Reactions of o-aminothiophenol and o-aminophenyl disulfide with itaconic anhydride and (-)-dimenthyl itaconate: Access to enantiomerically pure 1,5-benzothiazepines and benzothiazolyl-2-methylacrylic acid

Article abstract of DOI:10.1055/s-2006-958977

A facile chemo- and regioselective reactions of o-aminothiophenol (o-ATP) with itaconic anhydride is described. 1,5-Benzothiazepinyl-3-acetic acid is obtained in 81% yield via the exclusive Michael type addition of the thiol unit from o-ATP to the carbon-

Full text of DOI:10.1055/s-2006-958977

PAPER
457
Reactions of o-Aminothiophenol and o-Aminophenyl Disulfide with Itaconic
Anhydride and (–)-Dimenthyl Itaconate: Access to Enantiomerically Pure
1,5-Benzothiazepines and Benzothiazolyl-2-methylacrylic Acid1
C
hemo- and Regiosele
d
ctive Reactio
.
ns of
o
-Ami
M
nothiophenol
w
ith Itac
e
onic Anhyd
r
ride ajuddin Baag,a Manoj Kumar Sahoo,a Vedavati G. Puranik,b Narshinha P. Argade*a
a
b
Received 6 October 2006; revised 7 November 2006
O
R'
O
Abstract: A facile chemo- and regioselective reactions of o-ami-
nothiophenol (o-ATP) with itaconic anhydride is described. 1,5-
Benzothiazepinyl-3-acetic acid is obtained in 81% yield via the ex-
clusive Michael type addition of the thiol unit from o-ATP to the
carbon–carbon double bond in itaconic anhydride followed by an
intramolecular anhydride ring opening with an amine unit. The
moderately stereoselective Michael type addition of the thiol unit
from o-ATP to (–)-dimenthyl itaconate to obtain a mixture of dia-
stereomers in a 7:3 ratio in 82% yield has been demonstrated. The
reductive sulfur–sulfur bond cleavage in the dicarboxylic acid, 2-
({2-[2-(3-carboxybut-3-enoylamino)phenyldisulfanyl]phenylcar-
bamoyl}methyl)acrylic acid, to the corresponding benzothiazolyl-
2-methylacrylic acid in 84% yield, instead of the desired benzothio-
azocine is also reported.
HO
R
S
O
S
OH
N
R
N
H
benzothiazolylacrylic acids5a
(R = OH, OMe)
benzothiazinylacetic acids5b,c
(R = H, Me; R' = H, Me, Ph)
H
R
H
H
S
O
S
O
OH
OH
N
H
O
N
H
O
benzothiazinylacrylic acids5d
(R = Me)
benzothiazinylidineacetic acids5e
Key words: o-aminothiophenol, itaconic anhydride, dimenthyl ita-
conate, chemo-, regio- and stereoselective reactions, benzothiaz-
epines, benzothiazoles, synthesis
H
O
N
S
N
S
N
S
S
Heterocycles play a pivotal role in pharmaceutical and
agrochemical industries.2 The 1,5-benzothiazepines are
known to have antimitochondrial sodium–calcium ex-
changer (mNCE),3a angiotensin converting enzyme inhib-
itor,3b anti-inflammatory,3c anticancer,3d vasodilating,3e
antihypertensive,3f platelet aggregation inhibitory,3g an-
tipsychotic,3h antidiabetic,3i cardioprotective,3j antifun-
gal,3k antibacterial3l and anti-HIV3m activities.
Development of new facile routes to these seven-mem-
bered 1,5-benzothiazepines is a challenging task of cur-
rent interest.4 To date, the nucleophilic reactions of a
variety of cyclic anhydrides/imides with ortho-ami-
nothiophenol (o-ATP) have been used to design structur-
ally interesting and biologically important five and six-
membered thioaza-heterocyclic systems via the intramo-
lecular Michael addition, condensation and dehydration
pathway5 (Figure 1). In continuation of our studies6 on cy-
clic anhydride chemistry to design bioactive natural and
unnatural heterocyclic compounds, we felt that, with a
proper combination of reactivity and selectivity, the ita-
conic anhydride (2) and o-ATP (1) could be used as poten-
tial building blocks to synthesize higher-membered
heterocycles. We now report an easy access to enantio-
N
N
H
O
Ph
trans-bisbenzothiazine5f
pyrrolobisbenzothiazine5f
Figure 1 Benzothiazoles and benzothiazines designed from o-ami-
nothiophenol and maleic anhydrides/maleimide
merically pure 1,5-benzothiazepines and benzothiazolyl-
methylacrylic acid starting from anhydride 2 and o-ATP
(1) (Schemes 1– 3).
