New 2-sulfonamidothiazoles substituted at C-4: Synthesis of polyoxygenated aryl derivatives and in vitro evaluation of antifungal activity

Article abstract of DOI:10.1016/S0223-5234(99)00215-9

Polymethoxylated and polyhydroxylated derivatives of 2-amino-4- arylthiazoles bearing a halogenobenzenesulfonamide moiety at position 2 were synthesized as azole antifungal analogues. X-ray crystallography studies revealed the predominance of the 2-imino-2,3-dihydrothiazole form in the amino/imino tautomerism. In vitro assays against various pathogenic fungal strains (Candida and Trichophyton species) showed no activity in comparison to econazole as reference. These results are discussed on the basis of the estimated global lipophilicity of the molecules (Rekker's method) and the π- electron distribution (Mulliken population analysis, AM1 method) within the five-membered heterocycle.

Full text of DOI:10.1016/S0223-5234(99)00215-9

Eur. J. Med. Chem. 34 (1999) 773−779
© 1999 Editions scientifiques et médicales Elsevier SAS. All rights reserved
773
´
New products
New 2-sulfonamidothiazoles substituted at C-4: synthesis of polyoxygenated aryl
derivatives and in vitro evaluation of antifungal activity
Pierre Beucheta, Martine Varache-Lembègea, Arlette Neveua, Jean-Michel Légerb,
Joseph Vercauterena, Stéphane Larrouturea, Gérard Deffieuxa, Alain Nuhricha*
aGroupe d’Étude des Substances Naturelles d’Intérêt Thérapeutique (GESNIT), Faculté de Pharmacie,
Université Victor-Segalen (Bordeaux 2), 146, rue Léo-Saignat, 33076 - Bordeaux cedex, France
bLaboratoire de Chimie Analytique, Faculté de Pharmacie, Université Victor-Segalen (Bordeaux 2),
3, Place de la Victoire. 33076 -Bordeaux cedex, France
(Received 29 September 1998; revised 4 February 1999; accepted 10 February 1999)
Abstract – Polymethoxylated and polyhydroxylated derivatives of 2-amino-4-arylthiazoles bearing a halogenobenzenesulfonamide moiety at
position 2 were synthesized as azole antifungal analogues. X-ray crystallography studies revealed the predominance of the 2-imino-2,3-
dihydrothiazole form in the amino/imino tautomerism. In vitro assays against various pathogenic fungal strains (Candida and Trichophyton
species) showed no activity in comparison to econazole as reference. These results are discussed on the basis of the estimated global
lipophilicity of the molecules (Rekker’s method) and the π-electron distribution (Mulliken population analysis, AM1 method) within the
´
five-membered heterocycle. © 1999 Editions scientifiques et médicales Elsevier SAS
2,4-disubstituted thiazoles / sulfonamides / antifungal testing
1. Introduction
The most commonly used imidazole antifungal agents,
such as miconazole 1, econazole 2 and ketoconazole 3
(figure 1), exhibit side effects including interference with
steroidogenesis or hepatic toxicity [1]. Over the past few
years, the discovery of triazole compounds including
itraconazole 4 and fluconazole 5 with better tolerance
gave rise to the synthesis of numerous related ana-
logues [2].
Since the sulfonamide moiety seems to be a possible
pharmacophore in fungicidal agents [3], we decided to
introduce this functionality in position 2 of a thiazole
nucleus. On the other hand, the lack of hydrosolubility
which limits systemic distribution of azoles led us to
include hydrophilic fragments and thus to synthesize new
thiazole derivatives with a polyoxygenated phenyl com-
ponent (6–9), as represented in figure 1.
Figure 1. Structure of azole antifungals (1–5) and target com-
pounds (6–9).
