Feasible Approach to Tricyclic and Tetracyclic cyclododecanone

Article abstract of DOI:10.1002/jhet.2062

2-Bromocyclododecanone was utilized as precursor to synthesize polyfused heterocyclic cyclododecane ring systems. Transformation of 2-bromocyclododecanone (5) with 1H-benzimidazole-2-thiole (6), benzo[d]thiazole-2-thiol (9), 2-naphthol (12), and thiophenol (15) afforded thiazolo[2,3-b]benzimidazole (8), thiazolo[2,3-b]benzothaizole derivative (11) naphtho[1,2-d]furan derivative (14) and 2-(phenylthio)cyclododecanone (16), respectively.

Full text of DOI:10.1002/jhet.2062

May 2016
Feasible Approach to Tricyclic and Tetracyclic cyclododecanone
941
a
b
a
*
Hanafi H. Zoorob, Mohamed S. Elsherbini, and Wafaa S. Hamama
aChemistry Department, Faculty of Science, Mansoura University, El-Gomhoria Street, ET-35516, Mansoura, Egypt
bChemistry Department, Faculty of Science, Al Jouf University, Sakaka,Al Jouf, Saudi Arabia
*
E-mail: wshamama@yahoo.com
Received February 28, 2013
DOI 10.1002/jhet.2062
Published online 29 December 2015 in Wiley Online Library (wileyonlinelibrary.com).
2-Bromocyclododecanone was utilized as precursor to synthesize polyfused heterocyclic cyclododecane
ring systems. Transformation of 2-bromocyclododecanone (5) with 1H-benzimidazole-2-thiole (6), benzo
[d]thiazole-2-thiol (9), 2-naphthol (12), and thiophenol (15) afforded thiazolo[2,3-b]benzimidazole (8),
thiazolo[2,3-b]benzothaizole derivative (11) naphtho[1,2-d]furan derivative (14) and 2-(phenylthio)
cyclododecanone (16), respectively.
J. Heterocyclic Chem., 53, 941 (2016).
INTRODUCTION
The substitution product 2-(benzo[d]thiazol-2-ylthio)
cyclododecanone (10) was isolated in a moderate yield
from reaction of 5 with benzo[d]thiazole-2-thiol (9) in
refluxing ethanol in presence of sodium acetate. The IR
spectrum of 10 showed a sharp absorption at 1721 cmÀ1
Cyclododecanone is an important intermediate for the
synthesis of natural muscone (1) and macrocyclic fragrances
of musk-like odor, for example, (S)-muscolides: 2 and 3 as
well as (R)-12-methyltridecanolide 4 [1–5] (Fig. 1).
Cyclododecanone derivatives are important intermediates
for synthesis of spiro and fused heterocycles of different
classes [6,7]. In view of the aforementioned findings, we
report herein the synthesis of some new heterocyclic
systems incorporating cyclododecane moiety starting from
2-bromocyclododecanone (5) [8].
1
(CO group). In addition, its H NMR spectrum supported
its open structure where it displayed a triplet signal for
one proton at 5.2 ppm (proton on carbon bearing (benzo
[d]thiazol-2-yl)thio moiety) besides the other characteristic
signals. Treatment of the cyclododecanone derivative 10
with concentrated sulfuric acid catalyses its transformation
into thiazolo[2,3-b]benzothaizole derivative 11 (Scheme 1).
The chemical constitution of 11 was confirmed by IR,
1H NMR, 13C NMR, and DEPT 135 spectra. The IR
spectrum of 11 revealed its tetracyclic structure due to the
absence of the carbonyl absorption besides the presence
of a broad band at 3423 cmÀ1 corresponding to OH group.
Also, its 1H NMR spectrum supported its tetracyclic struc-
ture due to the absence of the triplet signal for one proton at
5.2 ppm characteristic to the open structure. The structure
of 11 was also ascertained by 13C NMR spectroscopy
where its spectrum displayed a signal at 117.01 ppm
corresponding to (S–C–OH) carbon [17] besides the other
characteristic signals. Also, its DEPT 135 spectrum disclosed
the presence of 10 CH2 groups and four CH groups.
The transformation of 10 into 11 was proposed to take
place via two consecutive nucleophilic additions in a domino's
manner as depicted in Scheme 2.
