Synthesis of arsenical adduct: Synthesis and transformation of dimercapto compound to arsenical adduct

Article abstract of DOI:10.1080/10426500210241

Reaction of isothiocyanates with thioamide in presence of pyridine afforded 1,3-dimercapto substrates in good yield. Adipoin reacts with phenylarsine oxide and triphenylarsine to give the bicyclic 1,3,2-dioxarsole derivatives. A variety of 1,3,2-arsadithiolane derivatives were obtained by reaction of 1,3-dimercapto substrate with arsenic trioxide, phenylarsine oxide, triphenylarsine triphenylarsine oxide in ethanol or better in chloroform.

Full text of DOI:10.1080/10426500210241

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Arsenical Adduct: Synthesis and
Transformation of Dimercapto Compound to Arsenical
Adduct
A. Z. M. Shaifullah Chowdhury a , Yasuyuki Shibata a , Masatoshi Morita a & Kunimitsu Kaya a
a Environmental Chemistry Division , National Institute for Environmental Studies , 16-2
Onogawa, Tsukuba, Ibaraki, 305-0053, Japan
Published online: 27 Oct 2010.
To cite this article: A. Z. M. Shaifullah Chowdhury , Yasuyuki Shibata , Masatoshi Morita & Kunimitsu Kaya (2002) Synthesis of
Arsenical Adduct: Synthesis and Transformation of Dimercapto Compound to Arsenical Adduct, Phosphorus, Sulfur, and Silicon
and the Related Elements, 177:2, 497-509, DOI: 10.1080/10426500210241
To link to this article: http://dx.doi.org/10.1080/10426500210241
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Phosphorus, Sulfur and Silicon, 2002, 177:497–509
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
SYNTHESIS OF ARSENICAL ADDUCT: SYNTHESIS
AND TRANSFORMATION OF DIMERCAPTO
COMPOUND TO ARSENICAL ADDUCT
A. Z. M. Shaifullah Chowdhury, Yasuyuki Shibata,
Masatoshi Morita, and Kunimitsu Kaya
Environmental Chemistry Division, National Institute
for Environmental Studies, 16-2 Onogawa, Tsukuba,
Ibaraki 305-0053, Japan
(Received April 25 2001.)
Reaction of isothiocyanates with thioamide in presence of pyridine
afforded 1,3-dimercapto substrates in good yield. Adipoin reacts with
phenylarsine oxide and triphenylarsine to give the bicyclic 1,3,2-
dioxarsole derivatives. A variety of 1,3,2-arsadithiolane derivatives
were obtained by reaction of 1,3-dimercapto substrate with arsenic
trioxide, phenylarsine oxide, triphenylarsine triphenylarsine oxide in
ethanol or better in chloroform.
Keywords: 1,3,2-arsadithiolane derivatives; 1,3-dithiol compounds;
1,3,2-dioxarsole derivatives; arsenic compounds; isothiocyanates;
thioamide
Epidemiological evidence indicates that ingestion of arsenic compounds
via drinking water can result in skin cancer and cancer of internal
organs,1 whereas occupational arsenic exposure seems to cause lung
cancer and possibly other cancers.2 Skin disorders such as hyperker-
atosis, hyperpigmentation, and depigmentation have been described in
relation to arsenic containing water and there are dermatologic mani-
festations in children.3 Noncirrhotic portal fibrosis is another disorder
reported after consumption of water containing arsenic.4 Peripheral
vascular disease and cardiovascular disease have been associated with
12
environmental exposure to inorganic arsenic in drinking water5
as
16
well as occupational exposures.13
Diabetes Mellitus has also been
reported a risk factor for peoples exposed to arsenic through drinking
water.17,18
Address correspondence to A. Z. M. Shaifullah Chowdhury, Environmental Chemistry
Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki
305-0053, Japan.
497

