A Facile and Practical One-Pot Synthesis of 2-[(Methylselenyl)Methyl]Benzoic Acid

Full text of DOI:10.1080/00304948.2019.1609811

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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A Facile and Practical One-Pot Synthesis of 2-
[(Methylselenyl)Methyl]Benzoic Acid
Divyaraj Puthran, Boja Poojary & Nikil Purushotham
To cite this article: Divyaraj Puthran, Boja Poojary & Nikil Purushotham (2019): A Facile and
Practical One-Pot Synthesis of 2-[(Methylselenyl)Methyl]Benzoic Acid, Organic Preparations and
Procedures International, DOI: 10.1080/00304948.2019.1609811
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Organic Preparations and Procedures International, 0:1–6, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1609811
OPPI BRIEF
A Facile and Practical One-Pot Synthesis of
2-[(Methylselenyl)Methyl]Benzoic Acid
Divyaraj Puthran,1,2 Boja Poojary,1 and Nikil Purushotham1
1Department of Studies in Chemistry, Mangalore University,
Mangalagangothri, Karnataka-574199, India
2Solara Active Pharma Sciences, No. 120 A&B, Industrial Area, Baikampady,
New Mangalore, Karnataka-575011, India
The structures of organo-selenium compounds are similar to those of organo-sulfur
compounds, but they vary drastically in some of their properties. Because of the toxicity
and enormously unpleasant odor of organo-selenium compounds, they have not been as
well explored as could be justified. For example, organo-selenium compounds are
reported as active antibacterial, antiviral, antifungal, anti-parastitic, anti-inflammatory
and antihistamine agents.1
Recently, Liotta and his co-workers reported the use of phenyl selenide anion as
the key reagent for the conversion of lactones to x-vinylcarboxylic acids.2 The choice
of phenyl selenide anion as the ring-opening reagent seemed attractive for two reasons.
First, a simple lactone possesses two sites which are potentially reactive to nucleo-
philes, the carbonyl carbon and the carbinolic carbon. Based on hard-soft acid-base
theory, a soft nucleophile, such as phenyl selenide anion, should exhibit a preference
for SN2-type attack at the carbinolic carbon and thus generate x-vinylcarboxylic acids.
An ample variety of aromatic acids have been used as key intermediates for the
synthesis of 1,3,4-oxadiazole rings, which occupy a key place in medicinal chemistry
due to their significant biological properties, including antimicrobial,3 antituberculosis4
and anticancer activity.5 It is well-known that the combination of two or more types of
heterocycles into one molecule may provide increased bioactivities due to the structural
synergistic effect. The synthesis of 1,3,4-oxadiazoles bearing selenium requires aro-
matic acids containing selenium.6 These acids are difficult to synthesize. In the course
of our current research, we developed a new process for the preparation of an aromatic
acid containing selenium, namely 2-[(methylselenyl)methyl]benzoic acid, by the SN2-
type cleavage of 2-benzofuran-1(3H)-one with methyl selenide anion generated from
dimethyl diselenide. We observed good yield and purity.
Only two methods7,8 are reported for the synthesis of 2-[(methylselenyl)methyl]-
benzoic acid. But both the methods involved multistep protocols with expensive starting
Received July 19, 2018; in final form December 10, 2018.
Address correspondence to Boja Poojary, Department of Studies in Chemistry, Mangalore
University, Mangalagangothri, Karnataka-574199, India. E-mail: bojapoojary@gmail.com
1

