Spin trapping of alkoxyl radicals generated from 5-methyl and 5-aryl-3-alkoxy-4-methylthiazole-2(3H)-thiones in photochemically induced and microwave-initiated reactions

Article abstract of DOI:10.1016/j.tet.2008.09.006

Methoxyl and isopropoxyl radicals were generated from N-alkoxy-4,5-dimethylthiazole-2(3H)-thiones (λ_max～320 nm) and 5-aryl derivatives (aryl=p-XC₆H₄; X=MeO, H, AcNH, Cl) (λ_max～335 nm) in photochemically and microwave-induced reactions. Alkoxyl radicals were trapped with dimethylpyrrolidine N-oxide and characterized as spin adducts via EPR. Cumyloxyl radicals were liberated in a similar manner from N-cumyloxy-5-(4-methoxyphenyl)-4-methylthiazole-2(3H)-thione. A noteworthy bathochromic shift was found for the lowest energy transition of N-(hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (λ_max=376 nm), if compared to the UV-vis absorption of N-hydroxy-4-methyl-5-phenylthiazole-2(3H)-thione (λ_max=338 nm). Syntheses of alkoxyl radical precursors and procedures for conducting N,O-homolysis are described in a full account.

Full text of DOI:10.1016/j.tet.2008.09.006

Tetrahedron 64 (2008) 10882–10889
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Spin trapping of alkoxyl radicals generated from 5-methyl and
5-aryl-3-alkoxy-4-methylthiazole-2(3H)-thiones in photochemically
induced and microwave-initiated reactions
*
Andreas Groß, Nina Schneiders, Kristina Daniel, Thomas Gottwald, Jens Hartung
Fachbereich Chemie, Organische Chemie, Technische Universita¨t Kaiserslautern, Erwin-Schro¨dinger-Straße, D-67663 Kaiserslautern, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2008
Received in revised form 2 September 2008
Accepted 3 September 2008
Available online 17 September 2008
Methoxyl and isopropoxyl radicals were generated from N-alkoxy-4,5-dimethylthiazole-2(3H)-thiones
(
lmaxw320 nm) and 5-aryl derivatives (aryl¼p-XC6H4; X¼MeO, H, AcNH, Cl) (lmaxw335 nm) in photo-
chemically and microwave-induced reactions. Alkoxyl radicals were trapped with dimethylpyrrolidine
N-oxide and characterized as spin adducts via EPR. Cumyloxyl radicals were liberated in a similar manner
from N-cumyloxy-5-(4-methoxyphenyl)-4-methylthiazole-2(3H)-thione. A noteworthy bathochromic
shift was found for the lowest energy transition of N-(hydroxy)indeno[2,1-d]thiazole-2(3H)-thione
Keywords:
EPR spectroscopy
Photochemistry
Heterocycle Synthesis
Microwave activation
Dimethylpyrrolidine N-oxide
(
lmax¼376 nm), if compared to the UV–vis absorption of N-hydroxy-4-methyl-5-phenylthiazole-2(3H)-
thione (lmax¼338 nm). Syntheses of alkoxyl radical precursors and procedures for conducting N,O-ho-
molysis are described in a full account.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
methylthiazole-2(3H)-thione (3). The bathochromic shift exerted
by the aromatic substituent onto electronic transitions in hetero-
The advent of O-alkyl thiohydroxamates as sources of oxygen-
centered radicals has significantly contributed to current
developments in synthetic heteroatom radical chemistry.1–3 Alkoxyl
radical generation from this type of precursor is feasible upon visible
light or near UV-excitation, microwave irradiation, or conductive
heating in the presence of an initiator.4,5 The ease of activation thereby
gradually decreases along the series of compounds N-(alkoxy)-
pyridine-2(1H)-thiones>N-(alkoxy)thiazole-2(3H)-thiones (e.g.,
1–3)>acyclic O-(alkyl)thiohydroxamates.6–9 Alkoxyl radicals that
are liberated under such conditions participate in efficient
tin-free chain reactions and have opened new perspectives
for C,H-activation,10,11 stereoselective tetrahydrofuran,12,13 and
tetrahydropyran synthesis,14 and norbornene functionalization.15
cycle 3 (lmaxw334 nm) raised the question about a control of
UV–vis-excitation energies in thiazole-derived cyclic thiohy-
droxamates in general.7 In the course of a time-dependent density
functional theoretical study on photophysical events leading to
N,O-homolysis, a larger set of thiazolethiones was therefore in-
vestigated on a computational level. A considerable number of
molecules of interest, however, were not included into the
original paper, since experimental data for referencing calcu-
lated electronic transitions were for reasons of synthetic
difficulties not available at that time. Other compounds were
included, although their potential to liberate alkoxyl radicals
upon photoexcitation had not been verified. Progress in micro-
wave-assisted synthesis of arylpropanones recently opened
new perspectives for preparing 5-aryl-3-hydroxy-4-methyl-
thiazolethiones having a moderately electron releasing group
(e.g., NHAc in 4) and an electron withdrawing substituent (e.g.,
Cl in 5) located in the aromatic subunit (Fig. 1), in order to
complete the series of compounds required for UV–vis spectra
correlation. A second input from theory related to a predicted
bathochromic shift in case of coplanar arrangement of aryl and
thiazole-2(3H)-thione entities.7 Since this arrangement poses
a transition structure associated with phenyl group rotation
about the C,C-bond connecting both fragments in 2, a synthesis
of 3-(hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (6) was de-
vised for testing theory.
N-Alkoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones
(lmaxw
320 nm, not shown) were for many years the reagents of choice in
this laboratory for pursuing mechanistic and synthetic aspects of
oxyl radical chemsitry.3,16 Steric encroachment imposed by the 4-
(p-chlorophenyl) substituent was found over the years, to hinder
formation of tertiary alkoxyl radical precursors, which led to the
development of compounds having an aryl group located
in position 5, such as in 3-hydroxy-5-(p-methoxyphenyl)-4-
* 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.006

A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
10883
Table 1
R
4
5
1
Formation of N-(hydroxy)thiazole-2(3H)-thiones from
a
-chloroketones
S
S
S
R
d
S
3
5
N
O
N
S
a
R
Cl
O
i–iii
O
H
H
S
N
O
1–5
6
H
7–11
1–5
R
1–5
1
Entry
R
7–11
1–5 [%]
lmax/nm (lg 3 )
/m2 molꢁ1
CH3
1
2
3
4
5
CH3
C6H5
p-(H3CO)C6H4
p-(AcNH)C6H4
p-ClC6H4
7
8
9
10
11
1: 74
2: 45
3: 66
4: 59
5: 21
316 (3.14)b
338 (3.12)b
334 (3.20)b
336 (3.14)c
333 (3.21)c
2
3
4
C6H5
p-(H3CO)C6H4
p-(AcNH)C6H4
p-ClC6H4
5
aReagents and conditions: (i) potassium O-ethyl xanthogenate, acetone, 25 ꢀC, 2 h;
(ii) NH2OH$HCl, pyridine, CH3OH, 0/25 ꢀC, 16 h; (iii) KOH, H2O, CH2Cl2, 0/25 ꢀC,
Figure 1. Structural formulae and indexing of cyclic thiohydroxamic acids.
2 h.
b
in MeOH.
in EtOH.