498
A. Z. M. S. Chowdhury et al.
Ground water pollution by arsenic compounds has drawn consid-
erable attention and raised serious concern in Bangladesh and other
locations.19 According to available information, millions of people are
“at risk,” endangered by arsenic in Bangladesh.19 Arsenic poisoning is
known to interfere with the cell’s sulfhydryl groups. In humans, the tox-
icity of trivalent arsenic is mainly due to its binding to the sulfhydryl
groups of lipoic acid.20 22 Therefore, arsenic intoxication can be amelio-
rated by the administration of dithiol compounds. In mammals, fungi,
and algae, detoxification of arsenic usually involves methylation and
other biotransformations such as incorporation of arsenic into organic
molecules by the formation of arsenocholine, arsenobetaine, or arseno-
25
sugars, for example.23
Three chelating agents sodium 2,3-dimercapto-1-propane sulfonate
(DMPS, Dimaval), meso-2,3-dimercaptosuccinic acid (DMSA, succimer)
and 2,3-dimercapto-1-propanol (BAL, British Antilewisite) are being
32
used therapeutically at the present time.26
DMPS, DMSA, and BAL
all have a vicinal dithiol groups as the arsenic binding site.26
As
32
is true with three therapeutic agents, each of these chelating agents
has advantages and disadvantages. It is generally accepted that all
of them form stable 1,3,2-arsadithiolane derivatives with bifunctional
arsenicals (Scheme 1).
SCHEME 1
Because of high affinity of thiols for arsenic compounds, in this paper
follows that line of research by reporting on a new series of dimercapto
substrate 4a–c, 7a,b which are more useful chelating agents for
arsenic compounds. Here, we report on the synthesis of five chelating
agents, dimercapto substrate 4a–c, 7a,b from isothiocyanates and their
reaction with arsenic trioxide, phenylarsine oxide, triphenylarsine,
or triphenylarsine oxide in solvent chloroform or ethanol afforded six
membered heterocyclic ring.

Arsenical Adduct
499
SYNTHESIS OF 1,3-DIMERCAPTO SUBSTRATE
35
Recently we have been reported33
the synthesis of mono mercapto
heterocycles from ethyl isothiocyanatoacetate. In this article we re-
port on dimercapto substrate by the reaction of various isothiocyanate
with thioamido moiety. For better result and smooth reaction firstly
we used very sensitive isothiocyanates: phenyl isothiocyanate (3a),
methyl isothiocyanate (3b), and ethyl isothiocyanatoacetate (3c) with
thioacetamide and thiobenzamide at reflux temperature in presence of
pyridine.
Thus, the desired and conceivable product, 1-thioacetyl-3-phenyl-
2-thiourea (4a) was synthesized from thioacetamide and phenyl
isothiocyanate (3a) at reflux for 4 h in pyridine medium. After usual
work up precipitated materials were collected by filtration and obtained
in 59% yield and mp 165–167 C as white needles after recrystallization
from ethanol. Similarly, 1-thiobenzoyl-3-methyl-2-thiourea (4b) was
prepared in 63% yield, m.p. 156–158 C as yellow needles by a direct
condensation of thiobenzamide with methyl isothiocyanate (3b). In a
similar manner, 1-thiobenzoyl-3-ethoxycarbonyl-2-thiourea (4c) was
also obtained as brown needles frequently from thiobenzamide and
ethyl isothiocyanatoformate (3c) (Scheme 2).
The reaction of thiobenzamide and ethyl isothiocyanatoacetate33 (6)
refluxing for 2 h in pyridine to afford open chain product 1-thiobenzoyl-
3-ethoxycarbonylmethyl-2-thiourea (7a) as yellow needles in 62% and
m.p. 122–124 C. By a similar method treatment of thioacetamide
and ethyl isothiocyanatoacetate (6) in pyridine for 2 h furnished
1-thioacetyl-3-ethoxycarbonylmethyl-2-thiourea (7b) as yellow needles
in 57% as shown in Table I.
The common type of prototropic tautomerism in heterocyclic com-
pounds involved the movement of a proton between a ring nitrogen
35
atom and substituent sulfur atom connected to the ring.33
In case of
compounds 4a–c, 7a,b the tautomeric equilibrium between thioamide
and imine-thiol form have been indicated by 1H and 13C NMR spectra
(Table II).
HETEROCYCLIC RING FROM ADIPOIN
When a solution of one equivalent of 2-hydroxycyclohexanone (adipoin40
1a) in dry dioxane was added to that of phenylarsine oxide, the re-
action was completed at reflux temperature for 24 h (Scheme 2).
The product was isolated in 63% yield and formulated as 2-phenyl-4,
5,6,7-tetrahydro-1,3,2-benzodioxarsole (2a). In the same way, 1a reacts

