Synthesis of optically active isothiazole derivatives from L-(α)-amino acids

Article abstract of DOI:10.1007/s00706-005-0353-4

Several enantiomerically pure 3,5-disubstituted isothiazol-5-ylideneamine hydrobromides were prepared by oxidation of chiral 3-amino-2,3-unsaturated thioamides. The starting thioamides derived from natural L-α-amino acids represent a novel group of synthe

Full text of DOI:10.1007/s00706-005-0353-4

Monatshefte f€ur Chemie 136, 2059–2066 (2005)
DOI 10.1007/s00706-005-0353-4
Synthesis of Optically Active Isothiazole
Derivatives from L-(a)-Amino Acids
Dariusz Ciez˙1;ꢀ and E. Szneler2
1
ꢀ
Department of Organic Chemistry, Jagiellonian University, 30-060 Krakow, Poland
NMR Laboratory, Faculty of Chemistry, Jagiellonian University, 30-060 Krakow, Poland
2
ꢀ
Received January 7, 2005; accepted (revised) January 27, 2005
Published online October 5, 2005 # Springer-Verlag 2005
Summary. Several enantiomerically pure 3,5-disubstituted isothiazol-5-ylideneamine hydrobromides
were prepared by oxidation of chiral 3-amino-2,3-unsaturated thioamides. The starting thioamides
derived from natural L-ꢀ-amino acids represent a novel group of synthetically useful chiral reactants.
Keywords. Unsaturated thioamides; Isothiazoles; Oxidations; Chirality; NMR spectroscopy.
Introduction
3,5-Disubstituted isothiazoles are known to show a wide range of biological activ-
ity [1]. They have also found applications in syntheses of highly selective 5-HT2B
receptor antagonists [2], human testosterone 5ꢀ-reductase inhibitors [3], dual
cyclooxygenase=S-lipoxygenase inhibitors [4], interferon inducing agents [5], and
antagonists of gonadotropin releasing hormon receptors [6]. A large group of
3,5-disubstituted isothiazole derivatives play an important role as highly selective
herbicides [7]. Derivatives of 2,3-dimethylisothiazol-5-ylideneamine have been
reported to be active indolamine N-methyltransferase inhibitors [8]. These various
biological and pharmacological properties of 3,5-disubstituted and other high-
substituted isothiazoles have brought about an increase of interest in isothiazole
chemistry [9].
There are two synthesis routes to 3,5-disubstituted isothiazoles known: either
construction of the isothiazole ring followed by substitution or preparation of
substituted acyclic precursors followed by cyclisation [10]. Direct functionalization
of the isothiazole ring is usually limited to reactions with electrophiles because of
its weak stability towards nucleophiles [11]. Therefore, the more convenient me-
thod for synthesis of high-substituted isothiazoles is the preparation of appropri-
ately substituted open-chain precursors.
ꢀ
Corresponding author. E-mail: ciez@chemia.uj.edu.pl

2060
D. Ciez˙ and E. Szneler
In our research we focused on syntheses of chiral unsaturated thioamides,
which serve as substrates for the preparation of novel chiral 3,5-disubstituted iso-
thiazoles. Our interest in these thioamides as precursors stemmed from their acces-
sibility and stability. In fact, simple 3-amino-2,3-unsaturated thioamides have been
known for many years as readily available and moderately reactive synthons [12]
for syntheses of miscellaneous heterocyclic compounds including isothiazole deri-
vatives [13].
Results and Discussions
Although a wide range of 2-amino-2,3-unsaturated thioamides has been reported
we were unable to find examples of optically active derivatives. Thus we adjusted
the well known procedure for the synthesis of 3-anilinothiocrotonate amides from
isothiocyanates and enamines [14]. Accordingly, we applied optically active
isothiocyanatocarboxylates 1 derived from natural L-ꢀ-amino acids and several
enamines obtained from acetophenone. We expected to convert them into chiral
2-amino-2,3-unsaturated thioamides unsubstituted at the C-2 carbon atom. Unfortu-
nately, all reactions failed due to the poor reactivity of isothiocyanatocarboxylates.
Therefore we were forced to replace enamines with the more reactive enaminone
4-anilinopent-3-en-2-one (2).
Syntheses were carried solvent-free according to the above mentioned proce-
dure and provided the optically active 3-anilinothiocrotonate amides 3 (Scheme 1).
