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Research Cite this article: Sharma MG, Rajani DP, Patel HM. 2017 Green approach for synthesis of bioactive Hantzsch 1,4-dihydropyridine derivatives based on thiophene moiety via multicomponent reaction. R. Soc. open sci. 4: 170006. http://dx.doi.org/10.1098/rsos.170006 Received: 1 February 2017 Accepted: 16 May 2017 Subject Category: Chemistry
Green approach for synthesis of bioactive Hantzsch 1,4-dihydropyridine derivatives based on thiophene moiety via multicomponent reaction M. G. Sharma1 , D. P. Rajani2 and H. M. Patel1 1 Department of Chemistry, Sardar Patel University, University Campus,
Vallabh Vidyanagr, 388 120 Gujarat, India 2 Microcare laboratory, Surat, Gujarat, India
HMP, 0000-0003-4740-7329 Subject Areas: green chemistry/organic chemistry/crystallography Keywords: Green approach, Hantzsch reaction, one-pot multicomponent reaction, ceric ammonium nitrate, single crystal study, microbial study Author for correspondence: H. M. Patel e-mail: [email protected] This article has been edited by the Royal Society of Chemistry, including the commissioning, peer review process and editorial aspects up to the point of acceptance. Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9. figshare.c.3796852.
A novel green and efficient one-pot multicomponent reaction of dihydropyridine derivatives was reported as having good to excellent yield. In the presence of the catalyst ceric ammonium nitrate (CAN), different 1,3-diones and same starting materials as 5-bromothiophene-2-carboxaldehyde and ammonium acetate were used at room temperature under solvent-free condition for the Hantzsch pyridine synthesis within a short period of time. All compounds were evaluated for their in vitro antibacterial and antifungal activity and, interestingly, we found that 5(b–f) show excellent activity compared with Ampicillin, whereas only the 5e compound shows excellent antifungal activity against Candida albicans compared with griseofulvin. The cytotoxicity of all compounds has been assessed against breast tumour cell lines (BT-549), but no activity was found. The X-ray structure of one such compound, 5a, viewed as a colourless block crystal, corresponded accurately to a primitive monoclinic cell.
1. Introduction More than a hundred years ago, the reaction to produce 1,4dihydropyridines (1,4-DHPs) was reported by Arthur Hantzsch [1]. These are important precursors due to their pharmacological and biological activities, such as antihypertensive, anti-anginal
2017 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
Br
2
Br
O
O CAN, R. T.
1 R2
R1 + O
R1
R2
1–3 hrs N H
O
2
O
3 NH4+
–OAc
5 (a–g)
4 R1 = –OCH3, –OC2H5, –CH3, –OC2H5, –OC2H5, –OCH3, dimedone R2 = –OCH3, –OC2H5, –CH3, –OCH3, –CH3, –CH3, dimedone
Scheme 1. Multicomponent reaction strategies for 1,4-DHP construction.
and as calcium channel blockade for cardiovascular disease. Consequently, several clinically important drugs appeared on the market with variable new active functional groups in their main skeleton, such as Nicardipine, Nifedipine, Nimodipine, Felodipine, Isradipine and Amlodipine [2–5]. Recently, various attempts have been taken up to improve the Hantzsch reaction using different alternative processes [6–10]. However, most of these reactions were reported with new trends as one-pot multicomponent reactions (MCRs) in the last 10–15 years; these reactions were carried out with certain disadvantages like: longer reaction time, expensive catalyst, higher temperature and tedious workup procedure. Great diversity in MCRs [11–13], developed using various ionic liquids as various Lowry-Bronsted acids, with several advantages has been well documented [14–16]. The clinical significance of pyran, thiophene derivatives of 3-acetylcoumarine based on 1,4-DHPs was the concern that they were reported to have an equivalent cytotoxic effect as the standard CHS 828 against a breast cancer cell line [17]. The above synthetic applications and their medicinal importance encourage us to develop and strive for the enhancement of the pharmacologically bioactive novel 1,4-DHP compounds using MCR. Moreover, the thrust of our work was to enhance the reactivity with suitable electron-releasing and withdrawing groups in reactants to minimize the by-products, and diminish the time of reaction and use of solvent, to establish our protocol with more economy and with a green concept. In this study, we illustrate our recent work on the synthesis of some novel thiophene-based 1,4-DHP derivatives from different 1,3-diones, and same starting materials as 5-bromothiophen-2-carboxaldehyde and ammonium acetate under room temperature and solvent-free conditions by using ceric ammonium nitrate (CAN) as the catalyst during a short period of time; good to excellent yield is reported with a simple workup procedure, which is shown in scheme 1.
2. Material and methods 2.1. General All reagents used in this study were purchased from commercially available sources without further purification unless specified otherwise. The synthesized compounds were characterized as anchored in ESI-MS spectra as determined by the Shimadzu GCMS-Qp 2010 spectrometer. Elemental analyses were performed in a Perkin-Elmer 2400 Series-II elemental analyser and the results were within ±0.4% of the theoretical values, unless otherwise noted. The stereochemistry and structure of all compounds were confirmed by 1 H-NMR and 13 C-APT spectra as recorded on Bruker Advance III (1 H: 400 MHz) and (13 C: 100 MHz), respectively, using CDCl3 as an internal standard. Splitting patterns were described as singlet (s), doublet (d), triplet (t), quartet (q) and broad (br). The values of chemical shift (δ) were given in ppm and coupling constants (J) in hertz (Hz). IR spectra were recorded on an ABB MB3000 spectrophotometer. Melting points were determined by an open capillary tube melting point apparatus and were uncorrected. The progress of reaction for compounds (5a–f) was monitored by silica gel 60 F254 (Merck)-coated thin-layer chromatography (TLC) plates. Reported Rf values correspond to elution with a 4 : 1 (n-hexane:ethyl acetate) mobile phase. Some of the compounds were separated
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S CHO
O
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S
Table 1. Solvent-free one-pot multicomponent reaction of 5-bromothiophene-2-carboxaldehyde (5BT-2C) and different 1,3-diones catalysed by CAN (ceric ammonium nitrate). 3
4
entry 1
5BT-2C
R1 OCH3
R2 OCH3
NH4 OAc
2
5BT-2C
OC2 H5
OC2 H5
3
5BT-2C
CH3
CH3
4
5BT-2C
OCH3
5
5BT-2C
CH3
6
5BT-2C
7
5BT-2C
time (h) 1.15
melting point (° C) 180–185
products 5(a–g) 5a
Rf value 0.56
yield (%) 77
NH4 OAc
1.15
140–145
5b
0.59
73
NH4 OAc
1.15
138–142
5c
0.19
75
OC2 H5
NH4 OAc
2.30
118–123
5d
0.44
51
OC2 H5
NH4 OAc
3.00
127–132
5b + 5c + 5e
0.40
73(21 + 23 + 29a )
CH3
OCH3
NH4 OAc
3.00
122–125
5a + 5c + 5f
0.46
75(22 + 20 + 33a )
dimedone
dimedone
NH4 OAc
2.30
210–213
5g
0.26
35
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a Indicates the % yield of pure compounds 5e and 5f.