500
A. Z. M. S. Chowdhury et al.
SCHEME 2
with triphenylarsine in dry dioxane at reflux temperature for 12 h to
give the 2,2,2-triphenyl-4,5,6,7-tetrahydro-1,3,2-benzodioxarsole (2b).
This adduct is a colorless crystalline substance with a sharp melt-
ing point and is remarkably stable. Reaction of triphenylarsine
with ortho-quinones in a manner rather different from the already
known.36

501

502

Arsenical Adduct
503
TABLE II
No.
1H NMR (CDCl3):
ppm
13C NMR (CDCl3):
ppm
C
H
4a
2.50 (s, 3H, Me), 7.20–7.50 (m,
5H, Ar H), 8.22 (s, 1H, NH),
10.80 (s, 1H, NH)
3.67 (s, 3H, Me), 7.25–7.40 (m,
5H, Ar H), 8.36 (s, 1H, NH),
9.82 (s 1H, NH)
1.40 (t, J = 7.20 Hz, 3H, Me),
4.20 (q, J = 7.2 Hz, 2H, OCH2),
7.25–7.40 (m, 5H, Ar H), 8.02
(s, 1H, NH), 9.10 (s, 1H, NH)
1.25 (t, J = 7.1 Hz, 3H, Me),
4.21 (q, J = 7.1 Hz, 2H, OCH2),
4.51 (s, 2H, CH2), 7.82 (m, 2H,
20-H and 60-H), 7.38 (m, 3H,
30-H, 40-H and 50-H) 8.09 (s, 1H,
NH), 8.70 (s, 1H, NH)
34.96 (s, Me), 126.79 (d, C-40), 127.22 (d, C-30
and C-50), 129.59 (d, C-20 and C-60), 137.19
(s, C-10), 179.70 (s, C S), 175.51 (s, C S)
50.14 (q, Me), 127.65 (d, C-40), 128.92 (d, C-30
and C-50), 129.20 (d, C-20 and C-60), 137.59
(s, C-10), 173.07 (s, C S), 177.15 (s, C S)
14.01 (q, Me), 127.28 (d, C-40), 128.76 (d, C-30
and C-50), 129.53 (d, C-20 and C-60),
137.28 (s, C-10), 167.24 (s, C O),
4b
4c
171.04 (s, C S), 200.53 (s, C S)
7a
13.99 (q, Me), 48.76 (t, CH2), 62.02 (t, OCH2),
126.88 (d, C-40), 128.38 (d, C-30 and C-50),
131.93 (d, C-20 and C-60), 139.05 (s, C-10),
166.92 (s, C O), 171.10 (s, C S), 183.94
(s, C S)
7b
2a
2b
2c
1.24 (t, J = 7.2 Hz, 3H, Me),
2.49 (s, 3H, Me), 4.17 (q,
J = 7.1 Hz, 2H, OCH2), 4.50 (s,
2H, CH2), 7.97 (s, 1H, NH),
9.85 (s, 1H, NH)
1.17–1.83 (m, 4H, 2CH2),
2.05–2.50 (m, 4H, 2CH2),
7.36–7.47 (m, 3H, 30-H, 40-H
and 50-H), 7.69–7.76 (m, 2H,
20-H and 60-H)
1.40–1.70 (m, 4H, 2CH2),
2.00–2.50 (m, 4H, 2CH2),
7.64 (m, 6H, 20-H and 60-H),
7.50 (m, 9H, 30-H, 40-H
and 50-H)
2.09–2.17 (m, 2H, CH2),
2.78–2.92 (t, 4H, CH2),
7.75–7.87 (m, 1H, 20-H and
60-H), 7.37–7.47 (m, 3H, 30-H,
40-H and 50-H)
13.95 (q, Me), 32.80 (q, Me), 48.76 (t, CH2),
62.03 (t, OCH2), 166.99 (s, C O), 171.99
(s, C S), 183.81 (s, C S)
25.24 (t, CH2), 27.56 (t, CH2), 37.72 (t, CH2),
39.48 (t, CH2), 128.55 (d, C-30 and C-50),
129.36 (s, C-10), 130.52 (d, C-40), 132.88
(d, C-20 and C-60), 144.21 (s, 2C
O As)
25.91 (t, CH2), 27.57 (t, CH2), 37.86 (t, CH2),
39.34 (t, CH2), 129.33 (d, C-30 and C-50),
131.51 (s, C-10), 132.16 (d, C-40), 132.53
(d, C-20 and C-60), 142.63 (s, 2C
O As)
25.92 (t, CH2), 28.28 (t, CH2), 36.90 (t, CH2),
128.58 (d, C-40), 129.14 (d, C-30 and C-50),
129.68 (d, C-20 and C-60) 132.35 (s, C-10)
5a
5b
5c
5d
2.46 (s, 3H, Me), 7.18–7.35 (m,
5H, Ar H), 8.10 (bs, 1H,
As OH)
2.87 (s, 3H, Me), 7.10–7.45
(m, 10H, Ar H)
26.45 (q, Me), 127.37 (d, C-40), 128.92 (d, C-30
and C-50), 129.69 (d, C-20 and C-60), 137.25
(s, C-10), 167.06 (s, C S), 175.51 (s, C S)
26.58 (s, Me), 127.31 (d, C-40), 128.78 (d, C-30
and C-50), 129.75 (d, C-20 and C-60), 137.68
(s, C-10), 167.84 (s, C S), 176.08 (s, C S)
26.78 (s, Me), 127.62 (d, C-40), 129.05 (d, C-30
and C-50), 129.85 (d, C-20 and C-60), 137.63
(s, C-10), 167.72 (s, C S), 175.41 (s, C S)
45.97 (q, Me), 127.53 (d, C-40), 128.90 (d, C-30
and C-50), 129.64 (d, C-20 and C-60), 137.21
(s, C-10), 146.43 (s, C-8a), 167.13 (s, C S),
175.50 (s, C S)
2.90 (s, 3H, Me), 7.40–7.80 (m,
20H, Ar H)
3.61 (t, 3H, Me), 7.10–7.35
(m, 5H, Ar H), 7.68 (bs, 1H,
As OH)

