An efficient non-ionic surfactant catalyzed multicomponent synthesis of novel benzylamino coumarin derivative via Mannich type reaction in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2011.06.040

An efficient non-ionic surfactant catalyzed multicomponent synthesis of novel benzylamino coumarin derivatives has been developed from secondary amines, aromatic aldehyde, and 4-hydroxy coumarin via Mannich type reaction in aqueous media. In this Mannich type reaction, surfactant forms stable colloidal medium to stabilize iminium ion which undergoes nucleophilic addition of 4-hydroxy coumarin to give benzylamino coumarin in very good yields.

Full text of DOI:10.1016/j.tetlet.2011.06.040

Tetrahedron Letters 52 (2011) 4521–4525
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An efficient non-ionic surfactant catalyzed multicomponent synthesis of novel
benzylamino coumarin derivative via Mannich type reaction in aqueous media
⇑
Atul Kumar , Maneesh Kumar Gupta, Mukesh Kumar
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient non-ionic surfactant catalyzed multicomponent synthesis of novel benzylamino coumarin
derivatives has been developed from secondary amines, aromatic aldehyde, and 4-hydroxy coumarin
via Mannich type reaction in aqueous media. In this Mannich type reaction, surfactant forms stable col-
loidal medium to stabilize iminium ion which undergoes nucleophilic addition of 4-hydroxy coumarin to
give benzylamino coumarin in very good yields.
Received 8 April 2011
Revised 9 June 2011
Accepted 10 June 2011
Available online 24 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Mannich type reaction
3-Substituted coumarin
Non-ionic surfactant
Water
Green synthesis
Recently, aqueous environment has attracted much attention in
organic synthesis.1 Water exhibits unique reactivity and selectiv-
ity, which cannot be attained in conventional organic solvents.
In recent years, multicomponent reactions (MCRs), involving
three or more reactants in one-pot have been used to synthesize
structurally diverse bioactive heterocyclic compounds.2 The advan-
tages of multicomponent reactions are high atom-economy, struc-
tural diversity, operational simplicity, and lack of waste products in
a multi-step reaction.
compounds,8 we wish to report herein a highly efficient procedure
for the preparation of 3-substituted coumarin derivatives via one
pot three-component Mannich type reaction using non-ionic sur-
factant (Triton X-100) in aqueous media (Scheme 2).
We selected benzaldehyde, 4-hydroxy coumarin, and piperdine
as a model reaction in methanol at room temperature. Surprisingly,
we obtained bis product 5 as a major product whereas, 4 was
formed as a minor product (10% yield). Various solvents were used
to improve the yield of 4 and reduce the formation of 5.
Coumarins and its derivatives are an important class of hetero-
cyclic compounds, which are widely distributed in various natural
products.3 They show wide range of biological activities such as
anti-HIV, antimalarial, insecticides, and antioxidants.4 Among var-
ious derivatives of 4-hydroxy coumarin, 3-(benzyl)-substituted
compounds have been used in important clinical applications
(Fig. 1).5 Therefore, we tried to synthesize 3-(benzyl)-substituted
coumarins via Mannich type reaction.
In non-polar solvents such as dichloromethane, tetrahydrofu-
ran, and acetonitrile, both 5 and 4 were obtained in poor yield.
However, in polar solvents like ethanol, DMF and DMSO, 5 was ob-
tained in higher yield in comparison to 4. When the reaction was
performed in water at room temperature, no product was formed.
On heating the reaction mixture gave 5 in high yield while 4 was
obtained in poor yield. However, when the reaction was carried
out under solvent-free condition at 100 °C, we found that only
product 5 was formed in high yield.
Mannich reaction6 is one of the most powerful synthetic meth-
ods for carbon–carbon bond-forming reactions for the synthesis of
novel nitrogen containing organic molecules.
