Synthesis of β-Aryl-β-sulfanyl ketones by a sequential one-pot reaction using kf/al2o3 in glycerol

Article abstract of DOI:10.1080/00397911.2013.788720

The title compounds were synthesized by a sequential one-pot reaction of aryl aldehydes, aryl-methyl ketones, and thiols promoted by KF/Al2O3. This methodology affords a large number of β-aryl-β-sulfanyl ketone derivatives from aliphatic and aromatic thiols in good yields and is also applicable for solid substrates. Taylor and Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.788720

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Synthesis of β-Aryl-β-sulfanyl Ketones by a Sequential
One-Pot Reaction Using KF/Al2O3 in Glycerol
Gelson Perin a , Katiúcia Mesquita a , Tainara P. Calheiro a , Márcio S. Silva a , Eder J.
Lenardão a , Diego Alves a & Raquel G. Jacob a
a Laboratory of Clean Organic Synthesis (LASOL) , Federal University of Pelotas , Pelotas ,
RS , Brazil
Accepted author version posted online: 15 Aug 2013.
To cite this article: Synthetic Communications (2013): Synthesis of β-Aryl-β-sulfanyl Ketones by a Sequential One-Pot
Reaction Using KF/Al2O3 in Glycerol, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.788720
To link to this article: http://dx.doi.org/10.1080/00397911.2013.788720
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SYNTHESIS OF β-ARYL-β-SULFANYL KETONES BY A SEQUENTIAL ONE-
POT REACTION USING KF/Al2O3 IN GLYCEROL
Gelson Perin1, Katiúcia Mesquita1, Tainara P. Calheiro1, Márcio S. Silva1, Eder J.
Lenardão1, Diego Alves1, Raquel G. Jacob1
1Laboratory of Clean Organic Synthesis (LASOL), Federal University of Pelotas|,
Pelotas, RS, Brazil
Abstract
The title compounds were synthesized by a sequential one-pot reaction of aryl aldehydes,
aryl-methyl ketones and thiols promoted by KF/Al2O3. This methodology affords a large
number of ?-aryl-?-sulfanyl ketone derivatives from aliphatic and aromatic thiols in good
yields and is applicable also for solid substrates.
[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.]
Keywords: sulfanyl ketones, Glycerol, one-pot reaction, KF/Al2O3, green chemistry
INTRODUCTION
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Conjugate addition reactions of sulfur nucleophiles to electron-deficient olefins are one
of the most important synthetic tools for the generation of carbon-sulfur bonds.
Organosulfur groups are valuable intermediates in organic synthesis[1] and this structural
unit is frequently present in naturally occurring and biologically active compounds.[2]
Particularly, the synthetic utility of β-sulfanyl ketones has been demonstrated in the
syntheses of naturally occurring spiroketal pheromones,[3] alkene protective group,[4] and
as versatile homoenolate equivalents.[5] More recently, these functionalized ketones were
found to have ant iproliferative activity of breast cancer cell lines (Figure 1).[6] Thus, the
development of efficient and new methodologies for synthesizing this class of
compounds has been emerged in organic synthesis.
Traditional methods for the formation of C-S bonds via thia-Michael addition commonly
make use of the already available α,β-unsaturated ketones. The 1,4-addition of thiols can
be catalyzed by alkali metal alkoxides[7] or Lewis acids.[8] Solid catalysts, such as acid
adsorbed on silica gel,[9] zeolites,[10] natural and synthetic phosphates,[11] montmorillonite
clays,[12] neutral alumina[13] and base supported on alumina[14] have been used to perform
the 1,4-addition of thiols to a series of electron-poor alkenes. Besides, the use of non-
volatile and non-toxic solvents, such as water[15] and ionic liquids[16] to perform the
Michael addition was also described. To the best of our knowledge, there are only a few
methods to obtained β-aryl-β-sulfanyl ketones by direct one-pot Claisen-Schmidt
condensation of aryl aldehydes with acetophenones and subsequent addition of thiols.[17]
Besides scarce, these methods have some disadvantages, such as, cumbersome workup,
low substrate scope and yield and, in some cases, they are not suitable to solid substrates.