504
A. Z. M. S. Chowdhury et al.
TABLE II (Continued)
No.
1H NMR (CDCl3):
ppm
13C NMR (CDCl3):
ppm
C
H
5e
3.54 (s, 3H, Me), 7.10–7.45
(m, 10H, Ar H)
45.75 (s, Me), 127.21 (d, C-40), 128.49 (d, C-30
and C-50), 129.81 (d, C-20 and C-60), 137.43
(s, C-10), 167.25 (s, C S), 174.59 (s, C S)
45.26 (s, Me), 127.09 (d,C-40), 128.18 (d, C-30
and C-50), 129.32 (d, C-20 and C-60), 136.56
(s, C-10), 167.84 (s, C S), 175.43 (s, C S)
13.82 (q, Me), 60.58 (t, OCH2), 127.90 (d, C-40),
128.81 (d, C-30 and C-50), 129.64 (d, C-20 and
C-60), 137.04 (s, C-10, 152.21 (s, C O),
167.94 (s, C S), 176.05 (s, C S)
5f
3.54 (s, 3H, Me), 7.10–7.65
(m, 20H, Ar H)
5g
1.35 (t, J = 7.00 Hz, 3H, Me),
4.25 (q, J= 7.00 Hz, 2H,
OCH2), 7.15–7.35 (m, 5H,
Ar H), 7.98 (bs, 1H, As OH)
1.35 (t, J = 7.00 Hz, 3H, Me),
4.30 (q, J = 7.00 Hz, 2H,
OCH2), 7.10–7.50 (m, 10H,
Ar H)
1.35 (t, J = 7.00 Hz, 3H, Me),
4.25 (q, J = 7.00 Hz, 2H,
OCH2), 7.10–7.55 (m, 20H,
Ar H)
5h
5i
13.19 (q, Me), 60.45 (t, OCH2), 127.98 (d, C-40),
128.72 (d, C-30 and C-50), 129.46 (d, C-20 and
C-60), 137.05 (s, C-10), 152.21 (s, C O),
166.97 (s, C S), 176.26 (s, C S)
13.89 (q, Me), 60.71 (t, OCH2), 128.31 (d, C-40),
128.91 (d, C-30 and C-50), 129.78 (d, C-20 and
C-60), 137.20 (s, C-10), 152.80 (s, C O),
167.32 (s, C S), 175.97 (s, C S)
8a
1.30 (t, J = 7.00 Hz, 3H, Me),
4.25 (t, J = 7.00 Hz, 2H,
OCH2), 5.20 (s, 2H, CH2),
7.20–7.40 (m, 5H, Ar H),
7.79 (bs, 1H, As OH)
13.49 (q, Me), 46.31 (t, CH2), 60.71 (t, OCH2),
127.73 (d, C-40), 128.46 (d, C-30 and C-50),
129.72 (d, C-20 and C-60), 137.25 (s, C-10),
156.84 (s, C O), 167.96 (s, C S), 176.15
(s, C S)
8b
8c
8d
8e
8f
1.30 (t, J = 7.00 Hz, 3H, Me),
4.25 (t, J = 7.00 Hz, 2H,
OCH2), 5.20 (t, 2H, CH2),
7.18–7.50 (m, 10H, Ar H)
13.76 (q, Me), 46.54 (s, CH2), 60.45 (t, OCH2),
127.69 (d, C-40), 128.35 (d, C-30 and C-50),
129.66 (d, C-20 and C-60), 137.24 (s, C-10),
156.87 (s, C O), 167.50 (s, C S), 175.51
(s, C S)
13.42 (q, Me), 46.65 (t, CH2), 60.39 (t, OCH2),
127.17 (d, C-40), 128.75 (d, C-30 and C-50),
131.98 (d, C-20 and C-60), 132.67 (s, C-10),
156.65 (s, C O), 167.96 (s, C S), 175.43
(s, C S)
1.25 (t, J = 7.00 Hz, 3H, Me),
4.20 (q, J = 7.00 Hz, 2H,
OCH2), 5.25 (s, 2H, CH2)
7.50–7.80 (m, 20H, Ar H)
1.30 (t, J = 7.00 Hz, 3H, Me),
2.50 (s, 3H, Me), 4.20 (q, 2H,
J = 7.00 Hz, OCH2), 5.20
13.71 (q, Me), 27.92 (q, Me), 46.31 (t, CH ),
c
2
60.72 (t, OCH2), 127.85 (d, C-40), 128.62
(d, C-30 and C-50), 129.28 (d, C-20 and C-60),
156.98 (s, C O), 167.06 (s, C S), 176.83
(s, C S)
(s, 2H, CH2), 7.15–7.35 (m, 5H,
Ar H), 7.95 (bs, 1H, As OH)
1.35 (t, J = 7.00 Hz, 3H, Me), 2.58 13.39 (q, Me), 27.42 (q, Me), 46.76 (t, CH2),
(s, 3H, Me), 4.25 (q, J = 7.00
Hz, 2H, OCH2), 5.20 (q, 2H,
CH2), 7.18–7.50 (m, 10H,
Ar H)
60.35 (t, OCH2), 127.86 (d,C-40), 128.90
(d, C-30 and C-50), 129.43 (d, C-20 and C-60),
137.20 (s, C-10), 157.09 (s, C O), 167.76
(s, C S), 176.31 (s, C S)
14.04 (q, Me), 27.09 (q, Me), 46.85 (t, CH2),
60.81 (t, OCH2), 126.97 (d, C-40), 128.69
(d, C-30 and C-50), 129.56 (d, C-20 and C-60),
137.04 (s, C-10), 157.02 (s, C O), 167.48
(s, C S), 176.33 (s, C S)
1.30 (t, J = 7.00 Hz, 3H, Me),
2.53 (s, 3H, Me), 4.20 (q, J =
7.00 Hz, 2H, OCH2), 5.20
(s, 2H, CH2), 7.10–7.55
(m, 15H, Ar H)