*Correspondence and reprints

774
Table I. Chemical and physical properties of compounds 6–9.
a
c
Compound
(RO)n
Hal
M.p.(°C)
Yield (%)
Formula (MW)
log Pcalc
6a
6b
6c
6d
4≠-Cl
130
136
148–150
140
75
36
51
31
C17H15ClN2O4S2 (410.90)
C17H15FN2O4S2 (394.43)
C17H14Cl2N2O4S2 (445.35)
C17H14F2N2O4S2 (412.44)
2.44
1.92
3.18
2.13
4≠-F
2,5-OMe
2≠,4≠-Cl
2≠,4≠-F
7a
7b
7c
7d
4≠-Cl
260
218
240
232
45
47
56
78
C15H11ClN2O4S2 (382.84)
C15H11FN2O4S2 (366.39)
C15H10Cl2N2O4S2 (417.29)
C15H10F2N2O4S2 (384.38)
1.25
0.73
1.99
0.94
4≠-F
2,5-OH
2≠,4≠-Cl
2≠,4≠-F
8a
8b
8c
8d
4≠-Cl
b
b
58
67
56
20
C18H17ClN2O5S2 (440.92)
C18H17FN2O5S2 (424.47)
C18H16Cl2N2O5S2 (475.37)
C18H16F2N2O5S2 (442.46)
2.51
1.99
3.25
2.20
4≠-F
3,4,5-OMe
3,4,5-OH
2≠,4≠-Cl
2≠,4≠-F
165–166
178–180
9a
9b
9c
9d
4≠-Cl
4≠-F
2≠,4≠-Cl
2≠,4≠-F
220
218–220
b
67
53
65
84
C15H11ClN2O5S2 (398.85)
C15H11FN2O5S2 (382.39)
C15H10Cl2N2O5S2 (433.29)
C15H10F2N2O5S2 (400.38)
0.73
0.20
1.47
0.42
219
aAll compounds were analysed for C, H, N, S and when present Cl or F; analytical results are within ± 0.4% of the theoretical values.
c
bDecomposition over 80 °C. According to Rekker fragmental system [10].
2. Chemistry
functionalization on the heterocyclic ring was therefore
established.
The target compounds (table I) were synthesized fol-
lowing figure 2. The key step in the preparation of
derivatives 6 and 8 resulted in the reaction of bromom-
ethylketones 13 with the appropriate arylsulfonylthio-
ureas 12 in refluxing THF, according to a modified
Hantzsch condensation [4]. The thioureas 12 were ob-
tained by reaction of N-cyanoarylsulfonamide sodium
salts 11 with thiosulfuric acid (generated in situ upon
treatment of sodium thiosulfate with aqueous-
H2SO4 [5]).
X-ray diffraction analysis of 6b (figure 3) confirmed a
structure close to that of a thiazoline derivative [7].
Noteworthy, the exocyclic C(9)-N(12) bond shows sig-
nificant shortening from the value of the endocyclic
N(8)-C(9) (table III). Consequently, this phenomenon is
indicative of an exocyclic C=N double bond and confirms
that the imino form is the predominant tautomer, at least
in the crystalline state. This conclusion agrees with
previous reports on 2-substituted thiazoles [8, 9].
4. Antifungal evaluation and discussion
3. Structural data
The antifungal activity of compounds 6–9 was evalu-
ated in vitro, against yeasts (Candida albicans
ATCC 10231 and Candida krusei CBS 573) and filamen-
tous fungi (Trichophyton mentagrophytes IP 1468-83 and
T. rubrum IP 2073-92), according to described meth-
ods [11, 12]. By comparison with econazole, used as
reference substance, all the tested thiazoles were found
inactive (data not shown). These results confirm that
lipophilicity plays a fundamental role for antifungal
1
As an example, H and 13C NMR data for 6a are
shown in table II. The chemical shifts for the carbon
atoms at positions 7, 8 and 9 are consistent with data of
substituted thiazoles [6] and therefore confirm the hetero-
cyclisation reaction. The main information is provided by
the long-range H -13C correlations (HMBC spectrum).
1
The quaternary carbon 7 exhibits correlation with proton
H6, belonging to the oxygenated ring The 7,9-

775
antifungals, might be a determining factor in the biologi-
cal response.
5. Experimental protocols
Melting points were determined with a Köfler appara-
tus and are uncorrected. NMR spectra were obtained in
CDCl3, at 29 °C, using a Bruker AMX 500 spectrometer
(1H: 500 MHz, 13C: 125 MHz). Chemical shifts are given
in ppm from TMS as an internal standard (coupling
constants J, in Hz). Multiplicities in 13C NMR spectra
were derived from JMOD experiments. When necessary,
HMQC, HMBC and 1H-1H COSY experiments were
used for structural assignments.