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Therefore, the development of efficient and practical methods for the synthesis of β-
sulfanyl ketones is attractive.
On the other hand, in recent years glycerol has emerged as a eco-friendly and secure
solvent for organic reactions,[18] including Pd-catalyzed Heck and Suzuki cross-couplings,
Cu-catalyzed cross-coupling of diaryl diselenides with aryl boronic acids, base- and acid-
promoted condensations, catalytic hydrogenation and asymmetrical reduction.[19] The low
toxicity, biodegradability, high boiling point and polarity, and ready availability from
biomass are some of the peculiar properties of glycerol.[20] More recently, the
electrophilic activation of carbonyl compounds in glycerol-promoted reactions, allowing
the elimination of the use of acidic catalysts was demonstrated.[21]
Because our interest in new uses for glycerol, and in continuation on our studies toward
the development of new and cleaner methods for the synthesis of organochalcogenium
compounds, we present here a sequential, one-pot procedure for the synthesis of β-
sulfanyl ketones using glycerol as solvent and KF/alumina as catalytic system (Scheme
1).
RESULTS AND DISCUSSION
Our initial studies were focused on the development of an optimum set of reaction
conditions to afford the intermediate chalcone 3a (Table 1). Initially, we reacted
acetophenone 1a (1.0 mmol) with benzaldehyde 2a (1.0 mmol) using KF/Al2O3 50%
(0.07g) as base system in glycerol (5.0 mL) at room temperature. Under these conditions,
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no product was observed. To our satisfaction, increasing the temperature to 90 °C, the
reaction proceeds smoothly and the desired product 3a was obtained in 78% yield (Table
1, entry 3). In another experiment, it was observed that using 1.2 mmol of 2a, the product
3a was obtained in 90% yield (Table 1, entry 4). When others solvents were used, such as
PEG-400, ethanol, THF and DMF, moderated to good yields of 3a were obtained (Table
1; entries 5-8).
The influence of the amount of thiol 4a was the next variable studied, aiming to obtain
via one pot procedure the 1,3-diphenyl-3-(phenylsulfanyl)propan-1-one 5a (Scheme 1).
We observed that the use of 1.0 or 1.5 mmol of benzenethiol 4a gives the desired product
5a in moderated yield (Table 1, entries 9 and 10). Fortunately, when the amount of thiol
4a was increased to 2.0 mmol, 5a was obtained in 78% yield (Table 1, entry 11).
In an optimized reaction, a mixture of acetophenone 1a (1.0 mmol), benzaldehyde 2a (1.2
mmol) and KF/Al2O3 50% (0,07g) in glycerol (5.0 mL) was stirred for 4 h at 90 °C under
N2 atmosphere. After that, benzenethiol 4a (2.0 mmol) was added and the stirring was
maintained for additional 3 h.
Using these reaction conditions, 1,3-diphenyl-3-(phenylsulfanyl)propan-1-one 5a was
obtained in 78% yield. The possibility of reuse of the KF/Al2O3/glycerol system was also
investigated. For this pourpose, after the time indicated in Table 1, the reaction was
extracted with a mixture of hexane/AcOEt 95:5 (3× 2.0 mL) and the remaining glycerol
phase was directly reused in a new reaction. Unfortunately, it was observed an
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incomplete consume of starting acetophenone and benzaldehyde, giving only 45% yield
of the intermediate chalcone 3a.
To extend the scope of our methodology, the possibility of performing the reaction with
other aryl-methyl ketones, aryl aldehydes and thiols was investigated and, in most cases,
the reaction proceeded smoothly to give the respective β-aryl-β-sulfanyl ketones 5b-j in
good yields.
