A method for the synthesis of fused 1,3-dioxolanes was developed by self-condensation of glyoxal generated in situ by oxidation of acetophenones with SeO2 in the presence of trifluoroacetic acid. Three molecules of the glyoxal generated by oxidation of ketone with SeO2 condensed to form architecturally novel oxygen-containing heterocycles (3a-aryldihydro-[1,3]dioxolo[4,5-d][1,3] dioxole-2,5-diyl)bis(phenylmethanones). This reaction provides a unique methodology for the construction of four C-O bonds in a concerted fashion, generating highly embedded oxygen heterocycles from readily available ketones using affordable shelf reagents and simple reaction conditions.
A method for the synthesis of fused 1,3-dioxolanes was developed by self-condensation of glyoxal generated in situ by oxidation of acetophenones with SeO2 in the presence of trifluoroacetic acid. Three molecules of the glyoxal generated by oxidation of ketone with SeO2 condensed to form architecturally novel oxygen-containing heterocycles (3a-aryldihydro-[1,3]dioxolo[4,5-d][1,3] dioxole-2,5-diyl)bis(phenylmethanones). This reaction provides a unique methodology for the construction of four C-O bonds in a concerted fashion, generating highly embedded oxygen heterocycles from readily available ketones using affordable shelf reagents and simple reaction conditions.
Oxygen-containing heterocyclic
molecules occur widely in nature
and constitute an important class of compounds because of their diverse
biological applications and utility as versatile intermediates in
organic synthesis.[1] A recent report revealed
that oxygen heterocycles are considered as the second most common
type of heterocycle that form part of the structural components in
many drugs.[2] Among them, 1,3-dioxolane
is an important moiety frequently encountered as structural motifs
in many oxygen-based drugs. Many such compounds have proven to be
an effective 5-lipoxygenase inhibitor,[3] anti-obesity,[4] anti-HIV, anti-cancer,[5] and anti-Alzheimer’s.[6] Over the past years, various synthetic protocols have been
successfully developed for the synthesis of 1,3-dioxolane-based compounds.[7] The literature review revealed a wide range of
heterocyclic compounds containing one or more 1,3-dioxolane moieties
in their molecular framework.[8] To the best
of our knowledge however, the only available method for the synthesis
of fused 1,3-dioxalane was reported by Diels and Jost[9] in 1902 by the reaction of biacetyl with HCl to give a
product, which was later deduced by Hudec and Turner[10] to be a fused dioxole biacetyl trimer (Scheme a). Therefore, development
of a first method for the synthesis of such compounds having novel
structural features will undoubtedly be of interest to synthetic organic
chemists, particularly those working in the field of drug development
and pharmaceuticals.
Scheme 1
(a, b) Synthesis of Compounds Containing
a Fused 1,3-Dioxolane Moiety
Earlier, we have successfully demonstrated that aryl/alkyl ketones
react with arenes in the presence of SeO2 and a Lewis acid
(BF3·Et2O) to give triaryl ethanones[11] via an Umpolung type of electrophilic addition
at the α-carbon of the ketones. In the presence of an organic
acid (PTSA) however, the aromatic ketones were converted to benzils[12] through the Riley oxidation pathway.[13] It was observed that the course of the SeO2-mediated reaction is dictated by the nature of the acid as
well as the solvent used in a particular set of reactions. Thus, as
part of our ongoing research on the synthetic utility of selenium
dioxide in organic synthesis,[11,12,14] we wish to report here a direct and efficient one-step protocol
for the synthesis of oxygen-based fused heterocyclic compounds (3a-aryldihydro-[1,3]dioxolo[4,5-d][1,3]dioxole-2,5-diyl)bis(phenylmethanones) by self-condensation
of arylglyoxals derived from arylketones in the presence of SeO2 and trifluoroacetic acid (TFA) (Scheme b).
Results and Discussion
For optimization
of the reaction conditions, acetophenone was chosen
as the model substrate. Initially, when 1 equiv of acetophenone 1a was treated with 0.5 equiv of SeO2 and 2 equiv
of TFA in the presence of nitrobenzene at 40 °C, the condensed
product 2a was obtained at only 30% yield (Table , entry 1). When the amounts
of SeO2 and TFA were simultaneously increased to 1 and
4 equiv, respectively, the yield of product 2a increased
to 65% (Table , entry
3). An attempt to further increase the amount of either SeO2 or the acid resulted in the formation of multiple spots while lowering
the yield of the desired product (Table , entries 4 and 5). To further investigate
the efficacy of the reaction, different solvents were screened and
it was found that the reaction proceeded well with aromatic solvents
like nitrobenzene, benzene, chlorobenzene, and toluene (Table , entries 3 and 6–8)
but showed negative results with non-aromatic solvents like DMSO,
acetonitrile, and DMF (Table , entries 9–11). Of all the aromatic solvents employed,
it was found that the optimum yields were obtained when the reactions
were carried out with nitrobenzene as the solvent (Table , entry 3). Next, the reactions
were performed under the standard condition using the Lewis acidBF3·Et2O and protonic acids such as acetic acid
and sulfuric acid to see if there was any improvement in the yields.