The structures of all the products were confirmed by their IR, NMR, and mass
spectra. Based on the IR and NMR spectra we found that 3-anilinothiocrotonate
amides 3 exist exclusively as (E) diastereomers. An NMR experiment indicated a
NOESY interaction between the acetyl group and both the amino groups. Although
a low barrier of rotation has been reported for similar compounds [15], we did
observe no traces of (Z) isomers. Rotation about the vinyl double bond was hin-
dered by a strong intramolecular hydrogen bonding between the 3-amino and
acetyl functionalities. In the IR spectra of 3 we observed two bands assigned to
carbonyl groups. An absorption at ꢁꢁ ¼ 1740 cmꢁ1 was attributed to the C¼O
stretch of the carbomethoxy group whereas a band at ꢁꢁ ¼ 1610 cmꢁ1 must have
been connected with the hydrogen-bonded, conjugated acetyl group. The 1H NMR
spectra showed crucial differences between two various NH protons supporting our
Scheme 1

Optically Active Isothiazole Derivatives
2061
Scheme 2
structural assignment. A signal of the NH–CS proton was observed at ꢂ ¼ 8.1 ppm
while the signal of the NH–Ph proton was shifted up to ꢂ ¼ 13.3 ppm indicating an
interaction with the neighboring acetyl group.
During our investigations we noted that 3 could loose the 2-acetyl substituent
under relative mild conditions. This observation allowed us to convey the deace-
tylation of some thioamides 3 to prepare 4 which were applied as educts for the
synthesis of 3,5-disubstituted isothiazoles. The deacetylations of 3 were carried
out in boiling, anhydrous methanol with sodium hydrogencarbonate to yield 4
(Scheme 2). They proceed nearly quantitative and the loss of the acetyl group
was confirmed by NMR and MS spectra. The absence of the 2-acetyl substituent
resulted in significant differences in chemical shifts of NH protons. Thus, signals of
the PhNH protons in 4 appeared at ꢂ ¼ 12.9 ppm whereas signals of thioamide
protons were shifted down to ꢂ ¼ 6.7 ppm. Taking into consideration the mentioned
spectra of 3 we assumed that 4 exist as (Z) diastereomers. In fact, the PhNH groups
of 4 could form intramolecular hydrogen bonds with the sulfur atoms in this case
only.
Generally, the preparation of isothiazoles from 4 consists in their oxidation
using some oxidants, such as halogens, chloramines, hydrogen peroxide, trifluoro-
methylsulfenyl chloride, and others [16]. We applied bromine as described by
Goerdeler and Gnad [17] yielding isothiazole hydrobromides 5 in very good yields
(Scheme 3).
The constitutions of 5 were confirmed by IR spectra where we observed an absorption at
ꢁꢁ ¼ 1740 cmꢁ1 characteristic for a carbonyl group. Two absorptions bands at ꢁꢁ ¼ 1200 and
1100 cmꢁ1 were attributed to the antisymmetric and symmetric stretches of the ester C–O bond. A
very strong and broad absorption was observed at ꢁꢁ ¼ 2400–3400 cmꢁ1, which was assigned to the
1
NHþ stretch. In the H NMR spectra of 5 a broad signal at ꢂ ¼ 10.3 ppm was assigned to NHþ. The
13C NMR spectra of 5 supported our structural assignments. As expected, we noticed an absence of
signals characteristic for thiocarbonyl groups at ꢂ ¼ 190–200 ppm while a new signal at 169.7 ppm
appeared, which was assigned to C-5 of the isothiazole ring.
Although 3, 4, and 5 were non-racemic and displayed optical activities it was not certain that
all reactions proceeded without partial racemisations. Determination of their enantiomeric purity by
means of chiral lanthanide shift reagents failed – no interactions of europium complexes with these
compounds were observed. Therefore we prepared a model amide 3e from natural L-ꢀ-isoleucine
containing two asymmetric centers. We assumed that any partial racemisation of 3e during its deace-
tylation and cyclisation to isothiazole derivative 5e was possible only on the C-ꢀ-carbon atom.