It was observed that the presence of electron-withdrawing and electron-donating groups
in the aryl thiols caused a slightly decrease in the yield of β-sulfanyl ketones 5 (Table 2,
entries 2-5). Thus, when p-chloro and p-bromo benzenethiol were added to the previous
formed chalcone 3a, the respective β-phenyl-β-(4-halophenylthio) ketones 5c and 5d
were obtained after 7 h in 60 and 63% yield respectively (entries 3 and 4), while o-chloro
benzenethiol 4e gave 5e in a similar yield after 8 h (Table 2, entry 5). The presence of
electron-donating group adversely affect the reaction time, being necessary 14 h to obtain
the functionalized ketone 5b, derived from p-methoxy benzenethiol 4b (Table 2, entry 2
). In contrast, no apparent effect was observed when substituted ketones 1b-c and
anisaldehyde 2b were used (Table 2, entries 8-10). Good results were obtained also using
dodecanethiol 4f, which reacted smoothly to afford 5f in 64% yield after 7 h (Table 2,
entry 6).
To our satisfaction, through of our methodology it is possible to obtain the final products
starting from both, liquid and solid substrates. Thus, for example, the reaction of
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acetophenone 1a, benzaldehyde 2a and β-naphthyl mercaptan 4g furnished the desired
product 5g exclusively in 57% yield after 14 h (Table 2, entry 7).
In summary, a sequential one-pot reaction of aryl aldehydes, aryl-methyl ketones and
thiols to synthesize β-aryl-β-sulfanyl ketones using KF/Al2O3 was developed. A range of
substituted β-sulfanyl ketones was obtained in good yields starting from solid and liquid
reagents and using glycerol as a green, environmentally friend solvent.
EXPERIMENTAL
General Remarks
The reactions were monitored by TLC carried out on Merck silica gel (60 F254) by using
UV light as visualizant agent and 5% vanillin in 10% H2SO4 and heat as developing
agents. The 1H and 13C NMR spectra of CDCl3 solutions were recorded with a 500 MHz
spectrometer (Bruker DRX), as noted. Chemical shifts are expressed as parts per million
(ppm) downfield from tetramethylsilane as an internal standard. Coupling constants (J)
are reported in Hertz. Low Resolution Mass Spectra (LRMS, EI) were measured on a
Shimadzu GCMS-QP2010-Plus mass spectrometer. High-Resolution Mass Spectra: HR-
ESI-MS were obtained on a LTQ Orbitrap Discovery mass spectrometer (Thermo Fisher
Scientific).
General Procedure For The Directly Synthesis Of β-Aryl-β-Sulfanyl Ketones22
To a round-bottomed flask containing the aryl-methyl ketone 1a (0.120 g, 1.0 mmol),
benzaldehyde 2a (0.127 g, 1.2 mmol) and KF/Al2O3 50% (0.07 g), was added glycerol
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(5.0 mL). The reaction mixture was allowed to stir at 90 °C for 4 hours under N2
atmosphere. After that, it was added the thiol 4d (0.376, 2.0 mmol) and the reaction
progress was followed by TLC. After the time indicated in Table 2, the mixture was
cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water
(3x 10 mL). The organic phase was dried over MgSO4 and concentrated under vacuum.
The residue was purified by flash chromatography on silica gel using ethyl
acetate/hexane as the eluent, yielding 1,3-diphenyl-3-(4-bromophenylsulfanyl)propan-1-
one 5d (0.249 g, 63%). Yellow solid, mp 106-107 °C; IR (νmax, cm-1): 1674 (C=O). 1H
NMR (500 MHz, CDCl3): δ 7.88 (d, J = 8.2 Hz, 2H); 7.54 (t, J = 7.4 Hz, 1H); 7.42 (t, J =
7.6 Hz, 2H); 7.31-7.33 (m, 2H); 7.25 (t, J = 7.6 Hz, 2H); 7.17-7.20 (m, 1H); 7.14 (d, J =
8.6 Hz, 2H); 4.92 (dd, J = 7.8 and 6.6 Hz, 1H); 3.62 (dd, J = 17.2 and 7.8 Hz, 1H); 3.56
(dd, J = 17.2 and 6.6 Hz, 1H). 13C NMR (125 MHz, CDCl3); δ (ppm): 196.6, 140.9,
136.6, 134.2, 133.3, 133.2, 131.9, 128.6, 128.5, 128.0, 127.7, 127.5, 121.8, 48.3, 44.5.
