Nucleophilic, heterocyclic, carbene-catalyzed, solvent-free, one-pot synthesis of polyhydroquinolines via multicomponent hantzsch reaction: An efficient and ecofriendly approach

Article abstract of DOI:10.1080/00397911.2013.876651

A simple, efficient, and ecofriendly one-pot method has been reported for the synthesis of polyhydroquinolines in excellent yield using nucleophilic heterocyclic carbene as catalyst. The generalized approach is the Hantzsch four-component reaction of arom

Full text of DOI:10.1080/00397911.2013.876651

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Nucleophilic, Heterocyclic, Carbene-
Catalyzed, Solvent-Free, One-Pot
Synthesis of Polyhydroquinolines via
Multicomponent Hantzsch Reaction: An
Efficient and Ecofriendly Approach
Shahin Fatma a , Preyas Ankit a , Mandavi Singh a , Shyam Babu Singh
a & Jagdamba Singh a
a Environmentally Benign Synthesis Laboratory, Department of
Chemistry , University of Allahabad , Allahabad , India
Accepted author version posted online: 18 Mar 2014.Published
online: 14 May 2014.
To cite this article: Shahin Fatma , Preyas Ankit , Mandavi Singh , Shyam Babu Singh & Jagdamba
Singh (2014) Nucleophilic, Heterocyclic, Carbene-Catalyzed, Solvent-Free, One-Pot Synthesis of
Polyhydroquinolines via Multicomponent Hantzsch Reaction: An Efficient and Ecofriendly Approach,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:12, 1810-1816, DOI: 10.1080/00397911.2013.876651
To link to this article: http://dx.doi.org/10.1080/00397911.2013.876651
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Synthetic Communications1, 44: 1810–1816, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.876651
NUCLEOPHILIC, HETEROCYCLIC, CARBENE-
CATALYZED, SOLVENT-FREE, ONE-POT SYNTHESIS
OF POLYHYDROQUINOLINES VIA MULTICOMPONENT
HANTZSCH REACTION: AN EFFICIENT AND
ECOFRIENDLY APPROACH
Shahin Fatma, Preyas Ankit, Mandavi Singh,
Shyam Babu Singh, and Jagdamba Singh
Environmentally Benign Synthesis Laboratory, Department of Chemistry,
University of Allahabad, Allahabad, India
GRAPHICAL ABSTRACT
Abstract A simple, efficient, and ecofriendly one-pot method has been reported for the
synthesis of polyhydroquinolines in excellent yield using nucleophilic heterocyclic carbene
Received July 25, 2013.
Address correspondence to Jagdamba Singh, Environmentally Benign Synthesis Laboratory,
Department of Chemistry, University of Allahabad, Allahabad 211002, India. E-mail: dr.jdsau@
gmail.com
1810

POLYHYDROQUINOLINES VIA HANTZSCH REACTION
1811
as catalyst. The generalized approach is the Hantzsch four-component reaction of aromatic
aldehyde, ethyl acetoacetate, cyclic 1,3-diketone, and ammonium acetate.
Keywords Hantzsch reaction; nucleophilic heterocyclic carbene (NHC); one-pot reac-
tion; polyhydroquinolines
INTRODUCTION
Dihydropyridine (DHP) is a common feature of various bioactive[1] compounds
such as antihypertension drugs,[2] vasodialators, bronchodialators, antiatherosclero-
tics, and geroprotective, hepatoprotective,[3,4] antitumor, and antidiabetic agents.
Recent studies have revealed that 1,4-DHPs also exhibit several other medicinal
applications, which include neuroprotectants, platelet antiaggregrators, and cerebral
antischaemic agents[5] in the treatment of Alzheimer disease, chemosensitizers[5] in
tumor therapy, drug resistance modifiers,[6] antioxidants,[7] and drugs for the treat-
ment of urinary urge incontinence.[8] These examples clearly demonstrate the remark-
able potential of novel DHP derivatives as sources of valuable drugs. Further,
4-aryl-1,4-DHPs have been explored for their calcium channel activity and are well
known Ca2þ channel blockers.[9–11] Amlodipine and nicardipine are specific examples
of 1,4-DHP containing biologically active heterocyclic compounds (Scheme 1).
The success of these calcium antagonists has led to the development of several
novel synthetic strategies along with improved classical methods of preparation,
which include the use of microwaves,[12,13] ionic liquids,[14] metal triflates,[15] solvent
reflux at high temperature,[16] TMSCl-NaI,[17] InCl3,[18] I2,[19] SiO2=HClO4,[20] SiO2=
NaHSO4,[21] ceric ammounium nitrate (CAN),[22] Na- and Cs-norit carbons,[23] tetra-
butylammonium hydrogen sulfate,[24] fermenting Baker’s yeast,[25] and application of
organocatalysts,[26] solar thermochemical method,[27] potassium dodecatungstoco-
baltate trihydrate,[28] thiamine hydrochloride,[29] and triphenylphosphine.[30] How-
ever, conditions such as the use of high temperature, expensive metal precursors,
and longer reaction time limit these methods to great extent. In this context, the
replacement of toxic and volatile organic solvents as reaction media with environ-
mentally acceptable alternatives such as water, preferential use of organocatalyst,
and solvent-free synthesis is an area of tremendous importance in modern organic
synthesis. Thus the development of simple, more efficient, and green methods for
the preparation of 1,4-DHP derivatives is an active area of research.
Scheme 1. Some biologically active heterocycles containing 1,4-DHP ring.

