Multicomponent diversity-oriented synthesis of symmetrical and unsymmetrical 1,4-dihydropyridines in recyclable glycine nitrate (GlyNO 3) ionic liquid: A mechanistic insight using Q-TOF, ESI-MS/MS

Article abstract of DOI:10.1039/c4ra02169j

Multicomponent reactions are compelling strategies for generating a chemically diverse set of multifunctionalized heterocyclic motifs with high atom economy, rendering the transformations green. These strategies can further become more prolific if catalyst recyclability, compatibility and exploration of precise mechanistic pathways are considered. To this end, an inexpensive and recyclable glycine nitrate (GlyNO₃) ionic liquid has been efficiently employed to obtain diversely substituted symmetrical and unsymmetrical 1,4-dihydropyridines with up to 93% yields via three and four components, respectively. The catalyst recyclability and compatibility to obtain both symmetrical and unsymmetrical 1,4 DHPs under identical reaction conditions are added benefits to its practical utility. Furthermore, progress of the reaction was monitored by Q-TOF, direct infusion electrospray ionization mass spectrometry (ESI-MS), and key cationic intermediates involved in the reaction have been further identified by a tandem MS experiment (Q-TOF, ESI-MS/MS), which served as the proof of concept to the mechanistic model. This is the first report which revealed that the Hantzsch reaction predominantly follows the diketone pathway among four competing reaction pathways. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02169j

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Multicomponent diversity-oriented synthesis
of symmetrical and unsymmetrical
Cite this: RSC Adv., 2014, 4, 19111
1,4-dihydropyridines in recyclable glycine
nitrate (GlyNO3) ionic liquid: a mechanistic
insight using Q-TOF, ESI-MS/MS†‡
c
a
a
abc
Rajesh Kumar,ab Nitin H. Andhare, Amit Shard, Richa and Arun Kumar Sinha
*
Multicomponent reactions are compelling strategies for generating
a chemically diverse set of
multifunctionalized heterocyclic motifs with high atom economy, rendering the transformations green.
These strategies can further become more prolific if catalyst recyclability, compatibility and exploration
of precise mechanistic pathways are considered. To this end, an inexpensive and recyclable glycine
nitrate (GlyNO3) ionic liquid has been efficiently employed to obtain diversely substituted symmetrical
and unsymmetrical 1,4-dihydropyridines with up to 93% yields via three and four components,
respectively. The catalyst recyclability and compatibility to obtain both symmetrical and unsymmetrical
1,4 DHPs under identical reaction conditions are added benefits to its practical utility. Furthermore,
progress of the reaction was monitored by Q-TOF, direct infusion electrospray ionization mass
spectrometry (ESI-MS), and key cationic intermediates involved in the reaction have been further
identified by a tandem MS experiment (Q-TOF, ESI-MS/MS), which served as the proof of concept to the
mechanistic model. This is the first report which revealed that the Hantzsch reaction predominantly
follows the diketone pathway among four competing reaction pathways.
Received 24th February 2014
Accepted 28th March 2014
DOI: 10.1039/c4ra02169j
www.rsc.org/advances
recognized as calcium channel modulators but were later
developed as cardiovascular and antihypertensive drugs, which
includes amlodipine, felodipine, nicardipine and nifedipine6
(Fig. 1). Beside this, these structural motifs are also credited
with such versatile biological properties as anticonvulsant,7
radioprotective,8 selective antagonism of adenosine-A3 recep-
tors,9 anticancer,10 HIV protease inhibition,11 and the treatment
of Alzheimer's disease.12
Introduction
The creation of multiple carbon–carbon or carbon–hetero
bonds in a one-pot reaction helps in minimizing the waste of
time and energy. These benets are broadly encompassed
under the periphery of green chemistry and are generally
accomplished by using the multicomponent reaction (MCRs),1
which have been used for the preparation of structurally
diverse, drug-like compounds.2 As a result, they have emerged
as signicant tool in organic synthesis.3
One prominent MCR that produces an interesting class of
nitrogen-based heterocycles is the venerable Hantzsch reaction,
which provides 1,4-dihydropyridines (1,4-DHPs) as privileged
pharmacophores.4 DHP derivatives exhibit a wide range of
pharmacological properties.5 Initially, these molecules were
aNatural Plant Products Division, CSIR-Institute of Himalayan Bioresource
Technology, Palampur-176061, H.P., India
bAcademy of Scientic and Innovative Research (AcSIR), New Delhi, India
cMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
BS10/1, Sector 10, Janakipuram Extension, Sitapur Road, Lucknow-226031, U.P.,
India. E-mail: aksinha08@rediffmail.com
† Some part of work carried out at CSIR-IHBT, Palampur (H.P.).
