Pseudo-five-component domino strategy for the combinatorial library synthesis of [1,6] naphthyridines - An on-water approach

Article abstract of DOI:10.1021/co400162m

This work features the base-promoted on-water synthesis of [1,6]-naphthyridines from methyl ketones, malononitrile and phenols or thiols. The reaction conditions were carefully tuned to drive the product selectivity from 3H-pyrroles to [1,6]-naphthyridines. The advantages of this method lie in its simplicity, cost effectiveness, and environmental friendliness, representing a new effort toward the on-water synthesis of [1,6]-naphthyridines without starting from a nitrogen-containing heterocycle and highlighting the versatility of the nitrile functional group.

Full text of DOI:10.1021/co400162m

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Article
Pseudo Five-component Domino Strategy for the Combinatorial
Library Synthesis of [1,6] Naphthyridines - An On Water Approach
Paramita Das, Tandrima Chaudhuri, and Chhanda Mukhopadhyay
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co400162m • Publication Date (Web): 14 Oct 2014
Downloaded from http://pubs.acs.org on October 17, 2014
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Pseudo Five-component Domino Strategy for the
Combinatorial Library Synthesis of [1,6]
Naphthyridines - An On Water Approach
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Paramita Das,a Tandrima Chaudhurib and Chhanda Mukhopadhyaya,*
aDepartment of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India
bDepartment of Chemistry, Dr. Bhupendranath Dutta Smriti Mahavidyalaya, Hatgobindapur,
Burdwan 713407, India
Keywords: on water, 1,6-naphthyridines, hydrophobic aggregation, selectivity
Abstract: This work features the base-promoted on water synthesis of [1,6]-naphthyridines from
methyl ketones, malononitrile and phenols or thiols. The reaction conditions were carefully tuned
to drive the product selectivity from 3H-pyrroles to [1,6]-naphthyridines. The advantages of this
method lie in its simplicity, cost effectiveness, and environmental friendliness, representing a
new effort towards the on water synthesis of [1,6]-naphthyridines without starting from a
nitrogen-containing heterocycle and highlighting the versatility of the nitrile functional group.
INTRODUCTION
Multicomponent reactions (MCRs)1a,b provide effective tools for combinatorial synthetic
chemistry because highly diverse compound libraries can be prepared via convenient one-pot
procedures. Attention is often focused on natural product scaffolds and drug-like molecules,1c
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with particular emphasis on heterocyclic compounds.1d,e As a consequence, multicomponent
reactions and related domino reactions have received much recent attention.1f
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Water is known to enhance the rates and to affect the selectivity of a wide variety of organic
reactions.2 Even when rate accelerations are modest, water provides advantages of large heat
capacity, making exothermic processes safer and more selective, and easily isolation of organic
compounds.
Functionalized [1,6]-naphthyridines and their benzo/hetero-fused analogues have attracted
much attention from synthetic and medicinal view points.3 Naphthyridine derivatives are widely
used for various pharmacological purposes (Figure 1) such as antiproliferative activity,4 HIV-1
integrase inhibition,5 allosteric inhibition of Akt1 and Akt2,6 and selective antagonism of 5-HT4
receptors.7
The majority of the synthetic strategies toward these units8 have relied on condensation of 2-
amino pyridine derivatives with carbonyl compounds containing an active methylene group or
with β-keto esters.9 Transition metal mediated cyclotrimerisation of dialkynyl nitriles has also
been recognized as a general method toward [1,6]-naphthyridines10 in addition to the common
approach of Lewis acid catalysis of intramolecular hetero Diels-Alder reactions of aldimines.11
Many of these methods suffer from the use of multistep sequences, expensive catalysts,12
hazardous organic solvents, inert atmosphere, lengthy reaction time, and laborious workup.13
Moreover, there are only a few reports of the simple and convenient synthesis of this moiety
from readily available and inexpensive starting materials.14,15
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R
N
N
O
OR'
N
N
N
N
N
O
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H
OR''
R
Aaptamine (R = H, R' = Me, R'' = Me)
Isoaaptamine (R = Me, R' = H, R'' = Me)
Demethylaaptamine (R = H, R' = H, R'' = Me)
8,9-demethylaaptamine (R = H, R' = H, R'' = H)
N
1,6-Naphthyridine:
HCMV-inhivitors
(R = OMe)
OH
labuanine A:
Neuronal Differentiation
inducers
Marine Natural Products
Figure 1. Examples of biologically active 1,6-naphthyridines.
