Next Article in Journal
Synthesis of Dimethyl Aryl Acylsulfonium Bromides from Aryl Methyl Ketones in a DMSO-HBr System
Previous Article in Journal
Characterization of the Nutraceutical Quality and Antioxidant Activity in Bell Pepper in Response to Grafting
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 18
Issue 12
10.3390/molecules181215704
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

An Efficient Approach to the Synthesis of Highly Congested 9,10-Dihydrophenanthrene-2,4-dicarbonitriles and Their Biological Evaluation as Antimicrobial Agents

by
Hassan M. Faidallah
1,*,
Khalid M. A. Al-Shaikh
1,
Tariq R. Sobahi
1,
Khalid A. Khan
1 and
Abdullah M. Asiri
1,2
1
Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
2
Center of Excellence for Advanced Materials Research, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(12), 15704-15716; https://doi.org/10.3390/molecules181215704
Submission received: 8 August 2013 / Revised: 20 November 2013 / Accepted: 10 December 2013 / Published: 16 December 2013
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
An efficient and novel method for the synthesis in moderate to good yield (72%–84%) of a series of 3-amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 1–5 via one-pot multi-component reactions of aldehydes, malononitrile, 1-tetralone and ammonium acetate has been delineated. Cyclocondensation attempts of aminocyanophenanthrene derivatives 1, 2, 4 and 5 with acetic anhydride in the presence of conc. H2SO4 failed and instead the diacetylamino derivatives 10–13 were obtained. All prepared compounds were structurally elucidated by various spectroscopic methods and X-ray crystallography. N,N-diacetylamino-derivatives of phenanthrene have shown good antimicrobial activity.

1. Introduction

The phenanthrene moiety is a structural component of many natural products and has been linked to important roles in the pharmaceutical and biological realms. It exhibits a broad spectrum of biological activities such as antimalarial [1], anticancer [2] antimycotic [3,4] anti-HIV [5] and emetic properties [6]. C9-substituted phenanthrene-based tylophorine derivatives have shown potential antiviral activity against tobacco mosaic virus (TMV) [7]. In addition, 3,7-dihydroxy-2,4,8-trimethoxyphenanthrene is known for its anti-inflammatory properties [8], while the derivative aristolochic acid exhibits tumor-inhibitory potential [9]. The phenanthrene derivatives 3-hydroxy-2,4-dimethoxy-7,8-methylenedioxyphenanthrene and 2,7-dihydroxy-1-methyl-5-vinylphenanthrene isolated from the rhizomes of Tamus communis exhibit cytotoxicity [10,11]. 9,10-Dihydrophenantherenes with pendant carboxyl groups at position-2 are reported as inhibitors of 5α-reductase and useful in the treatment of pharmacological disorders associated with elevated levels of dihydrotestosterone [12].
Various methods have been reported for the synthesis of phenanthrenes [13] and dihydrophenanthrenes [14,15,16,17,18,19,20] through ring annulation [21], intermolecular [22] and intramolecular [23] cyclization. A majority of the procedures have certain limitations of accessibility of the precursors, require multiple steps, have harsh reaction conditions, are incompatible with the presence of functional groups, have relatively overall low yields, and lack well-defined regiocontrol elements. Phenanthrenes were prepared from disubstituted biphenyls by intramolecular condensation [22], metal-catalyzed rearrangement of alkene-alkynes [24] and cycloisomerization [25] depending on the functionality present in the biphenyl moiety. Palladium-catalyzed cyclization of arynes with alkynes is an alternative route for the synthesis of phenanthrene [24] and 9,10-disubstituted phenanthrene derivatives [26].
The diverse pharmacological activities and limitations of convenient and efficient procedures prompted us to develop a concise, straight forward and economical route to the synthesis of this class of compounds without use of any catalyst.

