Microwave-assisted generation of alkoxyl radicals and their use in additions, β-fragmentations, and remote functionalizations

Article abstract of DOI:10.1039/b603480b

Microwave irradiation (2.45 GHz, 300-500 W) of N-(alkoxy)thiazole-2(3H)- thiones in low-absorbing solvents affords alkoxyl radicals, which were identified by (i) spin adduct formation (EPR-spectroscopy) and (ii) fingerprint-type selectivities in intramolecular additions (stereoselective synthesis of disubstituted tetrahydrofurans), β-fragmentations (formation of carbonyl compounds), and C,H-activation of aliphatic subunits, by δ-selective hydrogen atom transfer. C-Radicals formed from oxygen-centered intermediates were trapped either by Bu₃SnH, l-cysteine ethyl ester, the reduced form of glutathione (reductive trapping), or by bromine atom donor BrCCl₃ (heteroatom functionalization) The results suggest that microwave activation is superior to UV/Vis-photolysis and conductive heating for alkoxyl radical generation from N-(alkoxy)thiazolethiones. It offers by far the shortest reaction times along with the option to reduce the amount of trapping reagent significantly. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b603480b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Microwave-assisted generation of alkoxyl radicals and their use in additions,
b-fragmentations, and remote functionalizations†‡
Jens Hartung,* Kristina Daniel, Thomas Gottwald, Andreas Groß and Nina Schneiders
Received 7th March 2006, Accepted 28th March 2006
First published as an Advance Article on the web 9th May 2006
DOI: 10.1039/b603480b
Microwave irradiation (2.45 GHz, 300–500 W) of N-(alkoxy)thiazole-2(3H)-thiones in low-absorbing
solvents affords alkoxyl radicals, which were identified by (i) spin adduct formation (EPR-spectroscopy)
and (ii) fingerprint-type selectivities in intramolecular additions (stereoselective synthesis of
disubstituted tetrahydrofurans), b-fragmentations (formation of carbonyl compounds), and
C,H-activation of aliphatic subunits, by d-selective hydrogen atom transfer. C-Radicals formed from
oxygen-centered intermediates were trapped either by Bu3SnH, L-cysteine ethyl ester, the reduced form
of glutathione (reductive trapping), or by bromine atom donor BrCCl3 (heteroatom functionalization)
The results suggest that microwave activation is superior to UV/Vis-photolysis and conductive heating
for alkoxyl radical generation from N-(alkoxy)thiazolethiones. It offers by far the shortest
reaction times along with the option to reduce the amount of trapping reagent significantly.
Introduction
The potential of microwaves (2.45 GHz) to increase the rate,
selectivity, and efficiency of chemical transformations that pro-
ceed via polar intermediates has been well documented in the
literature.1,2 Considerably less, however, is known about the role
of microwave activation in radical-based transformations.3,4 The
issue of selective alkoxyl radical formation and a concise study on
the chemistry that follows under these conditions has, to the best
of our knowledge, not yet been addressed. In view of this back-
ground, the present investigation on the feasibility of microwave-
induced generation of oxygen-centered radicals starting from
N-(alkoxy)thiazole-2(3H)-thiones I5–8 has been performed with
the aim of documenting the applicability of such intermediates
in the three most relevant O-radical elementary reactions: (i)
intramolecular addition (II → III), (ii) b-fragmentation (IV →
V), and (iii) homolytic substitution (VI → VII) (Scheme 1).9
Results
Scheme 1 The consequent alkoxyl radical chemistry upon microwave
activation of N-(alkoxy)thiazole-2(3H)-thiones I [R1 = CH3 or p-ClC6H4
(CP);5,6 R2 = H or p-H3COC6H4 (An); Rꢀ = e.g. CH3, C6H5].7–9
1. Synthesis of N-(alkoxy)thiazole-2(3H)-thiones
O-Alkyl derivatives of N-(hydroxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione [MAnTTOR 1: R1 = CH3, R2
=
intramolecular additions (1e, 1h, 2e–h), b-fragmentations (1i, 1j),
and homolytic substitutions (1k, 1m) (Fig. 1), were prepared
by selectively O-alkylating the corresponding N-hydroxythiazole-
2(3H)-thione tetraethylammonium salt, in an extension of the
literature procedures.5,6,8,10–12
An (p-H3COC6H4)] and N-hydroxy-4-(p-chlorophenyl)thiazole-
2(3H)-thione [CPTTOR 2: R1 = CP (p-ClC6H4), R2 = H] that
were required for conducting spin-trapping experiments (1a–d),
Fachbereich Chemie, Organische Chemie, Erwin-Schro¨dinger Straße, Tech-
nische Universita¨t Kaiserslautern, D-67663, Kaiserslautern, Germany. E-
mail: hartung@chemie.uni-kl.de; Fax: +49 631 205 3921
† Electronic supplementary information (ESI) available: Standard in-
strumentation, analytical data and microwave-assisted transformations
for N-(alkoxy)-4-(p-chlorophenyl)thiazole-2(3H)-thiones (2). See DOI:
10.1039/b603480b
‡ Dedicated to Prof. Dr Hartmut Fuess on the occasion of his 65th birthday
in recognition of his contributions to structural chemistry and material
science.
2. Microwave-assisted transformations
2.1 Alkoxyl radical trapping by 5,5-dimethylpyrrolidine-
N-oxide (3). The feasibility of alkoxyl radical generation
upon microwave activation of N-(alkoxy)thiazole-2(3H)-thiones
was verified by heating solutions of 5-(p-methoxyphenyl)-
4-methyl-substituted heterocycles 1a–d (c0 = 10−2 M) and
5,5-dimethylpyrrolidine-N-oxide (3) (DMPO) (c0 = 1.8 × 10−2 M)
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Fig. 1 Numbering of N-(alkoxy)thiazole-2(3H)-thiones 1 and 2. An =
p-H3COC6H4. R1 = CH3, R2 = An for 18,10–12 and R1 = p-ClC6H4, R2 = H
for 2.5,6
in C6H6 to 120 ◦C in a mono-mode microwave device using
appropriate vessels, instrumentation, and control units for
temperature and pressure regulation (Scheme 2; see Experimental
section).§ EPR-spectra, which were recorded from likewise
prepared solutions, showed characteristic signals of spin adducts
Fig. 2 EPR spectra of spin adducts 4b (top) and 4d (bottom) in C6H6
(20 ◦C).
b
4a–d (for 4b and 4d see Fig. 2).13 Coupling constants aN, aH and
2.2 Bu3SnH-mediated reactions
aHc (Table 1) were calculated on the basis of spectrum simulation
(i) Additions – intramolecular C,O bond formation. Suit-
able conditions for pursuing microwave-accelerated syntheses of
substituted tetrahydrofurans were established using N-(2-phenyl-
4-penten-1-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1e) as a reporter molecule. The compound was converted
into 2-phenyl-4-penten-1-al (6e, 27%),15 2-phenyl-4-penten-1-ol
(7e, 16%),16 5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione
(9, 31%),17 5-(p-methoxyphenyl)-4-methylthiazole (10, 2%), and
and numerical analysis of fitted curves.14
◦
Scheme
2
Microwave-assisted reaction between N-(alkoxy)thiazole-
disulfide 11 (5%), if heated to 80 C for 10 min in a solution of
thiones 1a–d and DMPO (3). For indexing of nitroxyl radicals 4 see Table 1.
C6H5CF3 using a mono-mode microwave device (Table 2, entry 1).
