Lessons of 3-alkoxy-4-(p-chlorophenyl)4,3-thiazole-2(3H)-thione chemistry learned from structural investigations

Article abstract of DOI:10.1002/ejoc.200900069

Synthetic, spectroscopic, and structural investigations provided evidence that distinguished neat 3-alkoxy-4-(p-chlorophenyl)-l,3-thiazole-2(3H)-thiones (CPTTORs), once developed to serve as alkoxyl radical precursors for storage and use on demand, showed

Full text of DOI:10.1002/ejoc.200900069

FULL PAPER
DOI: 10.1002/ejoc.200900069
Lessons of 3-Alkoxy-4-(p-chlorophenyl)-1,3-thiazole-2(3H)-thione Chemistry
Learned from Structural Investigations
Jens Hartung,*[a] Kristina Daniel,[a] Uwe Bergsträßer,[a] Irina Kempter,[a] Nina Schneiders,[a]
Steffen Danner,[a] Philipp Schmidt,[b] Ingrid Svoboda,[c] and Hartmut Fuess[c]
Keywords: Radicals / Heterocycles / Isomerization / Molecular modeling / Rearrangement / Sulfur
Synthetic, spectroscopic, and structural investigations pro-
vided evidence that distinguished neat 3-alkoxy-4-(p-chlo-
rophenyl)-1,3-thiazole-2(3H)-thiones (CPTTORs), once de-
veloped to serve as alkoxyl radical precursors for storage and
use on demand, showed background reactivity. Selectivity in
these transformations was guided by the nature of the O-
alkyl substituent. Two pathways reflected the inherent weak-
ness of the N,O bond, leading to products of isomerization
and rearrangement. In a third instance, methyl translocation
from oxygen to sulfur occurred to furnish a heteroaromatic
N-oxide at the expense of a cross conjugated π-system. Con-
sistent X-ray crystallographic data sets served as a basis for
electronic structure method assessment in order to model as-
pects relevant to structure and decomposition chemistry that
were not available from diffraction data.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
3-Alkoxy-4-(p-chlorophenyl)-1,3-thiazole-2(3H)-thiones
(CPTTORs; e.g., 1a–d; Figure 1) were introduced in 1997
as reagents for alkoxyl radical generation in the absence of
strong oxidants and metal ions at neutral pH.[1–3] The com-
pounds are available in a straightforward manner through
O-alkylation of the acid CPTTOH,[4,5] which in turn can be
prepared in ca. 75 g batches according to a well-elaborated
protocol.[6] CPTTORs very effectively liberate oxygen-cen-
tered radicals through N,O bond homolysis upon photo-
chemical excitation (λՆ350 nm), microwave irradiation
(2.45 GHz), or heating (≈80–120 °C) in the presence of an
initiator.[7] Their application contributed to progress in vari-
ous fields of mechanistic,[8–10] photobiological,[11] and syn-
thetic alkoxyl radical chemistry.[5,12,13]
Figure 1. Structure formulae and indexing of 3-alkoxy-4-(p-chlo-
rophenyl)-1,3-thiazole-2(3H)-thiones (CPTTOR) relevant for the
present study (CP = p-ClC6H4).
CPTTORs form colorless solids that can be stored and
applied on demand.[14–16] In samples of heterocycles 1a–d,
which had been kept for extended periods of time, new
products unexpectedly appeared. As no comprehensive sys-
tematic study on O-alkyl thiohydroxamate reactivity existed
for classifying observed transformations, the new products
were separated and characterized in a combined spectro-
scopic, synthetic, and X-ray crystallographic study. Ener-
[a] Fachbereich Chemie, Organische Chemie, Technische Uni- getic aspects of CPTTOR reactivity that were not available
versität Kaiserslautern,
from structural and spectroscopic investigations were de-
Erwin-Schrödinger-Straße, 67663 Kaiserslautern, Germany
duced from model density functional theory calculations.
The lessons learned thereby showed that distinguished neat
CPTTORs selectively decomposed by (i) isomerization, (ii)
rearrangement, or (iii) fragmentation. None of the com-
pounds formed in the course of these reactions, however,
had the potential to serve as potent inhibitor for radical
chain reactions.
Fax: +49-631-205-3921
E-mail: hartung@chemie.uni-kl.de
[b] Institut für Organische Chemie, Universität Würzburg,
Am Hubland, 97074 Würzburg, Germany
[c] Technische Universität Darmstadt, Strukturforschung, FB11
Material- und Geowissenschaften,
Petersenstr. 23, 64287 Darmstadt, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900069.
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J. Hartung et al.