2. Results and Discussion

2.1. Chemistry

It has been reported [27,28] that 5,6-dihydrobenzo[h]quinoline derivatives are prepared by condensation of the corresponding 2-arylidene-1-tetralone with malononitrile in the presence of ammonium acetate or via one-pot multicomponent reactions (MCRs) of aldehydes, malononitrile, 1-tetralone and ammonium acetate. However, we found that one-pot MCRs of aldehydes, malononitrile, 1-tetralone and ammonium acetate yielded the corresponding phenanthrene derivatives instead of the expected 5,6-dihydrobenzo[h]quinolines (Scheme 1). The probable mechanism for the formation of phenanthrene derivatives is shown in Scheme 2. The structures of these phenanthrene derivatives were elucidated by analytical (Table 1) and spectroscopic data (see Experimental). The conclusive proof of the phenanthrene structure over the quinoline one was given by X-ray crystallography (Figure 1).
Molecules 18 15704 g002 550
Scheme 1. Synthesis of Compounds 1–9.
Scheme 1. Synthesis of Compounds 1–9.
Molecules 18 15704 g002
Molecules 18 15704 g003 550
Scheme 2. A possible mechanism of the formation of 9,10-dihydrophenanthrene-2,4-dicarbonitriles.
Scheme 2. A possible mechanism of the formation of 9,10-dihydrophenanthrene-2,4-dicarbonitriles.
Molecules 18 15704 g003
Table
Table 1. Physical and analytical data of compounds 1–13.
Table 1. Physical and analytical data of compounds 1–13.
Compd.RYieldm.p.Mol. FormulaCalc. %Found %
(%)(°C)CHNCHN
14-BrC₆H₄76244–246C22H14BrN366.013.5310.5065.983.6410.45
24-CH3OC₆H₄82214–216C23H17N3O78.614.8811.9678.484.6811.89
33,4-(CH3O)2C₆H378266–268C24H19N3O275.575.0211.0275.625.1610.87
43,4-(OCH2O) C₆H384276–278C23H15N3O275.604.1411.5075.524.2011.42
52-Thienyl72220–222C20H13N3S73.374.0012.8373.423.8912.72
6C6H532340–343C22H15 N382.224.7013.0882.344.6513.12
74-ClC₆H₄49238–240C22H14Cl N374.263.9711.8174.414.0211.68
8C6H550290–293C20H15 N380.785.0814.1380.825.1114.23
94-ClC₆H₄12222–225C20H14Cl N372.404.2512.6672.364.3212.61
104-BrC₆H₄82275–277C22H14BrN366.013.5310.5066.123.5110.75
114-CH3OC₆H₄80344–346C27H21N3O374.474.869.6574.614.689.55
123,4-(OCH2O) C₆H377265–267C27H19N3O472.154.269.3572.234.089.19
132-Thienyl76355–357C24H17N3O2S70.054.1610.2170.124.2210.31
Molecules 18 15704 g001 550
Figure 1. X-ray crystal structures of some dihydrophenanthrenes and dihydrobenzoquinolines.
Figure 1. X-ray crystal structures of some dihydrophenanthrenes and dihydrobenzoquinolines.
Molecules 18 15704 g001
a Source: reprinted from [29,30,31,32,33,34,35,36].
It is worthy to mention here that when the aromatic aldehyde is benzaldehyde, or 4-chlorobenzaldehyde two products were isolated; one is the expected benzoquinoline derivative 8 or 9 and the other is the unexpected phenanthrene 6 or 7. However, in case of the 4-chlorobenzaldehyde the major product is the phenanthrene derivative (phenanthrene/benzoquinoline 4:1) while with benzaldehyde the benzoquinoline derivative is the major product (benzoquinoline/phenanthrene 5:3).
The formation of the benzoquinoline may be explained according to the following mechanism (Scheme 3). The reaction seemed to be started by first addition of active hydrogen of 1-tetralone to the ethylenic double bond of compound A. Ammonia was added to the nitrile group in B to give C which looses a molecule of water to give D, which in turn was converted to the final product by auto-oxidation.
The IR spectra of compounds 1–9 revealed absorption bands at 3,359–3,389 cm−1 characteristic for the NH2 and at 2,318–2,226 cm−1 attributed to the CN group. Their 1H-NMR spectra exhibited, besides the aromatic protons at δ 7.17–8.02, two multiplets at δ 2.86–2.94 and 2.80–2.85 ppm corresponding to the benzylic protons (C9-H and C10-H respectively) as well as an exchangeable NH2 at δ 6.54–6.67. The structures were further supported by 13C-NMR which showed in addition to the expected number of aromatic carbons, two signals at δ 34.2–34.7 and 26.2–26.8 for the benzyl carbons (C-9 and C-10 respectively). More evidence for the structures of compounds 1–9 arise from their X-ray crystallography [29,30,31,32,33,34,35] data which confirm the phenanthrene structure for compounds 1–5 (Figure 1). However, when Ar = Ph or 4-Cl-C6H4, the X-ray crystallography confirms that they are a mixture of the benzoquinoline derivatives 6 and 7 and corresponding phenanthrene 8 and 9.
Molecules 18 15704 g004 550
Scheme 3. A possible mechanism of the formation of benzoquinoline derivatives.
Scheme 3. A possible mechanism of the formation of benzoquinoline derivatives.
Molecules 18 15704 g004
Attempts were made to prepare 2-methylpyrimidone derivative E by cyclization of the 3-aminophenanthrene derivatives 1, 2, 4 and 5 with acetic anhydride either in the presence or the absence of conc. H2SO4 adopting the same procedure reported in the literature [37,38,39,40], but these reactions afforded the N,N-diacetylaminophenanthrenes 10–13 instead of the expected pyrimidone derivatives (Scheme 4).
Molecules 18 15704 g005 550
Scheme 4. N,N-Diacetyl derivatives of dihyrophenenthrene 10–13.
Scheme 4. N,N-Diacetyl derivatives of dihyrophenenthrene 10–13.
Molecules 18 15704 g005
The IR spectra of compounds 10–13 were characterized by the absence of the NH2 absorption and the presence of two new sharp absorption bands in the 1,666–1,672 cm−1 region due to the new C=O groups. Their 1H NMR exhibited, besides aromatic protons at δ 7.14–7.48, two multiplets at δ 2.82–2.86 and 2.84–2.88 ppm corresponding to the H-9 and H-10 respectively, as well as a singlet of six proton intensity at δ 2.40–2.44 for the 2CH3 groups. The structures were further supported by 13C-NMR data which showed in addition to the expected number of aromatic carbons, two signals at δ 34.0–34.5 and 26.2–26.6 for C-9 and C-10 in addition to the CH3 carbons at δ 14.7–14.9. More evidence for the structure of compound 11 comes from its X-ray crystallography [36].

