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Synthesis of novel rhodanine based functionalized furans from the reaction of tert-butyl isocyanide with acetylenic esters in the presence of rhodanine acetic acid derivatives
⁎Corresponding author at: Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, P.O. Box 47415, Babolsar, Iran. Tel.: +98 1125342357; fax: +98 1125342350. baharfar@umz.ac.ir (Robabeh Baharfar)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
The reactive 1:1 intermediate produced from the reaction of tert-butyl isocyanide and dialkyl acetylenedicarboxylates was trapped by rhodanine-N-acetic acid derivatives to generate polyfunctionalized furan rings in fairly good yields.
Abstract
The reactive 1:1 intermediate produced from the reaction of tert-butyl isocyanide and dialkyl acetylenedicarboxylates was trapped by rhodanine-N-acetic acid derivatives to generate polyfunctionalized furan rings in fairly good yields.
Keywords
Dialkyl acetylenedicarboxylate
Multi-component reaction
Rhodanine-N-acetic acid
tert-Butyl isocyanide
1 Introduction
The chemistry of rhodanine and its derivatives, such as benzylidene rhodanine has been studied for over half a century because of their important chemical and biological applications. Rhodanine derivatives exhibit antibacterial, antiviral, anticonvulsant, anti-diabetic and anti-HIV-1 activities (Bursavich et al., 2007; Powers et al., 2006; Rawal et al., 2007; Zimenkovsky et al., 2006), and have been reported as uridinediphospho-N-acetylmuramate/l-alanine ligase inhibitors (Sim et al., 2002). Despite the fact that the rhodanine based compounds exhibit a wide variety of bioactivities, the prevalence of rhodanine containing compounds of pharmaceutical interest is very small (Boyd, 1997).
On the other hand, functionalized furans represent an important synthetic building block and are present in a variety of biologically relevant natural products, such as calicogorgins, furan fatty acids, cytotoxic furan ocembranes, gersolanes, pseudopteranes, rosefuran, agassizin, furodysin, mikanifuran or α-clausenan (Bach and Kruger, 1999; Konig, 2001). Furans can also serve as important intermediates for many organic transformations (Feng et al., 2008). A recent report identified 2-aryl-5-(4-oxo-3-phen-ethyl-2-thioxothiazolidinylidenemethyl)-furans with rhodanine as a core molecule exhibiting anti-HIV-1 activity (Kamila et al., 2011). Therefore the combination of these two pharmacophores in the same molecule can be an interesting challenge for the development of new pharmacologically active molecules.
In continuation of our studies on the development of new routes in the synthesis of novel heterocyclic compounds (Baharfar et al., 2011, 2008) such as uracil based furan derivatives (Baharfar and Baghbanian, 2012) and due to biological activities of rhodanine based compounds, we wish to report a simple multi-component reaction between tert-butyl isocyanide 1 and dialkyl acetylenedicarboxylates 2, in the presence of 1-(carboxy methyl) rhodanine 3 and benzylidene rhodanine derivatives 5 leading to highly functionalized diaminofuran derivatives 4 and 6 (Scheme 1).
Synthesis of diaminofuran derivatives.
Therefore, tert-butyl isocyanide undergoes a smooth 2:1:1 addition reaction with dialkyl acetylenedicarboxylates 2 in the presence of 1-(carboxy methyl) rhodanine derivatives 3 in tetrahydrofuran at ambient temperature, to produce highly functionalized 2,5-diaminofuran derivatives 4 and 6 in 70–85% yield. The results are shown in Scheme 1.
2 Material and methods
Chemicals were purchased from Fluka and Merck companies. Melting points were determined in open capillaries using an Electrothermal 9100 apparatus. IR spectra were recorded using a Perkin-Elmer FT-IR 550 spectrophotometer. 1H NMR and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer for the sample as indicated with the tetramethylsilane as an internal reference. MS spectra were recorded on a Finnigan MAT 44S, with an ionization voltage of 70 eV.
2.1 General synthesis of furan derivatives 4a–b
To a magnetically stirred solution of rhodanine-3-acetic acid (1 mmol) and dialkyl acetylenedicarboxylates (1 mmol) in THF (5 ml), was added dropwise a solution of tert-butyl isocyanide (2 mmol) in THF (3 ml) over 10 min. The mixture was stirred for 12 h at room temperature in THF. After completion of the reaction, as indicated by TLC, the solvent was removed and the residue was purified by Silica gel flash chromatography to afford products 4a,b.