1812
S. FATMA ET AL.
It is well knownthat thiamine hydrochloride (vitaminB1)isaninexpensiveandnon-
toxic reagent containing a pyrimidine ring and a thiazole ring. Hydrogen on the carbon
between S and N (i.e., at position 2) is acidic enough to be removed by the base, thereby
providing required functionality to carry out several reactions in our body (and other liv-
ing organisms), which include decarbonylation of pyruvic acid to acetaldehyde and con-
version of pyruvic acid to acetoin. Vitamin B1 (VB1) analogs have been used as powerful
catalysts for many carbon–carbon and carbon–heteroatom bond-formation reactions.
Because most of the Hantzsch reactions are reported using Lewis acids or protic catalysts,
only some nucleophiles such as triphenylphosphine, a Lewis base, are used as catalysts in
the Hantzsch reaction. With the elucidation of active compound of VB1 as a nucleophilic
carbene=zwitterions, we had the opportunity to explore for the first time a
thiazolium-based nucleophilic heterocyclic carbene as a green catalyst for the synthesis
of polyhydroquinolines (PHQs) using Hantzsch condensation reaction.
RESULTS AND DISCUSSION
We found thiazolium ion (NHC), a basic, soft, and reusable ecofriendly
species, can be used for the preparation of large number of PHQs in considerably
short time with good yields. To compare its efficiency with various catalytic systems,
we have used a range of catalysts. The results are summarized in Table 1. As evident
from Table 1, thiazolium NHC shows comparatively better yield in considerably less
time. The amount of catalyst is also comparatively very low, almost less than
one-tenth in comparison to most of the other catalysts. We have used these catalysts
for the synthesis of PHQs, but the best results were obtained when NHC was used as
a catalyst under solvent-free condition. See Scheme 2.
To estimate the influence of NHC concentration on reaction time and percent-
age yield, the amount of catalyst was varied from 0 to 10 mol%. As shown in Table 1
(entries 8–13), elevated amounts of catalyst improved the product yield and shortened
Table 1. Comparative account of the effects of different catalystsa
Entry
Catalyst
Solvent
Catalyst amount (mol%)
Time (h)
Yield (%)
1
2
None
ZnCl2
AlCl3
FeCl3
NdCl3
La(OTf)3
Yb(OTf)3
NHC
-Do-
Ethanol
-Do-
-Do-
0
150
200
200
25
15
5
24
12
36
44
3
12
12
43
48
4
-Do-
-Do-
5
12
15
76
6
-Do-
-Do-
84
7
5
90b
Trace
74
8
Solvent-free
-Do-
-Do-
0
4
9
1
45 min
45 min
40 min
20 min
20 min
10
11
12
13
-Do-
-Do-
2
83
89
-Do-
-Do-
3
-Do-
-Do-
5
10
92
92
-Do-
aBenzaldehyde (1 mmol), ethylacetoacetate (1 mmol), dimedone (1 mmol), and ammonium acetate
(1 mmol) þ 60 ꢀC.
bSee Ref. 37.