2.2. Biological Evaluation

2.2.1. In Vitro Antibacterial and Antifungal Activities

Compounds 1–13 were screened in vitro for their antimicrobial and antifungal activities against Escherichia coli, Staphylococcus aureus, Aspergillus niger and Candida albicans. The zones of inhibition formed for the compounds against bacteria and fungi are summarized in Table 2. The overall results suggested that compounds containing 3-(N,N-diacetylamino)-substituent exhibited relatively better antimicrobial and antifungal activities when compared with non-acetylated phenanthrene analogs thereby indicating a positive role of diacetyl-substitution in the present series. Compounds 10 and 13 were however, significantly active when compared with rest of the series. All test data in Table 2 were of average value from triplicate runs and the test compounds showed reduced antimicrobial activities when compared with their respective standards.
Table
Table 2. Anti-bacterial and anti-fungal data of compounds 1–13.
Table 2. Anti-bacterial and anti-fungal data of compounds 1–13.
CompoundZone of Inhibition in mmZone of Inhibition in mm
Escherichia coliStaphylococcus aureusAspergillus nigerCandida albicans
125241821
221201518
320211416
423201318
525221620
616151213
718171415
812131013
914151215
1030282022
1128261719
1226251920
1329292122
Ampicillin3029--
Clotrimazole--3332

3. Experimental

3.1. General Methods

Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. The infrared (IR) spectra were recorded on Shimadzu FT-IR 8400S infrared spectrophotometer using the KBr pellet technique. 1H- and 13C-NMR spectra were recorded on a Bruker DPX-400 FT NMR spectrometer using tetramethylsilane as the internal standard and DMSO-d6 as a solvent (chemical shifts in δ, ppm). Splitting patterns were designated as follows: s: singlet; d: doublet; m: multiplet; q: quartet. Elemental analyses were performed on a 2400 Perkin Elmer Series 2 analyzer and the found values were within ±0.4% of the theoretical values. Follow up of the reactions and checking the homogeneity of the compounds were made by TLC on silica gel pre-coated aluminum sheets (Type 60 F254, Merck) and the spots were detected by exposure to UV-lamp at λ 254.