The Michael-type additions of aromatic thiols to activated
carbon–carbon double bonds and nucleophilic ring open-
ing of cyclic anhydrides with primary aromatic amines are
well known in the litrature.7,8 We envisaged that in the re-
action of itaconic anhydride (2) with o-ATP (1), the
Michael type addition of thiol to a highly activated car-
bon–carbon double bond in itaconic anhydride (2) fol-
lowed by an intramolecular nucleophilic ring opening of
an adjacent anhydride carbonyl with an amine moiety
would provide benzothiazepinylacetic acid 4a. However,
the first nucleophilic regioselective ring opening of anhy-
dride 2 with o-ATP (1) at the unconjugated carbonyl with
primary amine moiety followed by intramolecular dehy-
drative condensation/Michael type addition of thiol unit
could also provide an easy access to the benzothiazole/
benzothioazocine system. Hence, we performed the reac-
tion of anhydride 2 with o-ATP (1) in tetrahydrofuran at
room temperature to test this reaction and obtained a sin-
SYNTHESIS 2007, No. 3, pp 0457–0463
x
x
.
x
x
.2
0
0
7
Advanced online publication: 08.01.2007
DOI: 10.1055/s-2006-958977; Art ID: Z20306SS
© Georg Thieme Verlag Stuttgart · New York

458
M. M. Baag et al.
PAPER
gle product in 81% yield (Scheme 1). The H and 13C
NMR data of the product revealed a very clean formation
of Michael type addition–condensation/condensation–
Michael-type addition products 4a/16, ruling out the for-
mation of thiazole 15 (Scheme 3). It was difficult to con-
clusively assign the structure 4a or 16 to the formed
product on the basis of NMR data and hence we carried
out the reaction of itaconic acid with o-ATP (1) at room
temperature and obtained the Michael adduct 5a in 70%
yield. Similarly the reaction of dimethyl itaconate with o-
ATP (1) also furnished the desired adduct 5b in 74%
yield. The water soluble carbodimide, N-ethyl-N¢-(3-di-
methylaminopropyl)carbodiimide hydrochloride (EDCI),
induced regioselective intramolecular dehydrative cy-
clization of diacid 5a to give the same product in 88%
yield, which was earlier obtained from the reaction of 1
and 2 (see above). Since the formation of seven-mem-
bered rings are preferred over the formation of 8-mem-
bered rings,9 we propose here the formation of
benzothiazepinylacetic acid 4a. The benzothiazepinylace-
tic acid 4a was further characterized as its methyl and eth-
yl esters 4b and 4c. Finally, we confirmed the formation
of seven-membered benzothiazepine 4a by X-ray crystal-
lographic data (Figure 2) ruling out the possibility of
formation of the eight-membered compound benzothio-
azocine 16. From these observations we propose that in
the reaction of itaconic anhydride (2) with o-ATP (1),
chemoselective Michael type addition of thiol takes place
first to form the unisolable intermediate 3, the amine moi-
ety of which condenses in an intramolecular fashion with
the adjacent anhydride carbonyl to furnish the benzothiaz-
epine 4a. Herein, an addition of thiol to the carbon–carbon
double bond on an anhydride system before the anhydride
ring opening with an amine moiety is shown as an exam-
ple of delicately balanced selectivity.
1
Figure 2 ORTEP diagram of 4a10
the (–)-dimenthyl itaconate (6) from the reaction of ita-
conic anhydride (2) with natural (–)-menthol in 80% yield
(Scheme 2). In our hands the reaction of o-ATP (1) with
dimenthyl ester 6 in THF at room temperature and also
under reflux condition was not successful and the TLC of
the reaction mixture indicated the clear presence of both
the starting materials along with slight formation of the
corresponding disulfide 12 (Scheme 3). The stereoselec-
tive reaction of o-ATP (1) with the chiral diester 6 in gla-
cial acetic acid at room temperature furnished the desired
adduct 7a in 82% yield in 36 hours. The 1H NMR data of
product 7a revealed that the reaction was moderately ste-
reoselective and the mixture of two diastereomers had
formed in nearly 7:3 ratio (from the comparison of the rel-
ative integrations of one of the a-methyl protons). The
TLC of the mixture of diastereomers in 7a did not show
any resolution and separation of these two diastereomers
by flash column chromatography was also not successful
in our hands. The adduct 7a on acid-catalyzed hydrolysis
gave the diacid 8a in 86% yield. As expected, the carbo-
diimide EDCI induced regioselective ring closure of 8a
yielded the 1,5-benzothiazepinyl-1,3-acetic acid (9a) in
88% yield. Finally, for the separation of the two enan-
tiomers of 9a and their stereochemical assignments, we
transformed 9a into two diastereomers 10 and 11 in 90%
yield, by reacting 9a with (+)-(R)-phenylethylamine. The
mixture of diastereomers 10 and 11 was easily separated
by flash column chromatography to obtain pure 10 and 11
with quantitative recovery (10:11 = 30:70).
Next, we planned to study the stereoselective addition of
thiol from o-ATP (1) to the itaconate system and prepared
O
O
O
SH
S
i
The mixture of diastereomers in 7a was semi-solid and af-
ter three successive recrystallizations from petroleum
ether, gave the minor diastereomer 7b as a fine powder
with only 11% recovery, but with 98% de. This observa-
tion indicates that the major isomer has higher solubility
in petroleum ether. Due to the powder nature of 7b, we
were unable to get the X-ray crystallographic data to fix
the stereochemistry of the newly generated chiral centre.
