Tandem photoarylation-photoisomerization of halothiazoles: Synthesis, photophysical and singlet oxygen activation properties of ethyl 2-arylthiazole-5-carboxylates

Article abstract of DOI:10.1002/ejoc.201000096

The photochemical reaction between ethyl 2-chlorothiazole5-carboxylate and benzene gave no product. In contrast, the reaction with ethyl 2-iodothiazole-5-carboxylate gave ethyl 3-phenylisothiazole-4-carboxylate. The same behaviour was observed if the reac

Full text of DOI:10.1002/ejoc.201000096

FULL PAPER
DOI: 10.1002/ejoc.201000096
Tandem Photoarylation–Photoisomerization of Halothiazoles: Synthesis,
Photophysical and Singlet Oxygen Activation Properties of Ethyl
2-Arylthiazole-5-carboxylates
Mario Amati,*[a] Sandra Belviso,[a] Maurizio D’Auria,[a] Francesco Lelj,[a]
Rocco Racioppi,*[a] and Licia Viggiani[a]
Keywords: Heterocycles / Photochemistry / Arylation / Isomerization / Density functional calculations
The photochemical reaction between ethyl 2-chlorothiazole-
tested compounds showed fluorescence [λem = 350–400 (λexc
5-carboxylate and benzene gave no product. In contrast, the = 300 nm), 360 and 410 nm (λexc = 320 nm), 412 nm (λexc
=
reaction with ethyl 2-iodothiazole-5-carboxylate gave ethyl
3-phenylisothiazole-4-carboxylate. The same behaviour was
observed if the reaction was performed in the presence of
furan, thiophene and 2-bromothiophene. The products thus
obtained were studied for their photophysical properties and
it was found that the observed absorptions [λmax=257 nm (ε
= 7000 M–1 cm–1) for ethyl 3-phenylisothiazole-4-carboxylate,
278 nm (ε = 7000 M–1 cm–1) for ethyl 3-(2-furyl)isothiazole-4-
carboxylate, 269 and 285 nm (ε = 7500 M–1 cm–1) for ethyl 3-
(2-thienyl)isothiazole-4-carboxylate] are mainly due to πǞπ*
transitions from the HOMO to the LUMO+1 orbital. The
340 nm) for ethyl 3-phenylisothiazole-4-carboxylate, 397 and
460 nm (λexc = 300 nm), 381, 394 and 460 nm (λexc = 320 nm),
381, 398 and 466 nm (λexc = 340 nm) for ethyl 3-(2-furyl)iso-
thiazole-4-carboxylate, 372, 377 and 414 nm (λexc = 300, 320
and 340 nm respectively) for ethyl 3-(2-thienyl)isothiazole-4-
carboxylate], possibly due to dual emission from different ex-
cited states. The use of the compound obtained as a sensi-
tizer in the photo-oxidation of trans-α,αЈ-dimethylstilbene
showed that all the new compounds are singlet-oxygen sen-
sitizers.
Introduction
The photochemical reaction of halogen-substituted
heterocyclic derivatives with aromatic and heteroaromatic
compounds represents a useful synthetic methodology for
obtaining the corresponding aryl and heteroaryl derivatives.
We have found that a photochemical procedure can be used
to obtain aryl-substituted furan, thiophene, pyrrole and
imidazole derivatives bearing an electron-withdrawing
group starting from the corresponding halogen-substituted
compounds (Scheme 1).[1]
The reaction can be carried out with aldehydes or
ketones in the starting material (1a–d, 1g) as well with an
ester function (1e). Substrates with more than one hetero-
atom (1h) can also be used in this type of reaction. The
presence of a nitro group does not modify the behaviour
when this substituent is present in a thiophene (1f) or in an
imidazole ring (1h). Only in the presence of polyhalogen-
ated thiophenes, such as 3, did we observe a transposition
of the halogen atom (Scheme 2). However, unusual behav-
iour was observed when 2-bromo-5-nitrothiazole (6) was
Scheme 1. Photochemical reaction of halogen-substituted penta-
atomic heterocycles with aromatic compounds.
used as the substrate (Scheme 2). In this case the photo-
chemical reaction in the presence of aromatic compounds
gave the corresponding 2-bromo-5-aryl derivatives with
substitution of the nitro group.[2]
Extension of the photoarylation reaction to the thiazole
ring could provide interesting results from a synthetic view-
point. In fact, Micrococcin P1, a member of the thiostrep-
ton group of antibiotics, bears in the side-chain a thiazole
linked to another thiazole through C-2 with a carboxamide
moiety at C-4.[3]
[a] Dipartimento di Chimica, Università della Basilicata,
Via N. Sauro 85, 85100 Potenza, Italy
Fax: +39-0971-202223
E-mail: mario.amati@unibas.it
rocco.racioppi@unibas.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000096.
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Tandem Photoarylation–Photoisomerization of Halothiazoles
Scheme 3. Synthesis of ethyl 2-iodothiazole-5-carboxylate (9) and
ethyl 2-chlorothiazole-5-carboxylate (10).
atom has been substituted with a phenyl group. However,
1
the H spectrum was not in agreement with the formation
of ethyl 2-phenylthiazole-5-carboxylate.[6] On the contrary,
1
the H NMR spectrum is in agreement with that reported
for ethyl 3-phenylisothiazole-4-carboxylate.[7] In particular,
although the proton at C-4 in ethyl 2-phenylthiazole-5-car-
boxylate was expected at ca. 8.4 ppm,[6] we observed a sig-
nal at δ = 9.4 ppm, in agreement with that reported for ethyl
3-phenylisothiazole-4-carboxylate (δ = 9.32 ppm).[7] The
13C NMR spectrum showed signals at δ = 168.9, 155.9 and
129.6 ppm, in agreement with those reported for the carbon
atoms in the isothiazole ring in ethyl 3-(4-methoxyphenyl)-
isothiazole-4-carboxylate (δ = 168.0, 155.5 and 128.8
ppm).[8] Conclusive identification of the reaction product
was obtained by performing a long-range HETCOR experi-
ment. Assuming a C-4–5-H coupling constant of 3.5 Hz,[9]
we observed a coupling between the signal at δ = 9.4 ppm
in the 1H NMR spectrum (the proton at C-5) and the signal
at δ 129.6 ppm in the 13C NMR spectrum (C-4).
Scheme 2. Photochemical reactions of a polyhalogenated thiophene
derivative and 2-bromo-5-nitrothiazole with benzene.