The starting material 1e was recovered in 52% yield. The stability
of thione 1e decreased considerably if heated in the presence of
Bu3SnH under otherwise identical conditions. Suitable parameters
that allowed the complete consumption of N-alkenoxy compound
1e on a reasonable time scale were established by varying the
temperature profiles, the tin hydride concentration and amount
(data not shown). As a baseline result of this screening, 2.5 equiv.
of Bu3SnH were required in order to convert thione 1e (within
1 min) into 2-methyl-4-phenyltetrahydrofuran (5e, 64%)18 and
the tributyltin adduct 8 (91%), besides minor amounts of the
aldehyde 6e (5%) and alkenol 7e (2%), as established by 1H
NMR analysis (Table 2, entry 2). The major compounds formed
in the latter reaction were isolated in similar but not identical
yields from a larger scale experiment (Table 2, entry 2, numbers
given in brackets). For comparison, 4.0 equiv. of Bu3SnH were
necessary in order to prepare tetrahydrofuran 5e (64%, cis : trans =
88 : 12) from thiazolethione 1e (within 5–10 min) by conductive
Table 1 Coupling constants of spin adducts 4a–d (C6H6, 20 ◦C)
Entry
4
R
g
aN/G
aHb/G
aHc/G
1
2
3
4
a
b
c
CH3
C2H5
CH(CH3)2
C(CH3)3
2.008
2.008
2.008
2.008
12.8
12.9
12.9
13.1
6.6
6.9
6.3
9.3
1.7
1.7
1.9
1.5
d
§ All microwave-assisted experiments were performed using special glass-
ware and microwave equipment. lW = Microwave irradiation. Chiral N-
(alkoxy)thiazolethiones 1 and 2 were used as racemates, thus leading to
racemic products.
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Table 2 Screening for reactivity – microwave-assisted transformations of N-(2-phenyl-4-penten-1-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1e)a
Entry
Bu3SnH (equiv.) t/min T/◦C
Solvent
5e (%) (cis : trans) 6e (%)
7e (%)
8 (%)
9 (%)
10 (%)
11 (%)
c
1
2
3
4
0
10b
1.0
3.0
1.5
80
80
60
80
C6H5CF3
C6H5CF3
C6H5CF3
C6H6
–
[27]
5
[16]
2
—
91 [87]
78
[31]
—
4
3
[2]
[5]
c
c
c
2.5
2.0
2.5
64 [53] (88 : 12)
56 (88 : 12)
59 (88 : 12)
—
—
—
—
c
c
c
c
—
—
c
c
c
c
—
—
89
—
—
a An = p-H3COC6H4. Yields were determined by 1H NMR, except for the values in square brackets, which are isolated yields. b 48% conversion of 1a.
c Not detected (1H NMR).
heating (oil bath). If photolyzed for 20 min (350 nm, 30 ◦C)
in a solution of C6H5CF3 and 4.0 equiv. of Bu3SnH, thione 1e
provided 2-methyl-4-phenyltetrahydrofuran (5e, 63%) (data for
the latter two experiments is not shown). A decrease of the bulk
temperature and the amount of Bu3SnH slightly reduced the yield
of target compound 5e (Table 2, entry 3, 1H NMR). Experiments
◦
in C6H6 (80 C) took 1.5 min in order to quantitatively convert
thiazolethione 1e in the presence of Bu3SnH into disubstituted
tetrahydrofuran 5e (Table 2, entry 4). As a standard, the use of
2.0–2.5 equiv. of Bu3SnH, with C6H5CF3 as solvent, a reaction
temperature of 80 ◦C, a total time of 2.0–2.5 min, and 500 W
microwaves were set as optimized conditions in order to perform
the succeeding experiments.
Control experiments on the stability of relevant prod-
ucts showed that 2-methyl-4-phenyltetrahydrofuran (5e) (cis :
trans = 88 : 12), and 5-(p-methoxyphenyl)-4-methyl-2-(tri-n-
butylstannylsulfanyl)thiazole (8) were quantitatively recovered,
whereas disulfide 11 afforded 9% 4,5-disubstituted thiazole 10,
if microwave-heated (80 ◦C) in C6H5CF3, according to 1H
NMR analysis. Treatment of [5-(p-methoxyphenyl)-4-methyl-2-
thiazyl]disulfide (11) with Bu3SnH under these conditions afforded
Scheme 3 Control experiments for investigating product stability under
28% of thiazolethione 9 (Scheme 3).
microwave conditions.
In order to obtain additional information on the selectivity
of alkoxyl radical cyclizations upon microwave activation of N-
(alkenoxy)thiazolethiones, 4-(p-chlorophenyl)-substituted com-
pounds 2e–h were treated with Bu3SnH under the established op-
timized conditions (see Table 2, entry 2). Each of the reactions fur-
nished the corresponding disubstituted tetrahydrofuran 5e–h (52–
70%) and 2-(tributylstannyl)sulfanyl-4-(p-chlorophenyl)thiazole
12 (74–93%, 1H NMR analysis).5 Cis-diastereoisomers were
favored in syntheses of 2,4-substituted heterocycles 5e (cis : trans =
88 : 12) and 5f (cis : trans = 90 : 10) (Table 3, entries 1–2), whereas
trans-diastereoisomers were favored in syntheses of 3-(tert-butyl)-
2-methyltetrahydrofuran (5g) (cis : trans <2 : 98) and 5-isopropyl-
2-phenyltetrahydrofuran (5h) (cis : trans = 30 : 70; Table 3, entries
3–4).11,19 Carbonyl compounds (6e: 8%, 6f: 12%, 6g: 4%, 6h: 11%;
1H NMR analysis), and alkenols (7e: 5%, 7f: 7%, 1H NMR
analysis, Table 3) were formed as minor products.11 If repeated
on a preparative scale (1 mmol), thiazolethione 2e provided 61%
of 2-methyl-4-phenyltetrahydrofuran (5e) (cis : trans = 88 : 12)
and 84% of tributyltin adduct 12 (Table 3, entry 1, numbers in
brackets) after purification of the reaction mixture.
A search for a substitute for Bu3SnH for possible future syn-
thetic applications of microwave-assisted alkoxyl radical reactions
under reductive conditions showed that derivatives of the a-
amino acid cysteine, i.e. L-cysteine ethyl ester hydrochloride (L-
CysOEt·HCl) or the reduced form of glutathione (GSH), were ad-
equate for this purpose.20 Since both compounds are water-soluble,
transformations between N-(2-phenylpentenoxy)thiazolethione
2e and GSH, or the reagent combination of L-CysOEt·HCl and
NaOH, were conducted in 1,4-dioxane–H2O (2 : 1, v/v), to provide
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Table 3 Conversion of N-(alkoxy)-4-(p-chlorophenyl)thiazolethiones 2e–h in the presence of Bu3SnH under microwave conditionsa
Entry
2, 5–7
Ra
Rb
Rc
Rd
5 (%) (cis: trans)
6 (%)
7 (%)
12 (%)
1
2
3
4
e
f
g
h
H
H
H
C6H5
C6H5
C(CH3)3
H
H
H
H
H
H
CH3
70 [61] (88 : 12)
54 (90 : 10)b
8
12
4
5
7
—
93 [84]
74
81
d
C(CH3)3
H
52 (<2 : 98)b,c
58 (30 : 70)
d
H
11
—
88
a CP = p-ClC6H4; 2.0–2.5 equiv. Bu3SnH. Yields of compounds 5–7 and 12 were determined by 1H NMR, except for the values in square brackets, which
are isolated yields. b GC. c Cis-5g was not detected (1H NMR). d Not detected (1H NMR).
