Hantzsch Reaction Starting Directly from Alcohols through a Tandem Oxidation Process

Article abstract of DOI:10.1155/2017/5646908

A Br?nsted acidic ionic liquid, 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen sulphate ([DDPA][HSO₄]), has been successfully applied to catalyze sequential oxidation of aromatic alcohols with NaNO₃ followed by their c

Full text of DOI:10.1155/2017/5646908

Hindawi
Journal of Chemistry
Volume 2017, Article ID 5646908, 5 pages
https://doi.org/10.1155/2017/5646908
Research Article
Hantzsch Reaction Starting Directly from Alcohols through
a Tandem Oxidation Process
Xiaobing Liu1 and Bin Liu2
1School of Chemistry and Chemical Engineering, Jinggangshan University, Ji’an 343009, China
2School of Basic Medicine and Pharmacy, Jinggangshan University, Ji’an 343009, China
Correspondence should be addressed to Xiaobing Liu; xiaobingliu928@126.com
Received 26 March 2017; Revised 15 May 2017; Accepted 15 June 2017; Published 16 July 2017
Academic Editor: Pedro M. Mancini
Copyright © 2017 Xiaobing Liu and Bin Liu. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
A Brønsted acidic ionic liquid, 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen sulphate ([DDPA][HSO ]),
4
has been successfully applied to catalyze sequential oxidation of aromatic alcohols with NaNO followed by their condensation
3
with dicarbonyl compound and ammonium acetate. e corresponding pyridine analogues of Hantzsch 1,4-dihydropyridines could
be obtained as a major product with high yields by the multicomponent reaction. e present work utilizing alcohols instead of
aldehyde in Hantzsch reaction is a valid and green alternative to the classical synthesis of the corresponding pyridine analogues of
Hantzsch 1,4-dihydropyridines.
1. Introduction
Garima et al. [17] reported an efficient oxidative access to
3,4-dihydropyrimidin-2-(1H)-ones directly from aromatic
alcohols. In the literature, a Brønsted acidic ionic liquid has
been successfully applied to catalyze sequential oxidation
1,4-Dihydropyridines and their derivatives are an important
class of heterocycles in biologically active and naturally
occurring molecules [1–3]. Many methods for the prepara-
tion of 1,4-dihydropyridines have been reported and most of
them are mainly confined to the modification and optimiza-
tion of the Hantzsch multicomponent synthesis between an
aldehyde, a 1,3-dicarbonyl compound, and a source of ammo-
nia [4–6]. At the same time, the oxidative aromatization of
1,4-dihydropyridines has also been extensively studied and
numerous oxidizing reagents, namely, CuBr [7], SiO /P O -
of aromatic alcohols with NaNO followed by their con-
3
densation with urea and dicarbonyl compounds.
Ionic liquids have attracted extensive interest and played
a dual solvent-catalyst role in organic synthesis due to
their favourable properties [18]. Brønsted acidic ionic liquids
combining the advantageous characteristics of solid acids
and mineral acids are designed to replace traditional mineral
liquid acids in catalytic action [19]. In continuation of
our interest in exploring green catalysis of ionic liquids
[20, 21], we herein report a Brønsted acidic ionic liquid
3-(N,N-dimethyldodecylammonium) propanesulfonic acid
2
2
2
5
SeO [8], H O /Co(OAc) [9], and Na S O /TBHP [10],
2
2
2
2
2
2
4
have been used for the aromatization of 1,4-dihydropyridines.
Some reports have observed that the direct oxidative pro-
cedure was very efficient for the preparation of Hantzsch
pyridines under microwave-assisted condition or solvent-
free condition [11–13]. However, the search for the new readily
available and green methods is still being actively pursued.
e aldehydes in Hantzsch reaction are more volatile,
toxic, or unstable than their corresponding alcohols.
Recently, tandem oxidative processes (TOP) [14–16] in which
the alcohol is oxidized to the aldehyde in situ have developed
into an innovative addition to synthetic organic chemistry.
hydrogen sulphate ([DDPA][HSO ]) catalyzed sequential
4
oxidation of aromatic alcohols with NaNO followed by their
3
condensation with dicarbonyl compound and ammonium
acetate. We have found that the corresponding pyridine
analogues of 1,4-dihydropyridines could be obtained as a
major product by the multicomponent reaction, whereas
only trace amounts of 1,4-dihydropyridines were detected
(Scheme 1).