RESULTS AND DISCUSSION
We explored the use of phenols and thiols as synthon for an unprecedented coupling with
methyl ketones and malononitrile to create highly substituted [1,6]-naphthyridines (Scheme 1).
In previous work,15 we have used ketones, malononitrile and aliphatic amines for the synthesis of
[1,6]-naphthyridines. While no base other than the reactant amine was required, the method
reported here needs an additional base catalyst. Scheme 2 shows the use of triethylamine as
catalysis for a one-pot, pseudo-five-component synthesis of 1,2-dihydro[1,6]-naphthyridines
from ketones, malononitrile and phenols in the ecofriendly solvent water. The products were
well characterized by H NMR, 13C NMR, 2D NMR, FTIR, elemental analysis, melting point
1
determination, and X-ray crystallographic analysis.
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Scheme 1. Previous15 and present approaches to substituted [1,6]-napthylpyridines.
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Our previous work
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H
N
R
NH2
N
O
H
H2O (2 mL), 3 h
reflux
R
CH3
NC CN
H3C
N
H
N
R
R = aryl, alkyl
2 mmol
CN
2 mmol
1 mmol
Our present work
R
NH2
N
O
Et3N (0.2 mmol)
H
OH
R5
NC CN
2 mmol
R
CH3
H3C
H2O (2 mL), 4 h
reflux
N
H
O
R = aryl, alkyl
2 mmol
R
R5
CN
1 mmol
R5 = H, alkyl, aryl
R
R
NH2
N
O
N
H
1 h, reflux
Et3N (0.2 mmol)
C
H
H
NC CN
CH3
R
N
H3C
H2O (2 mL), 4 h
reflux
R
C
SH
R6
N
N
H
S
R
R6
H3C
H
R = aryl, alkyl
2 mmol 2 mmol
C
N
CN
R6 = H, alkyl, aryl
1 mmol
Scheme 2. Pseudo-five component synthesis of [1,6]-naphthyridines
R
NH2
N
XH
O
Et3N (0.2 mmol)
H
NC CN
R
CH3
H3C
H2O (2 mL), 4 h
reflux
N
H
X
R
R1
3 (X=O)
1 mmol
R1
CN
4 (X=O)
1
2
2 mmol
30 Examples
2 mmol
Optimization of Reaction Conditions
To optimize the reaction conditions, a series of experiments were conducted with a
representative reaction of 4-chloro acetophenone (1{1}) (2 mmol), malononitrile (2{1}) (2 mmol)
and 4-tert-butyl-phenol (3{10}) (1 mmol) with variation of reaction parameters. The results,
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summarized in Table 1, showed that the nature of the catalyst and the reaction temperature had a
significant effect on the yield of the desired [1,6]-naphthyridines (4{1,1,10}) and 7-hydroxy-
[1,6]-naphthyridines (5{1,1}). Sodium hydroxide was ineffective, at both low and high
temperatures (Table 1, entries 1 and 2). In the latter case (100 °C), an unexpected compound
5{1,1} was isolated in 10% yield, presumably by nucleophilic attack of hydroxide in competition
with phenoxide. Therefore, the use of a higher concentration of NaOH as base catalyst gave
significant improvements in the yield of the 7-hydroxy compound 5{1,1}, isolated in greater
proportions relative to naphthyridine (4{1,1,10}) as the temperature was lowered (Table 1,
entries 3-5). No product was observed when a background reaction was carried out with no
catalyst (entry 6).
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Table 1. Optimization of Reaction Conditions for the Multicomponent Coupling Reactionsa
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Cl
Cl
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O
CH3
NH2
N
OH
NH2
N
H
conditions
catalyst
H
NC CN
H3C
H3C
N
H
O
N
H
OH
CN
CN
Cl
1{1}
2 mmol
Cl
2{1}
3{10}
Cl
5{1,1}
4{1,1,10}
2 mmol
1 mmol
amount
entry catalyst (mmol) solvent
temp (°C) time (h)
yield (%)b
4{1,1,10} 5{1,1}
1
2
NaOH
NaOH
NaOH
NaOH
NaOH
-
0.2
0.2
1.0
1.0
1.0
-
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMSO
DMF
35
100
12
3
0
0
10
40
55
65
-
15
20
25
15
-
3
100
3
4
80
3.5
4
5
70
6
100
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4
7
K2CO3
guanidine
DBU
Et3N
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
100
30
84
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41
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0
8
100
4
9
100
4
0
10
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100
4
0
Et3N
60
8
0
pyridine
Et3N
100
4
0
120-130
120-130
8
0
Et3N
8
0
Et3N
Toluene 100-110
8
0
Et3N
ACN
EtOH
MeOH
70-80
70-80
50-60
10
10
12
0
Et3N
0
Et3N
0
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Et3N
0.2
DCM
30-35
12
10
0
8
9
aReaction conditions: 4-chloro acetophenone (2 mmol), malononitrile (2 mmol), 4-tert-butyl-
phenol (1 mmol), different solvents (2 mL), different catalysts, different temperatures, different
times. bIsolated yields.