The use of BF3·Et2O resulted in an intractable
mass, while the two protonic acids did not give any product at all
(Table , entries 12–14).
It may be noted that product 2a was not obtained in the
absence of either TFA or SeO2 even when the reaction temperature
was increased up to 60 °C (Table , entries 15 and 16). Thus, the optimum condition for
the reaction to give a satisfactory yield of 65% for compound 2a requires 1 equiv of SeO2, 4 equiv of TFA, employing
nitrobenzene as the solvent at 40 °C, and a maximum reaction
time of 2 h (Table , entry 3).
Table 1
Optimization of Reaction Conditionsa
Sl no.
SeO2 (equiv)
acid (equiv)
solvent
temperature (°C)
yield (%)b
1
0.5
TFA (2)
nitrobenzene
40
30
2
0.5
TFA (4)
nitrobenzene
40
45
3
1
TFA (4)
nitrobenzene
40
65
4
1.5
TFA (4)
nitrobenzene
40
40
5
1
TFA (5)
nitrobenzene
40
55
6
1
TFA (4)
benzene
40
50
7
1
TFA (4)
chlorobenzene
40
60
8
1
TFA (4)
toluene
40
50
9
1
TFA (4)
DMSO
60
10
1
TFA (4)
acetonitrile
60
11
1
TFA (4)
DMF
60
12
1
BF3·EtOH
nitrobenzene
60
13
1
acetic acid
nitrobenzene
60
14
1
sulfuric acid
nitrobenzene
60
15
TFA
(4)
nitrobenzene
RT-60c
16
1
nitrobenzene
RT-60c
Reaction was carried out with 1
equiv of 1a.
Isolated yield.
Initially,
the reaction was carried
out at room temperature and then heated to 60 °C.
Reaction was carried out with 1
equiv of 1a.Isolated yield.Initially,
the reaction was carried
out at room temperature and then heated to 60 °C.Equipped with the optimized reaction
conditions, we proceeded to
investigate the generality of the method by carrying out reactions
with differently substituted aryl methyl ketones. It was observed
that both electron-donating and electron-withdrawing substituents
are equally compatible for the reaction to give products in moderate
to good yields. Thus, irrespective of the nature of substitution on
the benzene ring of the ketones, the p-substituted
aryl methyl ketones (p-CH3, p-OCH3, p-Br, p-Cl, and p-F) reacted easily to give the corresponding products in
satisfactory yields (2b, 70%; 2c, 68%; 2d, 70%; 2e, 72%; 2f, 75%) (Scheme ). Similarly, m-substituted ketones (m-Cl, m-Br, and m-CH3) displayed comparable
reactivity, generating the desired products (2g, 60%; 2h, 52%; 2i, 62%) in moderate yields. It may
be noted that o-substituted ketones (o-CH3 and o-OCH3) also reacted
albeit with lesser product yields (2j, 50% and 2k, 52%), presumably due to steric hindrance. The effect is
more pronounced with trisubstituted ketone (1n) when
the reaction failed to react altogether. Disubstituted ketone (1l) also reacted to give the product 2l in 55%
yield. The scope of the reaction was further extended to 2-acetylnaphthalene
(1m), which successfully underwent self-condensation
to give the product 2m in reasonable yield. With heteroaryl
methyl ketones (1o and 1p) however, the
reactions gave only trace amounts of the products (2o and 2p). The structures of some of these new compounds
(2a, 2b, 2e, 2j, 2k, and 2l) were confirmed by X-ray diffraction
analysis (included in the Supporting Information). The Oak Ridge Thermal-Ellipsoid Plot (ORTEP) diagram representation
of compounds 2a and 2e is shown in Figure . From the above
results, it is evident that the formation of the product is not defined by the nature of the
substituents on the benzene ring of the ketones but rather depends
on the position of the substituents where unsubstituted and p-substituted aryl methyl ketones (1a–f) gave the maximum yield of the condensed product, whereas substitution
at the o-position (1j–l) resulted
in lesser product yields. 1H NMR and ORTEP diagrams of
few products (2b, 2f, 2h, 2k, and 2m) indicated the presence of a mixture
of symmetrical and unsymmetrical isomers. Heteronuclear Multiple Bond
Coherence (HMBC) analysis of compound 2f confirmed the
presence of both the isomers. It was further observed from 1H NMR that o-substituted ketones (1j, 1k, and 1l) afforded the symmetric products 2j, 2k, and 2l, although 2k gave a mixture of symmetrical and unsymmetrical forms. The p- and m-substituted ketones however yielded
unsymmetrical isomers as the major product. Thus, it appears that o-substituents effect the formation of symmetric products
may be due to the steric repulsion.