‡ Electronic supplementary information (ESI) available: 1H and 13C NMR data and
spectra of symmetrical and unsymmetrical 1,4-DHPs. See DOI: 10.1039/c4ra02169j
Fig. 1 1,4 DHPs used as clinical drugs.
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Conventionally, 1,4-DHPs accessed through Hantzsch reac-
tion, reduction of pyridines, addition to pyridines, or cycload-
dition13 suffer from the limitations, including low to moderate
yields besides requiring harsh conditions and longer reaction
times. As a result, several modications have been developed
for the classical Hantzsch approach.14 However, despite their
potential usefulness, many of these methods still involve
expensive and toxic catalysts, cumbersome product isolation
procedures and incompatibility with certain functional groups.
Thus, these methods are not aligned with the principles of
green chemistry. Hence, the challenge for a sustainable envi-
ronment calls for more general and viable routes, which would
be of great relevance to both synthetic and medicinal chemists.
In this context, ionic liquids (ILs) is being hailed as the green
solvent of the future, which increases the portfolio of environ-
mentally benign organic synthesis due to their particular
properties such as undetectable vapour pressure, ease of
recovery and reuse.15 Thus far, ILs with cations derived from
imidazolium- and guanidinium-based ILs have been used as
catalysts for the Hantzsch reaction.16 Although these ILs help to
reduce the risk of air pollution, concerns are being raised over
their potential toxicity to aquatic environments and inacces-
sible biodegradability.17
Scheme 1 Synthesis of symmetrical and unsymmetrical 1,4-dihy-
dropyridines in GlyNO3 ionic liquid via three- and four-component
reactions.
Table 1 Optimization study for the synthesis of 1,4-dihydropyridinsa
Therefore, the development of bio-degradable ILs based on
amino acids and their derivatives to replace the above cations is
another promising approach because these compounds are the
most abundant natural source of quaternary nitrogen precur-
sors.18 Moreover, low cost, easy preparation, and their proper-
ties to act as both anions and cations are added advantage in
these amino acid ionic liquids18b,e,19 (AAILs).
As a continuation of our ongoing endeavours in developing
novel and practical multicomponent reactions to synthesize
useful heterocyclic compounds,20 we herein present the cata-
lytic efficiency of glycine nitrate (GlyNO3) ionic liquid under
microwave (MW) irradiation for the multicomponent synthesis
of aromatic/heterocyclic symmetrical and unsymmetrical 1,4-
DHPs under identical reaction conditions (Scheme 1).
Furthermore, a detailed Q-TOF-, ESI-MS- and ESI-MS/MS-based
mechanistic study revealed that the reaction predominately
follows the diketone pathway among four competing pathways.
S. No
Ammonium salt
Solvent
Ionic liquid
Yieldb (%)
1
2
3
4
NH4OAc
NH4BF4
NH4Cl
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlyNO3
GlySO4
GlyTFA
GlyOAC
GlyCl
45
30
20
70
73
82
80
87
19
34
20
30
40
66
40
59
57
29
26
55
65
20
NH4HCO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
5
6c
7d
8e
9
10
11
12
13
14
15
16
17
18
19
20f
21
22
DCM
DMSO
PEG 400
EtOH–H2O
EtOH
EtOH
EtOH
EtOH
—
EtOH
EtOH
EtOH
EtOH
GlyNO3
—
GlyNO3
Glycine
HNO3
Results and discussion
Aer an initial survey of reaction conditions, a mixture of
4-chlorobenzaldehyde (1a, 0.5 mmol), methylacetoacetate (2a, 2
a
Experimental conditions: 0.5 mmol of 4-chlorobenzaldehyde,
methylacetoacetate (2 equiv.), (NH4)2CO3 (2 equiv.), GlyNO3
(0.5 equiv.) in 1 mL of EtOH under MW at P ¼ 100 W, 90 ꢀC for
20 min. b Isolated yield (aer recrystallization in water and methanol).