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To prevent the intrusion of the 7-hydroxycompound (5{1,1}) and to acquire the desired
[1,6]-naphthyridine (4{1,1,10}) under environmentally benevolent conditions, we tested a panel
of organic bases. Guanidine and DBU provided only the desired [1,6]-naphthyridine (4{1,1,10}),
but yields were found to be slightly better with pyridine and Et3N at 100 °C (Table 1, entries 8-
12). Here, the weaker bases may induce less polymerization of the ketone as a competitive
side reaction, leading to higher yields. Triethylamine was chosen as the catalyst for further
tests of solvent effects. Interestingly, isolated yields were found to be comparatively low in
common high boiling organic solvents such as DMSO, DMF, and toluene (entries 13-15),
due mainly to difficulties in isolation. Also prolonged times were required for reaction
completion in these mixtures. Lower-boiling solvents (acetonitrile, EtOH, MeOH, DCM) did
not allow the required high temperatures with standard glassware, and afforded poor
yields of 4{1,1,10} (Table 1, entries 16-19). Thus, the best yield, cleanest reaction, and most
facile workup were achieved in water as a solvent employing 0.2 mmol Et3N (Table 1, entries
10).
Substrate scope
Various methyl ketones, phenols, and malononitrile were tested with the optimized reaction
conditions, giving 30 variants using this protocol (Figure 2, Table 2). Both aliphatic alcohols and
phenols afforded excellent yields, the latter tolerating both electron-withdrawing and electron-
donating substituents on the aromatic ring. Acid-sensitive (containing hydroxy groups) and
sterically bulky alcohol phenols (β-naphthol, α-naphthol) also reacted very efficiently with no
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side products. Therefore, the present protocol has general applicability, accommodating a variety
of substitution patterns.
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Good diversity in the ketone component was also tolerated. Especially noteworthy was the
successful
use
of
electron-rich
ketones
[4'-methoxyacetophenone
and
3',4'-
dimethoxyacetophenone], considering the difficulty usually associated with Knoevenagel
condensation reactions of these substrates (Table 2, 4{4,1,2}-4{5,1,10}). Sterically bulky 2-
acetylfluorene was readily converted into the desired product (4{6,1,10}), and aliphatic ketones
were also examined (4{7,1,1}). To further expand the scope of the reaction the use of heteroaryl
methyl ketones was investigated (4{2,1,1}-4{2,1,10}). Steric considerations seem to have limited
the process in one case (4{7,1,1}), in which the methyl ketone, but no other ketone, gave good
yield, perhaps because of crowding in intermediate 10 (Scheme 3). A representative structure
was confirmed by X-ray crystallographic analysis of compound (4{1,1,11}) (CCDC 926217)
(Table 2).
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R
NH2
N
O
H
Et3N (0.2 mmol)
OH
NC CN
R
CH3
R5
H3C
H2O (2 mL), 4 h
reflux, 100 0C
N
H
O
R
R5
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11
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CN
2{1}
3{1-11}
1{1-7}
2 mmol
2 mmol
1 mmol
4{1{1-7},2{1},3{1-11}}
OH
O
O
O
OH
OH
OH
S
OH
CH3
CH3
1{3}
CH3
1{1}
1{2}
Cl
Cl
3{1}
3{2}
OH
3{3}
O
3{4}
O
H3CO
H3CO
OH
OH
OH
CH3
CH3
1{5}
CH3
1{4}
H3CO
OH
3{7}
3{8}
3{6}
3{5}
OH
OH
CH3
O
O
CH2OH
OH
OH
OH
CH3
CH3
1{6}
1{7}
Chemset 1
CH3
3{9}
3{13}
3{11}
O2N
3{12}
NC CN
2{1}
3{10}
Chemset 2
Chemset 3
Figure 2. Components used for the synthesis of [1,6]-naphthyridines.
