Mannich bases as enone precursors for water-mediated efficient synthesis of 2,3,6-trisubstituted pyridines and 5,6,7,8-tetrahydroquinolines

Article abstract of DOI:10.1021/acscombsci.5b00046

A highly efficient, regioselective, and environmentally friendly method has been developed for water-mediated synthesis of 2,3,6-trisubstituted pyridines and 5,6,7,8-tetrahydroquinolines. The introduced method allows easy preparation of various polysubstituted pyridines and 5,6,7,8-tetrahydroquinolines via domino reaction of an enolizable ketone, ammonia and enones derived from different Mannich bases in mild reaction conditions. Montmorillonite K-10 promoted this one-pot three-component reaction and gave both new and known 2,3,6-trisubstituted pyridines and 5,6,7,8-tetrahydroquinolines in good yields. The reaction protocol provides a wide array of functionality in construction of polysubstituted pyridines and 5,6,7,8-tetrahydroquinolines from commercially available starting materials in easily applicable and environmentally friendly conditions.

Full text of DOI:10.1021/acscombsci.5b00046

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Article
Mannich Bases as Enone Precursors for Water Mediated Efficient Synthesis
of 2,3,6-Trisubstituted Pyridines and 5,6,7,8-Tetrahydroquinolines
Essam Hamied Ahmed Hanashalshahaby, and Canan Unaleroglu
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00046 • Publication Date (Web): 11 May 2015
Downloaded from http://pubs.acs.org on May 15, 2015
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Mannich Bases as Enone Precursors for Water Mediated Efficient Synthesis of 2,3,6-
Trisubstituted Pyridines and 5,6,7,8-Tetrahydroquinolines
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Essam Hamied Ahmed Hanashalshahaby and Canan Unaleroglu
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Hacettepe University, Chemistry Department, 06800 Beytepe, Ankara, Turkey
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Mannich Bases as Enone Precursors for Water Mediated Efficient Synthesis of 2,3,6-
Trisubstituted Pyridines and 5,6,7,8-Tetrahydroquinolines
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Essam Hamied Ahmed Hanashalshahaby and Canan Unaleroglu
Hacettepe University, Chemistry Department, 06800 Beytepe, Ankara, Turkey
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ABSTRACT
A highly efficient, regioselective and environmentallyꢀfriendly method has been developed
for water mediated synthesis of 2,3,6ꢀtrisubstituted pyridines and 5,6,7,8ꢀ
tetrahydroquinolines. The introduced method allows easy preparation of various
polysubstituted pyridines and 5,6,7,8ꢀtetrahydroquinolines via domino reaction of an
enolizable ketone, ammonia and enones derived from different Mannich bases in mild
reaction conditions. Montmorillonite Kꢀ10 promoted this oneꢀpot threeꢀcomponent reaction
and gave both new and known 2,3,6ꢀtrisubstituted pyridines and 5,6,7,8ꢀtetrahydroquinolines
in good yields. The reaction protocol provides a wide array of functionality in construction of
polysubstituted pyridines and 5,6,7,8ꢀtetrahydroquinolines from commercially available
starting materials in easily applicable and environmentallyꢀfriendly conditions.
KEYWORDS: 2,3,6ꢀtrisubstituted pyridines, 5,6,7,8ꢀtetrahydroquinolines, Mannich bases,
pyridine synthesis in water
INTRODUCTION
Polysubstituted pyridines constitute a significant place in synthetic and medicinal chemistry.
Dihydroꢀ6Hꢀquinolinꢀ5ꢀones also have considerable attention due to their biological activities.
