Hindered rotation in N-acyloxy-4-methylthiazole-2(3H)-thiones

Article abstract of DOI:10.1016/j.tet.2009.06.124

Experimentally determined barriers to O-acyl group topomerization in mixed anhydrides composed of β-disubstituted carboxylic acids and cyclic thiohydroxamic acid N-hydroxy-4-methylthiazole-2(3H)-thione were located in the range of ΔG^?₃₂₀

Full text of DOI:10.1016/j.tet.2009.06.124

Tetrahedron 65 (2009) 7527–7532
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journal homepage: www.elsevier.com/locate/tet
Hindered rotation in N-acyloxy-4-methylthiazole-2(3H)-thiones
,
a
a
a
a
Jens Hartung a , Christine Schur , Irina Kempter , Sabine Altermann , Georg Stapf ,
*
Uwe Bergstra¨ßer a, Thomas Gottwald b, Markus Heubes b
a
¨
¨
Fachbereich Chemie, Organische Chemie, Technische Universitat Kaiserslautern, Erwin-Schrodinger-Straße, D-67663 Kaiserslautern, Germany
b Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, 97074 Wu¨rzburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Experimentally determined barriers to O-acyl group topomerization in mixed anhydrides composed of b-
Received 27 May 2009
Accepted 29 June 2009
Available online 3 July 2009
disubstituted carboxylic acids and cyclic thiohydroxamic acid N-hydroxy-4-methylthiazole-2(3H)-thione
were located in the range of
D
Gz ¼68ꢀ8 kJ molꢁ1 (DNMR). According to modeling studies, the un-
320
derlying exchange process is proposed to occur via rotation about the N,O bond for torsional movement
of the O-acyl group past the heterocyclic 4-methyl substituent. The energetically lowest pathway for
passing the O-acyl entity by the thione sulfur, is predicted to occur via sequential rocking about the Csp2 ,O
single bond in combination with an interlaced twist about the N,O axis.
Keywords:
Mixed anhydride
Eyring analysis
Hindered rotation
Kinetics
Ó 2009 Elsevier Ltd. All rights reserved.
Modeling
Thiazolethione
Thiohydroxamic acid
Topomerization
Variable temperature NMR
Strain
X-ray diffraction
1. Introduction
4-methyl-2-thiooxo-2,3-dihydrothiaz-3-yl group (in 1) for 2-thio-
oxo-1,2-dihydropyrid-1-yl [in O-acylpyridine-2(1H)-thiones]. We
N-Acyloxy-4-methylthiazole-2(3H)-thiones1 (e.g., 1a–d) are
chemical more robust derivatives of the N-acyloxypyridine-2(1H)-
thiones, i.e., the prominent Barton-anhydrides.2,3 Both sets of
heterocycles share common chemical reactivity and therefore serve
nowadays as standard reagents for carbon radical generation from
carboxylic acids in solution.4 Due to thermal and photochemical
lability, the majority of N-acyloxypyridine-2(1H)-thione applica-
tions are, however, restricted to in situ transformations.5 Data on
structural properties and chemical behavior that would facilitate
new reagent development for specialized purposes, therefore are
surprisingly limiteddeven after a quarter of a century of their ex-
tensive use in radical chemistry.6
therefore chose to explore substituent effects onto energetics and
conformational behavior of the N,O bond in N-acyloxy-4-methyl-
thiazole-2(3H)-thiones 1a–d. The selected compounds were
expected to show hindered rotation thus allowing to derive the
requested information from variable temperature NMR studies.7 In
a static picture, an offset of a substituent at O from the thiazole-
2(3H)-thione plane gives rise to P (clockwise helicity of substituents
of highest CIP priority at either end of the N,O-axis, i.e., C¼S at N
and C¼O at O) or M configuration along this connectivity (anti-
clockwise helicity), thus creating a diastereotopic environment for
spectroscopically distinguishing otherwise prostereogenic subunits
of the O-acyl group (Scheme 1).7–9
The key connectivity to be homolytically cleaved in O-acylthio-
hydroxamates for their use as radical source is the N,O bond.
Notable differences in ground state stability in this product class
therefore are expected to originate from variations that occur upon
modifying electronic and in particular steric effects imposed by the
thiohydroxamate entity onto the acyl unit by substituting, e.g., the
The most important findings from the present study showed
that b-substituted N-acyloxythiazolethiones 1b–d underwent sur-
prisingly slow topomerization in solution at 25 ꢂC. Barriers asso-
ciated with the exchange processes were located in the range of
D
Gz ¼68ꢀ8 kJ molꢁ1 (DNMR). Results from a supporting model-
320
ing study provided evidence that the underlying exchange process
occurs via rotation about the N,O bond for torsional movement of
the O-acyl group past the heterocyclic 4-methyl substituent. The
energetically lowest pathway for passing the O-acyl entity by the
thione sulfur, is predicted to occur via sequential rocking about
* 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.2009.06.124

7528
J. Hartung et al. / Tetrahedron 65 (2009) 7527–7532
enantiomers
was virtually quantitative, as judged on the basis of a spotting test
on FeCl2-coated TLC sheets. Due to limited stability toward SiO2- or
Al2O3-based stationary phases thiones 1a–d were separated by
crystallization and not by chromatography, which lowered the
yields of analytically pure, tan crystalline thiones to 54–87%. At-
tempts to purify anhydride (R)-1d in a similar manner were for not
successful since the oily product resisted crystallization. Final ef-
forts to subject the material to chromatography using a short SiO2-
column resulted in complete decomposition of thione (R)-1d.
