Aspects of structural thiohydroxamate chemistry-on a systematic in the 5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione series

Article abstract of DOI:10.1016/j.tet.2009.01.067

Bond angles at thiohydroxamate oxygen in crystal structures of 3-alkoxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thiones gradually increased with the size of the 3-alkoxy substituent. This effect was attributed to strain on the basis of (i) a linear free energy relationship (Taft-Dubois correlation) and (ii) signal coalescence from resonances of diastereotopic CH₃ groups in solution (O-cumyl substituent; DNMR). Substitution at oxygen along the sequence OR (R=prim-, sec-, and tert-alkyl), OH, and OLi was reflected in a gradual decrease of N,O distances and lengthening of associated C,S bonds. The responsivity for these changes was more pronounced in the thiazole-2(3H)-thione than in the pyridine-2(1H)-thione series.

Full text of DOI:10.1016/j.tet.2009.01.067

Tetrahedron 65 (2009) 2567–2573
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Aspects of structural thiohydroxamate chemistrydon a systematic in the
5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione series
,
a
a
a
b
Jens Hartung a , Uwe Bergstra¨ßer , Kristina Daniel , Nina Schneiders , Ingrid Svoboda ,
*
Hartmut Fuess b
a
¨
¨
Fachbereich Chemie, Organische Chemie, Technische Universitat Kaiserslautern, Erwin-Schrodinger-Straße, D-67663 Kaiserslautern, Germany
b Technische Universita¨t Darmstadt, Strukturforschung, FB11 Material- und Geowissenschaften, Petersenstraße 23, D-64287 Darmstadt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Bond angles at thiohydroxamate oxygen in crystal structures of 3-alkoxy-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thiones gradually increased with the size of the 3-alkoxy substituent. This effect
was attributed to strain on the basis of (i) a linear free energy relationship (Taft–Dubois correlation) and
(ii) signal coalescence from resonances of diastereotopic CH3 groups in solution (O-cumyl substituent;
DNMR). Substitution at oxygen along the sequence OR (R¼prim-, sec-, and tert-alkyl), OH, and OLi was
reflected in a gradual decrease of N,O distances and lengthening of associated C,S bonds. The responsivity
for these changes was more pronounced in the thiazole-2(3H)-thione than in the pyridine-2(1H)-thione
series.
Received 14 November 2008
Received in revised form 6 January 2009
Accepted 7 January 2009
Available online 20 January 2009
Keywords:
Heterocycle
Lithium thiohydroxamate
Pyridinethione
Ó 2009 Elsevier Ltd. All rights reserved.
Steric substituent effect
Taft–Dubois parameter
Thiazolethione
Thiohydroxamic acid
X-ray crystallography
1. Introduction
non-hygroscopic crystalline solids that serve as starting materials
for the synthesis of O-acyl derivatives (e.g., 1g).21 The latter com-
Structural thiohydroxamate chemistry so far is dominated by
studies on transition metal complexes.1,2 Considerably less is known
about thiohydroxamic acid solid state chemistry3,4 and systematics
within series of O-alkyl- (esters)5,6 and O-acyl-derivatives (mixed
anhydrides).7 This lack in structural information makes it difficult to
convincingly answer long standing questions, for example, on the
origin of inherent problems in tertiary O-ester synthesis,8,15 or
rationalization of notable changes in alkylation selectivity that
occur upon rather subtle structural changes in heterocyclic thio-
hydroxamate subunits,9,10 although major aspects of this chemistry
in the fields of biocides,11,12,13,14 organic reagents,15,16 and radical
reactions9,17,18 have been pursued for decades.1,5,7
Based on recent progress in the synthesis of primary, secondary,
and even tertiary O-esters of the cyclic thiohydroxamic acid 3-hy-
droxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1a)
(Fig. 1),10,19,20 structural thiohydroxamate chemistry began to at-
tract our attention. The compounds (e.g., 1b–f) (Fig. 1) are applied
as valuable alkoxyl radical precursors under neutral pH and non-
oxidative conditions. Alkali salts (e.g., 2; Fig. 1) of acid 1a form
pounds constitute a potential new class of carbon radical pro-
genitors, to be stored and applied on demand.
The present study dealing with solid state chemistry of N-oxy-
substituted thiazole-2(3H)-thiones (1, 2) and their more prominent
pyridine-2(1H)-thione congeners (e.g., 3, 4) (Fig.1) nowshowed that
steric effects exerted by O-alkyl groups were predominantly
reflected by N–O–R angle widening. Variation of substitution at
oxygen along the sequence OR (R¼prim-, sec-, tert-alkyl), OH, and
OLi was paralleled by a gradual decrease in N,O bond lengths, while
thiohydroxamate C,S distances increased. The exocyclic C,S-con-
nectivity was in favor for a double bond in chelated N-(hydroxy)-
thiazole-2(3H)-thione-derived lithium salt 2B but close to the value
for a sulfanyl group for pyridine-2(1H)-thione analogue 3. Observed
systematics are summarizedand discussed in the following sections.
2. Results and interpretation
2.1. Preparation of N-(alkoxy)thiazole-2(3H)-thiones
Primary and secondary N-(alkoxy)thiazolethiones 1b–e were
prepared from 3-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione tetrabutylammonium salt and corresponding alkyl
* Corresponding author. Tel.: þ49 631 205 2431; fax: þ49 631 205 3921.
