An efficient approach for the synthesis of novel methyl sulfones in acetic acid medium and evaluation of antimicrobial activity

Article abstract of DOI:10.3906/KIM-2003-10

A series of nine methyl sulphones (3a-3i) starting from the aldehydes (1a-1i) were synthesized in two consecutive steps. In the first step, preparation of allyl alcohols (2a-2i) from their corresponding aldehydes by the reaction of sodium borohydride in methanol at room temperature is reported. Finally, methyl sulphones are synthesized by condensing sodium methyl sulfinates with allyl alcohols in the presence of BF3.Et2O in acetic acid medium at room temperature for about 2-3 h. The reaction conditions are simple, yields are high (85%-95%), and the products were obtained with good purity. All the synthesized compounds were characterized by their ¹H, ¹³C NMR, and mass spectral analysis. All the title compounds were screened for antimicrobial activity. Among the compounds tested, the compound 3f has inhibited both Gram positive and Gram negative bacteria effectively and compound 3i has shown potent antifungal activity. These promising components may help to develop more potent drugs in the near future for the treatment of bacterial and fungal infections.

Full text of DOI:10.3906/KIM-2003-10

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Turk J Chem
Turkish Journal of Chemistry
(2020) 44: 1386-1394
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-2003-10
Research Article
An efficient approach for the synthesis of novel methyl sulfones in acetic acid medium
and evaluation of antimicrobial activity
Gollapudi RAVI KUMAR1,2, Chandra Rao DASIREDDY3,4,
Ravi VARALA5, Vijay KOTRA6, Hari Babu BOLLIKOLLA1,*
1Department of Chemistry, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India
2Department of Chemistry, Government Degree College, Husnabad, Telangana, India
3CSIR-Indian Institute of Chemical Technology (IICT), Hydearabad, Telangana, India
4Retention Chromatography & Chemicals Pvt. Ltd., Secunderabad, Telangana, India
5Scrips Pharma, Hyderabad, Telangana, India
6Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Quest International University Perak, Ipoh, Negeri Perak, Malaysia
Received: 16.03.2020
Accepted/Published Online: 04.08.2020
Final Version: 26.10.2020
Abstract: A series of nine methyl sulphones (3a–3i) starting from the aldehydes (1a–1i) were synthesized in two consecutive steps.
In the first step, preparation of allyl alcohols (2a–2i) from their corresponding aldehydes by the reaction of sodium borohydride in
methanol at room temperature is reported. Finally, methyl sulphones are synthesized by condensing sodium methyl sulfinates with allyl
alcohols in the presence of BF3.Et2O in acetic acid medium at room temperature for about 2–3 h. e reaction conditions are simple,
yields are high (85%–95%), and the products were obtained with good purity. All the synthesized compounds were characterized by
their 1H, 13C NMR, and mass spectral analysis. All the title compounds were screened for antimicrobial activity. Among the compounds
tested, the compound 3f has inhibited both Gram positive and Gram negative bacteria effectively and compound 3i has shown potent
antifungal activity. ese promising components may help to develop more potent drugs in the near future for the treatment of bacterial
and fungal infections.
Keywords: BF3.OEt2, allyl alcohols, methyl sulphones, antibacterial, antifungal
1. Introduction
e alcohol functional group is one of the more important groups for the synthesis of many drugs which are being used
widely throughout the world [1–5]. As the alcohol functional group is not a good leaving group, it becomes the main
obstacle for producing versatile novel drugs in organic synthesis. e nucleophilic substitution in the alcohol group is very
difficult under mild conditions [6–12]. For the replacement of the OH group, one has to convert this alcohol group into
a Cl group which is a better leaving group. In the previous studies, it was revealed that the conversion of the OH group
into a mesylate group took place [13]. Direct conversion of alcohols into ethers, diaryl alkanes, and sulphonamides was
successful [14–16]. So, we have decided to optimize the convenient route for the conversion of alcohols into sulfones under
mild conditions. Earlier works revealed that direct conversion of alcohols into sulfones using bronsted acids like formic
acids, acetic acid, and HCl [17–20], could be generated from sodium sulfide, sodium sulfinates, sulfonic acids, potassium
meta bisulfite, sulfonyl chloride, and arenesulfonyl cyanide [21–27]. Among these reagents, sodium sulfinate is the best
reagent due to ease of handling, and from a stability point of view.