Hence, it would be interesting to verify if the above de-
scribed reactivity is related to the specific nature of the nitro
group, that is, its high electronegativity and deactivating
character, or to the specificity of the heteroatomic ring. The
ethyl 2-halothiazole-5-carboxylate (halogen: Cl and I) com-
pounds allow the effect of varying the electronegativity and
the presence of the deactivating ester moiety on the thiazole
ring to be verified.
To confirm the isomerization reaction we prepared ethyl
2-phenylthiazole 5-carboxylate (15) through a Suzuki reac-
tion between 9 and phenylboronic acid in the presence of
[Pd2(dba)3] (Scheme 5).[10] The spectral data of our synthe-
sized compound are in agreement with those reported in
the literature.[6] The irradiation of 15 in acetonitrile gave 11
as the only product, unequivocally revealed by the analyti-
cal data (Scheme 5).
Furthermore, quantitative photophysics characterization
and singlet-oxygen sensitizer properties of the coupling
products are reported. In fact, in our previous work, it has
been found that they can be used in the synthesis of natural
and synthetic photobioactive compounds, the properties of
which are related to their being singlet-oxygen sensitizers.[4]
This behaviour was confirmed by using other aromatic
compounds in the photochemical reaction: furan, thio-
Results and Discussion
We used ethyl 2-iodothiazole-5-carboxylate (9) as the phene and 2-bromothiophene. The irradiation of 9 in the
starting material in this work. This compound was prepared presence of furan gave ethyl 3-(2-furyl)isothiazole-4-carbox-
as described previously from 2-trimethylsilylthiazole (8) ylate (12; Scheme 4, Table 1). The same types of products,
(Scheme 3).[5] In that work ethyl 2-iodothiazole-5-carboxyl- 13 and 14, were obtained with thiophene and 2-bromothio-
ate was obtained in 10% yield as the only reaction product. phene, respectively (Scheme 4, Table 1).
To obtain higher yields of the product, we performed the
Also in these cases we observed the formation of a pho-
reaction in the presence of excess iodine. In this case 9 was toisomerized product. This indicates that in the photochem-
obtained in higher yields (34%) together with a significant ical reaction of 9 not only the iodine atom is replaced by the
amount of ethyl 2-chlorothiazole-5-carboxylate (10; 18%). aromatic moiety but an isomerization also occurs. Although
The higher yields could be attributed to the use of an excess there are several examples of photoisomerization of substi-
of iodine instead of the stoichiometric amount used in the tuted thiazoles in the literature,[11–19] this is the first exam-
original work.
ple of photoisomerization during an arylation reaction. The
Under photochemical conditions, compound 9 readily isomerization product is considered consistent with an in-
reacted with benzene and other aromatic heterocyclic com- ternal cyclization–isomerization (ICI) mechanism.
pounds. The irradiation of 9 in benzene gave a coupling
The isomerization of penta-atomic heterocyclic com-
product (Scheme 4, Table 1). The mass spectrum is in agree- pounds is one of the most important photochemical reac-
ment with the formation of a product in which the iodine tions of this type of compound.[20] Five mechanisms can be
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FULL PAPER
Scheme 5. Synthesis and photochemical isomerization of ethyl 2-
phenylthiazole-5-carboxylate (15).
Scheme 4. Photochemical reactions of 9 and 10 with aromatic and
heteroaromatic compounds.
Table 1. Photochemical arylation of ethyl 2-iodothiazole-5-carbox-
ylate (9).
Substrate
Solvent Aromatic
compound
Irradiation Product Yield [%]
time [h]
10
9
9
9
9
–
–
benzene
benzene
16
16
18
13.5
–
–
90
11
12
13
14
CH3CN furan
CH3CN thiophene
CH3CN 2-bromothio- 34
phene
89
96[a]
35
Scheme 6. Possible mechanisms for the photochemical isomeriza-
tion of penta-atomic heterocyclic compounds.
[a] Compound 13 was obtained as a 10:1 mixture of 2-thienyl and
3-thienyl derivatives.
invoked to justify the photochemical isomerization of state of a molecule is populated, the molecule can convert
penta-atomic aromatic heterocycles: i. ring contraction–ring into the corresponding triplet state or into the correspond-
expansion (RCRF; Scheme 6, A), ii. internal cyclization– ing Dewar isomer. The efficiency of these processes will de-
isomerization (ICI; Scheme 6, B), iii. the van Tamelen– pend on energetic factors. If the Dewar isomer is formed,
Whitesides general mechanism (VTW; Scheme 6, C), the isomeric product is obtained. If the triplet state is
iv. the zwitterion–tricycle route (ZT; Scheme 6, D) and formed, cleavage of the X–Cα bond can occur to give ring-
v. fragmentation–readdition (FR; Scheme 6, E).
opened products, decomposition products or ring-contrac-
Recently, we reported that the photochemical isomeriza- tion products. In this context, iodine favours intersystem
tion of penta-atomic aromatic heterocycles can be described crossing or the opening of the Dewar intermediate, as re-
by using a unifying hypothesis.[20] If the first excited singlet ported in Scheme 7.[14b]
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Tandem Photoarylation–Photoisomerization of Halothiazoles
orientations of the furyl and thienyl groups give rise to a
further two possible isomers for each compound (labelled
with a and b in Figure 1). Compounds 12a and 13a are
significantly more stable than 12b and 13b by 1.3 and
1.9 kcal/mol, respectively. Also in these cases, there are no
large differences in the computed spectroscopic properties
of the two isomers. Thus, only the most stable compounds
12a and 13a are the subject of the following discussion.
Scheme 7. Proposed mechanism for the photoisomerization of 2-
phenylthiazole.
Compound 10 did not react when it was irradiated in
benzene (Scheme 4); this lack of reactivity has already been
observed in the case of 5-bromo-2-cyanothiophene.[1f]
These results, together with the previous results of reac-
tions with nitro derivatives, strongly suggest that the reac-
tivity of the thiazole ring is strongly affected by the nature
of the substituent. In particular, the key step is the accessi-
bility to the substituents at the C-2 position of low-energy
σ radical species: both NO2 and I substituents are more
easily accessible and Cl, Br and CN or COOR groups are
less accessible.
Figure 1. Some optimized structures for 11–13 determined at the
B3LYP/6-31G(d,p) level of theroy.
Furthermore, the presence of a phenyl ring at the 2-posi-
tion can stabilize the diradical species thereby favouring the
cleavage of the S–C bond of the Dewar intermediate on the
excited-state energy surface.