The major findings of the present study showed that the
location of the lowest energy UV–vis band of N-hydroxy and
N-alkoxy-4-arylthiazole-2(3H)-thiones, relevant for inducing N,O-
homolysis, was only marginally dependent on the nature of the
p-substituent. 3-(Hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (6),
on the other hand, exhibited a significant bathochromic shift
(w38 nm), if compared to derivative 2. The compound, however,
also showed a number of peculiarities, which require future
investigation. N-Methoxy and isopropoxy derivatives that were
prepared from thiohydroxamic acids 1–5 furnished alkoxyl radicals
upon near UV or microwave excitation. In extension to this meth-
odology, cumyloxyl radicals were generated and trapped. The
efficiency of O-radical generation was in all instances equivalent, as
judged on the basis of EPR spectra of spin adducts. Major results of
the study are summarized and discussed in the following sections.
c
analysis. Thione 6 decomposed rapidly on standing as neat sample
at 20 ꢀC or in CDCl3 solution (1H NMR). Attempts to grow crystals
suitable for X-ray diffraction consistently provided 2-oxo-1-
indanonoxime.24
Cl
137.8
S
a
S
i–iii
11 %
O
189.3
N
146.8
O
H
28.3
12
6b
Scheme 1. Preparation of 3-(hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (6) from
1-chloro-2-indanone (12). Figures in italics refer to selected 13C NMR shift values
(CDCl3). (a) Reagents and conditions: (i) potassium O-ethyl xanthogenate, acetone,
25 ꢀC, 2 h (67%); (ii) NH2OH$HCl, pyridine, CH3OH, 0/25 ꢀC, 16 h (94%); (iii) KOH, H2O,
2. Results
CH2Cl2, 0/25 ꢀC, 2 h (25%). (b) lmax/nm (lg
3)¼376 (2.45),
3 .
in m2 molꢁ1
2.1. Synthesis of N-(alkoxy)thiazole-2(3H)-thiones
Deprotonation of thiohydroxamic acids 1–6 with tetrabutyl-
ammonium hydroxide furnished thiohydroxamate tetrabutyl-
ammonium salts as tan powders (not shown). Alkylation of the
latter with methyl or isopropyl p-toluenesulfonate in anhydrous
DMF at 25 ꢀC occurred selectively at oxygen to furnish O-esters
13a–17a (R1¼CH3; Table 2, entries 1–5) and 13b–17b
[R1¼CH(CH3)2; Table 2, entries 6–10] as colorless to tan solids in
45–82% yield. Since the reaction between N-(hydroxy)indeno[2,
5-Substituted N-(hydroxy)-4-methylthiazole-2(3H)-thiones 1–5
were prepared in extension to a procedure originally developed for
4-(p-chlorophenyl)thiazole-2(3H)-thione.17 The sequence started
from 3-substituted propanones (not shown). 2-(4-Chlorophenyl)-
and 2-(4-acetylaminophenyl)propan-2-one were prepared from
p-chloro- and p-nitrobenzaldehyde in microwave-assisted nitro-
aldol condensations or standard procedures thereof.18,19 Likewise
obtained b-nitrostyrenes (not shown) were converted with Fe/HCl
[formation of 1-(4-chlorophenyl)propan-2-one] or Fe/FeCl2$4H2O/
Ac2O/HOAc [synthesis of 1-(4-acetamidophenyl)propan-2-one] into
derived 1-aryl propanones.20,21 Treatment of the latter with SO2Cl2
1.2
2
6
1.0
at 0 ꢀC furnished
a
-chloroketones 7–11 in 65–90% yield.22
18b
Substitution of O-ethyldithiocarbonate for chloride provided a-keto
xanthogenates (Table 1, step i), which were treated with hydroxyl-
amine hydrochloride in the presence of pyridine (Table 1, step ii).
Vicinal oximino xanthogenates that were formed in the latter re-
action underwent efficient 5-exo-cyclizations in the presence of
KOH in H2O/CH2Cl2 (Table 1, step iii). 5-Substituted N-(hydroxy)-4-
methylthiazole-2(3H)-thiones 1–5 were obtained as colorless (1) or
tan (2–5) crystalline solids that decomposed (differential thermo-
analysis) either prior (e.g., 3: 158 ꢀC) or after melting (e.g., 1: mp
88 ꢀC, dec 131 ꢀC).
3-(Hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (6) was pre-
pared from 1-chloro-2-indanone (12)23 in 11% overall yield,
according to a similar sequence described for thiones 1–5 above
(Scheme 1, Table 1). The compound crystallized from petroleum
ether/Et2O as tan solid that decomposed on melting at 148 ꢀC. It
was identified via NMR (1H, 13C, HMBC, HMQC), UV–vis spectros-
0.8
0.6
0.4
0.2
0.0
250
300
350
Wavelength / nm
400
450
500
550
Figure 2. Superposition of normalized electronic spectra of N-hydroxy-4-methyl-5-
phenylthiazolethione 2, indene derivative 6 and 3-(isopropoxy)indeno[2,1-d]thiazole-
2(3H)-thione (18b) (MeOH, 20 ꢀC).
copy (l¼376 and 267 nm, in MeOH, Fig. 2), and combustion

10884
A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
Table 2
O-Alkylation of cyclic thiohydroxamic acids 1–6
R
S
S
S
conditions
S
or
1–6
N
O
N
O–R1
R1
13–17
18
Entry
1–6a
R1
Conditionsb
13–18/%
lmax/nm (lg 3 )
/m2 molꢁ1
1
2
3
4
5
6
7
8
1
2
3
4
5
1
2
3
4
5
6
3
CH3
CH3
CH3
CH3
iv, v
iv, v
iv, v
iv, v
iv, v
iv, vi
iv, vi
iv, vi
iv, vi
iv, vi
iv, vii
viii
13a: 68
14a: 45
15a: 64
16a: 64
17a: 59
13b: 82
14b: 62
15b: 73
16b: 53
17b: 71
18b: 9
321 (3.16)c
333 (3.28)c
333 (3.30)c
336 (3.22)d
335 (3.28)d
322 (3.14)c
334 (3.27)c
335 (3.29)c
337 (3.21)d
337 (3.21)d
279 (3.25)c
337 (3.26)c
CH3
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
C(CH3)2C6H5
9
10
11
12
Figure 3. EPR spectrum of 2-isopropoxy-substituted nitroxyl radical 19b recorded
from a photolyzed solution of thione 15b and DMPO in C6H6 at 20 ꢀC.
15c: 15
a
For indexing of compounds 1–5 see Table 1.
b
i
iv: NBu4OH, CH3OH, 25 ꢀC; v: TsOCH3, DMF, 25 ꢀC; vi: PrOTs, DMF, 25 ꢀC; vii:
to coupling constants of aN¼12.7 G, abH¼8.8 G, and aHg ¼1.4 G, which
were distinctively different from values recorded for 19b in ex-
periments starting from thiones 13b–17b.
iPrCl, DMF 25 ꢀC; viii: 2-phenyl-2-propanol, DIC, CuCl, CH2Cl2.
c
in MeOH.
in EtOH.
d
3. Discussion
i
1-d]thiazole-2(3H)-thione tetrabutylammonium salt and PrOTs in
DMF consistently provided a mixture of N-isopropoxy compound
18d and unspent tosylate that was not separable in our hands, 2-
chloropropane was used as alternative alkylating reagent (Table 2,
entry 11). This modification allowed to obtain pure thione 18b as
3.1. Preparation and properties of N-(alkoxy)thiazole-
2(3H)-thiones
The established synthesis of N-(hydroxy)thiazole-2(3H)-thio-
nes17,31,32 was modified in the present study, starting from
brown oil. Its electronic spectrum (l>200 nm) showed a broad and
a
-chloroketones instead of
less severe lachrymators and provided higher yields of purer
-haloketones 7–12. Sufficiently pure material for -chlorination
a-bromoketones. The former were
featureless band at
l
¼279 nm with a tail end reaching to w420 nm
(Fig. 2). N-(Cumyloxy)thiazolethione 15c was isolated as a tan
crystalline solid in gram quantities starting from N-(hydroxy)-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (3), 2-phenyl-2-
propanol, diisopropyl carbodiimide and CuCl in a solution of
anhydrous CH2Cl2 (Table 1, entry 12).25–27
a
a
of 1-(4-chlorophenyl)propan-2-one was obtained via the nitro-
olefin pathway (see Section 5). Alternative approaches using
arene-substitution (starting from chlorobenzene)33 or organo-
metallic reactions (starting from p-chlorophenylacetic acid)34–36
were not successful in our hands. The unexpectedly low yield in
the final step of N-(hydroxy)indenothiazolethione synthesis was
attributed to an inherent lability of compound 6 toward base. If
treated, for instance, with NEt4OH in a solution of CH3OH, as
2.2. Photochemically induced and microwave-initiated
transformations
Solutions of N-(alkoxy)thiazolethiones 13–17 (co¼10ꢁ2 M) and
2-dimethylpyrrolidine-N-oxide (DMPO; co¼1.8ꢂ10ꢁ2 M) in C6H6
were subjected to microwave irradiation (1 min, 300 W, mono-
mode apparatus)y in sealed tubes at 120 ꢀC. EPR spectra recorded
from solutions prepared from decomposition of N-(methoxy)
thiazolethiones 13a–17a and N-isopropoxy derivatives 13b–17b
provided signals at g¼2.0081–2.0082 G (e.g., Fig. 3). Spectra
simulation28,29 and numerical analysis of fitted curves allowed to
determine coupling constants aN, abH, and aHg (Table 3, entries 1–10),
which were diagnostic for spin adducts 19a and 19b (Table 3,
Fig. 3).30 Microwave heating of N-(cumyloxy)thiazolethione 15c
under similar conditions furnished a signal at g¼2.0080 G showing
larger abH and a smaller aHg value while aN was approximately con-
stant, thus pointing to cumyloxyl radical trapping by DMPO.
