P -TsOH-promoted synthesis of (E)-6-phenyl-7-styryl-5,6-dihydrodibenzo [b, h] [1,6]naphthyridines via cascade intramolecular aza-Michael addition/Friedlander condensation of 2′-aminochalcones in a SDS/H2O system

Article abstract of DOI:10.1039/c6ra04837d

Br?nsted acid-promoted cascade synthesis of novel (E)-6-phenyl-7-styryl-5,6-dihydrodibenzo[b,h][1,6]naphthyridines has been achieved via homodimerization of 2′-aminochalcones by employing sodium dodecylsulphate (SDS) as a surfactant in water. Besides water as an environmentally benign reaction medium, the reaction proceeds smoothly with high atom-economy under a sequential one-pot protocol.

Full text of DOI:10.1039/c6ra04837d

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DOI: 10.1039/C6RA04837D
Journal Name
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Received 00th
January 20xx,
p-TsOH-promoted synthesis of (E)-6-phenyl-7-styryl-5,6-
dihydrodibenzo[b,h][1,6]naphthyridines via cascade
intramolecular aza-Michael addition/Friedlander condensation of
2'-aminochalcones in a SDS/H2O system
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Makthala Ravi,a‡ Parul Chauhan,a‡ Shikha Singh,a Ruchir Kant b and Prem. P. Yadav*a
Brønsted acid-promoted cascade synthesis of novel (E)-6-phenyl-7-styryl-
Dependensin, an antiplasmodial natural product isolated
5,6-dihydrodibenzo[b,h][1,6]naphthyridines has been achieved via from Uvaria dependens and related antiparasitic dimeric
homodimerization of 2'-aminochalcones by employing sodium flavonoids isolated from Arrabidaea brachypoda are densely
dodecylsulphate (SDS) as
a surfactant in water. Besides water as functionalized fused benzopyranes bearing four stereocenters
environmentally benign reaction media, the reactions proceeds smoothly and one trans double bond (Scheme 1).6 Additionally, 1,6-
with high atom-economy under sequential one-pot protocol.
naphthyridines have been shown to be potent as HIV-1
integrase inhibitors,7 anticancer8 and antimalarial agents.9 The
extended benzenoid core of dibenzo[b,h][1,6]naphthyridine is
also an important class of fluorophore and reported as DNA
intercalating agents.10 In view of the medicinal and fluorescent
properties of 1,6-naphthyridines, the development of
sustainable and green methodologies towards the synthesis of
dibenzo[b,h][1,6]naphthyridines is highly desirable. Herein, for
the first time, a new route for the synthesis of aza-analogues
of dimeric flavonoids via Brønsted acid-promoted
homodimerization of 2'-aminochalcones in an aqueous
micellar (SDS/H2O) system is reported.
Bioactive natural products and natural product-inspired
molecules have played a pivotal role in the drug discovery
research.1 The synthesis of natural and unnatural complex
molecules generally involves a large number of synthetic steps
using various hazardous organic solvents and reagents, apart
from extraction and purification processes in each step. This
leads to a large amount of waste that increases the overall
cost. Designing cascade sequences to accomplish target-
oriented syntheses of structurally complex natural products
has remained a major challenge in the art of total synthesis.2
From the standpoint of green and sustainable approach,
the development of synthetic processes for the construction of
privileged scaffolds with high atom economy in water rather
than organic solvents is eco-friendly and economical.3 In
addition, being an ideal green solvent, water can also
accelerate organic reactions such as Michael additions,
intramolecular cyclizations, rearrangements and nucleophilic
substitutions due to its unique reactivity and selectivity at
elevated temperature.4 However, the use of aqueous reaction
media is often limited due to the poor solubility of organic
compounds in water. This can be overcome by the use of
Scheme 1 Dimeric flavonoids.
As a part of our ongoing efforts towards the development
of ecofriendly methods for the synthesis of novel bioactive
heterocycles,11 we became interested in natural product
surfactants as solubilizing agents via
a
spontaneous
aggregation in water to form a reactive micellar system having
a hydrophobic core and hydrophilic corona.5
inspired
synthesis
of
(E)-6-phenyl-7-styryl-5,6-
dihydrodibenzo[b,h][1,6]naphthyridines in a one-pot reaction
under aqueous conditions. The reported method for the total
synthesis of dependensin involved an acid-promoted ring
opening of flavene to a stable benzyl carbocation, which upon
further cyclization with another flavene molecule delivered the
homodimerized compound (Scheme 2).12 Based on the above
analysis and literature reports for the cascade synthesis of
a.Division of Medicinal and Process Chemistry, CSIR-Central Drug Research
Institute, Lucknow-226031, India. Fax: +91-522-2623405/2623938; Tel: :+91-522-
2612411-18, Ext. 4761/4762; E-mail: pp_yadav@cdri.res.in:
ppy_cdri@yahoo.co.in
b.Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute,
Lucknow-226031, India
† Electronic Supplementary Information (ESI) available: Experimental procedures,
compound characterization, X-ray crystal structure data and ORTEP drawing for 4i and
2s; copies of NMR spectra of all the final compounds. For ESI and crystallographic data
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
in CIF see DOI: 10.1039/b000000x/
‡These authors contributed equally.