Table 2. Antibacterial activity in microgram per millilitre of the synthesized compounds (5a–5f). E. coli, Escherichia coli; S. typhi, Salmonella typhi; B. subtilis, Bacillus subtilis; S. aureus, Streptococcus aureus; A*, Ampicillin; MTCC, Microbial Type Culture collection. compounds
E. coli MTCC443
S. typhi MTCC98
S. aureus MTCC96
B. subtilis MTCC441
5a
100
250
250
250
5b
200
500
200
100
125
250
200
......................................................................................................................................................................................................................... .........................................................................................................................................................................................................................
5c
62.5
.........................................................................................................................................................................................................................
5d
100
200
100
5e
250
250
100
5f
200
100
125
A*
100
100
250
62.5
.........................................................................................................................................................................................................................
100
.........................................................................................................................................................................................................................
62.5
.........................................................................................................................................................................................................................
250
.........................................................................................................................................................................................................................
and purified by column chromatography using an n-hexane:ethyl acetate (4 : 1) mobile phase. Single crystal X-ray data were collected on Rigaku SCX mini diffractometer by graphite monochromatic Mo-Kα radiation.
2.2. Synthesis of 1,4-dihydropyridines (5a–5c & 5 g) 5-Bromothiophene-2-carboxyaldehyde (1.91 g, 0.01 mol), ammonium acetate (0.77 g, 0.01 mol), different 1,3-diones (1–2.5 g, 0.01/0.02 mol) and CAN (0.28 g, 0.5 mmol) were added to a 100 ml round bottom flask. The mixture was stirred well for 1–2.5 h at room temperature, then the product was poured out and the mixture became solid. The progress of the reaction was monitored by TLC. The product was washed with water and then treated with n-hexane to remove impurities; after drying, the crude brown/yellow product was recrystallized using ethanol followed by charcoal treatment.
2.3. Synthesis of 1,4-dihydropyridines (5d) 5-Bromothiophene-2-carboxyaldehyde (1.91 g, 0.01 mol), ammonium acetate (0.77 g, 0.01 mol), ethylacetoacetate (1.3 ml, 0.01 mol), methylacetoacetate (1.1 ml, 0.01 mol) and CAN (0.28 g, 0.5 mmol) were added to a 100 ml round bottom flask. The mixture was stirred well for 2.5 h at room temperature; then the product was poured out and the mixture became solid. We obtained three possible products: 5a, 5b and 5d. Progress of the reactions was monitored by TLC and in the case of compound 5d, we confirmed the products by comparing spots on the TLC plate. We obtained the 5d product in pure form, by dissolving the crude material in a (1 : 4) mixture of ethyl acetate: n-hexane and separating it by filtration, with a very low amount of filtrate obtained. The remaining crude material may be a mixture of the products 5a and 5b. In the remaining filtrate, we obtained hazy crystals of product 5d (after 15–20 min).
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2
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3
Table 3. Antifungal activity in microgram per millilitre of the synthesized compounds 5(a–f). C. albicans, Candida albicans; A. niger, Aspergillus niger. A. niger >1000
5b
500
1000
5c
>1000
250
5d
>1000
500
5e
250
>1000
5f
500
500
griseofulvin
500
100
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Table 4. Cytotoxicity assay of compounds 5(a–f) on BT-549 Cell Line in EC50 (µM). sr. no. 1
compounds 5a
EC50 (µM) 42.0
2
5b
52.5
3
5c
>100
4
5d
45.5
5
5e
81.8
6
5f
77.7
7
doxorubicin
0.04
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2.4. Synthesis of 1,4-dihydropyridines (5e & 5f) 5-Bromothiophene-2-carboxyaldehyde (1.91 g, 0.01 mol), ammonium acetate (0.77 g, 0.01 mol), acetylacetone (1 ml, 0.01 mol), ethyl acetoacetate (1.3 ml, 0.01 mol) and CAN (0.28 g, 0.5 mmol) were added to a 100 ml round bottom flask. The mixture was stirred well for 3 h at room temperature; then the product was poured out and the mixture became solid. We obtained three possible products: 5b, 5c and 5e. The progress of the reaction was monitored by TLC and in case of compound 5e, we confirmed the products by comparing spots on the TLC plate. The Rf values for 5b, 5c and 5e are 0.59, 0.19 and 0.40, respectively. Moreover, in 5f we used methyl acetoacetate (1.1 ml, 0.01 mol) instead of ethylacetoacetate and obtained a mixture of the possible products 5a, 5c and 5f. The Rf values for 5a, 5c and 5f are 0.56, 0.20 and 0.46, respectively. The 5e and 5f compounds were separated and purified by column chromatography using an n-hexane: ethyl acetate (4 : 1) mobile phase. The antimicrobial activity of the synthesized compounds (5a–5f) was evaluated by the broth dilution method. The synthesized compounds were tested for their antibacterial activity against Gram-negative bacteria (E. coli MTCC 443, Salmonella typhi MTCC 98) and Gram-positive bacteria (Bacillus subtilis MTCC 441, Streptococcus pneumonia MTCC 1936). Ampicillin was used as the standard against bacteria. All compounds (5a–5f) were screened for antifungal activity against Candida albicans MTCC 227, Aspergillus niger, MTCC 282 and A. Clavatus MTCC 1323 at a concentration of 500 µg ml−1 in DMF. Nutrient agar and potato dextrose agars were used to culture the bacteria and fungi, respectively. The plates were inculcated by the bacteria or fungi and incubated for 24 h at 37°C for bacteria and for 72 h at 27°C for fungi and then the inhibition zones of microbial growth surrounding the filter paper disc (5 mm) were measured in millimetres. Griseofulvin was used as a standard drug for fungi. Test results are given in tables 2 and 3 for antibacterial and antifungal activity, respectively.