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slight decrease in the averaged O1–N3 distance
[1.38Ϯ0.01 Å] below the reference value for hydroxyl-
amines having planarized N [1.40Ϯ0.01 Å].[19]
Results and Interpretation
Lesson 1: X-ray Crystallography, Electronic Structure
Methods, and Conformational Analysis
The propensity of CPTTORs to crystallize in combina-
tion with a noteworthy stability toward X-rays allowed the
fundamentals of O-alkyl thiohydroxamate solid state chem-
istry to be systematically explored as a basis for subsequent
computational studies on structure and reactivity. Attempts
to crystallize CPTTOMe (1a), a compound that is available
+
from CPTTO–NBu4 (not shown) and methyl tosylate in
anhydrous DMF,[17] repeatedly furnished crystals of insuf-
ficient quality for structure determination by single-crystal
X-ray diffraction. Similar efforts were successful for thi-
azolethione 1b[5] but so far not for N-alkenoxy derivatives
1c,d. The conformity of distances (Table 1, Entries 1–5) and
angles (Table 1, Entries 6–10) determined for the heterocy-
clic core and the thiohydroxamate functionality of the new
structure (Figure 2; Table 1, Entries 11–17) in comparison
Figure 2. Projections of thiazolethione 1b displaying least obscured
view (left) and distal arrangement of thiazolethione substituents
(right) (ellipsoids are drawn at the 40% probability level; hydrogen
atoms are drawn as circles of an arbitrary radius; atom numbering
in the projection on the right was omitted for the sake of clarity).
A surprisingly narrow distribution was moreover found
to the values obtained from earlier solid-state studies[2,14,18] for dihedral angles that characterize major conformational
allowed the diagnostic mean values, including standard de- aspects of CPTTORs, that is, the offset of the O-alkyl group
viations, to be calculated, which would allow a reasonable from the thiohydroxamate plane (82Ϯ3°) and the biphenyl-
description of the major structural aspects of this product type twist between the p-chlorophenyl and thiazolethione
class (Table 1). Except for the distances within the thio- entities (45Ϯ3°; Table 1, Entries 19 and 20; Figure 2). Most
hydroxamate functionality, none of these parameters de- but not all CPTTOR structures showed distal orientation
served a comment. Bond lengths N3–C2 and C2–S2 of aryl and N-alkoxy groups (Figures 2 and 3). The offset of
(Table 1, Entries 2 and 11) were found to be close to mean C12 from the thiazolethione plane was attributed to steric
values determined for thioamides and thioureas, thus repulsion between the O-alkyl group and adjacent substitu-
pointing to a similar degree of electron delocalization ents. In view of an inherent preference of hydroxylamines
within the these entities [Csp2=S 1.68Ϯ0.02 Å, S=Csp2–N to adopt gauche-arranged minima,[20] it seemed reasonable
1.35Ϯ0.02 Å].[19] Transfer of electron density from nitrogen to also consider polar contributions from lone pair repul-
toward the C=S group, in turn, is considered to explain a sion for explaining positioning of this entity in CPTTOR
Table 1. Selected experimental (X-ray diffraction, 1b) and computed[22] (distal-1a) parameters of CPTTORs in comparison to averaged
(Ϯ standard deviation) experimental values.[a]
Entry
Parameter [Å] or [°]
X-ray crystallography
CPTTOR[a]
X-ray crystallography
B3LYP[b]
distal-1a
1b
1
2
3
4
5
S1–C2
C2–N3
N3–C4
C4–C5
C5–S1
1.703(7)
1.351(9)
1.405(9)
1.329(9)
1.730(8)
1.73Ϯ0.02
1.35Ϯ0.02
1.40Ϯ0.02
1.34Ϯ0.02
1.72Ϯ0.01
1.774
1.375
1.405
1.356
1.748
6
7
8
9
S1–C2–N3
C2–N3–C4
N3–C4–C5
C4–C5–S1
C5–S1–C2
108.0(5)
118.3(7)
108.2(8)
113.9(6)
91.6(4)
107Ϯ1
119Ϯ1
110Ϯ2
113Ϯ1
93Ϯ1
106.1
118.7
110.6
112.1
92.5
10
11
12
C2–S2
N3–O1
1.675(8)
1.380(7)
1.66Ϯ0.01
1.38Ϯ0.01
1.657
1.377
13
14
15
16
17
18
N3–O1–C12
C4–N3–O1
C2–N3–O1
S2–C2–N3
S1–C2–S2
110.3(6)
120.3(7)
121.3(6)
126.6(6)
125.4(5)
123.2(8)
110Ϯ2
121Ϯ1
120Ϯ1
128Ϯ1
125Ϯ1
124Ϯ3
111.5
120.7
120.7
127.9
126.0
122.6
N3–C4–C6
19
20
C2–N3–O1–C12
N3–C4–C6–C7
84.4(8)
–45.6(10)
82Ϯ3
Ϯ45Ϯ3
85.6
–44.5
[a] Mean value from six CPTTORs: R = 2-propyl, 1-phenylpent-4-en-1-yl, 4-phenylpent-4-en-1-yl (three independent molecules), and 5-
methyl-2-phenylhex-4-en-1-yl (in 1b).[2,14,18] [b] B3LYP/6-31+G**// B3LYP/6-31+G**.