These heterocycles are present in a large number of pharmaceutical agents1 as a key unit or in
supramolecular assemblies2 as building blocks; therefore there is currently a great interest in
the synthesis of these scaffolds. Many synthetic approaches have been developed for the
preparation of these scaffolds.3 The BohlmannꢀRahtz method is the first report for the
preparation of 2,3,6ꢀtrisubstituted pyridines 3 via addition of alkynone 1 and enamine 2 and
subsequent cyclodehydration reactions in ethanol (Figure 1).4
Scheme 1. The Bohlmann-Rahtz 2,3,6-Trisubstituted Pyridine Synthesis
Bagley has made a remarkable improvement in the BohlmannꢀRahtz synthesis.5 In this
variant, threeꢀcomponent condensation of an enolizable ketone, alkynone and ammonia under
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acidic condition afforded 2,3,6ꢀtrisubstituted pyridines with high yields. An important
advantage of this domino reaction is the use of an enolizable ketone and ammonia instead of
poorly available enamine substrate sited in BohlmannꢀRahtz pyridine synthesis.
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Troschütz prepared 2ꢀmethylnicotinates by cyclocondensation of acetophenoneꢀderived
Mannich bases with methyl 3ꢀaminocrotonate under reflux in ethanol.6 Keuper and Nikolaus
also used Mannich bases to prepare polycyclic pyridines from βꢀamino ketone
hydrochlorides, cyclic ketones and ammonium acetate in boiling acetonitrile. However in
many cases, yields were low, and the best results have been obtained in absolute ethanol.7 The
researchers generally applied this approach for construction of differentꢀshaped
oligopyridines.8
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Multicomponent reactions (MCRs) are very efficient methods for the synthesis of important
chemicals in a designated reaction conditions without a need of isolation and purification of
intermediates. MCRs have become important protocols for the preparation of pyridines.9 In
this study, we researched the availability and the scope of multicomponent oneꢀpot reactions
of a Mannich base, an enolizable ketone and NH4OAc in water working in environmentallyꢀ
friendly reaction conditions.
RESULTS AND DISCUSSION
On the basis of our retrosynthetic strategy, we envisioned that domino reaction of enones 5,
ketones 4 and ammonia would produce the desired 2,3,6ꢀtrisubstituted pyridines 6 (Scheme
2). According to the proposed retrosynthetic strategy, enones are easily prepared in situ from
Mannich bases (Figure 1). To the best of our knowledge, this advantage of Mannich bases
does not seem to have been adequately assessed in the synthesis of 2,3,6ꢀtrisubstituted
pyridines.
Scheme 2. Retrosynthetic Strategy for the Synthesis of 2,3,6-Trisubstituted Pyridines
In order to test the validity of the multicomponent oneꢀpot formation of polysubstituted
pyridines, we chose Nꢀmethylꢀ3ꢀoxoꢀNꢀ(3ꢀoxoꢀ3ꢀphenylpropyl)ꢀ3ꢀphenylpropanꢀ1ꢀaminium
chloride 7{1}, pentaneꢀ2,4ꢀdione 4{1} and ammonium acetate. Nꢀmethylꢀ3ꢀoxoꢀNꢀ(3ꢀoxoꢀ3ꢀ
phenylpropyl)ꢀ3ꢀphenylpropanꢀ1ꢀaminium chloride 7{1} was prepared according to the
reported procedure,10 and these three components were heated in water at 80 oC for two hours
(Figure 1). 1ꢀ(2ꢀMethylꢀ6ꢀphenylpyridinꢀ3ꢀyl)ethanone 6{1,1} formed as the only product in
1
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98% yield. The structure of 6{1,1} was characterized by H NMR, C NMR and MALDIꢀ
TOFꢀMS spectral data.
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Figure 1. Threeꢀcomponent reaction of Nꢀmethylꢀ3ꢀoxoꢀNꢀ(3ꢀoxoꢀ3ꢀphenylpropyl)ꢀ3ꢀ
phenylpropanꢀ1ꢀaminium chloride 7{1}, pentaneꢀ2,4ꢀdione 4{1} and ammonia in water.