5.1. Chemistry
5.1.1. General procedure for N-aminothioxomethyl-
arylsulfonamides 12a–d
To a stirred suspension of sodium cyanamide [16]
(0.08 mol) in anhydrous Et2O (20 mL) was added appro-
priate arylsulfonyl chloride 10a–d (0.04 mol). Stirring
was continued for 6 h under reflux, and the insoluble Na
salt of N-cyanoarylsulfonamide 11a–d was washed (dry
ether, then acetone) and dried (yields: 65–75%).
A cooled solution (0 °C) of the convenient sodium salt
11 (20 mmol) in H2O (10 mL) was neutralized with 2 N
H2SO4 (10 mL). Solid Na2S2O3, 5H2O (60 mmol) was
added in one portion under stirring and the mixture was
treated with more 2 N H2SO4 (15 mL). After further
stirring overnight at 20 °C, the resulting precipitate was
washed with cold H2O (2 × 10 mL), and recrystallized
from methanol/H2O (50:50) to afford the expected prod-
uct 12 as white needles (45–61%).
Figure 2. General synthetic pathway for 2,4-functionalized
thiazoles 6–9.
properties [13]: the estimated log P values for com-
pounds 6–9, ranging from 0.2–3.25 (table I) are signifi-
cantly lower than that calculated for econazole (log P =
5.17).
5.1.1.1. N-Aminothioxomethyl-4-chlorobenzenesulfon-
amide 12a
We have also investigated the electron density distri-
bution in econazole and compound 6b, respectively. The
AM1 method [14] with Mulliken population analysis was
selected for its usefulness in predicting the aromaticity of
5-membered heterocycles [15]. From the data presented
in figure 4, it is shown that the imidazole ring of
econazole displays a high level of aromaticity (π overlap
populations ranging from 23–40%), while in the thiazole
moiety, the π-electrons are unequally spread over the
intracyclic bonds (furthest values: 11–44%), thus indica-
tive of a weak aromatic character for 6b.
In conclusion, it appears that the association of a
polyoxygenated phenyl ring and an arylsulfonamido moi-
ety on a thiazolic framework does not lead to antifungal
activity. The electronic properties of the five-membered
ring, which differ strongly from those of the imidazole
1
M.p. = 149–151 °C. H-NMR δ 7.61 (d, J = 8.8, 2H);
7.94 (d, J = 8.8, 2H); 13C- NMR δ 130.0 (C2, C6); 130.6
(C3, C5); 139.3 (C4); 141.3 (C1); 182.3 (C7).
5.1.1.2.
N-Aminothioxomethyl-4-fluorobenzenesulfon-
amide 12b
M.p. = 120 °C. 1H- NMR δ 7.33 (dd, J = 8.8, 8.6, 2H);
8.02 (dd, J = 9.0, 5.0, 2H); 13C- NMR δ 117.5 (C3, C5);
131.4 (C2, C6); 136.8 (C1); 167.1 (C4); 182.4 (C7).
5.1.1.3. N-Aminothioxomethyl-2,4-dichlorobenzenesulfon-
amide 12c
M.p. = 205 °C. 1H- NMR δ 7.81 (dd, J = 2.0, 8.6, 1H);
7.94 (d, J = 2.0, 1H); 8.34 (d, J = 8.6, 1H); 13C- NMR δ
128.5 (C2); 132.5 (C4); 133.8 (C6); 134.3 (C1); 136.6
(C5); 140.9 (C3); 181.1 (C7).

776
1
Table II. NMR dataa and main HMQC, HMBC, and H-1H COSY correlations for 6a (CDCl3).
