Synthesis of new β,β'-diketodithioethers via swern oxidation and study of their hydrazone formation rate

Article abstract of DOI:10.1080/10426500802453989

The synthesis of β,β'-diketodithioethers 4b-j from corresponding β,β'-dihydroxydithioethers 3b-j was carried out by a Swern oxidation using DMSO-oxalyl chloride as oxidizing agent. β,β'- Dihydroxydithioethers 3b-j were prepared by the reaction of two molar equivalents of epoxides 1b-j with dimercaptoethane 2 in the presence of a saturated aqueous solution of potassium carbonate. The reactivity behavior of imine formation of the β,β'-diketodithioethers 4b-j by 2,4-dinitrophenylhydrazine was also investigated, and a mechanism was proposed by using molecular orbital (MO) calculations. To confirm the proposed mechanism, the role of the thia function to activate hydrazone formation by measuring HOMO-LUMO energy levels was also demonstrated.

Full text of DOI:10.1080/10426500802453989

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Phosphorus, Sulfur, and Silicon
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Synthesis of New β,β′-
Diketodithioethers via Swern
Oxidation and Study of Their
Hydrazone Formation Rate
Seyed Mohammad Seyedi a , Hamid Sadeghian a &
Zohreh Safari a
a Department of Chemistry, Faculty of Sciences ,
Ferdowsi University of Mashhad , Mashhad, Iran
Published online: 04 Sep 2009.
To cite this article: Seyed Mohammad Seyedi , Hamid Sadeghian & Zohreh Safari
(2009) Synthesis of New β,β′-Diketodithioethers via Swern Oxidation and Study of
Their Hydrazone Formation Rate, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:9, 2297-2306
To link to this article: http://dx.doi.org/10.1080/10426500802453989
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Phosphorus, Sulfur, and Silicon, 184:2297–2306, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802453989
Synthesis of New β,βꢀ-Diketodithioethers via Swern
Oxidation and Study of Their Hydrazone Formation Rate
Seyed Mohammad Seyedi, Hamid Sadeghian,
and Zohreh Safari
Department of Chemistry, Faculty of Sciences, Ferdowsi University
of Mashhad, Mashhad, Iran
The synthesis of β,βꢀ-diketodithioethers 4b–j from corresponding β,βꢀ-dihydroxy-
dithioethers 3b–j was carried out by a Swern oxidation using DMSO-oxalyl chloride
as oxidizing agent. β,βꢀ-Dihydroxydithioethers 3b–j were prepared by the reaction
of two molar equivalents of epoxides 1b–j with dimercaptoethane 2 in the presence
of a saturated aqueous solution of potassium carbonate. The reactivity behavior of
imine formation of the β,βꢀ-diketodithioethers 4b–j by 2,4-dinitrophenylhydrazine
was also investigated, and a mechanism was proposed by using molecular orbital
(MO) calculations. To confirm the proposed mechanism, the role of the thia function
to activate hydrazone formation by measuring HOMO-LUMO energy levels was also
demonstrated.
Keywords Ab initio; 2,4-dinitrophenylhydrazine; HUMO-LUMO; molecular orbital cal-
culation; neighboring group participation
INTRODUCTION
The Swern oxidation1 is one of the useful procedures for conversion of
a primary or secondary alcohol to an aldehyde or ketone. This oxida-
tion proceeds via an alkylsulfonium ylide intermediate, which is usu-
ally derived from DMSO or dimethylsulfide (SCHEME 1). Formation
of the activated intermediates [(CH3)2SX+ ] from DMSO and oxalyl
chloride,2,3 trifluroacetic anhydride,2,3 acetic anhydride,4–6 pyridine–
sulfur trioxide complex,7 and phosphoruspentaoxide8 have also been
reported.
Herein, we report the selective oxidation of β,βꢀ-dihydroxy-
dithioethers, leaving the two susceptible thia functions intact, via
Swern oxidation using DMSO-oxalyl chloride as an oxidizing agent. The
Received 5 April 2008; accepted 5 September 2008.
Address correspondence to Seyed Mohammad Seyedi, Department of Chemistry, Fac-
ulty of Sciences, Ferdowsi University of Mashhad, Mashhad, 91775, I. R. Iran. E-mail:
smseyedi@yahoo.com
2297