Arsenical Adduct
505
HETEROCYCLIC RING FROM DITHIOL
It was already reported21 that PhAsCl2 reacts with vicinal thiol groups
on a molecule to form a stable five membered heteroatom ring and to
the development of antidotes to arsenic poisoning. Based on, we synthe-
sized five chelating agents, 1,3-dimercapto substrates 4a–c, 7a,b from
isothiocyanates. Treatment of dimercapto substrate by arsenic trioxide,
phenylarsine oxide, triphenylarsine or triphenylarsine oxide in solvent
chloroform or ethanol afforded 1,3,2-arsadithiolane derivatives 5a–i,
8a–f as shown in Scheme 2. Here, this work is relevant to the develop-
ment of antidotes to arsenic poisoning by using 1,3-dithiol compounds
4a–b, 7a,b instead of 1,2-dithiols (vicinal thiols). Dithiol compounds
1b, 4a–c, 7a,b containing 1,3-dithiol groups and if a one-to-one adduct
is formed between the arsenical and compounds 1b, 4a–c, 7a,b a six
membered heteroatom ring should be produced.
Thus, when 1,3-propanedithiol (1b) was allowed to react with pheny-
larsine oxide in dry dioxane for 5 h to afford 1,3,2-arsadithiolane
derivative 2c, as a similar frequently observed from methylarsine oxide
(MeAs O) with the johnsongrass malic enzyme (MenzSH) and dithiols
described by Knowles.37 He also proposed that reaction of arsenic com-
pounds with dithiols yields cyclic compounds which are considerably
more stable than the noncyclic compounds obtained with monothiols.38
1-Thioacetyl-3-phenyl-2-thiourea (4a) was treated with arsenic tri-
oxide in chloroform to give arsenical adduct 5a as pale yellow crystals
in 45% yield. Cyclization of 4a occurred through its tautomeric equi-
librium structure. The IR spectrum of this compound 5a showed sharp
1
1
bands at 1639, 1607 cm and other signals at 1508 and 721 cm in-
dicating the stretchings of C N (two), C C and As OH bonds, respec-
1
tively (Table I). The H NMR spectrum of 5a exhibited three-proton
singlet at 2.46 for methyl group and another five-proton multiplet at
7.18–7.35 was indicated for phenyl group. Again 13C NMR spectrum
displayed singlets at 167.06 and 175.51 for two C S was indicative
of the formation of a new 1,3,2-arsadithiolane ring. The spectrum also
showed the presence of nine carbons corresponding to C9H9N2OS2As
and this molecular formula was also supported by elemental analy-
sis. Treatment of 4a with phenyl arsenic oxide in refluxing chloroform
gave the 1,3,2-arsadithiolane derivative 5b in 52% of yellow crystals.
A perusal of resulting 1,3,2-arsadithiolane derivative 5c was similarly
readily accessible from triphenylarsine or triphenylarsine oxide in 54%
and 34% respectively as shown in Table I. Reduction of such type of
trimethylarsine oxide to trimethylarsine by thiols and dithiols includ-
ing cystine glutathione and lipoic acid was also established by Cullen
et al.39