3. Results and discussion We prepared a number of 1,4-DHPs via MCR. According to a literature survey for the development of synthetic procedures [18–21], mainly catalyst can play an important role in the synthesis of 1,4-DHPs
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C. albicans >1000
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compounds 5a
4
Br1
C14
H11B
H14
H11C H9B
C9
C12
O4 C10 C4
H9C
C13 C3
C5
H13 H3
N
H1
C1
C2
C7
O2
H6C
H8C H6A H8B
C6 H6B
C8
O1 H8A
Figure 1. Ortep diagram for 5a.
Figure 2. Packing arrangements of 5a with hydrogen bonding.
[22–25]. Therefore, we selected the catalyst CAN to investigate their effect on product yield under solvent-free conditions at room temperature (table 1). Under these optimized reaction conditions, the simplicity and scope of a novel one-pot MCR protocol were explored. The reaction of 5BT-2C 1, ammonium acetate 4 as same starting materials and different 1,3-diones 2,3 was performed in the presence of CAN under solvent-free conditions to obtained desired 1,4-DHP derivatives with good to excellent yield at room temperature. Interestingly, we received the desired symmetrical products 5a, 5b, 5c and 5 g by using same 1,3-diones 2 or 3. If we use different 1,3-diones 2,3,
................................................
S1
C11
O3 H9A
C15
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H11A
5
Table 5. Crystal and experimental data of compound 5a.
6
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crystal description
colourless block crystal
crystal size
0.480 × 0.390 × 0.310 mm
empirical formula
C15 H16 BrNO4 S
formula weight
386.26
radiation, wavelength
MoKα(λ = 0.71075 Å) graphite monochromatic
unit cell dimensions
a = 8.0516(9) Å, b = 10.072(1) Å, c = 20.119(2) Å, β = 97.803(4)°
crystal system
monoclinic
lattice type
primitive
space ground
P21 /c (#14)
unit cell volume
V = 1616.4(3) Å3
calculated density
1.587 g cm−3
no. of molecules per unit cell, Z
4
µ (MoKα)
26.958 cm−1
F(000)
784.00
refinement of unit cell
full-matrix least-squares on F 2
......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... .........................................................................................................................................................................................................................
reflection/parameter ratio
18.61
residuals: R1 (I > 2.00 σ (I))
0.0437
Rint
0.0360
least-squares weights
w = 1/[σ 2 (Fo2 ) + (0.1000 . P)2 + 0.0000 . P], where P = (Max(Fo2 ,0) + 2Fc2 )/3
(/σ )max in the final cycle
15.000
goodness of fit indicator
1.125
maximum peak in final diff. map
0.75 e− Å−3
minimum peak in final diff. map
−0.53 e− Å−3
2θ max cut-off
55.0°
function minimized
Σ w (Fo2 − Fc2 )2
ω oscillation range
−120.0 − 60.0°
exposure rate
10.0 s per degree
detector swing angle
−30.80°
diffractometer
SCX mini
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then we get desired asymmetrical products 5d, 5e, 5f including symmetrical products 5a, 5b, 5c and 5f. We obtained a 5d product in pure form, by dissolving the crude material in a (1 : 4) mixture of ethyl acetate and n-hexane, which was filtered to separate out the undissolved crude, with a very low amount of filtrate obtained. The remaining crude may be a mixture of the products 5a, 5b (monitored by TLC). In the remaining filtrate, we got hazy crystals of product 5d (after 15–20 min). However, we hypothesized properly pre-functionalized 1,3-dione 2,3 and 5BT-2C. In this series, 5BT2C contains the electron-withdrawing group –Br, which increases the reactivity of aldehyde to C–C bond formation with 1,3-dione; the presence of a mild to moderate activating group in 1,3-dione increases the nucleophilicity of its methylene group to interact with 5BT-2C, as well as the susceptibility of its carbonyl groups to C–N bond formation by interaction with ammonium acetate. A series of smoothly controlled experiments clearly indicates that the 5BT-2C, ammonium acetate, 1,3-diones and CAN were all necessary substrates for this transformation, as mentioned in scheme 1. 1H-NMR data show signal in a range of 5.1–5.3δ, which confirms one proton present at the ipsolateral position on the aliphatic carbon. A singlet was observed at 1–3δ, which confirms the presence of two similar methyl groups in the meta position in the 1,4-dihydropyridine ring, with signals also for methyl
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1471153
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CCDC No
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In brief, we have confirmed a well-organized solvent-free green procedure for the multicomponent synthesis of dihydropyridine derivatives using the catalyst CAN. The result highlighted the solventfree procedure to be more efficient than the conventional method. The advantages of the Hantzsch pyridine synthesis are shorter reaction times, simplicity of the reaction, good product yield and easy workup procedures with regard to the build-up to the reaction, which is economical and easy, with CAN being a powerful catalyst for the many organic syntheses. The interesting finding of our work is that we obtained excellent antibacterial activity with compounds such as 5b, 5c, 5d, 5e and 5f, which were found highly active against S. aureus and B. subtillus compared with the standard drug Ampicillin, whereas compounds 5a and 5c showed equipotent activity. As far as antifungal activity is concerned, only compound 5e showed higher activity than the standard griseofulvin drug, and compounds 5b and 5f had equipotent activity. The cytotoxicity of all the compounds has been assessed against breast tumour cell lines (BT-549), but no activity was found. Ethics. We do not require any ethical approval from a local ethics committee to carry out these studies because we carried out some work with the help of other sources.
