Synthesis of novel, chiral, water-soluble isothiazole derivatives

Article abstract of DOI:10.3184/030823407X203396

This article describes an easy preparation of some optically active, water soluble N⁵,2,3,4-tetrasubstituted isothiazol-5(2H)-imine hydrobromides from modified L-α-amino acids. Isothiazole rings are created in two-step reactions by oxidation of

Full text of DOI:10.3184/030823407X203396

200 RESEARCH PAPER
APRIL, 200–202
JOURNAL OF CHEMICAL RESEARCH 2007
Synthesis of novel, chiral, water-soluble isothiazole derivatives
.
Dariusz Cieza* and Edward Sznelerb
aDepartment of Organic Chemistry, Jagiellonian University, 30-060 Kraków, Poland
bNMR Laboratory, Faculty of Chemistry, Jagiellonian University, 30-060 Kraków, Poland
This article describes an easy preparation of some optically active, water soluble N5,2,3,4-tetrasubstituted isothiazol-
5(2H)-imine hydrobromides from modified l-a-amino acids. Isothiazole rings are created in two-step reactions by
oxidation of chiral 3-amino-2,3-unsaturated thioamides.
Keywords: isothiazoles, chirality, unsaturated thioamides, oxidation, water solubility
Over the last decade a particular interest in the search
for more effective and simpler preparation of substituted
isothiazoles stemmed from their biological activity.1 Highly
substituted isothiazoles are known as antimicrobial,2
antitumoral,3 spasmolytic,4 herbicidal, insecticidal and
fungicidal5 agents. The application of substituted isothiazole
derivatives in pharmacotherapy has been significantly
broadened after the discovery of their antiviral properties.6 Of
all the antiviral drugs, isothiazole derivatives are the object
of intensive research. Recent investigations have shown that
some 3-methylthio-5-aryl-4-isothiazolecarbonitriles possess
remarkable antiviral activity against numerous serotypes of
rhinoviruses and enteroviruses, and inhibit the replication
of HIV-1 and HIV-2 viruses.7 The diamide of 3-methyl-
5-isothiazole-4,5-dicarboxylic acid, known as vratizolin,8
(ITLC, Denotivir) is a commercially available antiviral drug
recommended for the treatment of herpes simplex and varicella
zoster viral infections. The pharmacological application
of vratizolin and related isothiazoles is however wider then
previously expected owing to their antiinflammatory and
immunomodulatory properties.9 The biological activity of
the investigated isothiazole derivatives depends however
not only on their chemical structures but also on their
physical properties such as solubility and stability in aqueous
solution.7a
a previously described method,10 consisting in the oxidation
of 3-amino-2,3-unsaturated thioamides. The first step of
our investigation involved the preparation of the starting
unsaturated thioamides from isothiocyanates and enamines
using a standard procedure.11 As isothiocyanate we used
the chiral α-isothiocyanatocarboxylates12 1 derived from
protected l-α-aminoacids, and as enamine we used ethyl 3-
anilinocrotonate 2.13 The choice of the 3-anilinocrotonate
was predicated by the presence of an ester group which we
wished to introduce directly into isothiazole ring to enhance
its polarity. The optically active isothiocyanatocarboxylates
1 provided an amino acid group which, after cyclisation, we
wished to deprotect to obtain a pure carboxyl substituent.
Addition of the chiral isothiocyanatocarboxylates 1 to ethyl
3-anilinocrotonate 2 in a solvent-free system gave novel 3-
aminothiocrotonates 3 in good yields (Scheme 1).
The structures of the unsaturated thioamides 3 so obtained
were confirmed by NMR, IR and mass spectrometry. Based on
NOESY experiments, we found that 3-amino-2,3-unsaturated
thioamides 3 existed only as (E)-diastereomers; analogously
to earlier described 3-anilinothiocrotonate amides,14 we did
1
not observe any trace of (Z)-isomers. The H NMR signals
of both NH protons were observed at ca 10 ppm, indicating
strong hydrogen bonding between amino and ester groups.
The second step, the oxidation of the unsaturated thioamides
3 with bromine following the procedure of Goerdeler and
Gnad,15 ledtothedesiredisothiazolehydrobromides4. Isolation
Results
5
of the pure diesters of the Nꢀ ,2,3,4-tetrasubstituted isothiazol-
Water solubility is a very desirable feature of organic
compounds which are investigated as potential biologically
active agents. Although the isothiazole ring is hydrophobic,
the introduction of polar groups into this molecule may
considerably increase its solubility in water. In our
5(2H)-imines 4 was, however, not possible because of their
instability. Deesterification of the aminoester groups proceeded
spontaneously during isolation and purification, leading to
the stable final products, the ethyl 5-(1-carboxyalkylimino)-
3-methyl-2-phenyl-2,5-dihydroisothiazole-4-carboxylate
hydrobromides 5 (Scheme 2).