When benzaldehyde, 4-hydroxy coumarin, and piperdine were
stirred at room temperature using water as solvent and Triton
X-100 (5 mol %) as a surfactant the yield of 4 was improved. How-
In 1953, Robertson and Link reported the Mannich reaction on 4-
hydroxy coumarins.7 They obtained the Mannich base along with
bis coumarin as the major product. This is due to high reactivity
of 3-position of 4-hydroxy coumarins (Scheme 1).
In our preliminary work on multicomponent reactions (MCRs)
for the synthesis of various biologically important heterocyclic
ever, it was found that the amount of Triton X-100 (C14H22
O
(C2H4O)n) where n = 9–10, influenced the yield of 4. Further studies
revealed that on increasing the amount of surfactant, the yield of the
product 4 also increased (Table 1). The best results were obtained
when 20 mol % of catalyst was used (only 4 was formed).
In order to study the effect of surfactant,9 various ionic (cationic
and anionic) and non-ionic surfactants were tested for the reaction
of benzaldehyde, 4-hydroxy coumarin, and piperdine in water, and
⇑
Corresponding author.
E-mail address: dratulsax@gmail.com (A. Kumar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.040

4522
A. Kumar et al. / Tetrahedron Letters 52 (2011) 4521–4525
Br
O
OH
OH
O
O
O
OH
O
O
O
O
OH
Coumatetralyl
Warfarin
Difenacoum
O
OH
OH
O
O
O
O
N
O
O
O
Phenprocoumon
Carbochromen
Bromadialone
Figure 1. Biologically active 3-substituted coumarin.
O
OH
O
OH
OH
O
O
ethanol
N
HCHO
HN
O
HO
O
O
O
Scheme 1. Synthesis of 3-substituted aminomethyl-4-hydroxy coumarin.
R
O
OH
OH
O
OH
R1
R1
Organic solvent
H
HN
O
O
O
R
O
O
2
3
1
5
Water
OH
trtion x-100
R1
R1
N
O
R
O
4
Scheme 2. Synthesis of benzylamino coumarin derivatives catalyzed by surfactant (Triton X-100).
the results are summarized in Table 2. In the presence of SDS, the
desired product was obtained in very low yield (entry 1, Table 2).
Addition of catalytic amount of Lewis acid (boric acid) and
Brønsted acid (p-toluenesulfonic acid, methane sulfonic acid) did
not improve the yield of 4; whereas, p-dodecylbenzenesulfonic
acid (DBSA), which acts both as Brønsted acid and surfactant gave
products 5 and 4.
Scandium tris-(dodecyl sulfate) Sc(DS)3 which acts as Lewis
acid-surfactant-combined catalysts (LASCs)0, and cetyltrimethyl-
ammonium bromide (CTAB) which acts as cationic surfactant were
employed as catalysts for the formation of desired product in water
at room temperature in separate reactions. Unfortunately, 5 was
obtained as major product. A combination of two surfactants Tri-
ton X-100/Sc(DS)3, Triton X-100/CTAB, Triton X-100/DBSA has also
been used during the reaction, but they did not catalyze the reac-
tion efficiently.
Table 1
Effect of solvents on synthesis of benzylamino coumarina
Entry
Solvents
Yield of 5c (%)
Yield of 4c (%)
1
2
3
4
5
6
7
8
9
13
10
11
12
MeOH
EtOH
DCM
THF
ACN
DMF
52
52
20
22
25
50
52
62
80
85
20
8
10
10
8
8
10
12
10
8
9
—
64
78
89
DMSO
MeOHb
Waterb
No solvent
Water/Triton X-100d
Water/Triton X-100e
Water/Triton X-100f
—
a
The reaction was conducted with benzaldehyde (5 mmol), 4-hydroxy coumarin
(5 mmol), and piperdine (5 mmol) at room temperature.
Therefore, Triton X-100 was found to be the best surfactant for
the synthesis of benzylamino coumarin derivatives in water.
With the successful optimization of the synthesis of 3-substi-
tuted coumarin with benzaldehyde, piperidine, and 4-hydroxy-
coumarin we further studied the reactions of different aromatic
b
Reaction was carried out with heating.
