Synthesis, characterization, and investigations of antimicrobial activity of 6,6-dimethyl-3-aryl-3′,4′,6,7-tetrahydro-1′H,3H-spiro[benzofuran-2,2′-naphthalene]-1′,4(5H)-dione

Article abstract of DOI:10.1080/00397911.2017.1334918

Chalcone-like compounds 3a–l, 2-(benzylidene)-3,4-dihydronaphthalen-1(2H)-one, were synthesized from the addition of different benzaldehyde derivatives (2a–l) to 1,2,3,4-tetrahydro-1-napthalone (1) in basic medium. Mn(OAc)₃-mediated addition of

Full text of DOI:10.1080/00397911.2017.1334918

Synthetic Communications
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Synthesis, Characterization and
Investigations of Antimicrobial Activity of 6,6-
Dimethyl-3-Aryl-3′,4′,6,7-Tetrahydro-1′H,3H-
Spiro[Benzofuran-2,2′-Naphthalene]-1′,4(5H)-Dione
Dursun Ergüntürk, Meliha Burcu Gürdere, Yakup Budak & Mustafa Ceylan
To cite this article: Dursun Ergüntürk, Meliha Burcu Gürdere, Yakup Budak & Mustafa Ceylan
(2017): Synthesis, Characterization and Investigations of Antimicrobial Activity of 6,6-Dimethyl-3-
Aryl-3′,4′,6,7-Tetrahydro-1′H,3H-Spiro[Benzofuran-2,2′-Naphthalene]-1′,4(5H)-Dione, Synthetic
Communications, DOI: 10.1080/00397911.2017.1334918
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Date: 02 June 2017, At: 11:41

Synthesis, Characterization and Investigations of Antimicrobial Activity of 6,6-
Dimethyl-3-Aryl-3',4',6,7-Tetrahydro-1'H,3H-Spiro[Benzofuran-2,2'-Naphthalene]-
1',4(5H)-Dione
Dursun Ergüntürk1, Meliha Burcu Gürdere1, Yakup Budak1, Mustafa Ceylan1
1Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa University,
Tokat, Turkey
Corresponding author Mustafa Ceylan E-mail: mustafac.ceylan@gop.edu.tr
Abstract
Chalcone-like compounds 3a-l, 2-(benzylidene)-3,4-dihydronaphthalen-1(2H)-one, were
synthesized from the addition of different benzaldehyde derivatives (2a-l) to 1,2,3,4-
tetrahydro-1-napthalone (1) in basic medium. Mn(OAc)3-mediated addition of dimedone
(4) to chalcone-like compounds gave the spiro benzofuran derivatives (5a-l), 6,6-
dimethyl-3-aryl-3',4',6,7-tetrahydro-1'H,3H-spiro[benzofuran-2,2'-naphthalene]-1',4
(5H)-dione, in good yields. The structures of synthesized compounds 5a-l were
elucidated on basis of spectral data (NMR, IR) and elemental analysis. Addition their
antibacterial activities were screened against some human pathogenic microorganisms.
Graphical Abstract
1

KEYWORDS: Spiro-benzofuran, Tetralone, Dimedone, Mn(OAc)3, Antimicrobial
activity
INTRODUCTION
The dihydrofuran derivatives are found in several natural products and they exhibit a
wide range of biological activities.[1–4] Addition, benzofurans are present in naturally and
synthetic compounds and they posses very important biological activities such as
antimicrobial,[5–8] antitumour,[9] anti-inflammatory,[10] antihyperglycemic, analgesic,
antiparasitic, and kinase inhibitor activities.[11–16] Moreover, spiro benzofuran derivatives
have privileged structural skeletons and they are also found in many natural and
pharmaceutically significant compounds with a broad range of biological activities.[17–23]
All these compounds have become a great focus because of their diverse activities, and a
number of methods have been developed for their synthesis.[24–27] Among the methods,
one of the convenient methods is manganese(III)acetate-mediated oxidative free radical
addition of 1,3-dicarbonyl compounds to appropriate olefins.[6,28–32]
In this paper, 6,6-dimethyl-3-aryl-3',4',6,7-tetrahydro-1'H, 3H-spiro[benzofuran-2,2'-
naphthalene]-1',4(5H)-dione derivatives (5a-l) were synthesized from the Mn(OAc)3-
mediated oxidative free radical addition of dimedone (4) to 2-(benzylidene)-3,4-
dihydronaphthalen-1(2H)-one derivatives (3a-l). Addition in vitro antibacterial activities
of compounds 5a-l were screened against some human pathogenic microorganisms.
RESULTS AND DISCUSSION
2

