Highly efficient synthesis of 1,3-dioxanes via prins reaction in bronsted-acidic imidazolium ionic liquid

Article abstract of DOI:10.1080/00397911.2013.823644

The high-yielding synthesis of a wide variety of 1,3-dioxanes via the Prins reaction under mild conditions has been demonstrated using Bronsted- acidic imidazolium ionic liquid [bmim(SO₃H)][OTf] or bmimOTf. The use of ionic liquid makes this synthesis simple, convenient, cost-effective, and environmentally friendly. Furthermore, bmimOTf was conveniently separated from the products and can be easily recycled for the Prins reaction with excellent yields. This method works well with a variety of aliphatic aldehydes including formaldehyde, acetaldehyde, propionaldehyde, and cyclohexanecarboxaldehyde. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.823644

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Highly Efficient Synthesis of 1,3-
Dioxanes via Prins Reaction in Brønsted-
Acidic Imidazolium Ionic Liquid
Rajesh G. Kalkhambkar a & Yeon T. Jeong b
a Department of Chemistry , Karnatak University's Karnatak Science
College , Dharwad , Karnatak , India
b Department of Image Science and Engineering , Pukyong National
University , Busan , Republic of Korea
Published online: 20 Feb 2014.
To cite this article: Rajesh G. Kalkhambkar & Yeon T. Jeong (2014) Highly Efficient Synthesis of 1,3-
Dioxanes via Prins Reaction in Brønsted-Acidic Imidazolium Ionic Liquid, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:6, 762-771, DOI:
10.1080/00397911.2013.823644
To link to this article: http://dx.doi.org/10.1080/00397911.2013.823644
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Synthetic Communications1, 44: 762–771, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.823644
HIGHLY EFFICIENT SYNTHESIS OF 1,3-DIOXANES VIA
PRINS REACTION IN BRØNSTED-ACIDIC IMIDAZOLIUM
IONIC LIQUID
Rajesh G. Kalkhambkar1 and Yeon T. Jeong2
1Department of Chemistry, Karnatak University’s Karnatak Science College,
Dharwad, Karnatak, India
2Department of Image Science and Engineering, Pukyong National
University, Busan, Republic of Korea
GRAPHICAL ABSTRACT
Abstract The high-yielding synthesis of a wide variety of 1,3-dioxanes via the Prins reaction
under mild conditions has been demonstrated using Brønsted-acidic imidazolium ionic liquid
[bmim(SO3H)][OTf] or bmimOTf. The use of ionic liquid makes this synthesis simple,
convenient, cost-effective, and environmentally friendly. Furthermore, bmimOTf was
conveniently separated from the products and can be easily recycled for the Prins reaction
with excellent yields. This method works well with a variety of aliphatic aldehydes including
formaldehyde, acetaldehyde, propionaldehyde, and cyclohexanecarboxaldehyde.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aldehydes; dioxanes; ionic liquids; Prins reaction; styrenes
INTRODUCTION
Dioxanes are a common structural motif present in several bioactive
molecules such as (þ)-dactylolide, derivatives of 2-substituted-1,3-dioxanes, and
Received May 2, 2013.
Address correspondence to Yeon Tae Jeong, Department of Image Science and Engineering,
Pukyong National University, San 100, Yongdang-Dong, Nam-Gu, Busan 608-739, Republic of Korea.
E-mail: ytjeong@pknu.ac.kr
762