The single isomer 7b on hydrolysis followed by ring clo-
sure gave the desired enantiomerically pure 1,5-benzothi-
azepinylacetic acid 9b in 76% yield. The reaction of 9b
with (+)-(R)-phenylethylamine gave compound 10 in
90% yield. On the basis of X-ray crystallographic data of
diastereomer 10 (Figure 3), we could assign the R-config-
uration to the newly generated chiral centre in 7b and 10
and consequently, the S-configuration to the chiral center
in 11.
O
O
+
(81%)
NH2
NH2
O
1
[3]
2
iii (74%)
ii (70%)
O
O
OR
OR
S
(for 5a)
iv
S
CH2COOR
(88%)
N
H
O
NH2
4a (R = H)
5a (R = H)
v
(95/92%)
5b (R = Me)
4b,c (R = Me/Et)
Scheme 1 Reagents and conditions: (i) THF, r.t., 12 h (81%); (ii)
itaconic acid, THF, r.t., 36 h (70%); (iii) dimethyl itaconate, THF, r.t.,
24 h (74%); (iv) EDCI, DMAP (cat.), THF, r.t., 4 h (88%); (v) MeOH/
EtOH, H+/H2SO4, 50 °C, 2 h (95/92%).
Synthesis 2007, No. 3, 457–463 © Thieme Stuttgart · New York

PAPER
Chemo- and Regioselective Reactions of o-Aminophenyl Disulfide with Itaconic Anhydride
459
O
O
O
O
H
H
S
S
i
OM
OM
ii
OM
OM
OH
OH
iii
O
(80%)
(82%)
(86%)
NH2
NH2
2
O
O
8a (40% ee)
O
O
7a (40% de)
7b (98% de)
(11%)
vi
6 (M = l-menthyl)
(88%)
iv
S
S
N
O
Me
O
Me
S
O
H
H
H
v
+
N
H
Ph
N
Ph
(90%)
OH
N
H
H
N
H
O
O
H
O
11 (70%)
10 (30%)
9a (40% ee)
O
O
H
H
S
H
O
S
S
OH
OH
iv
(88%)
iii
(86%)
OM
OM
OH
NH2
N
NH2
H
O
O
8b (98% ee)
7b (98% de)
9b (98% ee)
O
(90%)
v
10
a: diastereomeric mixture with 40% de, b: diastereomeric mixture with 98% de
Scheme 2 Reagents and conditions: (i) l-menthol, p-TSA, toluene, reflux, 36 h (80%); (ii) o-aminothiophenol, anhyd AcOH, r.t., 36 h (82%);
(iii) (a) AcOH–HCl (3:1), reflux, 12 h, (b) 10% aq NaHCO3, (c) AcOH (86%); (iv) EDCI, DMAP (cat.), THF, r.t., 4 h (88%); (v) (R)-(+)-1-
phenylethylamine, EDCI, DMAP (cat.), THF, r.t., 4 h (10/11 = 3:7, 90%); (vi) three recrystallizations from petroleum ether (11%).
disulfide (12) with 2.2 equivalents of itaconic anhydride
(2) in tetrahydrofuran at room temperature and obtained
the dicarboxylic acid 13 in 81% yield (Scheme 3). The
triphenylphosphine-induced reductive cleavage of the sul-
fur–sulfur bond in diacid 13 formed the expected but
unisolable intermediate acid 14, which by an in situ in-
tramolecular dehydrative cyclization furnished the 2-ben-
zothiazo-2-ylmethylacrylic acid 15 in 84% yield. The
expected benzothioazocine 16 was not obtained, indicat-
ing the reluctance for the intramolecular Michael type ad-
dition of thiol in 14 to form the eight-membered
heterocycle.
Figure 3 ORTEP diagram of 1010
In summary, we have demonstrated chemo-, regio- and
stereoselective reactions of o-ATP (1) with itaconic anhy-
dride (2) and (–)-dimenthyl itaconate (6) to obtain the cor-
responding racemic and enantiomerically pure 1,5-
benzothiazepines in very good yields. The remarkably se-
lective addition of the thiol unit from o-ATP (1) to the ac-
tivated carbon–carbon double bond in itaconic anhydride
As the activation of a,b-unsaturated double bond by the
carboxylic acid unit in itaconic acid is sufficient for
Michael type addition of the thiol unit from o-ATP
(Scheme 1, 1 → 5a), we felt that the o-mercapto-a-meth-
ylenesuccinanilic acid 14 would be a potential precursor
for the synthesis of benzothioazocine 16. Hence to obtain
the acid 14, we performed the reaction of 2-aminophenyl
H
H
O
S
OH
H
H
N
S
S
S
S
15
O
SH
HN
O
NH2
ii
i
(84%)
OH
CO2H
(81%)
N
H
O
NH
NH2
S
13
COOH
[14]
12
O
x
HN
CO2H
O
16
Scheme 3 Reagents and conditions: (i) itaconic anhydride, THF, r.t., 8 h (81%); (ii) TPP, 1,4-dioxane–water (4:1), H+/HCl, r.t., 2 h (84%).
Synthesis 2007, No. 3, 457–463 © Thieme Stuttgart · New York

460
M. M. Baag et al.
PAPER
Anal. Calcd for C11H13NO4S: C, 51.75; H, 5.13; N, 5.49; S, 12.56.