Data accessibility. We include all the experimental data including spectral characterizations in the electronic supplementary material. ESI and crystallographic details of 5a compound are available on http://dx.doi.org/10. 5061/dryad.66gd7 [26], and other figures and electronic supplementary materials are available on https://doi.org/ 10.6084/m9.figshare.4990370. Authors’ contributions. H.M.P. designed the study. M.G.S. and H.M.P. synthesized and characterized the compounds, and wrote the manuscript. D.P.R. carried out the biological activity. All authors gave their final approval for publication. Competing interests. We declare we have no competing interests. Funding. We received no funding for this study. Acknowledgements. We honestly express our thanks to the Head, Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar for providing the necessary research facilities.
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4. Conclusion
7
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and ethyl groups of esters at the desired positions. The signals of a doublet appears at 6.0–7.0δ, which confirmed the presence of aromatic protons. 13C-APT spectra show peaks in a range of 13–20δ, which confirm the presence of methyl groups. Signals at 34–35δ confirm the presence of aliphatic –CH group, whereas carbon in the pyridine ring at a double bond gave a signal at 100–110δ. Signals at 120–130δ indicate aromatic –CH groups and signals at 165–170δ confirm the presence of carbonyl groups. In the IR data, we obtained a peak near 3340 cm−1, which is for N–H stretching, and a peak around 3000 cm−1 for tertiary –C–H stretching, whereas peaks that appear between 1700 and 1600 cm−1 indicate –C=O stretching. A peak that appears between 1350 and 1300 cm−1 indicates aromatic olefin stretching. The peak that appears near 1200 cm−1 provides the proof of –C–H stretching of the methyl group. The peak that appears at 510 cm−1 indicates –C–X (C–Br) stretching and some peaks observed between 1000 and 700 cm−1 confirmed the aromatic ortho- and para- di-substituents. In mass spectral analysis, we obtained peaks at the particular mass of the compound, which confirmed the present skeleton in the moiety, and different base peaks at m/z = 332, 318, 265, 230, 145, 57 and 45; these m/z values are the major base peaks in all compounds. All the synthesized compounds 5(a–f) were screened for Gram-positive bacteria and Gram-negative bacteria and results were compared with Ampicillin as the standard drug. Compound 5c was found highly active, and compounds 5a and 5d showed equipotent activity against E. coli compared with the standard. Compound 5f showed equipotent activity with S. typhi. The interesting finding of our work is to observe excellent antibacterial activity of the 5b, 5c, 5d, 5e and 5f compounds against Staphylococcus aureus and Bacillus subtillus compared with the standard drug, whereas compounds 5a and 5c showed equipotent activity. Similarly, the compounds 5(a–f) were screened for antifungal activity with C. albicans and A. niger as the microorganisms; obtained results were compared with griseofulvin as the standard drug shown in table 3. It was found that compound 5e showed higher activity than the standard. Whereas compounds 5b and 5f had equipotent activity with the standard, and the compounds 5a, 5c and 5d had lower activity. The cytotoxicity of all synthesized compounds was checked against breast tumour cell lines (BT-549) but no activity was found, which is illustrated in table 4. The compound 5a was confirmed by a single crystal XRD analysis, which is shown in figures 1 and 2. The crystallographic experimental data are described in table 5. The packing arrangement of the molecules viewed down in the a-axis is shown along with obtained crystal structure of compound 5a. From these series, three compounds, 5a, 5c and 5f, were selected for anticancer activity at National Cancer Institute (NCI), USA.
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Tetrahedron 64, 5649–5656. (doi:10.1016/j.tet. 2008.04.040) Kataria M, Pramanik S, Kumar M, Bhalla V. 2015 One-pot multicomponent synthesis of tetrahydropyridines promoted by luminescent ZnO nanoparticles supported by the aggregates of 6,6-dicyanopentafulvene. Chem. Com. 51, 1483–1486. (doi:10.1039/c4cc09058f) Shen L, Cao S, Wu J, Zhang J, Li H, Liu N, Qian X. 2009 A revisit to the Hantzsch reaction: unexpected products beyond 1,4-dihydropyridines. Green Chem. 11, 1414–1420. (doi:10.1039/b906358g) Patel HM, Patel KD, Patel HD. 2017 Facile synthesis and biological evaluation of New Mannich products as potential antibacterial, antifungal and antituberculosis agents: molecular docking study. Curr. Bioact. Compd. 13, 47–58. (doi:10.2174/1573 407212666160517145130) Sharma S, Hazarika D, Konwar PD. 2008 A simple, green and one-pot four-component synthesis of 1,4-dihydropyridines and their aromatization. Catal. Commun. 9, 709–714. (doi:10.1016/j.catcom. 2007.08.008) Wang L, Sheng J, Zhang L, Han J, Fan Z, Tian H. 2005 Facile Yb(OTf)3 promoted one-pot synthesis of polyhydroquinoline derivatives through Hantzsch reaction. Tetrahedron 61, 1539–1543. (doi:10.1016/ j.tet.2004.11.079) Ko S, Yao C. 2006 Ceric ammonium nitrate (CAN) catalyzes the one-pot synthesis of polyhydroquinoline via the Hantzsch reaction. Tetrahedron 62, 7293–7299. (doi:10.1016/j.tet. 2006.05.037) Zolfigol MA, Safaiee M. 2004 Synthesis of 1,4-dihydropyridines under solvent-free conditions. Synlett 5, 827–828. (doi:10.1055/ s-2004-820010) Mohareb RM, Abdo NYM. 2015 A simple and efficient one-pot synthesis of Hantzsch 1,4-dihydropyridines using silica sulphuric acid as a heterogeneous and reusable catalyst under solvent-free conditions. Chem. Pharma. Bull. 63, 678–687. (doi:10.2478/s11696-0110087-1)