Spectra similar to those from microwave experiments were
Table 3
Spin adduct formation from thiones 13–17 and DMPO
R
DMPO
conditions
S
H
S
N
O
OR1
C6H6
N
O
R1
13–17
19
Entry 13–18 Conditionsa 19
g
aN/G
abH/G
agH/G
b
1
2
3
4
5
6
7
8
13a
14a
15a
16a
17a
13b
14b
15b
16b
17b
15c
MW
MW
MW
MW
19a 2.0081
19a 2.0082
19a 2.0081
19a 2.0081
19a 2.0082
19b 2.0081/2.0081 13.0/13.0 6.4/6.5 1.8/1.7
19b 2.0082/2.0082 13.0/13.0 6.5/6.5 1.7/1.7
19b 2.0080/2.0080 12.9/13.0 6.3/6.5 1.9/1.7
19b 2.0081/2.0080 13.0/13.1 6.5/6.5 1.7/1.7
19b 2.0081/2.0080 12.9/13.0 6.5/6.5 1.7/1.7
12.8
12.8
12.8
12.8
12.7
6.5
6.7
6.5
6.5
6.3
1.7
1.7
1.7
1.6
1.6
recorded from solutions prepared by irradiating
(l¼350 nm)
MW
N-(isopropoxy)thiazolethiones 13b–17b for 1 min in C6H6 at 25 ꢀC
in the presence of DMPO (Table 3, entries 6–10). Photolysis of
N-(isopropoxy)indenothiazolethione 18b under such conditions
consistently furnished an EPR signal at g¼2.0082. Data analysis led
MW/h
MW/h
MW/h
MW/h
MW/h
MW
n
n
n
n
n
9
10
11
19c
2.0080
13.1
9.3
1.5
a
MW: 300 W, 120 ꢀC, h
indexing for spin adducts 19:
n
(
l
¼350 nm), 25 ꢀC.
y
b
The use of specialized microwave equipment for conducting micro-
a
for R1¼CH3,
b
for R1¼CH(CH3)2,
c
for
wave-assisted transformations is strongly advised.
R1¼C(C6H5)(CH3)2.

A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
10885
required for the synthesis of isopropyl ester 18b, acid 6 not only
4. Conclusion
got deprotonated but also underwent secondary transformations,
which have so far not been fully explored.24
5-Methyl- (lmax¼318 nm) and 5-aryl (aryl¼p-XC6H4; X¼MeO, H,
AcNH, Cl) w331–336 nm) substituted N-hydroxy-4-methyl-
13C NMR resonances of the thiocarbonyl group in N-hydroxy
compounds 1–6 (CDCl3) showed a gradual shift along the sequence
168.5 (1, R¼CH3) <169.3 (2, R¼C6H5) <170.2 (5, R¼p-ClC6H4CH3)
<172.0 (3, R¼p-MeOC6H4) <175.9 [4, R¼p-(AcNH)C6H4] <189.2 (6).
Although the origin of the underlying effect is not known, the lo-
cation of dC]S for 6 was similarly noteworthy as its lowest energy
UV–vis band (lmax¼376 nm, in MeOH), in particular if compared to
compound 2 (lmax¼338 nm, in MeOH). In view of the existing in-
formation from computational and X-ray crystallographic work7 it
seemed reasonable to assume that the most significantly populated
conformer of 5-phenyl-4-methylthiazolethione 2 showed a twist of
(l
thiazole-2(3H)thiones 1–5 were prepared in synthetically useful
yields and quantities. The general approach was successfully
adapted for the synthesis of N-(hydroxy)indeno[2,1-d]thiazole-
2(3H)-thione (6) (lmax¼376 nm). O-Alkylation of thiohydroxamic
acids was feasible, with the efficiency gradually decreasing along
the sequence of introduced alkyl group iPr>Me>cumyl. N-Alkoxy-
4-methylthiazole-2(3H)thiones 13–17 afforded alkoxyl radicals, if
photolyzed (
l
¼350 nm, 1 min, 20 ꢀC) or activated in a monomode
microwave instrument (1 min, 120 ꢀC) in the absence of AIBN, as
evident from spin-trapping experiments and subsequent EPR
analysis. These findings are expected open perspectives for new
developments in synthetic and mechanistic alkoxyl radical
chemistry.
w40ꢀ between phenyl and thiazolethione entities. The
p-system in
indenothiazolethione 6, on the other hand, is expected to be planar.
The bathochromic shift of w38 nm observed for the UV–vis ab-
sorption of fused tricyclic compound 6 therefore should reflect
a smaller HOMO–LUMO gap due to more extensive
p
-electron
5. Experimental
5.1. General
delocalization, compared to 5-phenylthiazolethione 2. The present
study also clarified that 5-aryl for 5-methyl substitution in
N-(hydroxy)thiazole-2(3H)-thiones causes a bathochromic shift of
w20 nm. p-Substituent variation, on the other hand, from OMe,
NHAc, H, to Cl was not associated with notable UV–vis spectral
changes (Tables 1 and 2).
Standard instrumentation and general remarks have been dis-
closed previously.13 3-Chlorobutan-2-one (7), 1-phenylpropan-2-
one, and 1-(p-methoxyphenyl)propan-2-one were commercially
available. 1-Chloro-1-phenylpropanone (8) (88%),22,32 1-chloro-1-
(p-methoxyphenyl)propanone (9) (93%),22 1-chloro-2-indanone
(12),23 3-(ethoxythiocarbonylsulfanyl)-2-butanone,38 N-methyl-5-
(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (15a), and
N-isopropoxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thi-
one (15b)4,7 were prepared according to published procedures.
Selective O-alkylation of N-(hydroxy)thiazolethione tetrabutyl-
ammonium salts was attainable using hard alkylating reagents
(alkyl tosylates and chlorides). The yields gradually decreased along
i
the sequence of introduced alkyl groups Pr>Me>cumyl.11,13,15,16
Although the yield of tertiary thiohydroxamic acid O-ester 15c did
not exceed 15%, it should be noted that alternative pathways
starting from cumyl halides, or 2-phenyl-2-propanol/acid combi-
nations, and a variety of thiohydroxamate salts, had completely
failed so far.
On storage in flasks exposed to conventional laboratory illumi-
nation at 20 ꢀC, stability of thiones gradually fell along the series of
ester substituents CH3>CH(CH3)2[C(C6H5)(CH3)2. Primary/sec-
ondary thiazolethiones 13a/b–17a/b therefore were kept in the
dark (e.g., in amber colored flasks) at 20 ꢀC, whereas tertiary de-
rivative 15c preferentially was stored in a freezer (–20 ꢀC).
5.1.1. Microwave and EPR instrumentation
DiscoverÒ (CEM), 300 W, quartz glass vessel (length 9 cm, inside
diameter 1.3 cm) equipped with a 20 bar excess pressure valve,
stirring device, cooling fan, temperature measurement via IR sen-
sor. EPR spectra were recorded with an ESP 300 spectrometer
(Bruker) operating in the X-band mode at 15 mW microwave
power and a modulation amplitude of 1.0 G at 20 ꢀC.
5.2. N-(Hydroxy)thiazole-2(3H)-thiones
3.2. Identification of reactive intermediates
5.2.1. Nitrostyrenes
Photochemical and microwave-induced activation of N-
(alkoxy)thiazolethiones 13–17 furnished derived alkoxyl radicals
as judged on the basis of spin-trapping experiments and sub-
sequent EPR analysis. Although the use of alternative solvents,
5.2.1.1. 1-Nitro-4-(2-nitro-propenyl)-benzene. A solution of p-nitro-
benzaldehyde (49.4 g, 359 mmol), nitroethane (28.1 g, 359 mmol)
and piperidine (8.1 mL) in toluene was refluxed for 16 h using
a Dean-Stark trap. The solvent was removed under reduced pres-
sure. The remaining viscous dark red oil was taken up in CH2Cl2
(400 mL) and washed with H2O (2ꢂ125 mL) and aq HCl (1 M,
2ꢂ75 mL). The aqueous phase was extracted with CH2Cl2 (200 mL).
Combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The remaining red solid was crystallized
from CH2Cl2/pentane. Yield: 48.0 g (231 mmol, 71%). Mp: 112–
such as a,a,a-trifluorotoluene, for synthetic purposes generally is
favored, trapping reactions were preferentially conducted in C6H6
(e.g., Fig. 3). The latter choice and the use of 5 mm diameter cu-
vettes increased signal to noise ratio considerably. Likewise
obtained spectra were assigned to spin adducts 19a–c on the basis
of g-values and diagnostic changes observed in going from
methoxy via isopropoxy to cumyloxy substitution. Differences in
terms of rate and efficiency of alkoxyl radical generation from
N-(alkoxy)thiazolethione under such conditions were not evident
from the present data. Since N-(alkoxy)- and N-(alkenoxyl)-5-(p-
methoxyphenyl)-4-methylthiazolethiones, for example, 15a–c and
derivatives thereof, have already been successfully applied in
a number of alkoxyl radical-based investigations, it is expected
that derivatives of thiones 13–14, and 16–17 will show similar
utility for such purposes. This circumstance is particularly of
interest for solid phase tethering of derivatives of p-acetamido-
substituted thiazolethiones,37 which, in addition to the chemistry
of N-(hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (6), is being
pursued at the moment in this laboratory.
113 ꢀC. 1H NMR (CDCl3, 400 MHz)
d 2.46 (s, 3H), 7.59 (d, 2H,
J¼8.0 Hz), 8.09 (s, 1H), 8.32 (d, 2H, J¼8.0 Hz). 13C NMR (CDCl3,
100 MHz) d 14.2, 124.2, 130.6, 130.9, 139.0, 148.2, 150.3. MS (EI) m/z
208 (Mþ, 0.04), 208 (6), 161 (19), 132 (21), 115 (100). Anal. Calcd for
C9H8N2O4: C, 51.93; H, 3.87; N 13.46; Found: 51.63; H, 3.75; N 13.54.
5.2.1.2. 1-Chloro-4-(2-nitro-propenyl)-benzene39. A suspension of
p-chloro-benzaldehyde (7.15 g, 50.9 mmol), piperidine (0.4 mL,
4 mmol) and nitroethane (3.5 mL, 44.6 mmol) was heated in
a closed vessel in a microwave device (1 min, 300 W, 120 ꢀC). The
reaction mixture was cooled afterward to 22 ꢀC. The heating-
cooling cycle was repeated for 6 consecutive times. The reaction

10886
A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
mixture was afterward allowed to stand for 24 h at 0 ꢀC, where-
upon a brown solid crystallized. The solids were removed by
filtration, washed with cold (0 ꢀC) EtOH, and dried to afford
1-chloro-4-(2-nitro-propenyl)benzene as a yellow solid (5.80 g,
chromatographic purification of the crude product [SiO2, petro-
leum ether/Et2O¼3/1 (v/v), Rf¼0.47]. 1H NMR (CDCl3, 400 MHz)
d
2.22 (s, 3H), 2.34 (s, 3H), 5.31 (s, 1H), 7.37 (m, 2H, J¼12.0 Hz), 7.54
(m, 2H, J¼8.0 Hz). 13C NMR (CDCl3, 100 MHz)
d 24.6, 26.1, 66.3,
29.3 mmol, 58% yield). 1H NMR (CDCl3, 400 MHz)
d
2.43 (s, 3H),
120.5, 127.3, 128.9, 135.5, 169.2, 200.4. Anal. Calcd for C11H12ClNO2:
C, 58.54; H, 5.36; N 6.21; Found: C, 58.84; H, 5.56; N 6.45.
7.35–7.37 (m, 2H), 7.41–7.44 (m, 2H), 8.02 (s, 1H). 13C NMR (CDCl3,
100 MHz)
d 13.9, 129.2, 130.8, 131.1, 132.1, 136.0, 148.1. MS (EI) m/z
199, 197 (Mþ) (13:4), 150 (17), 139 (15), 116 (49), 115 (100), 103 (14).
5.2.3.2. 1-Chloro-1-(4-chlorophenyl)propan-2-one (11). In exten-
sion of the general method, the reaction mixture was stirred an
additional 12 h at 22 ꢀC. 1-Chloro-1-(4-chlorophenyl)propan-2-one
was obtained as a viscious oil (10.3 g, 50.9 mmol, 78% yield)
and was used without further purification. An analytical pure
sample was obtained via chromatographic purification of the crude
product [SiO2, petroleum ether/Et2O¼3/1 (v/v), Rf¼0.61]. 1H NMR
5.2.2. Arylpropan-2-ones
5.2.2.1. 1-(4-Acetamidophenyl)propan-2-one. A slurryobtainedfrom
4-nitro-(2-nitropropenyl)benzene (20.0 g, 96 mmol), Fe powder
(75.0 g, 1.34 mol, w325 mesh), HOAc (250 mL), and Ac2O (500 mL)
was heated to reflux while FeCl2$(H2O)4 (5.0 g) was carefullyadded in
small portions. The suspension was mechanical stirred for 4 h. The
gray suspension was filted through a pad of cellite. The residue was
washed with H2O (3ꢂ50 mL) and aq concd HCl (10 mL). The pH of the
filtrate was adjusted to 0 ꢀC using aq HCl (37%). The acidic aqueous
phase was extracted with CH2Cl2 (2ꢂ100 mL). Combined organic
washings were dried (MgSO4) and concentrated under reduced
pressure. The remaining volatiles (H2O, acids, Ac2O) were removed at
5 mbar/150 ꢀC to furnisha solid thatwasdissolved inCH2Cl2 (100 mL)
and washed with an aqueous solution of KOH (2.5 M, 2ꢂ75 mL) in
H2O (150 mL). The organic layer was kept. Combined aqueous
washings were extracted with CH2Cl2 (100 mL). Combined organic
layers were dried (MgSO4) and concentrated under reduced pressure
to furnish1-(4-acetamidophenyl)propan-2-one asbrightyellowsolid
(CDCl3, 400 MHz)
d
¼2.24 (s, 3H), 5.30 (s, 1H), 7.36–7.39 (m, 4H).13
C
NMR (CDCl3, 100 MHz)
d 25.8, 65.5, 129.2, 129.3, 133.5, 135.3. MS
(EI) m/z 206, 204, 202 (Mþ, 1.4:8.5:13.7), 169, 167 (8.5:24), 161, 160,
159 (10:65:100), 89 (76). Anal. Calcd for C9H8Cl2O: C, 53.29; H, 3.97;
Found: C, 53.29; H, 3.99.
5.2.4. Preparation of xanthogenates
General method. To
a suspension of potassium O-ethyl-
dithiocarbonate (1 equiv) in acetone (1 mL/mmol) was added
a solution of a haloketone (7–11) (1 equiv) in acetone (1 mL/mmol)
over a period of 15 min at 20 ꢀC. The reaction mixture was stirred
for 2 h at 20 ꢀC. The solvent was evaporated under reduced pres-
sure. H2O (1 mL/mmol) was added. The brown solution was
extracted with Et2O (2ꢂ2 mL/mmol). Combined organic washings
were dried (MgSO4) and concentrated under reduced pressure to
furnish a crude material that was sufficiently pure for succeeding
transformations. An analytical pure sample was obtained via
chromatographic purification of the crude product (SiO2).
(13.5 g, 70 mmol, 73% yield). 1H NMR (DMSO-d6, 400 MHz)
d 1.99 (s,
3H), 2.06 (s, 3H), 3.64 (s, 2H), 7.06 (d, 2H, JH¼4.0 Hz), 7.47 (d, 2H,
J¼8.0), 9.89 (s, 1H). 13C NMR (DMSO-d6, 100 MHz)
d 24.7, 29.5, 50.5,
120.4, 130.1, 130.2, 137.1, 168.5, 206.7. MS (EI) m/z 191 (Mþ, 10), 148
(26), 106 (100), 77 (9). Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N
7.32; Found: C, 68.12; H, 6.65; N 7.24.