1
However, the H NMR spectra of 4e and 5e indicated no presence of a second diastereomer, thus
excluding racemisation. Accordingly, all reactions starting from 1e to the final 5e proceed with

2062
D. Ciez˙ and E. Szneler
Scheme 3
retention of configuration on both chiral centers. To examine the stability of the chiral center on C-2 in
3e during deacetylation we repeated this reaction under more basic conditions using a 6 equivalent
excess of sodium hydrogencarbonate in a small volume of methanol. After 2 hours reflux we obtained
4e containing a small quantity of the second diastereomer with (R) configuration. Using NMR spectro-
scopy we estimated its amount to 16%. The reaction of 3 with bromine did not lead to the desired
3,4,5-trisubstituted isothiazole derivatives, but tars were formed.
In conclusion, the described work gives a simple, convenient procedure for the
synthesis of chiral 3,5-disubstituted isothiazole derivatives of high enantiomeric
purity using easily accessible ꢃ-dicarbonyl compounds and naturally occurring
L-ꢀ-amino acids. The novel optically active 3-amino-2,3-unsaturated thioamides
4 proved to be very useful educts for the preparation of isothiazole derivatives 5
having a chiral ylidenamine group at C-5.
Experimental
NMR spectra were determined on a Bruker AMX 500 spectrometer (using TMS as an internal
standard), IR spectra were measured with a Bruker IFS 48 FT spectrometer in KBr pellets, and MS
were recorded on a Finnigan MAT 95S apparatus. Microanalyses were carried out using on Euro-EA
3018 analyser. Their results were in good agreement with the calculated values. Optical rotations were
measured on Polamat A polarimeter with 0.5 dm tube.
Methyl isothiocyanatocarboxylates 1a–1f were obtained from appropriate L-ꢀ-aminoacid methyl
ester hydrochlorides by the ‘‘thiophosgene method’’ [18]; 4-anilinopent-3-en-2-one (2) was synthe-
sized according to Ref. [19].
General Procedure for the Synthesis of 3a–3f
To a 25 cm3 flask protected against air moisture were added 20mmol 2 and 21mmol 1a–1f. The
mixture was stirred and heated for 60–90min at 85–95ꢂC. After cooling, the residue was triturated
with petroleum ether=n-hexane to remove an excess of the methyl isothiocyanatocarboxylate and the
crude product was purified by crystallization from cyclohexane.
Methyl (2-acetyl-3-(phenylamino)but-2-enethioylamino)acetate (3a, C15H18N2O3S)
Reagents were heated for 90min at 85ꢂC. Recrystallization from cyclohexane afforded 5.41 g (88%)
3a. Mp 163ꢂC; 1H NMR (500MHz, CDCl3): ꢂ ¼ 2.09 (s, CH3), 2.24 (s, CH3), 3.80 (s, OCH3), 4.51 (d,
J ¼ 5.05Hz, CH2), 7.10 (m, 2H), 7.25 (m, 1H), 7.36 (m, 2H), 8.24 (t, NH), 13.34 (s, NH) ppm; 13C
NMR (125 MHz, CDCl3): ꢂ ¼ 17.3 (CH3), 27.6 (CH3), 47.4 (CH2), 52.5 (OCH3), 115.9 (C), 125.6
(CH), 126.5 (CH), 129.2 (CH), 137.9 (C), 159.5 (C–NHPh), 168.9 (COO), 192.7 (C¼S), 202.8 (C¼O)
ppm; IR (KBr): ꢁꢁ¼ 3212, 3023, 1747, 1594, 1354, 1281, 1213cmꢁ1; MS (70 eV): m=z (%) ¼ 306
(Mþ, 16.0), 233 (7.8), 273 (20.8), 118 (19.1), 93 (100), 77 (38.4).

Optically Active Isothiazole Derivatives
2063
Methyl (S)-(ꢁ)-2-(2-acetyl-3-(phenylamino)but-2-enethioylamino)-
propionate (3b, C16H20N2O3S)
Reagents were heated for 70 min at 90ꢂC. Recrystallization from toluene:petroleum ether (2:1)
1
afforded 4.80g (75%) 3b. Mp 158ꢂC; H NMR (500MHz, CDCl3): ꢂ ¼ 1.59 (d, J ¼ 7.18 Hz, CH3),
2.07 (s, CH3), 2.24 (s, CH3), 3.78 (s, OCH3), 5.19 (m, CH), 7.10 (m, 2H), 7.24 (m, 1H), 7.36 (m, 2H),
8.18 (d, J ¼ 6.51 Hz, NH), 13.31 (s, NH) ppm; 13C NMR (125MHz, CDCl3): ꢂ ¼ 16.6 (CH–CH3), 17.1
(CH3), 27.5 (CH3), 47.4 (CH2), 52.6 (OCH3), 53.7 (CH), 116.0 (C), 125.6 (CH), 126.4 (CH), 129.2
(CH), 137.8 (C), 159.3 (C–NHPh), 172.2 (COO), 192.5 (C¼S), 201.6 (C¼O) ppm; IR (KBr):
20
ꢁꢁ¼ 3199, 3029, 1745, 1608, 1589, 1279, 1205, 1154 cmꢁ1; ½ꢀꢃD ¼ ꢁ14:3ꢂ cm2 gꢁ1 (c ¼ 5, CHCl3).