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1. Hantzsch A, Justus L. 1882 On the synthesis of pyridine-like compounds from aceto acetic ether and aldehyde ammonia. Ann. Cheime. 215, 1–82. (doi:10.1002/jlac.18822150102) 2. Bossert F, Meyer H, Wehinger E. 1981 4-Aryldihydropyridines, a new class of highly active calcium antagonists. Angew. Chem. Int. Ed. Engl. 20, 762–769. (doi:10.1002/anie.198107621) 3. Love B, Goodman M, Snader KM, Tedeschi R, Macko E. 1974 Hantzsch-type dihydropyridine hypotensive agents. J. Med. Chem. 17, 956–965. (doi:10.1021/ jm00255a010) 4. Gilpin PK, Pachla LA. 1999 Pharmaceuticals and related drugs. Anal. Chem. 71, 217–233. (doi:10.1021/ a1990008k) 5. Cosconati S, Marinelli L, Lavecchia A, Novellino E. 2007 Characterizing the 1,4-dihydropyridines binding interactions in the L-Type Ca2+ channel: model construction and docking calculations. J. Med. Chem. 50, 1504–1513. (doi:10.1021/ jm061245a) 6. Correa WH, Scott JL. 2001 Solvent-free, two-step synthesis of some unsymmetrical 4-aryl-1, 4-dihydropyridines. Green Chem. 3, 296–301. (doi:10.1039/B106397A) 7. Sapkal SB, Shelke KFB, Shingate B, Shingare MS. 2009 Nickel nanoparticle-catalyzed facile and efficient one-pot synthesis of polyhydroquinoline derivatives via Hantzsch condensation under solvent-free conditions. Tetrahedron Lett. 50, 1754–1756. (doi:10.1016/j.tetlet.2009. 01.140) 8. Bridgwood KL, Veitch GE, Ley SV. 2008 Magnesium nitride as a convenient source of ammonia: preparation of dihydropyridines. Org. Lett. 10, 3627–3629. (doi:10.1021/ol801399w) 9. Kumar A, Maurya RA. 2008 Efficient synthesis of Hantzsch esters and polhydroquinoline derivatives in aqueous micelles. Synlett 6, 883–885. (doi:10.1055/s-2008-1042908) 10. Mirela FL, Mladen L, Vladimir V. 2008 An efficient, metal-free, room temperature aromatization of Hantzsch1,4-dihydropyridines with urea–hydrogen peroxide adduct, catalysed by molecular iodine.
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Research Cite this article: Sharma MG, Rajani DP, Patel HM. 2017 Green approach for synthesis of bioactive Hantzsch 1,4-dihydropyridine derivatives based on thiophene moiety via multicomponent reaction. R. Soc. open sci. 4: 170006. http://dx.doi.org/10.1098/rsos.170006 Received: 1 February 2017 Accepted: 16 May 2017 Subject Category: Chemistry
Green approach for synthesis of bioactive Hantzsch 1,4-dihydropyridine derivatives based on thiophene moiety via multicomponent reaction M. G. Sharma1 , D. P. Rajani2 and H. M. Patel1 1 Department of Chemistry, Sardar Patel University, University Campus,
Vallabh Vidyanagr, 388 120 Gujarat, India 2 Microcare laboratory, Surat, Gujarat, India
HMP, 0000-0003-4740-7329 Subject Areas: green chemistry/organic chemistry/crystallography Keywords: Green approach, Hantzsch reaction, one-pot multicomponent reaction, ceric ammonium nitrate, single crystal study, microbial study Author for correspondence: H. M. Patel e-mail: [email protected] This article has been edited by the Royal Society of Chemistry, including the commissioning, peer review process and editorial aspects up to the point of acceptance. Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9. figshare.c.3796852.
A novel green and efficient one-pot multicomponent reaction of dihydropyridine derivatives was reported as having good to excellent yield. In the presence of the catalyst ceric ammonium nitrate (CAN), different 1,3-diones and same starting materials as 5-bromothiophene-2-carboxaldehyde and ammonium acetate were used at room temperature under solvent-free condition for the Hantzsch pyridine synthesis within a short period of time. All compounds were evaluated for their in vitro antibacterial and antifungal activity and, interestingly, we found that 5(b–f) show excellent activity compared with Ampicillin, whereas only the 5e compound shows excellent antifungal activity against Candida albicans compared with griseofulvin. The cytotoxicity of all compounds has been assessed against breast tumour cell lines (BT-549), but no activity was found. The X-ray structure of one such compound, 5a, viewed as a colourless block crystal, corresponded accurately to a primitive monoclinic cell.
1. Introduction More than a hundred years ago, the reaction to produce 1,4dihydropyridines (1,4-DHPs) was reported by Arthur Hantzsch [1]. These are important precursors due to their pharmacological and biological activities, such as antihypertensive, anti-anginal
2017 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
Br
2
Br
O
O CAN, R. T.
1 R2
R1 + O
R1
R2
1–3 hrs N H
O
2
O
3 NH4+
–OAc
5 (a–g)
4 R1 = –OCH3, –OC2H5, –CH3, –OC2H5, –OC2H5, –OCH3, dimedone R2 = –OCH3, –OC2H5, –CH3, –OCH3, –CH3, –CH3, dimedone
Scheme 1. Multicomponent reaction strategies for 1,4-DHP construction.
and as calcium channel blockade for cardiovascular disease. Consequently, several clinically important drugs appeared on the market with variable new active functional groups in their main skeleton, such as Nicardipine, Nifedipine, Nimodipine, Felodipine, Isradipine and Amlodipine [2–5]. Recently, various attempts have been taken up to improve the Hantzsch reaction using different alternative processes [6–10]. However, most of these reactions were reported with new trends as one-pot multicomponent reactions (MCRs) in the last 10–15 years; these reactions were carried out with certain disadvantages like: longer reaction time, expensive catalyst, higher temperature and tedious workup procedure. Great diversity in MCRs [11–13], developed using various ionic liquids as various Lowry-Bronsted acids, with several advantages has been well documented [14–16]. The clinical significance of pyran, thiophene derivatives of 3-acetylcoumarine based on 1,4-DHPs was the concern that they were reported to have an equivalent cytotoxic effect as the standard CHS 828 against a breast cancer cell line [17]. The above synthetic applications and their medicinal importance encourage us to develop and strive for the enhancement of the pharmacologically bioactive novel 1,4-DHP compounds using MCR. Moreover, the thrust of our work was to enhance the reactivity with suitable electron-releasing and withdrawing groups in reactants to minimize the by-products, and diminish the time of reaction and use of solvent, to establish our protocol with more economy and with a green concept. In this study, we illustrate our recent work on the synthesis of some novel thiophene-based 1,4-DHP derivatives from different 1,3-diones, and same starting materials as 5-bromothiophen-2-carboxaldehyde and ammonium acetate under room temperature and solvent-free conditions by using ceric ammonium nitrate (CAN) as the catalyst during a short period of time; good to excellent yield is reported with a simple workup procedure, which is shown in scheme 1.