Positions
1H
13C
HMQC
HMBC
1
2
3
4
5
6
7
8
–
–
117.0
149.6
116.0
113.0
154.1
113.2
134.4
102.2
168.4
140.8
127.8
128.9
138.4
128.9
127.8
C8, H8
–
C1, H8
C2, H6; C2, H4
–
C4, H6
C5, H6; C5, H4
C6, H4
C7, H6; C7, H8
–
C9, H8
C10, H12; C10, H14
C11, H15
C12, H14
C13, H11; C13, H15
C14, H12
C15, H11
6.94 (d, 8.8)b
C3, H3
C4, H4
–
C6, H6
–
C8, H8
–
–
C11, H11
C12, H12
–
C14, H14
C15, H15
6.92 (dd, 9.1, 2.6)b
–
7.02 (d, 2.6)b
–
6.62 (s)
–
9
10
11
12
13
14
15
–
7.91 (d, 8.6)b
7.42 (d, 8.6)
–
7.42 (d, 8.6)
7.91 (d, 8.6)b
aChemical shifts, ppm (multiplicity, J in Hz). b1H-1H COSY correlations. cThe methoxy protons appeared at 3.79 and 3.91 ppm, as singlets.
dThe NH-proton was not obviously identifiable.
Table III. Selected bond lengths (Å) for 6ba
5.1.1.4. N-Aminothioxomethyl-2,4-difluorobenzenesulfon-
amide 12d
C(1)–C(7)
1.477 (4)
S(10)–C(11)
1.740 (3)
1
M.p. = 102 °C. H- NMR δ 7.03–7.15 (m, 2H); 7.95
C(7)–C(11)
C(7)–N(8)
N(8)–C(9)
C(9)–N(12)
C(9)–S(10)
1.322 (4)
1.395 (4)
1.346 (3)
1.325 (4)
1.737 (3)
N(12)–S(13)
S(13)–O(15)
S(13)–O(14)
S(13)–C(16)
1.588 (2)
1.441 (2)
1.444 (2)
1.762 (3)
(ddd, J = 8.0, 6.0, 6.0, 1H); 13C- NMR δ 106.4 (C3);
112.4 (C5); 122.7 (C1); 131.8 (C6); 160.1 (C2); 166.9
(C4); 179.6 (C7).
aEstimated standard deviations are given in brackets
Figure 3. Molecular conformation of compound 6b with spe-
cial atom-numbering used in the crystallographic analysis.
(displacement ellipsoids are shown for non-hydrogen atoms at
50% probability level).
Figure 4. π-Interatomic overlap populations (%) calculated
using the Mulliken population analysis for the heterocycles of
econazole 2 and compound 6b (AM1 results from X-ray
structure data). Atomic charges are indicated in italic numbers.

777
5.1.2. General procedure for 1-aryl-2-bromoethanones 13
These products were obtained by bromination of com-
mercial acetophenones in CCl4 [17], and chromato-
graphed on silica gel column (eluent: hexane/CH2Cl2, 70:
30) prior to use.
(m, 1H); 13C-NMR δ 55.8; 56.3; 102.3; 105.2 (dd, 2JC, F
2
= 25, JC, F = 25); 111.1; 113.0; 113.3; 116.0; 117.0;
126.7; 131.1; 134.5; 149.7; 154.1; 160.1 (dd, 1JC, F = 250,
3JC, F = 10); 165.1 (dd, 1JC, F = 250, 3JC, F = 10); 169.0.
5.1.3.5. N-[2,3-Dihydro-4-(3,4,5-trimethoxyphenyl) thia-
zol-2-ylidene]-4-chlorobenzenesulfonamide 8a
1H-NMR δ 3.88 (s, 9H); 6.46 (s, 1H); 6.71 (s, 2H);
7.38 (d, J = 8.6, 2H); 7.89 (d, J = 8.6, 2H). 13C-NMR δ
56.3; 60.8; 101.2; 103.2; 123.9; 127.9; 128.9; 137.5;
138.6; 139.5; 140.2; 153.7; 168.7.
5.1.2.1. 1-(2,5-Dimethoxyphenyl)-2-bromoethanone 13a
M.p. = 80 °C. H- NMR δ 3.80 (s, 3H); 3.93 (s, 3H);
4.65 (s, 2H); 7.05 (m, 2H); 7.40 (d, J = 8.0, 1H).
1
5.1.2.2. 1-(3,4,5-Trimethoxyphenyl)-2-bromoethanone 13b
1
M.p. = 71 °C. H- NMR δ 4.00 (s, 9H); 4.46 (s, 2H);
7.30 (s, 2H).