The absorption spectra of 11–13 and 15 recorded in
CH3CN solution are reported in Figure 2 and the measured
It has been reported that some biaryl derivatives bearing absorption values are collected in Table 2. To ensure that
electron-withdrawing groups can be used as singlet-oxygen the photophysical properties measured were really due to
sensitizers and show photodynamic activity.[4] To character- the studied compounds and not to small impurities that
ize the electronic structures of the investigated molecules a could be present (especially in the case of fluorescence), the
combined photophysical and computational study was car- purity of 11–13 and 15 before and after the measurements
ried out.[21]
was carefully checked by GC–MS analysis. As can be easily
Concerning the computational study, in the cases of 11– seen from the reported data, no impurities were detected
13 and 15, the CO2Et group was replaced by a CO2Me (see the Supporting Information). Part a and b of Figure 2
group for computational convenience. Compound 11 show the experimental and computed absorption spectra of
showed two isomeric structures that differ in the orientation 15 and 11, respectively. Both the experimental spectra show
of the CO2Me group. They are reported in Figure 1 and a single broad band with a maximum at 304 (15) and
labelled as 11a and 11b. Structure 11a is slightly more stable 257 nm (11). It is clear that the thiazole and isothiazole de-
in energy (electronic energy in the Born–Oppenheimer rivatives present different UV/Vis spectra and that the com-
approximation plus nuclei–nuclei electrostatic potential), putations are able to reproduce such differences well.
differing by only 0.6 kcal/mol from 11b. However, the com-
According to the computations, excitation to the first ex-
puted spectroscopic properties of 11a and 11b are essen- cited state (S1) of 15 is responsible for the absorption band
tially equivalent such that only 11a is discussed in the fol- at 304 nm. On the other hand, the band at 257 nm of 11 is
lowing paragraph. Similar results were found for 12, 13 and assigned to transitions to S3 and (mostly) S4. In fact, S1 and
15. The two orientations of the CO2Me group are not rel- S2 are described as weak transitions the presence of which
evant for the spectroscopic analyses and thus only one of explains the tail of the absorption spectrum at longer wave-
the two isomers is discussed below. In 12 and 13, the relative lengths that is absent in the experimental spectrum of 15.
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Table 2. Photophysical results obtained in CH3CN solution for 11–
13.
Absorption
Emission
λabs [nm] (ε [–1cm–1]) λem [nm]
φF
τ[e] [ns]
11 257 (7000)
350–400[a] plateau 0.018[a]
0.20
360 sh, 410[b]
412[c]
0.021[b] 0.10[c] 1.0[f]
417[d]
12 278 (7000)
397, 460 sh[a]
381, 394, 460[b]
381, 398, 466[c]
466[d]
0.002[a]
0.022[b]
0.056[c]
2.0
13 269 sh, 285 (7500)
372[a]
0.002[a]
0.5,
1.4[f]
377[b]
414[c]
484[d]
0.005[b]
0.016[c]
[a] Excitation performed at 300 nm. [b] Excitation performed at
320 nm. [c] Excitation performed at 340 nm. [d] Excitation per-
formed at 375 nm. [e] Lifetimes measured under excitation at
375 nm. [f] Dual exponential emission.
transition. On the other hand, in the case of 11, the first
band is mainly assigned to the HOMOǞ(LUMO+1) (or-
bitals 57Ǟ59) monoelectronic excitation, which is the
major component of S4. From Figure 3 it is possible to note
a certain similarity between the Kohn–Sham orbitals in-
volved in the transitions. Orbital 58 in 15, the LUMO, be-
comes orbital 59 in 11, the LUMO+1, whereas orbital 57 is
almost the same in both compounds. The UV/Vis absorp-
tions S1 and S2 for 11 are πǞπ* transitions assigned to the
HOMOǞLUMO (orbitals 57Ǟ58) and (HOMO-
1)ǞLUMO (orbitals 56Ǟ58) monoelectronic excitations,
respectively.
The assignment of transitions in the cases of 12 and 13 is
similar to that of 11. Also in this case, the HOMOǞLUMO
monoelectronic excitation is the main component of S1, but
the transition to S1 is not assigned to the experimental ab-
sorption peaks at 278 (12) and 285 nm (13) (Figure 2 and
Table 4). In both 12 and 13, the intense absorption band is
assigned to the transition to S2, which is mainly due to the
HOMOǞ(LUMO+1) monoelectronic excitation, as in 11.
Note that according to the computations, the nǞπ* ex-
citations do not contribute to low-energy transitions. In the
case of 11, the first transition of this type is to S5 computed
at 248 nm. It involves a non-bonding occupied orbital local-
ized on the CO2Me carbonyl oxygen. The transition to S6
at 230 nm is the first nǞπ* transition that involves a non-
bonding orbital of an aromatic heteroatom (the nitrogen
non-bonding pair in the isothiazole ring).
Figure 2. Experimental absorption spectra of (a) 15, (b) 11, (c) 12
and (d) 13 and, superimposed, the computed electronic vertical
transitions of the structures 15, 11a, 12a and 13a.
The fact that nǞπ* transitions are relatively high in en-
ergy is due to the higher electronegativity of the oxygen,
Table 3 presents information about the low-energy ex- nitrogen and sulfur atoms in comparison with carbon
cited states of the compounds studied and Figure 3 shows atoms. The occupied π orbitals are mainly localized on the
the Kohn–Sham orbital shapes useful for understanding the less electronegative aromatic carbon atoms. Hence, they are
general characteristics of the excited states discussed. From closer in energy to π* orbitals and lead to low-energy
Table 3 and Figure 3, the intense first band of 15 can be πǞπ* transitions. Similar behaviour was observed for 12
assigned to the πǞπ* HOMOǞLUMO (orbitals 57Ǟ58) and 13.
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Tandem Photoarylation–Photoisomerization of Halothiazoles
Table 3. Computed UV/Vis transitions of 11–13 and 15.
