An efficient approach to the synthesis of highly congested 9,10-dihydrophenanthrene-2,4-dicarbonitriles and their biological evaluation as antimicrobial agents

Article abstract of DOI:10.3390/molecules181215704

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.

Full text of DOI:10.3390/molecules181215704

Molecules 2013, 18, 15704-15716; doi:10.3390/molecules181215704
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Efficient Approach to the Synthesis of Highly Congested
9,10-Dihydrophenanthrene-2,4-dicarbonitriles and Their
Biological Evaluation as Antimicrobial Agents
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; E-Mails: khalidyat@hotmail.com (K.M.A.A.-S.);
drtariq_s@hotmail.com (T.R.S.); kzsakhan@hotmail.com (K.A.K.); aasiri2@gmail.com (A.M.A.)
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; E-Mail: hfaidallahm@hotmail.com;
Tel.: +966-567-743-180.
Received: 8 August 2013; in revised form: 20 November 2013 / Accepted: 10 December 2013/
Published: 16 December 2013
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.
Keywords: dihydrophenanthrene; X-ray crystallography; dihydrobenzo[h]quinoline-3-
carbonitrile; 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

Molecules 2013, 18
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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 [14–20] 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 2013, 18
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Scheme 1. Synthesis of Compounds 1–9.
NH2
NC
CN
Ar
O
CN
NH4OAc
+
ArCHO
+
CN
Ar
1: 4-BrC6H4
2:
4-CH3OC6H4
3,4-(CH3O)2C6H3
3:
4:
5:
3,4-(OCH2O)C6H3
2-Theinyl
NH2
NH2
NC
CN
Ar
CN
Ar
N
+
C6H5
6:
7:
8: C6H5
9:
4-ClC6H4
4-ClC6H4
Scheme 2. A possible mechanism of the formation of 9,10-dihydrophenanthrene-2,4-dicarbonitriles.
CN
HC
CN
NC
NC
NC
CN
CN
O
CH
OH
CN
CN
NC
CN
O
Ar
H
Ar
CN
Ar-CHO
Ar
H
H N
NH
H
H2N
N
H2N
H
H
N
C
NC
CN
NC
NC
CN
NC
NC
CH
NC
CN
Ar
Ar
Ar
H2O
NH2
NH
NH2
CN
CN
Ar
NC
NC
NC
CN
Ar
NC
NC
H
Ar
- NH3
- HCN
- HCN
H
H

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Table 1. Physical and analytical data of compounds 1–13.
Yield
m.p.
Calc. %
H
Found %
H
Mol.
Compd.
R
Formula
(%)
76
82
78
84
72
32
49
50
12
82
80
77
76
(°C)
C
N
C
N
1
2
4-BrC₆H₄
244–246
214–216
266–268
276–278
220–222
340–343
238–240
290–293
222–225
275–277
344–346
265–267
355–357
C22H14BrN3
C23H17N3O
C24H19N3O2
C23H15N3O2
C20H13N3S
C22H15 N3
66.01 3.53
78.61 4.88
75.57 5.02
75.60 4.14
73.37 4.00
82.22 4.70
74.26 3.97
80.78 5.08
72.40 4.25
66.01 3.53
74.47 4.86
72.15 4.26
70.05 4.16
10.50
11.96
11.02
11.50
12.83
13.08
11.81
14.13
12.66
10.50
9.65
65.98 3.64 10.45
78.48 4.68 11.89
75.62 5.16 10.87
75.52 4.20 11.42
73.42 3.89 12.72
82.34 4.65 13.12
74.41 4.02 11.68
80.82 5.11 14.23
72.36 4.32 12.61
66.12 3.51 10.75
4-CH3OC₆H₄
3,4-(CH3O)2C₆H3
3,4-(OCH2O) C₆H3
2-Thienyl
3
4
5
6
C6H5
7
4-ClC₆H₄
C22H14Cl N3
C20H15 N3
8
C6H5
9
4-ClC₆H₄
C20H14Cl N3
C22H14BrN3
C27H21N3O3
C27H19N3O4
C24H17N3O2S
10
11
12
13
4-BrC₆H₄
4-CH3OC₆H₄
3,4-(OCH2O) C₆H3
2-Thienyl
74.61 4.68
72.23 4.08
9.55
9.19
9.35
10.21
70.12 4.22 10.31
Figure 1. X-ray crystal structures of some dihydrophenanthrenes and dihydrobenzoquinolines.
3-Amino-1-(4-bromophenyl)-9,10-dihydro-
3-Amino-1-(4-methoxyphenyl)-9,10-dihydrophenanthrene-
phenanthrene-2,4-dicarbonitrile (1) a
2,4-dicarbonitrile (2) a
3-Amino-1-(3,4-dimethoxyphenyl)-9,10-
3-Amino-1-(2H-1,3-benzodioxol-5-yl)-9,10-
dihydrophenanthrene-2,4-dicarbonitrile (3) a
dihydrophenanthrene-2,4-dicarbonitrile (4) a

