
O
O
-H2O
R
R
H
R
H
Table 1
Optimization of InCl3 catalyzed reaction of a
-benzylamino coumarinsa
OH
O
Entry
Catalystb
Solvent
Temp (°C)
Time (h)
Yieldc (%)
InCl3
O
O
1
2
3
4
5
6
7
8
9
10
FeCl3
BF3.OEt2
AlCl3
InCl3
InCl3
InCl3
InCl3
—
Toluene
Toluene
Toluene
Toluene
EtOH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
6
20
O
12
12
3
6
6
0.5
12
12
6
No reaction
R
20
90
40
50
50
15
20
50
O
OH
DCM
InCl3
N
H
HN
10
No solvent
Toluene
Toluene
Toluene
Amberlite
I2
Figure 3. Possible reaction mechanism of aryl indole coumarins.
a
The reactions were conducted with 4-bromobenzaldehyde (1 mmol), 4-hydroxy
coumarin (1 mmol), and pyrrolidine (1 mmol) at room temperature.
6–12 h). Next, we have studied the effect of solvent for this conver-
sion. In polar solvents like ethanol and in chlorinated solvents like
dichloromethane, desired product was obtained in low yields.
When the solvent was changed to a non-polar solvent such as tol-
uene, the yields were excellent.9 We have examined the reaction
under solvent-free conditions and found that reaction goes to com-
pletion in just 30 min at room temperature giving modest 50%
yield of the desired product (Table 1). In the absence of InCl3, the
products were obtained in low yields (10–15%) after long reaction
times (8–12 h).
Mechanistically, we presume that the reaction proceeds via the
formation of imine intermediate from secondary amine and alde-
hyde. Subsequent nucleophilic addition of 4-hydroxy coumarin re-
sults in the formation of only one product (Fig. 2). To test the
generality of this reaction, pyrrolidines, piperidines, and indoles
were reacted with 4-hydroxy coumarin and 1,3-dimedone
b
Catalyst 10 mol %.
Isolated yields.
c
O
O
InCl3
N
R
O
R
R
H
H2O
H
O
O
N
OH
NH
8
H
Figure 2. Possible reaction mechanism of a-benzylamino coumarins.
Table 2
InCl3 catalyzed synthesis of 3-benzylamino coumarin, and 2-benzylamino diketone derivatives
Entry
Diketonea
Aminea
Aldehydea
Product
Time (h)
Yieldb (%)
O
CHO
O
O
O
O
O
NH
8a
3
90
OH
O
N
O
OH
O
CHO
NH
NH
8b
8c
3
3
85
OH
O
N
O
OH
O
CHO
Cl
Cl
89
OH
OH
N
(continued on next page)

5316
P. Rao et al. / Tetrahedron Letters 53 (2012) 5314–5317
Table 2 (continued)
Entry
Diketonea
Aminea
NH
Aldehydea
Product
Time (h)
Yieldb (%)
O
CHO
O
O
Br
O
O
8d
8e
8f
3
85
OH
O
N
O
OH
Br
CHO
O
NO2
NH
NH
3
3
82
89
OH
O
N
O
OH
O
NO2
CHO
O
O
NO2
OH
O
N
O
OH
O
NO2
CHO
NO2
N
H
8g
3
89
OH
OH
N
NO2
O
O
CHO
O
NH
NH
NH
8h
8i
3
3
89
89
N
O
O
OH
CHO
CHO
N
O
O
OH
OH
O
O
O
Cl
O
8j
3
3
3
3
90
85
85
89
N
O
Cl
CHO
Br
NH
NH
8k
8l
N
O
O
O
OH
OH
Br
CHO
NO2
N
O
NO2
O
CHO
NH
NO2
8m
N
NO2
O
OH
O
O
O
CHO
O
N
H
10a
3c
75
OH
OH
HN

P. Rao et al. / Tetrahedron Letters 53 (2012) 5314–5317
5317
Table 2 (continued)
Entry
Diketonea
Aminea
Aldehydea
Product
Time (h)
Yieldb (%)
O
CHO
O
O
O
O
O
Cl
N
H
10b
3c
79
75
OH
O
OH
Cl
HN
CHO
O
NO2
N
H
10c
3c
OH
OH
NO2
HN
a
The reactions were conducted with aldehyde (1 mmol), 4-hydroxy coumarin/1,3-dimedone (1 mmol), secondary amine (1 mmol), and InCl3 (10 mol %) in toluene at room
temperature.
b
c
Isolated yields.