2
Journal of Chemistry
２1
２1
[DDPA][HS／4]-NaN／3
80∘C
H
O
H
HO
1
O
２1
O
O
２1
O
N（4OAc
２1
[DDPA][HS／4]-NaN／3
80∘C
O２2
２2O
+
O
２2O
O２2
+
O
H
O
O２2
1
N
H
4
N
3
2
＃（3
+
＃
（
−
12 25
．
３／3（
（３／4
＃（3
[DDAP][HSO]
２1 = ；ＬＳＦ
２2 = ＃（3, ＃2（5
Scheme 1: Synthesis of the corresponding pyridine analogues of 1,4-dihydropyridines directly from aromatic alcohols.
[DDPA][HS／4]-NaN／3
80∘C
H
HO
H
O
1a
O
O
O
O
N（4OAc
[DDPA][HS／4]-NaN／3
（3＃／
／＃（3
+
（3＃／
+
O
O
／＃（3
80∘C
N
H
4a
H
O
／＃（3
N
3a
1a
2a
Scheme 2: Model Hantzsch reaction directly from benzyl alcohol in [DDPA][HSO ].
4
2. Materials and Methods
was heated with stirring at 80∘C for 1–3 h. e reaction was
monitored by TLC afer an interval of 15 min. Afer comple-
tion, the reaction mixture was cooled to rt and extracted with
ethyl acetate. e organic layer was separated and washed
with brine solution and then dried over anhydrous Na SO .
2.1. General Reagents and Instrumentation. All starting
chemicals (AR grade) were purchased from commercial sup-
pliers and used without further purification. Melting points
were determined on a omas-Hoover capillary apparatus
and were uncorrected. e IR spectra were recorded with
a Bomem Michelson model 102 FTIR. 1H NMR spectra
were recorded on Bruker DRX (500 MHz) spectrometer. Gas
chromatography (GC) was recorded on a HP 6890 Plus GC
instrument. Elemental analyses were performed on a Yanag-
2
4
Solvent was removed in vacuo and the crude product was
purified by chromatography over silica gel. e aqueous layer
(containing the ionic liquid) could be reused directly in the
next run without further purification.
3. Results and Discussion
imoto MT3CHN recorder. e ionic liquid [DDPA][HSO ]
was synthesized according to the literature procedures [22].
4
In the initial experiments, the multicomponent reaction of
benzyl alcohol, ethyl acetoacetate, and ammonium acetate
was selected as a model reaction (Scheme 2). We studied
the tandem oxidative cyclocondensation of benzyl alcohol,
ethyl acetoacetate, and ammonium acetate in the presence
of [DDPA][HSO ] with NaNO at 80∘C, but no reaction
2.2. Experimental Procedures. A mixture of an aromatic alco-
hol (3 mmol), sodium nitrate (6 mmol), and [DDPA][HSO ]
4
(1.2 mmol) was heated with stirring at 80∘C for 5–30 min
in a round-bottomed flask. Afer oxidation of the aromatic
alcohol (monitored by TLC), dicarbonyl compound (3 mmol)
and ammonium acetate (3 mmol) were added. e mixture
4
3
took place even afer stirring the reaction mixture for 12 h.
However, we observed the formation of 1,4-dihydropyridine