Methyl (S)-(þ)-2-(2-acetyl-3-(phenylamino)but-2-enethioylamino)-3-phenylpropionate
(3c, C22H24N2O3S)
Reagents were heated for 60min at 90ꢂC. Recrystallization from cyclohexane afforded 7.13 g (90%)
3c. Mp 145ꢂC; 1H NMR (500 MHz, CDCl3): ꢂ ¼ 1.91 (s, CH3), 2.08 (s, CH3), 3.20 (dd, CHaHb), 3.42
(dd, CHaHb), 3.78 (s, OCH3), 5.51 (m, CH), 7.03 (m, 2H), 7.19–7.35 (m, 8H), 7.84 (d, J ¼ 7.1 Hz,
NH), 13.28 (s, NH) ppm; 13C NMR (125 MHz, CDCl3): ꢂ ¼ 16.9 (CH3), 27.4 (CH3), 36.9 (CH2), 52.5
(OCH3), 58.8 (CH), 115.9 (C), 125.5 (CH), 126.4 (CH), 127.4 (CH), 128.8 (CH), 128.9 (CH), 129.2
(CH), 135.4 (C), 137.7 (C), 159.3 (C–NHPh), 171.0 (COO), 192.7 (C¼S), 202.4 (C¼O) ppm; IR (KBr):
20
ꢁꢁ¼ 3205, 3023, 1743, 1606, 1594, 1279, 1210cmꢁ1; ½ꢀꢃD ¼ þ21:1ꢂ cm2 gꢁ1 (c ¼ 4.5, CHCl3).
Methyl (S)-(ꢁ)-2-(2-acetyl-3-(phenylamino)but-2-enethioylamino)-4-
methylpentanoate (3d, C19H26N2O3S)
Reagents were heated for 90min at 85ꢂC. Recrystallization from cyclohexane afforded 4.93 g (68%)
1
3d. Mp 134ꢂC; H NMR (500MHz, CDCl3): ꢂ ¼ 0.97 (d, J ¼ 6.4 Hz, 2CH3), 1.73 (m, CH), 1.82 (m,
CH2), 2.07 (s, CH3), 2.24 (s, CH3), 3.74 (s, OCH3), 5.21 (2d, J ¼ 7.6 Hz, CH), 7.09 (d, 2H), 7.23 (t,
1H), 7.34 (m, 2H), 8.03 (d, J ¼ 7.2 Hz, NH), 13.29 (s, NH) ppm; 13C NMR (125MHz, CDCl3):
ꢂ ¼ 17.1 (CH3), 21.9 (CH3), 22.7 (CH3), 26.9 (CH), 27.5 (CH3), 40.4 (CH2), 52.3 (OCH3), 56.9
(CH), 116.1 (C), 125.6 (CH), 126.4 (CH), 129.2 (CH), 137.9 (C), 159.3 (C–NHPh), 171.9 (COO),
192.6 (C¼S), 202.5 (C¼O) ppm; IR (KBr): ꢁꢁ¼ 3205, 3029, 1740, 1601, 1597, 1278, 1203cmꢁ1
;
20
½ꢀꢃD ¼ ꢁ9.3ꢂ cm2 gꢁ1 (c ¼ 3, CHCl3).