3.1.1. 3-Amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 1–5

A one-pot mixture of the appropriate aldehyde (10 mmol), 3,4-dihydro-2H-naphthalene-1-one (1.46 g, 10 mmol), malononitrile (0.66 g, 10 mmol) and ammonium acetate (6.2 g, 80 mmol) in absolute ethanol (50 mL) was refluxed for 6 h. The reaction mixture was allowed to cool, and the resulting precipitate was filtered, washed with water, dried and recrystallized from DMF. Yields, 72%–84%; IR: (cm−1, KBr): 3357–3361, 3420–3428 (NH2), 2220–2231 (CN).
3-Amino-1-(4-bromophenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (1): 1H-NMR (DMSO-d6) δ ppm: 2.86 (m, 2H, C-9 protons), 2.80 (m, 2H, C-10 protons), 7.12 (s, 1H, NH2), 7.24–7.48 (m, 9H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.2 (C-9), 26.3 (C-10), 116.6 (CN), 97.5, 126.2, 126.4, 127.3, 127.5, 128.6, 129.1, 129.5, 136.2, 136.7, 139.0, 145.2, 152.0 (Ar-C).
3-Amino-1-(4-methoxyphenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (2): 1H-NMR (DMSO-d6) δ ppm: 2.88 (m, 2H, C-9 protons), 2.83 (m, 2H, C-10 protons), 3.74 (CH3O), 6.98 (s, 1H, NH2), 6.85–7.49 (m, 8H, ArH). 13C-NMR (DMSO-d6) δ ppm: 33.8(C-9), 26.2 (C-10), 56.1 (CH3O), 116.5 (CN), 97.4, 114.4, 126.2, 126.6, 127.5, 128.4, 128.7, 129.4, 136.1, 139.4, 145.2, 151.8, 160.6 (Ar-C).
3-Amino-1-(3,4-dimethoxyphenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (3): 1H-NMR (DMSO-d6) δ ppm: 2.86 (m, 2H, C-9 protons), 2.82 (m, 2H, C-10 protons), 3.72 (CH3O), 3.73 (CH3O), 6.87 (s, 1H, NH2), 6.72–7.50 (m, 7H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.1 (C-9), 26.4 (C-10), 56.2 (CH3O), 56.3 (CH3O), 117.0 (CN), 97.3, 114.0, 115.5, 116.3, 120.7, 126.3, 127.4, 128.4, 129.6, 129.7, 135.9, 139.1, 145.2, 146.4, 148.2, 151.8 (Ar-C).
3-Amino-1-(benzo[d][1,3]dioxol-5-yl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (4): 1H-NMR (DMSO-d6) δ ppm: 2.87 (m, 2H, C-9 protons), 2.80 (m, 2H, C-10 protons), 5.91(CH2), 6.86 (s, 1H, NH2), 6.80–7.48 (m, 7H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.2 (C-9), 26.5 (C-10), 117.2 (CN), 91.2 (CH2), 97.5, 114.2, 115.6, 116.4, 120.7, 126.2, 127.6, 128.5, 129.4, 129.9, 136.0, 139.1, 145.3, 146.2, 148.4, 151.9 (Ar-C).
3-Amino-1-(thiophen-2-yl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (5): 1H-NMR (DMSO-d6) δ ppm: 2.89 (m, 2H, C-9 protons), 2.81 (m, 2H, C-10 protons), 6.75 (s, 1H, NH2), 6.98–7.47 (m, 7H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.3 (C-9), 26.3 (C-10), 116.9 (CN), 97.2, 98.6, 122.8, 125.2, 126.3, 127.4, 127.5, 128.3, 129.1, 136.0, 139.1, 142.4, 145.2, 151.8 (Ar-C).

3.1.2. 3-Amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 6 and 7 and 2-Amino-4- substituted-5,6-dihydrobenzo[h]quinoline-3-carbonitriles 8 and 9

A mixture of the 1-tetralone (1.46g, 10 mmol), the appropriate aldehyde (10 mmol), malononitrile (0.66 g, 10 mmol) and ammonium acetate (6.2 g, 80 mmol) in absolute ethanol (50 mL) was refluxed for 3–6 h. The reaction mixture was cooled and the resulting precipitate was filtered, washed with water, dried. The obtained solid was then subjected to column chromatography on silica gel (n-hexane/ethyl acetate 9:1) to give two products. IR: (cm−1, KBr): 3367–3372, 3429–3435 (NH2), 2219–2224 (CN).
3-Amino-1-phenyl-9,10-dihydrophenanthrene-2,4-dicarbonitrile (6): 1H-NMR (DMSO-d6) δ ppm: 2.86 (m, 2H, C-9 protons), 2.80 (m, 2H, C-10 protons), 7.12 (s, 1H, NH2), 7.24–7.48 (m, 9H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.2 (C-9), 26.2 (C-10), 116.6 (CN), 97.5, 126.2, 126.4, 127.3, 127.5, 128.6, 129.1, 129.5, 136.2, 136.7, 139.4, 145.2, 152.0 (Ar-C).
3-Amino-1-(4-chlorophenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (7): 1H-NMR (DMSO-d6) δ ppm: 2.84 (m, 2H, C-9 protons), 2.81 (m, 2H, C-10 protons), 7.03 (s, 1H, NH2), 7.16–7.47 (m, 9H, ArH). 13C-NMR (DMSO-d6) δ ppm: 33.3 (C-9), 26.9 (C-10), 117.4 (CN), 97.5, 126.1, 126.4, 127.0, 127.5, 128.4, 129.3, 129.6, 136.2, 137.2, 139.6, 145.4, 152.4 (Ar-C).
2-Amino-4-phenyl-5,6-dihydrobenzo[h]quinoline-3-carbonitrile (8): 1H-NMR (DMSO-d6) δ ppm: 2.56 (m, 2H, C-5 protons), 2.76 (m, 2H, C-6 protons), 6.45 (s, 1H, NH2) 7.16–7.98 (m, 9H, ArH). 13C-NMR (DMSO-d6) δ ppm: 25.2 (C-5), 28.5 (C-6), 117.0 (CN), 89.8, 125.5, 126.3, 126.8, 127.1, 128.4, 129.0, 138.2, 138.8, 139.2, 155.4, 160.6, 162.6 (Ar-C).
2-Amino-4-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile (9): 1H-NMR (DMSO-d6) δ ppm: 2.54 (m, 2H, C-5 protons), 2.72 (m, 2H, C-6 protons), 6.39 (s, 1H, NH2), 7.17–8.02 (m, 8H, ArH). 13C-NMR (DMSO-d6) δ ppm: 25.4 (C-5), 28.3 (C-6), 116.8 (CN), 90.0, 125.3, 126.1, 126.6, 127.1, 128.1, 129.2, 129.4, 134.3, 137.8, 138.6, 139.1, 154.4, 160.5, 162.4 (Ar-C).

