Reaction of 2-aminothiophenol with acrylic acid and conversion of the resultant adducts

Article abstract of DOI:10.1007/s10593-006-0076-4

The reaction of acrylic acid with 2-aminothiophenol gives 5-carboxyethyl-2,3-dihydro-5H-benzo[b][1,4]-thiazepin-4-one and N-[2-(carboxyethylthio)phenyl]-β-alanine, while the reaction of acrylic acid with bis(2-aminophenyl) disulfide gives bis[2-(carboxyet

Full text of DOI:10.1007/s10593-006-0076-4

Chemistry of Heterocyclic Compounds, Vol. 42, No. 2, 2006
REACTION OF 2-AMINOTHIOPHENOL
WITH ACRYLIC ACID AND CONVERSION
OF THE RESULTANT ADDUCTS
K. Rutkauskas and Z.-I. Beresnevicius
The reaction of acrylic acid with 2-aminothiophenol gives 5-carboxyethyl-2,3-dihydro-5H-
benzo[b][1,4]-thiazepin-4-one and N-[2-(carboxyethylthio)phenyl]-β-alanine, while the reaction of
acrylic acid with bis(2-aminophenyl) disulfide gives bis[2-(carboxyethylamino)phenyl] disulfide. The
action of potassium thiocyanate in acid medium on the carboxyethylamino derivatives yields
1-[2-carboxyethylthio)phenyl]dihydro-4(1H,3H)-pyrimidinone-2-thione,
bis-{2-[dihydro-4(1H,3H)-
pyrimidinone-2-thion-1-yl]phenyl} disulfide, and 3-(2-mercaptobenzothiazol-3-yl)propanoic acid.
Keywords: acrylic acid, β-alanine, 2-aminothiophenol, hydrobenzothiazepinone disulfide,
mercaptobenzothiazole, phenyldihydropyrimidinonethione.
The products of the reaction of aromatic amines with acrylic acid and its homologs, namely,
N-substituted β-alanines, are starting compounds for the synthesis of derivatives of hexahydropyrimidine,
quinolinone, quinolizidinedione, and other heterocyclic systems [1-3]. In most cases, the preparation of such
N-substituted β-alanines does not pose special difficulties and the reaction course is clearcut. However, in the
case of anilines with reactive groups in the ortho position, the direct preparation of the corresponding alanines is
not always possible.
Mills and Whitworth [4] described the reaction of 2-aminothiophenol (1) with a series of unsaturated
compounds, including acrylic acid, and found that, upon increasing the reaction temperature, 2,3-dihydro-5H-
benzo[b][1,4]-thiazepin-4-one (2) is formed in about 25% yield, i.e., the mercapto group undergoes nucleophilic
addition to the unsaturated α,β-bond in acrylic acid, while the amino group undergoes intramolecular acylation.
In a continuation of a study of the transformations of N-substituted β-alanines to give heterocyclic
products, we have thoroughly examined the reaction of 2-aminothiophenol with acrylic acid. Bicyclic
thiazepinone 2 is the major product isolated when the ratio of thiophenol 1 to acrylic acid is 1:1 both at room
temperature in toluene and upon heating. Increasing the amount of acrylic acid leads to the formation of
N-(2-carboxyethylthiophenyl)-β-alanine (3), which crystallizes out of the reaction mixture during the reaction
both at room temperature in toluene and upon heating. When the molar ratio of thiophenol 1 to acrylic acid is
1:3, the yield of β-alanine 3 reaches 65%, while bicyclic thiazepinone 2 separates out of the reaction mixture by
1
crystallization. The H NMR spectrum of 3 shows a set of four methylene group triplets. The NCH2 group
protons appear at lower field than the SCH2 group protons.
__________________________________________________________________________________________
Kaunas Technological Institute, LT-50254 Kaunas, Lithuania; e-mail: zigmuntas.beresnevicius@ktu.lt.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 256-261, February, 2006. Original article
submitted December 12, 2004.
0009-3122/06/4202-0227©2006 Springer Science+Business Media, Inc.
