Next Article in Journal
(5-Chloroquinolin-8-yl)-2-fluorobenzoate. The Halogen Bond as a Structure Director
Previous Article in Journal
3-{4-[(E)-{4-[(E)-Phenyldiazenyl]phenyl}diazenyl]phenoxy}propane-1,2-diol
Open AccessShort Note

Dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenylnaphthalene-2,2(1H)-dicarboxylate

Department of Chemistry, Kyonggi University, 154-42, Gwanggyosan-ro, Yeongtong-gu, Suwon 16227, Korea
Academic Editor: Norbert Haider
Molbank 2017, 2017(1), M933; https://doi.org/10.3390/M933
Received: 10 January 2017 / Revised: 28 February 2017 / Accepted: 1 March 2017 / Published: 3 March 2017
(This article belongs to the Section Organic Synthesis)

Abstract

A Friedel-Crafts–type ring-opening/intramolecular Michael addition cascade reaction of (E)-4-(3-(dimethylamino)phenyl)but-3-en-2-one with dimethyl 2-phenylcyclopropane-1,1-dicarbo-xylate catalyzed by Yb(OTf)3 has produced a new compound, dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenylnaphthalene-2,2(1H)-dicarboxylate. This reaction provided diastereoslective trans tetralin (7:3 dr) on the cyclohexyl ring. The structure of the newly synthesized compound was determined using 1H-, 13C-NMR, IR and mass spectral data.
Keywords: tetralin; Friedel-Crafts reaction; Michael addition; cascade reaction tetralin; Friedel-Crafts reaction; Michael addition; cascade reaction

1. Introduction

Tetralin is structurally essential scaffold in biologically active natural products and synthetic pharmaceutical compounds [1,2,3]. Especially the 1-aryltetralin is widely found in natural cyclolignans and synthetic derivatives with a broad spectrum of biological activities including antimalarial, antifungal, antibacterial, anti-inflammatory, antitumor, anti-HIV, and antidepressant activities [4,5,6]. In view of the significance of the aryltetralin structure in medicinal and organic chemistry, numerous synthetic methods for aryltetralines have been developed [7,8]. Based on our previous results of the cascade reaction for the synthesis of 1-aryltetralin compounds [9], we have successfully obtained a novel dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenyl-naphthalene-2,2(1H)-dicarboxylate.

2. Results

The synthesis of dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenylnaphthal-ene-2,2(1H)-dicarboxylate (3) was achieved in one step, as presented in Scheme 1, which was performed by a Friedel-Crafts–type ring-opening/intramolecular Michael addition cascade reaction of (E)-4-(3-(dimethylamino)phenyl)but-3-en-2-one (1) [10] with dimethyl 2-phenylcycloprop-ane-1,1-dicarboxylate (2) [11]. The reaction was carried out in CHCl3 in the presence of 10 mol % of Yb(OTf)3 as a catalyst and 4 Å molecular sieve as an additive at 60 °C. The desired product 3 was obtained in 72% yield with moderate diastereoselectivity (7:3 dr) via the ring-opening/Michael cascade reaction. The structure of compound 3 was confirmed by 1H- and 13C-NMR, IR, mass spectral data, and all data are in accordance with the proposed structure.

3. Experimental Section

3.1. General Information

All reagents were used as received without further purification. Organic solutions were concentrated under reduced pressure using a Büchi rotary evaporator. Chromatographic purification of the title compound 3 was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63. Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates (Merck, Darmstadt, Germany, 70–230 mesh). Developed chromatograms were visualized by fluorescence quenching (254 nm) and anisaldehyde stain. 1H- and 13C-NMR spectra were recorded on a Bruker Avance 400 spectrometer (Bruker BioSpin GmbH, Karlsruhe, Germany) in CDCl3. Chemical shifts are internally referenced to residual protio solvent signals (δ 7.26 ppm for 1H; δ 77.16 ppm for 13C). Data for 1H-NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), integration, coupling constant (Hz) and assignment. Data for 13C-NMR are reported in terms of chemical shift. IR spectra were recorded on ALPHA FT-IR spectrometer (Bruker Optics GmbH, Ettlingen, Germany), and reported in terms of frequency of absorption (cm−1). High-resolution mass spectrometry data was recorded on a JEOL JMS-700 MStation mass spectrometer (JEOL, Tokyo, Japan).