506
A. Z. M. S. Chowdhury et al.
The reaction of 1-thiobenzoyl-3-methyl-2-thiourea (4b) with arsenic
trioxide, phenylarsine oxide, triphenylarsine, or triphenylarsine oxide
in boiling chloroform afforded 1,3,2-arsadithiolane derivative 5d–f. Via
this method, other 1,2,6-arsadithiolane derivatives 5g–i were obtained
from 1-thiobenzoyl-3-ethoxycarbonyl-2-thiourea (4c) with arsenic tri-
oxide, phenylarsine oxide, triphenylarsine, or triphenylarsine oxide in
resonable yield. The IR spectrum of the compound 5g revealed a C O
1
absorption at 1720 cm and completely disappearance of absorption
1
1
at 872 cm for As O stretching indicate the formation of 5g. Its H
NMR spectrum revealed three-proton triplet at 1.35 and two-proton
quartet at 4.25 assignable ethyl ester peaks in the molecule. The rest
of the spectrum including 13C NMR spectrum and element analysis was
in conformity with the structure accorded to 5g.
Cyclization of 1-thiobenzoyl-3-ethoxycarbonylmethyl-2-thiourea
(7a) into the 1,3,2-arsadithiolane derivative 8a occurred in refluxing
chloroform with arsenic trioxide. The IR spectrum of this compound
exhibited the absorption band at 1720 cm 1 for C O and at 1645, 1632,
1
1505 cm
for C N (two), C C groups respectively. The 1H NMR
spectrum of compound 8a showed singlet two-proton at
5.20 for
CH2 peak and 1.30, 4.25 for OCH2CH3 peaks respectively. The
aromatic five-proton appeared as multiplet at 7.20–7.40 (Table II).
The formation of the compound 8a was also proved by its 13C NMR
spectrum and also supported by elemental analysis. The desired
arsenical adducts 8b was also obtained from 7a with phenylarsine
oxide in a similar manner. Same product 8c was obtained when 7a
reacts with either triphenylarsine or triphenylarsine oxide in refluxing
chloroform (Scheme 3) and gave 53% and 39% yield.
SCHEME 3