Found: C, 51.88; H, 5.26; N, 5.37; S, 12.66.
(2) in the presence of an internal amine unit is noteworthy.
We also feel that our present simple approach to 1,5-ben-
zothiazepines is general in nature and will be useful to de-
sign large number of its congeners for biological
screening. All our attempts to obtain the benzothioazocine
met with failure and instead we obtained the correspond-
ing benzothiazole.
2-(2-Aminophenylsulfanylmethyl)succinic Acid Dimethyl Ester
(5b)
To a solution of dimethyl itaconate (500 mg, 3.16 mmol) in THF (15
mL) was added o-aminothiophenol (0.40 mL, 3.79 mmol) and the
mixture was stirred under argon for 24 h at r.t. The mixture was con-
centrated in vacuo and the crude residue was purified by silica gel
column chromatography using petroleum ether–EtOAc (8:2) to fur-
nish 5b as a yellow thick oil; yield: 662 mg (74%).
Melting points are uncorrected. Column chromatographic separa-
tions were carried out on ACME silica gel (60–120 mesh). Com-
mercially available itaconic anhydride, itaconic acid, dimethyl
itaconate, o-aminothiophenol (1), 2-aminophenyldisulfide, l-men-
thol, (R)-(+)-1-phenylethylamine, N-ethyl-N¢-(3-dimethylamino-
propyl)carbodiimide hydrochloride (EDCI) and Ph3P were used.
Petroleum ether used had bp 60–80 °C.
IR (neat): 3460, 3364, 2847, 1740, 1726, 1611, 1479, 1439 cm–1.
1H NMR (CDCl3, 500 MHz): d = 2.71 (dd, J = 15, 5 Hz, 1 H), 2.83
(dd, J = 15, 5 Hz, 1 H), 2.95 (dd, J = 10, 5 Hz, 1 H), 3.02 (quintet,
J = 5 Hz, 1 H), 3.13 (dd, J = 10, 5 Hz, 1 H), 3.65 (s, 3 H), 3.66 (s,
3 H), 4.04 (br s, 2 H), 6.69 (t, J = 10 Hz, 1 H), 6.73 (d, J = 10 Hz,
1 H), 7.13 (t, J = 10 Hz, 1 H), 7.37 (d, J = 10 Hz, 1 H).
(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)acetic
Acid (4a)
13C NMR (CDCl3, 125 MHz): d = 34.5, 35.6, 41.2, 51.7, 51.9, 114.9,
116.1, 118.3, 130.0, 135.9, 148.3, 171.7, 173.3.
Method A: To a solution of itaconic anhydride (2; 1.00 g, 8.92
mmol) in THF (25 mL) was added o-aminothiophenol (1; 1.05 mL,
10.70 mmol) and the mixture was stirred under argon for 8 h at r.t.
A white precipitate was obtained, which was then filtered, washed
with Et2O and dried in vacuo to give 4a as a white solid; yield: 1.71
g (81%). Analytically pure 4a was obtained by recrystallization
from MeOH.
Anal. Calcd for C13H17NO4S: C, 55.11; H, 6.05; N, 4.94; S, 11.32.
Found: C, 54.99; H, 6.11; N, 5.07; S, 11.17.
(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)acetic
Acid Methyl Ester (4b)
To a solution of 4a (500 mg, 2.10 mmol) in MeOH (15 mL), were
added conc. H2SO4 (two drops) and the mixture was heated at 50 °C
for 2 h. The mixture was concentrated in vacuo and the residue was
dissolved in EtOAc (25 mL). The resulting solution was washed
successively with 5% aq NaHCO3 solution (10 mL), brine (15 mL),
dried (Na2SO4) and concentrated in vacuo. The residue obtained
was purified by silica gel column chromatography using petroleum
ether–EtOAc (7:3) to furnish 4b as a white solid; yield: 503 mg
(95%); mp 168 °C (EtOAc).
Method B: To a solution of 5a (300 mg, 1.18 mmol) and DMAP (5
mg) in THF (10 mL) was added EDCI (248 mg, 1.29 mmol) in THF
(5 mL) and the mixture was stirred under argon for 4 h at r.t. The
mixture was concentrated in vacuo and acidified with aq 2 N HCl
(10 mL). The precipitate was filtered, washed with H2O and dried
in vacuo to give 4a as a white solid; yield: 245 mg (88%); mp 234–
235 °C (MeOH).
IR (Nujol): 3171, 2725–2500, 1703, 1639, 1630, 1462, 1454 cm–1.
IR (Nujol): 3179, 1734, 1666, 1462, 1439 cm–1.
1H NMR (DMSO-d6, 500 MHz): d = 2.29 (dd, J = 20, 5 Hz, 1 H),
2.68 (dd, J = 18, 10 Hz, 1 H), 2.82–2.92 (m, 1 H), 2.96 (dd, J = 10,
8 Hz, 1 H), 3.47 (dd, J = 10, 5 Hz, 1 H), 7.12 (d, J = 10 Hz, 1 H),
7.17 (dt, J = 10, 2 Hz, 1 H), 7.41 (dt, J = 10, 2 Hz, 1 H), 7.56 (d,
J = 10 Hz, 1 H).