Hydrolysis of the 4-ethoxycarbonyl group to form the
dicarboxylic acid failed owing to the particular stability of this
substituent. All the structures of the isothiazole derivatives
5 synthesised here were confirmed by spectroscopic data.
In the 1H NMR spectrum of 5c (R = CH2Ph) we observed the
5
research we have focused on the synthesis of Nꢀ ,2,3,4-
tetrasubstituted isothiazol-5(2H)-imine derivatives bearing
a chiral l-α-aminoacid substituent. We wished to determine
if the presence of an amino acid group linked to a highly-
substituted isothiazole ring would be a sufficient requirement
for improvement of its water solubility. The synthesis of
N5,2,3,4-tetrasubstituted isothiazol-5(2H)-imines, based on
Et
H
O
CO2Me
R
N
S
O
N
OEt
H3C
Ph
CO2Me
NCS
R
H
N
O
H
CH3
Ph
1a-d
2
3a-d
a: R = H; b: R = CH3; c: R = CH2Ph; d: R = CH(CH3)C2H5
Scheme 1
* Correspondent. E-mail: ciez@chemia.uj.edu.pl
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JOURNAL OF CHEMICAL RESEARCH 2007 201
Et
O
O
EtO
EtO
Br
Br
CO2Me
C
H
C
H
N
H
O
CO2Me
R
N
S
O
N
CO2H
N
H3C
H3C
Br2
H
R
R
N
S
N
S
CH3
Ph
Ph
Ph
3a-c
4a-c
Scheme 2
5a-c
diastereotopic nonequivalence of the benzylic protons: the Jgem
thioamides were easy obtained from commercially available
l-α-amino acids and ethyl acetoacetate. The synthesised
N5,2,3,4-tetrasubstituted isothiazol-5(2H)-imine derivatives
5 show a structural similarity with some antiviral isothiazole
agents being currently investigated.7,9
coupling was 13.8 Hz, and they coupled with the neighbouring
3
proton at C-α with Jvic values of 4.2 and 9.0 Hz. According
to the Karplus-Conroy equation we estimate that the dihedral
angles of H–Cα–Cβ–Ha and H–Cα–Cβ–Hb are ca 43° and
5
171°. The obtained Nꢀ ,2,3,4-tetrasubstituted isothiazol-
5(2H)-imine hydrobromides 5a–c were stable as salts and
showed good solubility in water. Stoichiometric reaction of
the obtained hydrobromides 5 with triethylamine gave rise
to cleavage of the isothiazole ring with extrusion of sulfur.
This process was particularly rapid in polar protic solvents,
while neutralisation of the hydrobromides in methylene
chloride led to unstable isothiazol-5(2H)-imines which
decomposed during separation. Thus, the reaction of the
hydrobromide 5c with triethylamine in methanol led to several
decomposition products which were investigated using NMR
spectroscopy. We noted that a characteristic feature of these
compounds was a presence of the methoxyl group at C-5
carbon atom. This observation is in agreement with earlier
reported ring-opening processes of isothiazole rings on
reaction with nucleophiles.16
Experimental
NMR spectra were determined on a Bruker Avance II 300
MHz spectrometer, using TMS as internal standard. IR spectra
were measured with a Bruker IFS 48 FT spectrometer in KBr
pellets and EI mass spectra were recorded on a Finnigan MAT
95S apparatus. Mass spectrometric analysis of compound
5c using electrospray (ESI) technique was performed on an
Esquire 3000 mass spectrometer. The sample of 5c was mixed
with 30% methanol in water and analysed in the positive-ion
mode. Microanalyses were carried out using Euro-EA 3018
analyser. Optical rotations were measured on a Polamat A
polarimeter with 0.5 dm tube. Column chromatography was
performed using commercial silica gel 60 (70–230 mesh).
Melting points were measured on an Electrothermal 9100
apparatus.