Methyl (S,S)-(ꢁ)-2-(2-acetyl-3-(phenylamino)but-2-enethioylamino)-3-
methylpentanoate (3e, C19H26N2O3S)
Reagents were heated for 80min at 95ꢂC. Recrystallization from cyclohexane afforded 4.42 g (61%)
1
3e. Mp 141ꢂC; H NMR (500MHz, CDCl3): ꢂ ¼ 0.96 (d, J ¼ 6.71 Hz, CH3), 0.99 (t, J ¼ 7.43 Hz,
CH3), 1.34 (ddq, CH3–CHaHb), 1.58 (ddq, CH3–CHaHb), 2.06 (s, CH3), 2.17 (m, CH), 2.24 (s, CH3),
3.78 (s, OCH3), 5.23 (dd, CH), 7.10 (d, 2H), 7.23 (t, 1H), 7.36 (t, 2H), 7.99 (d, J ¼ 7.61 Hz, NH), 13.32
(s, NH) ppm; 13C NMR (125MHz, CDCl3): ꢂ ¼ 11.5 (CH3), 15.6 (CH3–CH2), 17.1 (CH3), 26.0 (CH3),
27.5 (CH3), 37.2 (CH), 52.2 (OCH3), 62.4 (CH), 116.3 (C), 125.6 (CH), 126.4 (CH), 129.2 (CH),
137.9(C), 159.1 (C–NHPh), 171.0 (COO), 192.6 (C¼S), 202.5 (C¼O) ppm; IR (KBr): ꢁꢁ¼ 3180, 3012,
20
1740, 1612, 1585, 1280, 1208 cmꢁ1; ½ꢀꢃD ¼ ꢁ0.7ꢂ cm2 gꢁ1 (c ¼ 3, CHCl3).
Methyl (S)-(þ)-2-(2-acetyl-3-(phenylamino)but-2-enethioylamino)-4-
(methylsulfanyl)butanoate (3f, C18H24N2O3S2)
Reagents were heated for 120 min at 90ꢂC. Recrystallization from toluene:petroleum ether ¼ 3:1
afforded 6.16g (81%) 3f. Mp 128ꢂC; 1H NMR (500 MHz, CDCl3): ꢂ ¼ 2.08 (s, CH3), 2.11 (s,
SCH3), 2.25 (s, CH3), 2.26 (m, CH–CHaHb), 2.37 (m, CH–CHaHb), 2.60 (t, J ¼ 7.32 Hz, SCH2),
3.77 (s, OCH3), 5.33 (m, CH), 7.10 (m, 2H), 7.24 (m, 1H), 7.36 (m, 2H), 8.36 (d, J ¼ 7.17Hz,
NH), 13.32 (s, NH) ppm; 13C NMR (125MHz, CDCl3): ꢂ ¼ 15.5 (CH–CH2), 17.2 (CH3), 27.6
(CH3), 30.2 (SCH3), 30.2 (SCH2), 52.6 (OCH3), 57.4 (CH), 116.0 (C), 125.6 (CH), 126.4 (CH),

2064
D. Ciez˙ and E. Szneler
129.2 (CH), 137.8 (C), 159.4 (C–NHPh), 171.1 (COO), 192.5 (C¼S), 202.4 (C¼O) ppm; IR (KBr):
20
ꢁꢁ¼ 3186, 3011, 1745, 1608, 1584, 1286, 1208 cmꢁ1; ½ꢀꢃD ¼ þ8.5ꢂ cm2 gꢁ1 (c ¼ 4, CHCl3).
Deacetylation of 3; General Procedure for the Synthesis of 4b–4e
A mixture of 8 mmol 3b–3e and 32 mmol NaHCO3 (2.688 g) in 100 cm3 of absolute methanol was
refluxed until TLC showed that all the starting material had been converted (90 min). After cooling
an inorganic precipitate was filtered off and the filtrate was evaporated. The crude product was
dried in vacuum at 50ꢂC and dissolved in anhydrous CH2Cl2. After filtration the solvent was
evaporated and oily products 4b–4e were purified by column chromatography on silica gel
(CHCl3:methanol ¼ 50:1).