3.1.1. Synthesis of (E)-4-(3-(Dimethylamino)phenyl)but-3-en-2-one (1)

To a solution of 3-dimethylaminobenzaldehyde [12] (149 mg, 1.0 mmol) in THF (5 mL) was added 1-(triphenylphosphoranylidene)-2-propane (382 mg, 1.2 mmol) at room temperature. The resulting mixture was refluxed for 72 h until complete consumption of 3-dimethylaminobenzaldehyde was observed as determined by TLC. The resulting mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography using EtOAc/hexane (1/10) as eluent to afford the desired title compound 1 (89%, 169 mg).
Yellow solid; m.p. 56–58 °C; 1H-NMR (400 MHz, CDCl3) δ 7.49 (d, J = 15.6 Hz, 1H, CHCH), 7.26 (t, J = 7.9 Hz, 1H, Ar-H), 6.92 (d, J = 7.6 Hz, 1H, Ar-H), 6.85 (d, J = 2.4 Hz, 1H, Ar-H), 6.78 (dd, J = 7.6, 2.4 Hz, 1H, Ar-H), 6.70 (d, J = 15.6 Hz, 1H, CHCH), 2.99 (s, 6H, N(CH3)2), 2.39 (s, 3H, COCH3); 13C-NMR (100 MHz, CDCl3) δ 204.34, 150.87, 144.07, 135.66, 129.45, 120.47, 115.90, 114.41, 112.88, 43.33, 40.52; IR (film) 2951, 2933, 2807, 1655, 1591, 1571, 1495, 1442, 1356, 1318, 1224, 1206, 1176, 1064 cm−1; HRMS (EI) m/z calcd for [M]+ C12H15NO: 189.1154 Found: 189.1144.

3.1.2. Synthesis of Dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenylnaphthalene-2,2(1H)-dicarboxylate (3)

To a solution of (E)-4-(3-(dimethylamino)phenyl)but-3-en-2-one (1) (19 mg, 0.10 mmol), Yb(OTf)3 (6.2 mg, 0.020 mmol), and 4 Å molecular sieve (20 mg) in CHCl3 (0.5 mL) was added dimethyl 2-phenyl-cyclopropane-1,1-dicarboxylate (2) (28 mg, 0.12 mmol). The resulting mixture was stirred at 60 °C for 72 h until complete consumption of (E)-4-(3-(dimethylamino)phenyl)but-3-en-2-one (1) was observed as determined by TLC. The resulting mixture was cooled to room temperature and was quenched with sat. NaHCO3 solution. The mixture was extracted with CH2Cl2. The combined organic layer were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography using EtOAc/hexane (1/10) as eluent to afford the desired title compound 3 (72%, 31 mg).
Inseparable mixture of diastereomers, colorless gum; 1H-NMR (400 MHz, CDCl3) δ 7.31 (d, J = 7.2 Hz, 2H minor stereoisomer, Ar-H), 7.23 (d, J = 7.2 Hz, 2H major stereoisomer, Ar-H), 7.16 (d, J = 7.5 Hz, 1H major, Ar-H), 7.15 (t, J = 7.5 Hz, 1H major, Ar-H), 7.02 (d, J = 7.2 Hz, 1H major + 3H minor, Ar-H), 6.70 (d, J = 8.6 Hz, 1H major, Ar-H), 6.59 (d, J = 8.4 Hz, 1H minor, Ar-H), 6.52 (dd, J = 8.6, 2.6 Hz, 1H major, Ar-H), 6.50–6.46 (m, 1H minor, Ar-H), 6.43 (d, J = 2.3 Hz, 1H major, Ar-H), 4.38 (t, J = 5.3 Hz, 1H minor, COCH2CH), 4.27 (t, J = 5.6 Hz, 1H major, COCH2CH), 4.21 (t, J = 6.7 Hz, 1H major + 1H minor, CCH2CH), 3.70 (s, 3H minor, CO2CH3), 3.67 (s, 3H major, CO2CH3), 3.66 (s, 3H minor, CO2CH3), 3.23 (s, 3H major, CO2CH3), 2.84–3.01 (m, 1H major + 1H minor COCH2CH and 1H major + 1H minor CCH2CH), 2.90 (s, 6H major, N(CH3)2), 2.89 (s, 6H minor, N(CH3)2), 2.78 (dd, J = 14.2, 7.5 Hz, 1H major + 1H minor COCH2CH), 2.69–2.61 (m, 1H minor CCH2CH), 2.57 (dd, J = 14.1, 6.0 Hz, 1H major CCH2CH), 2.17 (s, 3H major, COCH3), 2.13 (s, 3H minor, COCH3); 13C-NMR (100 MHz, CDCl3) δ 206.70 (major stereoisomer), 206.04 (minor stereoisomer), 171.54 (minor), 171.45 (major), 171.04 (major), 170.69 (minor), 149.45 (major), 149.22 (minor), 146.71 (minor), 146.51 (major), 140.28 (minor), 139.66 (major), 130.81 (major), 130.44 (minor), 128.88 (major), 128.59 (minor), 128.58 (minor), 128.14 (major), 126.44 (minor), 126.07 (major), 124.37 (minor), 123.58 (major), 112.02 (minor), 111.73 (major), 111.54 (minor), 111.10 (major), 57.22 (minor), 56.63 (major), 52.82 (minor), 52.81 (minor), 52.58 (major), 52.16 (major), 49.84 (minor), 48.22 (major), 42.26 (minor), 41.32 (major), 40.63 (major), 40.54 (minor), 38.39 (major), 37.85 (minor), 35.77 (major), 34.42 (minor), 30.49 (minor), 30.34 (major); IR (film) 2952, 2928, 2869, 1731, 1702, 1611, 1512, 1451, 1351, 1260, 1193, 1122, 1067, 1014 cm−1; HRMS (EI) m/z calcd for [M]+ C25H29NO5: 423.2046 Found: 423.2053.