13C NMR (DMSO-d6, 125 MHz): d = 34.9, 38.1, 38.8, 123.6, 125.8,
126.2, 130.0, 134.8, 142.4, 172.7, 173.4.
1H NMR (CDCl3, 300 MHz): d = 2.35 (dd, J = 18, 6 Hz, 1 H), 2.93–
3.06 (m, 2 H), 3.10–3.23 (m, 1 H), 3.52 (dd, J = 10, 5 Hz, 1 H), 3.63
(s, 3 H), 7.16 (d, J = 6 Hz, 1 H), 7.19 (t, J = 9 Hz, 1 H), 7.38 (t,
J = 9 Hz, 1 H), 7.60 (d, J = 6 Hz, 1 H), 7.80–8.20 (br s, 1 H).
1H NMR (DMSO-d6, 300 MHz): d = 2.38 (dd, J = 18, 6 Hz, 1 H),
2.74 (dd, J = 15, 9 Hz, 1 H), 2.58–3.05 (m, 2 H), 3.44–3.51 (m, 1
H), 3.52 (s, 3 H), 7.05–7.20 (m, 2 H), 7.42 (t, J = 9 Hz, 1 H), 7.57
(d, J = 9 Hz, 1 H), 9.93 (s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 34.7, 38.1, 39.1, 51.7, 123.6, 126.4,
126.8, 129.9, 135.0, 141.0, 171.8, 174.4.
13C NMR (DMSO-d6, 125 MHz): d = 34.4, 38.1, 38.6, 51.6, 123.6,
125.9, 126.1, 130.1, 134.9, 142.3, 171.9, 173.2.
Anal. Calcd for C11H11NO3S: C, 55.68; H, 4.67; N, 5.90; S, 13.51.
Found: C, 55.55; H, 4.49; N, 6.02; S, 13.47.
2-(2-Aminophenylsulfanylmethyl)succinic Acid (5a)
To a solution of itaconic acid (500 mg, 3.84 mmol) in THF (15 mL)
was added o-aminothiophenol (1; 0.50 mL, 4.61 mmol) and the
mixture was stirred under argon for 36 h at r.t. The mixture was con-
centrated in vacuo and the residue was dissolved in 10% aq
NaHCO3 solution. The resulting solution was washed with EtOAc
(3 × 10 mL), acidified with glacial AcOH and extracted with EtOAc
containing 5% MeOH (4 × 25 mL). The combined organic layers
were washed with brine (25 mL), dried (Na2SO4) and concentrated
in vacuo to give 5a. Analytically pure 5a was obtained by recrystal-
lization from MeOH; yield: 686 mg (70%); yellow solid; mp 146 °C
(MeOH).
Anal. Calcd for C12H13NO3S: C, 57.35; H, 5.21; N, 5.58; S, 12.76.
Found: C, 57.22; H, 5.29; N, 5.43; S, 12.63.
(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)acetic
Acid Ethyl Ester (4c)
Repetition of the procedure similar to that used for the synthesis of
4b in EtOH furnished the corresponding ethyl ester as a white solid;
yield: 514 mg (92%); mp 146 °C (EtOAc).
IR (Nujol): 3296, 1713, 1688, 1587, 1468 cm–1.
IR (Nujol): 3356, 3285, 2725, 1697, 1462, 1377 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.20 (t, J = 8 Hz, 3 H), 2.33 (dd,
J = 16, 4 Hz, 1 H), 2.85–3.25 (m, 3 H), 3.51 (dd, J = 10, 6 Hz, 1 H),
4.08 (q, J = 8 Hz, 2 H), 7.10–7.45 (m, 3 H), 7.60 (d, J = 6 Hz, 1 H),
8.05–8.30 (br s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 14.0, 34.9, 38.1, 39.0, 60.6, 123.5,
126.3, 126.8, 129.9, 135.0, 141.1, 171.3, 174.5.
1H NMR (CD3OD, 500 MHz): d = 2.69 (t, J = 5 Hz, 2 H), 2.87 (q,
J = 5 Hz, 2 H), 3.14 (q, J = 5 Hz, 1 H), 6.61 (t, J = 10 Hz, 1 H), 6.76
(d, J = 10 Hz, 1 H), 7.07 (t, J = 10 Hz, 1 H), 7.33 (d, J = 10 Hz, 1
H).
13C NMR (DMSO-d6, 125 MHz): d = 35.0, 35.6, 41.4, 114.8, 115.5,
116.9, 129.8, 135.3, 149.6, 173.0, 174.6.
Synthesis 2007, No. 3, 457–463 © Thieme Stuttgart · New York

PAPER
Chemo- and Regioselective Reactions of o-Aminophenyl Disulfide with Itaconic Anhydride
461
Anal. Calcd for C13H15NO3S: C, 58.85; H, 5.70; N, 5.28; S, 12.10.
Found: C, 59.02; H, 5.84; N, 5.13; S, 12.25.