5.2.4.1. 1-(Ethoxythiocarbonylsulfanyl)-1-(4-methoxyphenyl)-2-prop-
anone. Yield: 25.8 g (91.0 mmol, 91%); yellow solid [Rf¼0.66
petroleum ether/Et2O¼1/1 (v/v), eluent used for chromatography:
5.2.2.2. 1-(4-Chlorophenyl)propan-2-one21. 1-Chloro-4-(2-nitroprop-
1-enyl)-benzene (20.8 g, 106 mmol), Fe powder (44.0 g, 794 mmol,
w325 mesh), and FeCl2$(H2O)4 (1.80 g, 14.4 mmol) were suspended
inH2O/EtOH[375 mL, 4/3(v/v)].Thereactionmixturewasmechanical
stirred and heated to 70 ꢀC. Aq HCl [37% (w/w), 25 mL] was added and
stirringwascontinuedfor6.5 h. Thehotsuspensionwasfilteredunder
suction. The solids were washed with boiling EtOH (200 mL). Com-
bined filtrate and washingwereconcentratedunderreduced pressure
to furnish an aqueous solution, which was extracted with Et2O
(3ꢂ100 mL). Combined etheral washings were dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
distillation (bp 79–82 ꢀC, 0.4 mbar) to yield 1-(4-Chlor-
ophenyl)propan-2-one as yellowish oil (8.74 g, 51.8 mmol, 49% yield).
petroleum ether/Et2O¼2/1 (v/v)]. UV (EtOH) lmax (lg
3
/m2 molꢁ1
d 1.40 (t, 3H,
)
278 (3.37), 223 (3.42) nm. 1H NMR (CDCl3, 200 MHz)
J¼7.1 Hz), 2.27 (s, 3H), 3.80 (s, 3H), 4.60 (q, 2H, J¼7.1 Hz), 5.57 (s,
1H), 6.84–6.91 (mc, 2H), 7.21–7.23 (mc, 2H). 13C NMR (CDCl3,
63 MHz)
d 14.1, 29.1, 55.7, 64.3, 70.8, 115.1, 124.1, 130.7, 160.0,
201.5, 213.0. MS (EI) m/z 284 (7), 251 (20), 163 (100), 77 (19), 43
(21). Anal. Calcd for C13H16O3S2: C, 54.90; H, 5.67; Found: C,
54.88; H, 5.65.
5.2.4.2. 1-(Ethoxythiocarbonylsulfanyl)-1-(4-acetamidophenyl)-2-
propanone. Extractions were performed with CH2Cl2 instead of
Et2O. Yield 10.9 g (35 mmol, 92%) of a yellow solid [Rf¼0.12 (Et2O)].
1H NMR (CDCl3, 400 MHz)
d
2.18 (s, 3H), 3.68 (s, 2H), 7.11–7.15 (m, 2H),
1H NMR (CDCl3, 400 MHz)
d
1.37 (t, 3H, J¼7.09 Hz), 2.25 (s, 3H), 4.58
7.29–7.33 (m, 2H).13C NMR (CDCl3,100 MHz)
132.8, 133.2, 205.7.
d
29.5, 50.2,129.0,130.9,
(q, 2H, J¼7.10 Hz), 5.59 (s, 1H), 7.27–7.28 (m, 2H), 7.31–7.33 (m, 2H).
13C NMR (CDCl3, 100 MHz)
d 13.7, 28.8, 63.8, 70.7, 129.4, 130.5, 131.5,
135.0, 201.0 (C]O), 212.2 (C]S). MS (CI) m/z 312 (MþHþ, 20), 226
(4), 218 (9), 190 (100). Anal. Calcd for C14H17NO3S2: C, 53.99; H,
5.50; N 4.50; Found: C, 54.09; H, 5.56; N 4.46.
5.2.3. 2-Haloketones
General method. A solution of SOCl2 (1.1 equiv) in CH2Cl2
(1.5 mL/mmol) was added in a dropwise manner over a period of
5 min to an ice-cooled solution of a substituted propan-2-one
(1 equiv) in CH2Cl2 (0.5 mL/mmol). The reaction mixture was
stirred at 0 ꢀC for 2 h. The resulting red solution was washed with
H2O (2ꢂ0.5 mL/mmol) and NaHCO3 (saturated aqueous solution,
2ꢂ0.25 mL/mmol), dried (MgSO4), and concentrated under re-
duced pressure.
5.2.4.3. 1-(Ethoxythiocarbonylsulfanyl)-1-(4-chlorophenyl)-2-prop-
anone. The crude material was treated with petroleum ether (30–
50 ꢀC, 10 mL) and kept at 0 ꢀC for 48 h, to furnish a yellow solid that
was collected by filtration and dried (4.48 g, 15.6 mmol, 96% yield).
Rf¼0.34 [Et2O/pentane¼3/1 (v/v)]. 1H NMR (CDCl3, 600 MHz)
d 1.37
(t, 3H, J¼7.09 Hz), 2.25 (s, 3H), 4.58 (q, 2H, J¼7.10 Hz), 5.59 (s, 1H),
7.27–7.28 (m, 2H), 7.31–7.33 (m, 2H). 13C NMR (CDCl3, 150 MHz)
5.2.3.1. 1-Chloro-1-(4-acetamidophenyl)propan-2-one (10). 1-Chlo-
ro-1-(4-acetamidophenyl)propan-2-one was obtained as a yellow
solid (12.1 g; 54 mmol, 76% yield). It was used without further
purification. An analytical pure sample was obtained via
d 13.7, 28.8, 63.8, 70.7, 129.4, 130.5, 131.5, 135.0, 201.0 (C]O), 212.2
(C]S). MS (EI) m/z 290, 288 (Mþ, 0.1:0.3), 257, 255 (38:100), 228
(27), 200 (30), 185 (38), 157 (98). Anal. Calcd for C12H13ClO2S2: C,
49.90; H, 4.54; Found: C, 50.12; H, 4.40.

A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
10887
5.2.4.4. 1-(Ethoxythiocarbonylsulfanyl)-2-indanone. According to
the general procedure, a solution of 1-chloro-2-indanone23 (7.10 g,
42.6 mmol) in acetone (40 mL) was added to a suspension of po-
tassium-O-ethyldithiocarbonat (6.83 g, 42.6 mmol) in acetone
(70 mL) at 20 ꢀC. The crude product was recrystallized (Et2O, pen-
tane). Yield: 7.22 g (28.6 mmol, 67%), dark red solid. 1H NMR (CDCl3,
5.2.5.5. 3-(Ethoxythiocarbonylsulfanyl)-1-indanone oxime. To a so-
lution of 1-(ethoxythiocarbonylsulfanyl)-2-indanone (5.00 g,
19.8 mmol) and H2NOH$HCl (4.13 g, 59.4 mmol) in MeOH (70 mL)
and CH2Cl2 (30 mL) were added a few drops of pyridine at 0 ꢀC.
The mixture was stirred for 3 h at 20 ꢀC and worked up according
to the general procedure. Yield: 5.00 g (18.7 mmol, 94%) dark red
oil. An analytically pure sample was obtained upon purification of
the crude product by chromatography [SiO2, petroleum ether/
Et2O¼2/1 (v/v), Rf¼0.60)] to furnish the title compound as orange
oil, which solidified, if stored at –18 ꢀC. 1H NMR (400 MHz, CDCl3)
400 MHz)
1H, J¼22.4 Hz), 4.58 (mc, 2H), 5.24 (s, 1H), 7.32–7.34 (m, 3H), 7.42–
7.44 (m, 1H). 13C NMR (CDCl3, 100 MHz)
13.4, 42.8, 57.2, 70.9,
d
1.30 (t, 3H, J¼7.2 Hz), 3.65 (d, 1H, J¼22.4 Hz), 3.72 (d,
d
124.8,125.1,128.0,128.7,136.9,137.5, 209.4, 211.2 (C]S). MS (EI) m/z
252 (Mþ, 19), 163 (100), 103 (63).
d
1.39 (t, 3H, J¼7.2 Hz), 3.89 (d, 2H, J¼4.4 Hz), 4.68 (mc, 2H), 5.97
(s, 1H), 7.27–7.31 (m, 3H), 7.44–7.45 (m, 1H). 13C NMR (CDCl3,
5.2.5. (Ethoxythiocarbonylsulfanyl)alkanone oximes
100 MHz) d 14.1, 33.6, 54.2, 71.1, 124.9, 125.5, 128.2, 129.3, 138.8,
General method. To an ice-cooled suspension of a ethoxy-
thiocarbonylsulfanyl propanone (section 5.2.4) (1 equiv) and
NH2OH$HCl (1.1 equiv) in MeOH (0.5 mL/mmol) was added pyri-
dine (1.25 equiv). The reaction mixture was stirred for 16 h at 20 ꢀC.
The solvent was evaporated under reduced pressure to furnish
a residue that was taken up in Et2O (4 mL/mmol). The organic
phase was washed successively with aq 0.5 N HCl (2 mL/mmol) and
H2O (2 mL/mmol) and dried (MgSO4). The solvent was removed
under reduced pressure. The residue was purified by re-
crystallization or chromatography.