Supplementary Materials

1H- and 13C-NMR spectra for compound 3 are available online.
Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4

Acknowledgments

This work was supported by the Kyonggi University Research Grant 2015.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Xu, H.; Lv, M.; Tian, X. A review on hemisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: 2003–2007. Curr. Med. Chem. 2009, 16, 327–349. [Google Scholar] [CrossRef] [PubMed]
  2. Fiorentino, A.; D’Abrosca, B.; Pacifico, S.; Iacovino, R.; Izzo, A.; Uzzo, P.; Russo, A.; di Blasio, B.; Monaco, P. Carexanes from Carex distachya Desf.: Revised stereochemistry and characterization of four novel polyhydroxylated prenylstilbenes. Tetrahedron 2008, 64, 7782–7786. [Google Scholar] [CrossRef]
  3. Fiorentino, A.; D’Abrosca, B.; Pacifico, S.; Natale, A.; Monaco, P. Structures of bioactive carexanes from the roots of Carex distachya Desf. Phytochemistry 2006, 67, 971–977. [Google Scholar] [CrossRef] [PubMed]
  4. Ward, R.S. Lignans, neolignans and related compounds. Nat. Prod. Rep. 1999, 16, 75–96. [Google Scholar] [CrossRef]
  5. Imbert, T.F. Discovery of podophyllotoxins. Biochimie 1998, 80, 207–222. [Google Scholar] [CrossRef]
  6. Damayanthi, Y.; Lown, J.W. Podophyllotoxins: Current status and recent developments. Curr. Med. Chem. 1998, 5, 205–252. [Google Scholar] [PubMed]
  7. Sun, J.-S.; Liu, H.; Guo, X.-H.; Liao, J.-X. The chemical synthesis of aryltetralin glycosides. Org. Biomol. Chem. 2016, 14, 1188–1200. [Google Scholar] [CrossRef] [PubMed]
  8. Pan, J.-Y.; Chen, S.-L.; Yang, M.-H.; Wu, J.; Sinkkonen, J.; Zou, K. An update on lignans: Natural products and synthesis. Nat. Prod. Rep. 2009, 26, 1251–1292. [Google Scholar] [CrossRef] [PubMed]
  9. Sin, S.; Kim, S.-G. Stereoselective cascade reactions of donor-acceptor cyclopropanes with m-N,N-dialkylaminophenyl α,β-unsaturated carbonyls: Facile diastereoselective synthesis of cis- and trans-tetralins. Adv. Synth. Catal. 2016, 358, 2701–2706. [Google Scholar] [CrossRef]
  10. Carson, J.R. Aralykyl (arylethynyl)aralkyl Amines and Their Use as Vasodilators and Antihypertensives. U.S. Patent 4661635, 28 April 1987. [Google Scholar]
  11. Goldberg, A.F. G.; O’Connor, N.R.; Craig, R.A., II; Stoltz, B.M. Lewis acid mediated (3 + 2) cycloaddition of donor-acceptor cyclopropanes with heterocumulenes. Org. Lett. 2012, 14, 5314–5317. [Google Scholar] [CrossRef] [PubMed]
  12. Cody, J.; Fahrni, C.J. Fluorescence sensing based on cation-induced conformational switching: Copper-selective modulation of the photoinduced intramolecular charge transfer of a donor–acceptor biphenyl fluorophore. Tetrahedron 2004, 60, 11099. [Google Scholar] [CrossRef]
Scheme 1. Synthesis of dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenylnaphtha-lene-2,2(1H)-dicarboxylate (3).
Scheme 1. Synthesis of dimethyl 7-(dimethylamino)-3,4-dihydro-1-(2-oxopropyl)-4-phenylnaphtha-lene-2,2(1H)-dicarboxylate (3).
Molbank 2017 m933 sch001
Back to TopTop