Arsenical Adduct
507
1-Thioacetyl-3-ethoxycarbonylmethyl-2-thiourea (7b) was treated
with arsenic trioxide in chloroform at reflux temperature and gave com-
pound 8d in 39% yield. The IR spectrum of this compound 8d showed
absorption peaks at 1640, 1615 cm 1 for two C N and 1501 for C C. In
1
its H NMR spectra appeared a three-proton singlet at 2.50 for CH3
and a two-proton singlet at 5.20 for CH2 in the molecule. A two-proton
quartet at 4.20 and a three-proton triplet at 1.30 also suggested the
presence of ethyl group in the molecule. The compound 8d was further
proved by 13C NMR spectra, with the resonances at 27.92 for CH3,
46.31 for CH2, 167.06 and 176.83 C S carbons have been observed.
The presence of one ethyl ester group in the molecule was confirmed
resonances at 156.98 for C O, 60.72 for OCH2 and 13.71 for CH3
respectively.
Compound 7b with phenylarsine oxide, it gave the 1-phenyl-1,3,2-
arsadithiolane derivative 8e in 44% yield. On reaction with 7b, triph-
enylarsine or triphenylarsine oxide afforded the 2,2,2-triphenyl-1,3,2-
arsadithiolane derivative 8f as brown crystals in 46% and 31% yield.
The products 5a, 5b, 5d, 5g, 5h, 8a, 8e were purified by column
chromatography (eluent chloroform-acetone, 9:2). The 2-hydroxy-1,3,2-
arsadithiolane derivative 5a, 5d, 5g, 8a, 8d are moderately stable, only
for few days, toward atmospheric moisture and their spectral data are
vary considerably according to their sample history.
Thus, the above dimercapto substrate 4a–c, 7a,b has the advantage
of easy accessibility by simple method of available starting materials,
mild reaction conditions, also overall in good yields and the cyclization
step with high substitution in the 1,3,2-arsadithiolane six membered
heterocyclic ring 5a–i, 8a–f.
EXPERIMENTAL
Melting points were determined on a Yanaco hot stage apparatus and
1
are uncorrected. H and 13C NMR spectra were recorded on a JNM–
ALPHA 500 (500 MHz) spectrometer in CDCl3 using TMS as internal
standard and the chemical shifts are expressed in ppm. IR spectra
were recorded on KBr disc with a JASCO FT-IR spectrophotometer and
the data are given in cm 1. Elemental analyses were performed on an
EA 1108 (Fisons Instruments) Elemental Analyzer. Thin layer chro-
matography (TLC) was performed on Merck silica gel 60 F254 precoated
plastic sheets (layer thickness 0.2 mM) and spots were detected by UV
lamp (Model UVGL 58). Column chromatography was carried out at
room temperature with silica gel G60. All evaporations were conducted
under reduced pressure at bath temperature below 40 C.

508
A. Z. M. S. Chowdhury et al.
General Procedure for the Synthesis of Thiourea
Derivatives 4a--c, 7a,b
A solution of thioacetamide or thiobezamide (20 mmol) and appropriate
isothiocyanate (3a–c, 6, 20 mmol) in pyridine (12 ml) was refluxed for
5 h (4a–c) or for 2 h (7a,b). The reaction mixture was diluted with
ethanol and cooled. The resulting crystals were collected by filtration
and recrystallized from ethanol to give 4a–c, 7a,b as needles.
General Procedure for the Cyclization Reaction:
Synthesis of Compounds 2a--c, 5a--i, 8a--f
A mixture of 2-hydroxycyclohexanone40 or dimercapto compound
(4 mmol) and arsenic compound (4 mmol) in dry dioxane or chloroform
(7 ml) was refluxed for 5 to 6 h (except 2a, 24 h and 2b, 12 h). The solvent
was evaporated in vacuo. The obtained solid was choromatographed on
silica gel in chloroform-acetone (9:2) or recrystallizated from ethanol.
Alternatively, carrying out the above experiments, using the ethanol
instead of chloroform led, also to the formation of 5a–i, 8a–f in poor
yield.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to the Japan Science
Technology Agency (JST) and Japan International Science Technology
Exchange Centre (JISTEC) for their financial support.
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