5.1.3.6. N-[2,3-Dihydro-4-(3,4,5-trimethoxyphenyl) thia-
zol-2-ylidene]-4-fluorobenzenesulfonamide 8b
5.1.3.
General
procedure
for
N-(4-aryl-2,3-
1H-NMR δ 3.85 (s, 9H); 6.46 (s, 1H); 6.73 (s, 2H);
7.07 (dd, J = 8.6, 8.6, 2H); 7.97 (dd, J = 8.8, 5.1, 2H).
13C-NMR δ 56.3; 60.8; 101.3; 103.2; 115.7; 115.9; 124.5;
129.1; 137.6; 137.8; 139.2; 153.7; 164.8 (d, 1JC, F = 250);
168.7.
dihydrothiazol-2-ylidene) arylsulfonamides 6a–d and
8a–d
A suspension of N-aminothioxomethylbenzenesulfon-
amide 12a–d (4 mmol) and 1-aryl-2-bromoethanone 13a
or 13b (4 mmol) in anhydrous THF (30 mL) was heated
at reflux for 5 h under constant stirring. The mixture was
then cooled to 20 °C and after removal of the volatile
materials under vacuo, the crude residue was chromato-
graphed on a silica-gel column (eluent: CH2Cl2/EtOAc,
80:20), then recrystallized from heptane (yields:
40–51%).
5.1.3.7. N-[2,3-Dihydro-4-(3,4,5-trimethoxyphenyl) thia-
zol-2-ylidene]-2,4-dichlorobenzenesulfonamide 8c
1H-NMR δ 3.88 (s, 9H); 6.49 (s, 1H); 6.71 (s, 2H);
7.32 (d, J = 4.2, 1H); 7.45 (s, 1H); 8.10 (d, J = 4.2, 1H).
13C-NMR δ 56.3; 60.9; 101.4; 103.2; 123.9; 126.8;
131.1; 131.2; 133.4; 137.1; 137.8; 138.6; 139.5; 153.8;
169.3.
5.1.3.1. N-[2,3-Dihydro-4-(2,5-dimethoxyphenyl) thia-
zol-2-ylidene]-4-chlorobenzenesulfonamide 6a (see
table II for spectral data)
5.1.3.8. N-[2,3-Dihydro-4-(3,4,5-trimethoxyphenyl) thia-
5.1.3.2. N-[2,3-Dihydro-4-(2,5-dimethoxyphenyl) thia-
zol-2-ylidene]-4-fluorobenzenesulfonamide 6b
zol-2-ylidene]-2,4-difluorobenzenesulfonamide 8d
1H-NMR δ 3.85 (s, 9H); 6.50 (s, 1H); 6.67 (s, 2H);
1H- NMR δ 3.80 (s, 3H); 3.92 (s, 3H); 6.62 (s, 1H);
6.92 (dd, J = 9.0, 2.6, 1H); 6.95 (d, J = 9.0, 1H); 7.03 (d,
J = 2.6, 1H); 7.13 (dd, J = 8.8, 8.6, 2H); 7.99 (dd, J = 8.8,
5.2, 2H). 13C- NMR δ 55.8; 56.4; 102.2; 113.0; 113.3;
115.6; 115.8; 116.0; 117.0; 128.9; 129.0; 134.4; 138.5;
6.82 (m, 1H); 6.91 (m, 1H); 7.98 (m, 1H); 13C-NMR δ
2
2
56.3; 60.8; 101.3; 103.2; 105.4 (dd, JC, F = 25, JC, F
=
2
2
23); 111.2 (d, JC, F = 22); 123.9; 126.7 (d, JC, F = 23);
131.2 (d, 3JC, F = 10); 137.3; 139.3; 153.7; 159.9 (dd, 1JC,
F
= 250, 3JC, F = 10); 165.3 (dd, 1JC, F = 250, 3JC, F = 10);
1
149.6; 154.1; 164.8 (d, JC, F = 250); 168.4.
169.4.