E-mail address: hartung@chemie.uni-kl.de (J. Hartung).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.067

2568
J. Hartung et al. / Tetrahedron 65 (2009) 2567–2573
An
An
S
S
S
Li +
S
N
N
O
1
O–
2
R
R
1
a
b
c
d
H
CH3
N
S
O– Li+
3
(CH2)4CH3
(CH2)4C6H5
CH(CH3)2
C(CH3)2C6H5
C(O)C6H5
e
f
N
O
4
S
g
H
Figure 1. Structural formulae and indexing of cyclic thiohydroxamates 1–4
(An¼p-MeOC6H4).10,21,22
Figure 2. 1H NMR spectra (stacking plot, CDCl3) of N-cumyloxythiazolethione 1f in the
tosylates in solutions of dry DMF (Table 1).22 The yields of target
compounds increased along the series of introduced O-alkyl groups
(CH2)4C6H5 (1d)<CH3 (1b)<n-C5H11 (1c)<CH(CH3)2 (1e)10 (Table 1,
entries 1–5) thus reflecting the propensity of secondary alkyl
tosylates to afford most effective substitution at oxygen in thiohy-
droxamates.23 N-Cumyloxythiazolethione 1f was obtained in gram
quantities upon treatment of acid 1a with in situ prepared O-cumyl
N,N0-diisopropylisourea20,24–26 in a solution of CH2Cl2. The reaction
between LiOHꢀH2O and N-(hydroxy)thiazole-2(3H)-thione 1a in
a solution of EtOH afforded lithium salt 2 in quantitative yield as
yellowish non-hygroscopic powder (Table 1, entry 6).
Thiones 1 were characterized via NMR spectroscopy showing
diagnostic resonances at w2.3 ppm for the 4-CH3 singlet and at
w3.8 ppm for the p-OCH3 group. The former signal in N-cumyloxy
derivative 1f was high field-shifted (1.57 ppm), presumably due to
its proximity to the phenyl group (see also Fig. 4). The low field shift
temperature range of ꢃ47 to þ58 ꢂC showing coalescence of cumyl CH3 signals at 5 ꢂ
C
(left) and shifting of 4-CH3 signal (right).
observed at that temperature. At ꢃ47 ꢂC (referenced vs the MeOH
NMR thermometer),29,30 base line separated signals for CH3 reso-
nances were observed at dH¼1.90 and 2.12, being correlated with
13C NMR resonances at 22.4 and 31.8 ppm (HMQC). Signal
coalescence (1H NMR) occurred at 5 ꢂC. A sharp singlet at
d
¼2.04
due to fast CH3-exchange was observed at 58 ꢂC. The associated 13C
NMR signal at 27.6 ppm remained surprisingly low in intensity.
Attempts to further elevate the temperature for increasing its
magnitude were paralleled by decomposition of 1f, as evident from
a
-methyl styrene formation.31 The observed temperature effects
were interpreted as hindered rotation of the cumyl substituent
about the stereogenic N,O axis in 1f. The approximated free energy
of activation derived from coalescence temperature and Dni values
for this process (
derived from line shape analysis (variable temperature NMR) for
D
Gz ¼44 kJ molꢃ1) was comparable to barriers
278
experienced by
4) and to some extend by
a
-alkoxy protons (e.g., in 1b–e) (Table 1, entries 1–
-protons (e.g., in 1c–f) (Table 1, entries
b
N-isopropoxy-4-methyl- and -4-(p-chlorophenyl)-substituted
3–5) was attributed to anisotropy exerted by the thiocarbonyl
group.3,27,28 Resonances of thiohydroxamate C atoms showed
a gradual low field shift in going from Li salt 2 (165.5 ppm) to
O-esters 1b–f (178.9ꢁ0.3 ppm).
thiazolethiones (
D
Gz ¼42–46 kJ molꢃ1).6
200
Lowest energy UV–vis absorptions (EtOH or MeOH) remained
almost unchanged in going from N-methoxy compound 1b via N-
cumyloxy derivative 1f (both lmax¼333 nm) to Li salt 2 (lmax¼335),
pointing to similar chromophores. Macroscopic appearance of the
compounds varied from colorless (1a,b,d) to yellowish (1c,f, 2).
A broad singlet at
d
¼2.04 pointed to slow topomerization of
diastereotopic CH3 groups in N-cumyloxythiazolethione 1f at 25 ꢂC
(Fig. 2). The associated 13C NMR signal surprisingly was not
2.2. X-ray crystallographydN-oxy-substituted
thiazole-2(3H)-thiones
Table 1
Yields and selected spectral properties of N-(alkoxy)thiazolethiones 1
An
An
An
X-ray diffraction experiments were conducted at 100 K (2) and
in the range of 293–299 K (1b–f) (Table 2, entry 1). Selected bond
lengths, bond and torsion angles are listed in Tables 2 and 3.
N-Methoxythiazolethione 1b (Fig. 3) crystallized in acentric
space group Pna21. Thiones 1c–f and 2 (Figs. 3 and 4) formed
centrosymmetric crystal lattices. Absolute structure determination
of 1b was feasible with the aid of the Flack parameter.32 The two
independent molecules of 1b, i.e., 1bA and 1bB, showed almost
similar bond lengths and angles. Molecule 1bA was arbitrarily se-
lected for presentation and data analysis. Both molecules of 1b
exhibited (P)-configuration at the N,O-bond,33 whereas 1c–f were
racemic. The angle C2–N3–O1–C14 describing the offset of the ester
substituent from the thiazole-2(3H)-thione plane was approxi-
mately independent of steric size of the alkyl group attached to
oxygen (88ꢁ5ꢂ; Table 3, entry 9). In a similar manner, a compara-
tively small variation of torsion angle C4–C5–C7–C8 (42ꢁ5ꢂ),
reflecting the twist between p-methoxyphenyl and thiazolethione
planes, was noted (Table 3, entry 10, Fig. 3).