SYNTHESIS OF 1,3-DIOXANES
763
Figure 1. Structures of some biologically active 1,3-dioxanes.
novel activators of the lipoprotein receptor (þ)-SCH-351448.[1–3] Recently 1,3-
dioxanes have been evaluated as effective modulators for multidrug resistance,[4]
phenotypic and protein binding agents,[5,6] and histone deacetylase (HDAC)
inhibitors[7] (Fig. 1).
Traditionally, dioxanes could be obtained via the Prins reaction, which is an
important carbon–carbon bond-forming reaction in organic synthesis. In general,
dioxanes are also common products, which are widely used as solvents or intermedi-
ates.[8] Generally, strong protonic acid catalysts such as sulfuric acid and hydro-
chloric acid are required to synthesize dioxanes by the Prins reaction.[8] However,
the applications of these mineral acid catalysts is limited by their toxicity, corrosive-
ness, and tedious workup procedure.[9] The use of heterogeneous catalysts for the
Prins reaction, such as Lewis acids,[10] Brønsted acids,[11] and solid acids,[12] showed
little success. With increasing public concern over environmental degradation and
future resources, it is of great importance for chemists to come up with new
approaches that are less hazardous to human health and the environment.[13] In
recent years, ionic liquids (ILs) have attracted increasing interest and have been suc-
cessfully used in variety of catalytic reactions as environmentally benign solvents and
catalysts because of their relatively low viscosities, low vapor pressure, and high ther-
mal and chemical stability.[14]
Now many organic reactions with ILs (as catalysts or solvents) have been per-
formed with good results.[15] Owing to the useful characteristics of solid acids and
mineral acids, various types of Brønsted acidic ionic liquids are designed and used
as catalysts for the Prins reaction with a limited number of examples.[16] Further-
more, these ILs were also designed to replace traditional mineral acids, such as
sulfuric acid and hydrochloric acid in the chemical processes.[17]
In view of these merits of ILs, and in continuation of our work in studying
acid-catalyzed reactions in ionic liquids,[18] we describe here a direct and efficient
protocol of bmimOTf ionic liquid–mediated synthesis of dioxanes via the Prins
reaction from diversely substituted styrenes and aldehydes. In comparison with
the reported methods in the literature, we have demonstrated the advantages of
the use of bmimOTf make this synthesis simple, convenient, cost-effective, and envir-
onmentally friendly. Furthermore, bmimOTf was conveniently separated from the
products and can be easily recycled for the Prins reaction of different substrate with
excellent yields.

764
R. G. KALKHAMBKAR AND Y. T. JEONG
Scheme 1. Synthesis of 4-phenyl-1,3-dioxane using bmimOTf.
RESULTS AND DISCUSSION
The desired Brønsted acidic ionic liquid was prepared by the reaction of
1-methylimidazole and 1,4-butanesultone at room temperature and the resulting
zwitterionic imidazolium salt was treated with trifluoromethanesulfonic acid at
40 ꢀC to afford the IL in quantitative yield.[19] To establish its catalytic importance
for the Prins reaction, a preliminary experiment was carried out to synthesize
4-phenyl-1,3-dioxane from styrene and formaldehyde in anhydrous MeCN
(Scheme 1).
Unfortunately at 10 mol% of the catalyst (Table 1) the reaction did not go well
either at rt or at 50–80 ꢀC. A periodical increase in the molar ratio of catalyst
increases the conversion rate steadily. This gave a clue that the amount of catalyst
has more significant impact than the temperature and the nature of the solvent
(MeCN, tetrahydrofuran [THF], and H2O). To our delight, an almost complete con-
version (98% by gas chromatography–mass spectrometry GC-MS) was noticed in 6 h
at 60 ꢀC when IL was used in excess (to serve as both catalyst and solvent).
After optimization of bmimOTf, we carried out the series of reactions for the
synthesis of dioxanes via Prins reaction from diversely substituted styrenes and
aldehydes (Scheme 2).
Table 1. Optimization of catalytic activity of bmimOTf on model reaction (Scheme 1)
Entry bmimOTf (mol%) Solvent Temperature (ꢀC) Time (h) Conversiona (%) Yieldb (%)
1
2
10
10
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Rt
50
80
Rt
50
Rt
50
80
80
80
80
60
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
ꢁ12
6
10
18
21
14
26
22
35
41
52
30
00
98
NI
NI
NI
NI
NI
NI
20
3
10
15
4
5
15
20
6
7
20
20
8
27
43
9
30
30
10
11
10
NI
NI
82c
30
bmimOTf
H2O
aConversion based on GC-MS analysis.
bIsolated yields of pure products; NI: no isolation.
cReaction was carried out in bmimOTf (in absence of MeCN).