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Table 2. Synthesized [1,6]-naphthyridines and ORTEP representation of 4{1,1,11} (CCDC
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926217).
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Structure
R5OH Product Yield
(%)
3{1}
3{2}
3{3}
3{4}
3{5}
3{6}
3{7}
3{8}
3{9}
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,1,6}
4{1,1,7}
4{1,1,8}
4{1,1,9}
94
89
91
91
89
90
93
92
92
94
93
92
88
Cl
NH2
H
CH3
N
R5
N
H
O
CN
Cl
3{10} 4{1,1,10}
3{11} 4{1,1,11}
3{12} 4{1,1,12}
3{13} 4{1,1,13}
4{1,1,11} (CC
D
C 926217)
Structure
R5O
HH Product Yield
(%)
OMe
OMe
3{1}
3{2}
3{3}
3{4}
3{7}
3{8}
3{9}
4{2,1,1}
4{2,1,2}
4{2,1,3}
4{2,1,4}
4{2,1,7}
4{2,1,8}
4{2,1,9}
92
91
91
92
93
93
90
93
S
NH2
NH2
N
3{1}
3{10}
H
H
4{5,1,1}
4{5,1,10}
92
93
N
R5
CH3
R5
H3C
N
H
O
N
H
O
CN
CN
S
MeO
OMe
3{10} 4{2,1,10}
NH2
3{1}
3{10} 4{3,1,10}
4{3,1,1}
93
94
H
H3C
NH2
N
N
H
R5
3{10}
4{6,1,10}
93
N
H
O
H3C
R5
CN
N
H
O
CN
OCH3
3{2}
4{4,1,2}
3{10} 4{4,1,10}
3{11} 4{4,1,11}
91
94
93
NH2
N
H
R5
H3C
N
H
O
CN
H3CO
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A plausible mechanism for the multicomponent condensation process is shown in Scheme 3.
Initial Knoevenagel condensation of the carbonyl compound with malononitrile in the presence
of a base15,16 was supported by NMR observation of the resulting product [(7), (R = 4'-Cl-C6H4-)]
isolated after 30 min. This intermediate (7) is proposed to undergo Michael-type reaction with
another molecule of 7, with subsequent malonitrile elimination to form intermediate 10. Another
attack of malononitrile triggers ring closure to yield intermediate 11, which tautomerises to give
12. Though we could not isolate the intermediate 10, structures 12{1,1} and 12{2,1} were
characterized by X-ray analysis (Figure 3a,b). Finally the second ring is produced by attack of
phenols on the electrophilic nitrile group in intermediate 12, driven by aromatization in the target
compound.
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Scheme 3. A plausible mechanism for the formation of [1,6]-naphthyridines.
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Et
O
Et
N
Et
Et
H
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Et
Et
R
NC
R
C
OH
CH3
N
..
N
-H+/+H+
N
..
R
CH3
C
CN
R
NC
NC
NC
NC
NC
NC
1
H
CH2
H
+H+
H
-H+/+H+
H2C
. .
-H2O
7
8
N
2
6
Et
Et
Et
NC
R
CN
-H+/+H+
CH3
7
Et
N
Et
Et
R
R
N
N
NC
R
CN
-H+/+H+
-H+/+H+
NC
CN
CN
H
R
C
H
R
C
R
H
CN
H
C
C
CH
9
CH3
H
CN
CN
CN
CN
CH3
10
CH3
N
N
H
..
N
Et
Et
Et
R'
XH
3
R
Et3N
R
R
NH
N
H
N
H
H
-H+/+H+
H
H
C
C
H
N
N
N
H3C
R
C
R
C
C
X
N
H
12
N
N
H
X
R
H3C
H3C
C
N
CN
H
N
11
R'
R'
-H+/+H+
R
NH2
N
H
H3C
N
H
4
X
R
CN
R'
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(b)
(a)
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12{1,1}
12{2,1}
Figure 3. (a) ORTEP representation of intermediate 12{1,1} (CCDC 926218). (b) 12{2,1}
(CCDC 926219).