equiv.), ammonium acetate (3a,
2 equiv.) and GlyNO3
(0.4 equiv.) as a catalyst was irradiated under focused mono-
ꢀ
mode microwave (CEM, P ¼ 100 W, 90 C) for 20 min in EtOH
c
d
e
f
GlyNO3 (0.5 equiv.). GlyNO3 (0.6 equiv.). EtOH (1 mL). Reux for
(0.5 mL), producing 1,4-dihydropyridines 4a in 45% yield
(Table 1, entry 1). To further increase the yield of 4a, various
sources of ammonium salt were screened (Table 1, entries 2–5),
wherein the satisfactory yield of 4a up to 73% was obtained with
ammonium carbonate (Table 1, entry 5). Thereaer, the effect of
5 h. For entries 1–7, EtOH ¼ 0.5 mL; entries 8–22, solvent ¼ 1 mL.
A further increase in the amount of catalyst could not exert
the amount of catalyst (Table 1, entries 6–7) was considered, any positive inuence on the yields of 4a (Table 1, entry 7).
and a yield of 82% was obtained with 0.5 equiv. GlyNO3 (Table 1, Gratifyingly, the yield was improved to 87% with the increased
entry 6).
in volume of EtOH up to 1 mL (Table 1, entry 8). A further
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increase in the volume of EtOH fails to enhance the yields of 4a. the crucial role of solvents and catalysts. The reaction under
Thereaer, the effects of different solvents and co-solvents conventional conditions by reuxing the reaction mixture for
(Table 1, entries 9–13), and catalysts (Table 1, entries 14–17) 5 h failed to improve the yield of 4a (Table 1, entry 20).
were studied, but inferior yields were obtained compared with Surprisingly, an experiment with glycine (Table 1, entry 21) and
Table 1, entry 8.
HNO3 (Table 1, entry 22) resulted in a drastic decrease in the
Control experiments in the absence of solvents and catalysts yield of 4a, which emphasized the importance of GlyNO3 IL in
(Table 1, entries 18–19) produced 4a in low yield, demonstrating catalysis.
Table 2 Substrate scope of GlyNO3-catalyzed synthesis of symmetrical 1,4-dihydropyridinesa
a
Experimental conditions: 0.5 mmol of substituted benzaldehyde, methylacetoacetate (2 equiv.), (NH4)2CO3 (2 equiv.), GlyNO3 (0.5 equiv.) in 1 mL
of EtOH under MW at P ¼ 100 W, 90 ꢀC for 20 min. b Isolated yield (aer recrystallization in water and methanol).
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Table 3 Substrate scope of GlyNO3-catalyzed synthesis of unsymmetrical 1,4-dihydropyridinesa
a
Experimental conditions: 0.5 mmol of substituted benzaldehyde, 2a (1 equiv.), 3a (1 equiv.), (NH4)2CO3 (2 equiv.), GlyNO3 (0.5 equiv.) in 1 mL of
EtOH under MW at P ¼ 100 W, 90 ꢀC, for 20 min. b Isolated yield (aer recrystallization in water and methanol).
With the optimized reaction conditions in hand for the thiophene-2-carboxaldehyde and ammonium carbonate, which
synthesis of symmetrica1 1,4-DHPs (Table 1, entry 8), the afforded the desired compound in good yield (Table 2, entries
generality and scope of this one-pot, three-component 4j–l).