Previously we have proved that the oxidative cyclisation of
chiral optically active 2,3-unsaturated thioamides with bromine
proceeded without racemisation and all prepared isothiazole
derivatives were enantiomerically pure.14 To confirm that
our method also gives enantiomerically pure products and
proceed without partial racemisation we measured some NMR
spectra of the prepared compounds using europium tris[3-
(trifluoromethylhydroxymethylene)-(+)-camphorate],Eu(tfc)3,
as a chiral NMR shift reagent. However 3-anilinothiocrotonate
amides 3 did not interact with Eu(tfc)3, whereas isothiazole
derivatives 5 formed very stable complexes with Eu3+
ions replacing the chiral ligands. To check on the retention
of configuration during the synthesis we synthesised 3-
anilinothiocrotonate amide with two chiral centres starting from
l-isoleucine. After addition of isothiocyanatocarboxylate 1d to
3-anilinocrotonate (2) we observed only one diastereoisomer
3d. This observation encouraged us to assume that syntheses
Solvent-freeꢀ synthesisꢀ ofꢀ thiocarbamoylꢀ esters 3a–d: generalꢀ
procedure
Into a 25 ml flask protected against air moisture was added ethyl
3-anilinocrotonate13
2 (20 mmol) and methyl isothiocyanato-
carboxylate12 1a–d (21 mmol). The mixture was stirred and heated
for 90–120 min. at 105°C. After cooling, the residue was purged
with petroleum ether/n-hexane to remove excess of the methyl
isothiocyanatocarboxylate and the crude product was purified by
column chromatography using silica gel (cyclohexane:ethyl acetate
10:1) and then crystallised from methanol.
Ethylꢀ(E)-2-[N-(methoxycarbonylmethyl)thiocarbamoyl]-3-phenyl-
amino-but-2-enoate (3a): Pale yellow solid (85% yield), m.p. 112°C.
1
IR: νmax 3249, 1740, 1625, 1210 cm-1. H NMR (DMSO-d6): δ 1.17
(t, J = 7.1 Hz, 3H, OCH2CH3), 2.07 (s, 3H, CH3), 3.66 (s, 3H, OCH3),
4.08 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.36 (d, J = 5.8 Hz, 2H, CH2),
7.18 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz,
2H), 10.48 (t, J = 5.7 Hz, 1H, NH), 10.92 (s, 1H, NH) ppm. 13C
NMR (DMSO-d6): δ 14.3, 17.1, 40.5, 51.7, 59.1, 104.1, 124.5, 125.3,
129.3, 138.0, 156.2, 166.9, 168.5, 198.5 ppm. MS: m/z (%) 336 (M+,
27), 303 (40), 263 (17), 244 (13), 205 (22), 160 (21), 132 (23), 118
(100), 93 (23). Anal. Calcd for C16H20N2O4S: C, 57.13; H, 5.99; N,
8.33. Found: C, 57.18; H, 6.11; N, 8.30%.
of 3-anilinothiocrotonate amides
3 proceeded without
racemisation, leading to enantiomerically pure products.
In summary, we have discovered a novel class of chiral
5
Nꢀ ,2,3,4-tetrasubstituted
isothiazol-5(2H)-imine
hydro-
Ethylꢀ (S),(E)-2-[N-(1-Methoxycarbonylethyl)thiocarbamoyl]-3-ꢀ
phenylamino-but-2-enoate (3b): Pale yellow solid (78% yield),
bromides. Although the isothiazole rings are considerably
hydrophobic owing to the presence of methyl and phenyl
substituents, the introduction of one amino acid group into
the heterocyclic system results in significant increase in their
water solubility. Moreover, the 5-(1-carboxyalkylimino)-3-
m.p. 110°C. [a] -22.8° (c = 0.1, CHCl3). IR: νmax 3274, 1745, 1728,
D
1
1635, 1210 cm-1. H NMR (DMSO-d6): δ 1.18 (t, J = 7.0 Hz, 3H,
OCH2CH3), 1.40 (d, J = 7.3 Hz, 3H, CHCH3), 2.04 (s, 3H, CH3),
3.64 (s, 3H, OCH3), 4.08 (m, 2H, OCH2CH3), 4.92 (m, 1H, CHCH3),
7.22 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 10.44 (d, J = 6.8 Hz, 1H, NH),
10.89 (s, 1H, NH) ppm. 13C NMR (DMSO-d6): δ 14.2, 15.9, 17.1,
51.9, 53.6, 59.0, 104.2, 124.5, 125.3, 129.3, 138.4, 156.1, 166.9,
171.5, 197.2 ppm. MS: m/z (%) 350 (M+, 25), 317 (59), 258 (21), 233
(26), 205 (53), 200 (27), 160 (49), 132 (45), 118 (100), 93 (76). Anal.
