Synthesis of several types of 2,8-dioxabicyclo[3.3.1]nonanes using amberlyst-15 as an efficient recyclable heterogeneous catalyst

Article abstract of DOI:10.1080/00397911.2017.1365906

A facile synthesis of 2,8-dioxabicyclo[3.3.1]nonane derivatives starting from simple molecules, such as 2-hydroxychalcones as one component and dimedone, 4-hydroxycoumarin, 2-hydroxynaphthoquinone, 2-naphthol or 1-naphthol, as the other has been achieved by use of amberlyst-15, a sulfonated polystyrene resin, as a recyclable heterogeneous catalyst. The methodology involves a domino sequence of Michael addition and two-stage cyclisation.

Full text of DOI:10.1080/00397911.2017.1365906

Synthetic Communications
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Synthesis of several types of 2,8-
dioxabicyclo[3.3.1]nonanes using amberlyst-15 as
an efficient recyclable heterogeneous catalyst
Swati Samanta, Nayim Sepay, Sumitava Mallik, Rina Mondal, Mosidur
Rahaman Molla & Asok K. Mallik
To cite this article: Swati Samanta, Nayim Sepay, Sumitava Mallik, Rina Mondal,
Mosidur Rahaman Molla & Asok K. Mallik (2017): Synthesis of several types of 2,8-
dioxabicyclo[3.3.1]nonanes using amberlyst-15 as an efficient recyclable heterogeneous catalyst,
Synthetic Communications, DOI: 10.1080/00397911.2017.1365906
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1365906
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Date: 21 October 2017, At: 07:57

Synthesis of several types of 2,8-dioxabicyclo[3.3.1]nonanes
using amberlyst-15 as an efficient recyclable heterogeneous
catalyst
Swati Samanta
Department of Chemistry, Jadavpur University, Kolkata, India
Nayim Sepay
Department of Chemistry, Jadavpur University, Kolkata, India
Sumitava Mallik
Department of Chemistry, Jadavpur University, Kolkata, India
Rina Mondal
Department of Chemistry, Jadavpur University, Kolkata, India
Mosidur Rahaman Molla
Department of Chemistry, Jadavpur University, Kolkata, India
Asok K. Mallik
Department of Chemistry, Jadavpur University, Kolkata, India
Address correspondence to Asok K. Mallik. E-mail: mallikak52@yahoo.co.in
1

ABSTRACT
A facile synthesis of 2,8-dioxabicyclo[3.3.1]nonane derivatives starting from simple
molecules like 2-hydroxychalcones as one component and dimedone, 4-hydroxycoumarin, 2-
hydroxynaphthoquinone, 2-naphthol or 1-naphthol, as the other has been achieved by use of
amberlyst-15, a sulfonated polystyrene resin, as a recyclable heterogeneous catalyst. The
methodology involves a domino sequence of Michael addition and two-stage cyclisation.
GRAPHICAL ABSTRACT
KEYWORDS: 2,8-dioxabicyclo[3.3.1]nonanes, 2-hydroxychalcones, amberlyst-15, recyclable
heterogeneous catalyst
Introduction
Compounds containing the bicyclo[3.3.1]nonane framework with one or more
heteroatom in their structural motif are very important due to their cleft shaped structure.[1] Aꢀ
good number of 2,8-dioxabicyclo[3.3.1]nonanes are known as natural products and they are
reported to show interesting biological activities like anti-inflammatory, antioxidant, COX-2
enzyme inhibitory, antiviral, antitumor and immunomodulatory activities.[2] Several such
compounds[3] are shown in Figure 1.
2