Hantzsch reaction was then explored. For this, a wide range of
Aer the successful synthesis of three-component symmet-
substituted benzaldehyde compounds, including heterocyclic rical 1,4-DHPs, our goal was to synthesize four-component
moieties (1a–i), methylacetoacetate (2a), and ammonium unsymmetrical 1,4-DHPs, also known as polyhydroquinoline,
carbonate (3a), were irradiated under focused MW (P ¼ 100 W, which enjoys the status of being privileged motifs in terms of
90 ꢀC) for 20 min, which produced the corresponding 1,4-DHPs their diverse biological proles, compared with symmetrical
4a in good-to-excellent yields (Table 2, entries 4a–i). During the 1,4-DHPs.21
substrate scope study, it was observed that the catalyst exhibited
Recently, these motifs have been recognized as lead mole-
remarkable activity for heterocyclic-substituted benzaldehydes, cules in antidiabetic drug discovery.22 There are a plethora of
particularly for thiophene containing moiety (Table 2, entries reagents and catalyst reported in the literature for the synthesis
4d–i). Therefore, we further extended our substrate scope by of unsymmetrical 1,4-DHPs.23 However, some of these suffer
using various dicarbonyl compounds in conjunction with from limitations such as the usage of precious metal catalysts,
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longer reaction time (6–11 h), two-step synthesis, cumbersome 1,4-DHPs, we were also interested in investigating whether our
product isolation, selectivity and recyclability issues.
catalytic system could efficiently result in the synthesis of
In addition, Rajesh et al.23x have recently reported hydro- unsymmetrical 1,4-DHPs by overcoming the existing lacunae of
magnesite as a heterogeneous solid-based catalyst for the reported protocols.23
synthesis of 1,4-DHPs. Despite promising results, this meth-
odology has limited substrate scope due to the non-involvement thiophene-2-carboxaldehyde (1a), methylacetoacetate (2a), 5,5-
of any heterocyclic benzaldehydes. dimethyl-1,3-cyclohexanedione (2b) and ammonium carbonate
We were pleased to observe that the mixture of 5-bromo-
To the best of our knowledge, only a small number of reports (3a) successfully condensed in one pot under similar reaction
exist in literature in which the synthesis of unsymmetrical and conditions25 providing 5a in 83% yield. Thereaer, various
symmetrical 1,4-DHPs is carried out under identical reaction substituted aromatic or heterocyclic benzaldehydes (1a–i) were
conditions; these suffer from limitations such as longer reac- condensed with 2a, 2b and 3a to produce unsymmetrical 1,4-
tion times, poor substrate scopes and tedious synthesis of DHPs (Table 3, 5b–i) in excellent yields.
catalysts.24 Considering the sheer importance of unsymmetrical
From an economical point of view, the recyclability of
GlyNO3 was also considered. The IL retained high reactivity for
up to six cycles (Scheme 2).
Mechanistic study
Mechanistically, it was presumed that there are four plausible
pathways26 for the synthesis of symmetrical 1,4-DHPs (Fig. 2).
These are (i) enamine (ii) diketone, (iii) dienamine and (iv)
imine pathways (Fig. 2 and see ESI‡).
Q-TOF electrospray ionization mass spectrometry (ESI-MS) is
the preferred technique for studying reaction intermediates
because of its ability to “sh” ionic or ionized intermediates
Scheme 2 Recyclability study of catalyst for the synthesis of 1,4-
dihydropyridines.
Fig. 2 Various plausible pathways for the synthesis of 1,4-dihydropyridines.
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directly from reaction solutions into the gas phase with high
speed and sensitivity27 to prove the feasibility of precise path-
ways among four competing mechanisms involved in the
synthesis of 1,4-dihydropyridines. Moreover, its tandem
version, ESI-MS/MS, is rapidly becoming the technique of
choice for solution-phase mechanistic studies in chemistry.28
Therefore, we performed Q-TOF ESI (+ve) MS studies on
aliquots of samples withdrawn aer 10 min from the GlyNO3-
catalyzed reaction of 1g, 2a and 3a (Scheme 3)29 at capillary
voltage (3100 V), cone voltage (25 V), dissolution temp. (200 ꢀC)
Scheme 4 Key intermediates of four plausible pathways.