NMR spectra (1H, 13C) of mixed anhydrides 1b–d showed two-
fold signal sets for parts of the acyl and the heterocyclic component
(Table 2) in intensity ratios of 50:50 (for 1b and 1c) or 70:30
[(ꢀ)-1d, (S)-1d, (R)-1d, the latter not shown in Table 2]. The more
intense signal set was invariant from absolute configuration of
applied mandelic acid derivative [see Fig. 1 for (ꢀ)-1d]. The unit cell
of (ꢀ)-1d (Z¼4) comprised a racemate of (M,R)- and (P,S)-config-
ured molecules (Fig. 3). Efforts to correlate this information with
observed NMR data by dissolving crystals of (ꢀ)-1d at ꢁ78 ꢂC in
S
S
S
S
O
N
N O
O
RO
O
OR
H
H
R
R
(M,S)-1
(P,R)-1
diastereomers
S
S
S
S
O
N
N O
O
O
H
H
R
R
RO
(P,S)-1
OR
(M,R)-1
enantiomers
1
toluene-d8 for recording a H NMR spectrum at ꢁ70 ꢂC, however,
Scheme 1. Stereochemical relationship between axial chirality and centrochirality in
N-acyloxy-4-methylthiazole-2(3H)-thiones, e.g., 1c,d (see Table 1).
resulted in 70/30-mixture of diastereomeric thiones, presumably
due to equilibration within the 2 min required to shim the spec-
trometer. If the well-known propensity of O-alkylthiohydrox-
amates to adopt lowest energy conformation in the solid state was
taken as guideline for interpreting this observation, the major
stereoisomer in solution would be expected to reflect combinations
of axial-chirality and centrochirality equivalent to those found in
the crystal structure of (ꢀ)-1d.
the Csp2 ,O single bond in combination with an interlaced twist
about the N,O axis. The barriers are proposed to have beneficial
effects with respect to O-acyl thiohydroxamate ground state
stability.
2. Results and interpretation
Table 2
Split signal sets in NMR spectra of N-acyloxythiazolethiones 1b–d (25 ꢂC)a
2.1. Preparation and properties of N-acyloxy-4-
methylthiazole-2(3H)-thiones
Signal
Measurement
1bb
(ꢀ)-1c
(ꢀ)-1dc
4.82/5.04
81.0/82.2
dd
a
b
b
-CH
d
d
d
d
d
d
d
d
1H
(2.51)
(32.3)
1.01/1.15
18.6/18.9
dd
3.79/3.96b
75.2/75.4c
1.26/1.43b
18.6/18.9c
3.21/3.25b
58.1/58.3c
(1.30)b
The carboxylic acids that were selected for the pursuit of present
study were adequate for comparing structural data from NMR,
X-ray diffraction, and computational studies data in a straightfore-
ward manner (1a), bore prostereogenic entities suitable for variable
temperature NMR-spectroscopic analysis (1b), and showed a grad-
ual increase in steric demand of substituents attached to an
asymmetrically substituted Ca (1c and 1d). Synthesis of target
compounds 1a–d was feasible by extending published pro-
cedures10,11 starting from acyl chlorides in the presence of K2CO3
(Table 1, entry 1) or trispropanephosphonic acid anhydride-acti-
vated carboxylates (Table 1, entries 2–6) and thiohydroxamic acid 2.
The conversion of N-hydroxy compound 2 under such conditions
13C
1H
-CH3
-OCH3
13C
1H
dd
3.35/3.50
58.2/58.9
0.94/1.06
12.0/12.2
13C
1H
dd
4-CH3
(1.43)
(12.5)
13C
(12.5)c
a
Figures in parentheses indicate unsplit signals.
In toluene-d8.
In C6D6.
b
c
d
Not available.
Table 1
Preparation of N-acyloxy-4-methylthiazole-2(3H)-thiones 1a–d
S
S
cond. i or ii
S
S
N
N
O
OH
O
Cα
2
R1
R2
H
1a–d
Entry
1a
R1
H
CH3
CH3
CH3
C6H5
C6H5
R2
Conditionsb
Yield/%
drc
1
2
3
4
5
6
1a
1b
(ꢀ)-1c
(S)-1c
(ꢀ)-1d
(S)-1d
H
CH3
OCH3
OCH3
OCH3
OCH3
i
74
87
54
55
62
65
d
ii
ii
ii
ii
ii
50:50
50:50
50:50
70:30
70:30
a
Stereodescriptor refers to configuration at Ca; (ꢀ) denotes racemic mixture.