2298
S. M. Seyedi et al.
SCHEME 1
activity of the corresponding β,βꢀ-diketodithioether products for imine
formation by using 2,4-dinitrophenylhydrazine as a general reagent is
also studied.
RESULTS
Synthesis
β, βꢀ-Dihydroxydithioether 3a and the mixture of two diastereomers of
its derivatives 3b–j were prepared from two molar equivalents of oxi-
ranes 1a–j with dimercaptoethane 2 in the presence of a saturated
aqueous solution of potassium carbonate.9 Treatment of dihydroxy
compounds 3a–j with a mixture of DMSO and oxalyl chloride in dry
dichloromethane at −60◦C and then reacting with triethylamine led to
formation of corresponding diketo products 4b–j, except compound 3a,
which was not converted to the corresponding dialdehyde (SCHEME 2).
Kinetic Study
The relative rates of hydrazone formation of diketones 4b–j were mea-
sured in alcoholic solution at 363 nm (383 nm for compound 4d)
for 60 seconds.10 The final concentration of diketones 4b–j and 2,
4-dinitrophenylhydrazine in ethanol was 50 and 500 µM, respectively.
The experiment was repeated six times for each sample. The extent of
SCHEME 2 General procedure for synthesis of compounds 4b–j.

Synthesis of New β,βꢀ-Diketodithioethers
2299
TABLE I Relative Rates of Hydrazone Formation of Compounds 4b-j
and Butylthioacetone and the Data Obtained from Single Point
Calculations
Compd.
Relative rate
LUMO1
LUMO2
ꢀ E2−1
4b
4c
4d
4e
4f
4g
4h
4i
9.10e-2
5.88e-2
0.55e-2
25.0e-2
6.25e-2
50.0e-2
37.0e-2
1
3.75
3.74
2.29
3.54
3.59
3.68
3.60
3.47
3.64
3.25
3.26
2.23
3.06
3.12
3.09
3.16
2.85
3.09
+68.8
+74.3
+86.4
+60.0
+75.2
+58.6
+79.2
+52.3
+89.1
4j
BTA
0.22e-2
0.31e-2
BTA = Butylthioacetone
LUMO1 and LUMO2 refer to LUMO energy level (eV) of compounds 4b–j before and
after ring closing, respectively, and ꢀE2−1 is the energy difference between the
diketone derivative and the same molecule with carbonyl–sufur interaction.
increase in absorbance at the desired wavelength in comparison with
4i (most reactive of the synthetic diketones) was the basis of reaction
rate determination (Table I).
CALCULATION
Structures of desired molecules were simulated in Chem3D profes-
sional; Cambridge software.11 The geometry of the structures was first
modified under molecular mechanics calculations (MM+ method). In
the second optimization, output files were minimized under semi-
empirical RHF/PM3 methods (convergence limit = 0.05; iteration
limit = 50; RMS gradient = 0.05 kcal/mol; Polak–Ribiere optimizer
algorithm).12 Then the geometry optimization and single point proper-
ties of molecules were calculated using ab initio method with RHF/6-
31G* basis set (convergence limit = 1e-6; iteration limit = 100; the
initial guess of the MO coefficients is from eigenvectors of the core
Hamiltonian) in HyperChem7.5.12
DISCUSSION
For carbonyl compounds 4b–j, it was necessary to find out a method
that would be capable of converting hydroxyl groups of 3b–j to the

2300
S. M. Seyedi et al.
corresponding carbonyl groups while leaving 1,4-dithia function in-
tact. The lack of precedent would thus require a judicious choice of
appropriate oxidant as well as reaction conditions. We focused on
Swern oxidation and used an activated dimethylsulfoxide–based pro-
cedure, adopting the method reported by Fang et al.13 To a mixture of
dichloromethane and oxalyl chloride at −60◦C, DMSO was added fol-
lowed by gradual addition of the desired alcohols in dichloromethane.
The reaction mixture stirred for 25 min and then completed by the
addition of triethylamine. The mixture was allowed to reach 0◦C
or room temperature prior to quenching with water. This oxidation
was also modified by addition of the dialcohols to DMSO instead of
dichloromethane. The diketones so obtained were quite pure and could
be used directly for further reactions. We could not prepare and isolate
dialdehyde 4a via Swern oxidation.
Table I shows the relative rate of hydrazone formation of dike-
tones 4b–j along with buthylthioacetone. This comparison is due to
the existence of one α-thiacarbonyl groups in the chemical structure of
buthylthioacetone. By considering the data in Table I, we supposed that
high activity of these diketones towards hydrazone formation comes
from neighboring group participation14 of sulfur atoms cited at posi-
tion six from each carbonyl group when compared with buthylthioace-
tone with no such thia group. Each carbonyl group attacks a remoter
sulfur atom (π → d) and an unstable zwitterion structure appears. In
this structure, the β and β ’ carbons have higher activity and can be
attacked easily by amines (Figure 1). To prove this idea, the LUMO en-
ergy levels of compounds 4b–j, the corresponding zwitterions, and the
energy differences between the diketones and their closed ring form (ꢀ
E2−1) were calculated (Table I). This calculation showed that the main
density of the LUMO of the diketones belongs to carbonyl groups, and
by the carbonyl oxygen attacking the sulfur atom, the LUMO energy
of diketones decreases (Figure 2). The difference of LUMO energy lev-
els of each diketone before (LUMO1) and after (LUMO2) ring closing
with relative rate of hydrazone formation was also calculated. This cal-
culation showed two good nonlinear relationships of LUMO1-LUMO2
energy differences (except 4j) and (ꢀ E2−1) versus relative rate of all
compounds (Figure 3).
EXPERIMENTAL PROTOCOL
Instruments and Chemicals
Melting points were recorded on an Electrothermal type 9100 melting
point apparatus. The IR spectra were obtained on a 4300 Shimadzu