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3-Alkoxy-4-(p-chlorophenyl)-1,3-thiazole-2(3H)-thione Chemistry
crystal structures. In solution, torsional movement about suggested that these energetic aspects furthermore serve as
the N3,O1 bond occurs, as is evident from variable-tem- an explanation for statistically favoring the distal arrange-
perature NMR spectroscopic studies.[21]
ment in solid-state structures.[2,14,18] Energies of rotamers
having either the O-methyl or the p-chlorophenyl substitu-
ent positioned in the thiazolethione plane posed maxima as
evident from negative modes of vibration (not shown).
The first lesson in structural CPTTOR chemistry thus
exemplified that the B3LYP/6-31+G** level of theory is
able to reproduce almost all structural parameters within a
precision that is defined by experimental mean values from
X-ray analysis and associated standard deviations. The data
furthermore suggested that conformational aspects of
CPTTOR solid-state structures predominantly reflected in-
trinsic properties of the molecules.
Figure 3. Ball-and-stick presentation of computed (B3LYP/6-
31+G**) minima of CPTTOMe (1a) [see text, Supporting Infor-
298
mation, and Table 1; relative free energies Grel in kJmol–1].
Lesson 2: Isomerization
Thiazolethione 1a was used for an extended time to pio-
In order to reduce conformational freedom associated
with the N-alkoxy substituent, CPTTOMe (1a) was selected
as a model for an assessment of quantum chemical methods
that adequately reproduce ground-state characteristics of
this product class and derived decomposition products
(vide infra).[23,24] Minimum conformations of 1a were ob-
tained through stepwise (15°) dihedral angle variations as-
sociated with torsional movements of the p-chlorophenyl
and the O-methyl substituent with respect to the thi-
azolethione plane by using redundant variables in minimi-
zation of energy functions. Low-energy conformations ob-
tained from the dihedral angle scan provided input coordi-
nates for unconstrained energy minimization. This strategy
afforded two minima, one showing distal and the other
proximal arrangement of substituents (Figure 3). Calcula-
tion of second derivatives (Hessian matrix) that lacked in
negative eigenvalues or imaginary frequency by diagonal-
ization, characterized computed structures as minima.
Data analysis showed that parameters found for the
global minimum of CPTTOMe (1a) by using Becke’s three
parameter hybrid functional[25,26] and the 6-31+G** basis
set[27–29] agreed within a precision defined by experimental
mean values for this product class including standard devia-
tions (Table 1). The only distance that diverged from the
experimentally defined range related to S1–C2 (1.774 vs.
1.73Ϯ0.02 Å; cf. Table 1, Entry 1). Calculations using
Møller-Plesset perturbation theory second order
(MP2),[30–32] reproduced some of the bond lengths slightly
better (e.g., S1–C2 1.756 Å; Supporting Information). The
method was less accurate for bond and torsion angles. Fur-
ther investigations by using Becke’s half and half functional
(BHandHLYP)[33] in combination with the 6-31+G**-basis
set[27–29] agreed qualitatively and quantitatively to values
obtained from B3LYP theory (Supporting Information). In
view of these findings, we restricted ourselves to presenta-
tion and discussion of B3LYP/6-31+G**-calculated data.
According to density functional theory, distal-1a was
7.7 kJmol–1 favored by free energy (298.15 K) compared to
proximal-1a (Figure 3), presumably for reasons discussed
neer the chemistry of methoxyl radical addition to nor-
1
bornene.[15,17] In the course of routine H NMR spectro-
scopic analysis of a previously homogeneous sample, new
signals appeared, which grew in intensity at the expense of
resonances from CPTTOMe (1a). Shifts from 3.85 to
2.63 ppm for the CH3 resonance and from 6.53 to 7.33 ppm
for 5-H pointed to changes within the heterocyclic core and
the thiohydroxamate functional group (Scheme 1, top). The
chemical nature of the rearrangement product, that is, 4-(p-
chlorophenyl)-2-(methylsulfanyl)-1,3-thiazole N-oxide (2),
was, for reasons of inherent difficulties to obtain analyti-
cally pure material from the mixture by chromatographic
separation, clarified by independent synthesis. The crystal-
line residue that deposited from the reaction between
CPTTO–Na+ (3) and CH3I[34] in anhydrous DMF ac-
counted for a yield of 45% of analytically pure N-oxide 2
(Scheme 1, bottom). The supernatant contained a mixture
of alkylation products 1a and 2, which, for reasons given
above, was discarded. As a result of difficulties in earlier
studies to unambiguously verify the presence of the N-oxide
oxygen atom by IR and 13C NMR spectroscopy,[2,3] the
identity of heterocycle 2 was verified by X-ray diffraction
analysis (Figure 4).