Figure 2. Diversity of Reagents
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After obtaining compound 6{1,1} with excellent yield, we tested the reaction with β−keto
esters 4{2-4} under the same reaction conditions. All βꢀketo esters furnished the target
molecules regioselectively with moderate to high yields (Table 1, entries 1ꢀ4). After this
stage, we chose 1ꢀphenylbutaneꢀ1,3ꢀdione 4{5} to examine the preparation of 2,3,6ꢀ
trisubstituted pyridines from an unsymmetrical 1,3ꢀdiketone. With respect to a possible
reaction pathway outlined in Scheme 3, unsymmetrical 1,3ꢀdiketone 4{5} allows the
formation of two different enamines. Enamine A produced a new compound (2ꢀmethylꢀ6ꢀ
phenylpyridinꢀ3ꢀyl)(phenyl)methanone 6a{5,1} as the major product in 56% yield, and
enamine B produced 1ꢀ(2,6ꢀdiphenylpyridinꢀ3ꢀyl)ethanone 6b{5,1} as the minor product in
9% yield. These two compounds were separated by flash column chromatography and
characterized by 1H NMR, 13C NMR and HRMS spectral data. The structures of 6a{5,1} and
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6b{5,1} were identified on the basis of C NMR spectral signatures of the methyl carbon.
The reported chemical shift values for methyl carbons of 1ꢀ(2ꢀmethylꢀ6ꢀphenylpyridinꢀ3ꢀ
yl)ethanone,3b ethyl 2ꢀmethylꢀ6ꢀphenylnicotinate,3b,3e ethyl 6ꢀ(furanꢀ2ꢀyl)ꢀ2ꢀmethylnicotinate
and ethyl 6ꢀ(5ꢀfluoroꢀ2ꢀmethylꢀ2,3ꢀdihydrobenzofuranꢀ7ꢀyl)ꢀ2ꢀmethylnicotinate1d are between
25.2ꢀ25.3 ppm, whereas the chemical shift value of methyl carbon on acetyl group of 1ꢀ(2ꢀ
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methylꢀ6ꢀphenylpyridinꢀ3ꢀyl)ethanone3b is at 29.1 ppm. C NMR spectra that we obtained
displayed these methyl carbon signals at 23.9 ppm for the major product and at 30.4 ppm for
the minor. According to these values, the major product was identified as (2ꢀmethylꢀ6ꢀ
phenylpyridinꢀ3ꢀyl)(phenyl)methanone 6a{5,1} and the minor product was identified as 1ꢀ
(2,6ꢀdiphenylpyridinꢀ3ꢀyl)ethanone 6b{5,1}. These successful results have led us to test
diethyl (2ꢀoxobutyl)phosphonate 4{6} instead of 1,3ꢀdiketone to obtain phosphonate
substituted pyridine. However, this reaction generated the desired product diethyl (2ꢀethylꢀ6ꢀ
phenylpyridinꢀ3ꢀyl)phosphonate 6{6,1} with the lowest yield (18%). All compounds were
fully characterized by 1H NMR, 13C NMR and HRMS analysis.
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Table 1. Synthesis of 2,3,6-trisubstituted pyridines 6{1-6, 1} from the three-component
condensation reaction of N-methyl-3-oxo-N-(3-oxo-3-phenylpropyl)-3-phenylpropan-1-
aminium chloride 7{1}, active methylene compounds 4{1-6} and ammonia in watera
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Entry
1
Active Methylenes
R1
R2
Product Yieldb (%)
CH3
COCH3
6{1,1}
6{2,1}
6{3,1}
98
79
50
4{1}
4{2}
2
3
CH3
CH3
CO2C2H5
CO2CH(CH3)2
4{3}
4
CH3
CO2(CH2)2OCH3
6{4,1}
78
4{4}
4{5}
5
6
CH3
C6H5
COC6H5
COCH3
6a{5,1}
6b{5,1}
56
9
C2H5
PO(OC2H5)2
6{6,1}
18
4{6}
a All reactions were performed with 4{1-6}:7{1}:NH4OAc (1:1.5:4.4) molar ratios.
b Isolated yields.