Excited state Energy [nm; eV] Oscillator strength Composition (%)
15
11
S1
S1
312; 3.98
291; 4.25
0.6097
0.0230
57Ǟ58
57Ǟ58
57Ǟ59
54Ǟ58
56Ǟ58
54Ǟ58
54Ǟ59
56Ǟ59
57Ǟ59
57Ǟ60
57Ǟ61
54Ǟ58
55Ǟ58
56Ǟ59
57Ǟ59
57Ǟ61
54Ǟ55
54Ǟ56
54Ǟ55
54Ǟ56
58Ǟ59
58Ǟ60
57Ǟ59
58Ǟ59
58Ǟ60
57Ǟ59
58Ǟ60
81.09
88.67
2.26
S2
S3
275; 4.51
255; 4.86
0.0020
0.0629
2.01
93.31
16.02
4.89
37.34
21.11
4.74
3.92
5.05
4.99
14.50
60.12
4.16
90.18
3.94
S4
250; 4.96
0.2168
12
13
S1
S2
S1
S2
333; 3.72
274; 4.52
328; 3.78
291; 4.26
0.0282
0.4080
0.0266
0.2489
2.15
77.61
86.19
7.41
17.32
3.97
63.07
80.73
12.37
S3
277; 4.26
0.0887
The emission spectra of compounds 11–13 in CH3CN
were recorded after excitation at λex = 300, 320 and 340 nm,
in the absorption tail range (Table 2 and Figure 4). The
emission spectrum of the phenyl-substituted compound 11
obtained at λex = 300 nm shows a very broad, plateau-like
band in the 350–400 nm range, whereas at λex = 320 and
340 nm a single, well-defined emission band is observed at
around 410 nm. For compound 12, a maximum at 397 nm
was observed on excitation at λex = 300 nm, whereas at λex
= 320 nm three distinct peaks with maxima at 381, 394 (the
most intense) and 460 nm were observed. The same emis-
sion pattern is displayed on excitation at λex = 340 nm with
maxima at 381, 398 and 466 nm, the latter being the most
intense. Similarly to the other compounds, the emission
band of 13 evolves from a relatively weak band with a maxi-
mum at 372 nm to a more intense band with a maximum
at 414 nm when λex changes from 300 to 340 nm. For com-
pounds 11–13 the quantum yields at each excitation wave-
length were also measured by using anthracene in EtOH
solution as a standard. As inferred from Table 2, the highest
values are measured for λex = 340 nm for the three com-
pounds and, of these, the phenyl-substituted compound 11
Figure 3. Some Kohn–Sham orbitals computed for (a) 15, (b) 11
and (c) 12. The orbitals of 13 are very similar to those of 12, the
only difference is that the HOMO is the 58th orbital and the
LUMO is the 59th.
seems to be the best emitter (quantum yield: 0.10 for λex
=
340 nm).
To understand the nature (fluorescence or phosphores-
cence) of the observed emission phenomena, lifetime mea-
surements were also performed on the compounds 11–13.
The lifetimes were measured by using a 375 nm nanoLED
and measuring the resulting emission intensity at the appro-
priate wavelength. The lifetimes were evaluated by an ex-
ponential fitting of the experimental data. As reported in
Table 4. Computed S1 in its relaxed geometry (emission wave-
lengths).
Energy [nm; eV] Oscillator strength
Composition (%)
11
12
13
347; 3.58
400; 3.10
401; 3.09
0.0157
0.0210
0.0175
57Ǟ58
54Ǟ55
58Ǟ59
97.1
98.3
98.1
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FULL PAPER
yields. However, this does not influence the interpretation
of the nature of the emissive phenomena. In fact, excitation
at 375 nm of 11 and 12 gives rise to the same emission spec-
tra described for λex = 340 nm (Figure 4, a and b). There-
fore lifetimes of the same magnitude (ns) have to be ex-
pected. In contrast, in 13, for λex = 375 nm, the observed
emission band peak was redshifted by about 70 nm (Fig-
ure 4, c) and is similar to the emission band of 12 at λex
=
340 nm.
A computational analysis of the emission wavelengths of
the compounds studied has also been achieved by optimizing
the first and second singlet exited states of 11–13. The study
was focused only on the singlet excited states because lifetime
measurements indicate that the emission process in solution
at room temperature is due to fluorescence and not to phos-
phorescence. TD-DFT techniques were used as detailed in
the Exptl. Sect. Some of the results are reported in Table 4.
The computed emission peak wavelengths are not close to the
experimental ones as in case of the absorption wavelength
values. However, we note that very similar emission wave-
lengths are computed from S1 in 12 and 13. This fact could
allow the assignment of the emission band of 12 at 466 nm
and of 13 at 484 nm to S1. If this is the case, an error of
+0.45 and +0.42 eV is associated with the computation per-
formed on 12 and 13, respectively. In the case of 11, emission
from S1 is computed to be at 347 nm. As in other com-
pounds, it is blueshifted in comparison with the experimental
S1 emission peak that we place at 412 nm (Table 2). In this
case the computation has an error of +0.58 eV.
If the above assignment is correct, the experimental emis-
sion bands at 350–360 nm for 11, 381–398 nm for 12 and
372–414 nm for 13 (Table 2) should be assigned to emission
from higher excited states. It is reasonable to assign such
emissions to the S2 excited state in the cases of 12 and 13
(Table 3 and Figure 2). In the case of 11, S3 and S4 are
additional possibilities to be taken into account. The fact
that multiple decay times were recorded for 11 and 13 is a
further indication of the presence of two emissive states.
Figure 5 shows the scaled excitation spectra of 13 re-
corded in CH3CN solution. At the detection wavelength of
370 nm the excitation spectrum (spectrum 1 in Figure 5) is
similar to the absorption spectrum. It is characterized by a
peak wavelength of about 290 nm, which is very close to the
absorption maximum at 285 nm (Table 2). At the detection
wavelength of 470 nm (spectrum 3), the spectrum shows a
broad emission in the excitation range of 290–370 nm. This
spectrum should be associated with an emission process
from a lower excited state. A comparison with spectrum 1
allows the absorption band of this excited state to be placed
at wavelengths longer than 325 nm, in the long absorption
tail of 13 (Figure 2).
Figure 4. (a) Emission spectra of 11 recorded in CH3CN with exci-
tation wavelengths of (1) 300 nm and an absorbance of 0.0068, (2)
320 nm and an absorbance of 0.0207 and (3) 340 nm and an ab-
sorbance of 0.0010. (b) Emission spectra of 12 recorded in CH3CN
with excitation wavelengths of (1) 300 nm and an absorbance of
0.0238, (2) 320 nm and an absorbance of 0.0239 and (3) 340 nm
and an absorbance of 0.0150. (c) Emission spectra of 13 recorded
in CH3CN with excitation wavelengths of (1) 300 nm and an ab-
sorbance of 0.0130, (2) 320 nm and an absorbance of 0.0171, (3)
340 nm and an absorbance of 0.0039 and (4) 375 nm reported in
arbitrary units (cps: detector counts per seconds).