139.3, 162.4, 213.0 (C]S). MS (EI) m/z 267 (Mþ, 4), 178 (14), 146
(100). Anal. Calcd for C12H13NO2S2: C, 53.91; H, 4.90; N, 5.24;
Found: C, 53.86; H, 4.96; N, 5.48.
5.2.6. Cyclization of (ethoxythiocarbonylsulfanyl)alkanone oximes
General method. To an ice-cooled solution of KOH (4 equiv) in
H2O (4 mL/mmol) was added a solution of the corresponding
(ethoxythiocarbonyl-sulfanyl)acetoneoxime (1 equiv) in CH2Cl2
(3.5 mL/mmol). The reaction mixture was stirred for 2 h at 20 ꢀC
H2O (1 mL/mmol) was added and the phases were separated. The
aqueous phase was extracted twice with light petroleum (each
0.3 mL/mmol) and acidified to pH 2 with concd HCl. The aqueous
phase was extracted five times with CH2Cl2 (each 1 mL/mmol).
Combined organic phases were dried (MgSO4). The solvent was
evaporated under reduced pressure. The residue was recrystallyzed
from light petroleum/Et2O.
5.2.5.1. 3-(Ethoxythiocarbonylsulfanyl)-2-butanone oxime. Yield:
9.65 g (46.5 mmol, 93%), colorless solid from petroleum ether/
Et2O¼3/1 (v/v); mp 55 ꢀC; Rf¼0.77 [petroleum ether/Et2O¼3/1 (v/
v)]. UV (EtOH) lmax (lg
3
/m2 molꢁ1) 280 (3.43), 220 (3.33) nm. 1H
NMR (CDCl3, 200 MHz)
d
1.42 (t, 3H, J¼7.2 Hz),1.52 (d, 3H, J¼7.1 Hz),
1.96 (s, 3H), 4.51 (q, 1H, J¼7.2 Hz), 4.65 (q, 2H, J¼7.2 Hz), 8.7 (br s,
1H, OH). 13C NMR (CDCl3, 100 MHz)
d
12.1,13.7,17.9, 49.5, 70.2,157.2,
5.2.6.1. N-(Hydroxy)-4,5-dimethylthiazole-2(3H)-thione (1). Yield:
4.26 g (26.5 mmol, 88%), colorless solid from petroleum ether/
Et2O¼3/1 (v/v); mp: 88 ꢀC, 133 ꢀC dec Rf¼0.05 [petroleum ether/
212.7. MS (EI) m/z 207 (Mþ, 2), 174 (100), 86 (20), 42 (53). Anal.
Calcd for C7H13NO2S2: C, 40.58; H, 6.32; N, 6.76; Found: C, 40.71; H,
5.96; N, 6.58.
Et2O¼1/1 (v/v)]. UV (MeOH) lmax (lg
3
/m2 molꢁ1) 316 (3.14). 1H
NMR (CDCl3, 250 MHz)
d
2.22 (q, 3H, J¼0.9 Hz, 5-CH3), 2.27 (q, 3H,
5.2.5.2. 1-(4-Methoxyphenyl)-1-(ethoxythiocarbonylsulfanyl)-2-prop-
anone oxime. Yield: 12.9 g (43.2 mmol, 86%), yellow solid from
CH3OH; mp 86 ꢀC; Rf¼0.50 [petroleum ether/Et2O¼3/1 (v/v)]. UV
J¼0.9 Hz, 4-CH3), 9.8 (br s, 1H, OH). 13C NMR (CDCl3, 63 MHz)
d 11.0,
11.7, 114.8, 130.8, 168.5. MS (EI) m/z 161 (Mþ, 100), 144 (50), 85 (59),
59 (35). Anal. Calcd for C5H7NOS2: C, 37.28; H, 4.38; N, 8.69; Found:
C, 37.63; H, 4.53; N, 8.46. HRMS (ESI): calcd 160.9971(2), found
160.9969.
(EtOH) lmax (lg
(CDCl3, 250 MHz)
3
/m2 molꢁ1) 282 (3.47), 224 (3.63) nm. 1H NMR
d
1.38 (t, 3H, J¼7.1 Hz), 1.90 (s, 3H), 3.80 (q, 2H,
J¼7.1 Hz), 5.50 Hz (s,1H), 6.82–6.90 (mc, 2H), 7.26–7.33 (mc, 2H). 13
C
NMR (CDCl3, 63 MHz)
d
13.5,13.7, 55.3, 57.4, 70.2,114.3,128.0,129.8,
5.2.6.2. N-(Hydroxy)-5-phenyl-4-methylthiazole-2(3H)-thione (2).
156.0, 159.4, 212.1. MS (EI) 299 (Mþ, 1), 178 (100), 146 (40), 77 (17),
51 (5). Anal. Calcd for C13H17NO3S2: C, 52.15; H, 5.73; N, 4.68;
Found: C, 52.23; H, 5.44; N, 4.68.
Yield: 5.66 g (25.5 mmol, 14%), tan solid from Et2O; mp: 141 ꢀC. UV
(MeOH) lmax (lg
2.46 (s, 3H, CH3), 7.34–7.38 (m, 2H, Ph-H), 7.39–7.47 (m, 3H, Ph-H).
3
/m2 molꢁ1) 338 (3.12). 1H NMR (CDCl3, 400 MHz)
d
13C NMR (CDCl3, 100 MHz)
d 12.1, 119.5, 128.6, 128.9, 129.2, 129.9,
5.2.5.3. 1-(4-Acetamidophenyl)-1-(ethoxythiocarbonylsulfanyl)-2-
propanone oxime. A AcOEt/CH2Cl2 2/1 (v/v) mixture was used for
extraction instead Et2O. Yield: 3.42 g (11 mmol, 75%), yellow
130.2, 169.3. m/z (CI): 224 (MþHþ, 100), 208 (5), 148 (3), 130 (1).
Anal. Calcd for C10H9NOS2: C, 53.78; H, 4.06; N, 6.27; Found: C,
53.69; H, 4.11; N, 6.42.
solid. 1H NMR (CDCl3, 600 MHz)
d
1.37 (t, 3H, J¼7.1 Hz), 1.89 (s,
3H), 2.17 (s, 3H), 4.59 (q, 2H, J¼6.9 Hz), 5.50 (s, 1H), 7.32 (d, 2H,
5.2.6.3. N-(Hydroxy)-5-(4-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (3). Yield: 6.23 g (24.9 mmol, 83%), tan solid from CH3OH;
mp 158 ꢀC, decomp.; Rf¼0.05 [petroleum ether/Et2O¼1/1 (v/v)]. UV
J¼8.4 Hz), 7.46 (d, 2H, J¼8.4 Hz). 13C NMR (CDCl3, 150 MHz)
d 13.7,
14.3, 24.6, 57.5, 70.3, 120.2 (2C), 129.4, 132.2, 137.9, 155.9, 168.9,
212.0 (C]S). MS (CI) m/z 327 (MþHþ, 6), 293 (12), 277 (11), 231
(31), 205 (100).
(MeOH) lmax (lg
(CDCl3, 250 MHz)
(mc, 2H, Ar-H), 7.24–7.31 (mc, 2H, Ar-H). 13C NMR (CDCl3, 63 MHz)
3
/m2 molꢁ1) 334 (3.20), 250 (3.12) nm. 1H NMR
d
2.43 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.93–7.00
5.2.5.4. 1-(4-Chlorophenyl)-1-(ethoxythiocarbonylsulfanyl)-2-prop-
anone oxime. In modification of the general procedure, 2 equiv of
NH2OH$HCl were used. The reaction mixture was stirred for 1 h at
0 ꢀC and for 2.5 h at 22 ꢀC. Yield of 1-(4-chlorophenyl)-1-(ethox-
ythiocarbonylsulfanyl)-2-propanone oxime: 3.14 g (10.3 mmol,
d 12.0, 55.4, 114.7, 119.5, 122.1, 129.8, 130.0, 160.2, 169.2. MS (EI) m/z
253 (Mþ, 100), 177 (45), 77 (18), 63 (11). HRMS (ESI) C11H11NO2S2:
calcd 253.0231, found: 253.0236(1).
5.2.6.4. N-(Hydroxy)-5-(4-acetamidophenyl)-4-methylthiazole-2(3H)-
80%) as a red oil. 1H NMR (CDCl3, 600 MHz)
d
1.90 (s, 3H), 4.60 (q,
thione (4). Yield: 2.20 g (8 mmol, 85%), tan solid; mp 135 ꢀC dec.