Thus the present reaction comprises a relay processes of the following domino sequences:
(1) two-component Knoevenagel reaction, (2) two-component Michael-type reaction followed by
elimination, (3) two-component ring closure, and (4) two-component cyclization aromatization
process (Scheme 3). This pathway was examined by DFT calculations,17 in which the proposed
transition structures were identified (see Supporting Information, Fig S1-S6). All the optimized
geometries of reactants, products and corresponding TS are shown in energy profile diagrams in
Supporting Information (Fig S7), which identify reasonable “downhill” energetics for the
intermediates.
Rationale of rate acceleration in water
Even though Knoevenagel condensations accomplish a net dehydration event, the reaction
described here is favored in an aqueous medium. Both a standard hydrophobic effect (i.e., the
propensity of hydrophobic molecules to associate in order to minimize their contact surface with
water, leading to effective concentration of the reactants18
) and an “on-water” effect (in which
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OH groups at oil-water phase boundary can then play an important role in catalyzing reactions
via the formation of hydrogen bonds) can be proposed.
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Table 1 shows much faster and higher yielding reactions using the same catalyst and reactants
in water (entry 10) than in organic other solvents (entries 13-19). Since the aqueous reaction
mixture remains heterogeneous throughout the course of reaction, this qualifies as an on water
synthesis.
The replacement of phenols with thiols gave the anticipated thiol-substituted [1,6]
naphthyridines (Figure 4, Table 3). Both aromatic and aliphatic thiols afforded excellent yields,
including those with electron-withdrawing as well as electron-donating groups. Sterically bulky
naphthalene-2-thiol also reacted very efficiently (19{1,1,6}, 19{2,1,6}and 19{3,1,6}). We have
confirmed the structure of compound (19{4,1,1}) unambiguously by X-ray crystallographic
analysis (CCDC 956062) (Table 3).
R
R
NH2
N
O
N
C
H
1 h, reflux
Et3N (0.2 mmol)
C
H
H
NC CN
CH3
R
N
H3C
H2O (2 mL), 4 h
reflux
R
SH
R6
N
H
N
H
S
R
R6
H3C
C
N
CN
1{1-7}
2{1}
2 mmol
2 mmol
14{1-8}
1 mmol
19{1{1-7},2{1},14{1-11}}
12{1{1-7},2{1}}
25 Examples
SH
SH
Cl
SH
SH
14{3}
14{2}
14{1}
14{4}
Cl
H3C
SH
SH
SH
SH
14{7}
14{8}
14{6}
14{5}
Chemset 14
Figure 4. Components used for the synthesis of thiol-substituted naphthyridines.
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Table 3. Naphthyridines synthesized with thiol nucleophiles; ORTEP repr
(CCDC 956062).
eesentation of 19{4,1,1}
10
11
12
13
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18
19
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Structure
R6SH Product
Yield
(%)
93
93
95
Structure
R6S
H
Product
Yield
(%)
90
91
89
Cl
OMe
OMe
19{1,1,2}
19{1,1,3}
19{1,1,5}
19{1,1,6}
19{1,1,7}
19{5,1,1}
19{5,1,2}
19{5,1,3}
14{2}
14{3}
14{5}
14{6}
14{7}
14{1
14{2
14{3
}}
}}
NH2
NH2
H
CH3
H
H3C
}}
N
N
R6
90
91
R6
N
H
S
N
H
S
CN
CN
Cl
MeO
OMe
19{2,1,1}
19{2,1,2}
19{2,1,3}
19{2,1,4}
19{2,1,5}
19{2,1,6}
19{2,1,7}
93
93
92
93
91
91
90
14{1}
14{2}
14{3}
14{4}
14{5}
14{6}
14{7}
S
NH2
NH2
N
H
H
19{6,1,1}
19{7,1,1}
91
87
14{1
}}
N
CH
3
R6
H3C
N
H
S
R6
N
H
S
CN
S
CN
19{3,1,3}
19{3,1,5}
19{3,1,6}
19{3,1,7}
19{3,1,8}
93
92
90
92
90
14{3}
14{5}
14{6}
14{7}
14{8}
NH2
H
NH2
N
H
R6
14{1
}}
H3C
N
H3C
R6
N
H
S
N
H
S
CN
CN
OCH3
19{4,1,1}
19{4,1,2}
19{4,1,4}
91
90
91
14{1}
14{2}
14{4}
NH2
N
H
R6
H3C
N
H
S
CN
H3CO
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19{4,1,1} (CC
D
C 956062)
Hydroxide was similarly used as a nucleophile to prepare four 7-hydroxy-[1,6]-
naphthyridines (5). The optimized reaction condition and structures, obtained in moderate yields,
are shown in Figure 5.