S
S
S
conditions a
LiOH × H2O
EtOH
S
S
S
N
O
N
O
N
O– Li +
H
R
2
1a
1b–f
Entry Compound Conditionsa Yield (%) dC]S
d
1Ha (ppmc)
d
1Hb (ppmc)
b
1
2
3
4
5
6
1b
1c
1d
1e
1f
2
i, ii
i, ii
i, ii
i, ii
iii
64
71
44
73
15
Quant.
178.6 4.20
179.1 4.45
179.1 4.45
179.1 5.50
179.2 dd
165.5 dd
dd
de
2.72
1.36
2.60
dd
d
a
Reagents and conditions: i: NBu4OH, CH3OH; ii: TsOR, DMF, 25 ꢂC; iii: 2-phenyl-
2-propanol, diisopropylcarbodiimide (DIC), CuCl, CH2Cl2, 25 ꢂC, then 1a.
b
In CDCl3; dC]S¼172.0 for 1a and 182.3 for 1g.
In CDCl3; O–CHa; O–C–CHb.
Not available.
c
d
e
Not resolved.

J. Hartung et al. / Tetrahedron 65 (2009) 2567–2573
2569
Table 2
Selected parameters of N-substituted thiazole-2(3H)-thiones 1b–f and lithium salt 2dpart I: heterocycle core
Entry
1
Parameter
1bA R¼CH3
293(2)
1c R¼n-C5H11
299(2)
1d R¼(CH2)4Ph
299(2)
1e R¼CH(CH3)2
299(2)
1f R¼CMe2Ph
293(2)
2A (monodentate)
2B (bidentate)
T [K]
100(2)
100(2)
2
3
4
5
6
S1–C2 [Å]
C2–N3 [Å]
N3–C4 [Å]
C4–C5 [Å]
C5–S1 [Å]
1.731(3)
1.339(4)
1.400(4)
1.339(4)
1.741(3)
1.717(6)
1.343(6)
1.394(6)
1.355(6)
1.741(5)
1.726(2)
1.346(3)
1.401(3)
1.351(3)
1.748(2)
1.728(2)
1.357(3)
1.402(3)
1.347(3)
1.748(2)
1.726(3)
1.359(3)
1.405(3)
1.347(4)
1.740(3)
1.738(2)
1.345(2)
1.409(2)
1.366(2)
1.752(2)
1.742(2)
1.345(2)
1.401(2)
1.357(2)
1.753(2)
7
8
9
10
11
S1–C2–N3 [ꢂ]
C2–N3–C4 [ꢂ]
N3–C4–C5 [ꢂ]
C4–C5–S1 [ꢂ]
C5–S1–C2 [ꢂ]
105.7(2)
120.0(3)
109.8(3)
111.1(2)
93.3(2)
107.0(4)
118.4(4)
111.1(4)
109.8(4)
93.6(2)
106.7(2)
118.7(2)
110.9(2)
110.1(2)
93.5(1)
106.4(2)
118.6(2)
110.9(2)
110.5(2)
93.5(1)
106.6(2)
118.4(2)
110.3(3)
111.3(2)
93.3(1)
108.5(2)
117.0(1)
111.4(2)
110.3(1)
92.6(1)
108.1(1)
117.1(1)
112.0(2)
110.2(1)
92.5(1)
Lithium salt 2 crystallized as monohydrate in space group C2/c.
Layers of 5-(4-methoxyphenyl)-4-methyl-2-thiooxo-2,3-dihydro-
thiazole-3-olate were composed of two independent molecules,
i.e., 2A and 2B, which formed coordination polymers due to Li-
bridging and an extensive array of H-atom bonds originating from
metal-coordinated aqua ligands (Fig. 4). The distance Li1/
S2¼3.625(4) Å was equivalent to the sum of associated van der
Waals radii [3.62 Å]34 thus pointing to monodentate thiohydrox-
amate binding to Li1 in molecule 2A [Li1/O1¼1.926(3) Å]. Che-
lating of Li10 by the thiohydroxamate ligand occurred in 2B [Li10/
S20¼2.649(3) Å, Li10/O10¼2.098(3) Å].
Exocyclic bond lengths (Table 3, entries 1 and 2) showed
a gradual decrease of the N3–O1 distance along the sequence of O-
alkyl derivatives 1b–f, thiohydroxamic acid 1a, and lithium salt 2.
These changes were paralleled by C2–S2 lengthening as evident
from the relationship dN3–O1¼ꢃ0.66dC2–S2þ2.5 Å (correlation co-
efficient r¼0.87; Fig. 6). The distance C2–N3 remained approxi-
mately unchanged. Gradient and intercept were surprisingly
similar to a N3–O1/C2–S2 correlation using structural data of N-
alkoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones (primary and
secondary esters, 6 examples), N-hydroxy-4-(p-chlorophenyl)th-
iazole-2(3H)-thione, and sodium 4-(4-chlorophenyl)-2-thiooxo-
2,3-dihydrothiazole-3-olate (dN3–O1¼ꢃ0.69dC2–S2þ2.5 Å; r¼0.71,
not shown).33,47–49
2.2.1. The heterocyclic core
Endocyclic bond lengths (Table 2, entries 2–6) and angles in N-
alkoxy compounds 1b–f and lithium salt 2 (Table 2, entries 7–11)
corresponded to parameters reported for N-alkyl-substituted thi-
azole-2(3H)-thiones,35,36 cyclic conjugated thioureas,37 and cyclic
dithiocarbonic acid amides.38,39 Compared to the structure of 1,3-
thiazole,40 thiazole-2(3H)-thiones showed a more acute bond angle
at C2, a larger at N3, and more pronounced alternation of bond
lengths, probably due to less extensive cyclic conjugation.