2H, J¼7.10 Hz), 5.52 (s, 1H), 7.30–7.32 (m, 2H), 7.33–7.34 (m, 2H). 13C
UV (EtOH) lmax (lg
400 MHz) d 2.06 (s, 3H, 6-H), 2.28 (s, 3H, HNCOCH3), 7.37 (d, 2H,
3
/m2 molꢁ1) 335 (3.14). 1H NMR (DMSO-d6,
NMR (CDCl3, 150 MHz)
d
13.7, 13.8, 57.6, 70.5, 129.0, 130.1, 134.3,
3
135.2, 155.9 (C]O), 211.7 (C]S). MS (EI) m/z 272, 270 (1:3), 227,
225 (1:3), 182 (18), 146 (8), 115 (30), 76 (100).
J¼8.7 Hz, 30-H and 50-H), 7.68 (d, 2H, JH,H¼8.6 Hz, 20-H und 60-H),
10.15 (s, 1H, -NH), 12.32 (s, 1H, -OH). 13C NMR (DMSO-d6, 100 MHz)

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A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
d
12.1 (CH3), 23.8 (HNCOCH3), 116.7 (5-C), 119.0 (30-C und 50-C),
83 ꢀC. Rf¼0.37 [petroleum ether/Et2O¼1/1 (v/v)]. UV (MeOH)
124.2 (40-C), 128.4 (20-C und 60-C), 133.9 (4-C), 139.2 (10-C), 168.3
(HNCOCH3), 175.9 (C]S). MS (CI) m/z 281 (MþHþ, 100), 265 (10),
249 (8), 221 (27). Anal. Calcd for C12H12N2O2S2: C, 51.41; H, 4.31; N,
9.99; Found: C, 51.30; H, 4.31; N, 9.46.
lmax (lg 3
/m2 molꢁ1) 322 (3.14) nm. 1H NMR (CDCl3, 400 MHz)
d
1.31 (d, 6H, J¼6.2 Hz, CH(CH3)2), 2.12 (d, 3H, J¼0.8 Hz, 4-CH3),
2.14 (d, 3H, J¼0.8 Hz, CH3), 5.46 [sept, 1H, J¼6.2 Hz, CH(CH3)2].
13C NMR (CDCl3, 100 MHz)
d 11.5, 12.1, 20.5, 78.2, 114.3, 133.8,
178.7. MS (CI) m/z 204 (MþHþ, 100), 190 (39), 162 (39), 145 (15).
Anal. Calcd for C8H13NOS2: C, 47.26; H, 6.44; N, 6.89; Found: C,
47.54; H, 6.53; N, 6.75.
5.2.6.5. N-(Hydroxy)-5-(4-chlorophenyl)-4-methylthiazole-2(3H)-
thione (5). Yield: 641 mg (2.23 mmol, 59%), tan solid; mp 140–
141 ꢀC. UV (EtOH) lmax (lg /m2 molꢁ1) 334 (3.21) nm. 1H NMR
3
(CDCl3, 400 MHz)
d
2.44 (s, 3H, 4-CH3), 7.28–7.30 (m, 2H, Ph-H),
5.4.3. N-(Methoxy)-5-phenyl-4-methylthiazole-2(3H)thione (14a)
7.41–7.43 (m, 2H, Ph-H). 13C NMR (CDCl3, 100 MHz)
d
12.3, 118.3,
From CH3OTs (194 mg, 1.04 mmol); yield: 108 mg (455 mmol,
128.6, 129.6, 130.0, 131.3, 135.2, 170.2. MS (CI) m/z 258 (MþHþ, 100),
222 (7), 205 (3). Anal. Calcd for C10H8ClNOS2: C, 46.82; H, 3.10; N,
5.40; Found: C, 46.60; H, 3.13; N, 5.43.
45%), tan solid from petroleum ether/Et2O¼1/1 (v/v); mp: 86 ꢀC;
Rf¼0.31 [pentane/Et2O¼1/1 (v/v)]. UV (MeOH) lmax (lg
3 )
/m2 molꢁ1
d 2.39 (s, 3H, CH3), 4.23 (s,
333 (3.28) nm. 1H NMR (CDCl3, 400 MHz)
3H, OCH3), 7.31–7.34 (m, 2H, Ph-H), 7.36–7.46 (m, 3H, Ph-H). 13C
5.2.6.6. N-(Hydroxy)-(4H)-indeno[2,1-d]thiazole-2(3H)-thione (6).
NMR (CDCl3, 100 MHz) d 12.1 (CH3), 63.7 (NOCH3), 119.4, 128.5,
A
solution of 1-(ethoxythiocarbonylsulfanyl)-2-indane oxime
128.7, 129.1, 130.3, 132.5, 178.9 (C]S). MS (EI) m/z 237 (Mþ, 100),
207 (97), 173 (29), 162 (23), 147 (91), 130 (61), 121 (66), 115 (73), 103
(59), 77 (58). Anal. Calcd for C11H11NOS2: C, 55.67; H, 4.67; N, 5.90;
Found: C, 55.99; H, 4.70; N, 5.99.
(2.86 g, 10.7 mmol) in CH2Cl2 (10 mL) was added to KOH (1.20 g,
21.4 mmol) in H2O (23 mL) at 0 ꢀC. The mixture was stirred 2 h at
20 ꢀC. CH2Cl2 und H2O were added until two clear phases were
obtained. The solution was worked up according to general pro-
cedure 5.6.2. The crude product was purified by recrystallization
(Et2O). Yield: 580 mg (2.62 mmol, 25% yield) tan solid. UV (MeOH)
5.4.4. N-(Isopropoxy)-5-phenyl-4-methylthiazole-
2(3H)thione (14b)
lmax (lg
400 MHz)
1H, Ar-H), 7.65–7.69 (m, 1H, Ar-H), 7.87–7.89 (m, 1H, Ar-H). 13C NMR
(100 MHz, CDCl3) 28.3 (CH2), 124.7 (Ar-C), 126.9 (Ar-C), 128.1 (Ar-
3
/m2 molꢁ1) 376 (2.45), 267 (2.91). 1H NMR (CDCl3,
3.85 (s, 2H, CH2), 7.43–7.47 (m, 1H, Ar-H), 7.52–7.54 (m,
From iPrOTs (201 mg, 936
mmol); yield: 169 mg (637 mmol, 62%),
d
tan solid from petroleum ether/Et2O¼1/1 (v/v). Rf¼0.52 [petroleum
ether/Et2O¼1/1 (v/v)]. Mp 100 ꢀC. UV (MeOH) lmax (lg
3 )
/m2 molꢁ1
1.39 [d, 6H, J¼6.4 Hz,
d
334 (3.27) nm. 1H NMR (CDCl3, 400 MHz)
d
C), 136.1 (Ar-C), 137.8, 146.8, 155.2, 189.3 (C]S); MS (EI) m/z 221
(Mþ, 4), 205 (36), 146 (33), 103 (63). Anal. Calcd for C10H7NOS2: C,
54.28; H, 3.19; N, 6.33; Found: C, 54.36; H, 3.28; N, 6.41.
CH(CH3)2], 2.33 (s, 3H, CH3), 5.52 [sept, 1H, J¼6.0 Hz, CH(CH3)2],
7.31–7.34 (m, 2H, Ph-H), 7.35–7.45 (m, 3H, Ph-H). 13C NMR (CDCl3,
100 MHz) d 12.8 (CH3), 20.5, 78.6 [NOCH(CH3)2], 119.2, 128.5, 128.6,
129.1, 130.6, 134.1, 179.6 (C]S). MS (CI) m/z 266 (MþHþ, 100), 252
(16), 224 (10), 207 (15), 190 (1), 147 (1). Anal. Calcd for C13H15NOS2:
C, 58.83; H, 5.70; N, 5.28; Found: C, 59.03; H, 5.69; N, 5.25.
5.3. N-(Hydroxy)thiazole-2(3H)-thione tetralkyl-
ammonium salts
General method. To
a
solution of
a
N-(hydroxy)thiazole-
5.4.5. N-(Methoxy)-5-(4-acetamidophenyl)-4-methylthiazole-
2(3H)thione (16a)
2(3H)thione 1–6 (1.10 mmol) in MeOH (2 mL) was added a solution
of NEt4OH or NBu4OH in MeOH (1.10 mmol, 0.73 mL,1.5 M) at 20 ꢀC.
The solvent was evaporated under reduced pressure to furnish
a residue that was freeze-dried (12 h).
From CH3OTs (677 mg, 2.41 mmol); yield: 453 mg (1.53 mmol,
64%), tan solid. Rf¼0.21 [Et2O/AcOEt¼1/1 (v/v)]. Mp 130 ꢀC (dec).