The reported interesting biological activities shown by natural 2,8-
dioxabicyclo[3.3.1]nonanes encouraged us to undertake the synthesis different compounds
containing this framework, particularly because some of the recently reported methods for
synthesis of such compounds[4] suffer from drawbacks like use of expensive catalysts and
application of harsh reaction conditions. A common feature of the reported methods for synthesis
from 2-hydroxychalcones and cyclic active methylene compounds or phenols is that they involve
a domino sequence of Michael addition and ketalization.[4] Amberlyst-15, a sulphonated
polystyrene resin, has been known to be effective in Michael addition[5] and ketalization
reactions[6] and so we undertook a synthesis of compounds of the type 2-6 by reaction of 2-
hydroxychalcones with active methylene compounds and naphthols through use of amberlyst-15
as a heterogeneous catalyst in refluxing toluene. In this endeavor we became successful in
developing a simple methodology for synthesis of 2-6, wherein amberlyst-15 was found to be an
efficient recyclable catalyst.
Results and Discussion
The present study started with the reaction of 2-hydroxychalcone (1a) and dimedone
under amberlyst-15 catalyzed reaction condition. The initial success of the reaction to produce
the 2,8-dioxabicyclo[3.3.1]nonane derivative 2a inspired us to optimize the process by variation
of the solvent, amount of catalyst and temperature. The results of the optimization study are
given in Table 1. Under the optimized reaction conditions four more compounds of the series 2
were synthesized by using the 2-hydroxychalcones 1b-e and with variation of reaction time. This
reaction condition was then applied to other combinations of 2-hydroxychalcones (1) and cyclic
active methylene compounds (4-hydroxycoumarin and 2-hydroxynaphthoquinone) and 2-
3

hydroxychalcones (1) and naphthols (1-naphthol and 2-naphthol) for synthesis of different 2,8-
dioxabicyclo[3.3.1]nonane derivatives. The results are shown in Schemes 1 and 2.
Recyclability of the catalyst
The recyclability of the catalyst amberlyst-15inꢀ the above reactions was then investigated
by taking the synthesis of one compound in each of the series 2-6. It was observed that the
catalyst could be reused up to the fourth recycle without much decrease of catalytic activity.
Thus, the results obtained are presented in Table 2.
The formation of the 2,8-dioxabicyclo[3.3.1]nonane derivatives 2-6 from 2-
hydroxychalcones (1) and cyclic active methylene compounds (dimedone, 4-hydroxycoumarin or
2-hydroxynaphthoquinone) or naphthols under the amberlyst-15 catalysed condition follow
similar pathways and they are analogous to the reported ones.[4b,c,e,h,i] As an example, plausible
mechanism for formation of 2 is shown in Scheme 3.
Conclusions
We report simple methods for synthesis of five types of 2,8-dioxabicyclo[3.3.1]nonane
derivatives 2-6inꢀ moderate to good yield utilizing the heterogeneous catalyst amberlyst-15,
which can be recycled.
Experimental
General
Melting points were recorded on a Köfler block. IR spectra were recorded on a Perkin
Elmer FT-IR spectrophotometer (Spectrum BX II) in KBr pellets. 1H and 13Cꢀ NMR spectra were
4

recorded in CDCl3 on a Bruker AV-300 (300MHzꢀ) or a Bruker AVANCE III HD (400MHzꢀ)
spectrometer. HRMS data were recorded with a Waters Xevo G2QTof HRMS spectrometer.
Analytical samples were routinely dried in vacuo at room temperature. Microanalytical data were
recorded on two Perkin-Elmer 2400 Series II C, H, N analyzers. TLC was performed with silica
gel G made of SRL Pvt. Ltd. Petroleum ether had the boiling range 60-80°C.
General method for synthesis of the 2,8-dioxabicyclo[3.3.1]nonane derivatives 2-
6
To a mixture of 2-hydroxychalcone (1) (1 mmol) and dimedone / 4-hydroxycoumarin / 2-
hydroxynaphthoquinone / 2-naphthol / 1-naphthol (1 mmol) in distilled toluene (10mLꢀ)
amberlyst-15 (100mgꢀ) was added and the mixture was refluxed. The progress of the reaction
was monitored with TLC. The reaction mixture was then cooled to room temperature,
dichloromethane (DCM, 20mLꢀ) was added and the mixture was filtered to separate the catalyst
which can be reused after recovery. The filtrate was concentrated and subjected to column
chromatography using petroleum ether (PE)–ethyl acetate (EA) mixtures of increasing polarity
as eluents. The fractions containing pure compounds were then crystallized from DCM-PE when
the members of the series 2-6 were obtained in pure state. The products were characterized from
their physical and spectral data.
Characterization data for selected compounds
The synthesized 2,8-dioxabicyclo[3.3.1]nonane derivatives belonged to five different
series (2-6), and majority of them are known compounds. The characterization data of one new
compound of each series are given below:
5