2.3. N-Oxy-substituted pyridine-2(1H)-thiones
In order to test the generality of the N3–O1/C2–S2-systematic,
lithium salt 3 was prepared from N-(hydroxy)pyridine-2(1H)-thi-
one (4),23 crystallized, and investigated via X-ray diffraction (Fig. 7).
The compound crystallized in P21/m. The metal was chelated by the
2-thiooxo-1,2-dihydropyridine-1-olate ligand [Li1–O1¼1.930(6) Å,
Li1–S1¼2.431(5) Å]. One water molecule was attached to the fourth
site of Li1. It participated in H-atom bonding toward O1 and S1 of
two non-identical proximate molecules of 3 (not shown).
A plot of N1–O1 bond lengths of salt 3, corresponding acid
4,23 N-[4-trans-(tert-butylcyclohexyl-1-oxy)]pyridine-2(1H)-thione
(5),3 and N-[4-trans-(tert-butylcyclohexyl-1-carbonyloxy)]pyri
dine-2(1H)-thione (6)3 (the latter two compounds are not shown)
against associated C2–S1 distances were fitted with a first order
equation thus providing the correlation dN1–O1¼ꢃ0.48dC2–S1þ2.2 Å
(r¼0.98) (Fig. 8).
2.2.2. The thiohydroxamte functionality in thiazole-2(3H)-thiones
N3–O2–C14 bond angles (Table 3, entry 3) gradually increased
with the steric size of the alkyl substituent at oxygen in N-alkoxy-
thiazolethiones 1b–f. Geometric changes were linearly reflected in
a correlation with Taft–Dubois parameters41–43 ES’ of associated
ester substituents (Fig. 5). The ES’ value for the cumyl group thereby
was approximated with the corresponding parameter of the tert-
butyl substituent. The use of alternative parameters, for instance
the Winstein–Holness A-value for 1,3-interactions in cyclohex-
anes,44,45 or the solid angle US for description of minimum steric
substituent effects,46 provided less satisfactory correlations (not
shown). This analysis suggested that the magnitude of the N–O–C
bond angle in cyclic thiohydroxamic acid O-esters was guided by
strain, experienced by substituents in molecular environments of
restricted conformational flexibility.
2.4. Comparison between thiazole-2(3H)-thiones
and pyridine-2(1H)-thiones
Major structural differences between N-(Hydroxy)thiazole-
2(3H)-thiones (e.g. 1a) and N-(hydroxy)pyridin-2(1H)-thione (4)
Table 3
Selected parameters of N-substituted thiazole-2(3H)-thiones 1b–f and lithium salt 2dpart II: substituents
Entry
Parameter
1bA R¼CH3
1c R¼n-C5H11
1d R¼(CH2)4Ph
1e R¼CH(CH3)2
1f R¼CMe2Ph
2A Li (monodentate)
2B Li (bidentate)
1
2
C2–S2 [Å]
N3–O1 [Å]
1.650(3)
1.391(3)
1.671(7)
1.370(6)
1.663(3)
1.381(2)
1.657(2)
1.389(2)
1.649(3)
1.376(3)
1.701(2)
1.354(2)
1.685(2)
1.367(2)
3
4
5
6
7
8
N3–O1–R [ꢂ]
C4–N3–O1 [ꢂ]
C2–N3–O1 [ꢂ]
S2–C2–N3 [ꢂ]
S1–C2–S2 [ꢂ]
N3–C4–C6 [ꢂ]
110.7(3)
119.1(3)
120.1(3)
128.5(3)
125.8(2)
119.4(3)
111.0(4)
120.0(4)
121.0(4)
127.0(4)
125.9(3)
119.0(4)
112.0(2)
119.4(2)
120.9(2)
127.7(2)
125.6(2)
118.7(2)
112.4 (2)
120.6(2)
120.1(2)
128.1(2)
125.5(1)
119.4(2)
116.0(2)
120.8(2)
120.1(2)
128.4(2)
125.0(2)
120.4(3)
123.9(1)
120.2(1)
122.8(1)
128.0(1)
123.5(1)
117.6(1)
119.8(1)
120.9(1)
121.9(1)
125.8(1)
126.0(1)
117.9(1)
9
10
C2–N3–O1–R [ꢂ]
C4–C5–C7–C8 [ꢂ]
89.3(4)
44.5(5)
ꢃ90.4(5)
ꢃ44.3(7)
83.4(3)
ꢃ37.2(4)
81.4(2)
38.0(3)
95.7(3)
49.9(5)
ꢃ63.0(2)
ꢃ31.4(3)
104.9(2)
ꢃ39.7(3)

2570
J. Hartung et al. / Tetrahedron 65 (2009) 2567–2573
Figure 5. Correlation of N3–O1–C14 angles and Taft–Dubois parameter41–43 ES’
[kJ molꢃ1] (correlation coefficient r¼0.98). ES’ for the cumyl group was approximated
with the value for the tert-butyl substituent.