Isolated yield.
Triton X-100 (5 mol %).
Triton X-100 (10 mol %).
c
d
e
f
Triton X-100 (20 mol %) in water (10 ml).

A. Kumar et al. / Tetrahedron Letters 52 (2011) 4521–4525
4523
Table 2
aldehydes, secondary amine and 4-hydroxy coumarin under simi-
lar conditions.10 It was found that only 4 was formed without the
formation of bis coumarin (5). The results are shown in Table 3.
The formation of the desired product indicates that surfactants
play an important role to stabilize the imine intermediate which is
formed by aldehyde and secondary amine. Subsequent nucleo-
philic addition of 4-hydroxy coumarin results in the formation of
only one product (4). This imine formation is the most attractive
feature of our reaction in aqueous medium (Scheme 3).
In contrast to the other surfactant/catalysts, Triton X-100 does
not interact with reagent to provide a micelle due to which equilib-
rium position shifts toward the imine side. The water molecules
generated by imine formation, are expelled from the micelle due
to hydrophobic nature of their interior.
Effect of catalyst/surfactant on synthesis of benzylamino coumarina
Entry
Catalyst
Yield of 5b (%)
Yield of 4b (%)
1
2
3
4
5
6
7
8
9
SDS
Boric acid
TsOH
MSA
DBSA
Sc(DS)3
CTAB
Triton X-100
Triton X-100/Sc(DS)3
Triton X-100/CTABc
Triton X-100/DBSAc
60
56
69
65
70
55
60
—
10
8
8
8
12
14
16
89
30
34
28
c
55
60
57
10
11
a
The reaction was conducted with benzaldehyde (5 mmol), 4-hydroxy coumarin
(5 mmol), piperdine (5 mmol) and Triton X-100 (20 mol %) in water (10 ml) at room
temperature for 6 h.
In conclusion, we have demonstrated an easy, efficient, and
green protocol for the synthesis of novel benzylamino coumarin
derivatives in water.11 Non-ionic surfactant (Triton X-100) is a
b
Isolated yield.
10:10 mol % were used.
c
Table 3
Triton X-100 catalyzed synthesis of benzylamino coumarin derivativea
Entry
1
2
3
Productb (4)
Time (h)
6
Yieldc (%)
OH
OH
N
N
H
1
89
O
O
O
4a
O
O
N
OH
N
H
OH
Cl
2
5
92
O
4b
4c
O
O
N
Cl
OH
OH
N
H
3
4
6
5
90
91
O
O
O
O
O
O
N
OH
OH
N
H
Cl
O
O
O
N
Cl
4d
OH
Br
OH
Br
N
H
5
6
7
8
9
5
87
85
85
89
O
O
O
N
4e
OH
NO2
OH
NO2
N
H
4
O
O
O
O
O
O
O
N
4f
OH
O2N
OH
N
H
NO2
4
O
4g
4h
4i
O
O
N
OH
OH
N
H
O
6.5
4
O
O
O
N
O
OH
Cl
OH
Cl
N
H
90
Cl
O
O
O
Cl
(continued on next page)

4524
A. Kumar et al. / Tetrahedron Letters 52 (2011) 4521–4525
Table 3 (continued)
Entry
1
2
3
Productb (4)
Time (h)
5
Yieldc (%)
90
OH
Cl
OH
N
Cl
N
H
10
11
O
O
O
4j
O
O
N
OH
OH
N
H
F
3.5
4.5
93
87
O
O
O
N
F
4k
OH
OH
HN
12
13
O
O
O
O
O
O
4l
NO2
OH
O
OH
O
NO2
HN
HN
3.5
84
90
N
4m
Cl
OH
Cl
OH
O
O
O
14
5
N
O
4n
a
The reaction was conducted with benzaldehyde (5 mmol), 4-hydroxy coumrin (5 mmol), piperdine (5 mmol), and Triton X-100 (20 mol %) in water (10 ml) at room
temperature for given hours.
b
All products were characterized by 1H, 13C NMR, IR and mass spectroscopy.