According to our computations, the electronic transition
Table 2, the decay times were all in the range of 0.2–2.0 ns, to S1 is localized at 328 nm (Table 3), in good agreement
which suggests that emission processes are a result of with experimental observations. Thus, spectrum 3 in Fig-
fluorescence.
ure 5 is consistent with the presence of two concurrent phe-
As stated above, owing to the instrumental set-up, life- nomena: emission from S1 after a barely effective internal
times were measured at an excitation wavelength (375 nm) conversion from a higher excited state and direct emission
higher than those used for recording the emission quantum from S1 after the S0 ǞS1 transition. On the other hand,
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Tandem Photoarylation–Photoisomerization of Halothiazoles
triplet sensitizer reacts with the substrate or solvent by hy-
drogen abstraction or electron transfer. In Type II reactions
the triplet sensitizer reacts with oxygen to give, by energy
transfer, singlet oxygen or, by electron transfer, the superox-
ide ion (Scheme 8). If a compound is a singlet-oxygen sensi-
tizer, the efficiency of the process depends on the efficiency
of excited triplet-state generation.
Figure 5. Scaled excitation spectra of 13 recorded in acetonitrile
solution at detection wavelengths of (1) 370 nm, (2) 410 nm and (3)
470 nm. Spectrum 2 has been scaled by a factor 9.0 and spectrum 3
by a factor 34.5. Spectra 2 and 3 have been smoothed to reduce the
amount of instrumental noise.
spectrum 1 is consistent with emission from a higher excited
state (S2 according to our computation) before internal con-
version to S1 and intersystem crossing to triplet states take
place.
To add more support to this suggestion, it is important
to analyse the composition of the singlet states in terms of
monoelectronic transitions and their f0j oscillator strengths.
From Table 3 it can be seen that, in the case of 11, S3 and
S4 have a large contribution from the 56Ǟ59 and 57Ǟ59
monoelectronic excitations, whereas S1 has only a very
small contribution from the 57Ǟ59 (2.26%) monoelec-
tronic excitation. Similar behaviour can be observed for 12
(S2) and 13 (S2 and S3).
In a perturbative framework, the probability of transition
from an excited state j to another state k is given by the
relationship (1)[22] in which Hv is the vibronic operator de-
scribing the perturbation that couples the Sk and Sj states.
They in turn are expressed as a linear combination of mono-
electronic excitations within each Slater determinant
(Table 3). In these terms, if the two excited states have very
different compositions, the numerator of the previous equa-
tion is expected to be small enough to reduce the kinetic
constant of the non-radiative decaying process from higher-
to lower-energy excited states. This could prevent a fast
non-radiative decay from the higher Si to S1 and, together
with a large oscillator strength for the transition from Si to
S0, might allow emission from excited states higher than S1,
in contrast to the “Kasha principle”, which assumes a faster
non-radiative decay to S1 and then a possible radiative de-
cay to S0.
Scheme 8. Type I and Type II photodynamic activity.
It has been reported that irradiation of trans-α,αЈ-di-
methylstilbene (16) in acetonitrile in the presence of both
oxygen and a suitable sensitizer gives only compound 17
when the sensitizer produces singlet oxygen by a Type II
reaction whereas if the sensitizer can undergo a Type I pro-
cess, a completely different product mixture is obtained
(Scheme 9).[24] This behaviour has been shown to be a use-
ful method for distinguishing between Type I and Type II
photosensitizers giving good results with both singlet oxy-
gen[4f,4g,25] and electron-transfer sensitizers.[26]
(1)
Scheme 9. Reactions of trans-α,αЈ-dimethylstilbene.
Singlet-Oxygen Activation
Furthermore, the absence of electron-transfer products
Photodynamic activity is usually divided into two pro- in competition reactions[27] involving trans-α,αЈ-dimeth-
1
cesses named Type I and Type II.[23] In Type I reactions a ylstilbene (16) indicates that it is an efficient O2 acceptor
Eur. J. Org. Chem. 2010, 3416–3427
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3423

M. Amati, S. Belviso, M. D’Auria, F. Lelj, R. Racioppi, L. Viggiani
FULL PAPER
1
9: Oil. H NMR (500 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H,
and a suitable substrate for studying singlet-oxygen sensitiz-
ers. Compounds 11–14 showed photosensitizer activity and
in the photoreaction with 16 only the hydroperoxide 17 was
obtained, which strongly suggests that they are able to gen-
erate singlet oxygen. Furthermore, a non-negligible quan-
tum yield value of 0.07Ϯ0.01 for singlet oxygen generation
for the compound 11 was obtained by using α-terthiophene
as actinometer (Φ∆ = 0.81).[28]
CH3), 4.30 (q, J = 7.1 Hz, 2 H, CH2), 8.04 (s, 1 H, 4-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.4, 62.2, 108.2, 135.8, 149.4,
159.9 ppm. UV (CH3CN): λmax = 269 nm. MS: m/z (%) = 283 (63)
[M]+, 255 (100), 238 (86), 210 (24), 156 (11), 128 (6.6), 100 (8.2),
83 (22), 57 (12), 29 (9), 15 (0.3). C6H6INO2S (283.09): calcd. C
25.46, H 2.14, N 4.95, S 11.33; found C 25.53, H 2.05, N 5.01, S
11.25.
1
10: Oil. H NMR (500 MHz, CDCl3): δ = 1.28 (t, J = 7 Hz, 3 H,
CH3), 4.32 (q, J = 7 Hz, 2 H, CH2), 8.10 (s, 1 H, 4-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 14.4, 62.2, 131.7, 146.8, 157.2,
160.3 ppm. MS: m/z (%) = 191 (25) [M]+, 193 (8.1) [M + 2]+, 163
(73), 146 (100), 130 (7.1), 118 (82), 99 (11), 57 (36), 45 (17), 29 (30),
18 (3). C6H6ClNO2S (191.64): calcd. C 37.60, H 3.16, N 7.31, S
16.73; found C 37.52, H 3.08, N 7.39, S 17.80.
Conclusions
The photochemical reactions between ethyl 5-iodothiaz-
ole-2-carboxylate and aromatic compounds gave the corre-
sponding arylisothiazole derivatives in good yields. The re-
action probably occurs by photoarylation and subsequent
photoisomerization of the arylthiazole derivative. This is
the first case of photoisomerization during a photoaryl-
ation reaction. The photophysical properties of the prod-
ucts thus obtained were studied and it was found that the
observed absorptions are mainly due to πǞπ* transitions
from the HOMO to the LUMO+1 orbital. The compounds
studied showed fluorescence in solution at room tempera-
ture. We have also shown that the low fluorescence quan-
tum yields allow these compounds to be singlet-oxygen sen-
sitizers and potentially useful compounds for photodyn-
amic therapy.