Conditions i: K2CO3, acetone, 25 ꢂC, acyl chloride. Conditions ii: CH2Cl2, 1,4-di-
b
azabicyclo[2.2.2]octane (DABCO) or N-ethyl morpholine, carboxylic acid, trispropa-
nephosphonic acid anhydride (T3P or PPAA), and 40 ꢂC for 1b, 20 ꢂC for 1c–d.
Figure 1. Selected part of the HMQC-spectrum of mandelic acid derivative (ꢀ)-1d
(C6D6, 20 ꢂC) showing correlation between split resonances of diastereotopic protons
(top) and carbons (left).
c
Diastereomeric ratio (1H NMR, toluene-d8 or C6D6, 25 ꢂC).

J. Hartung et al. / Tetrahedron 65 (2009) 7527–7532
7529
2.2. Variable temperature NMR
In view of a rather low barrier to N,O rotation in N-isopropoxy-4-
methylthiazole-2(3H)-thione (
D
Gz ¼42ꢀ7 kJ molꢁ1) a more de-
200
Variable temperature NMR spectra were recorded from solu-
tions of thiones 1b, (ꢀ)-1c, and (ꢀ)-1d in toluene-d8 in the tem-
perature range between 298 K to w365 K. Temperatures were in all
instances calibrated with the methanol thermometer.12,13 Signal
coalescence was observed at 320 K (1c), 323 K (1d) and 330 K (1b).
Above 340 K, all spectra showed averaged data sets thus pointing to
fast exchange. For reasons of more pronounced 1H NMR signal
separation, we restricted ourselves to analysis of variable temper-
ature 1H NMR spectra. Rate constants of topomerization were de-
termined via line shape analysis (Experimental and Supplementary
data). Eyring-analysis14 of the data provided linear correlations for
thiazolethiones 1b and (ꢀ)-1c (Fig. 2). Free energies were calcu-
lated from the Gibbs–Helmholtz relationship using activation en-
thalpies and entropies that were taken from slope and intercept of
Eyring-plots (Table 3).
tailed description on the origin of the notable barrier in O-acyl
analogue 1c was considered in part to originate from repulsion be-
tween carbonyl and thiocarbonyl group. For further disussing this
aspect, a model for describing conformational characteristics of the
exchange process was devised (Section 2.3).
2.3. Modeling N-acyloxy group topomerization
The O-acyl substituent resides in crystal structures of anhydrides
1a and (ꢀ)-1d approximately at the vertical that divides the 4-
methylthiazole-2(3H)-thione nucleus into structurally different
hemispheres (Fig. 3). The carbonyl oxygen in both structures is ori-
ented toward the heterocycle thus directing the alkyl entity into op-
posite direction. This arrangement was observed previously for other
derivatives of this product class in the solid state11,19 and in solution.6
Figure 3. Geometry of N-acetyloxythiazolethione 1a (left, 299 K) and (P,S)-1d (right,
153 K) in the solid state (ellipsoids are drawn at the 50% probability level; the P-en-
antiomer was in both instances selected arbitrarily for presentation purposes from the
racemate; H-atoms were drawn as circles of an arbitrary radius).
Figure 2. Correlation of ln(k/T) and reciprocal temperatures for N-acyloxy-
thiazolethione topomerization (see also Supplementary data and Table 3).
Translation of structural information into a model that takes free
energy changes that occur upon conformational changes associated
with topomerization into account is feasible on the basis of an appro-
priate electronic structure method. According to a more detailed as-
sessment of methods suitable for O-alkylthiazole-2(3H)-thiones
conformational analysis,20 and the fact that major solid state structural
parameters of N-acetyloxythiazole-2(3H)-thione 1a were adequately
reproduced by Becke’s 3 parameter hybrid functional21,22 in combina-
tion with the 6-31þG** basis set,23–25 we selected the density func-
tional theory method for modeling O-acyl topomerization (Table 4).
Table 3
Activation parameters (Eyring analysis) for topomerization (variable temperature
NMR) of N-acyloxythiazolethiones 1b–c
Entry
Compound
D
Gz a/kJ molꢁ1
D
Hz/kJ molꢁ1
D
Sz/J molꢁ1 Kꢁ1
320
1
2
1b
(ꢀ)-1c
67ꢀ2
68ꢀ8
63ꢀ1
85ꢀ4
ꢁ12ꢀ4
52ꢀ14
a
experimental errors in
D
Hz and
D
Sz refer to standard deviation; experimental
errors in
D
Gz
were calculated on the basis of errors in
DH
z and Sz.
D
320
Table 4
Kinetic data determined for topomerization of mandelic acid
derivative (ꢀ)-1d in the temperature range between 300 and 367 K
provided a scatter in the Eyring-diagram (not shown). This obser-
vation was correlated with the propensity of thione (ꢀ)-1d to de-
compose upon elevating the temperature above w320 K. Since the
Experimental (X-ray crystallography) and computed26 (equilibrium structure) geo-
metrical parameters of selected N-acyloxythiazolethiones
ꢂ
Entry
Parameter/Å or
1a/299 K
X-ray cryst.