Isolated yield.
c
References and notes
Hydrophobic interior
CHO
NH
1. (a) Li, C.-J. Chem. Rev. 1993, 93, 2023; [b]Organic Synthesis in Water; Grieco, P. A.,
Ed.; Blacky Academic and Professional: London, 1998.
2. (a) Domling, A. Chem. Rev. 2006, 106, 17–89; (b) Ramón, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2005, 44, 1602–1634; (c)Multicomponent Reactions; Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005.
N
´
3. (a) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477; (b) Estvez-Braun, A.; Gonza
-H2O
OH
lez, A. G. Nat. Prod. Rep. 1997, 14, 465.
4. (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.; Helesbeux, J.-J.;
Seraphin, D.; Sevenet, T.; Richomme, P.; Bruneton, J. J. Nat. Prod. 2001, 64, 563.
5. (a) Hadler, M. R.; Shadbolt, R. S. Nature 1975, 253, 275; (b) Mizuno, T.;
Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N. Synthesis 1988,
257; (c) Clerici, A.; Porta, O. Synthesis 1993, 99; (d) Fiedler, V. B.; Scholtholt, J. J.
Pharmacol. Exp. Ther. 1981, 217, 306–313.
OHN
O
O
O
O
Scheme 3. Micelle-promoted multicomponent synthesis of benzylamino coumarin.
6. (a) Blatt, A. H.; Gross, N. J. Org. Chem. 1964, 29, 3306; (b) Manabe, K.; Kobayashi,
S. Org. Lett. 1999, 1, 1965; (c) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 827–833.
useful surfactant to form a stable colloidal medium which stablises
imine intermediate to accelerate the reaction in water. The advan-
tages of this method are the improvement in the synthesis of ben-
zylamino coumarin derivative without formation of any side
product as seen with the use of organic solvent.
7. Robertson, N. D.; Link, P. K. J. Am. Chem. Soc. 1953, 75, 1883–1885.
8. (a) Kumar, A.; Maurya, A. R. Tetrahedron 2008, 64, 3471–3482; (b) Kumar, A.;
Maurya, A. R. Tetrahedron Lett. 2008, 49, 5471–5474; (c) Kumar, A.; Sharma, S.;
Maurya, A. R. Tetrahedron Lett. 2009, 43, 5937–5940; (d) Kumar, A.; Kumar, M.;
Gupta, M. K. Tetrahedron Lett. 2009, 50, 7024–7027; (e) Kumar, A.; Sharma, S.;
Maurya, A. R.; Sarkar, J. J. Comb. Chem. 2010, 12, 20–24; (f) Kumar, A.;
Srivastava, S.; Gupta, G.; Chaturvedi, V.; Sinha, S.; Srivastava, R. ACS Comb. Sci.
2010, 13, 65–71; (g) Kumar, A.; Gupta, G.; Srivastava, S. J. Comb. Chem. 2010, 12,
458; (h) Kumar, A.; Gupta, M. K.; Kumar, M. Tetrahedron Lett. 2010, 51, 1582.
9. (a) Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72, 1373; (b) Kobayashi, S.;
Wakabayashi, T. Tetrahedron Lett. 1998, 39, 5389; (c) Bhattacharya, A.; Purohit,
C. V. Org. Process Res. Dev. 2003, 7, 254–258; (d) Lipshutz, H. B.; Aguinaldo, T. G.;
Ghorai, S.; Voigtritter, K. Org. Lett. 2008, 10, 1325–1328; (e) Nishikata, T.;
Lipshutz, H. B. Org. Lett. 2009, 11, 2377–2379.
Acknowledgments
M.K.G. and M.K. acknowledge the CSIR-UGC, New Delhi for the
award of SRF. The authors also acknowledge SAIF-CDRI for provid-
ing spectral and analytical data. CDRI communication No. is 8081.