Ethyl 3-Phenylisothiazole-4-carboxylate (11): Compound
9
(736 mg, 2.6 mmol) was dissolved in anhydrous benzene (80 mL).
The mixture was degassed with nitrogen for 1 h. The mixture was
irradiated in an immersion apparatus with a 125 W high-pressure
mercury arc and the reaction was monitored by TLC. After 16 h,
the mixture was washed with 20% sodium thiosulfate in water to
oxidize traces of iodine and then with brine, dried with Na2SO4
and the solvents evaporated under vacuum to afford a crude mix-
ture that was purified by chromatography over silica gel (eluent:
98:2 to 96:4 petroleum ether/ethyl acetate) to give 545 mg
(2.34 mmol, 90%) of 11 as an oil.
1H NMR (500 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH3),
4.28 (q, J = 7.1 Hz, 2 H, CH2), 7.64–7.44 (m, 5 H, phenyl), 9.4 (s,
1 H, 5-H) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ = 14.3
(CH3), 61.4 (CH2), 128.1 (CH), 129.3 (CH), 129.4 (CH), 129.6 (C),
135.3 (C), 155.9 (CH), 162.3 (C), 168.9 (C) ppm. UV (CH3CN):
λmax = 257 nm, ε = 7000 dm3 mol–1 cm–1. MS: m/z (%) = 233 (86.3)
[M]+, 204 (34.2), 188 (100), 161 (19.7), 116 (8.7), 85 (6.7), 77 (9),
57 (9.3), 29 (3.9). C12H11NO2S (233.29): calcd. C 61.78, H 4.75, N
6.00, S 13.74; found C 61.70, H 4.86, N 6.07, S 13.68.
Experimental Section
General: NMR spectra were recorded with a Bruker 300 AM or
Varian Inova 500 instrument operating at 500 MHz. Mass spectra
were obtained with a Hewlett–Packard 5890 gas chromatograph
[OV-1 capillary column between 70 and 250 °C (20 °C/min)] with
Hewlett–Packard 5971 mass-selective detector. UV spectra were re-
corded at room temperature in a double-ray UV/Vis/NIR 05E Cary
Varian spectrophotometer in 1.0 cm optical path quartz cuvettes.
Ethyl 3-(2-Furyl)isothiazole-4-carboxylate (12): Compound
9
(945 mg, 3.3 mmol) was added to furan (3 g) in acetonitrile
(80 mL). The mixture was degassed with nitrogen for 1 h. The mix-
ture was irradiated in an immersion apparatus with a 125 W high-
pressure mercury arc for 18 h. The mixture was then washed with
20% sodium thiosulfate in water to oxidize traces of iodine and
then with brine, dried with Na2SO4 and the solvents evaporated
under vacuum to afford a crude mixture that was purified by
chromatography over silica gel (eluent: 9:1 petroleum ether/ethyl
acetate) to give 655 mg (2.9 mmol, 89%) of 12 together with
100 mg of unreacted ethyl 2-iodothiazole-5-carboxylate.
Unless otherwise indicated, photochemical reactions were per-
formed in an immersion apparatus surrounded with a Pyrex water
jacket with a 125 W high-pressure mercury arc (Helios-Italquartz,
Milan, Italy).
Solvents used in physical measurements were spectroscopic or
HPLC grade and obtained from Aldrich and Fluka.
Ethyl 2-Iodothiazole-5-carboxylate (9) and 2-Chlorothiazole-5-carb-
oxylate (10): nBuLi (11.5 mL, 1.6  in hexane) was added to a
stirred solution of 2-trimethylsylilthiazole (8; 2.48 g, 16 mmol) in
dry diethyl ether (50 mL) cooled to –78 °C. After 30 min, ethyl
chloroformate (5.3 g, 48 mmol) was added and the resulting mix-
ture stirred at –78 °C for a further 30 min and then at room temp.
for 30 min. After recooling to –78 °C, excess I2 in dry THF (50 mL)
was added and the reaction slurry was slowly warmed to room
temp. and stirred for 15 h, then recooled to –78 °C and treated with
20% sodium thiosulfate in water to destroy excess I2. The mixture
was then extracted three times with diethyl ether and the organic
layers were washed with brine, dried with Na2SO4 and the solvents
evaporated under vacuum to afford a crude mixture that was puri-
fied by chromatography over silica gel (eluent: 95:5 petroleum
ether/ethyl acetate) to obtain 1.76 g of 9 (6.2 mmol, 34.2%) and
561 mg of 10 (2.0 mmol, 18.4%).
12: Oil. 1H NMR (500 MHz, CDCl3): δ = 1.36 (t, J = 7.1 Hz, 3 H,
CH3), 4.25 (q, J = 7 Hz, 2 H, CH2), 6.45 (dd, J1 = 3.5, J2 = 1.5 Hz,
1 H, furyl 4-H), 7.35 (dd, J1 = 3.5, J2 = 0.5 Hz, 1 H, furyl 3-H),
7.50 (dd, J1 = 1.5, J2 = 0.5 Hz, 1 H, furyl 5-H), 9.21 (s,1 H, 5-
H) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ = 14.4 (CH3),
61.6 (CH2), 111.7 (CH), 113.3 (CH), 128.4 (C), 144.1 (CH), 148.6
(C), 156.1 (CH), 157.5 (C), 161.9 (C) ppm. UV (CH3CN): λmax
=
278 nm, ε = 7000 dm3 mol–1 cm–1. MS: m/z (%) = 223 (100) [M]+,
178 (57.2), 166 (30.5), 151 (21.5), 138 (4.6), 122 (7.9), 111 (3.4), 99
(2.5), 85 (5.4), 57 (7.5), 45 (4.3), 29 (4), 18 (0.2). C10H9NO3S
(223.25): calcd. C 53.80, H 4.06, N 6.27, S 14.36; found C 53.67,
H 4.12, N 6.32, S 14.28.
Ethyl 3-(2-Thienyl)isothiazole-4-carboxylate (13): Compound
9
(74 mg, 0.26 mmol) was added to thiophene (3 g) in acetonitrile
(80 mL). The mixture was degassed with nitrogen for 1 h. The mix-
3424
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Eur. J. Org. Chem. 2010, 3416–3427

Tandem Photoarylation–Photoisomerization of Halothiazoles
ture was irradiated in an immersion apparatus with a 125 W high-
pressure mercury arc for 13.5 h. The mixture was then washed with
20% sodium thiosulfate in water to oxidize traces of iodine and
then with brine, dried with Na2SO4 and the solvents evaporated
under vacuum to afford a crude mixture that was purified by
chromatography over silica gel (eluent: 95:5 to 9:1 petroleum ether/
ethyl acetate) to give 62 mg (0.25 mmol, 96%) of 13 together with
4 mg of ethyl thiazole-5-carboxylate.