2-methyl-4-phenyltetrahydrofuran (5e) in 31% yield (with GSH
as the hydrogen atom donor) or 43% yield (with L-CysOEt·HCl,
Scheme 4). Both syntheses provided minor amounts (12–18%) of
2-phenylpentenal (6e) as a side product (Scheme 4). No evidence
(TLC and 1H NMR) for formation of the expected adduct of the
L-cysteine-derived S-radical to the thione sulfur in 2e was evident
from the crude reaction mixtures. On a qualitative basis, thiazole-
derived products resembled those specified for the conversion of
thione 1e in the absence of Bu3SnH (Table 2).20
(ii) b-C,C-cleavage – formation of carbonyl compounds. N-
(Cis-2-methylcyclopentoxy)-5-(p-methoxyphenyl)-4-methylthia-
zole-2(3H)-thione (1i) afforded hexanal (13i, 78%) (GC), 2-
(tributylstannyl)sulfanylthiazole (8, 96%) and a small amount of
5-(p-methoxyphenyl)-4-methylthiazole (10), if treated for 1 min
at 70 ◦C in a solution of C6H5CF3 with Bu3SnH (3.0 equiv.)
in a mono-mode microwave device (Table 4, entry 1). In order to
prevent loss of aldehyde 13i due to evaporation, the temperature
was constrained to 70 ◦C in this experiment. The same conditions
were applied to prepare 4-phenylpentanal (13j, 42%)21 (1H NMR),
and tributyltin adduct 8 (93%) from cis-2-phenylcyclopentoxy-
substituted thiazolethione 1j and Bu3SnH (Table 4, entry 2).
2.3 BrCCl3-mediated reactions
(i) Additions – 5-exo-trig bromocyclizations. The feasibility
of heteroatom-trapping of alkoxyl radical reaction products22
under microwave conditions was explored using BrCCl3 as
the heteroatom donor and N-(alkenoxy)-5-(p-methoxyphenyl)-
4-methylthiazolethiones 1e and 1h as O-radical sources. Based
Scheme 4 The use of water-soluble thiols as reactive hydrogen atom
donors in tetrahydrofuran syntheses starting from N-(2-phenyl-4-penten-
1-oxy)thiazolethione 2e (CP = p-ClC6H4). a Addition of 9 equiv. of NaOH
required. b 2 : 1, v/v.
Table 4 Formation of aldehydes from 2-substituted N-(cyclopentoxy)thiazolethiones 1i and 1j and Bu3SnH
Entry
1, 13
Re
13 (%)
8 (%)
10 (%)
1
2
i
j
CH3
C6H5
78b
42
96
93
4
—
c
a An = p-H3COC6H4; 3.0 equiv. of Bu3SnH. Yields were determined by 1H NMR, unless otherwise noted. b GC. c Not detected (1H NMR).
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a
Table 5 Microwave-assisted conversion of N-(alkenoxy)thiazolethiones 1e and 1h in the presence of BrCCl3
Entry
1, 6, 7, 14
Ra
Rb
Rd
14 (%) (cis : trans)
6 (%)
7 (%)
15 (%)
1
2
e
h
H
C6H5
C6H5
H
H
CH3
68 [62] (88 : 12)
51 (30 : 70)
18
15
12
16
84 [79]
76
a An = p-H3COC6H4; 3.0 equiv. of BrCCl3; 3.0–5.0 equiv. of AIBN. Yields were determined by 1H NMR, except for the values in square brackets, which
are isolated yields.
on results from a supplementary study (data not shown), AIBN
(3.0 equiv.) had to be added, in order to drive the bromination
reactions to completion within 2 min. Application of these
parameters furnished 2-bromomethyl-4-phenyltetrahydrofuran
(14e,23 68%, cis : trans = 88 : 12), aldehyde 6e (18%), alkenol
7e (12%) and 5-(p-methoxylphenyl)-4-methyl-2-(trichloromethyl-
sulfanyl)thiazole (15, 84%) from N-(alkenoxy) compound 1e
In a final bromocyclization experiment, a solution of N-(5-
methyl-1-phenyl-4-hexen-1-oxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1h) in C6H5CF3 was heated under opti-
mized microwave conditions to afford 2-(1-bromo-1-methylethyl)-
5-phenyltetrahydrofuran (14h, 51%, cis : trans = 30 : 70),22 5-
methyl-1-phenyl-4-hexen-1-one (6h, 15%), the derived alkenol 7h
(16%) and trichloromethylsulfanylthiazole 15 (76%) (Table 5,
entry 2).
1
(Table 5, entry 1; H NMR analysis).24 If repeated on a 1 mmol
scale, bromomethyltetrahydrofuran 14e (62%, cis : trans = 88 : 12),
and trichloromethyl adduct 15 (79%) were isolated as analytically
pure samples after chromatographic work up of the reaction
mixtures (Table 5, entry 1, figures in square brackets). In order
to compare the efficiency of microwave activation, conductive
heating, and photochemical reactions for initiating O-radical
reactions starting from N-(alkoxy)thiazolethiones, two further
experiments were performed. Under thermal condititions, (5–
10 min of heating in an oil bath at 80 ◦C in C6H5CF3), 10–
15 equiv. of AIBN and 5.0 equiv. of BrCCl3 were necessary for
converting thione 1e into bromocyclization product 14e (55%,
cis : trans = 88 : 12). In the photochemically induced reaction, 2-
bromomethyl-4-phenyltetrahydrofuran (14e, 59%, cis: trans = 88 :
12) was prepared upon irradiating (350 nm, 30 ◦C) a solution of
N-(2-phenylpentenoxy)thiazolethione 1e and 5.0 equiv. of BrCCl3
in C6H5CF3 for 20 min (data for the latter two experiments is not
shown).
(ii) Homolytic substitution – remote functionalization. Heat-
ing of
a solution of N-(1-pentoxy)-5-(p-methoxyphenyl)-4-
methylthiazolethione 1k, AIBN (3.0 equiv.), and BrCCl3 (5.0
equiv.) in C6H5CF3 for 2.5 min in a mono-mode microwave
instrument provided 4-bromopentan-1-ol (16k,6 64%) (1H NMR;
Table 6, entry 1). In a similar way, 4-bromo-4-phenylbutan-
1-ol (16m,25 37%) was obtained from thione 1m (1H NMR;
Table 6, entry 2). Attempts to purify phenyl-substituted d-
bromohydrine 16m by chromatography (SiO2, petroleum ether–
Et2O = 1 : 1, v/v) resulted in a quantitative conversion of
the bromoalcohol into 2-phenyltetrahydrofuran.26 The hetero-
cyclic subunit of radical precursors 1k and 1m was trans-
formed in both reactions into 5-(p-methoxyphenyl)-4-methyl-2-
(trichloromethylsulfanyl)thiazole (15, 81% from 1k and 82% from
1m) and bisthiazyl disulfide 11 (3%).
Table 6 Formation of d-bromohydrins 16 from N-(alkoxy)thiazolethiones 1a
Entry
1, 16
Rf
AIBN (equiv.)
16 (%)
15 (%)
11 (%)
1
2
k
m
CH3
C6H5
2.0
4.0
64
37
81
82
3
3
a An = p-H3COC6H4; 5.0 equiv. of BrCCl3. Yields were determined by 1H NMR.
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Discussion
(i) Alkoxyl radical precursors
The synthesis of N-substituted thiazolethiones 1 and 2 was
performed according to established procedures or extensions
thereof.6,8 The selectivity of product formation and the associated
yields followed trends that have been discussed in detail for
structurally related derivatives of compounds 1 and 2.6,9 In view of
the severe difficulties noted in earlier reports of preparing tertiary
O-alkyl derivatives of cyclic thiohydroxamates,5,6,27 the newly
developed synthesis of N-(tert-butoxy)thiazolethione 1d deserves a
comment. The compound was finally obtained in 25% yield using
O-tert-butyl-N,N-diisopropylisourea28 as the alkylating reagent.