3.1.3. 3-(N,N-Diacetylamino)-1-(4-bromophenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitriles 10–13

A mixture of the appropriate 3-aminophenanthrene derivative 1, 2, 4 or 5 (10.00 mmol), acetic anhydride (5 mL) and conc. H2SO4 (0.2 mL) was heated in a boiling water bath for 10 min, then cooled, poured on ice-cold water, treated with 20% NaOH solution until it reaches an alkaline pH (pH~11). The resulting solid product was filtered and recrystallized from ethanol. Yields, 76%–82%; IR: (cm−1, KBr): 2220–2228 (CN), 1692–1705 (C=O).
N-acetyl-N-(1-(4-bromophenyl)-2,4-dicyano-9,10-dihydrophenanthren-3-yl)acetamide (10): 1H-NMR (DMSO-d6) δ ppm: 2.40 (s, 6H, 2CH3), 2.88 (m, 2H, C-9 protons), 2.84 (m, 2H, C-10 protons), 7.17–7.46 (m, 9H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.2 (C-9), 26.4 (C-10), 116.8 (CN), 97.4, 126.3, 126.5, 127.3, 127.7, 128.7, 129.2, 129.8, 136.1, 136.7, 139.1, 144.6, 151.8 (Ar-C).
N-acetyl-N-(2,4-dicyano-1-(4-methoxyphenyl)-9,10-dihydrophenanthren-3-yl)acetamide (11): 1H-NMR (DMSO-d6) δ ppm: 2.88 (m, 2H, C-9 protons), 2.80 (m, 2H, C-10 protons), 3.72 (CH3O), 6.77–7.48 (m, 8H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 33.9 (C-9), 26.2 (C-10), 56.0 (CH3O), 116.7 (CN), 97.5, 114.3, 126.2, 126.4, 127.5, 128.5, 128.6, 129.6, 136.1, 139.1, 145.1, 151.9, 160.5 (Ar-C).
N-acetyl-N-(1-(benzo[d][1,3]dioxol-5-yl)-2,4-dicyano-9,10-dihydrophenanthren-3-yl)acetamide (12): 1H-NMR (DMSO-d6) δ ppm: 2.87 (m, 2H, C-9 protons), 2.82 (m, 2H, C-10 protons), 5.90 (CH2), 6.82–7.48 (m, 7H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.1 (C-9), 26.3 (C-10), 116.9 (CN), 91.2 (CH2), 97.4, 114.3, 115.5, 116.4, 120.5, 126.1, 127.5, 128.4, 129.3, 129.9, 136.0, 139.1, 145.4, 146.1, 148.3, 151.7 (Ar-C).
N-acetyl-N-(2,4-dicyano-1-(thiophen-2-yl)-9,10-dihydrophenanthren-3-yl)acetamide (13): 1H-NMR (DMSO-d6) δ ppm: 2.89 (m, 2H, C-9 protons), 2.82 (m, 2H, C-10 protons), 6.88–7.46 (m, 7H, Ar-H). 13C-NMR (DMSO-d6) δ ppm: 34.2 (C-9), 26.1 (C-10), 116.8 (CN), 97.1, 98.5, 122.6, 125.2, 126.2, 127.4, 127.6, 128.3, 129.2, 136.0, 139.1, 142.2, 145.4, 152.0 (Ar-C).

3.2. Biological Activity Evaluation

3.2.1. Anti-Microbial Activity Procedure

The preliminary anti-microbial activities of compounds 1–13 were measured in a concentration of 50 mg/L by disc diffusion method [41,42]. The prepared compounds were tested for their antimicrobial activity against Staphylococcus aureus (ATCC 25923) as Gram positive bacteria, Escherichia coli (ATCC 25922) as Gram negative bacteria, and the antifungal activity was performed using the pathogenic yeast strains Candida albicans and Aspergillus niger. DMSO was used as a solvent and the standard drugs used were ampicillin and griseofulvin. The disc diffusion method was performed using Muller-Hinton agar (Hi-Media) medium. The inhibition zones were measured in mm at the end of an incubation period of 24 h at 37 °C for bacteria and 72 h at 24 °C for fungi. The zone of inhibition in mm is expressed in Table 2. All test data in Table 2 were of average values from triplicate run.