SYNTHESIS OF 1,3-DIOXANES
765
Scheme 2. Synthesis of various substituted 1,3-dioxanes using bmimOTf.
All the reactions listed in Table 2 were carried out at 60–70 ꢀC and were mon-
itored by thin-layer chromatography (TLC) and GC-MS from 6–12 h. The results
revealed that both substituents in styrene (either F or Me) provided uniformly good
results (Table 2, entries 4–10). Encouraged by these results, we then extended our
protocol to various styrenes and aldehydes to check general applicability. It is obvi-
ous from Table 2 that all the reactions went smoothly at 60–70 ꢀC in a time interval
of 6–12 h. These results suggest that the nature of the substitution on the phenyl ring
has no influence on the product yield (Table 2, entries 11–14). Cyclic systems like
1,2-dihydronaphthalene and indene also worked well as noticed from the isolated
yield (Table 2, entries 15–18).
Further, to extend the scope of bmimOTf in the Prins reaction, bmimOTf was
recycled up to three times (Table 2, entries 2, 3, 5, 6, 8, 9, etc.) where the recovered
bmimOTf of a different reaction was used. The products obtained by using recycled
bmimOTf were clean and isolated without any significant loss in the product yield
(77–90%). (Table 2, entries 3, 6, 8, 9, 13, etc.).
Because there have been very few reports on the use of aliphatic aldehydes,
except formaldehyde, we have also attempted the study of reactivity of other ali-
phatic aldehydes such as acetaldehyde, propionaldehyde, and cyclohexanecarbox-
aldehyde besides formaldehyde. Interestingly, these substrates reacted well with
alkenes to produce the corresponding 2,4,6-trisubstituted 1,3-dioxane derivatives
under similar reaction conditions. Though the reaction was successful with ali-
phatic aldehydes, no coupling of aromatic aldehydes and heteroaromatic alde-
hydes with styrene was observed even by increasing the reaction temperature
(80–90 ꢀC) (Table 2, entries 19–21). In general, in the present methodology the
IL can be recycled for up to three attempts without any significant loss in the
product yield. The reactions were clean, the products containing stereo centers
were isolated as recemic mixture, and no other side products were detected under
these conditions as determined from the NMR spectra of the crude products. The
structures of the products were established from their spectral data and also by
comparison with authentic samples. A plausible reaction mechanism is depicted
in Scheme 3.
It should be noted that the reactions were faster with paraformaldehyde com-
pared to other aliphatic aldehydes. In addition, styrene derivatives gave greater
yields of products with paraformaldehyde when compared with other olefins
(Table 2, entries 1, 4, 7, and 11) as reported by Yadav et al. in iodine.[20] The scope
and generality of this process is illustrated with respect to various aldehydes and
alkenes.

766
R. G. KALKHAMBKAR AND Y. T. JEONG
Table 2. List of 1,3-dioxanes synthesized using bmimOTf
Entry
1
Olefin
Aldehyde
Product
Time (h) Yielda
2
n
(CH O)
6
82
2
10
68b
3
8
77c
4
5
(CH2O)n
8
89
12
64d
6
7
12
90b
(CH2O)n
6
92
(Continued )

SYNTHESIS OF 1,3-DIOXANES
767
Table 2. Continued
Entry
Olefin
Aldehyde
Product
Time (h) Yielda
8
6
8
85b
9
72c
10
11
12
13
14
12
12
12
8
70b
(CH2O)n
80
67b
80c
80
6
15
(CH2O)n
6
78b
(Continued )

768
R. G. KALKHAMBKAR AND Y. T. JEONG
Table 2. Continued
Entry
Olefin
Aldehyde
Product
Time (h) Yielda
16
17
12
80c
(CH2O)n
9
94
18
19
8
90
12
NR
20
12
NR
21
12
NR
aIsolated yields of pure products; NR; no reaction.
bThe reactions were carried out with recycled bmimOTf, cycle 1.
cThe reactions were carried out with recycled bmimOTf, cycle 2.
dThe reactions were carried out with recycled bmimOTf, cycle 3.