This procedure is under current investigation in order to improve
its yield and scope.
(ii) N,O-Cleavage, alkoxyl radical generation, and radical chain
mechanism
If dissolved in a low-absorbing solvent and heated in mi-
crowave device (2.45 GHz), N-(alkoxy)-5-(p-methoxyphenyl)-4-
methylthiazolethiones 1 undergo N,O-homolysis to furnish pri-
mary, secondary, or tertiary alkoxyl radicals, as shown by the
formation of spin adducts 4. The latter intermediates were iden-
tified by their characteristic g-values, magnitudes of the hyperfine
coupling constants aN, aHb, and aHc, and (decisively) by the changes
of EPR-parameter by gradually increasing the steric encroach-
ment at the c-position (Table 1).13 The yields of spin adducts 4a–d
were not quantified, and therefore the efficiency of N,O-homolyses
in thiones 1a–d under such conditions remained unclear. In
order to determine this crucial parameter, N-(2-phenyl-4-penten-
1-oxy)thiazolethione 1e, as a reporter molecule, was microwave-
irra◦diated in a mono-mode microwave instrument (500 W,
80 C).29–31 Approximately half of this compound decomposes
within 10 min at 80 ◦C to afford 2-phenyl-4-pentenal (6e), 2-
phenyl-4-penten-1-ol (7e), and a total of three thiazole derivatives
(Table 2). Although it is tempting to interpret these findings in
terms of alkoxyl radical generation and subsequent dispropor-
tionation, the mechanism that leads to formation of products 6e,
7e, and thiazole derivatives 9–11 has not hitherto been known.
The fact that no 5-exo-trig cyclization products were detected
(1H NMR) points to a non-radical fragmentation mechanism,
which requires future investigation. Selective N,O-fragmentation
by the alkoxyl radical mechanism, however, is attainable by adding
reactive atom-transfer reagents to microwave-irradiated solutions
of, e.g., thiones 1e or 2e, as documented by the formation of
2-methyl-4-phenyltetrahydrofuran (5e) and tributyltin adducts
8 or 12 (using Bu3SnH as mediator).9 The synthesis of these
compounds under such conditions is considered to occur by a
chain mechanism (Scheme 5). Experimental evidence to support
this interpretation originate from (i) results of spin-trapping
experiments, (ii) stereochemical preferences for formation of major
cyclization products of 5e–h, which follow the guideline for the 4-
penten-1-oxyl radical ring closure that is distinctively different
from selectivities in polar cyclizations,32 and (iii) the mass balance
between tributyltin adducts 8 and 12 and cyclic ethers 5e–h. The
sequence is considered to start by thermal activation of, for in-
stance, N-(2-phenyl-4-pentenoxy)thiazolethione 1e. Alkoxyl rad-
ical release furnishes intermediate 17e, which selectively cyclizes
Scheme
5
Elementary reactions for the formation of 2-methyl-4-
phenyltetrahydrofuran (5e) and 2-bromomethyl-4-phenyltetrahydrofuran
(14e) in radical chain reactions starting from N-(2-phenyl-4-pentenoxy)-
thiazolethione 1e. Step A: 5-exo-trig cyclization. Step B: hydrogen
(Bu3SnH) or bromine atom transfer (BrCCl3) onto cyclized radical 18e.
Step C: addition of the chain carrying the Y• radical (Bu3Sn• or •CCl3) to
a second molecule of thione 1e. X–Y = H–SnBu3, Br–CCl3.
in a 5-exo-trig manner in a fast, kinetically controlled reaction
to afford cyclized radical 18e.18 Trapping of tetrahydrofuryl-2-
methyl radical 18e with Bu3SnH (see also section (iii) in the
Discussion) provides 2-methyl-4-phenyltetrahydrofuran (5e) and
radical Bu3Sn . The tin radical adds to the C S group in 1e to
afford an adduct (not shown) that undergoes N,O-homolysis, thus
leading to the formation of tributylstannylsulfanyl-substituted
thiazole 8 and a second O-radical 17e.
•
=
(iii) Hydrogen atom trapping
Bu3SnH (BDE Sn–H = 326.4 kJ mol−1)33 in a solution of C6H5CF3
was the most effective mediator for performing alkoxyl radical
reactions in this study. Application of this reagent furnished disub-
stituted tetrahydrofurans (intramolecular additions) or aldehydes
(b-fragmentations) without the necessity to add AIBN for the
complete consumption of O-radical precursor 1 or 2.9 A change
of hydrogen donor to water-soluble non-toxic thiols (BDE S–H:
e.g. n-PrS–H = 365.7 kJ mol−1)34 offers the benefit to apply an
aqueous solvent at the expense of a slightly reduced yield of cyclic
ether 5e.20
(iv) Bromine atom trapping
Bromine atom trapping experiments (BDE Cl3C–Br = 231
4 kJ mol−1)35 required the use of at least 2.0 equiv. of AIBN,
in order to prepare organobromine compounds in synthetically
useful yields. By considering its decomposition parameters, it is
obvious that the azo compound cannot be completely consumed
within the time span applied for converting thiones 1 and 2 into
target compounds 14 or 16 under microwave conditions.36 Results
from additional experiments indicated that the only detectable
spin adduct that is formed in a microwave-heated solution
2318 | Org. Biomol. Chem., 2006, 4, 2313–2322
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of N-(methoxy)-5-(p-methoxyphenyl)-4-methylthiazolethione 1a,
AIBN, and DMPO (3) in C6H5CF3 (Tmax = 120 ◦C) originates
from •C(CH3)2CN addition to the nitrone (not shown in Table 1).
On the other hand, no products of C(CH3)2CN addition to
sulfur, similar to structures of sulfides 8, 12, 15, were detected
in any of the bromination reactions. The role of AIBN in these
reactions therefore has to be restricted to •CCl3 radical generation
Conclusions
Microwave activation constitutes a significant improvement for
the generation of O-radicals from N-(alkoxy)thiazolethiones.
The intermediates formed in the present study underwent effi-
cient cyclizations (synthesis of disubstituted tetrahydrofurans), b-
fragmentations (formation of carbonyl compounds), and C,H-
activation of aliphatic subunits by d-selective hydrogen atom
transfer under mild and neutral conditions. The advantage of
the microwave method originates from considerably shorter re-
action times and the use of smaller amounts of trapping reagents.
It is compatible with aqueous and organic solvents, without the
necessity to perform radical-based transformation in an inert gas
atmosphere.
•
from BrCCl3. A second pathway that provides CCl3 radicals
is associated with the closing homolytic substitution step of
the synthesis of bromocyclization products 14 (Scheme 5) or d-
•
bromohydrins 16. If a bimolecular rate law for CCl3 addition
=
to the C S p-bond in N-(alkoxy)thiazole-2(3H)-thiones applies,
the radical concentration is the key for controlling the rate of this
process in order to make it fit into the kinetic scheme of the
proposed chain mechanism (Scheme 5).9 The propensity of the
•CCl3 radical to carry a chain reaction in thiohydroxamate-
based free radical brominations has been well documented in the
literature.22,37 In view of the fact that 2.0 equiv. of AIBN (and
sometimes more) are required in order to obtain the yields of
organobromine compounds that are listed in Tables 5 and 6, it is,
however, unlikely that a very efficient chain reaction is maintained
under these conditions.