(3 × 10 mL), acidified with glacial AcOH and extracted with EtOAc
containing 5% MeOH (4 × 25 mL). The combined organic layer
was washed with brine (25 mL), dried (Na2SO4) and concentrated
in vacuo to give 8a as a yellow solid; yield: 2.19 g (86%). Similarly
compound 7b furnished compound 8b; yellow solid; mp 146 °C
(MeOH); [a]D25 +20.83 (c = 0.24, MeOH). Analytical and spectral
data obtained for 8a/b were identical with ( )-5a.
2-Methylenesuccinic Acid Bis(2-isopropyl-5-methylcyclohex-
yl)ester (6)
To a solution of itaconic anhydride (2; 5.20 g, 40 mmol) in toluene
(70 mL) was added L-menthol (12.48 g, 80 mmol) and p-TSA (100
mg, 40 mmol) and the mixture was refluxed under argon for 36 h
using a Dean–Stark apparatus. The mixture was allowed to cool to
r.t., concentrated in vacuo, and the residue was dissolved in EtOAc
(150 mL). The EtOAc layer was washed successively with 5% aq
NaHCO3 solution (25 mL), brine (25 mL) and dried (Na2SO4) and
concentrated in vacuo. The residue obtained was purified by silica
gel column chromatography using petroleum ether–EtOAc (9:1) to
give 6 as a thick oil; yield: 13.12 g (80%); [a]D25 – 85.12 (c = 1.77,
CHCl3).
(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)acetic
Acid (9a)
To a solution of 8a (1.28 g, 5 mmol) and DMAP (20 mg) in THF
(20 mL) was added EDCI (1.06 g, 5.50 mmol) in THF (5 mL) and
the mixture was stirred under argon for 4 h at r.t. The mixture was
concentrated in vacuo, dried and acidified with aq 2 N HCl (20 mL).
The precipitate was filtered, washed with H2O and dried in vacuo to
give 9a as a white solid; yield: 1.04 g (88%). Similarly compound
8b furnished compound 9b; white solid; mp 234–235 °C (MeOH);
[a]D25 +178.30 (c = 0.19, MeOH). Analytical and spectral data ob-
tained for 9a/b were identical with ( )-4a.
IR (neat): 1734, 1719, 1641, 1456, 1200 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.77 (d, J = 8 Hz, 6 H), 0.90 (d,
J = 6 Hz, 12 H), 0.75–1.25 (m, 6 H), 1.30-1.55 (m, 4 H), 1.55–1.75
(m, 4 H), 1.80–2.10 (m, 4 H), 3.31 (s, 2 H), 4.60–4.85 (m, 2 H), 5.65
(s, 1 H), 6.29 (s, 1 H).
2-(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)-N-(1-
phenylethyl)acetamides (10 and 11)
13C NMR (CDCl3, 50 MHz): d = 16.2, 20.6, 21.9, 23.3, 23.4, 26.0,
26.1, 31.2, 34.1, 37.9, 40.5, 40.6, 46.8, 46.9, 74.4, 74.6, 127.5,
134.4, 165.4, 170.0 (three carbon atoms from the two menthol units
did not show splitting).
To a solution of 9a (474 mg, 2 mmol), (R)-(+)-1-phenylethylamine
(290 mg, 2.40 mmol) and DMAP (10 mg) in THF (10 mL), was add-
ed a solution of EDCI (422 mg, 2.20 mmol) in THF (5 mL) and the
mixture was stirred under argon for 4 h at r.t. The mixture was con-
centrated in vacuo, the residue was dissolved in EtOAc (50 mL).
The EtOAc solution was washed with H2O (15 mL), brine (20 mL)
and dried (Na2SO4) and concentrated in vacuo. The residue obtained
was purified by silica gel column chromatography using petroleum
ether–EtOAc (8:2) to give a mixture of diastereomers 612 mg (90%
yield). The diastereoisomeric mixture was separated by flash col-
umn chromatography using petroleum ether–EtOAc (9:1) to give
the major isomer 11; white solid; yield: 428 mg (70%) and the mi-
nor isomer 10; white solid; yield: 183 mg (30%). Analytically pure
10 was obtained by recrystallization from petroleum ether–EtOAc
(7:3).
Anal. Calcd for C25H42O4: C, 73.85; H, 10.41. Found: C, 74.01; H,
10.33.
2-(2-Aminophenylsulfanylmethyl)succinic Acid Bis(2-isopro-
pyl-5-methylcyclohexyl)ester (7a)
To a solution of diester 6 (6.57 g, 15 mmol) in glacial AcOH (25
mL) was added o-aminothiophenol (1.63 mL, 15 mmol) and the
mixture was stirred under argon for 36 h at r.t. The mixture was con-
centrated in vacuo and the residue was dissolved in EtOAc (70 mL).
The EtOAc solution was washed with H2O (20 mL), brine (20 mL),
dried (Na2SO4) and concentrated in vacuo. The residue obtained
was purified by silica gel column chromatography using petroleum
ether–EtOAc (8:2) to give 7a as a thick oil/semi solid; yield: 6.92 g
(82%). The compound 7a (1.00 g, 40% de) on three recrystalliza-
tions from petroleum ether furnished compound 7b (white solid,
minor isomer, 110 mg, 98% de); mp 104 °C (petroleum ether);
[a]D25 –85.71 (c = 0.50, CHCl3).