(ꢀ)-1d/153 K
1a/0K
B3LYP/6-31þG**
X-ray cryst.
observed 70/30-population (DG
300w2.1 kJ molꢁ1) was fairly close
1
2
3
4
5
S1–C2
C2–N3
N3–C4
C4–C5
C5–S1
1.719(3)
1.339(3)
1.392(3)
1.332(4)
1.717(3)
1.732(3)
1.358(4)
1.394(4)
1.323(4)
1.739(3)
1.769
1.374
1.398
1.351
1.756
to an equipartition, the free activation energy for topomerization of
(ꢀ)-1d was approximated on the basis of Dni values and the co-
alescence temperature leading an estimated barrier of
D
Gz323w65 kJ molꢁ1 (Supplementary data).
The barriers to topomerization of thiones 1b–d (
6
7
8
9
S1–C2–N3
C2–N3–C4
N3–C4–C5
C4–C5–S1
C5–S1–C2
106.3(2)
119.5(2)
109.0(3)
112.5(2)
92.6(2)
105.7(2)
119.5(2)
109.7(3)
112.4(3)
92.7(2)
105.5
119.7
110.3
112.0
92.6
D
Gz ¼68-
320
ꢀ8 kJ molꢁ1) rank among the highest determined so far for substituted
hydroxylamines.7,9,15–18 Significantly lower barriers (w30 kJ molꢁ1
)
10
were found for hydroxylamine itself and N-isopropoxypyridine-2(1H)-
thione.7,15 The magnitude of the latter values was related to a lack in
significant steric encroachment at the N,O bond in H2NOH and lone
pair delocalization from N to C]S and thus lowering of lone pair re-
pulsion between N and O in N-isopropoxypyridine-2(1H)-thione. An
increase in steric demand of substituents attached at N and/or O in all
investigated instances was paralleled by a rise in barriers to N,O
11
12
C2–S2
N3–O1
1.654(3)
1.387(3)
1.656(3)
1.402(3)
1.656
1.381
13
14
15
16
17
18
N3–O1–R
C4–N3–O1
C2–N3–O1
S2–C2–N3
S1–C2–S2
N3–C4–C6
113.1(2)
120.1(3)
120.3(3)
127.0(2)
126.8(2)
120.1(3)
112.5(2)
120.3(2)
120.0(2)
127.6(2)
126.7(2)
119.7(3)
113.5
120.7
119.3
127.4
127.1
120.3
rotation from
N-aryloxysuccinimides, N-acyloxyhydroxylamides)9,16 to
60 kJ molꢁ1 (sterically demanding trisubstituted hydroxylamides).17,18
D
Gzw40 kJ molꢁ1 (cyclic O-alkyl thiohydroxamates,
Gzw50–
D
19
C2–N3–O1–R
ꢁ95.8(3)
ꢁ80.5(3)
87.6

7530
J. Hartung et al. / Tetrahedron 65 (2009) 7527–7532
Topomerization I/III in N-acyloxythiazolethiones was expected
localized and verified using adequate numerical procedures and
computer programs.26,27 The transition structure determined for
torsional movement of the acetyl group past the 4-methyl sub-
stituent showed coplanar arrangement between heterocyclic core
and the substituent at O (II-1a, Table 5, entry 2). This arrangement
was associated with a stretch of the N3,O1 bond to 1.404 Å (II-1a). Its
to occur either via N,O-rotation or a combination of C,O- and N,O-
rotation (Scheme 2). Contributions from nitrogen inversion were
considered not to interfere for its embedding into a rigid planar
frame.7,9 Conformation I poses the global and C,O-rotamer V a local
minimum (B3LYP/6-31þG**, Table 5, entries 1 and 4). The sum of
bond angles pointed to planar arrangement at N3. Negligible pyr-
amidalization was only found for the high energy conformer V-1a
(Table 4, entry 4). Population of the latter conformer in solution was
expected to be insignificant on the basis of its relative free energy.
From an experimental point of view, no evidence for close proximity
between methyl groups from the heterocycle and the acetyl sub-
stituent were evident from the NOESY spectrum of 1a (CDCl3, 25 ꢂC).
computed Gibbs energy
D
G298¼72.6 kJ molꢁ1 (II-1a) was surpris-
ingly close to experimentally determined barriers to topomerization
of thiones 1b–d.
The transition structure VI-1a for passing the acetyl group by the
thione sulfur shows puckered arrangement originating from w90ꢂ
rotations about adjascent C,O and the N,O bonds (Table 5, entry 3).
This arrangement was 69.7 kJ molꢁ1 higher in free energy than the
global minimum and thus in the same order of magnitude as the
barrier to acetyl group topomerization into the opposite direction,
i.e., past 4-CH3.