Experimental
1. General remarks
Standard instrumentation and general remarks have been dis-
closed previously (see also ESI†).22
Microwave and EPR instrumentation. The following mi-
R
crowave equipment was used: A MLS–Ethosꢀ 1600 mono-mode
instrument (Milestone) [500 W, quartz glass vessel (length 15 cm,
diameter 2 cm), equipped with a 20 bar excess pressure valve,
stirring device, cooling fan, and temperature measurement by fiber
(v) Comparison between radical precursors and methods for
initiating alkoxyl radical reactions
R
optics], and a Discoverꢀ instrument (CEM) [300 W, quartz glass
According to the results of the present study, microwave irradiation
is a powerful method for activating N-(alkoxy)thiazolethiones
by the alkoxyl radical pathway. Its use offers the advantage to
cut reaction times by a factor of about 10 and to lower the
required amount of trapping reagent by a factor of approximately
2, if compared to the parameters applied in experiments initiated
by conductive heating or UV/Vis photolysis. The O-radical
selectivities observed in microwave-assisted transformations con-
sistently agreed with those measured in related studies.9,22 The
observed microwave effect is therefore restricted to the alkoxyl
radical-forming step. Whereas AIBN is generally required for
initiating thermally induced alkoxyl radical generation from N-
(alkoxy)thiazolethiones 1 or 2 by conductive heating, its use under
microwave conditions was restricted to bromination reactions.
Free radical bromocyclizations that proceed in the absence of
additional AIBN, however, are attainable. In this case the reaction
between a given N-(alkoxy)thiazolethione 1 or 2 and BrCCl3 has
to be initiated using an appropriate light source.22,38
The differences between the ability of N-(alkoxy)-5-(p-meth-
oxyphenyl)-4-methylthiazolethiones 1 and 4-(p-chlorophenyl)-
substituted derivatives 2 to afford products of alkoxyl radical-
based transformations were small (see ESI†). In the present
study, the use of 5-(p-methoxyphenyl)-4-methylthiazolethiones 1
was favored, due their more efficient synthetic access, improved
characteristics, and reliable performance in 5-exo-trig cyclizations,
b-fragmentations, and remote functionalizations.
vessel (length 9 cm, inside diameter 1.3 cm) equipped with a 20 bar
excess pressure valve, stirring device, cooling fan, and temperature
measurement by an IR sensor; mode: power time]. 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.
Materials. NEt4OH (25% solution in MeOH, w/w), Bu3SnH,
ꢀ
BrCCl3, a,a -azobis(isobutyronitrile) (AIBN) were obtained
from commercial sources and were used as received (Fluka, Merck,
Lancaster).
N-(Hydroxy)-4-(p-chlorophenyl)thiazole-2(3H)-
thione tetraethylammonium salt,8 N-(hydroxy)-5-(p-methoxy-
phenyl)-4-methylthiazole-2(3H)-thione tetraethylammonium salt,8
2-phenyl-4-penten-1-yl p-toluenesulfonate,18 1-chloro-5-methyl-1-
phenyl-4-hexene,19 n-pentyl p-toluenesulfonate,19 trans-2-methyl-
cyclopentyl p-toluenesulfonate,21 trans-2-phenylcyclopentyl p-
toluenesulfonate,21 2-(1,1-dimethylethyl)-4-penten-1-yl p-toluene-
sulfonate,11 3-(1,1-dimethylethyl)-4-penten-1-yl p-toluene-sul-
fonate,11 N-methoxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1a),8 and N-(ethoxy)-5-(p-methoxyphenyl)-4-methyl-thia-
zole-2(3H)-thione (1a)6 were prepared according to published pro-
cedures. 4-Phenyl-1-butyl p-toluenesulfonate was prepared from
the corresponding alcohol by adapting a general procedure for the
preparation of alkyl tosylates.39 All solvents and reagents were
purified following recommended standard procedures.40 Petro-
leum ether refers to the fraction boiling in the range 45–55 ◦C.
As a final remark, it is worth mentioning that a removal of O2
using freeze–pump–thaw cycles (with Ar as inert gas), which was a
prerequisite for obtaining adequate yields in thermally (conductive
heating) or photochemically-induced reactions, was not necessary
for successfully performing synthetic alkoxyl radical chemistry
under microwave conditions. None of the latter experiments were
performed under Ar.
2. Synthesis of N-(alkoxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thiones
General procedure. A round-bottomed flask was charged
with N-(hydroxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione tetraethylammonium salt (0.84 g, 2.20 mmol), an
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appropriate alkyl chloride or tosylate (2.20 mmol), and DMF
(7 mL) under argon to exclude moisture. The reaction mixture was
stirred for 4–6 days at 20 ◦C in the dark. Afterwards, it was diluted
with tert-butyl methyl ether (30 mL). H2O (30 mL) was added and
the phases were separated. The aqueous layer was extracted with
tert-butyl methyl ether (3 × 20 mL). The combined organic phases
were washed with a saturated aqueous solution of NaHCO3
and brine (10 mL each). After drying (MgSO4), the solvent was
removed under reduced pressure to furnish an oil, which was
purified by chromatography (SiO2, petroleum ether–Et2O).
19.82; found C 59.64, H 6.42, N 4.34, S 19.48; kmax (EtOH)/nm (lg
e) 336 (4.76); dH (400 MHz; CDCl3) 0.94 (t, J = 7.2, 3 H), 1.41 (ddd,
J = 6.9, 7.7, 14.7, 2 H), 1.53–1.45 (m, 2 H), 1.85 (dd, J = 6.8, 13.5,
2 H), 2.32 (s, 3 H, CH3), 3.83 (s, 3 H, OCH3), 4.45 (t, J = 6.7, 2 H),
6.94 (mc, 2 H, Ar–H), 7.22 (mc, 2 H, Ar–H); dC (100 MHz; CDCl3)
12.4 (CH3), 14.3, 22.9, 27.9, 28.2, 55.8 (OCH3), 76.8, 114.7, 119.7,
+
=
123.0, 130.2, 132.6, 160.3, 179.1 (C S); m/z (EI, 70 eV) 323 [M ]
(28%), 307 (7), 237 (74), 221 (11), 178 (19), 146 (18), 70 (21).
N-(4-Phenyl-1-butoxy)-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione (1j). Yield: 0.85 g (44%) from 0.67 g of 4-phenyl-1-
butyl tosylate; Rf = 0.40 (SiO2, petroleum ether–Et2O = 2 : 1, v/v),
N-(Isopropoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1c). Yield: 0.47 g (73%) from 2-propyl tosylate (0.47 g,
2.20 mmol); Rf = 0.40 (SiO2, petroleum ether–Et2O = 2 : 1, v/v),
light orange powder. C14H17NO2S2 (295.42) requires C 56.92, H
5.80, N 4.74, S 21.71; found C 56.81, H 5.93, N 4.86, S 21.34; dH
(250 MHz; CDCl3) 1.38 (d, J = 6.1, 6 H, CH3), 2.29 (s, 3 H, CH3),
3.83 (s, 3 H, OCH3), 5.50 (sept., J = 6.1, 1 H, OCH3), 6.94 (d,
J = 8.8, 2 H, Ar–H), 7.24 (d, J = 8.8, 2 H, Ar–H); dC (63 MHz;
CDCl3) 12.7 (CH3), 20.6 (CH3), 25.4, 55.4 (OCH3), 78.6 (OCH),
◦
◦
colorless solid (petroleum ether), mp 71 C (DTA), dec. 116 C
(DTA); C21H23NO2S2 (385.55) requires C 65.42, H 6.01, N 3.63,
S 16.63; found C 64.85, H 5.89, N 3.68, S 16.35; dH (400 MHz;
CDCl3) 1.88 (mc, 4 H), 2.30 (s, 3 H, CH3), 2.72 (t, J = 7.1, 2 H),
3.84 (s, 3 H, OCH3), 4.45 (t, J = 5.9, 2 H), 6.94 (mc, 2 H, Ar–H),
7.22 (mc, 2 H, Ar–H), 7.18–7.32 (m, 5 H, Ph–H); dC (100 MHz;
CDCl3) 12.4 (CH3), 27.8, 27.9, 31.3, 55.8 (OCH3), 76.4, 114.9,
119.7, 122.9, 126.3, 128.7, 128.8, 130.2, 132.5, 142.2, 160.3, 179.1
+
=
(C S); m/z (EI, 70 eV) 237 [C11H11NOS2 ] (2%), 222 (1), 148 (8),
104 (100), 91 (43).