Methyl (S)-(ꢁ)-2-(3-(phenylamino)but-2-enethioylamino)propionate (4b, C14H18N2O2S)
Chromatography afforded 1.27g (57%) 4b. 1H NMR (500MHz, CDCl3): ꢂ ¼ 1.49 (d, J ¼ 7 Hz, CH3),
2.00 (s, CH3), 3.77 (s, OCH3), 5.09 (m, CH), 5.20 (s, CH), 6.67 (d, J ¼ 8 Hz, NH), 7.09–7.18 (m, 3H),
7.38 (t, J ¼ 7.5 Hz, 2H), 12.95 (s, NH) ppm; 13C NMR (125 MHz, CDCl3): ꢂ ¼ 16.8 (CH3), 21.7 (CH3),
51.1 (OCH3), 52.4 (CH), 97.5 (CH), 125.0 (CH), 129.0 (CH), 129.2 (CH), 138.9 (C), 157.5 (C–NHPh),
172.1 (COO), 188.7 (C¼S) ppm; IR (film): ꢁꢁ¼ 3312, 2982, 2948, 1728, 1610, 1582, 1403, 1198,
20
1165 cmꢁ1; ½ꢀꢃD ¼ ꢁ20.0ꢂ cm2 gꢁ1 (c ¼ 2, CHCl3).
Methyl (S)-(þ)-3-phenyl-2-(3-(phenylamino)but-2-enethioylamino)-
propionate (4c, C20H22N2O2S)
Chromatography afforded 2.41g (85%) 4c. 1H NMR (500MHz, CDCl3): ꢂ ¼ 2.00 (s, CH3), 3.23 (dd,
JHaH ¼ 5.5 Hz, JHaHb ¼ 14Hz, CHaHb), 3.35 (dd, JHbH ¼ 6.5 Hz, CHaHb), 3.73 (s, OCH3), 5.17 (s, CH),
5.54 (m, CH), 6.61 (d, J ¼ 6.5 Hz, NH), 7.15–7.36 (m, 10H), 12.97 (s, NH) ppm; 13C NMR (125 MHz,
CDCl3): ꢂ ¼ 21.7 (CH3), 37.5 (CH2), 52.2 (OCH3), 56.2 (CH), 97.6 (CH), 125.0 (CH), 125.4 (CH),
127.0 (CH), 128.5 (CH), 129.0 (CH), 129.3 (CH), 136.1 (C), 138.9 (C), 157.7 (C–NHPh), 172.2
(COO), 188.6 (C¼S) ppm; IR (film): ꢁꢁ¼ 3327, 1728, 1579, 1489, 1341, 1198, 1175 cmꢁ1; MS
(70 eV): m=z (%) ¼ 354 (Mþ, 97.4), 321 (35.2), 279 (49.2), 176 (92.7), 162 (70.3), 159 (78.0), 131
20
(100), 118 (84.7), 103 (28.0); ½ꢀꢃD ¼ þ42.7ꢂ cm2 gꢁ1 (c ¼ 2, CHCl3).
Methyl (S)-(ꢁ)-4-methyl-2-(3-(phenylamino)but-2-enethioylamino)-
pentanoate (4d, C17H24N2O2S)
1
Chromatography afforded 1.90 g (74%) 4d. H NMR (500 MHz, CDCl3): ꢂ ¼ 0.97 (d, J ¼ 5.97 Hz,
CH3), 0.98 (d, J ¼ 6.15 Hz, CH3), 1.66–1.81 (m, CH and CH2), 2.00 (s, CH3), 3.76 (s, OCH3), 5.21 (s,
CH), 5.26 (m, CH), 6.58 (d, J ¼ 6.41Hz, NH), 7.12–7.18 (m, 3H), 7.32 (t, 2H), 12.96 (s, NH) ppm; 13C
NMR (125MHz, CDCl3): ꢂ ¼ 21.7 (CH3), 22.3 (CH3), 22.7 (CH3), 25.0 (CH), 41.5 (CH2), 52.2
(OCH3), 54.0 (CH), 97.6 (CH), 125.0 (CH), 125.3 (CH), 129.0 (CH), 138.9 (C), 157.5 (C–NHPh),
173.7 (COO), 189.4 (C¼S) ppm; IR (film): ꢁꢁ¼ 3312, 3030, 2956, 1728, 1613, 1594, 1495, 1197,
20
1030 cmꢁ1; ½ꢀꢃD ¼ ꢁ18.4ꢂ cm2 gꢁ1 (c ¼ 2, CHCl3).