227

Heating 2 with acrylic acid in toluene gives 5-carboxyethyl-2,3-dihydro-5H-benzo[b][1,4]thiazepin-4-
one (4). The intramolecular acylation of dicarboxy derivative 3 upon heating in toluene at reflux until water is no
longer released also gives thiazepinone 4. The 1H NMR spectrum of 4 lacks the amide group proton at 5.51 ppm,
while its 13C NMR spectrum lacks the signal for the carboxyl group carbon at 172.78 ppm but shows a C=O
group signal at 170.73 ppm.
H
3
8
N
12
2
OH
NH2
SH
4
5
2
CH2=CHCOOH
7
O
S
1
10
6
9
11
1
OH
3
O
CH2=CHCOOH
∆
KSCN
+
∆
H
∆
O
H
,
N
CH =CHCOOH
,
2
5
O
S
6
4
3
∆
O
OH
9
2
12
8
11
7
1
S
S
OH
2
10
O
3
2
N
N
7
8
11
13
4
5
10
12
NH
1
S
9
6
4
O
5
Heating dicarboxylic acid 3 with potassium thiocyanate in acetic acid with the subsequent addition of
hydrochloric acid gives 1-[2-(carboxyethylthio)phenyl]dihydro-4(1H,3H)-pyrimidinone-2-thione (5). The
13C NMR spectrum of 5, in comparison with the spectrum of 3, lacks the carboxyl group signal for the
carboxyethylamino fragment at 173.28 ppm but shows new signals for heterocyclic C=S and C=O groups at
179.02 and 166.86 ppm, respectively. The signal for the SCH2 group at 33.78 ppm and signal for the methylene
group carbon of the CH2CO2H fragment at 28 ppm remain unchanged, while the other two signals for methylene
1
group carbons are shifted from 33.36 to 30.55 ppm and from 38.72 to 47.63 ppm. The H NMR signal for the
secondary amino group found at 5.51 ppm in starting 3 is lacking and a new heterocyclic amide group signal is
seen at 12.31 ppm. The hydrogen atoms of the heterocyclic methylene groups become nonequivalent, probably
due to hindered rotation about the nitrogen–carbon bond such that the NCH2 group protons give two doublet of
doublets of doublets with coupling constants 7.5 and 13.5 Hz, while the CH2CO group protons appear as
multiplets at 3.10-3.26 ppm (Scheme 1).
Since N-(2-mercaptophenyl)-β-alanine (8) cannot be obtained directly from 2-aminothiophenol, this
product was synthesized by the reductive cleavage of the disulfide bridge of bis[(2-carboxyethylamino)phenyl]
disulfide (7) obtained in the reaction of diaminodiphenyl disulfide 6 with acrylic acid in toluene. In turn, diamine
6 was synthesized by the oxidation of aminothiophenol (1) upon heating in DMSO.
Bis{2-[dihydro-4(1H,3H)-pyrimidinone-2-thion-1-yl]phenyl} disulfide (9) was synthesized from diacid
7 and potassium thiocyanate analogously to the synthesis of dihydropyrimidinonethione 5. The action of zinc
powder in a mixture of hydrochloric acid and 2-propanol on disulfide 9 leads to the reductive cleavage of the
disulfide bond to give 1-(2-mercaptophenyl)dihydro-4(1H,3H)-pyrimidinone-2-thione (10), which also may be
obtained directly from diacid 7 without isolation of disulfide 9. Bispyrimidinonethione 9 is converted to 10 also
228

Scheme 1
NH2
DMSO
CH2=CHCOOH
S
1
S
NH2
6
OH
O
HO
NH
HN
+
O
SH
Zn, H
S
S
OH
O
8
N
H
7
O
N
KSCN,
+
HN
H
, ∆
S
O
S
HN
KSCN
,
S
+
+
a) Zn, H
–
,
∆
H
N
S
N
S
SH
+
;
H
b) OH
9
NH
O
10
O
OH
H
N
CH2=CHCOOH
N
S
S
S
S
12
11
by the action of aq. NaOH with subsequent heating at reflux with hydrochloric acid. Opening of the
dihydrouracil ring can also occur upon the action of alkali solutions with renewed formation of this ring upon the
heating with strong acids [1, 2].
N-Phenyl-β-alanines with o-hydroxy or o-amino groups react with urea to form derivatives of
benzoxazole [5] or benzimidazole [6]. In our case, the action of potassium thiocyanate on
N-(2-mercaptophenyl)-β-alanine (6) gave 3-(2-mercaptobenzothiazol-3-yl)propanoic acid (11), which was also
obtained by heating mercaptobenzothiazole (12) with acrylic acid in toluene.