If computed data for N-acetylthiazolethione 1a served as
guideline for interpreting the mode of topomerization in O-acyl
derivatives of N-hydroxythiazole-2(3H)-thiones in general, the
following picture would result. The torsional movement of the acyl
component toward the thione sulfur occurred via a puckered en-
ergetic maximum, and that toward the heterocyclic methyl sub-
stituent via a coplanar transition state. Both processes are predicted
to occur with similar activation energy. These findings would imply
that an increase in steric demand of substituents attached to C4
(e.g., R0 in Fig. 4) would not neccessarily lead to a higher experi-
mental barrier since the system could topomerize by transposing
the substituent past the thione sulfur via an intermediate similar to
computed structure VI-1a. The barrier, however, is expected to rise
O
N,Orot
N,Orot
O
O
H
O N
S
P
N
M
H
H
O
N
S
S
S
O
S
S
I
II
+ 72.6
III
0.0
E ≡ 0.0
+ C,Orot
– C,Orot
O
N,Orot
N,Orot
H
O
N
S
P
M
O
N
O
N
S
H
S
S
O
O
S
S
IVa
VI
VII
H
+ 69.7
C,Orot
• strain
H
S
S
O
P
R'
S
R'
R'
S
S
N
O
N
O
O
N
S
R
R
S
V
disfavored
+ 19.8
•Coulomb repulsion
Scheme 2. Proposed pathway for topomerization of substituents in N-acyloxy-4-
methylthiazole-2(3H)-thiones 1a–d [symbols B and C refer to CH3, C6H5, or OCH3
S
S
••
••
••
R'
S
substituents; numbers refer to B3LYP/6-31þG**-calculated
DG298 values of computed
N
••
N
••
structures for acetyl derivative 1a (see Table 5)].
O
R
O
••
R
Starting from equilibrium structure I-1a, virtually every confor-
mational change is associated with an approach of substituents and
thus with an increase in free energy of the system. Conformations
with maximum energy pose transition structures, which may be
disfavored
favored
Figure 4. Proposed effects for explaining the origin of barriers to N,O-rotation in N-
acyloxythiazole-2(3H)-thiones, e.g., 1a–d.
Table 5
,
Computeda 26 energies and parameters of distinguished N-acetyloxy-4-methylthiazole-2(3H)-thione conformers
Entry
Compound
E/Hartreeb
ZPVE/Hartree
G298/Hartree
D
G298/kJ molꢁ1
N3–O1/Å
C2–S2/Å
Sai(N3)c/ꢂ
C2–N3–O1–C7/ꢂ
1
2
3
4
I-1a
ꢁ1234.411684
ꢁ1234.384544
ꢁ1234.385965
ꢁ1234.404883
0.126094
0.125689
0.124999
0.126108
ꢁ1234.324388
ꢁ1234.296724
ꢁ1234.297824
ꢁ1234.316843
h0.0
þ72.6
þ69.7
þ19.8
1.381
1.404
1.387
1.387
1.656
1.656
1.667
1.654
359.7
360.0
359.9
357.8
87.6
179.3
1.7
II-1ad
VI-1a
V-1ae
89.3
a
B3LYP/6-31þG**//B3LYP/6-31þG**
.
1 Hartree¼2625.5 kJ molꢁ1
.
b
c
sum of bond angles at N3.
NIMAG¼ꢁ133 cmꢁ1
.
.
d
e
NIMAG¼ꢁ157 cmꢁ1

J. Hartung et al. / Tetrahedron 65 (2009) 7527–7532
7531
according to this picture, if tertiary acyl groups were substituted for
acetyl or secondary derivatives.
4.2.3. Determination of Eyring parameters
Rate constants were calculated from line widths Wex(change)
¼
The fact that Coulomb-repulsion between lone pairs at hetero-
atoms15 have been entirely omitted from the discussion deserves
a final comment. In order estimate energetic contributions from
proposed repulsive orbital interactions (Fig. 4) on a more scientific
basis, experimental electron density studies are required. Since this
information was not available by the time the study was performed,
lone pair repulsion should be kept in mind as additional energetic
contribution when interpreting the phenomenon of hintered ro-
tation about N,O bonds in O-acyl thiohydroxamates.
Wobs(served)ꢁWref(erence) on the basis of Eqs. 1 and 2. Rate constants
were deduced from iterative line shape analysis using the Bruker
program WINDYNA. Fits were continually repeated until calculated
and experimental spectra matched. The error in k originating from
errors in line width Wex and shift differences Dni was estimated to be
5%. Temperatures were kept constant with a precision of ꢀ1 K. Eyr-
ing parameters were deduced on the basis of linear correlations of
ln(k/T) versus 1/T according to in Eq. 3 (Table 3, Fig. 2).
p
2Wex
ð
Dn
Þ
k ¼
k ¼
(1)
3. Concluding remarks
The present investigation stresses the significance of steric ef-
fects for describing barriers to topomerization in mixed anhydrides
composed of carboxylic and thiohydroxamic acids. Although ex-
perimental data for topomerization of the more prominent
N-acylpyridine-2(1H)-thiones were not available from the litera-
ture, it is expected that such barriers are notably smaller due to the
lack of steric repulsion from the CH3 substituent next to the thio-
hydroxamate group. A lower barrier, in turn, correlates with higher
frequency for the incidence of coplanar acyloxy and thiohydrox-
amate arrangement. Even in the simplest orbital picture, this ar-
rangement implies repulsive and therefore destabilizing
interactions between heteroatoms that are connected by a com-
paratively weak bond (Fig. 4). Steric repulsion between the 4-CH3
and the N-acyloxy entity in this interpretation is expected to in-
crease population of less reactive conformations having the acyl
group oriented in orthogonal position with respect to the hetero-
cyclic core (Fig. 3), which in turn contributes to N-acyloxythiazole-
2(3H)-thione stabilization. Whether a methyl group attached to the
thiazole-2(3H)-thione nucleus constitutes the most suitable com-
bination for this purpose remains to be uncovered in future studies.