2. Material and methods 2.1. General All reagents used in this study were purchased from commercially available sources without further purification unless specified otherwise. The synthesized compounds were characterized as anchored in ESI-MS spectra as determined by the Shimadzu GCMS-Qp 2010 spectrometer. Elemental analyses were performed in a Perkin-Elmer 2400 Series-II elemental analyser and the results were within ±0.4% of the theoretical values, unless otherwise noted. The stereochemistry and structure of all compounds were confirmed by 1 H-NMR and 13 C-APT spectra as recorded on Bruker Advance III (1 H: 400 MHz) and (13 C: 100 MHz), respectively, using CDCl3 as an internal standard. Splitting patterns were described as singlet (s), doublet (d), triplet (t), quartet (q) and broad (br). The values of chemical shift (δ) were given in ppm and coupling constants (J) in hertz (Hz). IR spectra were recorded on an ABB MB3000 spectrophotometer. Melting points were determined by an open capillary tube melting point apparatus and were uncorrected. The progress of reaction for compounds (5a–f) was monitored by silica gel 60 F254 (Merck)-coated thin-layer chromatography (TLC) plates. Reported Rf values correspond to elution with a 4 : 1 (n-hexane:ethyl acetate) mobile phase. Some of the compounds were separated
................................................
S CHO
O
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S
Table 1. Solvent-free one-pot multicomponent reaction of 5-bromothiophene-2-carboxaldehyde (5BT-2C) and different 1,3-diones catalysed by CAN (ceric ammonium nitrate). 3
4
entry 1
5BT-2C
R1 OCH3
R2 OCH3
NH4 OAc
2
5BT-2C
OC2 H5
OC2 H5
3
5BT-2C
CH3
CH3
4
5BT-2C
OCH3
5
5BT-2C
CH3
6
5BT-2C
7
5BT-2C
time (h) 1.15
melting point (° C) 180–185
products 5(a–g) 5a
Rf value 0.56
yield (%) 77
NH4 OAc
1.15
140–145
5b
0.59
73
NH4 OAc
1.15
138–142
5c
0.19
75
OC2 H5
NH4 OAc
2.30
118–123
5d
0.44
51
OC2 H5
NH4 OAc
3.00
127–132
5b + 5c + 5e
0.40
73(21 + 23 + 29a )
CH3
OCH3
NH4 OAc
3.00
122–125
5a + 5c + 5f
0.46
75(22 + 20 + 33a )
dimedone
dimedone
NH4 OAc
2.30
210–213
5g
0.26
35
............................................................................................................................................................................................................................................................... ............................................................................................................................................................................................................................................................... ............................................................................................................................................................................................................................................................... ............................................................................................................................................................................................................................................................... ............................................................................................................................................................................................................................................................... ............................................................................................................................................................................................................................................................... ...............................................................................................................................................................................................................................................................
a Indicates the % yield of pure compounds 5e and 5f.
Table 2. Antibacterial activity in microgram per millilitre of the synthesized compounds (5a–5f). E. coli, Escherichia coli; S. typhi, Salmonella typhi; B. subtilis, Bacillus subtilis; S. aureus, Streptococcus aureus; A*, Ampicillin; MTCC, Microbial Type Culture collection. compounds
E. coli MTCC443
S. typhi MTCC98
S. aureus MTCC96
B. subtilis MTCC441
5a
100
250
250
250
5b
200
500
200
100
125
250
200
......................................................................................................................................................................................................................... .........................................................................................................................................................................................................................
5c
62.5
.........................................................................................................................................................................................................................
5d
100
200
100
5e
250
250
100
5f
200
100
125
A*
100
100
250
62.5
.........................................................................................................................................................................................................................
100
.........................................................................................................................................................................................................................
62.5
.........................................................................................................................................................................................................................
250
.........................................................................................................................................................................................................................
and purified by column chromatography using an n-hexane:ethyl acetate (4 : 1) mobile phase. Single crystal X-ray data were collected on Rigaku SCX mini diffractometer by graphite monochromatic Mo-Kα radiation.
2.2. Synthesis of 1,4-dihydropyridines (5a–5c & 5 g) 5-Bromothiophene-2-carboxyaldehyde (1.91 g, 0.01 mol), ammonium acetate (0.77 g, 0.01 mol), different 1,3-diones (1–2.5 g, 0.01/0.02 mol) and CAN (0.28 g, 0.5 mmol) were added to a 100 ml round bottom flask. The mixture was stirred well for 1–2.5 h at room temperature, then the product was poured out and the mixture became solid. The progress of the reaction was monitored by TLC. The product was washed with water and then treated with n-hexane to remove impurities; after drying, the crude brown/yellow product was recrystallized using ethanol followed by charcoal treatment.
2.3. Synthesis of 1,4-dihydropyridines (5d) 5-Bromothiophene-2-carboxyaldehyde (1.91 g, 0.01 mol), ammonium acetate (0.77 g, 0.01 mol), ethylacetoacetate (1.3 ml, 0.01 mol), methylacetoacetate (1.1 ml, 0.01 mol) and CAN (0.28 g, 0.5 mmol) were added to a 100 ml round bottom flask. The mixture was stirred well for 2.5 h at room temperature; then the product was poured out and the mixture became solid. We obtained three possible products: 5a, 5b and 5d. Progress of the reactions was monitored by TLC and in the case of compound 5d, we confirmed the products by comparing spots on the TLC plate. We obtained the 5d product in pure form, by dissolving the crude material in a (1 : 4) mixture of ethyl acetate: n-hexane and separating it by filtration, with a very low amount of filtrate obtained. The remaining crude material may be a mixture of the products 5a and 5b. In the remaining filtrate, we obtained hazy crystals of product 5d (after 15–20 min).