Calcd for C17H22N2O4S: C, 58.27; H, 6.33; N, 7.99. Found: C, 58.19;
H, 6.40; N, 7.94%.
methyl-2-phenyl-2,5-dihydroisothiazole-4-carboxylic
acid
ethyl ester hydrobromides (5) are very stable, although only as
the salts, and they did not further hydrolyse in water, although
they decompose easily under basic conditions. The presence
of the carboxylic functional group had a strong effect on the
chelating properties of these isothiazoles. The products are
prepared in enantiomerically pure form in a simple and direct
way in two steps from chiral 3-anilinothiocrotonate amides.
All reactants used for syntheses of the starting unsaturated
Ethylꢀ(S),(E)-2-[N-[(1-Methoxycarbonyl)-2-phenylethyl]thiocarbamoyl]ꢀ
-3-phenylamino-but-2-enoate (3c): Pale yellow solid (95% yield),
m.p. 136°C. [a] = 74.1° (c = 0.1, CHCl3). IR: νmax 3155, 1755,
D
1
1645, 1205 cm-1. H NMR (DMSO-d6) δ 1.06 (t, J = 7.1 Hz, 3H,
PAPER: 07/4395

202 JOURNAL OF CHEMICAL RESEARCH 2007
OCH2CH3), 1.85 (s, 3H, CH3), 3.13 (dd, J = 9.9 and 14.4 Hz, 2H,
PhCHaHb), 3.19 (dd, J = 4.9 and 14.4 Hz, 2H, PhCHaHb), 3.64 (s,
3H, OCH3), 3.97 (ddq, J = 7.0, 7.1 and 10.8 Hz, 2H, OCH2CH3), 5.20
(ddd, J = 4.9, 7.3 and 9.9 Hz, 1H, CH), 7.14 (d, J = 7.7 Hz, 2H), 7.22
(m, 2H), 7.29 (m, 4H), 7.39 (t, J = 8.0 Hz, 2H), 10.52 (d, J = 7.3 Hz,
1H, NH), 10.88 (s, 1H, NH) ppm. 13C NMR (DMSO-d6): δ 14.1,
16.8, 35.7, 51.9, 58.9, 59.3, 104.2, 124.0, 125.2, 126.6, 128.2, 128.7,
129.3, 137.0, 138.3, 155.9, 166.8, 170.5, 198.1 ppm. Anal. Calcd for
C23H26N2O4S: C, 64.77; H, 6.14; N, 6.57. Found: C, 64.76; H, 6.10;
N, 6.61%.
Ethylꢀ (S)-5-[(1-carboxy-2-phenylethyl)imino]-3-methyl-2-phenyl-
2,5-dihydroisothiazole-4-carboxylateꢀhydrobromideꢀ(5c): Colourless
solid (82% yield), m.p. 82°C. [a] = 17.3° (c = 0.1, CHCl3). IR: νmax
D
3580–2350, 1741, 1730, 1683 cm-1. 1H NMR (CDCl3): δ 1.36 (t,
J = 6.9 Hz, 3H, OCH2CH3), 2.53 (s, 3H, CH3), 3.17 (dd, J = 9.0, 13.8
Hz, 1H, PhCHaHb), 3.56 (dd, J = 4.2, 13.8 Hz, 1H, PhCHaHb), 4.38
(q, J = 6.9 Hz, 2H, OCH2CH3), 4.62 (br. s, 1H, CH), 7.28 (m, 4H),
7.36 (m, 3H), 7.57 (m, 3H), 9.55 (br. s, 1H, NH) ppm. 13C NMR
(CDCl3): δ 14.1, 17.7, 38.2, 62.4, 64.0, 104.8, 127.4, 127.6, 129.0,
129.9, 130.6, 131.6, 133.6, 136.2, 162.9, 166.3, 171.6, 174.5 ppm.
ES MS: m/z (%) 411 (M+, 100), 365 (9), 332 (7); EI MS: m/z (%) 411
(M+, 2), 348 (4), 231 (41), 203 (10), 181 (23), 160 (30), 131 (26),
105(100), 91, (40), 85 (49), 77 (45). Anal. Calcd for C22H23BrN2O4S:
C, 53.77; H, 4.72; N, 5.70. Found: C, 53.85; H, 4.79; N, 5.63%.