=
114.3, 114.5, 119.3, 122.7, 129.9, 130.4, 133.4, 159.9, 179.2 (C S);
kmax (EtOH)/nm (lg e) 334 (4.48), 258 sh; m/z (EI, 70 eV) 295 [M+]
(55%), 237 [C11H11NOS2 ] (100), 178 [C10H10SO+] (35).
+
N-(Cis-2-methylcyclopentoxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1k). Yield: 0.75 g (77%) from trans-2-
methylcylopentyl tosylate (0.56 g); Rf = 0.30 (SiO2, petroleum
ether–Et2O = 3 : 1, v/v), yellowish solid (petroleum ether–Et2O),
mp 62 ◦C (DTA), dec. 106 ◦C (DTA); C17H21NO2S2 (335.49)
requires C 60.86, H 6.31, N 4.18, S 19.11; found C 60.60, H 6.45,
N 4.12, S 18.59; kmax (EtOH)/nm (lg e) 338 (4.11), 230 (4.15); dH
(400 MHz; CDCl3) 1.27 (s, 3 H, CH3), 1.62 (mc, 1 H), 1.70 (mc, 1
H), 1.78 (mc, 1 H), 1.87–1.97 (m, 1 H), 1.92 (mc, 1 H), 1.98 (mc,
1 H), 2.22–2.15 (m, 1 H), 2.30 (s, 3 H, CH3), 3.83 (s, 3 H, OCH3),
5.62 (dt, J = 4.8, 4.9, 1 H), 6.94 (mc, 2 H, Ar–H), 7.24 (mc, 2 H, Ar–
H); dC (100 MHz; CDCl3) 12.5 (CH3), 13.6, 21.9, 29.6, 31.4, 39.3,
N-(2-Phenyl-4-penten-1-oxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1e). Yield: 0.87 g (67%) from 2-phenyl-
4-penten-1-yl tosylate (0.70 g, 2.20 mmol); Rf = 0.35 (SiO2,
petroleum ether–Et2O = 2 : 1, v/v), colorless solid (petroleum
ether–Et2O), mp 69 ◦C (DTA), dec. 105 ◦C (DTA); C22H23NO2S2
(397.57) requires C 66.47, H 5.83, N 3.52, S 16.13; found C 66.31,
H 5.97, N 3.48, S 15.87; dH (400 MHz; CDCl3) 1.96 (s, 3 H, CH3),
2.54 (ddd, J = 1.4, 8.1, 14.2, 1 H), 2.73 (ddd, J = 1.1, 6.1, 13.1,
1 H), 3.29 (ddt, J = 6.3, 7.5, 13.6, 1 H), 3.83 (s, 3 H, OCH3), 4.50
(t, J = 7.5, 1 H), 4.76 (dd, J = 6.3, 7.6, 1 H), 5.00 (dd, J = 1.9,
12.2, 1 H), 5.07 (dd, J = 1.8, 17.1, 1 H), 5.74 (dddd, J = 6.9, 10.4,
13.9, 17.2, 1 H), 6.91 (mc, 2 H, Ar–H), 7.16 (mc, 2 H, Ar–H) (mc =
centred multiplet), 7.22–7.30 (5 H, m, Ph); dC (100 MHz; CDCl3)
11.6 (CH3), 36.5, 44.4, 55.4 (OCH3), 79.2, 114.5, 117.1, 122.5,
55.4 (OCH3), 89.8, 114.5, 119.3, 122.7, 129.8, 133.6, 159.8, 179.3
+
=
(C S); m/z (EI, 70 eV) 335 [M ] (27%), 237 (100), 151 (15), 98 (42).
N -(Cis-2-phenylcyclopentoxy)-5-(p-methoxyphenyl)-4-methyl-
thiazole-2(3H)-thione (1m). Yield: 0.87 g (53%) from trans-2-
phenylcyclopentyl tosylate (0.70 g); Rf = 0.35 (SiO2, petroleum
ether–Et2O = 2 : 1, v/v), yellow solid (petroleum ether–Et2O), mp
85 ◦C (DTA), dec. 100 ◦C (DTA); C22H23NO2S2 (397.56) requires
C 66.47, H 5.83, N 3.52, S 16.13; found C 66.22, H 5.93, N 3.40, S
15.85; kmax (EtOH)/nm (lg e) 338 (4.14), 232 (4.16); dH (400 MHz;
CDCl3) 1.94 (s, 3 H, CH3), 1.84–2.38 (m, 6 H), 3.34 (ddd, J = 4.4,
7.2, 1 H), 3.82 (s, 3 H, OCH3), 6.01 (t, J = 3.9, 1 H), 6.91 (mc,
2 H, Ar–H), 7.13 (mc, 2 H, Ar–H), 7.21 (mc, 1 H, Ph), 7.32 (mc,
2 H, Ph), 7.50 (mc, 2 H, Ph); dC (100 MHz; CDCl3) 12.6 (CH3),
22.3, 29.4, 30.3, 50.7, 55.8 (OCH3), 89.2, 114.8, 123.1, 126.9, 128.4,
=
127.0, 128.0, 128.5, 129.8, 135.4, 140.8, 159.9, 178.7 (C S); m/z
(EI, 70 eV) 237 [C11H11NOS2 ] (5%), 222 (1), 131 (78), 91 (100).
+
N-(5-Methyl-1-phenyl-4-hexen-1-oxy)-5-(p-methoxyphenyl)-4-
methylthiazole-2(3H)-thione (1h). Yield: 0.94 g (52%) from
1-chloro-5-methyl-1-phenyl-4-hexene (0.46 g, 2.20 mmol); Rf =
0.35 (SiO2, petroleum ether–Et2O = 3 : 1, v/v), yellowish solid,
mp 78–80 ◦C; C24H27NO2S2 (425.61) requires C 67.73, H 6.39,
N 3.29, S 15.07, found C 67.78, H 6.48, N 3.48, S 15.37; dH
(400 MHz; CDCl3) 1.48 (s, 3 H, CH3), 1.59 (s, 3 H, CH3), 1.68
(s, 3 H), 2.03–2.19 (m, 4 H), 3.79 (s, 3 H, OCH3), 5.09 (dt, J =
1.2, 5.2, 1 H), 6.09 (dd, J = 6.2, 8.0, 1 H), 6.85 (d, J = 6.2, 2 H,
Ar–H), 7.01 (d, J = 7.0, 2 H, Ar–H), 7.34–7.40 (m, 5 H, Ph); dC
(100 MHz; CDCl3) 12.6 (CH3), 18.1, 24.7, 26.1, 32.3, 86.5, 114.8,
=
129.2, 130.2, 134.0, 138.9, 160.2, 180.1 (C S); m/z (EI, 70 eV) 397
[M+] (0.1%), 160 (45), 118 (17), 104 (100), 91 (22).