Reaction carried out at reflux temperatures.
3. (a) Patil, A. D.; Freyer, A. J.; Eggleston, D. S.; Haltiwanger, R. C.; Bean, M. F.;
Taylor, P. B.; Caranfa, M. J.; Breen, A. L.; Bartus, H. R.; Johnson, R. K.; Hertzberg,
R. P.; Westley, J. W. J. Med. Chem. 1993, 36, 4131; (b) Guilet, D.; Hélesbeux, J.-J.;
Séraphin, D.; Sévenet, T.; Richomme, P.; Bruneton, J. J. Nat. Prod. 2001, 64, 563.
4. (a) Hadler, M. R.; Shadbolt, R. S. Nature 1975, 253, 275; (b) Takumi, M.; Ikuzo,
N.; Tsuneaki, H.; Akiya, K.; Kambe, N.; Sonoda, N. Synthesis 1988, 257; (c)
Angelo, C.; Ombretta, P. Synthesis 1993, 99; (d) Fiedler, V. B.; Scholtholt, J.
Pharmacol. Exp. Ther. 1981, 217, 306.
5. (a) Babu, G.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16; (b) Ghosh, R. Indian J.
Chem. 2001, 40B, 550; (c) Clarke, P. A.; Zaytzev, A. V.; Whitwood, A. C.
Tetrahedron Lett. 2007, 48, 5209; (d) Shanthi, G.; Perumal, P. T. Tetrahedron Lett.
2009, 50, 3959; (e) Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2008, 49, 7139;
(f) Yadav, J. S.; Reddy, B. V. S.; Satheesh, G.; Narasimhulu, G.; Portier, Y.;
Madhavi, C.; Kunwar, A. C. Tetrahedron Lett. 2008, 49, 3341; (g) Kumar, R.;
Nandi, G. C.; Verma, R. K.; Singh, M. S. Tetrahedron Lett. 2010, 51, 442.
6. Mulakayala, N.; Kandagatla, B.; Ismail; Rapolu, R. K.; Rao, P.; Mulakayala, C.;
Kumar, C. S.; Iqbal, J.; Oruganti, S. Bioorg. Med. Chem. Lett. 2012, 22, 5063.
7. Kumar, A.; Gupta, M. K.; Kumar, M. Tetrahedron Lett. 2011, 52, 4521.
8. Ghosh, P. P.; Das, A. R. Tetrahedron Lett. 2012, 53, 3140.
(Table 2). All the products 8a–m were characterized and confirmed
by 1H NMR, 13C NMR, and mass.1H NMR spectra of the compounds
8h–m showed a characteristic singlet at around d 5.01 indicating
that the products exist exclusively in their enol forms.10
Interestingly, reactions of 4-hydroxy coumarin with indole and
aromatic aldehydes furnished product 10a–c (Scheme 2, and Ta-
ble 2), wherein the most acidic C-3 proton of indole was involved.
Compound 10 is obtained via a conjugate addition product of the
enone formed from 4-hydroxy coumarin and aromatic aldehyde
with indole (Fig. 3).
In summary, we have developed a convenient methodology for
the synthesis of
via a three-component reaction using InCl3 catalyst. This reaction
has been extended to -benzylamino diketone derivatives and rep-
a-benzylamino coumarin derivatives in high yields
a
resents a mild and convenient route.