4. Conclusions

The present paper describes an efficient and simple method for the synthesis of a series of 3-amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 1–5 via one-pot multicomponent reactions (MCRs). The structures of these phenanthrene derivatives were elucidated by analytical and spectroscopic data. The conclusive proof of the phenanthrene structure was given by X-ray crystallography. The prepared compounds were screened in vitro for their antimicrobial and antifungal activities. The overall results suggested that compounds containing 3-(N,N-diacetylamino)- substituent exhibited relatively better antimicrobial and antifungal activities when compared with non-acetylated phenanthrene analogs, indicating a positive role of diacetyl group in the present series. Compounds 10 and 13 were however, significantly active when compared with the rest of the series.

Acknowledgments

The authors are grateful to the Biology Department, Faculty of Science, University of Alexandria for their help in biological activity evaluation.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Huffmann, C.W.; Traxler, J.T.; Krbechek, L.; Riter, R.R.; Wagner, R.G. Syntheses of halogenated phenanthrene amino alcohols as antimalarials. J. Med. Chem. 1971, 14, 90–94. [Google Scholar] [CrossRef]
  2. Wilson, S.; Ruenitz, P.C. Structural characterization and biological effects of photocyclized products of tamoxifen irradiation. J. Pharm. Sci. 1993, 82, 571–574. [Google Scholar] [CrossRef]
  3. Fisch, M.H.; Flick, B.H.; Arditti, J. Structure and antifungal activity of hircinol, loroglossol and orchinol. Phytochemistry 1973, 12, 437–441. [Google Scholar] [CrossRef]
  4. Kelly, T.R.; Li, Q.; Bhushan, V. Intramolecular biaryl coupling: Asymmetric synthesis of the chiral b-ring diol unit of pradimicinone. Tetrahedron Lett. 1990, 31, 161–164. [Google Scholar] [CrossRef]
  5. Hoshino, H.; Seki, J.-I.; Takeuchi, T. New Antifungal Antibiotics, benanomocins A and B inhibit infection of T-cell with human immunodeficiency virus (HIV) and syncytium formation by HIV. J. Antibiot. 1989, 42, 344–346. [Google Scholar] [CrossRef]
  6. Cannon, J.G.; Khonje, P.R.; Long, J.P. Centrally acting emetics. 9. Hofmann and Emde degradation products of nuciferine. J. Med. Chem. 1975, 18, 110–112. [Google Scholar] [CrossRef]
  7. Wang, K.; Hu, Y.; Liu, Y.; Mi, N.; Fan, Z.; Liu, Y.; Wang, Q. Design, synthesis, and antiviral evaluation of phenanthrene-based tylophorine derivatives as potential antiviral agents. J. Agric. Food Chem. 2010, 58, 12337–12342. [Google Scholar] [CrossRef]
  8. Bordat, P.; Tarroux, R.; Charveron, M.; David, B. Phenanthrene Derivatives, Their Synthesis, Anti-Inflammatory Activity, and Use in Treating Inflammatory Skin Diseases. France Demande WO Patent 2006089881, 2006. [Google Scholar]
  9. Kupchan, S.M.; Wormser, H.C. Tumor inhibitors. X. Photochemical synthesis of phenanthrenes. Synthesis of aristolochic acid and related compounds. J. Org. Chem. 1965, 30, 3792–3800. [Google Scholar] [CrossRef]
  10. Kovacs, A.; Forgo, P.; Zupko, I.; Rethy, B.; Falkay, G.; Szabo, P.; Hohmann, J. Phenanthrenes and a dihydrophenanthrene from Tamus communisand their cytotoxic activity. Phytochemistry 2007, 68, 687–691. [Google Scholar] [CrossRef]
  11. Dellagreca, M.; Fiorentinob, A.; Isidorib, M.; Lavorgna, M.; Monaco, P.; Previtera, L.; Zarrelli, A. Phenanthrenoids from the wetland Juncus acutus. Phytochemistry 2002, 60, 633–638. [Google Scholar] [CrossRef]
  12. Boger, D.L.; Mullican, M.D. Regiospecific total synthesis of juncusol. J. Org. Chem. 1984, 49, 4045–4050. [Google Scholar] [CrossRef]
  13. Floyd, A.J.; Dyke, S.F.; Ward, S.E. The synthesis of phenanthrenes. Chem. Rev. 1976, 76, 509–562. [Google Scholar] [CrossRef]
  14. Orchin, M.; Woolfolk, E.O. Aromatic cyclodehydrogenation. I. 4-Methylfluorene from 2,2'-Dimethylbiphenyl. J. Am. Chem. Soc. 1945, 67, 122–124. [Google Scholar] [CrossRef]
  15. Ram, V.J.; Goel, A. An Expeditious synthesis of 9,10-Dihydrophenanthrene by condensation of 2H-Pyran-2-ones with α-Tetralone. J. Chem. Res. (S) 1997. [Google Scholar] [CrossRef]
  16. Erdman, H.; Ronlan, A. Phenol dehydrogenation. Part 11. Intramolecular oxidative coupling of dihydropiceatannol. Acta Chem. Scand. 1969, 23, 249–254. [Google Scholar] [CrossRef]
  17. Gilchrist, T.L.; Summersell, R.J. Synthesis of chrysenes and other a-fused phenanthrenes by a palladium(0) coupling—Electrocyclic ring closure sequence. J. Chem. Soc. Perkin Trans. 1988, 1, 2595–2601. [Google Scholar] [CrossRef]
  18. Rabideau, P.W.; Marcinow, Z. Silicon modified reduction and reductive alkylation-application to the phenanthrene system. Tetrahedron Lett. 1988, 29, 3761–3764. [Google Scholar] [CrossRef]
  19. Bowden, B.F.; Read, R.W.; Ritchie, E.; Taylor, W.C. Synthesis of 9,10-dihydrophenanthrenes including orchinol methyl ether. Aust. J. Chem. 1975, 28, 65–80. [Google Scholar] [CrossRef]
  20. Pratap, R.; Ram, V.J. An efficient de novo synthesis of partially reduced phenanthrenes through C−C insertion. J. Org. Chem. 2007, 72, 7402–7405. [Google Scholar] [CrossRef]