Scheme 3. Plausible formation pathway of 6a{5,1} and 6b{5,1}
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The above observations showed that this reaction protocol gave the target molecules in
moderate high yields except 6{6,1}. Accordingly, we next explored the Mannich base
diversity on the threeꢀcomponent oneꢀpot reaction of Mannich base, enolizable ketone and
NH4OAc under the same reaction conditions. Pentaneꢀ2,4ꢀdione 4{1} and ethyl 3ꢀ
oxobutanoate 4{2} were chosen as representative active methylenes. Reaction of 3,3'ꢀ
(methylazanediyl)bis(1ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀone)
hydrochloride
7{2},
3,3'ꢀ
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(methylazanediyl)bis(1ꢀ(furanꢀ2ꢀyl)propanꢀ1ꢀone) hydrochloride 7{3} and NꢀmethylꢀNꢀ(2ꢀ
morpholinoethyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxamide 7{4} shown on Figure 2 with 4{1} and 4{2},
respectively, allowed the oneꢀpot synthesis of corresponding pyridines 6{1-2, 2-4}.
However, the target molecules were obtained with unsatisfactory yields (Table 2, entries 1ꢀ6).
Table 2. Examining the scope of the Mannich bases in the synthesis of 2,3,6-
trisubstituted pyridines
Entry Active Methylenes Mannich
R1
R2
Product Yielda (%)
Bases
1
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OC2H5
CH3
7{2}
4{1}
6{1,2}
6{2,2}
6{1,3}
6{2,3}
6{1,4}
6{2,4}
57
42
58
43
32
25
2
7{2}
4{2}
3
7{3}
4{1}
4
OC2H5
CH3
7{3}
4{2}
5
7{4}
4{1}
6
OC2H5
7{4}
4{2}
a Isolated yields.
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In order to increase the yields of products, we tested the effect of different catalysts on the
reaction of 3,3'ꢀ(methylazanediyl)bis(1ꢀ(thiophenꢀ2ꢀyl)propanꢀ1ꢀone) hydrochloride 7{2}
with ethyl 3ꢀoxobutanoate 4{2} and ammonium. Ce(OTf)3, Cu(OTf)2 and CAN showed no
catalytic effect on the reaction (Table S1, entries 2, 5 and 6). KSF significantly increased the
yield of ethyl 2ꢀmethylꢀ6ꢀ(thiophenꢀ2ꢀyl)nicotinate 6{2,2} from 42% to 74% (Table S1, entry
3). Further increases up to 82% yield were obtained with Kꢀ10 catalyst (Table S1, entry 4).
When the reaction was performed only in glacial acetic acid, the target product was obtained
with 81% yield (Table S1, entry 6). After obtaining these results, the previously worked
reactions, except the one that yielded 98%, were run with the environmentallyꢀfriendly
montmorillonite Kꢀ10 catalyst in water and the results were summarized in Table 3. Reactions
of Mannich base 7{1} with 4{2} or 4{3} and ammonia in the presence of Kꢀ10 gave the
products with increased yields, 89% and 66%, respectively (Table 3, entries 2 and 3). For the
reaction of 7{1} with 4{4}, 4{5} or 4{6} and ammonia, the Kꢀ10 catalyst does not seem to
have a clear effect on the reaction yields (Table 3, entries 4ꢀ6). A remarkable effect of Kꢀ10
was observed in the yields of 6{1-2, 2-4} (Table 3, entries 7ꢀ12). Synthesis of ethyl 2ꢀmethylꢀ
6ꢀ(thiophenꢀ2ꢀyl)nicotinate 6{2,2} with 84% yield has been previously reported by the
reaction of (E)ꢀ3ꢀ(dimethylamino)ꢀ1ꢀ(thiophenꢀ2ꢀyl)propꢀ2ꢀenꢀ1ꢀone with 4{2} and
ammonium acetate in the presence of CeCl3.H2OꢀNaI in 2ꢀpropanol,1d whereas the introduced
reaction protocol with metalꢀfree conditions provided 6{2,2} with a comparable yield (82%)
in the presence of Kꢀ10 in water. New indolyl substituted pyridines 6{1,4} and 6{2,4} were
also synthesized in 77% and 54% yields, respectively (Table 3, entries 11 and 12).
