Thiourea dioxide promoted efficient organocatalytic one-pot synthesis of a library of novel heterocyclic compounds

Article abstract of DOI:10.1039/c1ob05818e

The utility of thiourea dioxide as an efficient organocatalyst for the library synthesis of novel heterocyclic compounds via one-pot multicomponent coupling reactions is disclosed. Thiourea dioxide is an inexpensive and readily accessible catalyst, resulting in better product yields as compared to the corresponding thiourea as catalyst. Thiourea dioxide is found to be insoluble in various organic solvents and therefore at the end of the reaction products can be separated by extraction with diethyl ether and the recovered catalyst can be used several times with consistent catalytic activity.

Full text of DOI:10.1039/c1ob05818e

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Thiourea dioxide promoted efficient organocatalytic one-pot synthesis of a
library of novel heterocyclic compounds†
Sanny Verma, Subodh Kumar, Suman L. Jain and Bir Sain*
Received 24th May 2011, Accepted 10th August 2011
DOI: 10.1039/c1ob05818e
The utility of thiourea dioxide as an efficient organocatalyst
for the library synthesis of novel heterocyclic compounds
via one-pot multicomponent coupling reactions is disclosed.
Thiourea dioxide is an inexpensive and readily accessible
catalyst, resulting in better product yields as compared to the
corresponding thiourea as catalyst. Thiourea dioxide is found
to be insoluble in various organic solvents and therefore at the
end of the reaction products can be separated by extraction
with diethyl ether and the recovered catalyst can be used
several times with consistent catalytic activity.
Owing to the presence of two extra oxygen atoms it forms strong
hydrogen bonding and can provide higher activation than the
corresponding thiourea. In addition, thiourea dioxide is insoluble
in common organic solvents and therefore can easily be recovered
at the end of the reaction for its reuse. Despite its high potential,
the use of thiourea dioxide as organocatalyst for organic reactions
is not much reported in the literature.13 So far, to the best of our
knowledge except our report, there is no report available on the
use of TUD as an organocatalyst for organic transformations13
Our previous results led us to explore the potential of TUD as
organocatalyst for developing “greener” methodologies for other
organic reactions as well. Accordingly we planned to use TUD as
catalyst to develop an efficient organocatalytic multicomponent
synthetic approach for the library synthesis of novel hetero-
cycles of potential biological applications for various purposes
(Scheme 1).
Development of “greener synthetic methodologies” along with
fast access toward the desired compounds is one of the prime
objectives to speed up current organic synthesis.1 In this regard,
several advancements such as microwave synthesis,2 use of ionic
liquids,3 sonication,4 multicomponent couplings5 and combinato-
rial synthesis6 have been recognized to be efficient tools to accel-
erate the reaction rates. Among them, multicomponent coupling
reactions (MCRs) represent a valuable synthetic approach for the
library synthesis of novel heterocyclic compounds of tremendous
importance.7 Synthesis of these compounds by an MCR approach
provides a number of advantages over conventional synthesis,
such as simple synthesis, lower costs, shorter reaction times, and
environmental friendliness. Among the recently developed ad-
vancements, the discovery of catalysis by small organic molecules
termed as “organocatalysts” has become a break-through, which
offers numerous advantages including lower activation energy,
high stability, metal free environment, reduced toxicity, and mild
reaction conditions.8 Small molecules such as urea9 and thiourea10
derivatives due to their strong hydrogen-bonding activity have
also emerged to be potential organocatalysts in developing a
variety of synthetically important organic reactions. Owing to the
growing environmental concerns, there is continued pressure on
chemical and pharmaceutical industries to reduce chemical waste.
In this regard utilization of heterogeneous catalysts may offer the
advantages of facile recovery and recycling of the catalyst.11
Thiourea dioxide (TUD)12 easily prepared by the oxidation of
thiourea with hydrogen peroxide is highly stable and possesses the
ability to activate organic substrates through hydrogen bonding.
Scheme 1 TUD catalyzed one-pot synthesis of heterocycles.
Initially, the catalytic efficiency of the thiourea dioxide and
thiourea was tested for the reaction of salicylaldehyde (2 mmol)
and ethyl acetoacetate (2 mmol) under solvent free conditions. The
reaction was found to occur very slowly and provided a poor yield
of the corresponding product. On the other hand, the reaction
occurred efficiently in the presence of a catalytic amount of TUD
and provided excellent product yield (>90%) as listed in Table
1, entry 1. In the absence of catalyst, no reaction was occurred
under described reaction conditions. Next, we studied the effect
of various solvents such as acetonitrile, dichloromethane, water
Chemical Sciences Division, Indian Institute of Petroleum, Dehradun, India,
248005. E-mail: suman@iip.res.in
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05818e
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Table 1 TUD mediated synthesis of functionalized coumarinsa
Entry
1
Substrate
Product
Time (h)
—
Yield (%)b
c
—
4.0
5.0
4.0, 3.5
4.0
4.0
85. 60d, 60e
65f
90g 92h
40i, 65j, 72k, 85l, 82m, 86n
84
2
3
4
5
6
4.0
4.0
4.0
4.0
84
86
85
83
7
8
4.0
4.0
83
85
9
8.0
65
40
10
12.0
11
12
13
3.5
3.0
4.0
90
90
85
14
4.0
90
15
16
4.0
5.0
90
59
17
18
3.5
3.0
90
90
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Table 1 (Contd.)