observation suggested that strain imposed by sterically demanding
substituents at thiohydroxamate oxygen, for instance from a ter-
tiary alkyl group, should be more effectively compensated by
structural parameter variation in the former than in the latter type
of cyclic thiohydroxamic acid O-ester. This interpretation offers
a possible explanation for the diverse chemistry of tertiary O-esters
in the thiazole-2(3H)-thione series,10,20,24,31 which in turn is rather
limited for N-(hydroxy)pyridine-2(1H)-thione (4).3,9
The N,O-distance shortening seemed to be correlated with the
propensity of substituents attached to oxygen to withdraw negative
charge. The most pronounced effect was observed for Li and least
for alkyl groups, leaving the hydrogen atom in between. The N,O
bond in N-cumylthiazolethione 1f would have been expected to be
the longest, since steric congestion added to polar contributions
from the substituent. The value of N3–O1¼1.376(3) Å, however, was
located at the lower end of N,O distances for alkyl substitution
(Fig. 6). From the unusual C14–O1 distance in 1f [1.512(3) Å, com-
pared to 1.434(4) Å for 1b] and a noteworthy deshielding at C14
(92.6 ppm, compared to 64.1 for 1b) it seemed that additional pa-
rameter existed that contributed to exact data point positioning in
N,O/C,S-bond length correlation diagrams. Clarification of these
aspects was not possible on the basis of the existing data and
therefore deserves a separate computational analysis.
Figure 3. Ellipsoid graphics (50% probability level) of N-(alkoxy)thiazolethiones 1b–f.
Hydrogen atoms are drawn as circles of an arbitrary radius.
differed in structural responsivity upon variation of the thiohy-
droxamate oxygen-bound substituent.
The stronger gradient of inverse N,O/C,S-bond length correla-
tions pointed to a more pronounced responsivity of N-oxy-
substituted thiazole-2(3H)-thiones upon substitution at oxygen
than in the pyridine-2(1H)-thione series (Figs. 6 and 8). This
Figure 6. Correlation of N3–O1 and C2–C2 distances of thiazolethiones 1a [N3–O1¼
1.373(3) Å, C2–S2¼1.676(3) Å at 299(2) K],22 1b–f (Table 1), and N-benzoyl-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione 1g [N3–O1¼1.389(2) Å, C2–S2¼1.662
(2) Å at 100(2) K]21 (dN3–O1¼ꢃ0.66 dC2–S2þ2.5 Å; r¼0.87).
Figure 4. Ellipsoid graphics (50% probability level) of lithium 5-(4-methoxyphenyl)-4-
methyl-2-thiooxo-2,3-dihydrothiazole-3-olate monohydrate (2)ꢀH2O. Hydrogen
atoms are drawn as circles of an arbitrary radius.

J. Hartung et al. / Tetrahedron 65 (2009) 2567–2573
2571
3. Concluding remarks
The pursuit of structural chemistry in the series of N-alkoxy-5-
(p-methoxyphenyl)-4-methylthiazolethiones 1b–f, acid 1a, lithium
salt 2 and its pyridinethione congener 3 provided three distinctive
results.
(i) Bond angles at thiohydroxamate oxygen gradually increased
along the series of substituents CH3 (1b) via primary alkyl (e.g.,
1c,d), secondary alkyl (1e) to tertiary alkyl (1f). The magnitude
of angle widening correlated with Taft–Dubois parameter of
associated ester substituents thus pointing to strain as major
effect.
Figure 7. Ellipsoid graphics (50% probability level) of lithium 2-thiooxo-1,2-dihyd-
ropyridine-1-olate monohydrate (3) [100(2) K, symmetry code for O2
: x, ꢃyþ1/2, z].
*
Hydrogen atoms are drawn as circles of an arbitrary radius. Selected bond lengths
[Å]: C2–S1¼1.723(3), N1–O1¼1.360(3), N1–C2¼1.371(4), C2–C3¼1.416(4), C3–
C4¼1.376(4), C4–C5¼1.399(4), C5–C6¼1.367(4), C6–N1¼1.365(4). Selected angles [ꢂ]:
N1–O1–Li1¼121.2(2), C2–N1–O1¼120.3(2), C6–N1–O1¼117.1(2), S1–C2–N1¼120.1(2),
S1–C2–C3¼123.4(2), N1–C2–C3¼116.6(3), C2–C3–C4¼121.4(3), C3–C4–C5¼119.6(3),
C4–C5–C6¼119.1(3), C5–C6–N1¼120.8(3), C6–N1–C2¼122.6(3), C2–N1–O1–Li1¼0.0(2).
(ii) In
a set of N-hydroxy-, N-alkoxy-, and N-benzoyloxy-
substituted compounds 1a–g and lithium salt 2, N,O and C,S
bond lengths were inversely correlated. The stronger gradient
of underlying N,O/C,S relationships upon substitution at exo-
cyclic oxygen pointed to
a more pronounced structural
responsivity in the thiazole-2(3H)-thione than in the pyridine-
2(1H)-thione series. This aspect is considered to facilitate O-
alkylation with sterically demanding, e.g., tertiary substituents
in thiazole-2(3H)-derived thiohydroxamates.