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dibenzo[b,h][1,6]naphthyridines from a 2'-amino-substituted precipitated solid without any further work up, however,
View Article Online
carbonyl precursor,10,13 we speculated that 2'-aminochalcones column chromatography was required DtOoI:a10c.h10ie3v9e/C6aRnAa0l4y8ti3c7aDl
may undergo homodimerization via an intramolecular aza- purity. Next, the experiment was carried out at room
Michael addition in the presence of an acid to give aza- temperature and 60 °C; no product formation was observed
flavanone, which may subsequently react with another 2'- under either of these conditions (Table 1, entries 8 and 9).
aminochalcone under the same acidic conditions to finally Encouraged by these results, a variety of Brønsted acids and
deliver the homodimerized product.
Lewis acids were screened based on their ability to promote
the Friedlander condensation17,18 (Table 1, entries 10-16).
Among the tested acids TfOH and InCl3 provided
homodimerized product 2a in 60% and 67% yields respectively
(Table 1, entries 13 and 15). However, p-TsOH produced the
best yield of 2a (Table 1, entry 5). Also, various anionic, non-
ionic and cationic surfactants (see the SI, Table 1, entries 17-
21) such as SLS, PF-127, Tween 80, Triton-X100 and TBAI were
screened with varying results.
Table 1 Optimization of reaction conditionsa
Reagent
(equiv)
Surfactant Reaction media
Yieldb
3a
Entry
SDS (20
mol%)
2a
1c
2c
3
p-TsOH (3)
p-TsOH (1)
p-TsOH (3)
p-TsOH (1)
p-TsOH (1)
p-TsOH (1)
p-TsOH (0.5)
p-TsOH (1)
p-TsOH (1)
TFA (1)
-
-
Ethanol
Ethanol
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
76
68
64
10
78
55
42
-
-
20
-
52
60
46
20
18
24
10
20
18
24
15
17
30
25
35
33
20
Scheme 2 Key analysis for acid-promoted homodimerized molecules.
-
4
-
To test this hypothesis initially, the starting material 2'-
aminochalcone was synthesized from 2'-aminoacetophenone
and benzaldehyde in the presence of base in ethanol.14 The
hypothesis was actualized when 2'-aminochalcone 1a was
treated with 3 equiv. of p-toluenesulfonic acid (p-TsOH) in
EtOH at 80 °C for 4h. The reaction proceeded well to yield 76%
of homodimerized product 2a and 20% of aza-flavanone 3a
(Table 1, entry 1). However, 1 equivalent of p-toluenesulfonic
acid in EtOH at 80 °C delivered the desired product 2a in 68%
yield (Table 1, entry 2). Based on the compatibility of Bronsted
acids with aqueous solutions and the feasibility of cyclization
reaction in water15, the reaction was attemped in aqueous
medium with 3 equiv of p-TsOH at 100 °C for 4h, which
afforded homodimerized product 2a in 64% yield (Table 1,
entry 3). Delighted with this result, the reaction was
performed with 1 equiv of p-TsOH, which drastically reduced
the yield of 2a to 10% (Table 1, entry 4), which may be due to
the poor solubility of the substrate. To overcome the solubility
issue and the possibility of dehydration reactions in the
presence of surfactants,16 the reaction with 20 mol% of
sodium dodecyl sulfate (SDS) and 1 equiv. of p-TsOH in water
was performed at 100 °C for 4h. The reaction proceeded
smoothly and afforded 78% of homodimerized product 2a and
20% of aza-flavanone 3a (Table 1, entry 5), Decreasing the
amount of SDS to 10 mol% and p-TsOH to 0.5 equiv. reduced
the yield to 55% and 42%, respectively (Table 1, entries 6 and
7). It is noteworthy that the product can be obtained as
5
6d
7
8e
9f
10
11
12
13
14
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
AcOH (1)
MeSO3H (1)
TfOH (1)
FeCl3 (1)
15
16
InCl3 (1)
I2 (1)
SDS
SDS
Water
Water
67
15
25
51
aReaction conditions: 1a (1.0 mmol), reagent (1.0 mmol), surfactant (20 mol%),
reaction media (10 mL) at 100 °C. bIsolated yields, cAt 80 °C, d10 mol% of SDS was
used. eAt room temperature. At 60 °C.
f
Among the screened surfactants (see the SI, Table 1,
entries 17 and 20), only SLS and Triton-X100 provided >70%
yield of homodimerized product 2a and other surfactants did
not provide a satisfactory result in comparison to SDS (Table 1,
entries 17-21 vs entry 5, see the supporting Information).
Further solvent optimization with protic solvents such as
methanol and isopropanol delivered the homodimerized
product 2a in 60% and 30% yields respectively (Table 1, entries
22 and 23, see the supporting Information), however, aprotic
solvents such as acetonitrile and toluene were ineffective for
homodimerization, but produced aza-flavanone 3a exclusively
(Table 1, entries 24 and 25, see the supporting information).