229

EXPERIMENTAL
1
13
The H and C NMR spectra were taken on a JOEL FX-100 spectrometer at 100 MHz and Varian 300
spectrometer at 300 MHz using TMS or HMDS (δ 0.05 ppm) as the internal standard and DMSO-d6 as the
solvent (acetone-d6 for 11). The mass spectra were taken on a Waters (micromas) ZQ 2000 mass spectrometer
with chemical ionization and 20 eV ionizing voltage. The reaction course and purity of the products were
monitored by thin-layer chromatography on Silufol 254 and Silufol UV-254 plates.
2,3-Dihydro-5H-benzo[b][1,4]thiazepin-4-one (2). A mixture of 2-aminothiophenol (6.25 g, 50 mmol),
acrylic acid (3.4 ml, 50 mmol), and toluene (20 ml) was heated at reflux for 2 h and then cooled. The crystalline
precipitate was filtered off and washed with ether to give 3.5 g (39.5%) 2; mp 220-221°C (2-propanol–water,
1
1:1; mp 220-221°C [4]). H NMR spectrum, δ, ppm (J, Hz): 9.73 (1H, s, NH); 7.51 (1H, d, J = 7.3, ArH); 7.34
(1H, d, J = 7.3, ArH); 7.12 (2H, t, J = 7.3, ArH); 3.37 (2H, t, J = 6.9, SCH2); 2.43 (2H, t, J = 6.9, COCH2). Mass
spectrum, m/z (Irel, %): 179.3 [M]+ (40). Found, %: C 59.80; H 5.60; N 7.90. C9H9NOS. Calculated, %: C 60.31;
H 5.06; N 7.81.
N-[2-(Carboxyethylthio)phenyl]-β-alanine (3). A. A mixture of aminothiophenol 2 (8.8 g, 70 mmol),
acrylic acid (10.2 ml, 15 mmol), and toluene (20 ml) was heated at reflux for 5 h. The solvent was decanted off
and remaining solid was crystallized from 1:1 2-propanol–water to give 5.6 g (29.5%) 3; mp 129-130°C.
B. A mixture of 2-aminothiophenol (1.25 g, 10 mmol) and acrylic acid (2.1 ml, 30 mmol) in toluene
(10 ml) was maintained at room temperature for 72 h. The light-greenish crystalline precipitate was filtered off,
1
washed with ether, and crystallized from 1:1 2-propanol–water to give 1.76 g (65.4%) 3. H NMR spectrum,
δ, ppm (J, Hz): 12.31 (2H, s, 2OH); 7.31 (1H, d, J = 7.5, ArH); 7.19 (1H, t, J = 7.5, ArH); 6.67 (1H, d, J = 7.5,
ArH); 6.58 (1H, t, J = 7.5, ArH); 5.51 (1H, s, NH); 3.38 (2H, t, J = 6.8, NCH2); 2.84 (2H, t, J = 6.8, SCH2); 2.55
(2H, t, J = 6.8, COCH2); 2.40 (2H, t, J = 6.8, COCH2). 13C NMR spectrum, δ, ppm: 173.8 (C(12)); 172.78 (C(11));
148.55 (C(2)); 135.77 (C(3)); 130.12 (C(4)); 116.24 (C(5)); 116.05 (C(6)); 109.96 (C(1)); 38.72 (C(7)); 33.77 (C(10));
33.36 (C(8)); 29.04 (C(9)). Mass spectrum, m/z (Irel, %): 270.3 [M]+ (100), 252 [M - H2O]+ (5). Found, %: C 53.91;
H 5.63; N 5.40. C12H15NO4S. Calculated, %: C 53.56; H 5.57; N 5.20.