The distance C2–S2 in thiazolethione 2B [chelating,
1.685(2) Å] was closer to the mean value of a thiocarbonyl group,
whereas distance C2–S1 in pyridinethione
3
[chelating,
1.723(3) Å] approximately agreed with the mean value for a Csp2,
S-single bond, e.g., in 2-alkylsulfanylpyridine-N-oxides.50,51 If
interpreted in terms of charge distribution, a major fraction of
the negative charge was expected to be localized at thiohy-
droxamate oxygen in thiazole derivative 2B and at sulfur in
pyridine analogue 3. Hard electrophiles therefore should favor
substitution of, e.g., p-toluenesulfonate for thiohydroxamate at
oxygen, if derivatives of thiazole-2(3H)-thione served as ambi-
dent nucleophile. Structure and bonding of pyridinethione-
derived lithium salt 3 suggested that thiohydroxamate alkylation
should occur to notable extend at sulfur, even if treated with
a hard alkylating reagent. These interpretations are consistent
with experimental findings.23,31,52 Since bond lengths in the
present work showed a marked dependency on the mode of
thiohydroxamate binding to lithium, a similar change is expected
to occur in case of complete separation of anion and cation, e.g.,
in solvents of strong donicity. If the trends outlined for thiohy-
droxamate salts 2A and 3 prevailed in case of solvation, the
present findings offered an explanation for notable differences in
alkylation selectivity for the investigated types of thiohydrox-
amates on a structural basis.
(iii) Exocyclic C,S-bonds in lithium salts of a N-hydroxythiazole-
2(3H)-thione (compound 2) and N-hydroxypyridine-2(1H)-
thione (compound 3) differed notably in length, being in
favor for a thione group in the former and a sulfanyl entity
in the latter case. If interpreted in terms of charge distri-
bution, this picture correlated with the unusual O-selectivity
in alkylations of thiazolethione-derived thiohydroxamate
salts.
The results outlined in the present study are expected to guide
reagent selection, particularly for the synthesis of tertiary thiohy-
droxamic acid O-esters. These compounds serve as valuable sources
of derived oxyl radicals and have the potential to further de-
velopments in this area of research.
4. Experimental
4.1. General
For spectroscopic equipment and general laboratory practice
see Ref. 10. UV–vis spectra: Varian Cary 100 spectrophotometer at
20 ꢂC using analytical grade solvents in 1 cm quartz cuvettes.
Single crystal analysis: Xcalibur diffractometer (Oxford Diffrac-
tion) equipped with the fine-focus sealed tube and Sapphire CCD
detector in
4 and u-scan mode (compounds 1c–e) and a STOE-
IPDS diffractometer (1b,f). For single crystal data collection of
lithium salts 2 and 3, crystals were placed in pre-mounted
cryoloops from Hampton Research. N-Hydroxy-5-(p-methoxy-
phenyl)-4-methylthiazole-2(3H)-thione (1a),10 N-methoxy-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1b),22 lithium
2-thiooxo-1,2-dihydropyridine-1-olate (3),23 and N-hydroxy-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione tetraalkylammo-
nium salt were prepared according to published procedures.22
Isopropyl p-toluenesulfonate, 1-pentyl p-toluenesulfonate, and
4-phenyl-1-butyl p-toluenesulfonate were prepared according to
procedure given in Section 4.2.1.
4.2. Alkyl para-toluenesulfonates
4.2.1. General procedure53
Figure 8. Correlation of N1–O1 and C2–S1 distances of pyridinethione 3 (Fig. 4),
N-hydroxypyridinethione
4
[N1–O1¼1.377(3) Å, C2–S1¼1.684(2) Å at 297(2) K],23
A solution of an alcohol (2.5 mmol) and 1,4-diazabicyclooctane
(5.0 mmol) in CH2Cl2 (30 mL) was treated in small portions at 0 ꢂC
with p-toluenesulfonic acid chloride (3.75 mmol). The slurry was
stirred for 2 h at 25 ꢂC and poured into a mixture of tert-butyl
N-[4-trans-(tert-butylcyclohexyl-1-oxy)]pyridine-2(1H)-thione
5
[N1–O1¼1.384(4) Å,
C2–S1¼1.666(4) Å at 297(2) K],3 and N-[4-trans-(tert-butylcyclohexyl-1-carbon-
yloxy)]pyridine-2(1H)-thione 6 [N1–O1¼1.392(5) Å, C2–S1¼1.662(6) Å at 300(2) K]3
(dN1–O1¼–0.48 dC2–S1þ2.2 Å; r¼0.98).

2572
J. Hartung et al. / Tetrahedron 65 (2009) 2567–2573
methyl ether (TBM)/H2O [60 mL, 2:1, (v/v)]. The layers were sepa-
rated. The aqueous phase was extracted with TBM (3ꢀ30 mL).
Combined organic washings were extracted with aq HCl (2 M), satd
aq NaHCO3, and H2O (20 mL each). The solvent was dried (MgSO4)
and removed under reduced pressure. The residue was purified by
column chromatography [SiO2, petroleum ether/Et2O] to afford
analytically pure alkyl tosylates.
150 MHz) d 13.2 (4-CH3), 55.8 (OCH3), 115.4 (Ar–C), 120.1, 125.6,
130.7 (Ar–C), 138.2, 161.0 (Ar–C), 165.5 (2-C).