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R
NH2
N
O
H2O (2 mL), 4 h
H
NaOH
NC CN
R
CH3
H3C
70 0C
N
H
OH
R
10
11
12
13
14
15
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19
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1{1-4}
2 mmol
2{1}
2 mmol
Cl
CN
1 mmol
5{1{1-4},2{1}}
4 Examples
S
NH2
N
NH2
H
H
N
Cl
N
H
OH
N
H
OH
S
H3C
H3C
CN
CN
5{2,1}, 70%
5{1,1}, 72%
OCH3
NH2
NH2
H
H
N
N
H3CO
N
OH
N
OH
H3C
H3C
H
CN
H
CN
5{3,1}, 70%
5{4,1}, 69%
Figure 5. Synthesis of hydroxy-inserted [1,6]-naphthyridines.
CONCLUSION
We highlight here the synergistic effects of the combined use of multi-component
reactions between methyl ketones, malononitrile, and phenols or thiols in water as an
environmentally benevolent solvent for the preparation of functionally rich heterocycles. This is
an excellent example of a true on water synthesis since the rate enhancement in water in
comparison to organic solvents is vividly discernible and thus it adds a new entry to the list of on
water transformations. By controlling the addition time of thiol nucleophiles, we were able
selective prepare either 3H-pyrroles or[1,6]-naphthyridines. This protocol not only represents a
promising green route to an interesting new class of compounds, involving the creation of three
C-C, two C-N, and one C-S or C-O bond in a single operation. Two nitrogen-containing rings are
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made without starting from any nitrogen-containing heterocyclic moiety, and the presence of a
cyano group in the naphthyridines makes them useful synthetic intermediates for the preparation
of other nitrogen-containing heterocycles.19
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ASSOCIATED CONTENT
Supporting Information.
Supporting Information Detailed computational studies, Molecular coordinate of optimized
geometries, IRC plots of the Transition states, experimental procedure, spectral data, copies of
13
1H and C NMR spectra of all the new compounds are provided. This material is available free
of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
E-mail: cmukhop@yahoo.co.in
Author Contributions
All authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
One of the authors (PD) thanks the Council of Scientific and Industrial Research, New Delhi for
her fellowship (SRF), the CAS Instrumentation Facility, Department of Chemistry, University of
Calcutta for spectral data.
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16. Mukhopadhyay, C.; Ray, S. Synthesis of 2-amino-5-alkylidenethiazol-4-ones from
ketones, rhodanine, and amines with the aid of re-usable heterogeneous silica-pyridine
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18. (a) Breslow, R. Artificial enzymes. Science. 1982, 218, 532-537. (b) Kirby, A. J. Enzyme
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Pseudo Five-component Domino Strategy for the
Combinatorial Library Synthesis of [1,6]
Naphthyridines - An On Water Approach
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GRAPHICAL ABSTRACT
R
NH2
N
H
H3C
N
H
S
R
CN
25 New compounds
R4
1 h, reflux
SH
R4
R
N
H
C
H
R
N
C
N
H3C
H
C
N
H2O (2 mL), 4 h
reflux
Et3N (0.2 mmol)
Et3N (0.2 mmol)
H2O (2 mL), 4 h
reflux
H2O (2 mL)
4 h, 70 0
C
OH
R
NH2
N
NaOH
R
NH2
N
H
H
H3C
H3C
R1
R1
R
N
H
O
N
H
OH
R
CN
CN
4 New compounds
30 New compounds
23
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ACS Combinatorial Science
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Pseudo Five-component Domino Strategy for the
Combinatorial Library Synthesis of [1,6]
Naphthyridines-An On Water Approach
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Paramita Das, Tandrima Chaudhuri and Chhanda Mukhopadhyay*
R
NH2
N
H
H3C
N
H
S
R
CN
25 New compounds
R4
1 h, reflux
SH
R4
R
N
H
C
H
N
R
C
N
H3C
H
C
N
H2O (2 mL), 4 h
reflux
Et3N (0.2 mmol)
Et3N (0.2 mmol)
H2O (2 mL), 4 h
reflux
H2O (2 mL)
4 h, 70 0C
OH
R
NH2
N
NaOH
R
NH2
N
H
H
H3C
H3C
R1
R1
N
H
O
N
H
OH
R
R
CN
CN
4 New compounds
30 New compounds
ACS Paragon Plus Environment
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