Synthetic Chemistry
Firstly, the starting materials, chalcone-like derivatives (3a-l) were prepared according to
published procedures.[33–35] The Claisen-Schmidt condensation of 1,2,3,4-
tetrahydronaphthalone (1-Tetralone) (4) with benzaldehyde derivatives (2a-l) in the
presence of NaOH in EtOH gave the starting compounds 3a-l. The structure of the
compounds 3a-l was elucidated by spectroscopic data (NMR, IR and elemental analysis)
and comparison with their authentic samples.[33,36,37]
Then, the chalcone-like derivatives (3a-l) were submitted to the reaction with the
dimedone to get spiro benzofuran derivatives (5a-l). Reaction of 3a-l with dimedone (4)
was performed in the presence of Mn(OAc)3 at refluxing condition for 2h. The reaction
was resulted in the formation of the spiro benzofuran derivatives (5a-l) via addition
follow oxidative-cyclization (Scheme 1, Table 1). The structures of the compounds were
explained on the basis of spectral data (NMR and IR) and elemental analysis. All spectral
data are in good agreement with the proposed structures of the compounds.
In principle, addiiton of dimedone to compound 3 is expected to furnish compounds 5
and 6. A distinction between these structures has been made on the basis of 1H-NMR
spectral studies. If the compound 6 had been obtained by addition of dimedone to
compound 3 then bezylic proton C1-H must have resonated in the downfield region
around δ 5,5-6,5 ppm in their 1H-NMR spectra. However, no such signal in the
downfield region was observed in the isolated products 5a-l, and C1-H appeared in the
region at 4.52-4.67 ppm, therefore, formation of 6 stands rejected.
3

Biological Evaluations
The synthesized compounds (5a-l) were tested for their antibacterial activity against six
different types of human pathogenic bacterial strains. The microorganisms used were:
Staphylococcus aureus (ATCC®29213), B. subtilis (ATCC®6633) which are Gram-
positive bacteria and Escherichia coli (AÜ tıp), Pseudomonas aeruginosa
(ATCC®9027), Proteus vulgaris (KUEN 1329), which are Gram-negative bacteria and
Candida albicans (ATCC®1213) which are Gram-positive maya. In these tests, SCF
(Sulbactam/Cefoperazone) were used as standard, and DMSO was used as negative
control. The tests were performed by published method, and the growth inhibition
activities were given as mm (diameter of inhibitory zone) in Table 2.
According to table 2, most of the compounds 5a-l display moderate to good activity
against 6 bacterial strains. The most active compound was 5k (containing 2 methoxy
groups) against S. aureus with 16 mm of inhibition zone. Compounds (5j, 5k and 5l)
show good activity against B. subtilis with 15 mm of inhibition zone. Also, compound 5d
(containing methoxy group) exhibits the highest activity against E. coli with 16 mm of
inhibition zone. Moreover, Compounds (5d, 5f and 5l) demonstrate good activity against
P. aeruginosa with 15 mm of inhibition zone. Compound 5k (containing chlorine atom)
show remarkable activity against P. vulgaris with 15 mm of inhibition zone. C. albicans
was good inhibited by six of the compounds, 4-methyl (5c, 15 mm), 4-methoxy (5d, 15
mm), 4-fluorine (5e, 15 mm), 4-chlorine (5f, 14 mm), 3-methyl (5h, 14 mm) and 2,5-
4

dimethoxy (5l, 15 mm). Among the compounds, compounds containing methoxy group
(5d and 5l) were more active than the others.
In this paper, spiro benzofuran derivatives, 6,6-dimethyl-3-aryl-3',4',6,7-tetrahydro-
1'H,3H-spiro[benzofuran-2,2'-naphthalene]-1',4(5H)dione, 5a-l were synthesized using
Mn(OAc)3-mediated-oxidative free radical additions between tetralone-based chalcone-
like compounds 3a-l and dimedone (4), and their antibacterial activities were screened
against human pathogen Gram-positive and Gram-negative bacteria. Especially,
compounds 5d and 5l (containing methoxy group) exhibited good antibacterial activity as
compared with SCF (Sulbactam/Cefoperazone).
Experimental
The major chemicals were purchased from Sigma-Aldrich and Fluka. Melting points
were measured on Electrothermal 9100 apparatus. IR spectrums (KBr disc) were
recorded on a Jasco FT/IR-430 spectrometer. 1 H- and 13C-NMR spectrum was recorded
on a Bruker Avance DPX-400 instrument. As internal standards served TMS ( 0.00) for
1H-NMR and CDCl3 ( 77.0) for 13C-NMR spectroscopy, J values are given in Hz.
Elemental analyses were obtained from a LECO CHNS 932 Elemental Analyzer.
General Procedure For The Synthesis Of Chalcone-Like Compounds, 2-(Benzylidene)-
3,4-Dihydronaphthalen-1(2H)-On, 3a-L
Chalcone-like Compounds, 2-(Benzylidene)-3,4-dihydronaphthalen-1(2H)-on, 3a-l were
synthesized by modified published procedures [33–35]. To a solution of 1,2,3,4-tetrahidro-
5