(CH), 161.7 (C), 173.5 (C) ppm. UV (CH3CN): λmax = 304 nm.
MS: m/z (%) = 233 (100) [M]+, 205 (48), 188 (50), 160 (42), 104
(20), 57 (43). C12H11NO2S (233.29): calcd. C 61.78, H 4.75, N 6.00,
S 13.74; found C 61.69, H 4.84, N 6.09, S 13.70.
Photolysis of Ethyl 2-Phenylthiazole-5-carboxylate: Compound 15
(40 mg) was dissolved in acetonitrile (20 mL) in a Pyrex water
jacket and irradiated with a 500 W high-pressure mercury arc. The
reaction was monitored by GC–MS and stopped after 80 h (43%
conversion). The solvent was then evaporated under vacuum to af-
ford 45 mg of a crude mixture that was purified by semi-preparative
TLC (1.0 mm layer, eluent: 9:1 petroleum ether/ethyl acetate) to
give 9 mg of pure 11 (spectroscopic data identical to those re-
ported).
1
13: Oil H NMR (500 MHz, CDCl3): δ = 1.38 (t, J = 7 Hz, 3 H,
CH3), 4.37 (q, J = 7 Hz, 2 H, CH2), 7.10 (dd, J1 = 5, J2 = 4 Hz, 1
H, thienyl 4-H), 7.43 (dd, J1 = 5, J2 = 1 Hz, 1 H, thienyl 5-H), 7.93
(dd, J1 = 4, J2 = 1 Hz, 1 H, thienyl 3-H), 9.31 (s, 1 H, 5-H) ppm.
13C NMR and DEPT (125 MHz, CDCl3): δ = 14.4 (CH3), 61.6
(CH2), 127.6 (CH), 128.4 (C), 128.5 (CH), 129.5 (CH), 137.2 (C),
Irradiation of trans-α,αЈ-Dimethylstilbene in the Presence of 11–14:
156.6 (CH), 161.5 (C), 162.2 (C) ppm. UV (CH3CN): λmax
=
A solution (50 mL) containing 2ϫ10–4  of 11–14 and 5ϫ10–2

285 nm, ε = 7500 dm3 mol–1 cm–1. MS: m/z (%) = 239 (100) [M]+,
211 (31), 194 (68), 167 (35), 151 (22), 122 (15). C10H9NO2S2
(239.31): calcd. C 50.19, H 3.79, N 5.85, S 26.80; found C 50.27,
H 3.70, N 5.91, S 26.92.
trans-α,αЈ-dimethylstilbene[29] (16) in acetonitrile was irradiated in
the presence of oxygen in a Pyrex tube surrounded by a Pyrex water
jacket connected to a Haake F3 thermostat to maintain the tem-
perature at 13.0Ϯ0.1 °C in a Rayonet chamber with an 8 W lamp
the output of which was centred at 350 nm. After 2 h, the solvent
was removed under vacuum and the residual oil was analysed by
1H NMR spectroscopy. Compound 17 showed peaks at δ = 2.42
(s, 1.5 H), 2.58 (s, 1.5 H), 5.97 (s, 0.5 H), and 6.18 (s, 0.5 H) ppm.
1
Ethyl Thiazole-5-carboxylate: Oil. H NMR (500 MHz, CDCl3): δ
= 1.18 (t, J = 7 Hz, 3 H, CH3), 4.36 (q, J = 7 Hz, 2 H, CH2), 8.45
(s, 1 H, 4-H), 8.88 (s, 1 H, 2-H) ppm. MS: m/z (%) =157 (20)
[M]+, 130 (21.4), 129 (66.75), 112 (100), 101 (8), 85 (9), 84 (22.7),
58 (8), 57 (26.7), 45 (12), 29 (8), 15 (0.7).
UV/Vis and Emission Spectroscopy: Solution electronic spectra in
the region 230–400 nm were recorded at room temperature with a
UV/Vis/NIR 05E Cary spectrophotometer by using 1.0 cm path
length quartz cells. Absorption spectra were recorded at a scan rate
of 200 nm/min at room temperature. Steady-state emission and ex-
citation spectra were recorded with a HORIBA Jobin–Yvon FL3-
11 Fluorolog-3 spectrometer at room temperature with a scan rate
of 1 nm/s using solutions at concentrations 10–5–10–6 , giving rise
to absorbance values less than 0.02 at the chosen excitation wave-
lengths. Excitation and emission spectra were corrected for source
intensity (lamp and grating) and emission spectral response (detec-
tor and grating) by standard correction curves.
Ethyl 3-(5-Bromo-2-thienyl)isothiazole-4-carboxylate (14): Com-
pound 9 (170 mg, 0.6 mmol) was added to 2-bromothiophene
(1.5 g) in acetonitrile (80 mL). The mixture was degassed with ni-
trogen for 1 h. The mixture was irradiated in an immersion appara-
tus with a 125 W high-pressure mercury arc for 34 h. The mixture
was then washed with 20% sodium thiosulfate in water to oxidize
traces of iodine and then with brine, dried with Na2SO4 and the
solvents evaporated under vacuum to afford a crude mixture that
was purified by chromatography over silica gel (eluent: 95:5 to 9:1
petroleum ether/ethyl acetate) to give 66 mg (0.21 mmol, 35%) of
14 as an oil.
1H NMR (500 MHz, CDCl3): δ = 1.30 (t, J = 7 Hz, 3 H, CH3),
4.37 (q, J = 7 Hz, 2 H, CH2), 7.07 (d, J = 5 Hz, 1 H, thienyl 3-H),
7.42 (d, J = 5 Hz, 1 H, thienyl 4-H), 9.32 (s, 1 H, 5-H) ppm. 13C
NMR and DEPT (125 MHz, CDCl3): δ = 14.4 (CH3), 61.8 (CH2),
127.6 (CH), 128.4 (C), 128.5 (CH), 132.3 (C), 137.2 (C), 156.7
(CH), 161.4 (C), 162.2 (C) ppm. MS: m/z (%) = 319 (0.8) [M]+, 317
(0.8), 274 (3), 238 (51), 210 (100), 193 (14). C10H8BrNO2S2
(318.21): calcd. C 37.74, H 2.53, N 4.40, S 20.15; found C 37.63,
H 2.60, N 4.35, S 20.07.