p
Wex
(2)
(3)
kb
h
D
Hz
D
Sz
lnðk=TÞ ¼ ln
ꢁ
þ
RT R
4.3. N-acyloxythiazole-2(3H)-thiones 1a–d
4.3.1. From acyl chlorides
In a typical run, K2CO3 (0.41 g, 3.00 mmol) was added to a so-
lution of thiohydroxamic acid 2 (147 mg, 1.00 mmol) in acetone
(9 mL). The slurry was stirred for 10 min at 20 ꢂC and treated
hereafter with neat acid chloride (1.10 mmol). Stirring was con-
tinued at 20 ꢂC (30–90 min). Consumption of acid 2 was evident
from the absence of a green color upon spotting a drop of the re-
action mixture onto FeCl2-coated TLC sheets. Solids were removed
by filtration. The filtrate was evaporated to dryness to leave a resi-
due that was purified by (re)crystallization.
4.3.1.1. N-Acetyloxy-4-methylthiazole-2(3H)-thione (1a). Yield: 280 mg
(74%); tan solid from Et2O/petroleum ether; mp 94–96 ꢂC (dec). 1H
NMR (CDCl3, 600 MHz)
d
2.17 (s, 3H, 4-CH3), 2.44 (s, 3H,
a
-CH3), 6.23 (s,
1H, 5-H); 13C NMR (CDCl3, 150 MHz)
d
13.3 (4-CH3), 18.8 (
a-CH3), 102.4
4. Experimental
4.1. General
(C5), 136.8 (C4), 165.9 (C]O), 180.8 (C]S). Anal. Calcd for C6H7NO2S2:
C, 38.08; H, 3.73; N, 7.40. Found: C, 37.95; H, 3.67; N, 7.35. Crystals
suitable for X-ray diffraction were grown from a saturated solution in
For general laboratory practice and instrumentation see Ref. 28
and Supplementary data. DTA is short for differential thermal
analysis, whereby endothermic signals refer to melting, and exo-
thermic signals to decomposition of 1.
CH2Cl2. X-ray crystallography: T¼293(2) K, ¼0.71073 Å, monoclinic,
l
P21/n, a¼7.410(2) Å, b¼13.452(3) Å, c¼8.910(2) Å,
b
¼96.50(3)ꢂ, Z¼2,
m
¼0.554 mmꢁ1
,
completeness to
2
q
¼95.5%, goodness-of-fit on
F2¼0.774, final R indices [I>2
(I)]: R1¼0.0322, wR2¼0.0630.
s
4.2. Variable temperature NMR
4.3.2. From carboxylic acids
In a typical run, trispropanephosphonic acid anhydride (PPAA)
[955 mg, 3.00 mmol,1.91 g, 50% in DMF (w/w)] was added at 0 ꢂC to
a solution of thiohydroxamic acid 2 (294 mg, 2.00 mmol), DABCO
(674 mg, 3.00 mmol) or N-ethyl morpholine (0.6 ml, 4.70 mmol)
and a carboxylic acid (2.00 mmol) in dry CH2Cl2 (16 mL). The re-
action mixture was refluxed (for 1b) or stirred at 20 ꢂC (for 1c and
1d) for 16 h. The solvent was removed under reduced pressure
(10 mbar, 20 ꢂC) to furnish a residue that was taken up in H2O (5 mL)
and Et2O (10 mL). The organic phase was separated, washed suc-
cessively with aq NaHCO3 [5 mL, 50% (w/w)] and H2O (5 mL), and
dried (MgSO4). The solvent was removed under reduced pressure to
leave a residue that was (re)crystallized from Et2O/petroleum ether
[1:1 (v/v)], to afford compounds 1b–d as tan solids.
Bruker DMX 600 operating at 600.13 MHz equipped with
a temperature control assembly B-VT-2000, display and control
unit BTO-2000-E and probe head heater BMT 05.
4.2.1. Sample preparations
Solutions of thiones 1b–d (40 mg) in toluene-d8 were injected in
high precision 5 mm tubes (Varian 507 PP) and frozen to 77 K. The
samples were sealed with a torch and very slowly allowed to warm
to room temperature. Rapid warming may result in hazardous NMR
tube breakage.
4.2.2. NMR experiments
Samples were thermally equilibrated for 15 min. Temperatures
inside the spectrometer cavity were measured with the aid of the
MeOH thermometer. Receiver circuit impedance was compensated.
NMR spectra were recorded with the spinning velocity set to zero.
Zero filling to four times the number of measured data points was
performed. Particular attention was paid to appropriate phase and
the baseline corrections.