9. General experimental procedure: To a solution of aldehyde (1 mmol), 4-hydroxy
coumarin (1 mmol), and InCl3 (0.1 mmol) in anhydrous toluene (4 mL),
secondary amine (1 mmol) was added and the reaction mixture was
vigorously stirred at room temperature for 3 h. After the starting materials
disappeared (by TLC) the reaction mixture was quenched by water extracted
with dichloromethane (2 Â 10 mL), dried over anhydrous sodium sulfate.
Evaporation of the solvent under reduced pressure furnished the crude residue
which was triturated in hexane to afford desired product in 80–90% yield.
Acknowledgement
The authors thank the Institute of Life Sciences for its support.
S.K. thanks UGC, New Delhi, for the award of research fellowship.
10. Compound 8a: m.p: 170–172 °C; 1H NMR (400 MHz, CDCl3):
d 7.97 (d,
Supplementary data
J = 7.99 Hz, 1H), 7.64 (d, J = 8.35 Hz, 2H), 7.49–7.44 (m, 1H), 7.31 (d,
J = 8.41 Hz, 2H), 7.23 (d, J = 8.45 Hz, 3H), 5.15 (s, 1H), 3.68–3.62 (m, 1H),
3.18–3.07 (m, 2H), 2.72–2.64 (m, 1H), 2.10–2.0 (m, 4H); 13C NMR (100 MHz,
CDCl3): d 195.4, 167.2, 151.0, 148.5, 143.9, 127.1, 126.3, 125.7, 124.1, 124.1,
123.9, 123.4, 122.7, 122.2, 111.6, 105.5, 60.0, 50.7, 32.7, 30.6; IR (KBr): 3068,
1657, 1456 cmÀ1; ESI (M+): 321.9. Compound 8h: M.P: 132–134 °C; 1H NMR
(400 MHz, CDCl3): d 7.55 (d, J = 6.4 Hz, 2H), 7.32–7.28 (m, 3H), 5.07 (s, 1H),
3.53–3.44 (m, 1H), 2.96–2.90 (m, 2H), 2.57–2.47 (m, 1H), 2.25–2.17 (m, 4H),
2.05–1.87 (m, 4H), 0.99 (s, 6H); 13C NMR (100 MHz, CDCl3): d 174.6, 162.7,
139.2, 129.2, 128.8, 128.2, 127.6, 110.0, 107.6, 69.6, 68.7 (2C), 49.2, 32.4 (2C),
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.07.098.
References and notes
28.6(2C), 23.8, 23.3; IR (KBr): 2952, 1749, 1417 cmÀ1 ESI (M++1): 300.
;
1. (a) Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J.
Tetrahedron 1995, 51, 8135; (b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123; (c) Ramón, D. J.; Yus,
M. Angew. Chem., Int. Ed. 2005, 44, 1602; (d) Dömling, A. Chem. Rev. 2006, 106,
17.
2. (a) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477; (b) Estévez-Braun, A.;
González, A. G. Nat. Prod. Rep. 1997, 14, 465; (c) Lacy, A.; O’Kennedy, R. Curr.
Pharm. Des. 2004, 10, 3797.
Compound 10a: m.p: 110–112 °C; 1H NMR (400 MHz, CDCl3): d 7.91 (brs, 1H),
7.41–7.33 (m, 6H), 7.29 (d, J = 7.16 Hz, 1H), 7.23–7.14 (m, 3H), 6.99 (dd,
J = 11.06, 3.97 Hz, 2H), 6.66 (d, J = 1.40 Hz, 2H), 5.89 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 189.4, 167.8, 144.0, 136.6, 132.4, 128.9, 128.4, 128.4,
127.9, 127.0, 126.3, 125.9, 123.7, 123.5, 122.0, 121.6, 120.1, 119.6, 119.3, 119.0,
111.2, 110.8, 68.2, 40.0; IR (KBr): 3413, 1721, 1454 cmÀ1; ESI (M+): 367.9.