1
2b: Colorless crystalline solid, mp 115°C, H NMR (CDCl3, 300MHzꢀ): δ = 0.97 (s, 3H,
Aliph. CH3), 1.12 (s, 3H, Aliph. CH3), 2.14-2.31(m, 4H), 2.41 (br. s, 2H), 2.43 (s, 3H, Ar-CH3),
4.24 (br. s, 1H), 6.93 (br. t, 1H, J = 7.5Hzꢀ), 7.02 (br. d, 1H, J = 7.1Hzꢀ),7.16 (dt, 1H, J = 9.0 and
13
1.5Hzꢀ), 7.28 (d, 2H, J = 8.1Hzꢀ), 7.40 (dd, 1H, J = 7.2 & 1.2Hzꢀ) 7.56 (d, 2H, J = 8.1Hzꢀ), Cꢀ
NMR (75MHzꢀ, CDCl3): δ = 21.2, 25.2, 27.9, 28.8, 32.4, 33.0, 41.7, 50.4, 99.9, 115.4, 116.0,
121.5, 125.5, 126.6, 127.5, 128.1, 129.1, 137.4, 139.0, 151.5, 167.7, 195.8, HRMS (ESI) m/z for
+
C24H25O3 [M + H] , calcd. 361.1804, found 361.1089, Anal. calcd. for C24H24O3: C, 79.97; H,
6.71. Found: C, 79.72; H, 6.53.
3f: Colorless crystalline solid, mp 195°C, 1H NMR (300MHzꢀ, CDCl3) δ 2.42 (br. s, 5H),
4.35 (br.s, 1H), 6.97 (d, J = 8.5Hzꢀ, 1H), 7.13 (dd, J = 8.5 and 2.5Hzꢀ, 1H), 7.24-7.33 (m, 4H),
13
7.49-7.54 (m, 2H), 7.62 (d, J = 7.9Hzꢀ, 2H), 7.86 (d, J = 7.8Hzꢀ, 1H); Cꢀ NMR (75MHzꢀ,
CDCl3) δ 21.2, 27.2, 32.6, 100.4, 105.4, 114.9, 116.7, 117.6, 122.8, 124.1, 125.5, 126.7, 126.9,
127.8, 128.3, 129.3, 132.2, 136.4, 139.6, 150.1, 152.5, 158.4, 162.3, Anal. calcd. for C25H17ClO4:
C, 72.03; H, 4.11. Found: C, 71.87; H, 4.24.
4b: Yellow crystalline solid, mp 230-231°C, 1H NMR (300MHzꢀ, CDCl3) δ 2.30 (dd, J =
13.5 and 2.9Hzꢀ, 1H), 2.43 (s, 3H), 2.47 (dd, J = 13.5 and 2.7Hzꢀ, 1H), 4.57 (t, J = 2.7Hzꢀ, 1H),
6.98 (t, J = 7.5Hzꢀ, 1H), 7.06 (d, J = 8.1Hzꢀ, 1H), 7.20 (br. t, J = 7.8Hzꢀ, 1H), 7.30 (d, J = 8.2Hzꢀ,
2H), 7.49 (br. d, J = 7.5Hzꢀ, 1H), 7.66 (d, J = 8.1Hzꢀ, 2H), 7.65-7.76 (m, 2H), 8.10-8.12 (m, 2H),
13Cꢀ NMR (75MHzꢀ, CDCl3) δ 21.2, 26.2, 32.1, 100.2, 116.6, 121.9, 124.2, 124.7, 125.7, 126.2,
126.5, 128.4, 128.5, 129.2, 131.0, 131.8, 133.4, 134.0, 136.5, 139.2, 151.9, 153.3, 178.8, 182.8,
Anal. calcd. for C26H18O4: C, 79.17; H, 4.60. Found: C, 79.29; H, 4.39.
5b: Light yellow crystalline solid, mp 230-232°C, 1H NMR (300MHzꢀ, CDCl3) δ 2.45 (s,
3H), 2.43-2.55 (m, 2H), 4.88 (s, 1H), 6.90 (t, J = 7.2Hzꢀ,1H), 7.06-7.15(m, 3H), 7.30-7.33 (m,
6