10. General procedure for the synthesis of compound 4. In a typical experiment,
the aldehyde (5 mmol), secondary amine (5 mmol), 4-hydroxy coumarin
Supplementary data
(5 mmol) and Triton X-100 (20 mol %) were taken in water (10 ml) in
a
round-bottom flask. The reaction mixture was vigorously stirred at room
temperature. After the reaction was completed, the solid compound obtained
was filtered off and the crude products were purified by recrystallization from
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.040.

A. Kumar et al. / Tetrahedron Letters 52 (2011) 4521–4525
4525
EtOH. In case of liquid (4n) the reaction mixture was extracted with EtOAc,
322 (M+H). IR (KBr): 3257, 1670, 1624, 1497, 1396, 1219, 1169, 749 cmꢀ1
.
dried over sodium sulfate and evaporated under vacuum. The residue was
purified by silica gel column with hexane/ethyl acetate (2:3) as eluent to afford
the corresponding product.
Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C, 74.67; H, 5.88;
N, 4.28. 4-Hydroxy-3-((3-nitrophenyl)(pyrrolidin-1-yl)methyl)-2H-chromen-2-
one (4g): Yellow solid; mp: 188–190 °C 1H, 300 MHz (CDCl3 + DMSO-d6): d
2.11 (br, 4H), 3.31 (br, 4H), 5.62 (s, 1H), 7.13–7.20 (m, 2H), 7.39–7.56 (m, 2H),
7.99 (d, 1H, J = 7.62 Hz), 8.14 (t, 2H, J = 6.99 Hz), 8.71 (s, 1H). 13C, 50 MHz
(CDCl3 + DMSO-d6): 172.96, 163.02, 153.03, 147.11, 139.28, 133.19, 130.06,
128.75, 123.60, 122.08, 121.67, 121.57, 120.83, 115.13, 92.93, 76.36, 66.74,
52.77, 22.63. ESIMS: m/z 367 (M+H). IR (KBr): 3252, 1670, 1622, 1492, 1390,
1219, 1162, 759 cmꢀ1. Anal. Calcd for C20H18N2O5: C, 65.57; H, 4.95; N, 7.65.
Found: C, 65.48; H, 4.83; N, 7.58. 4-Hydroxy-3-((4-methoxyphenyl)(pyrrolidin-1-
yl)methyl)-2H-chromen-2-one (4h): White solid; mp: 140 °C 1H, 300 MHz
(CDCl3): d 2.07 (br, 4H), 2.72 (br, 1H), 3.13 (br, 2H), 3.61 (br, 1H), 3.76 (s,
3H), 5.15 (s, 1H), 6.82 (br, 2H), 7.21–7.27 (m, 2H), 7.43 (br, 1H), 7.59 (br, 2H),
7.97 (br, 1H). 13C, 50 MHz (CDCl3): 173.31, 163.09, 153.10, 147.07, 139.21,
133.14, 130.09, 128.70, 123.62, 122.11, 121.63, 121.59, 120.81, 115.09, 92.91,
76.32, 66.70, 55.89, 52.72, 22.60. ESIMS: m/z 352 (M+H). IR (KBr): 3251, 1674,
1621, 1500, 1399, 1213, 1161, 754 cmꢀ1. Anal. Calcd for C21H21NO4: C, 71.78;
H, 6.02; N, 3.99. Found: C, 71.65; H, 5.92; N, 3.89. 3-((Dibutylamino)
(phenyl)methyl)-4-hydroxy-6-methyl-2H-pyran-2-one (4l): White solid; mp:
151–152 °C 1H, 300 MHz (CDCl3): d 0.72 (t, 6H, J = 7.2 Hz), 1.15–1.25 (m, 4H),
1.49–1.62 (m, 4H), 2.11 (s, 3H), 2.84 (t, 4H, J = 7.5 Hz), 5.75 (s, 1H), 5.83 (s, 1H)
7.06–7.19 (m, 5H), 13C, 50 MHz (CDCl3): 169.25, 159.69, 128.01, 126.48,
125.58, 106.11, 102.48, 48.04, 35.38, 28.03, 19.73, 19.43, 13.30. ESIMS: m/z 344
(M+H). IR (KBr): 3251, 1668, 1629, 1492, 1389, 1212, 1161, 754 cmꢀ1. Anal.