(3R)-2-(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)-
N-(1R-phenylethyl)acetamide (10, Minor Isomer)
Mp 198 °C; [a]D25 +45.45 (c = 0.08, CHCl3).
IR (Nujol): 3287, 3190, 1665, 1632, 1551, 1466, 1377 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.44 (d, J = 6 Hz, 3 H), 2.24 (dd,
J = 14, 4 Hz, 1 H), 2.80 (dd, J = 24, 14 Hz, 1 H), 2.99 (d, J = 10 Hz,
1 H), 3.05–3.30 (m, 1 H), 3.53 (dd, J = 10, 6 Hz, 1 H), 5.01 (q, J = 8
Hz, 1 H), 6.49 (br s, 1 H), 7.00 (d, J = 8 Hz, 1 H), 7.14 (d, J = 8 Hz,
1 H), 7.20–7.40 (m, 6 H), 7.57 (dd, J = 8, 2 Hz, 1 H), 8.15 (br s, 1
H).
13C NMR (CDCl3, 50 MHz): d = 22.0, 37.2, 39.1, 39.7, 48.8, 123.7,
126.0, 126.7, 127.0, 127.1, 128.5, 130.0, 135.2, 140.6, 143.2, 169.5,
175.0.
IR (Nujol): 3468, 3371, 1724, 1607, 1215 cm–1.
1H NMR (CDCl3, 400 MHz): d = 0.74 (d, J = 4 Hz, 3 H), 0.77 (d,
J = 4 Hz, 3 H), 0.80–0.95 (m, 12 H), 0.95–1.10 (m, 6 H), 1.25–1.53
(m, 4 H), 1.62–1.72 (m, 4 H), 1.77–1.87 (m, 1 H), 1.90–2.05 (m, 3
H), 2.63 (dd, J = 16, 8 Hz, 1 H), 2.76 (dd, J = 16, 8 Hz, 1 H), 2.89
(dd, J = 12, 8 Hz, 1 H), 2.98 (q, J = 8 Hz, 1 H), 3.11 (dd, J = 12, 8
Hz, 1 H), 4.38 (br s, 2 H), 4.67 (dt, J = 8, 4 Hz, 1 H), 4.71 (dt, J = 8,
4 Hz, 1 H), 6.69 (t, J = 8 Hz, 1 H), 6.72 (d, J = 8 Hz, 1 H), 7.13 (t,
J = 8 Hz, 1 H), 7.38 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): d = 16.0, 16.3, 20.8, 22.0, 23.1, 23.4,
26.0, 26.2, 31.3, 34.2, 34.3, 35.6, 36.1, 40.6, 40.7, 42.0, 46.8, 46.9,
74.6, 75.0, 115.0, 116.8, 118.5, 130.1, 136.1, 148.4, 170.7, 172.6
(one of the carbon atom from the two menthol units did not show
splitting).
Anal. Calcd for C19H20N2O2S: C, 67.02; H, 5.92; N, 8.22; S, 9.42.
Found: C, 67.20; H, 6.04; N, 8.13; S, 9.36.
(3S)-2-(4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,5]thiazepin-3-yl)-
N-(1R-phenylethyl)acetamide (11, Major Isomer)
Mp 104 °C; [a]D25 +172.83 (c = 0.08, CHCl3).
IR (Nujol): 3296, 3192, 1663, 1635, 1535, 1475 cm–1.
1H NMR (CDCl3, 200 MHz): d = 1.40 (d, J = 8 Hz, 3 H), 2.21 (dd,
J = 14, 2 Hz, 1 H), 2.77 (dd, J = 24, 12 Hz, 1 H), 2.94 (d, J = 12 Hz,
1 H), 3.10–3.30 (m, 1 H), 3.45 (dd, J = 12, 6 Hz, 1 H), 4.99 (q, J = 8
Hz, 1 H), 6.68 (br s, 1 H), 7.00–7.40 (m, 8 H), 7.56 (d, J = 6 Hz, 1
H), 8.74 (br s, 1 H).
Anal. Calcd for C31H49NO4S: C, 70.01; H, 9.29; N, 2.63; S, 6.03.
Found: C, 69.93; H, 9.27; N, 2.55; S, 6.12.
2-(2-Aminophenylsulfanylmethyl)succinic Acid (8a)
A solution of 7a (5.63 g, 10 mmol) in AcOH–HCl (3:1, 30 mL) was
refluxed for 12 h. The mixture was allowed to cool to r.t. and con-
centrated in vacuo, and the residue was dissolved in 10% aq
NaHCO3 solution. The resulting solution was washed with EtOAc
Synthesis 2007, No. 3, 457–463 © Thieme Stuttgart · New York

462
M. M. Baag et al.
PAPER
Agrochemicals; ACS Symposium Series 355, American
13C NMR (CDCl3, 50 MHz): d = 21.8, 36.8, 38.7, 39.5, 48.8, 123.7,
126.0, 126.6, 126.8, 127.1, 128.4, 129.9, 135.1, 140.7, 143.3, 169.6,
175.5.
Chemical Society: Washington, 1987.
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Willems, P. H. G. M. J. Biol. Chem. 2004, 279, 40328.