5.1.3.3. N-[2,3-Dihydro-4-(2,5-dimethoxyphenyl) thia-
zol-2-ylidene]-2,4-dichlorobenzenesulfonamide 6c
1H-NMR δ 3.80 (s, 3H); 3.92 (s, 3H); 6.64 (s, 1H);
6.92 (dd, J = 9.1, 2.6, 1H); 6.95 (d, J = 8.8, 1H); 7.04 (d,
J = 2.4, 1H); 7.34 (dd, J = 8.0, 2.0, 1H); 7.47 (d, J = 2.0,
1 H); 8.16 (d, J = 8.5, 1H). 13C-NMR δ 55.8; 56.3; 102.2;
113.0; 113.3; 116.0; 117.0; 126.8; 131.1; 131.2; 133.5;
134.5; 138.4; 149.7; 154.1; 169.0.
5.1.4. General procedure for phenolic compounds 7a–d
and 9a–d
To a cooled (0 °C) solution of 6a–d or 8a–d (1 mmol)
in anhydrous CH2Cl2, boron tribromide was added drop-
wise (2.2 mmol for dimethoxy compounds 6a–d, or
3.3 mmol for trimethoxy compounds 8a–d) under nitro-
gen. The mixture was stirred at 0 °C for 1 h, then
quenched cautiously with H2O (50 mL). Following
15 min hydrolysis, the resulting precipitate was collected,
washed with cold H2O and recrystallized from 50%
ethanol, affording the expected polyhydroxylated com-
pound in 53–78% yield.
5.1.3.4. N-[2,3-Dihydro-4-(2,5-dimethoxyphenyl) thia-
zol-2-ylidene]-2,4-difluorobenzenesulfonamide 6d
1H-NMR δ 3.80 (s, 3H); 3.92 (s, 3H); 6.65 (s, 1H);
6.89 (m, 2H); 6.95 (m, 1H); 7.05 (d, J = 2.7, 1H); 8.03

778
5.1.4.1. N-[2,3-Dihydro-4-(2,5-dihydroxyphenyl) thia-
zol-2-ylidene]-4-chlorobenzenesulfonamide 7a
13C-NMR δ 101.9; 106.4; 121.3; 129.0; 132.4; 134.5;
136.1; 139.5; 139.6; 139.7; 147.5; 171.4.
1H-NMR δ 4.77 (s, 2H); 6.69 (dd, J = 8.7, 2.8, 1H);
6.74 (d, J = 8.7, 1H); 6.88 (d, J = 2.8, 1H); 6.93 (s, 1H);
7.50 (d, J = 8.6, 2H); 7.88 (d, J = 8.6, 2H). 13C-NMR δ
105.3; 114.7; 117.1; 118.3; 118.7; 129.1; 130.0; 137.1;
139.4; 142.2; 148.8; 151.6; 170.
5.1.4.8. N-[2,3-Dihydro-4-(3,4,5-trihydroxyphenyl) thia-
zol-2-ylidene]-2,4-difluorobenzenesulfonamide 9d
1H-NMR δ 6.57 (s, 2H); 6.60 (s, 1H); 7.06–7.11 (m,
2H); 7.98 (ddd, J = 8.0, 6.0, 6.0, 1H); 13C-NMR δ 102.0;
2
2
106.3 (dd, JC, F = 25, JC, F = 22); 106.4; 112.2 (d,
2JC, F = 22); 121.3; 126.9; 132.3; 136.0; 139.7; 147.5;
5.1.4.2. N-[2,3-Dihydro-4-(2,5-dihydroxyphenyl) thia-
zol-2-ylidene]-4-fluorobenzenesulfonamide 7b
1H-NMR δ 4.76 (s, 2H); 6.69 (dd, J = 8.7, 2.8, 1H);
6.74 (d, J = 8.7, 1H); 6.89 (d, J = 2.8, 1H); 6.92 (s, 1H);
7.22 (dd, J = 8.9, 8.8, 2H); 7.99 (dd, J = 8.9, 5.1, 2H).
13C-NMR δ 105.2; 114.7; 116.7; 116.9; 117.1; 118.3;
118.7; 130.2; 130.3; 139.7; 148.7; 151.6; 166.2 (d, 1JC, F
= 250); 170.0.
1
3
1
161.2 (dd, JC, F = 250, JC, F = 10); 166.8 (dd, JC, F
=
3
250, JC, F = 10); 171.4.