Molecules 2013, 18
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Figure 1. Cont.
3-Amino-1-(thiophen-2-yl)-9,10-dihydrophenanthrene-
2-Amino-4-phenyl-5,6-dihydro-benzo[h]quinoline-
2,4-dicarbonitrile (5) a
3-carbonitrile (8) a
3-Amino-1-phenyl-9,10-dihydro-phenanthrene-2,4-
N-Acetyl-N-[2,4-dicyano-1-(4-methoxyphenyl)-9,10-
dicarbonitrile (7) a
dihydrophenanthren-3-yl]acetamide (11) a
a Source: reprinted from [29–36].
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 [29–35] data which confirm the phenanthrene structure for compounds 1–5 (Figure 1).

Molecules 2013, 18
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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.
Scheme 3. A possible mechanism of the formation of benzoquinoline derivatives.
O
NC
OH
CN
CN
CN
CN
NH4OAc
CN
Ar
ArCHO
+
Ar
A
B
H2N
CN
NH2
N
NH2
HN
OH
CN
Ar
CN
Ar
N
Ar
- H2
- H2O
C
D
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 [37–40], but these
reactions afforded the N,N-diacetylaminophenanthrenes 10–13 instead of the expected pyrimidone
derivatives (Scheme 4).
Scheme 4. N,N-Diacetyl derivatives of dihyrophenenthrene 10–13.
N H 2
N (CO C H 3
C N
)
2
NC
C N
A r
N C
A c 2O
A r
A r
1 0: 4 -B rC 6 H 4
C H 3
N H
4 -C H 3 O C 6 H 4
1 1:
1 2:
3,4 -( O C H 2 O )C 6 H 3
N
1 3: 2 -T h e iny l
N C
O
A r
E
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
13
intensity at δ 2.40–2.44 for the 2CH3 groups. The structures were further supported by C-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].

Molecules 2013, 18
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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 2. Anti-bacterial and anti-fungal data of compounds 1–13.
Zone of Inhibition in mm
Zone of Inhibition in mm
Compound
Escherichia coli Staphylococcus aureus Aspergillus niger Candida albicans
1
25
21
20
23
25
16
18
12
14
30
28
26
29
30
-
24
20
21
20
22
15
17
13
15
28
26
25
29
29
-
18
15
14
13
16
12
14
10
12
20
17
19
21
-
21
18
16
18
20
13
15
13
15
22
19
20
22
-
2
3
4
5
6
7
8
9
10
11
12
13
Ampicillin
Clotrimazole
33
32
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
1
13
the KBr pellet technique. H- and C-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

Molecules 2013, 18
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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,
13
Ar-H). C-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).
1
3-Amino-1-(4-methoxyphenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (2): H-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),
13
6.85–7.49 (m, 8H, ArH). C-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).
1
3-Amino-1-(3,4-dimethoxyphenyl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (3): H-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,
13
NH2), 6.72–7.50 (m, 7H, Ar-H). C-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,
13
NH2), 6.80–7.48 (m, 7H, Ar-H). C-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).
1
3-Amino-1-(thiophen-2-yl)-9,10-dihydrophenanthrene-2,4-dicarbonitrile (5): H-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,
13
Ar-H). C-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

Molecules 2013, 18
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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).
1
3-Amino-1-phenyl-9,10-dihydrophenanthrene-2,4-dicarbonitrile (6): H-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,
13
ArH). C-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).
1
2-Amino-4-(4-chlorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile (9): H-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,
13
ArH). C-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).
1
N-acetyl-N-(1-(4-bromophenyl)-2,4-dicyano-9,10-dihydrophenanthren-3-yl)acetamide (10): H-NMR
(DMSO-d6) δ ppm: 2.40 (s, 6H, 2CH3), 2.88 (m, 2H, C-9 protons), 2.84 (m, 2H, C-10 protons),
13
7.17–7.46 (m, 9H, Ar-H). C-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),
13
6.77–7.48 (m, 8H, Ar-H). C-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),

Molecules 2013, 18
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13
6.82–7.48 (m, 7H, Ar-H). C-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.

Molecules 2013, 18
15714
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