Scheme 2
Scope of Self-Condensation of Aryl Methyl Ketonesa in
the Presence of SeO2 and TFA
The reaction was carried out
with 1a (2.0 mmol, 1 equiv), SeO2 (0.222 g,
2.0 mmol, 1 equiv), and TFA (0.6 mL, 4 equiv) in nitrobenzene at 40
°C.
Isolated yield.
Figure 1
ORTEP of 2a (CCDC 1991160)
and 2e (CCDC
1991162), with thermal ellipsoids at the 50% probability level.
ORTEP of 2a (CCDC 1991160)
and 2e (CCDC
1991162), with thermal ellipsoids at the 50% probability level.
Scope of Self-Condensation of Aryl Methyl Ketonesa in
the Presence of SeO2 and TFA
The reaction was carried out
with 1a (2.0 mmol, 1 equiv), SeO2 (0.222 g,
2.0 mmol, 1 equiv), and TFA (0.6 mL, 4 equiv) in nitrobenzene at 40
°C.Isolated yield.The plausible mechanistic pathway is depicted
in Scheme . Evidently,
the initial step
of the reaction involves the well-established Riley oxidation of the
acetophenone 1a by SeO2 to gyloxal 3, which, in the presence of TFA, existed in equilibrium with its
monohydrated substrate 4.[15] A concerted acid-catalyzed double acetalization of the glyoxal with
two molecules of its monohydrate resulted in the formation of the
condensed product 2a with elimination of water. The above
proposed mechanism was further strengthened by the condensation of
2,2-dihydroxy-1-(p-tolyl)ethan-1-one 4b in the presence of acid TFA under the standard reaction condition
to give the expected product 2b in 76% yield (Scheme ).
Scheme 3
Plausible Mechanism
Scheme 4
Condensation of 2,2-Dihydroxy-1-(p-tolyl)ethan-1-one
to 2b
Conclusions
In
summary, this work highlights a new TFA-mediated intermolecular
oxidative self-condensation reaction of three molecules of aromatic
ketone via multiple C–O bond formations using a common shelf
reagent, SeO2, as the oxidant under mild reaction conditions
to afford (3a-phenyldihydro-[1,3]dioxolo[4,5-d][1,3]dioxole-2,5-diyl)bis(phenylmethanones),
a structurally unique class of oxygen heterocycles.
Experimental
Section
All chemicals and reagents were purchased from available
commercial
companies and were used without further purification. Reactions were
monitored by thin-layer chromatography using pre-coated aluminum sheets
(silica gel 60 F254, 0.2 mm thickness). Formation of the
desired product was confirmed by infrared (IR), 1H NMR, 13C NMR, and mass spectra (LC–MS/HRMS). IR spectra were
recorded on a Perkin Elmer Spectrum 400 FTIR instrument, and the frequencies
are expressed in cm–1. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance II-400 spectrometer
in CDCl3, and chemical shifts were recorded in ppm with
TMS as the internal standard. The HMBC spectrum was recorded on an
ECZR series 600 MHz NMR spectrometer (Jeol, Japan). Melting points
were recorded by an open capillary tube method. Mass spectral data
were obtained with a Waters UPLC-TQD mass spectrometer (ESI-MS). High-resolution
mass spectra (ESI-HRMS) were recorded on an Agilent 6545 Quadrupole
Time-of-Flight. All reactions were purified by column chromatography
over silica gel (100–200 mesh) using ethyl acetate and hexane
as the eluent.
General Procedure for the Preparation of (3a-Aryldihydro-[1,3]dioxolo[4,5-d][1,3]dioxole-2,5-diyl)bis(phenylmethanone)
To
a solution of nitrobenzene (5 mL) and aryl methyl ketone (1a–p) (2.0 mmol, 1 equiv) in a 25 mL dry round-bottom flask, SeO2 (0.222 g, 2.0 mmol, 1 equiv) was added and the mixture was
allowed to stir in an ice bath where TFA (0.6 mL) was added dropwise.
The reaction was then allowed to stir at 40 °C for 2 h using
a temperature-controlled magnetic stirrer in an oil bath. After the
reaction is completed, ethyl acetate (20 mL) was added to dilute the
reaction mixture, which was then washed with a saturated solution
of sodium bicarbonate and thereafter with brine solution. The organic
layer was then collected separately and dried over anhydrous sodium
sulfate and reduced in a rotatory evaporator to a minimum amount.
The compound was then purified by column chromatography over a silica
gel 100–200 mesh using ethyl acetate:hexane as the eluent.
Scheme 1
Scheme 2
Figure 1
Scheme 3
Scheme 4