4.5. X-ray crystallography
4.5.1. N-(Methoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1b)
Crystals suitable for X-ray diffraction were grown from a satd
solution of 1b in Et2O. C12H13NO2S2 (267.35), T¼293(2) K,
4.3. N-(Alkoxy)thiazole-2(3H)-thiones
l
¼0.71073 Å, orthorhombic, Pna21, a¼13.352(3) Å, b¼7.9280(16) Å,
c¼24.621(5) Å, Z¼8,
m
¼0.397 mmꢃ1, completeness to 2
¼99.7%,
q
4.3.1. General method
goodness-of-fit on F2¼0.780, final R indices [I>2
(I)]: R1¼0.0336
s
A solution of an alkyl tosylate (2.20 mmol) in dry DMF (2 mL)
was added to a solution of N-(hydroxy)thiazole-2(3H)-thione tet-
raalkylammonium salt (2.20 mmol) in dry DMF (5 mL) in an at-
mosphere of Ar. The mixture was stirred at 20 ꢂC for 4–6 days in the
dark. It was poured into a mixture of H2O/TBM [60 mL, 2:1 (v/v)].
The phases were separated and the aqueous phase was extracted
with MTB (3ꢀ20 mL). Combined organic washings were extracted
with satd aq NaHCO3 solution and brine (10 mL each). The organic
phase was dried (MgSO4) and concentrated under reduced pres-
sure. The residual oil was purified by column chromatography
[SiO2, petroleum ether/Et2O] or crystallized from petroleum ether/
Et2O to afford N-alkoxythiazolethione 1 as colorless to yellowish
crystalline solid.
and wR2¼0.0648, absolute structure parameter¼0.06(7).
4.5.2. N-(Pentoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1c)
Crystals suitable for X-ray diffraction were grown by slowly
allowing petroleum ether to diffuse into a satd solution of 1c in
CH2Cl2. C16H21NO2S2 (323.46), T¼299(2) K,
l
¼0.71073 Å, mono-
¼111.85
¼97.4%, goodness-of-
clinic, C2/c, a¼35.499(1) Å, b¼7.844(1) Å, c¼13.536(1) Å,
b
(1)ꢂ, Z¼8,
m
¼0.308 mmꢃ1, completeness to 2
q
fit on F2¼1.060, final R indices [I>2
(I)]: R1¼0.0733, wR2¼0.1966.
s
4.5.3. N-(4-Phenylpent-1-oxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione (1d)
Crystals suitable for X-ray diffraction were grown by slowly
allowing petroleum ether to diffuse into a satd solution of 1d in
4.3.2. N-(1-Pentoxy)-5-(p-methoxyphenyl)-4-(methyl)thiazole-2(3H)-
thione (1c)
CH2Cl2. C21H23NO2S2 (385.52), T¼299(2) K,
l
¼0.71073 Å, mono-
Yield of 0.80 g (71%) from N-(hydroxy)-5-(p-methoxyphenyl)-4-
(methyl)thiazole-2(3H)-thione tetraethylammonium salt [1.33 g
(3.48 mmol)] and 1-pentyl p-toluenesulfonate [0.84 g (3.48 mmol)],
colorless solid, Rf¼0.35 [SiO2, petroleum ether/Et2O¼2:1 (v/v)]. 1H
clinic, P21/c, a¼9.916(1) Å, b¼12.725(1) Å, c¼16.483(1) Å,
b
¼105.68(1)ꢂ, Z¼4,
m
¼0.281 mmꢃ1, completeness to 2
¼99.8%,
q
goodness-of-fit on F2¼1.120, final R indices [I>2
s
(I)]: R1¼0.0472,
wR2¼0.1374.
NMR (CDCl3, 400 MHz)
14.7 Hz, 2H), 1.53–1.45 (m, 2H), 1.85 (mc, 2H), 2.32 (s, 3H, CH3), 3.83
d
0.94 (t, J¼7.2 Hz, 3H), 1.41 (ddd, J¼6.9, 7.7,
4.5.4. N-(2-Propoxy)-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione (1e)
Crystals suitable for X-ray diffraction were grown by slowly
allowing petroleum ether to diffuse into a satd solution of 1e in
(s, 3H, OCH3), 4.45 (t, J¼6.7 Hz, 2H), 6.94 (mc, 2H, Ar–H), 7.22 (mc,
2H, Ar–H). 13C NMR (CDCl3, 100 MHz)
d 12.4, 14.3, 22.9, 28.0, 28.2,
55.8 (OCH3), 76.8, 114.7, 119.7,123.0, 130.2, 132.6, 160.3, 179.1 (C]S).
Anal. Calcd for C16H21NO2S2: C, 59.41; H, 6.54; N, 4.33; S, 19.82.
Found: C, 59.64; H, 6.42; N, 4.34; S, 19.48.
CH2Cl2. C14H17NO2S2 (295.41), T¼299(2) K, ¼0.71073 Å, triclinic,
l
P1, a¼7.713(1) Å, b¼9.883(1) Å, c¼10.781(2) Å,
a
¼87.56(1)ꢂ,
b
¼79.13(1)ꢂ,
g
¼70.04(1)ꢂ, Z¼2,
m
¼0.348 mmꢃ1, completeness to
4.3.3. N-(4-Phenyl-1-butoxy)-5-(p-methoxyphenyl)-4-(methyl)
thiazole-2(3H)-thione (1d)
2
q
¼96.5%, goodness-of-fit on F2¼1.059, final R indices [I>2
s(I)]:
R1¼0.0364, wR2¼0.0959.