UV (EtOH) lmax lg
d6, 400 MHz)
3H, NOCH3), 7.37 (d, 2H, J¼8.8 Hz), 7.68 (d, 2H, J¼8.8 Hz), 10.14
(s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz)
12.0, 24.1, 63.7, 117.7,
3
/m2 molꢁ1) 336 (3.22) nm. 1H NMR (DMSO-
d
2.06 (s, 3H, CH3), 2.34 (s, 3H, HNCOCH3), 4.14 (s,
5.4. N-(Alkoxy)thiazole-2(3H)-thiones
d
General method. N-(Hydroxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)thione tetraalkylammonium salt (1.00 mmol) was
disolved in anhydrous DMF (2 mL). An alkyl tosylate or alkyl halide
(1.00–1.10 mmol) was added. The reaction mixture was stirred for
12 h at 20 ꢀC. Water (10 mL) was added. The aqueous phase was
extracted with Et2O (3ꢂ5 mL). Combined organic washings were
dried (MgSO4) and concentrated under reduced pressure to furnish
a crude product, which was purified by recrystallization or chro-
matography. For synthesis of N-cumyloxythiazolethione 15c see
section 5.5.
119.4 (2C), 124.2, 128.8 (2C), 133.1, 139.8, 168.7, 177.0 (C]S). MS
(CI) m/z 295 (MþHþ, 100), 279 (61), 233 (40), 192 (33). Anal.
Calcd for C13H14N2O2S2: C, 53.04; H, 4.79; N, 9.52; Found: C,
52.76; H, 4.86; N, 8.98.
5.4.6. N-(Isopropoxy)-5-(4-acetamidophenyl)-4-methylthiazole-
2(3H)thione (16b)
i
From PrOTs (430 mg, 2.01 mmol); yield: 341 mg (1.06 mmol,
53%), tan solid. Mp 153–154 ꢀC dec. UV (EtOH) lmax (lg /m2 molꢁ1
3 )
337 (3.21) nm. 1H NMR (DMSO-d6, 400 MHz)
d 1.32 [d, 6H,
J¼6.4 Hz,-CH(CH3)2], 2.06 (s, 3H, CH3), 2.32 (s, 3H, HNCOCH3), 5.29
[sept, 1H, J¼6.2 Hz, CH(CH3)2], 7.39 (d, 2H, J¼8.8 Hz), 7.68 (d, 2H,
J¼8.8 Hz, 20-H und 60-H), 10.13 (s, 1H, -NH). 13C NMR (DMSO-d6,
5.4.1. N-(Methoxy)-4,5-dimethylthiazole-2(3H)thione (13a)
From CH3OTs (172 mg, 1.00 mmol); yield: 0.13 g (0.68 mmol,
68% yield), tan solid from CH3OH. Mp 54 ꢀC. Rf¼0.45 [petroleum
400 MHz)
d 12.4, 20.0, 23.8, 78.8, 117.4, 119.0 (2C), 124.0, 128.5,
ether/Et2O¼2/1 (v/v)]. UV (MeOH) lmax (lg
3
/m2 molꢁ1) 321 (3.16)
133.9, 139.4, 168.4, 177.4 (C]S). MS (CI) m/z 323 (MþHþ, 100), 307
(33), 265 (23), 233 (9). Anal. Calcd for C15H18N2O2S2: C, 55.87; H,
5.63; N, 8.69; Found: C, 55.96; H, 5.82; N, 8.52.
nm. 1H NMR (CDCl3, 400 MHz)
d
2.12 (q, 3H, J¼0.9 Hz, CH3), 2.19 (q,
3H, J¼0.9 Hz, CH3), 4.13 (s, 3H, NOCH3). 13C NMR (CDCl3, 100 MHz)
d
11.3, 12.4, 63.9, 115.0, 132.6, 178.6244 (3.38). MS (EI) m/z 175 (Mþ,
100),144 (12), 85 (44). Anal. Calcd for C6H9NOS2: C, 41.12; H, 5.18; N,
7.99; Found: C, 41.24; H, 5.24; N, 8.06.
5.4.7. N-(Methoxy)-5-(4-chlorophenyl)-4-methylthiazole-
2(3H)thione (17a)
From CH3OTs (768 mg, 4.57 mmol); yield: 553 mg (0.68 mmol,
59%), colorless solid. Mp 117–118 ꢀC. Rf¼0.29 [petroleum ether/
5.4.2. N-(Isopropoxy)-4,5-dimethylthiazole-2(3H)thione (13b)
From iPrOTs (236 mg, 1.05 mmol); yield: 175 mg (862
mmol,
Et2O¼5/2 (v/v)]. UV (EtOH) lmax (lg
3
/m2 molꢁ1) 335 (3.28) nm.
82%), colorless solid from petroleum ether/Et2O¼1/1 (v/v). Mp
1H NMR (CDCl3, 600 MHz)
d 2.36 (s, 3H, CH3), 4.22 (s, 3H,

A. Groß et al. / Tetrahedron 64 (2008) 10882–10889
10889
NOCH3), 7.24–7.26 (m, 2H), 7.40–7.41 (m, 2H). 13C NMR (CDCl3,
N-(alkoxy)-thiazolthione in C6H6 (1 mL, 0.01 Mꢁ1
)
and the
150 MHz)
d
12.2, 63.9, 118.1, 128.8, 129.5, 129.9, 133.0, 134.9, 179.0
mixture heated for 1 min (MW power 300 W, Tmax: 120 ꢀC,
pmax10 bar).
(C]S). MS (CI) m/z 272 (MþHþ, 100), 241 (12), 236 (8). Anal.
Calcd for C11H10ClNOS2: C, 48.79; H, 3.54; N, 5.08; Found: C,
48.61; H, 3.71; N, 5.15.
Acknowledgements
5.4.8. N-(Isopropoxy)-5-(4-chlorophenyl)-4-methylthiazole-
2(3H)thione (17b)
This work was supported by the Deutsche Forschungs-
gemeinschaft (Grant Ha1705/5–2 and Graduiertenkolleg 690:
ElektronendichtedTheorie und Experiment) and the state of
Rheinland-Pfalz (scholarschip for A.G.). We also wish to express our
grattitude to Ms. Christine Schur for technical assistance in syn-
theses of thiazolethiones 4 and 5.
From iPrOTs (283 mg, 1.32 mmol); yield: 257 mg (857
mmol,
71%), tan solid. Mp 121–122 ꢀC. Rf¼0.45 [petroleum ether/Et2O¼2/
1 (v/v)]. UV (EtOH) lmax (lg 3
/m2 molꢁ1) 337 (3.21) nm. 1H NMR
(CDCl3, 400 MHz)
CH3), 5.45–5.43 [sept., 1H, J¼6.3 Hz, CH(CH3)2], 7.26–7.28 (m, 2H,
Ar-H), 7.39–7.41 (m, 2H, Ar-H). 13C NMR (CDCl3, 100 MHz)
12.7,
d
1.38 [d, 6H, J¼6.3 Hz, CH(CH3)2], 2.23 (s, 3H,
d
Supplementary data
20.5, 76.7, 117.6, 129.0, 129.3, 129.6, 129.7, 134.5, 170.2 (C]S). MS
(CI) m/z 300 (MþHþ, 100), 286 (14), 258 (9), 241 (17). Anal. Calcd
for C13H14ClNOS2: C, 52.24; H, 4.71; N, 4.67; Found: C, 52.07; H,
4.73; N, 4.66.
13C NMR spectra of selected compounds (4 pages). Supple-
mentary data associated with this article can be found in the online
version at doi:10.1016/j.tet.2008.09.006.
5.4.9. N-(Isoproxy)-(4H)-indeno[2,1-d]thiazole-2(3H)-thione (18b)
From 2-chloropropane (132 mg, 1.68 mmol); yield: 40.6 mg
(9%), brown oil from pentane/Et2O 1/1 (v/v). Rf¼0.49 [pentane/
References and notes
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ˇ
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d
1.38 [d, 6H, J¼6.3 Hz, -CH(CH3)2], 3.81 (s,
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anhydrous CH2Cl2 (5 mL) was stirred for 24 h at 25 ꢀC. A solution of
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ˇ
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lution of the corresponding thiazolthione (0.01 Mꢁ1) and 20
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mL
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ˇ
36. Spehar, K. Ph.D Thesis, Universita¨t Wu¨ rzburg, 2004.
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experiments DMPO (20
m
L) was added to a solution of the an
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