Methyl (S,S)-(þ)-3-methyl-2-(3-(phenylamino)but-2-enethioylamino)-
pentanoate (4e, C17H24N2O2S)
1
Chromatography afforded 1.74 g (68%) of 4e. H NMR (500MHz, CDCl3): ꢂ ¼ 0.94 (d, J ¼ 6.90 Hz,
CH3), 0.97 (t, J ¼ 7.34 Hz, CH3), 1.28 (ddq, CH3–CHaHb), 1.58 ( ddq, CH3–CHaHb), 1.99 (s, CH3),
2.03 (m, CH), 3.75 (s, OCH3), 5.22 (s, CH), 5.26 (dd, CH), 6.71 (d, J ¼ 7.07 Hz, NH), 7.12 (d, 2H),
7.17 (t, 1H), 7.33 (t, 2H), 12.97 (s, NH) ppm; 13C NMR (125 MHz, CDCl3): ꢂ ¼ 11.6 (CH3), 15.3
(CH3–CH2), 21.7 (CH3), 25.9 (CH3), 38.0 (CH), 51.9 (OCH3), 59.4 (CH), 97.7 (CH), 115.1 (CH),
125.0 (CH), 129.0 (CH), 138.9 (C), 157.4 (C–NHPh), 172.5 (COO), 189.3 (C¼S) ppm; IR (film):
20
ꢁꢁ¼ 3315, 3020, 2955, 1731, 1610, 1595, 1495, 1188, 1026 cmꢁ1; ½ꢀꢃD ¼ þ2.7ꢂ cm2 gꢁ1 (c ¼ 2.5,
CHCl3).

Optically Active Isothiazole Derivatives
2065
Oxidation of 4 with Bromine; General Procedure for the Synthesis of 5
A three-necked, 150 cm3 flask equipped with a stirrer, an Ar inlet, a condenser, and an addition funnel
was charged under Ar with 60 cm3 of anhydrous CHCl3 and 5 mmol 4b–4e. The mixture was cooled to
0ꢂC on an ice bath and then a solution of 6 mmol (0.96 g, 0.31cm3) Br2 in 10cm3 CHCl3 was added
dropwise over 20 min. The reaction mixture was stirred for 30min at 0ꢂC and allowed to warm to room
temperature over 1 h, then filtered and evaporated on a rotatory evaporator. The crude products were
dried and purified by chromatography using silica gel (Rf ¼ 0.25–0.31, CHCl3:CH3OH¼ 8:1).
Methyl (S)-(ꢁ)-2-(3-methyl-2-phenyl-2H-isothiazol-5-ylideneamino)-propionate
hydrobromide (5b, C14H17N2O2SBr)
Column chromatography afforded 1.34 g (75%) 5b. Mp 108ꢂC; 1H NMR (500 MHz, CDCl3): ꢂ ¼ 1.67
(d, JHH ¼ 6.94 Hz, CH3), 2.23 (s, CH3), 3.77 (s, OCH3), 4.22 (m, CH), 6.05 (s, CH), 7.29–7.31 (m, 2H),
7.49–7.50 (m, 3H), 10.08 (br. s, NH) ppm; 13C NMR (125MHz, CDCl3): ꢂ ¼ 15.8 (CH3), 17.2 (CH3),
52.7 (OCH3), 54.7 (CH), 99.9 (CH), 127.3 (CH), 130.1 (CH), 130.7 (CH), 134.8 (C), 161.4 (C–NPh),
170.8 (S–C¼NHþ), 171.4 (COO) ppm; IR (KBr): ꢁꢁ¼ 3095, 2958, 2927, 1743, 1559, 1214,
20
1142 cmꢁ1; ½ꢀꢃD ¼ ꢁ7.7ꢂ cm2 gꢁ1 (c ¼ 1.5, CHCl3).