Synthesis of New β,βꢀ-Diketodithioethers
2301
FIGURE 1 Proposed mechanism for the formation of β -thiahydrazone (Ar =
2,4-dinitrophenyl).
spectrometer. The 1H NMR (100 MHz) spectra were recorded on a
Bruker AC 100 spectrometer in CDCl3. Elemental analyses were ob-
tained on a Thermo Finnigan Flash EA microanalyzer. All measure-
ments of hydrazone formation rate were carried out using an Agilent
8453 spectrophotometer.
General Procedure for the Synthesis of β,βꢀ-Diketodithioethers
(4b–j)
To a stirring solution of oxalyl chloride (2.5 mL, 30 mmol) in
dichloromethane (50 mL), dimethylsulfoxide (4 mL, 57 mmol) in
dichloromethane (15 mL) was added over 3 min and cooled to −60◦C
using an external cooling bath. After 10 min, the hydroxyl compound
3a–j (15 mmol) in dried dimethylsulfoxide (6 mL) was added, and the
reaction mixture was stirred for a further 25 min. Triethylamine was
distilled and added (20 mL) dropwise to the stirring solution. After
15 min, the cooling bath was removed, and the reaction mixture was

2302
S. M. Seyedi et al.
FIGURE 2 LUMO1 (above) and LUMO2 (below) graph of compound 4b before
and after ring closing, respectively.
allowed to warm to room temperature. Water (50 mL) was added,
and the dichloromethane layer was separated. The aqueous layer
was extracted with dichloromethane (2 × 20 mL). The combined
dichloromethane extracts were washed successively with HCl 1%
(200 mL), sodium carbonate 5% (50 mL), and water (2 × 50 mL) and
then dried over anhydrous sodium sulfate. The pale yellow filtrate
was concentrated to give crude products. Thin layer chromatography
(dichloromethane) indicated the presence of a small quantity of colored
polar impurity, which was not easily removed. The crude products

Synthesis of New β,βꢀ-Diketodithioethers
2303
FIGURE 3 Diagrams of relative rates versus ꢀ E2−1 of compounds 4b–j
(above) and ꢀ (LUMO1 and LUMO2) of compounds 4b–i (below).