2
Poojary et al.
Table 1
Optimization of Reaction Conditions
Percentage
Yield
HPLC
Trial
Reagent
NaH
Solvent
Yield (%)
obtained (g)
Purity (%)
1
2
3
4
5
6
7
DMFa
18.96
28.80
24.12
29.27
34.66
50.13
55.41
08.09
12.30
10.30
12.50
15.49
21.41
23.70
–
Na metal
LiAlH4
NaBH4
NaBH4
NaBH4
NaBH4
NaOH
THFb
–
THFc
–
Methanold
Ethanole
THFf
–
–
–
H2O þ THFg
99.962
a-g
See Experimental Section, optimization of reaction conditions, 0.18 mole scale.
materials. Therefore, we explored a simple, effective and optimized process for its syn-
thesis. Model reactions were conducted using dimethyl diselenide and different bases
and solvents under mild conditions. The results of these studies are summarized in
Table 1.
In the first method, dimethyl diselenide was treated with sodium hydride in dime-
thylformamide9 to generate the methyl selenide anion which was then treated with 2-
benzofuran-1(3H)-one to get methyl selenyl benzoic acid. But the sodium hydride used
here requires caution, recovery of dimethyl formamide was difficult and the yield was
also low. The reaction was repeated by replacing sodium hydride with sodium metal.10
Though the yield was improved, the impurity profile remained the same. Moreover,
sodium metal is difficult to handle, especially in scaled-up reactions. Sodium metal was
then replaced with lithium aluminium hydride. But the process gave even more impur-
ities and the yield was further reduced. The reaction conditions were further modified
by employing sodium borohydride11 in solvents such as methanol, ethanol and THF.12
The optimum conditions used 1.5 mole-equiv of NaBH4 and 0.5 mole-equiv of NaOH in
THF-water medium (Scheme 1). A plausible mechanism is shown in Scheme 2.
Previous reports on preparation of the title compound suffer from several disadvan-
tages in chemical handling difficulties, high cost, multiple steps or complications in
scale-up. The present method circumvents all these disadvantages. In conclusion, we
have reported on a convenient synthesis of the title compound under mild conditions.
Compared to previous methods, the preparation is simple to perform, gives good yields
and produces pure product. Future work may explore the scope of this reaction. We
hope that the process will aid in the wider exploration of selenium-based organic frame-
works for new pharmacophores.
Experimental Section
Solvents and reagents were obtained from commercial sources and used without purifica-
tion. Recrystallization was used for purification instead of column chromatography.
Melting points were determined by the open capillary method and were uncorrected. IR
spectra were obtained in KBr discs on a Shimadzu FT-IR 157 spectrometer. NMR spectra
were recorded on a Bruker WH-200 (400 MHz) in DMSO-d6 as solvent and TMS as an
internal standard. Chemical shifts and coupling constants were expressed as ppm (d) and

2-[(Methylselenyl)Methyl]Benzoic Acid
3
Scheme 1. The previous and present methods for the synthesis of the title compound.
Scheme 2. Optimized synthesis of 2-[(methylselenyl)methyl]benzoic acid.
Hz (J) respectively. Mass spectra were recorded on a Jeolsx 102/Da-600 mass spectrom-
eter/data system using argon/xenon (6 kV, 10mA) as the FAB gas. The accelerating volt-
age was 10 kV and spectra were recorded at room temperature. The elemental analyses
(CHN) were performed using VARIO EL-III (Elemental Analysis system GmBH). The
progress of the reactions was monitored by TLC on pre-coated silica gel G plates. All the
spectral data of newly synthesized compounds were consistent with proposed structures.
The purity of the samples was analysed by Agilent HPLC with UV detector. A complete
protocol for the HPLC analysis was submitted for review by the editors and is available
from the corresponding author upon request. Safety Notes:13,14 Throughout experiments,
workers must use protective equipment, to include safety goggles, chemical splash eye-
wear, a half face respirator with organic vapor cartridge, safety shoes, nitrile hand gloves,
disposable head caps, apron, laboratory fume hoods containing 50% sodium hydroxide
solution, local exhaust ventilation, fire extinguisher, smoke/heat detector, a spill control
kit containing sand, sodium bicarbonate, waste pan and broom.
Optimization of Reaction Conditions for 0.18 Mole Each of Furanone and
Dimethyl Diselenide (Keyed to Notes a-g in Table 1)
a: 75 mL of DMF and 20.56 g (4.6 mole-equiv) of 60% NaH at room temperature.
Product was isolated by adding 250 mL of ice cold water, followed by adjusting the pH
to 3-4 by acetic acid and extraction with 75 mL of ethyl acetate.

4
Poojary et al.
Scheme 3. Plausible mechanism for the formation of 2-[(methylselenyl)methyl]benzoic acid.
b: 150 mL of THF and 8.57 g (2 mole-equiv) of Na metal at room temperature. Reaction
mixture was completely distilled under reduced pressure and resulting solid was slowly
added to 250 mL water, adjusted the pH to 3-4 by acetic acid and extracted with 75 mL
of ethyl acetate.
c: 150 mL of THF and 8.10 g (2 mole-equiv) of LiAlH4 at room temperature. Reaction
mixture was completely distilled under reduced pressure and resulting solid was slowly
added to 250 mL water, adjusted the pH to 3-4 by acetic acid and extracted with
3 ꢀ 75 mL of ethyl acetate.
d: 150 mL of methanol and 14.10 g (2 mole-equiv) of NaBH4 at room temperature.
Product was isolated by adding 250 mL of ice cold water, followed by adjusting the pH
to 3-4 by acetic acid and extraction with 3 ꢀ 75 mL of ethyl acetate.
e: 150 mL of ethanol and 14.10 g (2 mole-equiv) of NaBH4 at room temperature.
Product was isolated by adding 250 mL of ice cold water, followed by adjusting the pH
to 3-4 by acetic acid and extraction with 3 ꢀ 75 mL of ethyl acetate.
f: 125 mL of THF and 14.10 g (2 mole-equiv) of NaBH4 at room temperature. Product
was isolated by adding 250 mL of ice cold water, followed by adjusting the pH to 3-4
by acetic acid and extraction with 3 ꢀ 75 mL of ethyl acetate.
g: 125 mL of THF, 6.25 mL of H2O, 3.72 g (0.5 mole-equiv) NaOH and 10.57 g
(1.5 mole-equiv) of NaBH4 at 45-50 ꢁC. Product was isolated by adding 250 mL of ice
cold water, followed by adjusting the pH to 3-4 by acetic acid and extraction with
162.5 mL of ethyl acetate at 60-65 ꢁC.
Full Optimized Procedure for the Synthesis of 2-[(methylselenyl)methyl]benzoic Acid
In a 500 mL 3 necked round bottom flask, 125 mL of THF was taken and 35.2 g (0.18 mole)
of dimethyl diselenide ((Caution! See Safety Notes above). All workers must be thoroughly
instructed in working with selenium compounds prior to experiments.) under a nitrogen
atmosphere. The reaction mass was chilled to 5-10 ꢁC. Then, 10.67 g (0.29 moles) of sodium
borohydride was added in 4 equal lots during one hour and was stirred for 3-4 hours. Color
changes were observed from dark yellow to pale yellow along with the release of yellow
vapors of methyl selenol (Caution! See Safety Notes above). The reaction mass was brought
to room temperature, 3.71 g (0.093 mole) of sodium hydroxide dissolved in 6.0 mL of water
was added and stirred for 15 minutes. To this reaction mass, 25 g (0.18 mole) of 2-benzo-
furan-1(3H)-one was added in 4 equal lots in one hour and stirred for 12-16 hours with TLC

2-[(Methylselenyl)Methyl]Benzoic Acid
5
monitoring (hexane:EtOAc, 3:2 (v/v)) followed by heating up to 40-45ꢁC for an hour. Then,
THF was distilled out to 62 mL residual volume under reduced pressure. The resulting reac-
tion mass was cooled to room temperature and then to 0-5 ꢁC, followed by the addition of
250 mL of water and stirring for 30 minutes. The pH of the reaction mass was adjusted to
3.0-4.0 using acetic acid with the release of methyl selenol vapor (Caution! See Safety
Notes above). to get the white precipitate of the product. The reaction mass was filtered,
washed with water and drained.
In a three-necked round bottom flask, the wet crude material was taken and dis-
solved in 162.5 mL of ethyl acetate. The resulting solution was heated up to 65-68 ꢁC
and treated with 12.5 mL of 1% sodium bicarbonate solution with stirring to remove
polar impurities. The organic layer was separated and washed with 125 mL of water.
The aqueous layer was extracted with half the volume of ethyl acetate at 65-68 ꢁC. The
combined organic layers were decolorized using 1.25 g of 5% DCW charcoal at 65-
ꢁ
R
R
V
V
68 C and passed through a Hyflo Super-Cel bed (prepared by making a slurry of
R
V
R
V
3 g of the Hyflo Super-Cel with 50 mL of ethyl acetate followed by filtration over
Whatman filter paper). Ethyl acetate was distilled out to 75 mL residual volume under
vacuum distillation. Then, the reaction mass was chilled to 0-5 ꢁC and maintained at
this temperature for 2 hours. The solid formed was washed with a little chilled ethyl
acetate followed by water. It was then dried in vacuo at 50-55 ꢁC for 8 hours. The dried
material was packed in a black polythene bag to avoid exposure to sunlight.
2-[(Methylselenyl)methyl]benzoic Acid
White crystalline solid; Yield: 55.41% (23.70 g); Mp.: 162-163 ꢁC (Lit.: 164 ꢁC)8; IR
1
(KBr, v/cmꢂ1): 3600 (O-H), 3068.85 (Ar-H), 2985.91, 2883 (C-H), 1678 (C ¼ O); H
NMR (400 MHz, DMSO-d6): d 1.87 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.31-7.32 (m, 2H,
Ar-H), 7.45-7.48 (m, 1H, Ar-H), 7.85 (d, 1H, J¼ 8 Hz, Ar-H), 12.92 (s, 1H, -COOH);
13C NMR (100 MHz, DMSO-d6): d 168.8, 132.0, 131.3, 131.2, 129.8, 127.4, 127.1,
26.5, 4.4; MS (ESI-Q-Tof): m/z, calcd.for C9H10O2Se [M-H]þ: 228.98, Found: 228.80.
Anal. Calcd for C9H10O2Se: C, 47.18; H, 4.40. Found: C, 47.12; H 4.39.
Acknowledgments
One of the authors, Divyaraj Puthran, is grateful to the management of Solara Active
Pharma Sciences, New Mangalore, for supporting the research work and to the Central
Instrumentation Facility, MIT Manipal, for providing IR, 1H NMR and 13C NMR
spectral facilities.
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