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Tang, X.-Q.; Yu, J.; Nazarbaghi, R.; Hunter, A.; Anderson,
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Anal. Calcd for C19H20N2O2S: C, 67.02; H, 5.92; N, 8.22; S, 9.42.
Found: C, 66.97; H, 5.85; N, 8.30; S, 9.50.
2-({2-[2-(3-Carboxybut-3-enoylamino)phenyldisulfanyl]phe-
nylcarbamoyl}methyl)acrylic Acid (13)
To a solution of itaconic anhydride (2; 695 mg, 6.20 mmol) in THF
(15 mL) was added a solution of 2-aminophenyl disulfide (12; 700
mg, 2.81 mmol) in anhyd THF (15 mL) and the mixture was stirred
under argon for 8 h at r.t. The mixture was concentrated in vacuo
and the residue was stirred with Et2O (30 mL) for 1 h. The precipi-
tate was filtered and washed with Et2O. Analytically pure 13 was
obtained by recrystallization from MeOH as a yellow solid; yield:
1.08 g (81%); mp 192–193 °C (MeOH).
IR (Nujol): 3242, 2725, 2633, 1697, 1659, 1634, 1578, 1535 cm–1.
1H NMR (CD3OD, 200 MHz): d = 3.38 (br s, 4 H), 5.88 (br s, 2 H),
6.35 (s, 2 H), 7.11 (t, J = 8 Hz, 2 H), 7.31 (t, J = 8 Hz, 2 H), 7.47 (d,
J = 8 Hz, 2 H), 7.68 (d, J = 8 Hz, 2 H).
13C NMR (DMSO-d6, 50 MHz): d = 39.3, 126.3, 127.0, 128.2,
128.5, 129.2, 131.8, 136.0, 136.3, 168.0, 169.5.
Anal. Calcd for C22H20N2O6S2: C, 55.92; H, 4.27; N, 5.93; S, 13.57.
Found: C, 56.09; H, 4.13; N, 6.02; S, 13.72.
2-Benzothiazol-2-ylmethylacrylic Acid (15)
To a solution of 13 (500 mg, 1.06 mmol) in dioxane–H2O (4:1, 15
mL), was added Ph3P (278 mg, 1.06 mmol) and conc. HCl (two
drops) and the mixture was stirred at r.t. for 2 h. The mixture was
concentrated in vacuo and extracted with EtOAc (4 × 25 mL). The
combined organic phases were washed with brine (30 mL), dried
(Na2SO4), concentrated in vacuo and the residue was purified by sil-
ica gel column chromatography using petroleum ether–EtOAc (7:3)
to furnish 15 as a white solid; yield: 390 mg (84%); mp 139–142 °C
(EtOAc).
IR (Nujol): 2700–2500, 1701, 1690, 1630, 1462, 1456 cm–1.
(4) (a) Prakash, O.; Kumar, A.; Sadana, A.; Prakash, R.; Singh,
S. P.; Claramunt, R. M.; Sanz, D.; Alkorta, I.; Elguero, J.
Tetrahedron 2005, 61, 6642. (b) Amblard, M.; Raynal, N.;
Averlant, P. M.-C.; Didierjean, C.; Calmes, M.; Fabre, O.;
Aubry, A.; Marraud, M.; Martinez, J. Tetrahedron Lett.
2005, 46, 3733. (c) Van Otterlo, W. A. L.; Morgans, G. L.;
Khanye, S. D.; Aderibigbe, B. A. A.; Michael, J. P.; Billing,
D. G. Tetrahedron Lett. 2004, 45, 9171. (d) Giordano, C.;
Restelli, A. Tetrahedron: Asymmetry 1991, 2, 785.
1H NMR (CD3OD, 200 MHz): d = 4.12 (s, 2 H), 5.92 (s, 1 H), 6.41
(s, 1 H), 7.30–7.55 (m, 2 H), 7.80–8.00 (m, 2 H).
13C NMR (CD3OD, 50 MHz): d = 37.4, 122.8, 123.0, 126.2, 127.3,
129.7, 136.3, 138.3, 153.8, 169.0, 172.0.
Anal. Calcd for C11H9NO2S: C, 60.26; H, 4.14; N, 6.39; S, 14.63.
Found: C, 60.28; H, 4.09; N, 6.51; S, 14.54.
(e) Yang, X.; Buzon, L.; Hamanaka, E.; Liu, K. K.-C.
Tetrahedron: Asymmetry 2000, 11, 4447.
(5) (a) Balasubramaniyan, V.; Balasubramaniyan, P.; Shaikh, A.
S.; Argade, N. P. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1989, 28, 123. (b) Okafor, C. O.; Akpuaka, M.
U. J. Chem. Soc., Perkin Trans. 1 1993, 159.
Acknowledgment
M.M.B. and M.K.S. thank CSIR, New Delhi, for the awards of re-
search fellowships.
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Synthesis 2007, No. 3, 457–463 © Thieme Stuttgart · New York

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Chemo- and Regioselective Reactions of o-Aminophenyl Disulfide with Itaconic Anhydride
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Synthesis 2007, No. 3, 457–463 © Thieme Stuttgart · New York