RESULTS AND DISCUSSION
α-haloketones have been attracting increasing attention
in view of their high reactivity as building blocks for the
synthesis of compounds of various classes due to their
selective transformations with different reagents. They are
widely used in construction of different heterocyclic ring
systems, such as thiazoles [9,10], quinoxalines [11],
indoles [12], furans and their fused derivatives [13,14],
thiophenes and their fused derivatives [15], and many other
ring systems [16]. This promoted us to explore the validity
of 2-bromocyclododecanone (5) for construction of hetero-
cyclic systems fused to cyclododecane ring skeleton.
Treatment of 2-bromocyclododecanone (5) with 1H-
benzimidazole-2- thiole (6) in boiling DMF containing
one equivalent of pyridine furnished 4,5,6,7,8,9,10, 11,12,
13-decahydrocyclododeca[d]thiazolo[2,3-b]benzimidazole
(8) in good yield without isolation of the expected open
intermediate 7 (Scheme 1).
In addition, naphthofuran derivative 14 was synthesized in
an analogous manner to 11 via the successful substitution,
acid catalyzed cyclization reaction sequence. Thus, the
© 2015 HeteroCorporation

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H. H. Zoorob, M. S. Elsherbini, and W. S. Hamama
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Figure 1. (S)-muscone (VII) (S)-muscolide (VIII) (S)-muscolide (IX) (R)-12-methyltri decanolide (X).
Scheme 1. Reactivity of 5 toward different reagents.
Scheme 2. Proposed mechanism for transformation of 10 into 11.
reaction of 5 with 2-naphthol (12) in EtONa/EtOH afforded
2-(2-naphthyloxy)cyclododecanone (13), which then cyclized
to 8,9,10,11,12,13,14,15,16,17-decahydrocyclododeca[b]
naphtho[1,2-d]furan (14) under the influence of polyphosphoric
acid (Scheme 1).
the 2-(phenylthio)cyclododecanone (16) in 76% yield. Whereas,
all our trials to synthesize 8,9,10,11,12,13,14,15,16,17-
decahydrocyclododeca[b]benzo[1,2-d] thiophene (17) via
cyclization of 16 under the influence of polyphosporic acid
or concentrated sulfuric acid were failed, and 16 was recovered
unchanged (Scheme 1).
Structures of 13 and 14 were supported by IR, 1H NMR,
and 13C NMR spectra. Besides, the 13C NMR signals of
compound 14, taken as a typical example of the annulated
products of this series are appeared together with signal
assignments as shown in Figure 2.
The IR spectrum of 16 showed a strong absorption band
1
at 1699cmÀ1 corresponding to carbonyl group. The H
NMR spectrum showed a signal for one proton at 4.0
(1H, dd) corresponding to the proton of cyclododecanone
carbon bearing the thiophenyl moiety, besides the other
characteristic signals. In addition, the 13C NMR signals
Furthermore, nucleophilic substitution of bromoketone 5 with
benzothiolate anion proceeded easily in EtONa/EtOH to afford
Journal of Heterocyclic Chemistry
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Tricyclic and Tetracyclic cyclododecanone
943
2-
2-(Benzo[d]thiazol-2-ylthio)cyclododecanone
(10).
Bromocyclododecanone (5) (0.3 g, 1.65 mmol) was added to a
mixture of benzo[d]thiazole-2-thiol (9) (0.28 g, 1.65 mmol) and
sodium acetate (0.62 g, 7.6 mmol) in absolute methanol (15 mL).
The reaction mixture was refluxed over a steam bath for 2 h, left
to cool overnight whereby a pale yellow precipitate was formed,
filtered off, washed with cold water, air dried, and recrystallized
from absolute ethanol to furnish 10, (0.3 g; 53%); mp 112–114°C;
IR: 2939, 2863, 1721, 1451 cmÀ1; 1H NMR (DMSO-d6): δ 1.0–1.8
(18H, m), 2.0–2.2 (2H, m), 5.2 (1H, t), 7.18–8 ppm (4H, m). Anal.
Calcd for C19H25NOS2: C, 65.66; H, 7.25; N, 4.03. Found: C,
65.77; H, 7.26; N, 4.04.
Figure 2. 13C NMR signals of naphtho[1,2-d]furan (14) and 2-(phenylthio)
cyclododecanone (16).
of compound 16, taken as a typical example of the open
products of this series, are appeared together with signal
assignments in Figure 2. In addition, the DEPT 135
spectrum of 16 revealed the presence of 10 CH2 groups
and six CH groups.