POLYHYDROQUINOLINES VIA HANTZSCH REACTION
1813
Scheme 2. Generation of N-heterocyclic carbene.
Scheme 3. General reaction for the synthesis of polyhydroquinoline.
the reaction time. When catalyst concentration was 1 mol%, the yield was found to be
74% in 45 min, but when the catalyst concentration was increased to 5 mol%, the yield
was found to be 92% in 20 min. Further increase in concentration of catalyst
(10 mol%) did not show any significant improvement in the yield. Therefore, the
one-pot condensation was carried out taking 5 mol% as catalyst concentration.
To examine the extent of the catalyst’s application in condensation reaction
(Scheme 3), we have applied the optimized catalyst concentration (i.e., 5 mol% thia-
zolium ion) to a large number of aromatic aldehydes having both electron-
withdrawing and electron-donating substituents, at 60 ꢀC. It was found that almost
all studied aldehydes react efficiently to give excellent yields in shorter reaction time
(as shown in Table 2). We have also used aliphatic aldehydes for the Hantzsch
condensation using NHC as promoter of the reaction and found that these aliphatic
Table 2. Synthesis of polyhyroquinolines in presence of catalytic amounts of NHCa
Entry
R1
Product
Time (min)
Yield (%)
1
2
Ph
4-OMe-Ph
4-Cl Ph
4a
4b
4c
4d
4e
4f
20
25
25
25
25
30
25
30
20
25
25
30
92
92
94
90
88
90
92
89
92
89
86
88
3
4
4-Me- Ph
3-NO2 Ph
2-Cl Ph
5
6
7
3,4 OMePh
4-OH, 3-OMe Ph
2,4-Cl Ph
C6H11 Ph
C2H5CHCH3
C2H5
4g
4h
4i
8
9
10
11
12
4j
4k
4l
aAraldehydes þ ethylacetoacetate þ dimedone þ ammonium acetate þ NHC (5 mol%).

1814
S. FATMA ET AL.
aldehydes also react smoothly to produce corresponding dihydropyridines in
excellent yields with just 5 mol% of NHC.
Scheme 4. Mechanistic pathway for the synthesis of product 4.

POLYHYDROQUINOLINES VIA HANTZSCH REACTION
1815
The plausible mechanistic pathway for the synthesis of product 4 is shown in
Scheme 3. Identity of the products was confirmed by comparison of the physical
1
and spectral data (IR and H NMR) with those of the reported compounds[19–30]
(see the supporting information).
CONCLUSION
In summary, we have reported that thiazolium ion (nucleophilic heterocyclic
carbene) is a highly efficient and green catalyst for the synthesis of PHQs by means
of four-component condensation of an aldehyde, b-dicarbonyl compounds, and
ammonium acetate in one pot. This method is applicable to a wide range of substrates
including aromatic and aliphatic, providing the corresponding PHQs in excellent
yields. The present methodology offers many advantages such as reduced reaction
time and economic viability of the catalyst compared with other conventional cata-
lysts. Most importantly, the proposed method seems to be one of the best examples
of green methodology.
EXPERIMENTAL
Preparation of Catalyst (NHC)
Thiamine hydrochloride (0.5 g) was dissolved in 1.6 ml of water and 6 ml of
95% ethanol was added. The solution was cooled in an ice bath and then 1 ml of
3M NaOH was added dropwise with stirring in a manner such that the temperature
remained below 20 ꢀC. Intense yellow-colored solution changed to pale yellow
solution, resulting in the formation of thiazolium ion (N-heterocyclic carbene).
Synthesis of PHQs (4a–l) Using NHC as Catalyst
Aldehyde (5 mmol), ethylacetoacetate (5 mmol), dimedone (5 mmol), and
ammonium acetate (5.2 mmol) were added to 5 mol% of NHC, and the resulting
mixture was heated to 60 ꢀC for an appropriate time (monitored by thin-layer chro-
matography, TLC). The reaction mixture, after being cooled to room temperature,
was poured into cold water and extracted with ethylacetate. The organic layer was
washed with brine and dried over Na2SO4 under reduced pressure (formation of
crude yellow products). The products were purified by recrystallization from ethanol
to afford PHQs in 90–96% yield.
ACKNOWLEDGMENT
We sincerely thank SAIF, Punjab University, Chandigarh, for providing
microanalyses and spectra.
FUNDING
The authors are also grateful to the Council of Scientific and Industrial
Research, New Delhi, for the award of research fellowships.

1816
S. FATMA ET AL.
SUPPLEMENTARY DATA
General information and spectral data can be accessed on the publisher’s
website.
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