4.3.2.1. N-(2-Methylpropionyloxy)-4-methylthiazole-2(3H)-thione
(1b). Yield: 377 mg (87%); Rf¼0.30 [SiO2, Et2O/petroleum ether¼1:1
(v/v)]; tan solid from Et2O/petroleum ether; DTA 51 ꢂC (endotherm.),
82 ꢂC (exotherm.).1H NMR (600 MHz, toluene-d8)
d
1.01 (d, J¼6.9 Hz,
3H,
b
-CH3),1.15 (d, J¼6.9 Hz, 3H, -CH3),1.43 (d, J¼1.2 Hz, 3H, 4-CH3),
b
2.51 (sept, J¼6.9 Hz, 1H,
a
-H,), 5.09 (q, J¼1.2 Hz, 1H, 5-H); 13C NMR

7532
J. Hartung et al. / Tetrahedron 65 (2009) 7527–7532
(100 MHz, toluene-d8)
d
12.5 (4-CH3),18.6 (
b
-CH3),18.9 (
b
-CH3), 32.3
127.3, 127.7, 128.0, 128.4, 128.5, 129.0, 129.3, 129.4 (Ph–H), 135.7
(C4), 135.8 (C4), 136.3 (Ph–C), 167.1 (C]O), 167.5 (C]O), 181.2
(C]S).
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication [CCDC
733594 (1a), CCDC 733595 (1d)]. 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).
(Ca), 101.3 (C5), 136.4 (C4), 172.2 (C]O), 181.0 (C]S). m/z (EI) 217
(Mþ, 55%), 147 (88), 71 (30), 43 (100). Anal. Calcd for C8H11NO2S2: C,
44.21; H, 5.10; N, 6.45. Found: C, 44.06; H, 4.96; N, 6.33.
4.3.2.2. (ꢀ)-N-(2-Methoxypropionyloxy)-4-methylthiazole-2(3H)-
thione (ꢀ)-(1c). Yield: 250 mg (54%); Rf¼0.20 [SiO2, Et2O/petro-
leum ether¼1:1 (v/v)]; tan solid from Et2O/petroleum ether; DTA
51 ꢂC (endotherm.); 62 ꢂC (exotherm.). 1H NMR (600 MHz, toluene-
d8)
J¼6.5 Hz, 1.5H,
3.79 (q, J¼7.3 Hz, 0.5H,
1H, 5-H). 13C NMR (63 MHz, C6D6)
58.1 ( -OCH3), 58.3 (b-OCH3), 75.2 (Ca), 75.4 (Ca), 101.6 (C5), 101.7
d
1.26 (d, J¼7.3 Hz, 1.5H,
-CH3), 3.21 (s, 1.5H,
-H), 3.96 (q, J¼6.5 Hz, 0.5H,
12.5 (4-CH3), 18.6 (Cb), 18.9 (Cb),
b
-CH3), 1.30 (s, 3H, 4-CH3), 1.43 (d,
-OCH3), 3.25 (s, 1.5H, -OCH3),
-H), 4.90 (s,
b
b
b
a
a
Acknowledgements
d
b
This work was supported by the Deutsche Forschungsge-
meinschaft (Grant Ha1705/5-2).
(C5), 136.2 (C4), 165.6 (C]O), 181.0 (C]S). m/z (EI) 233 (Mþ, 15%),
147 (41), 71 (11), 59 (100). Anal. Calcd for C8H11NO3S2: C, 41.18; H,
4.75; N, 6.00. Found: C, 41.39; H, 4.59; N, 5.89.
Supplementary data
4.3.2.3. (2S)-N-(2-Methoxypropionyloxy)-4-methylthiazole-2(3H)-
Instrumentation, kinetic data for topomerization of 1b–c,
atomic coordinates and energies of computed structures I-1a, II-1a,
V-1a, VI-1a (B3LYP), HMQC for (ꢀ)-1d (10 pages). Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2009.06.124.
thione (S)-(1c). Yield: 254 mg (55%) as tan solid from Et2O/petro-
25
leum ether; Rf¼0.20 [SiO2, Et2O/petroleum ether¼1:1 (v/v)]. [
6.7 (c 0.1, EtOH). 1H NMR (250 MHz, C6D6)
-CH3), 1.31 (s, 3H, 4-CH3), 1.44 (d, J¼7.0 Hz, 1.5H,
1.5H, -OCH3), 3.25 (s, 1.5H,
-OCH3), 3.81 (q, J¼6.8 Hz, 0.5H,
3.97 (q, J¼7.0 Hz, 0.5H,
-H), 4.91 (s, 1H, 5-H). 13C NMR (63 MHz,
C6D6) 12.5 (4-CH3), 18.7 (Cb), 18.9 (Cb), 58.2 ( -OCH3), 58.3 (
a]
D
d
1.27 (d, J¼6.8 Hz, 1.5H,
-CH3), 3.21 (s,
-H),
b
b
b
b
a
a
References and notes
d
b
b-
OCH3), 75.2 (Ca), 75.5 (Ca), 101.6 (C5), 101.7 (C5), 136.2 (C4), 165.4
(C]O), 181.1 (C]S).
1. Barton, D. H. R.; Crich, D.; Kretschmar, G. J. Chem. Soc., PerkinTrans. 11986, 39–53.
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University Press: Cambridge, 1993; Chapter 5, pp 46–90.
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o1738–o1740.