Journal of Chemistry
3
100
80
91
90
88
87
85
60
40
20
1
2
3
4
5
Reuse times
Figure 1: Reusability of the ionic liquid [DDPA][HSO ].
4
Table 1: Model of Hantzsch reaction directly from benzyl alcohol in
[DDPA][HSO ] and the obtained results are summarized
4
different ionic liquidsa.
in Table 2. It can be seen that the tandem oxidation of
aromatic alcohols followed by their condensation with dicar-
bonyl compound and ammonium acetate in the presence
Entry
1
2
3
4
Ionic liquid
[DDPA][HSO ]
Ratiob
3a : 4a = 93 : 7
3a : 4a = 86 : 14
—
Yield (%)c
91
37
—
—
4
of [DDPA][HSO ] proceeded smoothly to give the corre-
4
[Hmim][H PO ]
2
4
sponding products in good yields. Aromatic alcohols with
a strong electron-withdrawing group required a longer time
for the reaction (Table 2, entries 8 and 9), whereas aromatic
alcohols with electron-donating substitutes gave excellent
yields (Table 1, entries 2, 4, 5, and 6) in a shorter reaction time.
An important feature of the present protocol is the ability to
tolerate variation in all components simultaneously.
[Hmim]NO
3
[bmin]BF
—
4
aBenzyl alcohol (3 mmol), ethyl acetoacetate (3 mmol), ammonium acetate
(3 mmol), ionic liquid (1.2 mmol), and NaNO (6 mmol), 1 h. bYields and
3
ratios were based on GC analysis. cYields referred to the desired product 3a.
A plausible mechanism for the sequential oxidation of
and its corresponding pyridine when ethyl acetoacetate and
ammonium acetate were added to the reaction afer the
oxidation of the alcohol to the aldehyde was complete.
Subsequently, different ionic liquids were screened for the
same model reaction. e results are summarized in Table 1. It
aromatic alcohols with NaNO followed by their condensa-
3
tion with dicarbonyl compound and ammonium acetate is
depicted in Scheme 3. In acidic ionic liquid [DDPA][HSO ],
4
aromatic alcohols were oxidized to aromatic aldehydes with
NaNO . Afer the oxidation completion, a multicomponent
3
was shown that the reaction was unsuccessful in [Hmim]NO
3
reaction of the aromatic aldehydes, dicarbonyl compound,
and [bmin]BF because an acidic hydrogen is absent in the
4
and ammonium acetate was conducted in [DDPA][HSO ]
4
two ionic liquids. e reaction could proceed effectively
and then the Hantzsch 1,4-dihydropyridines were formed.
Subsequently, the Hantzsch 1,4-dihydropyridines could be
further oxidized to the desired corresponding pyridine ana-
logues with NaNO -[DDPA][HSO ] in air.
in [DDPA][HSO ] but relatively low yields of product in
4
[Hmim][H PO ]. is is probably due to the lower Brønsted
2
4
acidity associated with [H PO ]. us, [DDPA][HSO ] plays
2
4
4
3
4
a dual role as an acid catalyst and as a solvent for both the
oxidation of alcohol and the subsequent condensation. e
product 4a could be converted to product 3a in the exposure
of air and the NaNO -[DDPA][HSO ] system could speed up
4. Conclusions
3
4
In conclusion, we have described an efficient protocol for
the process.
Hantzsch reaction starting from alcohols using NaNO -
3
To explore the stability of the ionic liquid afer reaction,
the recycling performance of [DDPA][HSO ] in the same
[DDPA][HSO ] system. e protocol involves [DDPA][HSO ]
4
4
4
catalyzed sequential oxidation of aromatic alcohols with
model reaction was investigated. Afer the reaction, the prod-
ucts were separated from the catalytic system by extraction
with ethyl acetate. e aqueous layer (containing the catalyst)
was reused in the next run without further purification. As
shown in Figure 1, the catalyst could be reused at least five
times without significant decrease in catalytic activity.
NaNO followed by their condensation with dicarbonyl
3
compound and ammonium acetate. e corresponding pyri-
dine analogues of Hantzsch 1,4-dihydropyridines could be
obtained as a major product with high yields by the mul-
ticomponent reaction. e present work utilizing alcohols
instead of aldehyde in Hantzsch reaction is a valid and green
alternative to the classical synthesis of the corresponding
pyridine analogues of Hantzsch 1,4-dihydropyridines.
With these results in hand, we decided to explore the
scope of this method. A variety of substituted aromatic
alcohols was extended in the procedure in the presence of

4
Journal of Chemistry
Table 2: Hantzsch reaction of different substrates catalyzed by [DDPA][HSO ]a.
4
Entry
1
R1
R2
CH
CH
CH
Time (h)
Yield (%)b
Mp ∘C (lit. Mp ∘C)c
118 (118) [7]
C H
1
1
2
1
1
1
2
3
3
91
93
85
90
93
91
83
76
72
6
5
5
6
3
3
3
2
3
4
5
6
7
8
9
4-MeO-C H
91 (92) [7]
118 (120) [7]
6
4
4-Cl-C H
6
4
C H
CH CH
60-61 (63-64) [23]
58 (55–57) [24]
52 (51-52) [7]
66 (65–67) [23]
60 (60) [7]
6
3
2
2
2
2
2
2
2-MeO-C H
CH CH
6
4
3
4-MeO-C H
CH CH
6
4
3
4-Cl-C H
CH CH
4
3
3-NO -C H
CH CH
2
6
4
3
4-NO -C H
CH CH
115 (114-115) [23]
2
6
4
3
aBenzyl alcohol (3 mmol), ethyl acetoacetate (3 mmol), ammonium acetate (3 mmol), ionic liquid (1.2 mmol), and NaNO (6 mmol). bYields were based on
3
GC analysis and referred to the desired product 3. cMp of product 3.
O
（2／
−
O
２1
O
[DDPA][HS／4]
N
O
O
+
２1＃（2OH
２1＃（2O（2
２1＃（／
N
O
−（2／
H
−（．／2
．／ + ．／2
∙∙
．（2
O
O
[DDPA][HS／4]
O
２1＃（／
．（4／！＝
／２2
+
+
２2／
+
O
／２2
２1
O
２1
O
O
２1
２1
O
O
OH
O
−（2／
／２2
／２2
２2／
２2／
／２2
２2／
+
N
H
O
（2．
O
．（2
２1
O
２1
O
O
O
NaN／3-[DDPA][HS／4]
２2／
／２2
２2／
／２2
Exposure to air
N
H
N
Scheme 3: Plausible mechanism for Hantzsch reaction directly from alcohol in [DDPA][HSO ].
4
Conflicts of Interest
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