Methyl (S)-(ꢁ)-2-(3-methyl-2-phenyl-2H-isothiazol-5-ylideneamino)-3-phenylpropionate
hydrobromide (5c, C20H21N2O2SBr)
Column chromatography afforded 1.75g (75%) 5c. Mp 98ꢂC; 1H NMR (500MHz, CDCl3): ꢂ ¼ 2.15
(s, CH3), 3.29 (dd, JHaH ¼ 8.76Hz, JHaHb ¼ 13.85 Hz, CHaHb), 3.37 (dd, JHbH ¼ 5.61Hz, CHaHb), 3.75
(s, OCH3), 4.27 (m, CH), 5.88 (s, CH), 7.23–7.49 (m, 10H), 10.30 (br. s, NH) ppm; 13C NMR
(125 MHz, CDCl3): ꢂ ¼ 15.6 (CH3), 38.1 (CH2), 52.8 (OCH3), 61.7 (CH), 99.8 (CH), 127.3 (CH),
127.3 (CH), 128.7 (CH), 129.5 (CH), 130.1 (CH), 130.6 (CH), 134.9 (C), 161.1 (C–NPh), 169.7
(S–C¼NHþ), 171.6 (COO) ppm; IR (KBr): ꢁꢁ¼ 3088, 2948, 2923, 1743, 1549, 1487, 1208,
1029 cmꢁ1; MS (70 eV): m=z (%) ¼ 352 (3.4), 321 (12.2), 293 (21.0), 261 (100), 215 (38.0), 176
20
(31.8), 169 (16.8), 163 (8.8), 131 (16.6), 118 (81.0); ½ꢀꢃD ¼ ꢁ24.1ꢂ cm2 gꢁ1 (c ¼ 1, CHCl3).
Methyl (S)-(ꢁ)-4-methyl-2-(3-methyl-2-phenyl-2H-isothiazol-5-ylideneamino)pentanoate
hydrobromide (5d, C17H23N2O2SBr)
1
Column chromatography afforded 1.43 g (72%) 5d. Mp 83ꢂC; H NMR (500MHz, CDCl3): ꢂ ¼ 0.95
(d, J ¼ 6.42Hz, CH3), 1.01 (d, J ¼ 6.45 Hz, CH3), 1.87 (m, CHaHb), 1.97 (m, CH), 2.02 (m, CHaHb),
2.26 (s, CH3), 3.78 (s, OCH3), 4.14 (ddd, J ¼ 6.74Hz, CH), 6.05 (s, CH), 7.32–7.34 (m, 2H),
7.51–7.53 (m, 3H), 10.08 (br. s, NH) ppm; 13C NMR (125 MHz, CDCl3): ꢂ ¼ 15.7 (CH3), 21.6
(CH3), 22.5 (CH3), 24.7 (CH3), 40.1 (CH2), 52.6 (OCH3), 58.0 (CH), 99.5 (CH), 127.3 (CH), 130.1
(CH), 130.6 (CH), 134.9 (C), 161.3 (C–NPh), 170.8 (S–C¼NHþ), 171.4 (COO) ppm; IR (KBr):
20
ꢁꢁ¼ 3098, 2954, 2922, 1744, 1555, 1487, 1210, 1139 cmꢁ1; ½ꢀꢃD ¼ ꢁ26.4ꢂ cm2 gꢁ1 (c ¼ 1.4, CHCl3).
Methyl (S,S)-(ꢁ)-3-methyl-2-(3-methyl-2-phenyl-2H-isothiazol-5-ylideneamino)pentanoate
hydrobromide (5e, C17H23N2O2SBr)
Column chromatography afforded 1.29g (65%) 5e. Mp 87ꢂC; 1H NMR (500MHz, CDCl3): ꢂ ¼ 0.97
(t, J ¼ 7.39Hz, CH3), 1.11 (d, J ¼ 6.86 Hz, CH3), 1.55 (ddq, CH3–CHaHb), 1.67 (ddq, CH3–CHaHb),
2.22 (m, CH), 2.24 (s, CH3), 3.79 (s, OCH3), 3.89 (dd, CH), 5.99 (s, CH), 7.30 (m, 3H), 7.52 (t, 2H),
10.11 (br s, NH) ppm; 13C NMR (125 MHz, CDCl3): ꢂ ¼ 11.3 (CH3), 15.7 (CH3–CH2), 15.8 (CH3),
25.3 (CH3), 37.3 (CH), 52.5 (OCH3), 64.6 (CH), 99.4 (CH), 127.3 (CH), 130.1 (CH), 130.6 (CH),
135.0 (C), 161.1 (C–NPh), 170.1 (S–C¼NHþ), 171.8 (COO) ppm; IR (KBr): ꢁꢁ¼ 3092, 2955, 2927,
20
1740, 1555, 1219, 1150 cmꢁ1; ½ꢀꢃD ¼ ꢁ8.1ꢂ cm2 gꢁ1 (c ¼ 1.5, CHCl3).
Acknowledgements
This project was partially supported by CRBW=IX-6=2004.

2066
D. Ciez˙ and E. Szneler: Optically Active Isothiazole Derivatives
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