  21. Catellani, M.; Motti, E.; Baratta, S. A novel palladium-catalyzed synthesis of phenanthrenes from ortho-Substituted Aryl Iodides and Diphenyl- or Alkylphenylacetylenes. Org. Lett. 2001, 3, 3611–3614. [Google Scholar] [CrossRef]
  22. Paredes, E.; Biolatto, B.; Kneetmann, M.; Mancini, P. One-step synthesis of 2,9-disubstituted phenanthrenes via Diels-Alder reactions using 1,4-disubstituted naphthalenes as dienophiles. Tetrahedron Lett. 2002, 43, 4601–4603. [Google Scholar] [CrossRef]
  23. Almedida, J.F.; Castedo, L.; Fernandez, D.; Neo, A.G.; Romero, V.; Tojo, G. Base-induced photocyclization of 1,2-Diaryl-1-tosylethenes. A mechanistically novel approach to phenanthrenes and phenanthrenoids. Org. Lett. 2003, 5, 4939–4941. [Google Scholar] [CrossRef]
  24. Katz, T.J.; Sivavec, T.M. Metal-catalyzed rearrangement of alkene-alkynes and the stereochemistry of metallacyclobutene ring opening. J. Am. Chem. Soc. 1985, 107, 737–738. [Google Scholar] [CrossRef]
  25. Furstner, A.; Mamane, V. Flexible synthesis of phenanthrenes by a PtCl2-Catalyzed cycloisomerization reaction. J. Org. Chem. 2002, 67, 6264–6267. [Google Scholar] [CrossRef]
  26. Ram, V.J.; Nath, M.; Srivastava, P.; Sharkhel, S.; Maulik, P.R. A facile access to the synthesis of functionalised unsymmetrical biaryls from 2H-pyran-2-ones through carbanion induced C–C bond formation. J. Chem. Soc. Perkin Trans. 2000, 1, 3719–3723. [Google Scholar]
  27. Aly, A.S.; El-Ezabawy, S.R.; Abdel-Fattah, A.M. Reactions with α-substituted cinnamonitriles: Synthesis of benzo[h]quinolines and naphtho[1,2, b] pyrans. Egypt. J. Pharm. Sci. 1991, 32, 827–834. [Google Scholar]
  28. Al-Mutairi, T.M.; Al-Hazimi, H.M.; El-Baih, F.E.M. One-pot multicomponent synthesis of some 5,6-dihydro-benzo[h]quinoline derivatives. J. Saudi Chem. Soc. 2009, 13, 199–207. [Google Scholar] [CrossRef]
  29. Asiri, A.M.; Faidallah, H.M.; Al-Youbi, A.O.; Ng, S.W. 3-Amino-1-(4-bromophenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, E67, o2745. [Google Scholar]
  30. Asiri, A.M.; Al-Youbi, A.O.; Faidallah, H.M.; Ng, S.W.; Tiekink, E.R.T. 3-Amino-1-(4-methoxy­phenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, E67, o2449. [Google Scholar]
  31. Asiri, A.M.; Al-Youbi, A.O.; Faidallah, H.M.; Ng, S.W.; Tiekink, E.R.T. 3-Amino-1-(2H-1,3-benzodioxol-5-yl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, E67, o2438. [Google Scholar]
  32. Al-Youbi, A.O.; Asiri, A.M.; Faidallah, H.M.; Ng, S.W.; Tiekink, E.R.T. 3-Amino-1-(3,4-dimethoxyphenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile. Acta Crystallogr. Sect. E Struct. Rep. Online 2012, E68, o1027–o1028. [Google Scholar]
  33. Asiri, A.M.; Faidallah, H.M.; Alamry, K.A.; Ng, S.W.; Tiekink, E.R.T. 3-Amino-1-(3,4-dimeth­oxyphenyl)-9,10-dihydro­phenanthrene-2,4-dicarbonitrile. Acta Crystallogr. Sect. E Struct. Rep. Online 2012, E68, o1118–o1119. [Google Scholar]
  34. Asiri, A.M.; Al-Youbi, A.O.; Faidallah, H.M.; Ng, S.W. 2-Amino-4-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile–3-amino-1-(4-chlorophenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (1/4). Acta Crystallogr. Sect. E Struct. Rep. Online 2011, E67, o2874. [Google Scholar]
  35. Asiri, A.M.; Al-Youbi, A.O.; Faidallah, H.M.; Ng, S.W. 2-Amino-4-phenyl-5,6-dihydrobenzo-[h]quinoline-3-carbonitrile–3-amino-1-phenyl-9,10-dihydrophenanthrene-2,4-dicarbonitrile (5/3). Acta Crystallogr. Sect. E Struct. Rep. Online 2011, E67, o2872. [Google Scholar]
  36. Asiri, A.M.; Faidallah, H.M.; Al-Thabaiti, S.A.; Ng, S.W.; Tiekink, E.R.T. N-Acetyl-N-[2,4-dicyano-1-(4-methoxyphenyl)-9,10-dihydrophenanthren-3-yl]acetamide. Acta Crystallogr. Sect. E Struct. Rep. Online 2012, E68, o1177–o1178. [Google Scholar]
  37. El-Baih, F.E.M. Synthesis of some Naphtho[1,2-b]Pyran, Naphtho[1,2-d]Pyrimidine and Benzo[h]Quinoline derivatives. J. Saudi Chem. Soc. 2004, 8, 279–288. [Google Scholar]
  38. El-Baih, F.E.M.; Al-Rasheed, H.H.; Al-Hazimi, H.M. Synthesis of some pyridine and pyrimidine derivatives via michael-addition. J. Saudi Chem. Soc. 2006, 9, 575–596. [Google Scholar]
  39. Otto, H.H.; Schmelz, H. Reaktionen von arylidentetralonen mit cyanessigsäurederivaten. Monatsh. Chem. 1979, 110, 249–256. [Google Scholar] [CrossRef]
  40. Bedair, A.H.; El-Hady, N.A.; Abd El-Latif, M.S.; Fakery, A.H.; El-Agrody, A.M. 4-Hydroxycoumarin in heterocyclic synthesis: Part III. Synthesis of some new pyrano[2,3-d]pyrimidine, 2-substituted[1,2,4]triazolo[1,5-c]pyrimidine and pyrimido[1,6-b][1,2,4]triazine derivatives. Il Farmaco 2000, 55, 708–714. [Google Scholar] [CrossRef]
  41. Kirkpatrick, W.R.; Turner, T.M.; Fothergill, A.W.; McCarthy, D.I.; Redding, S.W.; Rinaldi, M.G.; Patterson, T.F. Fluconazole disk diffusion susceptibility testing of Candida species. J. Clin. Microbiol. 1998, 36, 3429–3432. [Google Scholar]
  42. Premkumar, T.; Govindarajan, S. Antimicrobial study of pyrazine, pyrazole and imidazole carboxylic acids and their hydrazinium salts. World J. Microbiol. Biotechnol. 2005, 21, 479–480. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of the compounds 1–13 are available from the authors.