2.2 General synthesis of furan derivatives 6a–e
To a magnetically stirred solution of benzylidene rhodanine-3-acetic acid (1 mmol) and dialkyl acetylenedicarboxylates (1 mmol) in THF (5 ml), was added dropwise a solution of tert-butyl isocyanide (2 mmol) in THF (3 ml) over 10 min. The mixture was stirred for 12 h at reflux temperature in THF. After completion of the reaction, as indicated by TLC, the solvent was removed and the residue was purified by gradual removal of the solvent to afford products 6a–e.
3 Results and discussion
The structures of isolated products 4a,b and 6a–e were deduced on the basis of IR, 1H and 13C NMR spectra, mass spectroscopy and elemental analysis. The mass spectrum of 4a displayed the molecular ion (M+) peak at m/z 499, which is consistent with the 2:1:1 adduct of tert-butyl isocyanide, dimethyl acetylenedicarboxylate and 1-(carboxymethyl) rhodanine derivative. The 1H NMR spectrum of 4a in CDCl3 exhibited four sharp singlets, readily recognized, arising from two tert-butyl (δ = 1.36 and 1.47) and two methoxy groups (δ = 3.78 and 3.92) protons a long with two AB systems (δ = 4.05 and 4.09, 2JAB = 18.0 Hz), (δ = 4.29 and 5.04, 2JAB = 16.0 Hz) for four protons of two methylene groups. Also, one broad singlet was observed at δ = 6.98 for the NH group. The 1H decoupled 13C NMR spectrum of 4a showed 21 distinct resonances in agreement with the structure of 4a.
A mechanistic rationalization for this reaction is provided in Scheme 2. On the basis of the well-established chemistry of isocyanides (Raut, 1995; Domling, 2006; Gulevich et al., 2010; Shaabani et al., 2011), it is reasonable to assume that the functionalized rhodanine based 2,5-diaminofurans 4 and 6 could result from an initial addition of the isocyanide 1 to the acetylenic ester 2 and subsequent protonation of the 1:1 adduct 7 by carboxylic acid 3. Then, the positively charged ion 9 can be attacked by the carboxylate anion 8 to form imidoyl carboxylate 10, which undergoes a Mumm rearrangement (Domling and Ugi, 2000; Ugi, 1997) under the reaction conditions, to produce the α,β-unsaturated intermediate 11, followed by its trapping with isocyanide, to give the corresponding rhodanine based 2,5-diaminofurans 4 and 6.
Mechanistic pathways for the synthesis of the functionalized rhodanine based 2,5-diaminofurane derivatives.
3.1 Physical and spectral data for the synthesized compounds
3.1.1 Dimethyl 2-(tert-butylamino)-5-{tert-butyl[(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetyl]amino}furan-3,4-dicarboxylate (4a)
Yellow powder, m.p. 138–143 °C, yield: 75%, IR (KBr) (νmax, cm−1): 3346 (NH), 1605, 1680 and 1740 (4 C⚌O), 1254 (C⚌S), 1H NMR (400.13 MHz, CDCl3): δ = 1.36 and 1.47 (2s, 18H, 2t-Bu), 3.78 and 3.92 (2s, 6H, 2OCH3), 4.05 and 4.09 (2d, 2H, AB system, 2JHH = 18.0 Hz, CH2), 4.29 and 5.04 (2d, 2H, AB system, 2JHH = 16.0 Hz, CH2), 6.98 (1s, 1H, NH). 13C NMR (100.6 MHz, CDCl3): δ = 27.9 and 29.7 (2CMe3), 35.6 (CH2), 46.9 (CH2), 51.2 and 61.6 (2CMe3), 52.6 and 52.9 (2OCH3), 85.8 (C4 of furan), 115.6 (C3 of furan), 136.7 (C5 of furan), 160.0 (C2 of furan), 162.7, 165.0, 165.7 and 173.1 (4 C⚌O), 200.9 (C⚌S).
3.1.2 Diethyl 2-(tert-butylamino)-5-{tert-butyl[(4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetyl]amino}furan-3,4-dicarboxylate (4b)
Yellow powder, m.p. 176–179 °C, yield: 70%, IR (KBr) (νmax, cm−1): 3345 (NH), 1601, 1664, 1701 and 1744(4 C⚌O), 1257 (C⚌S), 1H NMR (400.13 MHz, CDCl3): δ = 1.31 and 1.40 (2t, 6H, 3JHH = 7.2 Hz, 2CH3), 1.38 and 1.47 (2s, 18H, 2t-Bu), 4.04 and 4.10 (2d, 2H, AB system, 2JHH = 18.0 Hz, CH2), 4.21–4.42 (m, 4H, 2OCH2), 4.31 and 5.05 (2d, 2H, AB system, 2JHH = 16.0 Hz, CH2), 6.95 (s, 1H, NH), 13C NMR (100.6 MHz, CDCl3): δ = 14.1 and 14.3 (2CH3), 27.9 and 29.8 (2CMe3), 35.6 (CH2), 47.1 (CH2), 52.9 and 59.9 (2CMe3), 61.5 and 61.8 (2OCH2), 86.1 (C4 of furan), 116.0 (C3 of furan), 136.0 (C5 of furan), 159.8 (C2 of furan), 162.5, 164.6, 165.9 and 173.1 (4 C⚌O), 200.9 (C⚌S).