5-Carboxyethyl-2,3-dihydro-5H-benzo[b][1,4]thiazepin-4-one (4). A solution of alanine 3 (1.39 g, 5.2
mmol) in toluene (30 ml) was heated at reflux with a Dean–Stark trap for 10 h. The solvent was distilled off to
1
give 0.35 g (27%) 4; mp 105-106°C (2-propanol). H NMR spectrum, δ, ppm (J, Hz): 11.71-12.72 (1H, br. s,
OH); 7.30 (1H, d, J = 15, H-6 Ar); 7.20 (1H, t, J = 15, H-4 Ar); 6.62 (1H, t, J = 15, H-5 Ar); 6.56 (1H, d, J = 15,
H-3 Ar); 3.37 (2H, t, J = 6.6, NCH2); 2.84 (2H, t, J = 6.6, COCH2); 2.55 (2H, t, J = 7.2, COCH2); 2.40 (2H, t, J =
7.2, SCH2). 13C NMR spectrum, δ, ppm: 173.4 (C(12)); 170.7 (C(11)); 145.2 (C(2)); 135.2 (C(6)); 130.1 (C(5)); 127.2
(C(3)); 127.12 (C(4)); 109.9 (C(1)); 44.5 (C(7)); 39.2 (C(9)); 33.4 (C(8)); 29.1 (C(10)). Found, %: C 57.52; H 5.41; N
5.62. C12H13NO3S. Calculated, %: C 57.36; H 5.21; N 5.57.
1-[2-(Carboxyethylthio)phenyl]dihydro-4(1H,3H)-pyrimidinone-2-thione (5). A mixture of diacid 3
(1.35 g, 5 mmol), potassium thiocyanate (2.5 g, 25 mmol), and glacial acetic acid (10 ml) was heated at reflux
for 8 h. Then, concentrated hydrochloric acid (5 ml) was added and heating at reflux was continued for
additional 30 min. Water (100 ml) was added to the reaction mixture. The precipitate formed was filtered,
1
washed with water and ethanol, and dried to give 0.7 g (23%) 5; mp 181-182°C (2-propanol). H NMR
spectrum, δ, ppm (J, Hz): 11.36 (1H, s, NH); 7.55 (1H, d, J = 7.5, ArH); 7.31-7.37 (3H, m, ArH); 3.88 (1H, ddd,
J = 7.5, J = 13.5, NCH)); 3.71 (1H, ddd, J = 7.5, J = 13.5, NCH); 3.26-3.10 (2H, m, J = 7.5, COCH2); 2.82 (2H,
t, J = 7.5, COCH2); 2.54 (2H, t, J = 7.5, SCH2). 13C NMR spectrum, δ, ppm: 179.21 (C(12)); 172.62 (C(11));
166.86 (C(13)); 143.59 (C(2)); 133.98 (C(3)); 129.31 (C(4)); 128.68 (C(6)); 128.45 (C(5)); 127.12 (C(1)); 47.63 (C(7));
33.78 (C(8)); 30.54 (C(10)); 27.49 (C(9)). Found, %: C 50.83; H 5.62; N 9.11. C13H14N2O3S2. Calculated, %:
C 50.33; H 5.55; N 9.03.
Bis(2-aminophenyl) Disulfide (6) was obtained in 77% yield according to Karabinos [7] from
2-aminothiophenol by heating in DMSO at 80-90°C for 8 h.
230

Bis[2-(carboxyethylamino)phenyl] Disulfide (7). A mixture of disulfide 6 (4.96 g, 20 mmol), acrylic
acid (2.9 g, 40 mmol), and toluene (30 ml) was heated for 5 h at 70-80°C. The liquid fractions were distilled off
in vacuum. The remaining thick mass was washed with water, dissolved in 10% aq. NaOH, and extracted with
three 20-ml ether portions. The alkaline solution was treated with activated charcoal, filtered, and brought to
pH 4-5 by adding acetic acid. The precipitate formed was filtered off to give 1.95 g (25%) 7; mp 98-99.5°C
1
(2-propanol–water, 1:1). H NMR spectrum, δ, ppm (J, Hz): 9.74 (2H, s, 2NH); 7.05-7.60 (8H, m, ArH); 2.43
(4H, t, J = 7.2, 2NCH2); 3.4 (4H, t, J = 7.2, 2COCH2). Mass spectrum, m/z (Irel, %): 393.4 [M]+ (20). Found, %:
C 55.42; H 5.34; N 7.28. C18H20N2O4S2. Calculated, %: C 55.10; H 5.10; N 7.14.