5.2. X-ray structure determination
A suitable crystal of 6b (size 0.30 × 0.15 × 0.01 mm)
was obtained from a CHCl3 solution. C17H15FN2O4S2, M
= 394.43, triclinic, space group P-1, a = 7.026(4), b =
9.068, c = 14.442(7) Å, α = 88.74(4), â = 77.70(5), γ =
80.63(4)°, V = 886.9(8) Å3, Z = 2, D = 1.477 Mg m–3. The
data collection was performed on a Nonius CAD4 dif-
fractometer using graphite monochromated Cu Kα radia-
tion (λ = 1.54178 Å). 2 977 independent reflexions were
measured, of which 2 461 were used in the refinements.
Refinement was carried out by the full-matrix least-
squares method based on F2 with the SHELXL-93
program [18]. (Final R indices: R1 = 0.0466, WR2 =
0.1546). Full experimental details are available as supple-
mentary material.
5.1.4.3. N-[2,3-Dihydro-4-(2,5-dihydroxyphenyl) thia-
zol-2-ylidene]-2,4-dichlorobenzenesulfonamide 7c
1H-NMR δ 6.93 (dd, J = 8.7, 2.9, 1H); 7.03 (d, J = 8.7,
1H); 7.24 (s, 1H); 7.25 (d, J = 2.9, 1H); 7.69 (dd, J = 8.5,
2.0, 1H); 7.77 (d, J = 2, 1H); 8.3 (d, J = 8.5, 1H).
13C-NMR δ 104.8; 114.4; 116.8; 118.5; 118.6; 127.9;
131.9; 132.2; 134.0; 138.7; 140.1; 147.9; 151.7; 171.4.
5.1.4.4. N-[2,3-Dihydro-4-(2,5-dihydroxyphenyl) thia-
zol-2-ylidene]-2,4-difluorobenzenesulfonamide 7d
1H-NMR δ 6.69 (dd, J = 8.8, 2.8, 1H); 6.75 (d, J = 8.8,
1H; 6.90 (d, J = 2.8, 1H); 6.95 (s, 1H); 7.05–7.13 (m,
2H); 6.69 (dd, J = 8.4, 6.3, 1H); 13C-NMR δ 105.5; 106.5
(dd, 2JC, F = 25; 2JC, F = 23); 112.2; 114.7; 117.0; 118.3;
5.3. Computational studies
Calculations were performed using the MOPAC [19]
program implemented in Chem3D, V 3.5 [20]. The
atomic coordinates of the heavy atoms considered in the
calculations were those obtained by crystallographic data
(compound 6b: see above; econazole: see reference [21]).
The atomic charges were analysed using the AM1 poten-
tial function with the “Mulliken charges” option and the
“PI” keyword.
1
118.8; 127.7; 132.3; 137; 148.8; 151.7; 161.2 (dd, JC, F
= 250, 3JC, F = 10); 166.9 (dd, 1JC, F = 250, 3JC, F = 10);
170.4.
5.1.4.5. N-[2,3-Dihydro-4-(3,4,5-trihydroxyphenyl) thia-
zol-2-ylidene]-4-chlorobenzenesulfonamide 9a
1H-NMR δ 6.55 (s, 1H); 6.57 (s, 2H); 7.49 (d, J = 8.8,
2H); 7.86 (d, J = 8.8, 2H). 13C-NMR δ 101.7; 106.4;
121.4; 129.0; 130.0; 136.1; 139.4; 139.7; 142.3; 147.4;
171.1.
Acknowledgements
The authors thank E. Bezançon for his able technical
assistance in providing high resolution NMR spectra. The
secretarial help of A. Carrère is gratefully acknowledged.
5.1.4.6. N-[2,3-Dihydro-4-(3,4,5-trihydroxyphenyl) thia-
zol-2-ylidene]-4-fluorobenzenesulfonamide 9b
1H-NMR δ 6.55 (s, 1H); 6.57 (s, 2H); 7.21 (dd, J = 8.8,
8.7, 2H); 7.93 (dd, J = 8.8, 5.2, 2H); 13C-NMR δ 101.6;
106.4; 116.7; 116.8; 121.4; 130.1; 130.2; 136.0; 139.7;
1
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