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2
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1
3
Table 3. Antifungal activity in microgram per millilitre of the synthesized compounds 5(a–f). C. albicans, Candida albicans; A. niger, Aspergillus niger. A. niger >1000
5b
500
1000
5c
>1000
250
5d
>1000
500
5e
250
>1000
5f
500
500
griseofulvin
500
100
......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... .........................................................................................................................................................................................................................
Table 4. Cytotoxicity assay of compounds 5(a–f) on BT-549 Cell Line in EC50 (µM). sr. no. 1
compounds 5a
EC50 (µM) 42.0
2
5b
52.5
3
5c
>100
4
5d
45.5
5
5e
81.8
6
5f
77.7
7
doxorubicin
0.04
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2.4. Synthesis of 1,4-dihydropyridines (5e & 5f) 5-Bromothiophene-2-carboxyaldehyde (1.91 g, 0.01 mol), ammonium acetate (0.77 g, 0.01 mol), acetylacetone (1 ml, 0.01 mol), ethyl acetoacetate (1.3 ml, 0.01 mol) and CAN (0.28 g, 0.5 mmol) were added to a 100 ml round bottom flask. The mixture was stirred well for 3 h at room temperature; then the product was poured out and the mixture became solid. We obtained three possible products: 5b, 5c and 5e. The progress of the reaction was monitored by TLC and in case of compound 5e, we confirmed the products by comparing spots on the TLC plate. The Rf values for 5b, 5c and 5e are 0.59, 0.19 and 0.40, respectively. Moreover, in 5f we used methyl acetoacetate (1.1 ml, 0.01 mol) instead of ethylacetoacetate and obtained a mixture of the possible products 5a, 5c and 5f. The Rf values for 5a, 5c and 5f are 0.56, 0.20 and 0.46, respectively. The 5e and 5f compounds were separated and purified by column chromatography using an n-hexane: ethyl acetate (4 : 1) mobile phase. The antimicrobial activity of the synthesized compounds (5a–5f) was evaluated by the broth dilution method. The synthesized compounds were tested for their antibacterial activity against Gram-negative bacteria (E. coli MTCC 443, Salmonella typhi MTCC 98) and Gram-positive bacteria (Bacillus subtilis MTCC 441, Streptococcus pneumonia MTCC 1936). Ampicillin was used as the standard against bacteria. All compounds (5a–5f) were screened for antifungal activity against Candida albicans MTCC 227, Aspergillus niger, MTCC 282 and A. Clavatus MTCC 1323 at a concentration of 500 µg ml−1 in DMF. Nutrient agar and potato dextrose agars were used to culture the bacteria and fungi, respectively. The plates were inculcated by the bacteria or fungi and incubated for 24 h at 37°C for bacteria and for 72 h at 27°C for fungi and then the inhibition zones of microbial growth surrounding the filter paper disc (5 mm) were measured in millimetres. Griseofulvin was used as a standard drug for fungi. Test results are given in tables 2 and 3 for antibacterial and antifungal activity, respectively.
3. Results and discussion We prepared a number of 1,4-DHPs via MCR. According to a literature survey for the development of synthetic procedures [18–21], mainly catalyst can play an important role in the synthesis of 1,4-DHPs
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C. albicans >1000
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compounds 5a
4
Br1
C14
H11B
H14
H11C H9B
C9
C12
O4 C10 C4
H9C
C13 C3
C5
H13 H3
N
H1
C1
C2
C7
O2
H6C
H8C H6A H8B
C6 H6B
C8
O1 H8A
Figure 1. Ortep diagram for 5a.
Figure 2. Packing arrangements of 5a with hydrogen bonding.
[22–25]. Therefore, we selected the catalyst CAN to investigate their effect on product yield under solvent-free conditions at room temperature (table 1). Under these optimized reaction conditions, the simplicity and scope of a novel one-pot MCR protocol were explored. The reaction of 5BT-2C 1, ammonium acetate 4 as same starting materials and different 1,3-diones 2,3 was performed in the presence of CAN under solvent-free conditions to obtained desired 1,4-DHP derivatives with good to excellent yield at room temperature. Interestingly, we received the desired symmetrical products 5a, 5b, 5c and 5 g by using same 1,3-diones 2 or 3. If we use different 1,3-diones 2,3,
................................................
S1
C11
O3 H9A
C15
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H11A
5
Table 5. Crystal and experimental data of compound 5a.
6
.........................................................................................................................................................................................................................
crystal description
colourless block crystal
crystal size
0.480 × 0.390 × 0.310 mm
empirical formula
C15 H16 BrNO4 S
formula weight
386.26
radiation, wavelength
MoKα(λ = 0.71075 Å) graphite monochromatic
unit cell dimensions
a = 8.0516(9) Å, b = 10.072(1) Å, c = 20.119(2) Å, β = 97.803(4)°
crystal system
monoclinic
lattice type
primitive
space ground
P21 /c (#14)
unit cell volume
V = 1616.4(3) Å3
calculated density
1.587 g cm−3
no. of molecules per unit cell, Z
4
µ (MoKα)
26.958 cm−1
F(000)
784.00
refinement of unit cell
full-matrix least-squares on F 2
......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... ......................................................................................................................................................................................................................... .........................................................................................................................................................................................................................