Share and Cite

MDPI and ACS Style

Faidallah, H.M.; Al-Shaikh, K.M.A.; Sobahi, T.R.; Khan, K.A.; Asiri, A.M. An Efficient Approach to the Synthesis of Highly Congested 9,10-Dihydrophenanthrene-2,4-dicarbonitriles and Their Biological Evaluation as Antimicrobial Agents. Molecules 2013, 18, 15704-15716. https://doi.org/10.3390/molecules181215704

AMA Style

Faidallah HM, Al-Shaikh KMA, Sobahi TR, Khan KA, Asiri AM. An Efficient Approach to the Synthesis of Highly Congested 9,10-Dihydrophenanthrene-2,4-dicarbonitriles and Their Biological Evaluation as Antimicrobial Agents. Molecules. 2013; 18(12):15704-15716. https://doi.org/10.3390/molecules181215704

Chicago/Turabian Style

Faidallah, Hassan M., Khalid M. A. Al-Shaikh, Tariq R. Sobahi, Khalid A. Khan, and Abdullah M. Asiri. 2013. "An Efficient Approach to the Synthesis of Highly Congested 9,10-Dihydrophenanthrene-2,4-dicarbonitriles and Their Biological Evaluation as Antimicrobial Agents" Molecules 18, no. 12: 15704-15716. https://doi.org/10.3390/molecules181215704

Article Metrics

Back to TopTop