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Table 3. K-10 catalyzed three-component reaction of Mannich bases 7{1-4}, active
methylene compounds 4{1-6} and ammonia in watera
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Entry Active Methylenes
1
Mannich
Bases
R1
R2
Product
Yieldb
(%)
7{1}
7{1}
7{1}
6{1,1}
6{2,1}
6{3,1}
98c
89
66
CH3
CH3
CH3
COCH3
CO2C2H5
4{1}
2
4{2}
3
CO2CH(CH3)2
4{
4{
3
}
}
4
CH3
CO2(CH2)2OCH3
7{1}
6{4,1}
79
4
5
6
CH3
C6H5
COC6H5
COCH3
6a{5,1}
6b{5,1}
57
9
7{1}
7{1}
4{
5}
C2H5
PO(OC2H5)2
6{6,1}
22
4{
6}
7
CH3
CH3
CH3
CH3
CH3
CH3
COCH3
CO2C2H5
COCH3
7{2}
7{2}
7{3}
7{3}
7{4}
7{4}
6{1,2}
6{2,2}
6{1,3}
6{2,3}
6{1,4}
6{2,4}
74
82
80
60
77
54
4{1}
4{2}
4{1}
4{2}
4{1}
4{2}
8
9
10
11
12
CO2C2H5
COCH3
CO2C2H5
aAll reactions were performed with 4{1-6}:7{1-4}:NH4OAc (1:1.5:4.4) molar ratios in the
presence of Kꢀ10. b Isolated yields. c Kꢀ10 free.
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A plausible mechanism for this threeꢀcomponent heteroannulation reaction taking into
account the experimental results and literature reports3d,6 is outlined in Scheme 4. Firstly, the
Mannich base 7 produces the enone compound 5 in situ, and the reaction of ammonia with
ketone 4 produces enamine I. In the next step, the Michael addition reaction gives
intermediate II, subsequent intramolecular cyclization forms intermediate III and the
following aromatization affords 2,3,6ꢀtrisubstituted pyridine 6.
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Scheme 4. A Plausible Mechanism for the Synthesis of 2,3,6-Trisubstituted Pyridines
Me
R3
R3
R2
Michael
addition
.HCl
R3
R2
N
AcONH4
heat
R1
+
R2
R1
R1
R1
H2N
H N
O
O
O
2
O
7
O
4
I
5
II
R3
R2
R3
R2
intramolecular
cyclization
aromatization
R1
N
-H2O
R1
N
H
III
6
In
order
to
expand
the
applicability
of
the
current
method,
2,2'ꢀ
((methylazanediyl)bis(methylene))dicyclohexanone hydrochloride 8 shown on Figure 2 was
used as a Mannich base to derive 5,6,7,8ꢀtetrahydroquinoline. Kꢀ10 catalyzed threeꢀ
component reactions were performed with 8, the corresponding compounds 4{1-7} and
ammonia in water (Table 4, entries 1ꢀ7). The reaction of 8 with 4{1} and ammonia yielded
2,3ꢀdimethylꢀ5,6,7,8ꢀtetrahydroquinoline 9{1} with excellent yield even in the absence of a
catalyst (Table 4, entry 1). β−keto esters 4{2-4} gave the corresponding quinolines 9{2-4}
with low to moderate yields (44%ꢀ70%). 9a{5} and 9b{5} were obtained from the reaction of
Mannich base 8 with 4{5} and ammonia. These two compounds 9a{5} and 9b{5} were
separated by flash column chromatography and identified on the basis of 13C NMR spectral
signatures of methyl carbon on acetyl group. The reported chemical shift values of methyl
carbons of C(3)ꢀacetyl functionalized pyridines were between 29.0ꢀ29.3 ppm.3b 13C NMR
spectrum of 9b{5} showed a peak at 30.3 ppm besides the methylene peaks of pyridineꢀfused
13
cyclohexane. This peak was absent in the C NMR spectrum of 9a{5} while a another peak