Scheme 1. Isomerization of CPTTOMe (1a) by methyl transfer
from oxygen to sulfur (top) and independent synthesis of N-oxide
2 (bottom) [figures in bold refer to diagnostic 13C NMR shifts data,
1
above. If correlated to findings from X-ray analysis, it is numbers in italics to H NMR shifts values (CDCl3, 25 °C)].
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Table 2. Selected experimental (X-ray diffraction) and computed[22]
parameters of N-oxide 2 (cf. Schemes 1 and 2).
Entry
Parameter [Å] or [°]
X-ray crystallography
B3LYP[a]
2
anti-2[b]
1
2
3
4
5
S1–C2
C2–N3
N3–C4
C4–C5
C5–S1
1.710(2)
1.331(3)
1.409(3)
1.348(3)
1.704(2)
1.737
1.342
1.420
1.363
1.738
Figure 4. Ellipsoid graphics (50% probability level) of N-oxide (2)
in the solid state (hydrogen atoms are drawn as circles of an arbi-
trary radius).
6
7
8
9
S1–C2–N3
C2–N3–C4
N3–C4–C5
C4–C5–S1
C5–S1–C2
112.3(2)
113.5(2)
110.6(2)
113.5(2)
90.0(1)
112.4
113.6
111.4
112.7
89.9
Attempts to accelerate the conversion into 2 at elevated
temperatures (80 °C) resulted in unspecific decomposition
of neat CPTTOMe (1a). Photoactivation (350 nm, 25 °C)
of solid 1a provided disulfide 4[11] (13% after 4 d) along
with 2% of substituted bithiazyl 5[11] and CH3OH, without
providing evidence for formation of N-oxide 2 (1H and 13C
NMR; Scheme 2). Bithiazyl 5 is a familiar photodecompo-
sition product of disulfide 4.[11] The methanol balance re-
mained unfortunately erratic, even if the reaction was con-
ducted in a sealed tube. The current data point to the for-
mation of ca. 0.5 equiv. of CH3OH per decomposed mole-
cule of CPTTOMe (1a), which is under further investiga-
tion.
10
11
12
C2–S2
N3–O1
1.722(2)
1.311(2)
1.745
1.295
13
14
15
16
17
18
19
C4–N3–O1
C2–N3–O1
S2–C2–N3
S1–C2–S2
N3–C4–C6
124.5(2)
122.0(2)
118.6(2)
129.0(1)
121.9(2)
33.5(3)
124.7
121.6
117.9
129.7
121.6
32.5
N3–C4–C6–C7
N3–C2–S2–C12
–178.8(2)
–179.5
[a] B3LYP/6-31+G**//B3LYP/6-31+G**. [b] Antiperiplanar ar-
rangement of segment N–C–S–C in 2 (for gauche-2 refer to
Scheme 3; for data and computed structure of gauche-2 see the Sup-
porting Information).
According to theory, rearrangement of CPTTOMe (1a)
into N-oxide 2 was predicted to be endothermic by
2.5 kJmol–1 (Scheme 3). If the methyl transfer occurred
from the higher energy rotamer having the N-methoxy and
the p-chlorophenyl group located in proximal position, the
rearrangement became weakly exothermic (∆RH
=
–5.8 kJmol–1, Scheme 3). Calculated energy differences be-
tween isomers 1a and 2, and those for the respective isomer-
ization of N-methoxy-4-methyl-1,3-thiazole-2(3H)-thione
into 2-methylsulfanyl-4-methyl-1,3-thiazole N-oxide (∆RH
Scheme 2. Products formed from photochemical decomposition of
neat CPTTOMe (1a).