MS (relative intensity) m/z: 396 (2), 207 (9), 105 (100), 77 (26). HRMS (ESI): m/z calcd.
for C21H17BrOS [M + H]+: 397.0262; found: 397.0266.
ACKNOWLEDGEMENTS
The authors are grateful to FAPERGS and CNPq (PRONEX 10/0005-1, PRONEM
11/2026-4 and PqG 11/0719-3), CAPES and FINEP for the financial support.
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glycerol as recyclable solvent. Tetrahedron Lett. 2010, 51, 4354; (b) Radatz, C. S.; Silva,
R. B.; Perin, G.; Lenardão, E. J.; Jacob, R. J.; Alves, D. Catalyst-free synthesis of
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benzodiazepines and benzimidazoles using glycerol as recyclable solvent. Tetrahedron
Lett. 2011, 52, 4132.
22. Supporting Information: Full experimental detail 1H and 13C NMR spectra. This
material can be found via the “Supplementary Content” section of this article’s webpage.
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Table 1. Optimization in the syntheses of chalcone 3a and β-phenyl-β-sulfanyl ketone
5aa
Entry
2a (mmol) 4a (mmol)
Solvent
Temperature (oC) Product
(Yield, %)b
3a (42)
1
1.0
1.0
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
-
glycerol
glycerol
glycerol
glycerol
PEG-400
ethanol
THF
50
2
-
75
3a (53)
3a (78)
3a (90)
3a (70)
3a (60)
3a (30)
3a (61)
5a (59)
5a (65)
5a (78)
3
-
90
4
-
90
5
-
90
6
-
reflux
reflux
90
7
-
8
-
DMF
9
1.0
1.5
2.0
glycerol
glycerol
glycerol
90
10
90
11
90
aReactions performed in the presence of 1a (1.0 mmol), 2a, KF/Al2O3 (0.07 g), and
solvent (5.0 mL) under N2 atmosphere for 4 h to obtain 3a and additional 3 h to 5a.
bYields are given for isolated product 3a or 5a.
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Table 2. Scope and generality of the synthesis of the β-aryl-β-sulfanyl ketones 5a-j.
Entr Aryl-Methyl Aldehyde 2
Thiol 4
Product 5
Tim Yiel
y
Ketone 1
e (h)
d
(%)a
78
O
O
1
3
SH
H
H
O
S
4a
1a
2a
5a
OCH3
O
O
2
10
65
CH3O
SH
O
S
4b
1a
2a
5b
Cl
Br
O
2a
O
O
3
4
5
3
3
5
60
63
60
Cl
Br
SH
H
H
H
O
S
4c
4d
1a
5c
O
SH
O
S
1a
2a
5d
Cl
O
Cl
O
SH
O
S
2a
1a
4e
5e
O
SC12H25
O
O
C12H25SH
6
7
3
64
57
4f
H
H
1a
2a
O
5f
SH
O
10
O
S
4g
1a
2a
5g
O
O
8
3
61
SH
H
O
S
4a
2a
1b
CH3O
5h
CH3O
CH3
O
O
9
7
55
57
CH3
SH
H
O
S
4h
1b
2b
CH3O
CH3O
CH3O
OCH3
5i
O
O
10
12
SH
H
O
S
4a
1c
2a
HO
HO
5j
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aReactions performed in the presence of 1 (1.0 mmol), 2, KF/Al2O3 (0.07 g), and solvent
(5.0 mL) under N2 atmosphere for 4 h to obtain 3.
bYields are given for isolated products.
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Scheme 1.
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Figure 1. Drugs containing β-sulfanyl ketone unit in their structure
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