SYNTHESIS OF 1,3-DIOXANES
769
Scheme 3. Plausible mechanism of formation of 1,3-dioxanes from bmimOTf.
EXPERIMENTAL
The reagents employed were high-purity commercial samples, which were used
as received. Reactions were carried out in an oven-dried round-bottom flask.
Column chromatography was performed on silica gel (200–400 mesh). TLC was per-
formed on alumina silica gel 60F254 (Fischer) detected by ultraviolet light (254 nm)
and iodine vapors. The melting points were determined by open capillaries on a
Buchi apparatus and are uncorrected. The infrared (IR) spectra were recorded on
1
a Nicolet-impact-410 FT-IR spectrometer, using KBr pellets. H NMR and 13C
NMR spectra were recorded on a Bruker AC-300F 300-MHz spectrometer in
dimethylsulfoxide (DMSO-d6) using tetramethyl silane (TMS) as an internal stan-
1
dard with H resonance frequency of 300 MHz and 13C resonance frequency of
75 MHz. GC analyses were performed on a Nucon 5700 series gas chromatograph.
GC-MS analyses were performed on a Shimadzu 2010 series mass selective detector
instrument. Elemental analysis was carried out by using a Heraus CHN rapid ana-
lyzer. All the compounds gave C, H, and N analysis within ꢂ0.4% of the theoretical
values.
Typical Procedure for the Synthesis of 1,3-Dioxanes
In a typical experiment, styrene (10.0 mmol) and formaldehyde (20.0 mmol)
were added successively into an oven-dried Schlenk tube. Upon efficient magnetic
stirring (for 10–20 min) the reaction mixture was then charged with bmimOTf (2–
3 mL). The reaction mixture was stirred at 60–70 ꢀC and the progress of the reaction
was monitored by TLC and GC-MS (Table 2). After the completion of the reaction
(TLC and GC-MS), the mixture was cooled to room temperature and the product
was extracted in dichloromethane (DCM). The pure product was obtained by
column chromatography (80:20 hexane–ethyl acetate mixture) and was fully charac-
1
terized by GC-MS, H NMR, 13C NMR, and elemental analysis. The spectral data
were found to be in agreement with the reported values.[20] The ionic liquid left after
the extraction of product was dried and reused again.

770
R. G. KALKHAMBKAR AND Y. T. JEONG
Typical Method for the Reusability of bmimOTf
The crude ionic liquid left after the extraction of products was dissolved in
MeCN and filtered through sintered crucible to remove the suspended particals (if
present). Pure IL was obtained after the removal of MeCN under reduced pressure;
it was dried under high vacuum and directly reused in subsequent reactions. The
ionic liquid as catalyst and solvent were reused up to three times.
Supporting Information
Details of analysis of [bmim(SO3H)][OTf] and full experimental details, IR, 1H
and 13C NMR spectra, and elemental analysis of various 1,2-benzisoxazoles deriva-
tives can be found via the Supplementary Content section of this article’s webpage.
CONCLUSIONS
In summary, bmimOTf has proved to be a useful, novel, efficient, recyclable
catalyst and environmentally benign solvent for the Prins reaction to produce vari-
ous substituted 1,3-dioxanes in excellent yield. The experimental procedure is simple
and convenient and the reaction conditions are amenable to scale-up. This method
provides easy access to a wide range of 1,3-dioxanes with diverse chemical structures.
Further work, including the development of synthetic applications of bmimOTf as a
reagent=catalyst and solvent in organic synthesis, is under way in our laboratory.
ACKNOWLEDGMENTS
The authors thank the University Sophisticated Instrument Center, KUD, for
IR, GC, GC-MS, and 1H and 13C NMR. The authors also thank M. V. Kulkarni for
useful discussion.
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