Calcd for C20H17Cl2NO3: C, 61.55; H, 4.39; N, 3.59. Found: C, 61.48; H, 4.28; N,
3.48.
11. Analytical data for few representative compounds. 4-hydroxy-3-(phenyl
(piperidin-1-yl)methyl)-2H-chromen-2-one(4a): White solid; mp: 182–184 °C
1H, 300 MHz (CDCl3): d 1.64–1.90 (m, 6H), 2.37 (t, 1H, J = 12.36 Hz), 2.78 (t, 1H,
J = 12.03), 2.99 (d, 1H, 12.03), 3.85 (d, 1H, J = 11.94), 5.12 (s, 1H), 7.24 (d,
J = 7.77 Hz), 7.34–7.26 (m, 2H), 7.48–7.43 (m, 1H), 7.61 (m, 2H), 8.01 (d, 1H,
J = 8.43). 13C, 75 MHz (CDCl3): 173.83, 164.20, 154.08, 136.04, 131.28, 129.15,
124.15, 122.98, 120.87, 116.55, 94.84, 76.58, 71.43, 53.85, 50.53, 29.66, 24.35,
23.36, 22.59. ESIMS: m/z 336 (M+H). IR (KBr): 3255, 1671, 1625, 1498, 1393,
1217, 1167, 751 cmꢀ1. Anal. Calcd for C21H21NO3 C, 75.20; H, 6.31; N, 4.18;
Found: C, 75.12; H, 6.23; N, 4.13. 3-((4-Chlorophenyl)(piperidin-1-yl)methyl)-4-
hydroxy-2H-chromen-2-one (4b): White solid; mp: 188–190 °C 1H, 300 MHz
(CDCl3): d 1.69–1.90 (m, 6H), 2.41 (t, 1H, J = 12.20 Hz), 2.80 (t, 1H, J = 12.0 Hz),
3.01(d, 1H, 12.60), 3.84 (d, 1H, J = 11.96 Hz), 5.11 (s, 1H), 7.20–7.32 (m, 5H),
7.43–7.47 (m, 1H), 7.43–7.48 (m, 1H), 7.99 (d, 1H, J = 6.58 Hz).13C, 75 MHz
(CDCl3): 173.55, 164.0, 154.07, 135.13, 134.69, 131.44, 130.44, 129.34, 124.12,
123.08, 120.59, 116.57, 94.84, 70.58, 53.87, 50.56, 40.97, 24.38, 22.58. ESIMS:
m/z 370 (M+H). IR (KBr): 3253, 1673, 1627, 1494, 1392, 1213, 1164, 754 cmꢀ1
.
Anal. Calcd for C21H20ClNO3: C, 68.20; H, 5.45; N, 3.79. Found: C, 68.11; H, 5.38;
N, 3.63. 4-Hydroxy-3-(phenyl(pyrrolidin-1-yl)methyl)-2H-chromen-2-one (4c):
White solid; mp: 170–172 °C 1H, 300 MHz (CDCl3): d 2.08 (br, 4H), 2.72 (br,
1H), 3.14 (br, 2H) 3.64 (br, 1H), 5.20 (s, 1H), 7.19–7.26 (m, 2H), 7.30–7.33 (m,
3H), 7.41–7.46 (m, 1H), 7.68–7.71(m, 2H), 7.99 (d, 1H, J = 7.71 Hz). 13C, 50 MHz
(CDCl3): 173.85, 164.03, 154.08, 137.73, 131.23, 129.02, 128.96, 128.25,
124.07, 122.94, 121.10, 116.48, 95.49, 75.14, 70.55, 23.72, 23.28. ESIMS: m/z