Entry
19
Substrate
Product
Time (h)
4.0
Yield (%)b
85
20
4.0
90
21
22
4.0
5.0
90
60
a Reaction conditions: hydroxyl aromatic compound (2 mmol), b-keto ester (2 mmol), TUD (5 mol%) under solvent free conditions. b Isolated yields.
c Without catalyst. d By using urea as catalyst. e Using thiourea as catalyst. f Using TUD 2 mol%. g 10 mol%. h 20 mol%. i Using water as solvent. j In
acetonitrile solvent. k In dichloroethane. l Using methyl acetoacetate. m Using tert-butyl acetoacetate. n Using acetylacetone.
Table 2 TUD mediated synthesis of heterocyclic dipyrromethanesa
and no solvent under similar reaction conditions. The results
revealed solvent free condition to be the best choice for the present
Reaction
transformation. Low yield of the product was obtained when
water was employed as the solvent. The reaction was significantly
affected by increasing the amount of TUD from 2 to 5 mol%,
whereas no improvement could be observed upon increasing the
catalyst loading to 10 mol% (Table 1, entry 1). Other b-keto esters
such as methyl acetoacetate, tert-butyl acetoacetate and acetyl
acetone were also proved to be an excellent substrate, giving
good yields of the corresponding product under identical reaction
conditions (Table 1, entry 1).
Entry
1
Substrate
Product
time (min)
15
Yield (%)b
80, 70c, 62d
2
3
15
15
80
75
Since the thiourea dioxide is insoluble in common organic
solvents it can be considered as a heterogeneous catalyst. To
investigate the reusability of the catalyst which is one of the
most important features of heterogeneous catalysts, we studied the
reaction of salicylaldehyde and ethyl acetoacetate under similar
reaction conditions. At the end of the reaction, the reaction
mixture was diluted with the diethyl ether to extract the reaction
products. The insoluble TUD could easily be separated form the
reaction mixture by simple filtration and was successfully reused
for subsequent experiments (4 runs) with high catalytic efficiency.
The scope of the reaction under optimized conditions was
explored using a variety of substituted salicylaldehydes and other
1,3-dicarbonyl compounds, the results are summarized in Table 1
(entry 1–8). In general, all the salicylaldehydes bearing functional
groups at different positions reacted with ethyl or methyl
acetoacetate smoothly to give the corresponding heterocyclic
products in good to excellent yields. Next, we studied the coupling
of various hydroxyl aromatic compounds such as phenol and
resorcinol with ethyl acetoacetate under the described reaction
conditions, an the results are summarized in Table 1 (entry 9–20).
In all cases the reaction was found to occur efficiently and the
provided corresponding heterocyclic compounds, coumarins, in
almost quantitative yields. Furthermore we studied the reaction
of various aldehydes (1 mmol) with pyrrole (2 mmol) under the
described experimental conditions (Table 2, entry 1–9). In general
aromatic aldehydes bearing both electron donating or withdrawing
groups were found to react smoothly and provided excellent yield
of the corresponding products. However, the reaction of aliphatic
4
5
18
18
70
69
6
7
30
30
70
72
8
9
30
30
80
65
a Reaction conditions aldehyde (2 mmol) and pyrrole (4 mmol), catalytic
amount of TUD (5 mol%). b Isolated yields. c Using thiourea as catalyst.
d Using urea as catalyst.
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Table 3 TUD-catalyzed synthesis of piperidinesa
Entry
1
Substrate
Product
Reaction time (h)
4
Yield (%)b
80, 65c, 55d
anti/syn
97/3
2
3
4
85
82
94/6
97/3
4.5
4
5
6
4.5
6.0
5.0
85
80
85
96/4
95/5
96/4
7
8
10
8
50
90
85/15
92/8
9
10
12
50
50
90/10
86/14
10
11
—
12
trace
—
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Table 3 (Contd.)