2304
S. M. Seyedi et al.
were dissolved in 50 mL of hot dichloromethane containing 0.1 g of
activated charcoal and filtered through a short plug of Celite filter
aid. The plug was washed with further hot solvent, and the combined
filtrate was concentrated to give the desired compounds 4b–j (55–93%).
Analytically pure materials were obtained by column chromatography
(Silicagel 230–400; dichloromethane:hexane 50:50).
1-(2-[(2-Oxopropyl)sulfanyl]ethylsulfanyl)acetone (4b)
Colorless oil, (85%), IR: 1709 cm−1 (C O). δH 2.30 (6H, s, 2 × CH3),
2.71 (4H, s, 2 × CH2S), 3.25 (4H, s, 2 × COCH2S). Anal. Calcd. for
C8H14O2S2: C, 46.57; H, 6.84; S, 31.08. Found: C, 46.81; H, 6.77; S,
30.89%.
1-(2-[(2-Oxobutyl)sulfanyl]ethylsulfanyl)-2-butanone (4c)
Yellow solid, (90%), mp: 45◦C, IR: 1709 cm−1 (C O). δH 1.05 (6H, t,
J = 6Hz, 2 × CH3), 2.30 (4H, q, J = 6Hz, 2 × CH2), 2.66 (4H, s, 2 ×
CH2S), 3.21 (4H, s, 2 × COCH2S). Anal. Calcd. for C8H18O2S2: C, 51.24;
H, 7.74; S, 27.36. Found: C, 51.51; H, 7.69; S, 27.22%.
2-(2-[(2-Oxo-2-phenylethyl)sulfanyl]ethylsulfanyl)-1-phenyl-1-
ethanone (4d)
Yellow oil, (55%), IR: 1713 cm−1 (C O). δH 2.79 (4H, s, 2 × CH2S),
3.80 (4H, s, 2 × COCH2S), 7.41–8.05 (10H, m, aromatic H). Anal. Calcd.
for C18H18O2S2: C, 65.42; H, 5.49; S, 19.41. Found: C, 65.81; H, 5.57; S,
19.22%.
1-(allyloxy)-3-[(2-[3-(allyloxy)-2-oxopropyl]sulfanylethyl)
sulfanyl]acetone (4e)
Yellow solid, (93%), mp: 46◦C, IR: 1720 cm−1 (C O). δH 2.75 (4H, s,
2 × CH2S), 3.31 (4H, s, 2 × COCH2S), 4.12 (4H, d, J = 7 Hz, 2 × CH2O),
4.22 (4H, s, 2 × COCH2O). Anal. Calcd. for C14H22O4S2: C, 52.80; H,
6.96; S, 20.14. Found: C, 52.91; H, 6.89; S, 20.21%.
1-Isopropoxy-3-(2-[(3-isopropoxy-2-oxopropyl)sulfanyl]
ethylsulfanyl)acetone (4f)
Yellow oil, (74%), IR: 1722 cm−1 (C O). δH 1.20 (12H, d, J = 6Hz, 4 ×
CH3), 2.74 (4H, s, 2 × CH2S), 3.35 (4H, s, 2 × COCH2S), 3.65 (2H, m,
CH), 4.19 (4H, s, 2 × COCH2O). Anal. Calcd. for C14H26O4S2: C, 52.14;
H, 8.13; S, 19.89. Found: C, 52.01; H, 8.26; S, 19.67%.

Synthesis of New β,βꢀ-Diketodithioethers
2305
1-Butoxy-3-(2-[(3-butoxy-2-oxopropyl)sulfanyl]
ethylsulfanyl)acetone (4g)
Yellow solid, (81%), mp: 37◦C, IR: 1721 cm−1 (C O). δH 0.92 (6H, t,
J = 6Hz, 2 × CH3) 1.20–1.60 (8H, m, 2 × CH2CH2), 2.74 (4H, s, 2 ×
CH2S), 3.34 (4H, s, 2 × COCH2S), 3.51 (4H, t, J = 6Hz, 2 × CH2O),
4.20 (4H, s, 2 × COCH2O). Anal. Calcd. for C16H30O4S2: C, 54.82; H,
8.63; S, 18.29. Found: C, 54.91; H, 8.57; S, 18.27%.
1-(tert-Butoxy)-3-[(2-[3-(tert-butoxy)-2-oxopropyl]
sulfanylethyl)sulfanyl]acetone (4h)
Yellow oil, (78%), IR: 1719 cm−1 (C O). δH 1.22 (18H, s, 6 × CH3),
2.73 (4H, s, 2 × CH2S), 3.35 (4H, s, 2 × COCH2S), 4.12 (4H, s, 2 ×
COCH2O). Anal. Calcd. for C16H30O4S2: C, 54.82; H, 8.63; S, 18.29.
Found: C, 55.02; H, 8.72; S, 18.07%.
1-(2-[(2-Oxo-3-phenoxypropyl)sulfanyl]ethylsulfanyl)-3-
phenoxyacetone (4i)
Yellow solid, (83%), mp: 96◦C, IR: 1723 cm−1 (C O). δH 2.78 (4H,
s, 2 × CH2S), 3.44 (4H, s, 2 × COCH2S), 4.76 (4H, s, 2 × COCH2O),
6.80–7.40 (10H, m, aromatic H). Anal. Calcd. for C20H22O4S2 : C, 61.51;
H, 5.68; S, 16.42. Found: C, 61.63; H, 5.63; S, 16.37%.
2-(2-[(2-Oxocyclohexyl)sulfanyl]ethylsulfanyl)-1-
cyclohexanone (4j)
Yellow oil, (61%), IR: 1701 cm−1 (C O). δH 1.20–2.60 (16H, m,
CH2CH2CH2CH2), 2.68 (2H, s, 2 × CH2S), 2.84 (2H, s, 2 × CH2S),
3.36 (2H, m, 2 × COCHS). Anal. Calcd. for C14H22O2S2: C, 58.70; H,
7.74; S, 22.39 Found: C, 58.94; H, 7.91; S, 22.28%.
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