Reddy and co-workers [28–29] reported that the reaction between p-toluenesulfonyl cyanide, and allylic alcohols leads
to the formation of p-toluenesulfonyl cyanide, in the presence of diisopropylethylamine, later the adduct gets converted
into a sulfonyl rearrangement product. Direct substitution of the allylic amine with sodium sulfinates in the presence
of boronic acid [30] and the use of FeCl3 as a catalyst and chlorotrimethylsilane as an additive [31], were also reported.
Direct substitution of alcohols in the presence of boron trifluoride etherate with sodium sulfinates was prepared in
which dichloromethane as a solvent was used under optimized parameters at 50 °C with 82% yield [32]. Oxidation of the
methylthio derivative to the corresponding sulfones using m-CPBA was reported by Pujol et al [33]. Cu-catalyzed aerobic
oxidation to synthesize from aryl halides and DMSO is described by Yuan et al. [34]. Fe(OH)3-catalyzed synthesis of aryl
* Correspondence: dr.b.haribabu@gmail.com
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RAVI KUMAR et al. / Turk J Chem
sulfones using aryl sulfonyl chloride with arenes is also reported [35]. e L-Proline sodium salt/CuI-mediated coupling
reaction of aryl halides with sulfinic acids is also documented by Ma and Zhu [36]. Yuan et al. have recently synthesized
aryl ethyl sulfones from sodium sulfinate and di-tert-butyl peroxide in the H O medium [37]. Very recently, an eco-
friendly approach to the construction of aryl methyl sulfone from SO and met2hyl reagents is exemplified by Jiang et al.
[38]. An excellent review on sulfones was presented very recently by Tr2ost et al. [39]. In view of this and as an extension to
our search for novel antimicrobial agents [40–44], the authors herein made an attempt to synthesize the titled sulfones and
screen their antimicrobial properties.
2. Present work
We synthesized allyl alcohols, which were derived from respective aldehydes by reduction with sodium borohydride.
A total of 9 aryl methyl sulfones were synthesized using BF3.OEt2 as a catalyst and AcOH as a solvent in the present
methodology shown in Scheme 1.
Huang et al. [32] reported on the synthesis of sulfinates using BF3.OEt2 in CH2Cl2 solvent medium optimized at 45–50
°C moderate temperatures via the more favourable SN1 mechanism through the conversion of sodium p-toluenesulfinate
into corresponding nucleophile sulfinic acid, i.e. O-attack. Surprisingly, when acetic acid was used as a solvent, we could
observe the formation of sulfones possibly via S-attack following the SN2 mechanism, thereby indicating the significant
role of solvent in product formation. e aim was achieved with various benzyl alcohols and sodium methyl sulfinates.
Shorter reaction times and direct isolation of products were the added advantages in using the previous method.
Baidya et al. [45] explained about the thermal stability of the sulfones over the sulfinates. According to their studies,
PhSO2− reacts with highly stabilized benzhydrylium ions to give sulfone derivatives exclusively, but in the case of highly
reactive benzhydrylium ions it gives mixtures of sulfinates Ar2CH-OS(O)Ph and sulfones Ar2CH-SO Ph; the latter
rearranges to the thermodynamically more stable sulfones through an ionization recombination sequence.2
In the given Scheme 2, the reaction mechanism was explained schematically. Using acetic acid as a solvent instead
of dichloromethane favors reaction at room temperature. Initially, BF3.OEt2 activates the hydroxyl group to become
protonated and subsequent elimination of water molecule occurs. As a result carbonium ion formation took place at room
temperature itself. e formed carbonium ion was attacked by nucleophile of the sodium methyl sulfinates leading to the
formation of sulfinate derivatives. Later, the product rearranged into thermodynamically more stable sulfones.
We chose the benzyl alcohol, and sodium methyl sulfinates as substrates for optimization of the reaction initially in
the presence of BF3.OEt2.e authors carried out a couple of reactions by changing the concentration of BF .OEt2, varying
from 0.2 equivalents to 2.0 equivalents. Finally, we could achieve the yields of the target molecule variables f3rom 15 to 92%
as shown in Table 1.
O
BF3.OEt2
Solvent
S
OH
S
O
O
O Na
3
2
1
Scheme 1: Synthesis of aryl methylsulfones.
R
R
R
H+
BF3.OEt2
OH
OH
OH2
BF3.OEt2
R
R
O
Na O
S
R
O
S
O
S
O
O
Scheme 2: Possible reaction mechanism for conversion of alcohol into sulfones.