Entry
12
Substrate
Product
—
Reaction time (h)
—
Yield (%)b
—
anti/syn
—
a Reaction conditions: b-keto ester (1.0 mmol), aldehyde (2.0 mmol), amine (2 mmol), and TUD (5 mol%) under solvent free conditions. b Isolated yields.
c Using thiourea as catalyst. d Using urea as catalyst.
aldehydes was found to be slow with the formation of very
poor yield of the desired product, as shown in (Table 2,
entry 9). Lastly, we studied the synthesis of functionalized
tetrahydropyridines via the one-pot coupling of b-keto ester,
aromatic aldehyde, and amine under the similar reaction
conditions (Table 3, entry 1–12). In general, aromatic aldehydes
bearing electron-donating or electron-withdrawing functional
groups at different positions reacted faster and afforded high
to excellent yield of the corresponding products. On the other
hand, aromatic amines were found to be effective substrates
and afforded the corresponding tetrahydropyridine derivatives
in high yields. However, aliphatic amines were found to be less
reactive substrates and gave moderate yields, probably due to
the higher basicity of aliphatic amines. All the compounds were
characterized by comparing their physical and spectral data
with those of authentic sample. The purity of the products was
identified by 1H NMR spectroscopy.
The exact mechanism of the reaction is not known at this stage;
however a proposed mechanism for this reaction may involve
the activation through hydrogen bonding between TUD and
substrates. The probable mechanism for the synthesis of coumarin
is shown in Scheme 2. The presence of two more oxygen atoms in
TUD may possibly be responsible for its higher catalytic activity
as compared to the thiourea and it can promote several other
transformations in a similar fashion.
strong hydrogen bonding ability TUD can also be served as
an efficient organocatalyst for other organic transformations
also.
Experimental
Synthesis of thiourea dioxide11
◦
Thiourea (45 g) was added into hot water (350 ml) at 40 C and
the resulting mixture stirred to dissolve the thiourea completely.
Further, the aqueous solution of thiourea thus prepared was
cooled and added to hydrogen peroxide (aq. 50 wt%, 80 ml)
slowly at a rate such that the solution temperature was held below
10 ◦C. Thereafter, the solution was cooled to 0 ◦C. and stirring
continued for about 30 min to allow the crystals to be aged. After
the crystallization, the resulting solid–liquid mixture was filtered
off immediately at 0 ◦C and the crystals so obtained were dried at
50 ◦C, yield of thiourea dioxide 40 g (64%).
General procedure for the preparation of functionalized coumarins
(Table 1, entry 1–20)
To a mixture of salicylaldehyde or hydroxyl aromatic compound
(phenol, resorcinol) (2 mmol) and b-keto ester (2 mmol) was added
a catalytic amount of TUD (5 mol%). The resulting mixture was
heated with stirring at 80 ◦C for the time as given in Table 1.
The progress of the reaction was monitored by TLC (SiO2). After
the completion of the reaction, the reaction mixture was diluted
with diethyl ether to isolate the product. The recovered catalyst
was separated by filtration for its reuse. The organic solvent was
evaporated under reduced pressure to afford the crude product,
which was then purified by column chromatography by using ethyl
acetate and hexane (4 : 6) as eluent.
General procedure for the synthesis of derivatives of
dipyrromethanes (Table 2, entry 1–9)
Scheme 2 Probable mechanistic pathway.
In conclusion, we have developed an efficient organocatalytic
synthetic approach for the synthesis of a series of pharmaco-
logically important heterocyclic compounds via a one-pot multi-
component coupling reaction by using a catalytic amount of TUD
under solvent free conditions. The salient features of this procedure
are the easy synthesis and facile recovery of the catalyst, mild
reaction conditions, clean reaction profiles, inexpensive starting
materials, and environmentally friendly protocol. Owing to its
Into a stirred mixture of aldehyde (2 mmol) and pyrrole (4 mmol),
a catalytic amount of TUD (5 mol%) was added. The resulting
mixture was stirred at room temperature. Progress of the reaction
was checked by TLC (SiO2). At the end of the reaction, the
reaction mixture was subjected to usual work-up to afford the
corresponding dipyrromethane. The crude product was purified
by column chromatography by using ethyl acetate: hexane (4 : 6)
as eluent.
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General experimental procedure for the synthesis of functionalized
piperidines (Table 3, entry 1–12)
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A mixture of b-keto ester (1.0 mmol), aldehyde (2.0 mmol), amine
(2 mmol), and TUD (5 mol%) was stirred at room temperature for
an appropriate time (Table 3). After completion of the reaction,
as indicated by TLC, the mixture was diluted with ethyl acetate
(20 ml), washed with water and dried with anhydrous Na2SO4.
The filtrate was concentrated to yield crude product was purified
by silica gel column chromatography.
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Acknowledgements
We kindly acknowledge the Director, IIP for his kind permission to
publish these results. SV and SK thanks to CSIR for his fellowship.
DST, New Delhi is acknowledged for research funding.
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6948 | Org. Biomol. Chem., 2011, 9, 6943–6948
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