3.1.3 Dimethyl 2-[{[(5E)-5-benzylidine-4-oxo-2-thioxo-1,3-thiazolidine-3-yl]acetyl}(tert-butyl)amino]-5-(tert-butylamino)furan-3,4-dicarboxylate (6a)
Yellow powder, m.p. 178–180 °C, yield: 85%, IR (KBr) (νmax, cm−1): 3360 (NH), 1603, 1680, 1713 and 1742(4 C⚌O), 1280 (C⚌S), 1H NMR (400.13 MHz, DMSO-d6): δ = 1.29 and 1.44 (2s, 18H, 2t-Bu), 3.69 and 3.84 (2s, 6H, 2OCH3), 4.28 and 5.02 (2d, 2H, AB system, 2JHH = 16.4 Hz, CH2), 6.90 (s, 1H, NH), 7.54–7.68 (m, 5H, 5CH, Ar), 7.89 (s, 1H, CH). 13C NMR (100.6 MHz, DMSO-d6): δ = 27.8 and 29.6 (2CMe3), 47.1 (CH2), 51.6 and 61.3 (2CMe3), 53.1 and 53.2 (2OCH3), 85.8 (C4 of furan), 115.8 (C3 of furan), 122.5 (Cq, Ar), 130.0, 131.2 and 131.7 (5CH, Ar), 133.3 (Cq), 134.3 (CH), 136.2 (C5 of furan), 159.5 (C2 of furan), 163.0, 164.0, 166.0 and 166.7 (4 C⚌O), 193.8 (C⚌S).
3.1.4 Diethyl 2-[{[(5E)-5-benzylidine-4-oxo-2-thioxo-1,3-thiazolidine-3-yl]acetyl}(tert-butyl)amino]-5-(tert-butylamino)furan-3,4-dicarboxylate (6b)
Yellow powder, m.p. 156–162 °C, yield: 80%, IR (KBr) (νmax, cm−1): 3333 (NH), 1604, 1667, 1709 and 1736 (4 C⚌O), 1252 (C⚌S), 1H NMR (400.13 MHz, DMSO-d6): δ = 1.22 and 1.32 (2t, 6H, 3JHH = 7.2 Hz, 2CH3), 1.29 and 1.43 (2s, 18H, 2t-Bu), 4.12–4.33 (m, 4H, 2OCH2), 4.30 and 5.00 (2d, 2H, AB system, 2JHH = 16.4 Hz, CH2), 6.89 (s, 1H, NH), 7.53–7.59 (m, 3H, 3CH, Ar), 7.66 (d, 2H, 3JHH = 6.8 Hz, 2CH, Ar), 7.88 (s, 1H, CH). 13C NMR (100.6 MHz, DMSO-d6): δ = 14.4 and 14.6 (2CH3), 27.8 and 29.7 (2CMe3), 47.2 (CH2), 53.1and 60.0 (2CMe3), 61.3 and 62.0 (2OCH2), 85.9 (C4 of furan), 116.2 (C3 of furan), 122.5 (Cq, Ar), 130.0, 131.2 and 131.6 (5CH, Ar), 133.3 (Cq), 134.3 (CH), 135.8 (C5 of furan), 159.5 (C2 of furan), 162.5, 163.7, 166.0 and 166.7 (4 C⚌O), 193.8 (C⚌S).