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RAVI KUMAR et al. / Turk J Chem
Table 1. Reaction conditions for optimization.
Entry
BF3.Et2O
Solvent
T °C
Time (h) Yield (%)
1
2
3
4
5
6
7
8
0.2
1.0
1.4
1.6
1.8
2.0
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
CH2Cl2
50
28
28
28
28
28
30
28
28
28
28
28
28
28
28
28
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
40
80
82
86
92
90
25
20
37
15
39
40
42
25
38
30
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
DMSO
THF
CHCl3
9
10
11
12
13
14
15
16
Cyclohexane
CH3NO2
C2H5NO2
1,4-Dioxane
CH3CN
DMF
Acetone
e highest yields of the compound were obtained with 1.8 equivalents of BF .OEt2. A couple of reactions were
conducted with 1.8 equivalents of BF3.OEt2 at various time periods ranging from 1 to 83h. During the time period from 1 to
3 h, the yields found increased, and when the time period was prolonged from 3 to 8 h, the yields decreased. is reaction
conversion was tremendously effective on the solvent which was used. For this reason, several trial reactions were carried
out with both the polar solvents and nonpolar solvents. Lesser yields were reported with the nonpolar solvent cyclohexane
(Table 1, entry 10). Next to cyclohexane, polar solvents like DMSO, and THF gave the yields of 25%, and 20% respectively.
With the exception of acetic acid other solvents got the yields of the desired product below 50%. e best yields ranging
from 80% to 92% (Table 1, entries 2–6) were obtained with the acetic acid. So, finally, we have concluded that the reaction
is more favorable with the protic solvents.
e above optimized reaction conditions were verified and or generalized with structurally different types of alcohols.
e obtained yields of desired products were mentioned in Table 2, entries 1–9.
e best yield (95%) of the desired molecule was obtained with the nitro alcohol derivatives (3i), under the optimized
reaction condition. e lowest yields were obtained with the electron donating groups, which existed in the substrates.
Electron withdrawing groups, which were present in the substrate molecules favor the conversion with excellent yields.
e alcohol 1a having three donation groups present in the ortho and para position gave less yield (Table 2, entry 1). Due
to the presence of orthosteric effect, alcohol derivatives 3a and 3e gave less yields (Table 2, entries 1, 5). e fewer number
of donating groups present in the alcohol substrates increase the yields from 85% to 88%. e phenyl ring has a lesser
withdrawing effect than the nitro group results and yields almost the highest yields.
3. Biological activity
All the synthesized compounds were screened for antimicrobial activity and results were depicted in Table 3. Among
the screened compounds (3a–3i), compound 3f with dimethoxy, hydroxyl benzyl group showed the highest inhibition
zone followed by compounds 3a, 3c, and 3h. Further, the compound 3i was found to be effective on fungal strains. e
remaining compounds showed moderate activity.
4. Conclusion
is method is a modified method for methyl sulfones and reaction yields of 85% to 95% were obtained. In this method,
the solvent acetic acid was used, which is inexpensive when compared with the solvent dichloromethane solvent, and this
reaction is carried out at room temperature. We have applied this method for the synthesis of 9 compounds of which 7 are
novel (3a–3i).
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RAVI KUMAR et al. / Turk J Chem
Table 2. Sulfonation of various alcohols with sodium methyl sulfinates.
Entry
Compound structure
Number
3a
Yield (%)a
O
O
S
O
O
1
85
O
O
O
S
2
3
O
3b
3c
88
90
OH
OH
O
OH
O
S
O
O
O
S
4
5
3d
3e
91
88
O
O
O
S
O
O
OH
O
O
S
O
O
6
7
3f
86
88
O
S
O
S
O
3g
O
O
S
O
HO
O
S
O
8
9
3h
3i
92
95
O
S
O
O2
N
aYields refer to pure products afer column chromatography
Reaction conditions: 1a–1i (1.96 μmol), 2 (1.96 μmol), BF3.OEt2 (3.5 mL), Acetic acid
(3 mL), at rt for 3h.
e compounds bearing dimethoxy, hydroxyl benzyl group have shown prominent antibacterial activity when
compared to compounds without these groups. It was also confirmed that the compounds bearing nitro group have shown
prominent antifungal activity when compared to other compounds. Further investigation in this area may help to create
more potent drugs for the treatment of bacterial and fungal infections.
1389