Yield of 0.45 g (44%) from N-(hydroxy)-5-(p-methoxyphenyl)-4-
(methyl)thiazole-2(3H)-thione tetraethylammonium salt [1.01 g
(2.65 mmol)] and 4-phenyl-1-butyl p-toluenesulfonate [0.81 g
(2.65 mmol)], colorless solid, Rf¼0.40 [SiO2, petroleum ether/
4.5.5. 5-(p-Methoxyphenyl)-4-methyl-3-(1-phenyl-1-methyleth-1-
oxy)-thiazole-2(3H)-thione (1f)
Crystals suitable for X-ray diffraction were from a satd solution
Et2O¼2:1 (v/v)]. 1H NMR (CDCl3, 400 MHz)
d 1.88 (mc, 4H), 2.30 (s,
3H, CH3), 2.72 (t, J¼7.1 Hz, 2H), 3.84 (s, 3H, OCH3), 4.45 (t, J¼5.9 Hz,
of 1f in Et2O. C20H21NO2S2 (371.50), T¼293(2) K,
l
¼0.71073 Å,
monoclinic, C2/c, a¼22.938(5) Å, b¼8.5795(17) Å, c¼20.167(4) Å,
2H), 6.94 (mc, 2H, Ar–H), 7.22 (mc, 2H, Ar–H), 7.18–7.32 (m, 5H, Ph).
b
¼105.76(3)ꢂ, Z¼8,
m
¼0.291 mmꢃ1, completeness to 2
¼99.4%,
q
13C NMR (CDCl3, 100 MHz)
d 12.4 (CH3), 27.9, 27.9, 31.3, 55.8 (CH3O),
goodness-of-fit on F2¼0.679, final R indices [I>2
s
(I)]: R1¼0.0358,
76.4, 114.9, 119.7, 122.9, 126.3, 128.7, 128.8, 130.2, 132.5, 142.2, 160.3,
179.1 (C]S). MS (EI) m/z 237 (2), 148 (8), 104 (100), 91 (43). Anal.
Calcd for C21H23NO2S2: C, 65.43; H, 6.02; N, 3.64; S, 16.60. Found: C,
64.85; H, 5.89; N, 3.68; S, 16.35.
wR2¼0.0655.
4.5.6. Lithium 5-(4-methoxyphenyl)-4-methyl-2-thiooxo-2,
3-dihydrothiazole-3-olate monohydrate (2)ꢀH2O
Crystals suitable for X-ray diffraction were grown from a satd
solution of lithium salt 2 in CH3CN, which was kept in an atmo-
sphere of pentane. C44H50Li4N4O13S8 (1127.12), T¼100(2) K,
4.4. Lithium 5-(4-methoxyphenyl)-4-methyl-2-thiooxo-2,
3-dihydrothiazole-3-olate (2)
l
¼0.71073 Å, monoclinic, C2/c, a¼25.7198(10) Å, b¼16.4021(9) Å,
A solution of N-hydroxythiazolethione 1a (243 mg, 959
m
mol) in
c¼12.2578(6) Å,
b
¼95.706(4)ꢂ, Z¼4,
m
¼0.412 mmꢃ1, completeness
EtOH (5 mL) was treated with LiOHꢀH2O (40.2 mg, 959
m
mol) and
to 2
q
¼99.5%, goodness-of-fit on F2¼1.049, final R indices [I>2
s(I)]:
stirred for 1 h at 25 h. The reaction mixture was protected with
aluminum foil from light. The solvent was removed under reduced
pressure (200 mbar, 40 ꢂC) to furnish lithium salt 2 as yellow
R1¼0.0284, wR2¼0.0690.
4.5.7. Lithium 2-thiooxo-1,2-dihydropyridine-1-olate monohydrate
(3)ꢀH2O
powder. UV (MeOH) lmax (lg
1H NMR (CD3OD, 600 MHz)
6.97 (mc, 2H, Ar–H), 7.28 (mc, 2H, Ar–H). 13C NMR (CD3OD,
3
/m2 molꢃ1) 335 nm (3.15), 251 (3.17).
2.30 (s, 3H, 4-CH3), 3.81 (s, 3H, OCH3),
d
Crystals suitable for X-ray diffraction were grown from a satu-
rated solution of lithium salt 3 in CH3CN, which was kept in an

J. Hartung et al. / Tetrahedron 65 (2009) 2567–2573
19. Hartung, J.; Gottwald, T.; Spehar, K. Synlett 2003, 227–229.
2573
ˇ
atmosphere of pentane. C5H8LiNO3S (169.12), T¼100(2) K,
20. Groß, A.; Schneiders, N.; Gottwald, T.; Daniel, K.; Hartung, J. Tetrahedron 2008,
l
¼0.71073 Å, monoclinic, P21/m, a¼7.5034(11) Å, b¼6.9955(8) Å,
64, 10882–10889.
c¼8.1024(13) Å,
b
¼114.554(19)ꢂ, Z¼2,
m
¼0.369 mmꢃ1, complete-
21. Hartung, J.; Altermann, S.; Svoboda, I.; Fuess, H. Acta Crystallogr. 2005, E61,
o1738–o1740.
ness to 2
q
¼99.5%, goodness-of-fit on F2¼1.067, final R indices
ˇ
22. Hartung, J.; Spehar, K.; Svoboda, I.; Fuess, H.; Arnone, M.; Engels, B. Eur. J. Org.
[I>2s
(I)]: R1¼0.0398, wR2¼0.0957.
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Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication [1b
CCDC 708992, 1c CCDC 708986, 1d CCDC 708987, 1e CCDC 708988,
1f 708991, 2ꢀH2O CCDC 708989, 3ꢀH2O CCDC 708990]. Copies of
the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
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Acknowledgements
Thiswork wassupportedbythe Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 690: ElektronendichtedTheorie und Experiment).
We wish furthermore to express our gratitude to Ms. Christiane Mu¨ller
for recording variable temperature NMR spectra.
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