1-naftalone (1) (1 mmol) in EtOH (15 ml) was added benzaldehyde derivatives (3a-l) (1
mmol) in EtOH (10 ml) and NaOH (2.5 M, 8 ml) at r.t. The mixture was stirred for 3 h,
neutralized with dilute HCl, and extracted with CHCl3 The organic layer was dried over
Na2SO4 and evaporated. The residue was purified by crystallized in CHCl3/hexane (3:7)
and/or CHCl3/hexane (1:1).
General Procedure For The Synthesis Of Spiro Benzofuran Derivatives, 6,6-Dimethyl-
3-Aryl-3',4',6,7-Tetrahydro-1'H,3H-Spiro[Benzofuran-2,2'-Naphthalene]-1',4(5H)-
Dione, (5a-L)
A solution of Mn(OAc)3 (8 mmol) in AcOH (15 ml) was heated for 2 h at 80 °C under
N2 atmosphere. After the temperature has dropped to 60 °C, to this solution was added
solution of 3a-l (1 mmol) and dimedone (4) (3 mmol) in AcOH (5 ml) dropwise over a
period of 25 min. The mixture was refluxed for 2 h. under N2 atmosphere. The reaction
mixture was extracted with CHCl3 and dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude products were purified on a silica gel column eluting
with ethylacetate/hexane (1:4).
6,6-Dimethyl-3-(P-Tolyl)-3',4',6,7-Tetrahydro-1'H,3H-Spiro[Benzofuran-2,2'-
Naphthalene]-1',4(5H)-Dione. (5a)
Yield 90%. Viscous oil. IR (KBr, cm-1): 2960, 1693, 1644, 1513, 1455, 1390, 1226,
1012, 923, 827, 736. 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.0, Hz, 1H), 7.53 (t, J
= 7.6, Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H),
7.03 (d, J = 8.0 Hz, 2H), 4.54 (s, 1H), 2.85 (dt, J = 17.6, 5.6 Hz, 1H), 2.71 (ddd, J = 17.6,
6

8.8, 5.6 Hz, 1H), 2.58 (d, J = 17.6 Hz, 1H), 2.49 (d, J = 17.6 Hz, 1H), 2.34 (s, 3H), 2.30
(d, J = 16.4 Hz, 1H), 2.25 (ddd, J = 14.0, 8.4, 5.2, Hz, 1H), 2.19 (d, J = 16.4 Hz, 1H),
2.09 (dt, J = 14.0, 5.6 Hz, 1H), 1.21 (s, 3H), 1.20 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 193.6, 192.2, 175.7, 143.0, 137.2, 134.8, 134.1, 129.9, 129.2 (3C), 128.8 (2C), 128.6,
127.0, 116.0, 93.1, 51.1, 48.7, 37.6, 34.1, 29.6, 29.1, 28.5, 25.3, 21.1. Anal. calc. for
C26H26O3: C, 80.80; H, 6.78. Found: C, 80.68; H, 6.69.
Biology: In Vitro Antibacterial Activity
The in vitro antibacterial activities of spiro benzoforan derivatives 5a-l were tested
according to published methods.[33–35,38]
ACKNOWLEDGEMENT
The authors are indebted to the Gaziosmanpasa University, Scientific Research Projects
Commission (Project No: BAP-2014/74) for financial supports.
This material can be found via the “Supplementary Content” section of this article’s
webpage.
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10

Table 1. Synthesized compounds 5a-l.
5
R
Molecular formula
C25H23BrO3
C25H24O4
Yield (%)
72
4-Br
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-OH
4-Me
4-OMe
4-F
73
C26H26O3
71
C26H26O4
95
C25H23FO3
C25H23CIO3
C25H23BrO3
C26H26O3
98
4-Cl
70
3-Br
80
3-Me
3-OMe
3-Cl
66
C26H26O4
80
C25H23CIO3
C25H23CIO3
C27H28O5
86
5j
5k
5l
2-Cl
65
2,5-OMe
71
11

Table 2. Antibacterial activities of synthesized compounds 5a-l
Compoun Diameter of growth inhibition zone (mm)
d
Gram-positive bacteria
S. aureus B. subtilis
(ATCC®2921 (ATCC®663 (AU
Gram-positive bacteria
Gram-positive maya
E. coli P. aeruginosa P. vulgaris C. albicans
(ATCC®9027 (KUEN
(ATCC®121
3)
3)
TIP)
13
6
)
1329)
13
11
10
14
11
14
14
13
12
13
15
14
20
6
3)
8
12
13
11
11
13
12
14
10
12
14
11
16
25
6
12
13
8
10
12
11
15
13
15
11
12
11
12
13
15
20
6
5a
10
15
15
15
14
11
14
8
5b
5c
11
16
6
12
14
10
12
12
15
12
15
15
21
6
5d
5e
6
5f
13
13
6
5g
5h
5i
13
6
8
5j
7
5k
5l
13
26
6
15
19
6
SCF
DMSO
12

Scheme 1. Synthesis of spiro benzofuran derivatives (5a-l).
13

Figure 1. Possible structures
14