In conclusion, 2-bromocyclododecanone is a valuable
synthetic building block used for construction of different
heterocyclic ring systems fused to the macrocyclic
cyclododecane ring skeleton via sequence of nucleophilic
substitution followed by cyclization reaction.
4,5,6,7,8,9,10,11,12,13-Decahydrocyclododeca[1′,2′:4,5]thiazolo
[2,3-b]benzothiazole (11).
A mixture of 10 (0.2 g, 0.58 mmol)
and conc. H2SO4 (2.5 mL, 1.84 g/cm3) was heated over steam bath
for 5 h. Cooled, basified with sodium bicarbonate solution then
extracted with chloroform (3× 10mL). The combined chloroform
extract was dried over anhydrous sodium sulfate, filtered off, and
solvent removed under vacuum to give 11 as white crystalline
solid (52.6%), which was satisfactorily pure as confirmed by
TLC. mp 138–140°C; IR: 4372, 2919, 2847, 1469cmÀ1 1H
;
NMR (DMSO-d6): δ 1.12–1.95 (16H, m), 3.0 (2H, t), 3.2 (2H, t),
7.8 (2H, m), 8.45ppm (2H, d); 13C NMR (125 MHz, DMSO): δ
20.97, 22.42, 22.51, 22.87, 23.70, 23.97, 24.80, 25.18, 25.52,
28.71, 117.01, 125.03, 127.69, 128.15, 134.16, 135.70, 138.35,
139.80 ppm; 13C NMR (DEPT 135, T = 60°C, DMSO): indicates
the presence of 10 CH2 and four CH groups. Anal. Calcd for
C19H25NOS2: C, 65.66; H, 7.25; N, 4.03. Found: C, 65.76; H,
7.26; N, 4.04.
EXPERIMENTAL
All melting points are in degree centigrade (uncorrected) and
were determined on Gallenkamp electric melting point apparatus.
The IR spectra were recorded (KBr) on a Mattson 5000 FTIR
spectrophotometer at Microanalytical Unit, Faculty of Science;
Mansoura University. The 1H NMR data were obtained in
DMSO-d6 using TMS as internal standard, and chemical shifts
2-(2-Naphthyloxy)cyclododecanone (13). 2-Bromocyclododecanone
(5) (0.65g, 2.5 mmol) was added to a solution of sodium
naphthalen-2-olate [prepared by dissolving sodium metal (0.058 g,
2.5 mmol) in absolute ethanol (15 mL) containing 2-naphthol
(0.36 g, 2.5 mmol)]. The homogeneous mixture was heated under
reflux over steam bath for 2 h and then left to cool overnight. The
white precipitate that formed was filtered off, washed with cold
water and air dried, then recrystallized from ethanol, to give 13
(0.65 g; 80%); mp 118–120°C; IR: 2942, 2865, 1713, 1628,
1598 cmÀ1; 1H NMR (DMSO-d6): δ 1.2–1.35 (14H, m), 1.52–1.7
(2H, m), 2.1 (4H, m), 5.05 (1H, t), 7.1 (1H, d), 7.17 (1H, dd), 7.35
(1H, m), 7.45 (1H, m), 7.75 (1H, d), 7.85 ppm (2H, m). Anal.
Calcd for C22H28O2: C, 81.44; H, 8.70. Found: C, 81.53; H, 8.72.
1
were reported in ppm (δ) downfield from internal TMS. The H
NMR spectra were recorded on a Bruker Avance 500 spectrometer
(500 MHz; Billerica, MA) in Bioorganic Chemistry Department,
University of Saarland, Saarbrüken, Germany. 13C NMR spectra
at 125 MHz were performed on a Bruker Avance 500 spectrometer
in Bioorganic Chemistry department, University of Saarland,
Saarbrüken, Germany. Mass spectra were recorded on a Finnigan
MAT 212 mass spectrometer instrument, Microanalytical Unit,
Cairo University, Egypt. Elemental analyses were carried out in Mi-
croanalytical Unit, Cairo University, Egypt. Reactions were moni-
tored by TLC using EM science silica gel coated plates with
visualization by irradiation with ultraviolet lamp.