2H), 7.41 (t, J = 7.2Hzꢀ,1H), 7.55 (d, J = 7.2Hzꢀ,1H), 7.61-7.74 (m, 4H), 7.82 (d, J = 7.8Hzꢀ, 1H),
13
8.37 (d, 1H, J = 7.8Hzꢀ); Cꢀ NMR (75MHzꢀ, CDCl3) δ 21.2, 28.8, 33.3, 98.4, 116.7, 118.2,
118.6, 121.1, 121.8, 123.7, 125.7, 126.1, 126.8, 127.2, 127.8, 128.3, 128.9, 129.1, 129.7, 130.9,
138.5, 138.7, 149.8, 152.6; HRMS (ESI) m/z for C26H20NaO2 [M + Na] +, calcd. 387.1361, found
387.1313, Anal. calcd. for C26H20O2: C, 85.69; H, 5.53. Found: C, 85.82; H, 5.63.
1
6e: Light yellow crystalline solid, mp 178°C, H NMR (300MHzꢀ, CDCl3) δ 2.44 (br. s,
2H), 4.15 (br. s, 1H), 6.97 (d, J = 8.6Hzꢀ, 1H), 7.09 (dd, J = 8.7 and 2.2Hzꢀ, 1H), 7.31-7.37 (m,
2H), 7.45-7.55 (m, 6H), 7.79 (br. d, J = 8.4Hzꢀ, 1H), 7.86 (d, J = 6.7Hzꢀ, 2H), 8.35 (br. d, J =
13
8.4Hzꢀ, 1H); Cꢀ NMR (75MHzꢀ, CDCl3) δ 33.1, 34.2, 99.1, 118.1, 119.5, 121.4, 121.8, 124.6,
125.2, 125.9, 126.0, 126.3, 126.7, 127.6, 127.9, 128.2, 128.5, 129.0, 133.7, 141.2, 147.0, 150.8,
162.3, Anal. calcd. for C25H17ClO2: C, 78.02; H, 4.45. Found: C, 77.82; H, 4.71.
Recovery of the catalyst
The catalyst was separated from the reaction mixture by filtration and washed thoroughly
with ethyl acetate-acetone (1:1) till the washings became colorless. It was then dried in a hot air
oven at 100°C for 8hꢀ. The recovered catalyst (weight 85-90% of the amount taken for the
reaction) was then used in the next cycle by taking proportionate amount of the starting
materials.
Acknowledgements
Financial assistance from the UGC-CAS and DST-PURSE programs, Department of
Chemistry is gratefully acknowledged. The authors acknowledge the DST-FIST program to the
Department of Chemistry, Jadavpur University for providing the NMR spectral data. The UPE-II
7

program of the UGC is also thanked for financial assistance. SS is thankful to the CSIR and NS,
SM and RM to the UGC, New Delhi for their Research Fellowships.
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8

Table 1. Optimization of reaction condition for synthesis of 2aa
Entry
Solvent
Amount of
Time (h)
Yield (%)b
Catalyst (mg)
1
2
Ethanol
Isopropanol
THF
100
100
100
100
100
100
100
100
50
9
9
9
9
9
4
9
9
9
9
5
7
–
24
12
45
44
46
56
64
36
56
45
52
3
4
Acetonitrile
Dioxane
o-Xylene
DMF
5
6
7
9
o-Xylene
Toluene
Toluene
Toluene
Toluene
10
11
12
13
80
100
100
9

14
15
16
17
Toluene
Toluene
Toluene
Toluene
100
100
100
120
8
9
61
66
66
64
10
10
aThe reaction were carried out with 1 mmol of each of the reactants under refluxing condition.
bIsolated yield for this table.
10

Table 2. Results of recyclability study of amberlyst-15 in the synthesis of 2a, 3a, 4a, 5a and 6a
Synthesis of
2,8-
Reaction
time (h)
Yield of product (%)
Fresh
First
Second
recycle
Third
Fourth
recycle
dioxabicyclo-
[3.3.1]nonane
catalyst
recycle
recycle
9
6
66
65
67
74
40
65
62
63
72
37
63
62
61
71
37
63
60
61
69
35
61
59
58
69
34
2a
3a
4a
5a
6a
6
10
14
11

Figure 1. Some biologically active natural 2,8-dioxabicyclo[3.3.1]nonanes3
12

Scheme 1. Synthesis of five types of 2,8-dioxabicyclo[3.3.1]nonanes from 2-hydroxychalcones
13

Scheme 2. 2,8-Dioxabicyclo[3.3.1]nonane derivatives synthesized [reaction time, yield]
14

Scheme 3. Plausible mechanism of formation of 2,8-dioxabicyclo[3.3.1]nonane derivatives
15