Endocyclic bond lengths in the crystal structure of N- = –0.3 kJmol–1, Supporting Information) were small and
oxide 2 (Table 2, Entries 1–10) were similar to those of sub- pointed to a marked stability of the cross-conjugated π-elec-
stituted thiazoles.[35–38] Values of ca. 112° for bond angles tron system in thiazolethiones.[3] It is worth mentioning that
at C2 and N3 differed from respective parameters in thi- the N-(methoxy)pyridine-2(1H)-thione to 2-methylsulfanyl-
azolethiones (Table 2, Entries 6 and 7). A close contact be- pyridine N-oxide rearrangement according to theory was
tween N-oxide and methylsulfanyl entities [O1···S2 predicted to be notably exothermic (∆RH = –30.5 kJmol–1,
2.880(3) Å], and the magnitude of bond angles at C2 (S1– Supporting Information). This result was in accord with the
C2–S2 Ͼ S2–C2–N3) and N3 (O1–N3–C4 Ͼ C2–N3–O1) observation that alkyl shifts in pyridine-derived cyclic O-
pointed to nOǞσ*C,S attraction, similar to interactions ob- alkyl thiohydroxamates are fairly common reactions. Isom-
served in 2-alkylsulfanylpyridine N-oxides.[19,39]
erizations of this kind generally occur quantitatively to fur-
The computed (B3LYP/6-31+G**) global minimum of nish 2-alkylpyridine N-oxides from neat N-(alkoxy)pyr-
N-oxide 2 showed a gauche arrangement of the N3–C2–S2– idine-2(1H)-thiones within ca. 14 h at ca. 5 °C, in particular
C12 segment (58.5°; i.e., gauche-2). This conformation was for N-benzyloxy derivatives having at least one electron-re-
favored by ∆G298 = 6.3 kJmol–1 (gas phase) to an anti- leasing group attached to the aromatic substituent.[16,41,42]
periplanar positioning of the N3–C2–S2–C12 entity (anti- Because data for distinguishing kinetic order of reactants in
2). The latter arrangement was found in the crystal struc- O-alkyl thiohydroxamate to S-alkylthiohydroximate re-
ture of 2. Important structural aspects, for instance the arrangements were not available from the literature, it was
O1···S2 distance (2.872 Å) that fell short of the sum of asso- refrained from extending the computational analysis be-
ciated van der Waals radii (3.32 Å)[40] and bond angles de- yond this point.[43,44]
scribing the N-oxide bent toward the methylsulfanyl group
in anti-2, were precisely reproduced by theory (Table 2, En- CPTTOMe (1a) selectively isomerized through methyl
tries 13–16). transfer from thiohydroxamate O to thione S. The reaction
In summary, the second lesson demonstrated that solid
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3-Alkoxy-4-(p-chlorophenyl)-1,3-thiazole-2(3H)-thione Chemistry
phase) probably shows strong media effects similar to those
reported for the 2-mercaptopyridine/pyridine-2(1H)-thione
equilibrium.[46]
Scheme 3. Energetics associated with (i) conformational changes in
thiazole derivatives 1a and 2, and (ii) isomerization 1aǞ2 [B3LYP/
6-31+G**; figures in italics refer to reaction enthalpies (in kJmol–1,
zero-point vibrational energy corrected, 0 K), numbers in bold de-
scribe computed free-energy changes (kJmol–1, 298.15 K)].
Scheme 5. Thermochemistry of (i) CPTTOMe fragmentation and
(ii) thiolactim/thiolactam equilibrium [B3LYP/6-31+G**; figures in
italics refer to reaction enthalpies (kJmol–1, zero-point vibrational
energy corrected, 0 K), numbers in bold describe computed free-
energy changes (kJmol–1, 298.15 K); the syn/anti notation refers to
was slow and according to theory weakly endothermic. The
reverse reaction 2 Ǟ 1a and further examples of alkyl mi- arrangement of segment N–C–S–H].
gration, for example, of primary or secondary substituents,
have so far not been observed. Although the mechanism of
the rearrangement remains unknown, the fact that the small
methyl group in 1a and not the secondary benzyl group
in 1c migrated seemed to favor nucleophilic to homolytic
substitution (cf. Lesson 4).
Thiazole-2(3H)-thiones form H-atom bridged thiolactam
dimers in the solid state.[51] In solution (CDCl3), the 5-H
resonance from the heterocyclic core of 3 (δ =7.18 ppm)
differed to some extent from chemical shifts reported for
this site in alkylsulfanylthiazole cis-9 (δ =7.32 ppm, vide in-
fra) and derivatives thereof (7.44–7.55 ppm).[36–38]
To summarize, the third lesson taught that thiazolethione
1c underwent fragmentation through formal 1,5-H-atom
shift. It remained unclear whether the reaction proceeded
via radical or polar intermediates. Alternative CPTTOR de-
composition products were not observed. Apart from 1c,
none of the structurally related CPTTOR explored in our
studies, that is, neat samples of 4-(p-chlorophenyl)-N-(1-
phenyl-1-ethoxy)- and 4-(p-chlorophenyl)-N-(1-phenylpent-
4-en-1-oxy)-1,3-thiazole-2(3H)-thione (not shown) exhib-
ited similar reactivity. The latter two compounds were
stable, if stored as neat samples for 5 years at ca. 5 °C.[47]
Lesson 3: Fragmentation
Thiazolethione 1c served as a key reagent for developing
a free radical version of bromo- and iodocyclization.[5,45]
While working with the compound, its propensity to un-
dergo fragmentation was noted (Scheme 4). A neat sample
that, for instance, was stored for 5 months at –18 °C pro-
vided 37% each of thiazolethione 6 and 7. The residual ma-
terial accounted for thione 1c. Products of O-alkylthio-
hydroxamate to S-alkylthiohydroximate rearrangement,
that is, the reaction N-(5-methyl-1-phenylhex-4-ene-1-oxy)-
pyridine-2(1H)-thione would quantitatively undergo,[16,39]
were not observed.