at 22.9 ppm arose assigning the methyl carbon attached to pyridine. According to the
chemical shift values of methyl carbon in the 13C NMR spectra of 9a{5} and 9b{5}, the major
product was identified as (2ꢀmethylꢀ5,6,7,8ꢀtetrahydroquinolinꢀ3ꢀyl)(phenyl)methanone
9a{5} and the minor as 1ꢀ(2ꢀphenylꢀ5,6,7,8ꢀtetrahydroquinolinꢀ3ꢀyl)ethanone 9b{5}. Herein,
the introduced procedure provided the target molecules in higher yields from easily available
compounds under more favorable conditions. Three component reaction of 4{6} or 4{7} with
8 and ammonia formed new compounds diethyl (2ꢀethylꢀ5,6,7,8ꢀtetrahydroquinolinꢀ3ꢀ
yl)phosphonate 9{6} and 2,2,2ꢀtrifluoroꢀ1ꢀ(2ꢀ(thiophenꢀ2ꢀyl)ꢀ5,6,7,8ꢀtetrahydroquinolinꢀ3ꢀ
yl)ethanone 9{7}, respectively. However, 9{6} (15%) and 9{7} (40%) were obtained in the
lowest yields (Table 4, entries 6 and 7).
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Table 4. Synthesis of 2,3-substituted-5,6,7,8-tetrahydroquinolinea
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Entry
1
Active Methylenes
R1
R2
Product
Yieldb (%)
96c
CH3
COCH3
9{1}
4{1}
4{2}
2
3
CH3
CH3
CO2C2H5
9{2}
9{3}
70
44
CO2CH(CH3)2
4{3}
4
CH3
CO2(CH2)2OCH3
9{4}
65
4{4}
4{5}
5
6
CH3
C6H5
COC6H5
COCH3
9a{5}
9b{5}
51
8
C2H5
CF3
PO(OC2H5)2
COC4H3S
9{6}
9{7}
15
40
4{6}
7
4{7}
a
All reactions were performed with 4{1-7}:8:NH4OAc (1:1.5:4.4) molar ratios in the
presence of Kꢀ10. b Isolated yields. c Kꢀ10 free.
In conclusion, we have successfully developed a facile waterꢀmediated threeꢀcomponent oneꢀ
pot reaction of Mannich base, enolizable ketone and NH4OAc in the presence of
environmentallyꢀfriendly heterogeneous catalyst Kꢀ10. Easilyꢀprepared Mannich bases as
enone precursors can be alternative starting materials for pyridine synthesis. This simple and
practical reaction protocol provides the synthesis of 2,3,6ꢀtrisubstituted pyridines and 5,6,7,8ꢀ
tetrahydroquinolines from easilyꢀavailable compounds in good yields. The diversity of
Mannich bases and enolizable ketones makes these compounds good candidates for
construction of pyridine and pyridine base skeletons to be used in combinatorial processes
such as drug discovery.
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EXPERIMENTAL PROCEDURES
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General Information. All reagents were commercial and purchased from Acros Organics,
SigmaꢀAldrich and Merck. 1H NMR (400 MHz) and 13C NMR (100 MHz) data were recorded
on a Bruker DPXꢀ400ꢀultra shield FTꢀNMR spectrometer in CDCl3 with chemical shifts
given in ppm relative to TMS as internal standard. Melting points were determined with
Gallenkamp electrothermal digital melting point apparatus and are uncorrected. HRMS
spectra were recorded on an Agilent (1200/6210) TOF LC/MS spectrometer. Reactions were
monitored by TLC using preꢀcoated silica gel alumina plates (Kieselgel 60, F254, E. Merck),
visualization UV lamp. Flash column chromatography was performed by using silica gel
(0.05ꢀ0.63 nm 230ꢀ400 mesh ASTM, Merck).