For further structure elucidation in the context of diketone
pathways and product formation, tandem MS/MS experiments
were carried out for a few selected ions observed in the TIC
(Fig. 3) at m/z 308.17 ¼ m1, 325.29 ¼ m2, 344.31 ¼ m3 and 327.31
¼ m4. The MS/MS or MS2 spectra derived from the ion of m/z
308.17 ¼ m1 showed peak m/z at 276.14 and 224.15 assigned as
[4g ꢁ OCH3]+ and [4g ꢁ C4H3S + H]+ (Fig. 4), respectively,
conrmed the product formation.
ꢀ
and source temp. (80 C).
The total ion chromatogram (TIC) revealed the presence of
ions at m/z 308.26 (m1), 325.29 (m2), 344.31 (m3), 327.31 (m4),
224.15 (m5),30 211.16 (m6), 179.09 (m7), and 117.13 (m8), which
corresponds to [4g + H]+, [4g + NH3 +H]+, [11a + H]+, [10a + H]+,
[19a + H]+, [7a + H]+, [7a ꢁ OMe]+ and [2a + H]+, respectively. The
presence of characteristic peaks m3 ¼ [11a + H]+, m4 ¼ [10a + H]+
and m6 ¼ [7a + H]+ in Fig. 3 revealed the possibility of diketone
pathways (Fig. 2), and the absence of key intermediate 6a
(enamine), 13a (dienamine) and 17a (imine) (Scheme 4) in the
TIC (Fig. 3) ruled out the possibility of enamine, dienamine and
imine pathways.
In the case of m2, the MS2 spectra (Fig. 5) exhibited the
parent ion m2 ¼ [4g + NH3 + H]+ and daughter ion with m/z at
308.17 and 224.28 corresponded to [4g ꢁ NH3 + H]+ and [4g ꢁ
C4H3S + H]+, respectively, conrming the ammoniated adduct
of desired product, i.e. 4g (Scheme 3).
To further conrm the presence of the intermediate (m3) in
the context of diketone pathways, the MS2 experiment was
carried out of m3 ¼ [11a + H]+ ion (Fig. 6). The MS/MS spectra
revealed the presence of the ion with m/z 327.34, 309.31, 295.29
and 211.21, which were diagnosed as [11a ꢁ NH2]+, [11a ꢁ NH2
ꢁ H2O]+, [11a ꢁ NH2 ꢁ H2O ꢁ CH3]+ and [11a ꢁ NH2 ꢁ H2O ꢁ
CH3 ꢁ C4H4O2]+, respectively, conrmed the fragments of m3
and their involvement in diketone pathways.
Most importantly, the key intermediate involved in diketone
pathway m4 ¼ [10a + H]+ was also ascertained by the MS2
Scheme 3 The one-pot, three-component Hantzsch reaction.
Fig. 3 TIC of Q-TOF, ESI(+) MS of sample withdrawn after 10 min for three-component Hantzsch reaction of 1g, 2a and 3a catalyzed by GlyNO3.
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Fig. 4 On line Q-TOF, ESI(+) MS/MS of peak m1 ¼ 308.17 as shown in Fig. 2.
Fig. 5 On line Q-TOF, ESI(+) MS/MS of peak m2 ¼ 325.29, as shown in Fig. 2.
experiment. The MS2 spectra (Fig. 7) exhibited the parent ion m4
On the basis of the Q-TOF, ESI-MS/MS studies, it is deter-
¼ [10a + H]+ and daughter ions with m/z 295.18, 243.21 and mined that GlyNO3 IL-catalyzed three-component Hantzsch
211.13 correspond to [10a ꢁ OCH3]+, [10a ꢁ C4H3S]+ and [10a ꢁ reaction follows the diketone pathway among four competing
C5H7O3]+, respectively, conrmed the fragments of ion m4 and mechanistic pathways (Fig. 2).
their involvement in diketone pathways.
On the other hand, the possibility of enamine pathways cannot
be ignored because of the observation of peak m6 ¼ [7a + H]+
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Fig. 6 On line Q-TOF, ESI(+) MS/MS of peak m3 ¼ 344.31, as shown in Fig. 2.
Fig. 7 On line Q-TOF, ESI(+) MS/MS of peak m4 ¼ 327.31, as shown in Fig. 2.