8,9,10,11,12,13,14,15,16,17-Decahydrocyclododeca[1′,2′:2,3]
furo[4,5-a] naphthalene (14). 2-(2-Naphthyloxy)cyclododecanone
(13) (0.15 g, 0.46 mmol) was heated for 3 h at 130°C in polyphosporic
acid [prepared by stirring P2O5 (4.5 g) and H3PO4 (2.5 mL) at 60°C
overnight] for 3 h, poured into ice-cold water and left overnight.
The white precipitate that formed was filtered off and air dried to
afford 14 (0.71g, 50%), which was satisfactorily pure as
confirmed by TLC. mp 96–98°C; IR: 2934, 2857cmÀ1; 1H NMR
(DMSO-d6): δ 1.3–1.8 (16H, m), 2.85 (2H, t), 2.98 (2H, t), 7.5
(1H, t), 7.6 (1H, t), 7.68 (1H, d), 7.75 (1H, d), 8.0 (1H, d),
8.57ppm (1H, d); 13C NMR (125MHz, DMSO): δ 21.42, 21.45,
22.23, 22.43, 23.37, 24.34, 24.46, 24.62, 25.63, 27.05, 112.16,
116.25, 121.65, 122.95, 123.85, 124.37, 126.24, 127.57, 128.95,
130.23, 151.17 and 154.45 ppm. Calcd for C22H26O: C, 86.23; H,
8.55%. Found: C, 86.35; H, 8.57%.
2-Bromocyclododecanone (5) was prepared according to literature
method [8].
4,5,6,7,8,9,10,11,12,13-Decahydrocyclododeca[1′,2′:4,5]thiazolo
[3,2-a]benzoimidazole (8). 2-Bromocyclododecanone (5) (0.65 g,
2.5 mmol) was added to a solution of 1H-benzo[d]imidazol-2-thiol
(6) (0.37g, 2.5 mmol) in DMF (7mL) containing pyridine
(0.21 mL, 2.5mmol). The reaction mixture was heated under
reflux for 4 h, left to cool over night and diluted with methanol
(20 mL) whereby a crystalline material was formed within 30min
then filtered off and washed with methanol to give 8, (0.58 g;
74%). This product was satisfactorily pure without recourse to
chromatography as confirmed by TLC. mp 126–128°C; IR: 2933,
2850, 1617, 1473, 1447cmÀ1 1H nmr (DMSO-d6): δ 1.3–1.85
;
(16H, m), 2.8 (2H, t), 3.15 (2H, t), 7.25 (1H, t), 7.3 (1H, t), 7.65
(1H, d), 7.85 ppm (1H, d); MS (70eV): m/z = 312 (14.6, M+), 93
(100) [base peak]. Anal. Calcd for C19H24N2S: C, 73.03; H, 7.74;
N, 8.97. Found: C, 73.12; H, 7.76; N, 8.99.
2-(Phenylthio)cyclododecanone (16). 2-Bromocyclododecanone
(5) (0.5 g, 1.9 mmol) was added to ethanolic solution of sodium
benzenethiolate [prepared by dissolving sodium metal (0.044 g,
1.9 mmol) in absolute ethanol (10 mL) containing thiophenol
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H. H. Zoorob, M. S. Elsherbini, and W. S. Hamama
Vol 53
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(0.21 g, 0.2 mL, 1.9 mmol)]. The homogeneous mixture was heated
under reflux over steam bath for 2 h. The reaction mixture was
cooled in ice bath, a light yellow precipitate that formed, was
filtered off, washed with cold water and air dried, then
recrystallized from ethanol to afford 14 (0.42 g, 76%); mp 56–58°C;
1
IR: 3288, 2926, 2860, 1709, 1581 cmÀ1; H NMR (DMSO-d6):
δ 1.0–1.8 (18H, m), 2.4 (2H, t), 5.0 (1H, dd), 7.1–7.3 ppm (5H, m);
13C NMR (125 MHz, DMSO): δ 21.42, 21.45, 22.23, 22.43, 23.37,
24.34, 24.46, 24.62, 25.63, 27.05, 112.16, 116.25, 121.65, 122.95,
123.85, 124.37, 126.24, 127.57, 128.95, 130.23, 151.17 and
154.45 ppm. 13C NMR (DEPT 135, T = 60°C, DMSO): showed 10
CH2 and six CH groups. Anal. Calcd for C18H26OS: C, 74.43; H,
9.02. Found: C, 74.53; H, 9.04.
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2000, 30, 1825.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet