Condensation of Propan-2-one with Formaldehyde and Propane-2-thiol

Article abstract of DOI:10.1134/S1070363220040015

Abstract: Three-component condensation of propan-2-one with formaldehyde and propane-2-thiol in the presence of sodium hydroxide afforded 3-{[(propan-2-yl)sulfanyl)]methyl}but-3-en-2-one or 4-[(propan-2-yl)sulfanyl]-3-{[(propan-2-yl)sulfanyl]methyl}butan-

Full text of DOI:10.1134/S1070363220040015

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 4, pp. 567–571. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 4, pp. 495–500.
Condensation of Propan-2-one with Formaldehyde
and Propane-2-thiol
L. A. Baevaa,*, R. M. Nugumanova, L. F. Biktashevaa, and R. L. Safiullina
a Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences, Ufa, 450054 Russia
*e-mail: sulfur@anrb.ru
Received October 31, 2019; revised October 31, 2019; accepted November 7, 2019
Abstract—Three-component condensation of propan-2-one with formaldehyde and propane-2-thiol in the
presence of sodium hydroxide afforded 3-{[(propan-2-yl)sulfanyl)]methyl}but-3-en-2-one or 4-[(propan-2-yl)-
sulfanyl]-3-{[(propan-2-yl)sulfanyl]methyl}butan-2-one, depending on the amount of the base. The formation
of 4-[(propan-2-yl)sulfanyl]-3-{[(propan-2-yl)sulfanyl]methyl}butan-2-one from 4-[(propan-2-yl)sulfanyl]-
butan-2-one involved aldol condensation of the latter with formaldehyde and subsequent nucleophilic addition of
propane-2-thiol to the C=C double bond of intermediate 3-{[(propan-2-yl)sulfanyl]methyl}but-3-en-2-one in the
presence of sodium hydroxide.
Keywords: thiol, formaldehyde, γ-keto sulfide, β-mercaptoketone, three-component condensation, thia-Michael
reaction
DOI: 10.1134/S1070363220040015
In recent time, multicomponent reactions satisfying
the “green chemistry” principles have been widely used in
organic synthesis. Such reactions include three-component
condensations of ketones and diketones with aldehydes
and amines [1–4] or thiols [5–10]. Reactions of ketones
with aldehydes and thiols give rise to polyfunctionalized
γ-keto sulfides (β-mercaptoketones) which can be used as
noble metal extractants [11, 12], flotation agents for gold-
containing sulfide ores [13], hydrogen sulfide corrosion
inhibitors [14], and intermediate products in medicinal,
extraction, agricultural, and heterocyclic chemistry [8,
10, 15–18]. Since the reactions can be performed in the
presence of a base, the source of thiols may be alkaline
sulfide solutions obtained upon alkaline treatment of
gas condensates and petrochemicals to remove sulfur-
containing compounds [19].
in this work we studied the condensation of accessible
propan-2-one (acetone) with formaldehyde and propane-
2-thiol in alkaline medium.
The three-component condensation of propan-2-
one with equimolar amounts of formaldehyde and
propane-2-thiol in the presence of 0.03–1.25 equiv of
sodium hydroxide at 20°C gave a mixture of 4-[(propan-
2-yl)sulfanyl]butan-2-one (1), previously unknown
3-{[(propan-2-yl)sulfanyl]methyl}but-3-en-2-one (2),
and 4-[(propan-2-yl)sulfanyl]-3-{[(propan-2-yl)sulfanyl]-
methyl}butan-2-one (3) (Scheme 1).
Keto sulfides 1 and 3 are products resulting from
successive introduction of alkylsulfanylmethyl group into
the propan-2-one molecule. Compound 2 is formed via
aldol condensation of keto sulfide 1 with formaldehyde.
Compounds 1–3 were isolated by vacuum distillation
(3) or column chromatography (1, 2), and their structure
was determined on the basis of their elemental analyses
and spectral data. The 1H NMR spectrum of 2 contained
singlets at δ 5.94 and 6.08 ppm due to nonequivalent
olefinic protons, which were not observed in the spectrum
of initial keto sulfide 1, and signals at δ 145.6 (C3) and
125.9 ppm (C4) were present in its 13C NMR spectrum.
The IR spectrum of 2 showed C=O, C=S, and =C–H
stretching bands at 1681, 1626, and 3096 cm–1,
Ketones with a methylene group at the carbonyl
carbon atom (e.g., butan-2-one, 1-phenylpropan-1-one)
were reported to react with formaldehyde and thiols to
produce alkylsulfanylmethyl ketones [19, 20]. Under the
same conditions, reactions of methyl ketones (propan-2-
one, 1-phenylethanone) afforded bis(alkylsulfanylmethyl)
derivatives. The yields of monosubstituted compounds
did not exceed 31%. In order to find out optimal
conditions for the formation of various γ-keto sulfides,
567

568
BAEVA et al.
Scheme 1.
O
+ CH2O + i-PrSH
Me
Me
O
O
O
NaOH
Pr-i
Pr-i
Pr-i
+
+
Me
S
Me
S
Me
S
20qC
CH2
2
Pr-i
S
1
3
respectively. The spectral characteristics of 1 and 3 were
in a good agreement with those reported in [21, 22].
30, and 23% in 2 h, and they did not change further to
an appreciable extent.
The maximum conversion of i-PrSH (99%) was attain
in 5 h at a ketone : CH2O : i-PrSH : NaOH molar ratio of
1 : 1 : 1 : 0.4; in this case, the major product was bis-
sulfide 3 (Fig. 2). In 1 h after the reaction started, the
yields of 2 and 3 were 33 and 35%, respectively. As the
reaction progressed further, the yield of 2 decreased due
to its transformation to 3. In the presence of an equimolar
amount of sodium hydroxide, the conversion of propane-
2-thiol was almost complete, and maximum yield of 3
(65%) was attained in 15 min (Table 1, run no. 3).
According to the data of functional group analysis and
GLC analysis of the reaction mixtures, the conversion
of propane-2-thiol and the product ratio depended on
the amount of sodium hydroxide. When the molar ratio
acetone : CH2O : i-PrSH : NaOH was 1 : 1 : 1 : 0.03,
the conversion of propane-2-thiol did not exceed 47%
(1 h). After 5 min, the reaction mixture contained mainly
keto sulfide 1, whereas no appreciable amount of 2 or 3
was detected (Fig. 1a). After 10 min, the concentration
of 1 decreased due to its transformation into compounds
2 and 3, and the yields of the latter reached 37 and 5%
(calculated on the initial thiol), respectively, after 30 min.
The concentrations of 2 and 3 did not change significantly
during the subsequent 30 min. Increase of the amount
of sodium hydroxide to 0.13 mol led to increase of the
conversion of i-PrSH to 58% (2 h). The yields of 1, 2,
and 3 were, respectively, 4, 34, and 18% in 1 h and 5,
Our results indicated that propan-2-one reacted with
equimolar amounts of formaldehyde and propane-2-thiol
in the presence of 0.03 equiv to give in 5 min keto sulfide
1 as the primary product which was then converted almost
completely into compound 2 (60 min). The yield of 2
was 40% (calculated on i-PrSH) or 81% (with respect to
formaldehyde), and the conversion of formaldehyde was
ꢀɚꢁꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢀEꢁ
IJ, min
IJ, min
Fig. 1. Yields of compounds (1) 1, (2) 2, and (3) 3 in the condensation of propane-2-thiol with formaldehyde and propan-2-one at ketone :
CH2O : thiol : NaOH molar ratios of (a) 1 : 1 : 1 : 0.03 and (b) 1 : 1 : 1 : 0.4; temperature 20°C.
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CONDENSATION OF PROPAN-2-ONE WITH FORMALDEHYDE
569
Table 1. Condensation of propan-2-one with formaldehyde and propane-2-thiol in the presence of sodium hydroxide at 20°Ca
Yield,b %
Molar ratio
Me2CO : CH2O : i-PrSH : NaOH
1 : 1 : 1 : 0.13
Conversion
of i-PrSH, %
Reaction
time, min
Run no.
1
4
–
8
6
–
2
2
34
72
2
34
67
12
11
3
40
17
2
3
18
5
65
67
86
49
60
57
6
1
2
3
5
6c
7d
8
9
10
56
73
99
99
95
99
99
97
97
60
60
15
15
30
15
15
15
15
1 : 2 : 1 : 0.13
1 : 1 : 1 : 1
1 : 1 : 1 : 1.25
1 : 1.25 : 1 : 1
1 : 2 : 1 : 1
1 : 2 : 2 : 2
5 : 1 : 1 : 0.75
10 : 1 : 1 : 0.75
1
a Diisopropyl disulfide was also detected in 2–4 (run nos. 3–7, 9) and 12% yield (run nos. 8, 10).
b Calculated on the initial propane-2-thiol.
c The reaction was carried out in ethanol.
d The reaction was accompanied by formation of a polymeric product.
87% by that time. In order to improve the selectivity for
bis-sulfide 3, an additional amount of sodium hydroxide
(0.4 equiv) should be added, and the reaction time should
be prolonged to 5 h. The yield of 3 and the rate of its
formation increased in parallel with the amount of alkali
(Fig. 1b) and decreased when excess formaldehyde was
used (Table 1; run nos. 2, 7).
{[(propan-2-yl)sulfanyl]methyl}butan-2-one is the
product of addition of propane-2-thiol to 3-{[(propan-2-
yl)sulfanyl]methyl}but-3-en-2-one.
EXPERIMENTAL
Freshly distilled propane-2-thiol (reagent-grade),
32% aqueous formaldehyde (GOST 1625-2016), and
analytical-grade propan-2-one, sodium hydroxide, and
chloroform were used.
These findings can be rationalized assuming formation
of 3 from 1 according to Scheme 2. Initially, the
condensation of propan-2-one with formaldehyde and
propane-2-thiol gives keto sulfide 1 which reacts with
formaldehyde to produce 3-{[(propan-2-yl)sulfanyl]-
methyl}but-3-en-2-one (2). The final stage is base-
catalyzed thia-Michael addition of propane-2-thiol to
the C=C double bond of α,β-unsaturated carbonyl
compound 2.
The IR spectra were recorded from films on a Shimadzu
IR Prestige-21 spectrometer. The 1H and 13C NMR spectra
were recorded on a Bruker Avance III spectrometer at
500.13 and 125.76 MHz, respectively, using CDCl3 as
Thus, the optimal conditions for the synthesis of
compounds 1–3 are as follows. Sulfide 2 is formed as the
major product in the presence of 2 equiv of formaldehyde
and 0.13 equiv of sodium hydroxyde, whereas 10 equiv of
acetone and 0.75 equiv of alkali should be used to obtain
preferentially keto sulfide 1 (Table 1, run nos. 2 and 10,
respectively). The reaction in ethanol at a ketone : CH2O :
i-PrSH : NaOH ratio of 1 : 1.25 : 1 : 1 gives mainly
compound 3 in 86% yield (run no. 6).
In summary, we have found that the product ratio
in the three-component condensation of propan-2-one
with formaldehyde and propane-2-thiol depends on the
amount of sodium hydroxide. 3-{[(Propan-2-yl)sulfanyl]-
methyl}but-3-en-2-one is formed as a result of aldol
condensation of 4-[(propan-2-yl)sulfanyl]butan-2-one
with formaldehyde, and 4-[(propan-2-yl)sulfanyl]-3-
nNaOH, mol
Fig. 2. Yields of compounds (1) 1, (2) 2, and (3) 3 and (4)
conversion of propane-2-thiol in the condensation of propane-
2-thiol with formaldehyde and propan-2-one at a molar ratio
of 1 : 1 : 1 versus amount of sodium hydroxide; temperature
20°C.
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570
BAEVA et al.
Scheme 2.
O
O
O
CH2O, i-PrSH
CH2O
NaOH
Pr-i
Pr-i
Me
S
Me
S
Me
Me
NaOH
CH2
1
2
O
i-PrSH
NaOH
Pr-i
Me
S
Pr-i
3
S
solvent and reference. GLC analyses were performed on a
Chrom 5 chromatograph equipped with a flame ionization
detector and a 2.4-m×3-mm column packed with 5% SE-
30 on Chromaton N-AW-DMCS (0.16–0.20 mm), oven
temperature 50–300°C, carrier gas helium; compounds
1–3 were quantitated by the internal standard method
using hexadecane as internal standard. The calibrating
factors were determined using artificial mixtures of 1–3
and internal standard. The mass spectra (electron impact,
70 eV) were obtained on a Thermo Finnigan MAT 95
XP instrument with direct sample admission into the ion
source. Column chromatography was performed on MN
Kieselgel 60 silica gel (0.063–0.2 μm). The progress
of reactions was monitored by potentiometric titration
with ammoniacal silver nitrate to determine thiol sulfur
[23]. The spectral and analytical data were obtained at
the Chemistry joint center, Ufa Institute of Chemistry,
Russian Academy of Sciences.
After completion of the reaction, the organic layer was
separated, and the alkaline aqueous layer was diluted with
water (1 : 1) and extracted with chloroform (2×5 mL). The
extracts were combined with the organic layer, washed
with 10% aqueous HCl (4 mL) and water (2×4 mL), and
dried over MgSO4, the solvent was distilled off, and the
residue was analyzed as described above.
The molar ratio ketone–formaldehyde–propane-2-
thiol–sodium hydroxide was varied in the ranges (0.5–10) :
(1–2) : (1–2) : (0.03–2).
4-[(Propan-2-yl)sulfanyl]butan-2-one (1). Mass
spectrum, m/z (Irel, %): 146 (62) [M]+·, 131 (2) [M –
CH3]+, 113 (2) [M – SH]+, 103 (12) [M – C3H7]+, 89 (8),
75 (40) [SC3H7]+, 71 (46) [C4H7O]+, 61 (32), 43 (100)
[C2H3O]+, [C3H7]+. The IR and 1H and 13C NMR spectra
were identical to those reported in [21].
3-{[(Propan-2-yl)sulfanyl]methyl}but-3-en-2-one
(2). IR spectrum, ν, cm–1: 3096 w (=CH), 1681 s (C=O),
1626 w (C=C), 883 w (δ=C–H). 1H NMR spectrum, δ,
ppm: 1.25 d [6H, SCH(CH3)2, 3J = 6.7 Hz], 2.36 s (3H,
Condensation of propan-2-one with formaldehyde
and propane-2-thiol. The reactions were carried out
in a glass reactor equipped with a magnetic stirrer,
maintaining the temperature at 20°C. The reactor was
charged with 1.23 mL (13 mmol) of propane-2-thiol, and
0.30 mL (0.39 mmol) of 5% aqueous sodium hydroxide
was added with stirring. The mixture was stirred for 15
min, 0.97 mL (13 mmol) of propan-2-one and 1.13 mL
(13 mmol) of 32% aqueous formaldehyde were added
in succession, and the mixture was stirred for a required
time (5 min to 5 h). The mixture was then treated with
brine (1 : 1), the organic layer was separated, washed
with water (2 mL), dried over MgSO4, and analyzed by
GLC, and the products were isolated by silica gel column
chromatography (EtOAc–hexane, 1 : 15) or vacuum
distillation.
3
C1H3), 2.84 sept (1H, SCH, J = 6.7 Hz), 3.39 s (2H,
CH2S), 5.94 s and 6.08 s (1H each, =CH2). 13C NMR
spectrum, δC, ppm: 23.1 [CH(CH3)2], 26.0 (C1H3),
29.9 (CH2S), 34.9 (SCH), 125.9 (C4), 145.6 (C3), 198.5
(C2). Found, %: C 60.78; H 8.97; S 20.31. C8H14OS.
Calculated, %: C 60.71; H 8.92; S 20.26. The mass
spectrum of 2 was similar to that reported in [24].
4-[(Propan-2-yl)sulfanyl]-3-{[(propan-2-yl)-
sulfanyl]methyl}butan-2-one (3). nD20 = 1.4956, d420
=
0.994. The IR and 1H and 13C NMR spectra were identical
to those reported in [22].
2,2′-(Disulfanediyl)dipropane (diisopropyl disulfide)
was identified by comparing with an authentic sample.
If an equimolar or larger amount of sodium hydroxide
was used, the mixture was treated in a different way.
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CONDENSATION OF PROPAN-2-ONE WITH FORMALDEHYDE
571
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FUNDING
This study was performed under financial support
by the Ministry of Science and Higher Education of the
Russian Federation in the framework of state assignment no.
AAAA-A19-119011790021-4.
https://doi.org/10.1134/S1070363218120113
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CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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