(Fig. 3) during the analysis of aliquots of samples withdrawn aer
Finally, on the basis of control experiments and the Q-TOF,
10 min, which is also one of the intermediates of enamine path- ESI-MS/MS studies, we can say that the most predominant
ways (Fig. 2). Therefore, two control experiments or experiments pathway for the synthesis of symmetrical 1,4-DHPs is diketone,
to validate our perception regarding diketone pathways were rather than enamine, dienamine and imine. This is the rst
carried out in sequential one-pot two-step ways (Schemes 5 and 6). report that proved the participation of diketone pathways in the
The results revealed that 61% of the product yield (Scheme 5) was synthesis of symmetrical 1,4-DHPs by using the Q-TOF, ESI-MS/
obtained via diketone pathways, compared with a 22% yield via MS studies.
enamine pathways (Scheme 6).
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Scheme 5 Sequential one-pot, two-step synthesis of 1,4-DHP via diketone pathway.
Scheme 6 Sequential one-pot, two-step synthesis of 1,4-DHP via enamine pathway.
General procedure for the synthesis of unsymmetrical
1,4-dihydropyridins from substituted benzaldehydes
Conclusion
In summary, an operationally simple and highly efficient (Table 3, 5a–i)
one-pot multicomponent reaction for the synthesis of
Substituted benzaldehyde (0.5 mmol), methylacetoacetate
(1 equiv.), 5,5-dimethyl-1,3-cyclohexanedione (1 equiv.),
ammonium carbonate (2 equiv.) and glycine nitrate (0.5 equiv.)
were taken in 1 mL ethanol in a round-bottomed ask, and the
reaction mixture was subjected to microwave irradiation by
using a CEM monomode microwave at P ¼ 100 W, 90 ꢀC for
20 min. Aer completion, the crude reaction mixture was
ltered to obtain GlyNO3. The ltrate was vacuum evaporated
and then recrystallized from water–methanol, which gave an
isolated yield of 5a–i in the range of 52–93% yields. Products
were identied and conrmed by their 1H, 13C NMR spectra and
HRMS values.
symmetrical and unsymmetrical 1,4 DHPs has been devel-
oped, which could have great importance for synthetic and
medicinal chemistry. The methodology is practical, recy-
clable and economical, in addition to being exible, because
it also allows heterocyclic benzaldehydes to participate in the
synthesis of both symmetrical and unsymmetrical 1,4 DHPs
under identical reaction conditions. Furthermore, mecha-
nistic studies using Q-TOF, ESI-MS/MS revealed that the
synthesis of symmetrical 1,4 DHPs predominately follows the
diketone pathway among four competing reaction pathways.
Finally, we anticipate that this catalytic system will nd
applications in both academia and industry. The Q-TOF, ESI-
MS/MS-based studies may also helpful to reveal the mecha-
nistic details of numerous other reactions. The mechanistic
study related to unsymmetrical 1,4 DHPs is currently under
investigation.
Acknowledgements
RK, NHA and AS are indebted to CSIR and UGC, New Delhi, for
the award of research fellowships. The authors gratefully
acknowledge Director(s) CDRI, Lucknow and IHBT, Palampur
for their kind cooperation and encouragement. This work was
supported by Council of Scientic and Industrial Research
(project CSC-0108 and ORIGIN). Thanks to Mr Shiv Kumar and
Pawan Kumar for providing spectral data. CDRI Communica-
tion No. 8644.
Experimental section
General procedure for the synthesis of symmetrical
1,4-dihydropyridins from substituted benzaldehydes
(Table 2, 4a–l)
Substituted benzaldehyde (0.5 mmol), dicarbonyl compound
(2 equiv.), ammonium carbonate (2 equiv.) and glycine nitrate
(0.5 equiv.) were taken in 1 mL ethanol in a round-bottomed
ask and the reaction mixture was subjected to microwave
irradiation by using a CEM monomode microwave at P ¼ 100 W,
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dimethyl 2,6-dimethylpyridine-3,5-dicarboxylate [19a + H]+
(see ESI‡).
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 19111–19121 | 19121