N-(Tert-butoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1d). A solution of tert-butanol (74.1 mg, 1.00 mmol)
and diisopropyl carbodiimide (139 mg, 1.10 mmol, 0.17 mL)
was treated with CuCl (2.00 mg, 20.2 lmol) and stirred for
24 h at 20 ◦C. This mixture was treated at −40 ◦C with a
solution of N-(hydroxy)-5-(p-methoxyphenyl)-4-methylthiazole-
2(3H)-thione (0.38 g, 1.50 mmol) in CH2Cl2 (2 mL). Stirring
was continued for 24 h at 20 ◦C. The solids were removed by
=
123.5, 129.0, 129.2, 129.6, 130.0, 130.3, 134.2, 137.2, 180.0 (C S);
m/z (EI, 70 eV) 188 [C13H16O+] (13%), 105 (100), 77 (38).
N -(1-Pentoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-
thione (1i). Yield: 0.72 g from 1-pentyl tosylate (0.53 g,
2.20 mmol); Rf = 0.35 (SiO2, petroleum ether–Et2O = 2 : 1, v/v),
◦
◦
colorless solid (petroleum ether), mp 50 C (DTA), dec. 114 C
(DTA); C16H21NO2S2 (323.48) requires C 59.41, H 6.54, N 4.33, S
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filtration to afford a clear solution, which was concentrated under
reduced pressure. The residue was purified by chromatography
(SiO2, petroleum ether–Et2O = 2 : 1, v/v) to afford 77.8 mg
(25%) of N-(tert-butoxy)thiazolethione 1d. Rf = 0.31 (petroleum
ether–Et2O = 2 : 1, v/v); C15H19NO2S2 (309.44) requires C 58.22,
H 6.19, N 4.53, S 20.72; found C 58.21, H 6.02, N 4.36, S 20.38;
dH (400 MHz; CDCl3) 1.63 (s, 9 H, 2-H), 2.31 (s, 3 H, 4ꢀ-CH3),
3.83 (s, 3 H, O-CH3), 6.94 (mc, 2 H, Ar–H), 7.25 (mc, 2 H, Ar–H);
dC (100 MHz; CDCl3) 14.2 (CH3), 28.9, 55.4 (OCH3), 91.9, 114.5,
119.3, 123.0, 129.9, 134.3, 159.8, 182.5; m/z (EI, 70 eV) 309
methylthiazole-2(3H)-thione (1) (50 lmol) and a defined amount
of n-tetradecane (internal standard) were dissolved in C6H5CF3
(1 mL). Bu3SnH (2.0 equiv., 36 lL, 0.14 mmol) was added
to the mixture. The reaction vessel was closed, placed into
the microwave device and irradiated according to TP 4. The
reaction mixture was immediately analyzed by GC. For yields
refer to Tables 3 and 4. (ii) L-Cysteine derivatives as hydrogen
atom donors. A quartz glass vessel equipped with a 20 bar pres-
sure valve was charged with N-(2-phenyl-4-penten-1-oxy)-4-(p-
chlorophenyl)thiazole-2(3H)-thione (2e) (26.4 mg, 0.068 mmol),
L-cysteine ethyl ester hydrochloride (0.126 g, 0.68 mmol), NaOH
(27.2 mg, 0.61 mmol), 1,4-dioxane (1 mL), and H2O (0.5 mL).
The vessel was closed and irradiated according to TP 5. The
reaction mixture was analyzed by GC as described previously.20
The yields of 2-methyl-4-phenyltetrahydrofuran (5e) and 2-phenyl-
4-pentenal (6e) are compiled in Scheme 4. The reaction between
N-alkoxythiazolethione 2e and the reduced form of glutathione
(0.209 g, 0.68 mmol) and thiazolethione 2e was conducted and
analyzed as in the previous experiment.
[M+] (21%), 253 [C11H11NO2S2 ] (100), 160 [C10H10NO+] (30), 77
+
+
+
[C6H5 ] (7), 57 [C4H9 ] (11).
3. Microwave-assisted transformations
Temperature programs (TPs). For reactions using the MLS–
R
Ethosꢀ 1600 instrument (500 W, stirring device and cooling fan
turned on): TP1 (reactions in C6H6): 20 → 80 ◦C (1.5 min),
Tiso = 80 ◦C (1.0 min), 80 → 20 ◦C (3.0 min). TP 2 (reactions in
C6H5CF3): 20 → 80 ◦C (1.5 min), Tiso = 80 ◦C (for reaction times
refer to Schemes and Tables), 80 → 20 ◦C (5.0 min). TP 3:
(reactions in C6H5CF3): 20 → 60 ◦C (1.0 min), Tiso = 60 ◦C
(3.0 min), 60 → 20 ◦C (3.0 min). TP 4 (reactions in C6H5CF3):
20 → 70 ◦C (1.0 min), Tiso = 70 ◦C (1.0 min), 70 → 20 ◦C
(3.0 min). TP 5 (reactions in 1,4-dioxane–H2O): 20 → 80 ◦C
Preparative scale transformations. (i) In the absence of addi-
tional trapping reagents. A quartz glass vessel equipped with a 20
bar pressure valve was charged with N-(2-phenyl-4-penten-1-oxy)-
5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1e) (0.40 g,
1.01 mmol). C6H5CF3 (10 mL) was added. The vessel was closed
and irradiated according to TP 2 (Tiso = 10 min). The solvent was
evaporated under reduced pressure, and the residue was purified by
column chromatography (SiO2, petroleum ether–tert-butyl methyl
ether = 9 : 1, v/v) and thiazoles 9–11 to furnish 2-phenyl-4-
pentenal (5e) (43.7 mg, 27%, Rf = 0.48), 2-phenyl-4-penten-1-ol
(6e) (26.2 mg, 16%, Rf = 0.19 for petroleum ether–ethyl acetate =
9 : 1, v/v). 5-(p-Methoxyphenyl)-4-methylthiazole-2(3H)-thione
(9). Yield: 0.24 g (31%); Rf = 0.72 (SiO2, petroleum ether–
acetone = 2 : 1, v/v), colorless crystals (MeOH); C11H11NOS2
(237.33) requires C 55.67, H 4.67, N 5.90, S, 27.02; found C 55.43,
H 4.51, N 5.75, S 26.13. HR MS calcd. 237.0282, found 237.0282;
kmax (EtOH)/nm (lg e) 284 (4.23); dH (250 MHz; CDCl3) 2.31 (s,
3 H, CH3), 3.84 (s, 3 H, OCH3), 6.94 (d, J = 8.6, 2 H, Ar–H). 7.25
(d, J = 8.6, 2 H, Ar–H); dC (63 MHz; CDCl3) 33.7 (CH3), 36.6, 55.4,
114.4, 130.0, 159.8, 171.5; m/z (EI, 70 eV) 237 [M+] (100), 222 (17),
178 (5), 163 (14). 5-(p-Methoxyphenyl)-4-methylthiazole (10).