reflection/parameter ratio
18.61
residuals: R1 (I > 2.00 σ (I))
0.0437
Rint
0.0360
least-squares weights
w = 1/[σ 2 (Fo2 ) + (0.1000 . P)2 + 0.0000 . P], where P = (Max(Fo2 ,0) + 2Fc2 )/3
(/σ )max in the final cycle
15.000
goodness of fit indicator
1.125
maximum peak in final diff. map
0.75 e− Å−3
minimum peak in final diff. map
−0.53 e− Å−3
2θ max cut-off
55.0°
function minimized
Σ w (Fo2 − Fc2 )2
ω oscillation range
−120.0 − 60.0°
exposure rate
10.0 s per degree
detector swing angle
−30.80°
diffractometer
SCX mini
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then we get desired asymmetrical products 5d, 5e, 5f including symmetrical products 5a, 5b, 5c and 5f. We obtained a 5d product in pure form, by dissolving the crude material in a (1 : 4) mixture of ethyl acetate and n-hexane, which was filtered to separate out the undissolved crude, with a very low amount of filtrate obtained. The remaining crude may be a mixture of the products 5a, 5b (monitored by TLC). In the remaining filtrate, we got hazy crystals of product 5d (after 15–20 min). However, we hypothesized properly pre-functionalized 1,3-dione 2,3 and 5BT-2C. In this series, 5BT2C contains the electron-withdrawing group –Br, which increases the reactivity of aldehyde to C–C bond formation with 1,3-dione; the presence of a mild to moderate activating group in 1,3-dione increases the nucleophilicity of its methylene group to interact with 5BT-2C, as well as the susceptibility of its carbonyl groups to C–N bond formation by interaction with ammonium acetate. A series of smoothly controlled experiments clearly indicates that the 5BT-2C, ammonium acetate, 1,3-diones and CAN were all necessary substrates for this transformation, as mentioned in scheme 1. 1H-NMR data show signal in a range of 5.1–5.3δ, which confirms one proton present at the ipsolateral position on the aliphatic carbon. A singlet was observed at 1–3δ, which confirms the presence of two similar methyl groups in the meta position in the 1,4-dihydropyridine ring, with signals also for methyl
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CCDC No
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In brief, we have confirmed a well-organized solvent-free green procedure for the multicomponent synthesis of dihydropyridine derivatives using the catalyst CAN. The result highlighted the solventfree procedure to be more efficient than the conventional method. The advantages of the Hantzsch pyridine synthesis are shorter reaction times, simplicity of the reaction, good product yield and easy workup procedures with regard to the build-up to the reaction, which is economical and easy, with CAN being a powerful catalyst for the many organic syntheses. The interesting finding of our work is that we obtained excellent antibacterial activity with compounds such as 5b, 5c, 5d, 5e and 5f, which were found highly active against S. aureus and B. subtillus compared with the standard drug Ampicillin, whereas compounds 5a and 5c showed equipotent activity. As far as antifungal activity is concerned, only compound 5e showed higher activity than the standard griseofulvin drug, and compounds 5b and 5f had equipotent activity. The cytotoxicity of all the compounds has been assessed against breast tumour cell lines (BT-549), but no activity was found. Ethics. We do not require any ethical approval from a local ethics committee to carry out these studies because we carried out some work with the help of other sources.
Data accessibility. We include all the experimental data including spectral characterizations in the electronic supplementary material. ESI and crystallographic details of 5a compound are available on http://dx.doi.org/10. 5061/dryad.66gd7 [26], and other figures and electronic supplementary materials are available on https://doi.org/ 10.6084/m9.figshare.4990370. Authors’ contributions. H.M.P. designed the study. M.G.S. and H.M.P. synthesized and characterized the compounds, and wrote the manuscript. D.P.R. carried out the biological activity. All authors gave their final approval for publication. Competing interests. We declare we have no competing interests. Funding. We received no funding for this study. Acknowledgements. We honestly express our thanks to the Head, Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar for providing the necessary research facilities.
................................................
4. Conclusion
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and ethyl groups of esters at the desired positions. The signals of a doublet appears at 6.0–7.0δ, which confirmed the presence of aromatic protons. 13C-APT spectra show peaks in a range of 13–20δ, which confirm the presence of methyl groups. Signals at 34–35δ confirm the presence of aliphatic –CH group, whereas carbon in the pyridine ring at a double bond gave a signal at 100–110δ. Signals at 120–130δ indicate aromatic –CH groups and signals at 165–170δ confirm the presence of carbonyl groups. In the IR data, we obtained a peak near 3340 cm−1, which is for N–H stretching, and a peak around 3000 cm−1 for tertiary –C–H stretching, whereas peaks that appear between 1700 and 1600 cm−1 indicate –C=O stretching. A peak that appears between 1350 and 1300 cm−1 indicates aromatic olefin stretching. The peak that appears near 1200 cm−1 provides the proof of –C–H stretching of the methyl group. The peak that appears at 510 cm−1 indicates –C–X (C–Br) stretching and some peaks observed between 1000 and 700 cm−1 confirmed the aromatic ortho- and para- di-substituents. In mass spectral analysis, we obtained peaks at the particular mass of the compound, which confirmed the present skeleton in the moiety, and different base peaks at m/z = 332, 318, 265, 230, 145, 57 and 45; these m/z values are the major base peaks in all compounds. All the synthesized compounds 5(a–f) were screened for Gram-positive bacteria and Gram-negative bacteria and results were compared with Ampicillin as the standard drug. Compound 5c was found highly active, and compounds 5a and 5d showed equipotent activity against E. coli compared with the standard. Compound 5f showed equipotent activity with S. typhi. The interesting finding of our work is to observe excellent antibacterial activity of the 5b, 5c, 5d, 5e and 5f compounds against Staphylococcus aureus and Bacillus subtillus compared with the standard drug, whereas compounds 5a and 5c showed equipotent activity. Similarly, the compounds 5(a–f) were screened for antifungal activity with C. albicans and A. niger as the microorganisms; obtained results were compared with griseofulvin as the standard drug shown in table 3. It was found that compound 5e showed higher activity than the standard. Whereas compounds 5b and 5f had equipotent activity with the standard, and the compounds 5a, 5c and 5d had lower activity. The cytotoxicity of all synthesized compounds was checked against breast tumour cell lines (BT-549) but no activity was found, which is illustrated in table 4. The compound 5a was confirmed by a single crystal XRD analysis, which is shown in figures 1 and 2. The crystallographic experimental data are described in table 5. The packing arrangement of the molecules viewed down in the a-axis is shown along with obtained crystal structure of compound 5a. From these series, three compounds, 5a, 5c and 5f, were selected for anticancer activity at National Cancer Institute (NCI), USA.
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