20. Hartung, J.; Daniel, K.; Bergstra¨sser, U.; Kempter, I.; Schneiders, N.; Danner, S.;
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200900069
4.3.2.4. (ꢀ)-N-(2-Methoxy-2-phenylacetyloxy)-4-methylthiazole-
2(3H)-thione (ꢀ)-(1d). Yield: 364 mg (62%), Rf¼0.20 [SiO2, Et2O/
petroleum ether¼1:1 (v/v)].1H NMR (250 MHz, C6D6)
d 0.94 (s, 2.1H,
4-CH3), 1.06 (s, 0.9H, 4-CH3), 3.35 (s, 2.1H,
b
-OCH3), 3.50 (s, 0.9H,
-H), 6.97–
12.0 (4-CH3), 12.2
b-OCH3), 81.0 (Ca), 82.2 (Ca),101.5 (C5),
b-
OCH3), 4.82 (s, 0.3H,
7.14 (m, 5H, Ph–H). 13C NMR (63 MHz, C6D6)
(4-CH3), 58.2 ( -OCH3), 58.9 (
a-H), 4.86 (s, 1H, 5-H), 5.04 (s, 0.7H, a
d
b
101.6 (C5), 125.7, 126.7, 127.3, 127.5, 128.9, 129.6 (Ph–C), 135.8 (C4),
136.3 (C4),167.0 (C]O),181.2 (C]S). Anal. Calcd for C13H13NO3S2: C,
52.86; H, 4.44; N, 4.74. Found: C, 52.62; H, 4.32; N, 4.67. Crystals
suitable for X-ray diffraction were grown from a saturated solution
in CHCl3/pentane. X-ray crystallography: T¼153(2) K, ¼1.54184 Å,
l
monoclinic, P21/c, a¼8.2215(3) Å, b¼17.0689(7) Å, c¼9.8572(5) Å,
b
¼98.039(4)ꢂ, Z¼4,
m
¼3.564 mmꢁ1, completeness to 2
¼97.2%,
q
goodness-of-fit on F2¼0.974, final R indices [I>2
s
(I)]: R1¼0.0433,
wR2¼0.1163.
4.3.2.5. (2S)-N-(2-Methoxy-2-phenylacetyloxy)-4-methylthiazole-
2(3H)-thione (S)-(1d). Yield: 384 mg (65%); Rf¼0.20 [SiO2, Et2O/pe-
troleum ether¼1:1 (v/v)]; tan solid from Et2O/petroleum ether; DTA
89 ꢂC (exotherm.). [ 25 176.0 (c 0.1, EtOH). 1H NMR (250 MHz, C6D6)
a]
D
d
0.95 (s, 2H, 4-CH3), 1.06 (s, 1H, 4-CH3), 3.34 (s, 2H,
(s,1H, -OCH3), 4.81 (s, 0.3H, -H), 4.85 (s,1H, 5-H), 5.03 (s, 0.7H,
7.00–7.12 (m, 5H, Ph–H). 13C NMR (100 MHz, toluene-d8)
12.0 (4-
CH3), 12.1 (4-CH3), 58.2 ( -OCH3), 58.9 ( -OCH3), 80.9 (Ca), 82.2 (Ca),
b
-OCH3), 3.50
21. Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
b
a
a-H),
22. Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. 1988, B37, 785–789.
23. Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724–728.
24. Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257–2261.
25. Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209–214.
26. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.;
Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Mo-
rokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.7; Gaussian:
Pittsburgh, PA, 1998.
d
b
b
101.3 (C5),101.4 (C5),125.7,127.2,127.7,128.6 (Ph–C),135.9 (C4),136.2
(C4), 137.3 (Ph–C), 166.9 (C]O), 181.2 (C]S). Anal. Calcd for
C13H13NO3S2: C, 52.86; H, 4.44; N, 4.74. Found: C, 52.78; H, 4.22; N,
4.66.
4.3.2.6. (2R)-N-(2-Methoxy-2-phenylacetyloxy)-4-methylthiazole-
2(3H)-thione (R)-(1d). 1H NMR (600 MHz, C6D6)
d
0.98 (s, 2H, 4-
-OCH3), 3.49 (s, 1H, -OCH3),
-H), 4.92 (s, 1H, 5-H), 5.04 (s, 0.7H, -H), 7.03–7.09
(m, 3H, Ph–H), 7.38 (d, J¼6.9 Hz,1.3H, Ph–H), 7.49 (d, J¼6.4 Hz, 0.6H,
Ph–H). 13C NMR (150 MHz, C6D6)
12.0 (4-CH3), 12.2 (4-CH3), 58.2
-OCH3), 58.7 ( -OCH3), 80.9 (Ca), 82.2 (Ca), 101.7 (C5), 101.8 (C5),
CH3), 1.11 (s, 1H, 4-CH3), 3.33 (s, 2H,
4.88 (s, 0.3H,
b
b
a
a
27. Jensen, F. Introduction to Computational Chemistry; Wiley: Chichester, UK, 1999.
28. Hartung, J.; Bergstra¨sser, U.; Daniel, K.; Schneiders, N.; Svoboda, I.; Fuess, H.
Tetrahedron 2009, 65, 2567–2573.
d
(b
b