Yield: 4.1 mg (2%); Rf = 0.54 (SiO2, petroleum ether–acetone =
2 : 1, v/v), colorless powder (petroleum ether–Et2O); C11H11NOS
(205.28) requires C 64.36, H 5.40, N 6.82, S 15.62; found C 64.96,
H 5.23, N 6.54, S 15.47; HR MS calcd. 205.0561, found 205.0563;
dH (250 MHz; CDCl3) 2.55 (s, 3 H, CH3), 3.86 (s, 3 H, OCH3),
6.97 (d, J = 8.9, 2 H, Ar–H), 7.37 (d, J = 8.9, 2 H, Ar–H), 8.77
(s, 1 H); dC (63 MHz; CDCl3) 15.5 (OCH3), 55.4 (CH3), 107.9,
114.3, 123.4, 130.5, 146.8, 149.9, 159.7; m/z (EI, 70 eV) 205 [M+]
(100), 190 (44), 178 (11), 163 (23). 2,2ꢀ-Bis[5-(p-methoxyphenyl)-
4-methylthiazyl]disulfide (11). Yield: 4.8 mg (5%). Yellow needles
(MeOH); Rf = 0.63 (SiO2, petroleum ether–Et2O = 5 : 1, v/v);
C22H20N2O2S4 (472.65) requires C 55.91, H 4.27, N 5.93, S 27.13;
found: C 55.27, H 4.08, N 5.36, S 27.02; HR MS calcd. 472.0408,
found 472.0407; kmax (EtOH)/nm (lg e) 330 nm (4.37), 300sh (4.12);
dH (250 MHz; CDCl3) 2.46 (s, 6 H, CH3), 3.84 (s, 6 H, OCH3), 6.94
(d, J = 8.3, 4 H, Ar–H), 7.33 (4 H, d, J 8.3, Ar–H). m/z (EI, 70 eV)
472 [M+] (20), 237 (100), 205 (9), 178 (23), 163 (28). (ii) Bu3SnH
as hydrogen atom donor. A quartz glass vessel equipped with a
(1.0 min), Tiso = 80 ◦C (1.0 min), power off (1 min), Tiso
=
◦
◦
80 C (1.0 min), 80 → 20 C (3.0 min). For reactions using the
R
CEM-Discoverꢀ instrument (300 W, stirring device and cooling
fan turned to on): TP 6 (reactions in C6H6): 30 s reaction time,
which includes heat ramp 20 → 120 ◦C.
1
Experiments analyzed by H NMR spectroscopy. (i) Bu3SnH
as trapping reagent. In a typical run, an N-(alkoxy)-4-(p-
chlorophenyl)thiazole-2(3H)-thione (2) (0.054 mmol) was dis-
solved in C6H6 (1 mL) or C6H5CF3 (1 mL). Bu3SnH (36 lL,
0.14 mmol) was added to the reaction mixture. The reaction
vessel was closed, placed into the microwave device, and irradiated
according to TP 1–4. The solvent was evaporated under reduced
pressure to afford a residue, which was taken up with CDCl3
(0.6 mL). Anisole (8.6 mg, 0.08 mmol) was added as internal stan-
dard. The yields of reaction products (Tables 2–4) were deduced
from the relative intensities of proton resonances, referenced to the
anisole OCH3 signal (1H NMR). Control experiments, which were
performed in C6D6 using TP 1, gave identical results, within ex-
perimental error. (ii) BrCCl3 as trapping reagent. N-(Alkoxy)-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (1) (0.054 mmol)
was dissolved in C6H5CF3 (1 mL). BrCCl3 (3.0 equiv., 0.16 mmol,
16 lL) and AIBN (3.0 equiv., 0.48 mmol, 79 mg) were added.
The reaction vessel was closed, placed into the microwave device,
and irradiated according to TP 2. The solvent was evaporated
under reduced pressure to afford a residue, which was taken up
with CDCl3 (0.6 mL). Anisole (8.6 mg, 0.08 mmol) was added
as internal standard. The yields of reaction products (Tables 2–4)
were deduced from the relative intensities of proton resonances,
referenced to the anisole OCH3 signal (1H NMR). Control
experiments, which were performed in C6D6 using TP 1, gave
identical results, within experimental error.
Experiments analyzed by GC. (i) Bu3SnH as trapping
reagent. In a typical run, an N-(alkoxy)-5-(p-methoxyphenyl)-4-
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20 bar pressure valve was charged with N-(2-phenyl-4-penten-
1-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1e)
(0.40 g, 1.01 mmol), C6H5CF3 (10 mL), and Bu3SnH (0.53 mL,
2.02 mmol). The vessel was closed and irradiated according to
TP 2. The solvent was evaporated under reduced pressure to
furnish a residue, which was purified by column chromatography
(SiO2, petroleum ether–Et2O = 2 : 1, v/v) to afford 2-methyl-
4-phenyl tetrahydrofuran (5e) (86.8 mg, 53%) as colorless liquid
(cis-5e : trans-5e = 88:12), and 5-(p-methoxyphenyl)-4-methyl-2-
(tri-n-butylstannylsulfanyl)thiazole (8). Yield: 0.46 g (87%). Rf =
0.45 (SiO2, petroleum ether–Et2O = 5 : 1, v/v), colorless oil;
C23H37NOS2Sn (526.39) requires C 52.48, H 7.08, N 2.66, S 12.18;
found C 52.23, H 7.45, N 2.54, S 11.27; HR MS calcd. 527.1339,
found 527.1338; kmax (EtOH)/nm (lg e) 318 (4.17); dH (250 MHz;
CDCl3) 0.94 (t, J = 7.3, 9 H, CH3), 1.35 (mc, J = 7.3, 8.3, 12
H, CH2CH2), 1.62 (mc, J = 8.3, 6 H, CH2), 2.32 (s, 3 H, CH3),
3.83 (s, 3 H, OCH3), 6.91 (d, J = 8.8, 2 H, Ar–H), 7.29 (d, J
8.8, 2 H, Ar–H); dC (63 MHz; CDCl3) 13.7 (CH3), 15.9 (CH2Sn),
27.1 (CH2), 28.6 (CH2), 55.3 (CH3), 107.8, 114.0, 114.2, 124.8,
130.2, 158.9, 171.6 (2 × C); m/z (EI, 70 eV) 526 [M+] (0.2%),
470 [M+ − C4H9] (100), 356 (34), 237 (18), 204 (9), 177 (8).
(iii) In the presence of BrCCl3. A quartz glass vessel equipped with
a 20 bar pressure valve was charged with N-(2-phenyl-4-penten-
1-oxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (1e)
(0.40 g, 1.01 mmol), C6H5CF3 (10 mL), BrCCl3 (3.03 mmol,
0.3 mL), and AIBN (3.03 mmol, 497 mg). The vessel was
closed and irradiated according to TP 2 with Tiso extended to
2.5 min. The solvent was concentrated under reduced pressure
and purified by column chromatography (SiO2) to furnish 2-
bromomethyl-4-phenyltetrahydrofuran (14e) (151.0 mg, 62%) as
a colorless liquid [Rf = 0.45 (SiO2, petroleum ether–tert-butyl
methyl ether = 9 : 1, v/v)] and 5-(p-methoxyphenyl)-4-methyl-2-
(trichloromethylsulfanyl)thiazole (15). Yield: 0.28 g (79%). Rf =
0.77 (SiO2, petroleum ether–acetone = 4 : 1, v/v), yellowish
crystals (MeOH). C12H10Cl3NOS2 (354.70) requires C 40.63, H
2.84, N 3.95, S 18.08; found C 40.27, H 2.77, N 3.75, S 16.52;
HRMS: calcd. 352.9269, found 352.9269; kmax (CH3CN)/nm (lg
e) 324 (4.33); dH (250 MHz; CDCl3) 2.59 (s, 3 H, CH3), 3.86 (s,
3 H, OCH3), 6.99 (d, J = 7.5, 2 H, Ar–H), 7.41 (d, J = 7.5, 2
H, Ar–H); dC (63 MHz; CDCl3) 16.3 (CH3), 55.4 (OCH3), 114.4,
123.0, 130.6, 141.6, 150.3, 160.1, 182.5; m/z (EI, 70 eV) 354 [M+]
(15), 236 (100), 177 (42).
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Acknowledgements
This work was supported by the Deutsche Forschungsge-
meinschaft (Grant Ha1705/5–2 and Graduiertenkolleg 690:
Elektronendichte-Theorie und Experiment). We thank Prof. Dr
U. Holzgrabe for providing access to the MLS–Ethosꢀ 1600
microwave device, Dr E. Heller for helpful discussions, and CEM
for providing the Discoverꢀ device.
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2322 | Org. Biomol. Chem., 2006, 4, 2313–2322
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©