Methylꢀ
(S,S)-2-[[(E)-2-ethoxycarbonyl-3-(phenylamino)but-2-
enethioyl]amino]-3-methylpentanoate (3d): Yellow solid (64% yield),
m.p. 92°C. [a] = 2.4° (c = 0.1, CHCl3). IR: νmax 3260, 1743, 1647,
D
1
1202 cm-1. H NMR (CDCl3): δ 0.98 (d, J = 6.9 Hz, 3H, CHCH3),
0.99 (t, J = 7.3 Hz, 3H, CH2CH3), 1.28 (t, J = 7.1 Hz, 3H, OCH2CH3),
1.32 (ddq, J = 5.1, 5.1 and 7.8 Hz, 1H, CH3CHaHb), 1.58 (ddq,
J = 5.1, 5.4 and 7.8 Hz, 1H, CH3CHaHb), 2.13 (s, 3H, CH3), 2.15 (m,
1H, CH), 3.77 (s, 3H, OCH3), 4.20 (q, J = 6.9 Hz, 2H, OCH2CH3),
5.22 (dd, J = 5.1, 5.5 Hz, 1H, CH), 7.11 (d, J = 7.9 Hz, 2H), 7.23
(t, J = 7.9 Hz, 1H), 7.32 (t, J = 5.4 Hz, 2H), 8.44 (br s, 1H, NH),
10.14 (s, 1H, NH) ppm. 13C NMR (CDCl3): δ 11.6, 14.3, 15.5, 25.2,
26.9, 37.4, 52.1, 60.0, 61.8, 105.0, 125.7, 126.2, 129.1, 138.1, 157.1,
167.1, 171.4, 200.6 ppm. Anal. Calcd for C20H28N2O4S: C, 61.20; H,
7.19; N, 7.14. Found: C, 61.26; H, 7.22; N, 7.17%.
This project was partially supported by CRBW/IX-6/2004.
Receivedꢀ5ꢀJanuaryꢀ2007;ꢀacceptedꢀ3ꢀAprilꢀ2007ꢀ
Paperꢀ07/4395ꢀ doi:ꢀ10.3184/030823407X203396
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2
A three-necked, 150 ml flask equipped in a stir bar, a condenser and
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6
7
Ethylꢀ
5-(carboxymethylimino)-3-methyl-2-phenyl-2,5-dihydro-
isothiazole-4-carboxylateꢀhydrobromide (5a): Colourless solid (68%
1
yield), m.p. 103°C. IR: νmax 3400–2400, 1722, 1684 cm-1. H NMR
(CDCl3): δ 1.40 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.63 (s, 3H, CH3),
4.45 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.48 (d, J = 4.0 Hz, 2H, CH2),
7.58 (m, 3H), 7.66 (m, 2H), 9.51 (br s, 1H, NH) ppm. 13C NMR
(CDCl3): δ 14.2, 18.0, 50.6, 62.6, 105.4, 128.1, 130.6, 131.9, 133.7,
162, 4, 167.3, 168.7, 174.2 ppm. Anal. Calcd for C15H17BrN2O4S: C,
44.90; H, 4.27; N, 6.98. Found: C, 45.01; H 4.33; N, 6.92%.
8
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Ethylꢀ (S)-5-[(1-carboxyethyl)imino]-3-methyl-2-phenyl-2,5-dihydro-ꢀ
isothiazole-4-carboxylateꢀhydrobromide (5b): Colourless solid (71%
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yield), m.p. 93°C. [a] = 2.0° (c = 0.1, CHCl3). IR: νmax 3500–2450,
D
1734, 1683 cm-1. 1H NMR (CDCl3): δ 1.41 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.64 (d, J = 6.4 Hz, 3H, CHCH3), 2.59 (s, 3H, CH3), 4.34
(q, J = 6.4 Hz, 1H, CHCH3), 4.44 (q, J = 7.1 Hz, 2H, OCH2CH3), 7.22
(m, 1H), 7.57 (m, 4H), 10.32 (br. s, 1H, NH) ppm. 13C NMR (CDCl3):
δ 14.1, 16.9, 17.7, 57.3, 62.4, 104.9, 127.8, 130.6, 131.7, 133.7,
163.2, 166.7, 171.3, 173.4 ppm. Anal. Calcd for C16H19BrN2O4S: C,
46.27; H, 4.61; N, 6.74. Found: C, 46.31; H, 4.80; N, 6.71%.
PAPER: 07/4395