N-(2-Mercaptophenyl)-β-alanine (8). Disulfide 7 (3.92 g, 10 mmol) was dissolved in 2-propanol
(15 ml). Then, 10% hydrochloric acid (20 ml) and zinc powder (3 g) were added and the mixture was heated for
15 min. The solution was cooled and the precipitate formed was filtered off to give 3.75 g (90%) 8;
1
mp 132-133.5°C (2-propanol). H NMR spectrum, δ, ppm (J, Hz): 7.27 (1H, d, J = 9.4, ArH); 7.03 (1H, d,
J = 9.4, ArH); 6.85-6.89 (2H, m, ArH); 5.47 (1H, s, 1NH); 4.95 (1H, s, SH); 2.49 (2H, t, J = 5.5, NHCH2); 2.43
(2H, t, J = 5.5, COCH2). Mass spectrum, m/z (Irel, %): 198.3 [M]+ (100), 180.3 [M - 18]+ (35). Found, %:
C 54.98; H 5.81; N 7.22. C9H11NO2S. Calculated, %: C 54.80; H 5.62; N 7.10.
Bis{2-[dihydro-2(1H,3H)-pyrimidinone-2-thion-1-yl]phenyl} Disulfide (9). A mixture of diacid 7 (3.7
g, 10 mmol), potassium thiocyanate (7.8 g, 80 mmol), and acetic acid (20 ml) was heated at reflux for 18 h.
Then, concentrated hydrochloric acid (5 ml) was added and the mixture was heated for an additional 15 min.
After cooling, the thick mass precipitated was crystallized from 2-propanol to give 5.7 g (60%) 9;
1
mp 286-287.5°C. H NMR spectrum, δ, ppm (J, Hz): 10.2 (2H, s, 2NH); 7.30-7.62 (8H, m, ArH); 3.5 (4H, t,
J = 7.1, 2NCH2); 2.54 (4H, t, J = 7.1, 2COCH2). Mass spectrum, m/z (Irel, %): 465.7 [M]+ (20). Found, %:
C 50.41; H 4.02; N 12.05. C20H18N4O2S4. Calculated, %: C 50.61; H 3.82; N 11.80.
1-(2-Mercaptophenyl)dihydro-2(1H,3H)-pyrimidinone-2-thione (10). A. Disulfide 9 (2.37 g,
50 mmol) was heated at reflux in 10% aq. NaOH (30 ml) for 10 min. The reaction mixture was filtered and the
filtrate was brought to pH 3 by adding hydrochloric acid and then heated at reflux for 10 min to give 1.6 g
(67.2%) 10; mp 241-242.5°C.
B. Disulfide 9 (2.37 g, 50 mmol) was dissolved in 2-propanol (10 ml) and 10% hydrochloric acid
(15 ml) was added. Then, zinc powder (3 g) was added to the stirred solution heated to 60-70°C. Heating was
continued until the brown color disappeared. The hot solution was filtered and cooled. The precipitate formed
1
was filtered off to give 1.62 g (68%) 10. H NMR spectrum, δ, ppm (J, Hz): 11.62 (1H, s, NH); 7.28-7.60 (4H,
m, ArH); 3.2 (2H, t, J = 7.1, NCH2); 2.51 (2H, t, J = 7.1, COCH2). Mass spectrum, m/z (Irel, %): 239.5 [M]+ (20).
Found, %: C 50.82; H 4.13; N 11.87. C10H10N2OS2. Calculated, %: C 50.40; H 4.23; N 11.75.
3-(2-Mercaptobenzothiazol-3-yl)propanoic Acid (11). A mixture of 2-mercaptobenzothiazole (12)
(3.34 g, 20 mmol), acrylic acid (1.58 g, 22 mmol), and toluene (15 ml) was heated at reflux for 10 h. The
reaction mixture was cooled and the precipitate formed was filtered off to give 2.2 g (45.8%) 11; mp 141-142°C
(2-propanol–water, 1:1). 1H NMR spectrum, δ, ppm (J, Hz): 7.3-8.2 (4H, m, ArH); 3.54 (2H, t, J = 6.9, NCH2);
2.92 (2H, t, J = 6.9, COCH2). Found, %: C 50.71; H 3.93; N 5.98. C10H9N2O2S2. Calculated, %: C 50.21; H 3.76;
N 5.86.
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