2 | J. Name., 2012, 00, 1-3
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Table 2 Scope of homodimerization of 2'-aminochalconesa
Using optimized reaction conditions, the scope and
generality were further investigated. The reactions of 2
View Article Online
DOI: 10.1039/C6RA04837D
'
-
aminochalcones bearing electron withdrawing groups such as
chloro, bromo, fluoro, 2,4-dichloro, 3,4-dichloro, 2,5-dibromo,
nitro and cyano, afforded the corresponding homodimerized
products in moderate to good yields (Table 2, products 2a-2n).
2'-Aminochalcones bearing electron donating groups such as
methyl and methoxy on the phenyl ring and furyl substituted
2'-aminochalcone produced homodimerized products, albeit in
low yields (Table 2, products 2p-2r). The lower yields in cases
with electron donating groups may result from a decrease in
the electrophilicity at the carbonyl carbon, which is
unfavourable for the Friedlander condensation.
The
synthesized
(E)-6-phenyl-7-styryl-5,6-
dihydrodibenzo[b,h][1,6]naphthyridines were further oxidized
to (E)-6-phenyl-7-styryldibenzo[b,h][1,6]naphthyridines in the
presence of DDQ in DCM for 5-10 min at room temperature.
The reaction proceeded smoothly and provided excellent
yields of the corresponding oxidized products (Scheme 3). The
structure of oxidized product 4i was unambiguously confirmed
by X-ray analysis (CCDC 1025096, see the SI).
Scheme 3 Oxidation of homodimerized compounds.
To prove that the exact mechanism involved aza-flavanone
formation followed by Friedlander condensation, an
experiment was conducted with aza-flavanone (3a) and 2'-
aminochalcone 1l under the optimized conditions. The
reaction afforded desired Friedlander condensation product 2s
in 50% yield along with 30% of the homodimerized product 2l
(Scheme 4). The structure of 2s was unambiguously confirmed
by X-ray analysis (CCDC 1058218, see the SI).
aReaction conditions: 1 (1.0 mmol), p-TsOH (1.0 mmol), SDS (0.2 mmol), H2O (10
mL) at 100 °C, time and isolated yields are given, c (E)-1-(2-aminophenyl)-3-
(furan-2-yl)prop-2-en-1-one was used.
Based on our experimental results and literature
reports,17,18 we proposed
a
plausible mechanism for
homodimerization as shown in (scheme 5). 2 -Aminochalcone
] undergoes an intramolecular aza-Michael addition in the
presence of acid to form aza-flavanone ], which
subsequently reacts with another molecule of
aminochalcone in the presence of acid via a Friedlander
condensation to afford homodimerized product [ ].
'
[
A
[
B
2'-
Scheme 4 Control experiment.
C
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Khodaei and A. Nejati, Green Chem., 2010, 12, 1237; (d) M.
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6
7
Scheme 5 Plausible mechanism.
In conclusion, we have developed an efficient and
straightforward methodology for the synthesis of (E)-6-phenyl-
7-styryl-5,6-dihydrodibenzo[b,h][1,6]naphthyridines
in
aqueous media by using SDS as a surfactant with good yields.
This methodology offered a sequential one-pot synthetic
operation with high atom economy, under greener conditions,
using water as the medium and no workup with organic
solvent. Application of the present methodology towards
exploration of unique cascade sequences is under progress.
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Singh, K. S. R. Raju, V. Bajpai, B. Kumar, Wahajuddin and P. P.
Acknowledgements
M.R., P.C. and S.S. are thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi, for Fellowship. Mr. A. K.
Srivastava for providing technical support and SAIF-CDRI,
Lucknow for providing spectral and analytical data. This work
was supported by CSIR network project “HOPE” (BSC0114). We
thank Dr. Tejender S. Thakur of the Molecular and Structural
Biology Division, CSIR-Central Drug Research Institute (CDRI)
for supervising the X-ray data collection and structure
determination of our compound reported in this paper. This is
CDRI communication No. xxxx.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA04837D
p-TsOH-promoted
dihydrodibenzo[b,h][1,6]naphthyridines
synthesis
of
(E)-6-phenyl-7-styryl-5,6-
via cascade
intramolecular aza-Michael addition/Friedlander condensation of
2'-aminochalcones in a SDS/H2O system
Makthala Ravi, Parul Chauhan, Shikha Singh, Ruchir Kant and Prem. P. Yadav
MeO
OMe
OMe
Friedlander
condensation
aza-Michael
addition
OMe
OMe
N
O
H
O
MeO
NH
R
H
H
O
p-TsOH (1 equiv.)
SDS (20 mol%)
H2O, 100 °C, 3-5 h
NH2
H
R
.Water as solvent
.Highly atom-economic
.2 C-N and 1 C-C bond formation in a single step
R
19 examples,
24-78% yield
Natural product "Dependensin''
p-TsOH-promoted one-pot cascade synthesis of novel (E)-6-phenyl-7-styryl-5,6-
dihydrodibenzo[b,h][1,6]naphthyridines via homodimerization of 2'-aminochalcones has
been developed in a SDS/H2O system.