3.1.5 Dimethyl 2-(tert-Butylamino)-5-(tert-butyl{[(5E)-5-(4-methylbenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetyl}amino)furan-3,4-dicarboxylate (6c)
Yellow powder, m.p. 180–182 °C, yield: 75%, IR (KBr) (νmax, cm−1): 3364 (NH), 1597 and 1724 (4 C⚌O), 1279 (C⚌S), 1H NMR (400.13 MHz, DMSO-d6): δ = 1.29 and 1.44 (2s, 18H, 2t-Bu), 2.38 (s, 3H, CH3), 3.69 and 3.84 (2s, 6H, 2OCH3), 4.28 and 5.01 (2d, 2H, AB system, 2JHH = 16.0 Hz, CH2), 6.90 (1s, 1H, NH), 7.39 (d, 2H, 3JHH = 8.0 Hz, 2CH, Ar), 7.56 (d, 2H, 3JHH = 8.4 Hz, 2CH, Ar), 7.84 (s, 1H, CH). 13C NMR (100.6 MHz, DMSO-d6): δ = 21.6 (CH3, Ar), 27.8 and 29.6 (2CMe3), 47.1 (CH2), 51.6 and 61.3 (2CMe3), 53.1 and 53.2 (2OCH3), 85.8 (C4 of furan), 115.8 (C3 of furan), 121.2, 131.3 (2Cq, Ar), 130.6 and 130.7 (4CH, Ar), 134.4 (Cq), 136.3 (C5 of furan), 142.2 (CH), 159.5 (C2 of furan), 163.0, 164.1, 166.0 and 166.8 (4 C⚌O), 193.7 (C⚌S).
3.1.6 Dimethyl 2-(tert-butylamino)-5-(tert-butyl{[(5E)-5-(4-chlorobenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]-acetyl}amino)furan-3,4-dicarboxylate (6d)
Yellow powder, m.p. 180–183 °C, yield: 85%, IR (KBr) (νmax, cm−1): 3366 (NH), 1598, 1646 and 1704 (4 C⚌O) 1279 (C⚌S), 1H NMR (400.13 MHz, DMSO-d6): δ = 1.29 and 1.44 (2s, 18H, 2t-Bu), 3.69 and 3.84 (2s, 6H, 2OCH3), 4.28 and 5.02 (2d, 2H, AB system, 2JHH = 16.0 Hz, CH2), 6.90 (1s, 1H, NH), 7.63 and 7.69 (2d, 4H, AB system, 3JHH = 8.4 Hz, 4CH, Ar), 7.88 (s, 1H, CH). 13C NMR (100.6 MHz, DMSO-d6): δ = 27.8 and 29.6 (2CMe3), 47.2 (CH2), 51.6 and 61.3 (2CMe3), 53.1 and 53.2 (2OCH3), 85.8 (C4 of furan), 115.9 (C3 of furan), 123.2 and 132.2 (2Cq, Ar), 130.1, 132.8 (4CH, Ar), 133.5 (Cq), 136.2 (CH), 136.3 (C5 of furan), 159.5 (C2 of furan), 163.0, 164.0, 165.9 and 166.7 (4 C⚌O), 193.5 (C⚌S).
3.1.7 Dimethyl 2-(tert-butylamino)-5-(tert-butyl{[(5E)-5-(2-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]-acetyl}amino)furan-3,4-dicarboxylate (6e)
Yellow powder, m.p. 190–196 °C, yield: 85%, IR (KBr) (νmax, cm−1): 3354 (NH), 1597, 1675 and 1708 (4 C⚌O), 1252 (C⚌S), 1H NMR (400.13 MHz, CDCl3): δ = 1.38 and 1.49 (2s, 18H, 2t-Bu), 3.80, 3.91 and 3.95 (3s, 9H, 3OCH3), 4.43 and 5.20 (2d, 2H, AB system, 2JHH = 16.0 Hz, CH2), 6.94 (d, 1H, 3JHH = 8.0 Hz, CH, Ar), 7.00 (s, 1H, NH), 7.05 (t, 1H, 3JHH = 8.0 Hz, CH, Ar), 7.41 (d, 1H, 3JHH = 8.4 Hz, CH, Ar), 7.42 (t, 1H, 3JHH = 8.4 Hz, CH, Ar), 8.14 (s, 1H, CH). 13C NMR (100.6 MHz, CDCl3): δ = 27.9 and 29.8 (2CMe3), 46.9 (CH2), 51.2 and 61.6 (2CMe3), 52.7, 52.9 and 55.5 (3OCH3), 85.8 (C4 of furan), 111.2, 121.0, 122.8, 129.7 (4CH, Ar), 115.5 (C3 of furan), 122.5 and 160.0 (2Cq), 130.2 (Cq), 132.7 (CH), 136.9 (C5 of furan), 158.6 (C2 of furan), 162.7, 165.0, 165.9 and 167.3 (4 C⚌O), 194.2 (C⚌S).
4 Conclusions
In summary, we have described a novel, efficient and simple method for the synthesis of rhodanine based furan derivatives of potential synthetic and pharmaceutical interest. Further investigation into the present method will be required to establish its utility and scope.
Acknowledgment
We are thankful to the Research Council of Mazandaran University for the financial support of this work.
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