Lesson 4: Rearrangement
Thiazolethione 1d played a major role in the develop-
ment of a model for predicting stereoselectivity in alkenoxyl
radical 5-exo-trig cyclizations.[8] In routine analysis, signifi-
cant amounts of thiazole cis-9 (Scheme 6, Figure 5) were
identified in a sample of previously homogeneous thione
1d, which was kept for ca. 2 years at 8 °C in the dark.
Scheme 4. Fragmentation of thiazolethione 1c.
Theory stated that fragmentation of CPTTOMe (1a) into
formaldehyde and thiazolethione 6 poses a strongly exo-
thermic reaction (Scheme 5). For thermochemical reasons,
thiazolethiol 8 is expected to be formed in the initial step,
with rotamer anti-8 being slightly higher in energy than syn-
8 (Scheme 5). The latter compound is predicted to be
16.8 kJmol–1 higher in free energy than its thione tautomer
298
6. The associated equilibrium constant (K4
= 286, gas Scheme 6. Rearrangement of thiazolethione 1d.
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J. Hartung et al.
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followed by radical cyclization and combination in the solid
state, with the low temperature and possibly the crystal lat-
tice contributing to improved diastereoselectivity.
In summary, the fourth lesson of structural CPTTOR
chemistry exemplified that thiazolethione 1d rearranged in
the solid state, without being photoactivated or subjected
to higher temperatures (ca. 80 °C).
Figure 5. Ellipsoid graphics (50% probability level) of thiazole cis-9
in the solid state (one enantiomer from the racemate was arbitrarily
selected for presentation; hydrogen atoms are depicted as circles of
an arbitrary radius).
Concluding Remarks
CPTTORs originally were designed to solve the long-
standing problem of alkoxyl radical generation under mild
conditions from sources that are easy to prepare and han-
dle. A decade of experience with this product class shows
that the major aims in this sense have been fulfilled. Longer
term projects now have uncovered that at least three modes
of CPTTOR decomposition exist, which are distinctively
different from homolytic substitutions in radical chain reac-
tions.
Two out of three pathways reflected the inherent weak-
ness of the N,O bond, which, after all, is the conditio sine
qua non for the product class to serve as selective oxyl radi-
cal precursor. The third mode of decomposition furnished
4-(p-chlorophenyl)-2-methylsulfanyl-1,3-thiazole N-oxide
through methyl translocation from oxygen to sulfur. None
Heterocycle cis-9 crystallized in the centrosymmetric
space group P21/c, thus pointing to formation of its race-
mate. Bond lengths and angles of the heterocyclic core were
within the experimental error similar to parameters deter-
mined for 1,3-thiazole through microwave spectroscopy.[35]
Shortening of the N3–C2 distance, a more acute endocyclic
angle at N3, and a widening of S1–C2–N3 distinguished
the 1,3-thiazole entity in cis-9 from the thiazolethione nu-
cleus[48–51] (Tables 1, 2, and 3, Entries 2, 6, 7).[2,14] The alk-
ylsulfanyl side chain showed antiperiplanar arrangement
with respect to the N3–C2–S2–C12 unit [180.0(4)°].
Table 3. Selected experimental (X-ray diffraction) and computed[22] of the reactions, however, provides a potent inhibitor for
parameters of thiazole cis-9 and 2-thiazolethiol anti-8 (cf. Figure 5,
radical chain reactions.
Schemes 4 and 5).
The newly discovered pathways occurred in neat solid
Entry
Parameter [Å] or [°] X-ray crystallography
cis-9
B3LYP[a]
anti-8
CPTTOR samples selectively, within detection limits
(NMR) even specifically. The examples so far are limited
by number. From the available data it seems that structural
prerequisites exist for the reactions to become relevant and
to occur in a specific manner. In solution, if not applied
for the purpose they were designed for, the compounds and
structurally related 3-alkoxy derivatives thereof, decompose
at more or less the same rate, leading to a diversity of thi-
azole derivatives, carbonyl compounds, and alkoxyl radical
derived products.[7] This observation suggests that the key
for the observed specificity resides in CPTTOR crystal lat-
tices. A systematic pursuit of solid state chemistry, however,
requires knowledge about crystal structures of those
CPTTORs that underwent the reactions outlined above. Al-
though this information was not available by the time the
study was performed, it has the potential to open a new
chapter of CPTTOR chemistry.