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General Procedure for the Synthesis of 2,3,6-Trisubstituted Pyridines: A mixture of
diketoꢀbase hydrochloride 7{1} (0.22 g, 0.66 mmol), active methylene 4{1} (0.045 mL, 0.44
mmol) and ammonium acetate (0.2 g, 2.6 mmol) in 3 mL of water was heated at 80 ºC for 2
hours. After completion the reaction (monitored by TLC), the mixture was cooled to room
temperature and 20 mL of water was added. The product was extracted with EtOAc (2x5 mL)
and dried (MgSO4). Solvent was removed under reduced pressure and the residue was
purified by flash column chromatography (Silica gel, EtOAcꢀhexane, 1:6). Experimental data
o
of 6{1,1} is as follows: White solid; Yield: 98%, mp: 91ꢀ92 C; ¹H NMR (400 MHz,
CDCl3) δ 8.03ꢀ8.07 (m, 3H, ArHꢀPyrH), 7.64 (d, J= 8.0 Hz, 1H, PyrH), 7.44ꢀ7.50 (m, 3H,
ArH), 2.83 (s, 3H, CH3), 2.60 (s, 3H, COCH3); ¹³C NMR (100 MHz, CDCl3) δ 200.0, 158.7,
158.6, 138.4, 138.0, 130.7, 129.7, 128.9, 127.3, 117.3, 29.4, 25.4; HRMS (ESI): Calcd for
C14H14NO [M+H]+: 212.1075, found: 212.1075.
General Procedure for the Synthesis of 2,3,6-Trisubstituted Pyridines in the Presence of
K-10 Catalysis: To the mixture of diketoꢀbase hydrochloride 7{1} (0.22 g, 0.66 mmol),
active methylene 4{2} (0.045 mL, 0.44 mmol) and ammonium acetate (0.2 g, 2.6 mmol) in 3
mL of water was added Kꢀ10 (0.44 g) and heated at 80 ºC for 2 hours. After completion the
reaction (monitored by TLC), reaction mixture was cooled to room temperature and 20 mL of
water was added. The product was extracted with EtOAc (2x5 mL) and dried (MgSO4).
Solvent was removed under reduced pressure and the residue was purified by flash column
chromatography (Silica gel, EtOAcꢀhexane, 1:6). Experimental data of 6{2,1} is as follows:
Pale yellow solid; Yield: 89%, mp: 54ꢀ56 oC; ¹H NMR (400 MHz, CDCl3,) δ 8.26 (d, J= 8.2
Hz, 1H, PyrH), 8.06 (d, J= 8.0 Hz, 2H, ArH), 7.62 (d, J= 8.2 Hz, 1H, PyrH), 7.42ꢀ7.51 (m,
3H, ArH), 4.40 (q, J=7.1 Hz, 2H, CH2CH3), 2.91 (s, 3H, CH3), 1.42 (t, J= 7.1 Hz, 3H,
CH2CH3); ¹³C NMR (100 MHz, CDCl3) δ 166.7, 160.0, 159.1, 139.3, 138.5, 129.7, 128.8,
127.3, 123.7, 117.4, 61.1, 25.3, 14.3; HRMS (ESI): Calcd for C15H16NO2 [M+H]+: 242.1181,
found: 242.1183.
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ASSOCIATED CONTENT
Supporting Information
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Further details on the experimental procedures and results. This information is available free
of charge via the Internet at http://pubs.acs.org/.
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AUTHOR INFORMATION
Corresponding Author
Eꢀmail: canan@hacettepe.edu.tr, Phone:+90ꢀ3122977962, Fax: +90ꢀ3122992163.
ACKNOWLEDGMENT
Authors are grateful for financial support from The Scientific and Technological Research
Council of TURKEY (No. 113Z044) and E.A is thankful to TUBITAK for research
fellowships.
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