1
2
3
4
5
S1–C2
C2–N3
N3–C4
C4–C5
C5–S1
1.731(4)
1.307(4)
1.398(4)
1.344(5)
1.722(4)
1.762
1.296
1.387
1.373
1.735
6
7
8
9
S1–C2–N3
C2–N3–C4
N3–C4–C5
C4–C5–S1
C5–S1–C2
115.2(3)
109.7(3)
115.6(3)
110.6(3)
88.9(2)
114.6
111.9
114.4
110.8
88.4
10
11
15
16
17
18
19
C2–S2
S2–C2–N3
S1–C2–S2
N3–C4–C6
1.733(4)
120.4(3)
124.4(2)
118.4(3)
159.2(3)
178.7(3)
1.769
121.1
124.3
118.9
9.0
N3–C4–C6–C7
N3–C2–S2–R[b]
176.9
[a] B3LYP/6-31+G**//B3LYP/6-31+G**. [b] R = C12 in cis-9 and
H in anti-8.
Experimental Section
The observed selectivity for the solid state reaction 1d Ǟ
cis-9 is similar but not identical to the 2-tert-butylpent-4-
en-1-oxyl radical ring closure in solution, which occurs with
90:10 cis/trans diastereoselectivity (25 °C).[8] Extension of
this interpretation to the formation of cis-9 would require
N,O-homolysis to occur in the initial step. The computed
dissociation energy for the N,O bond in N-methoxy-4-
methylthiazole-2(3H)-thione is ca. 160 kJmol–1,[52] which
underlines the inherent weakness of this connectivity in O-
General Remarks: For spectroscopic equipment, preparation of N-
alkoxythiazolethiones 1a–d, general laboratory practice, and instru-
mentation see ref.[8] and the Supporting Information.
4-(4-Chlorophenyl)-3-[(5-methyl-2-phenylhex-4-enyl)oxy]-1,3-thiaz-
ole-2(3H)-thione (1b):[5] Crystals suitable for X-ray diffraction were
grown by slowly allowing petroleum ether to diffuse into a satu-
rated solution of 1b in CH2Cl2. C22H22ClNOS2 (415.98), T =
301(2) K, λ = 0.71093 Å, monoclinic, P21/c, a = 18.993(8) Å, b =
alkyl thiohydroxamates. Homolysis of this entity may be 6.313(2) Å, c = 18.241(7) Å, β = 95.52(5)°, Z = 4, µ = 0.379 mm–1,
4140
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4135–4142

3-Alkoxy-4-(p-chlorophenyl)-1,3-thiazole-2(3H)-thione Chemistry
completeness to 2θ = 99.6%, goodness-of-fit on F2 = 0.862, final
R indices [IϾ2σ(I)]: R1 = 0.0714, wR2 = 0.1571.
0.428 mm–1, completeness to 2θ = 99.7%, goodness-of-fit on F2 =
0.991, final R indices [I Ͼ 2σ(I)]: R1 = 0.0540, wR2 = 0.1439.
Photochemical Decomposition of 4-(4-Chlorophenyl)-3-methoxy-1,3-
thiazole-2(3H)-thione (1a): Thiazolethione 1a (100 mg, 0.39 mmol)
was irradiated in a closed reaction vessel using a Rayonet photore-
actor (350 nm, 25 °C) for 4 d. CDCl3 was added through the stop-
cock, and the resulting solution was analyzed by NMR spec-
troscopy for qualitative and quantitative product analysis. The sol-
vent was afterwards removed under reduced pressure, and the resi-
due was purified by column chromatography (SiO2; petroleum
ether/CH2Cl2, 1:1; Rf = 0.31) to afford a colorless solid that con-
sisted of as 93:7 mixture of compounds 4 and 5. Analysis for 4/5
(93:7): calcd. C 48.16, H 2.25, N 6.24; found C 47.51, H 2.24, N
6.16. Data for 2,2Ј-bis[4-(p-chlorophenyl)thiazyl]disulfide (4):
4-(4-Chlorophenyl)-2-(methylsulfanyl)-1,3-thiazole-N-Oxide (2): A
solution of 4-(p-chlorophenyl)-N-hydroxy-1,3-thiazole-2(3H)-
thione (1.22 g, 5.00 mmol) in MeOH (25 mL) was treated with
NaOH (200 mg, 5.00 mmol) and stirred for 1 h at 25 °C in the dark.
The solvent was removed under reduced pressure (200Ǟ20 mbar,
40 °C). The residue was freeze dried to furnish 4-(4-chlorophenyl)-
3-hydroxy-1,3-thiazole-2(3H)-thione sodium salt 3 as a tan powder.
The sodium salt was dissolved in anhydrous DMF (25 mL) and
treated with CH3I (710 mg, 5.00 mmol). The reaction mixture was
stirred for 4 d in the dark. The crop of colorless crystals that de-
posited from the solution was collected by filtration, washed
(Et2O), and dried (580 mg, 45%). M.p. 188–190 °C. Rf = 0.02
(SiO2; pentane/Et2O, 1:1). UV/Vis (MeOH): λ (logε) = 255 (3.41)
1
Yield: 13%. H NMR (600 MHz, CDCl3): δ = 7.38 (m, 4 H, Ar-
H), 7.50 (s, 2 H, 5-H), 7.80 (m, 4 H, Ar-H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 116.0 (5-C), 127.5 (Ar-C), 128.9 (Ar-C),
132.0 (Ar-C), 134.3 (Ar-C), 155.9 (4-C), 165.0 (2-C) ppm. Data for
2,2Ј-bis[4-(p-chlorophenyl)thiazyl] (5): Yield: 2%. 1H NMR
(600 MHz, CDCl3): δ = 7.34 (m, 4 H, Ar-H), 7.44 (s, 2 H, 5-H),
7.72 (m, 4 H, Ar-H) ppm.
nm. IR (KBr): ν = 3128 (m), 1482 (m), 1429 (w), 1388 (s), 1327
˜
1
(w), 1287 (s), 1231 (s), 1092 (s), 1022 (m), 977 (m) cm–1. H NMR
(400 MHz, CDCl3): δ = 2.63 (s, 3 H, SCH3), 7.33 (s, 1 H, 5-H),
7.41 (d, J = 11.2 Hz, 2 H, Ar-H), 7.91 (d, J = 11.2 Hz, 2 H, Ar-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 15.4 (SCH3), 112.4 (5-C),
127.5, 129.1, 129.2, 129.8, 136.3 (Ar-C), 146.3 (2-C) ppm. MS
(70 eV, EI): m/z (%) = 257/259 (37/16), 240/242 (100/45), 168/170
(20/8), 159 (7), 136 /138 (21/9), 117 (85), 103 (20). C10H8ClNOS2
(257.75): calcd. C 46.70, H 3.14, N 5.45, S 24.88; found C 46.52,
H 3.28, N 5.47, S 24.96. Crystals suitable for X-ray diffraction were
grown from a saturated solution in MeOH. T = 294(2) K, λ =
0.71073 Å, monoclinic, P21/n, a = 7.247(1) Å, b = 6.317(1) Å, c =
24.003(5) Å, β = 93.10(3)°, Z = 4, µ = 0.698 mm–1, completeness
to 2θ = 94.9%, goodness-of-fit on F2 = 1.093, final R indices
[IϾ2σ(I)]: R1 = 0.0278, wR2 = 0.0710.
CCDC-699514 (for 1a), -699515 (for cis-9), and -699516 (for 2)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic
data_request/cif.
Data
Centre
via
www.ccdc.cam.ac.uk/
Supporting Information (see footnote on the first page of this arti-
cle): Instrumentation, calculated energies (BHandHLYP/6-
31+G**), Gaussian archives and atomic coordinates of computed
structures (B3LYP, BHandHLYP, MP2); computational data on N-
methoxy-4-methyl-1,3-thiazole-2(3H)-thione to 2-methylsulfanyl-4-
methylthiazole N-oxide and N-methoxypyridine-2(1H)-thione to 2-
methylsulfanylpyridine N-oxide rearrangements.
4-(4-Chlorophenyl)-1,3-thiazole-2(3H)-thione (6): A sample of ana-
lytically pure 1c was stored for ca. 5 months in a refrigerator (8 °C)
to furnish a mixture of 37% 6, an equivalent amount of 7 and 73%
of 1c (1H NMR). The mixture was purified by chromatography
(SiO2; petroleum ether/Et2O, 2:1; Rf = 0.25) to furnish thione 6 as
pale-yellow prisms. M.p. 207–210 °C. 1H NMR (250 MHz, [D6]-
acetone): δ = 7.18 (s, 1 H, 5-H), 7.53 (m, 2 H, Ar-H), 7.83 (m, 2
H, Ar-H) ppm. MS (70 eV, EI): m/z (%) = 227 (100) [M+], 168
(50), 133 (49), 89 (35). HRMS: calcd. 226.9628; found 226.9629.
C9H6ClNS2 (227.73): calcd. C 47.58, H 2.66, N 6.17, S 28.17; found
C 47.69, H 2.81, N 6.36, S 28.48.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 690: Elektronendichte – Theorie und Experi-
ment).
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Received: January 22, 2009
Published Online: July 9, 2009
4142
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4135–4142