Photoluminescent quantum yields were measured by the method
described by Demas and Crosby using anthracene (quantum yield:
0.27 in EtOH at room temperature) as the standard.[30]
Time-resolved measurements were performed with a HORIBA
Jobin–Yvon IBH FL-322 Fluorolog-3 spectrometer using the time-
correlated single-photon counting (TCSPC) option. NanoLED
(375 nm; fwhm Ͻ 200 ps) with repetition rates between 10 kHz and
1 MHz was used to excite the sample. The excitation source was
mounted directly on the sample chamber at 90° to a double-grating
emission monochromator (2.1 nm/mm dispersion; 1200 grooves/
mm) and collected with a TBX-4-X single-photon-counting detec-
tor. The photons collected at the detector are correlated by a time-
to-amplitude converter (TAC) to the excitation pulse. Signals were
collected by using an IBH Data Station Hub photon-counting
module and data analysis was performed by using the commercially
available DAS6 software (HORIBA Jobin Yvon IBH). The good-
ness of fit was assessed by minimizing the reduced χ2 and visual
inspection of the weighted residuals.
Ethyl 2-Phenylthiazole-5-carboxylate (15): Compound 9 (200 mg,
0.7 mmol), phenylboronic acid (110 mg, 0.9 mmol) and [Pd2(dba)3]
(32 mg, 0.035 mmol) were added to 1,2-dimethoxyethane (1.75 mL)
in a conical vial and the resulting solution was degassed with a
stream of nitrogen. Distilled water (0.1 mL) and 2  K2CO3 in
water (0.7 mL) were added and the mixture was stirred and heated
at 100 °C for 6 h. The mixture was then diluted with ethyl acetate,
dried with Na2SO4, passed through a short pad of Celite and the
solvents evaporated under vacuum to give a crude product that was
purified by chromatography over silica gel (eluent: 98:2 petroleum
ether/ethyl acetate) to give 110 mg (0.47 mmol, 67%) of 15 as a
white solid. M.p. 65–67.5 °C (lit.:[7] 64–65 °C).
Computational Methods: Gaussian03 (revision D02) was used for
the discussions of the computed geometries and UV/Vis spectra
assignment.[31] The Turbomole 5.9 program was used to confirm
the Gaussian03 UV/Vis assignments and to relax excited-state geo-
metries for the emission peak wavelength computations.[32]
1H NMR (500 MHz, CDCl3): δ = 1.41 (t, J = 7.5 Hz, 3 H, CH3),
4.40 (q, J = 7.5 Hz, 2 H, CH2), 7.52–7.46 (m, 3 H, phenyl, p- and
m-H), 8.02–7.98 (m, 2 H, phenyl, o-H), 8.43 (s, 1 H, 4-H) ppm. 13
C
All the computations were based on density functional theory
(DFT)[33] and time-dependent DFT (TD-DFT)[34] by using the
B3LYP hybrid xc functional.[35] Geometry optimizations and TD-
NMR and DEPT (125 MHz, CDCl3): δ = 14.5 (CH3), 61.9 (CH2),
127.1 (CH), 129.3 (CH), 129.3 (C), 131.4 (CH), 133.2 (C), 149.4
Eur. J. Org. Chem. 2010, 3416–3427
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M. Amati, S. Belviso, M. D’Auria, F. Lelj, R. Racioppi, L. Viggiani
FULL PAPER
dron 1992, 48, 9315–9322; h) M. Herrnreiter, J. Kagan, X.
Chen, K. Y. Lau, M. D’Auria, A. Vantaggi, Photochem. Pho-
tobiol. 1993, 58, 49–52; i) M. D’Auria, Tetrahedron Lett. 1994,
35, 3151–3154; j) M. D’Auria, G. Mauriello, Photochem. Pho-
tobiol. 1994, 60, 542–545; k) M. D’Auria, J. Photochem. Pho-
tobiol. A: Chem. 1995, 91, 187–192; l) M. D’Auria, E. De Luca,
G. Mauriello, R. Racioppi, Synth. Commun. 1999, 29, 35–42.
DFT results from the Gaussian03 program were obtained at the
B3LYP/6-31G(d,p) level of theory. For compounds 11 and 13, the
basis set accuracy was tested by using the 6-311G(2d,p) basis set.
No significant changes in the description of the geometries and
excited states were observed in comparison with the 6-31G(d,p)
basis set.
[5]
L. R. Beard, F. D. Colon, T. K. Song, P. J. A. Davies, D. M.
Kochhar, R. A. S. Chandraratna, J. Med. Chem. 1996, 39,
3556–3563.
M. Fong, W. J. Janowski, R. H. Prager, M. R. Taylor, Aust. J.
Chem. 2004, 57, 599–604.
M. Muraoka, T. Yamamoto, K. Enomoto, T. Takeshima, J.
Chem. Soc. Perkin Trans. 1 1989, 1241–1252.
R. M. Paton, F. M. Robertson, J. F. Ross, J. Crosby, J. Chem.
Soc. Perkin Trans. 1 1985, 1517–1521.
R. E. Wasylishen, H. M. Hutton, Can. J. Chem. 1977, 55, 619–
624.
V. J. Majo, J. Prabhakaran, J. J. Mann, J. S. Dileep Kumar, Tet-
rahedron Lett. 2003, 44, 8535–8537.
J. P. Catteau, A. Lablache-Combier, A. Pollet, J. Chem. Soc. C
1969, 1018.
Geometry optimizations were performed with default settings on
geometry convergence (gradients and displacements), integration
grid and electronic density (SCF) convergence. Redundant coordi-
nates were used for the geometry optimization carried out with the
Gaussian03 program. Analytical evaluation of the second-energy
derivative matrix w. room temp. Cartesian coordinates (Hessian
matrix) at the B3LYP/6-31G(d,p) level of theory confirmed the na-
ture of the minima on the energy surface associated with the opti-
mized structures.
[6]
[7]
[8]
[9]
Excited-state geometry optimizations were performed with the
B3LYP xc functional and DZP basis set, as provided by the Tur-
bomole 5.9 package. The Turbomole 5.9 default parameters were
used for SCF, geometry optimization and integration grids. Geo-
metries and UV/Vis spectra were computed to verify the
Gaussian03 predictions.
[10]
[11]
[12]
[13]
[14]
J. W. Pavlik, C. R. Pandit, C. J. Samuel, A. C. Day, J. Org.
Chem. 1993, 58, 3407–3410.
G. Vernin, J.-C. Poite, J. Metzger, J.-P. Aune, H. J. M. Dou,
Figures 1 and 3 were produced by using the Molekel 4.3 pro-
gram.[36]
Bull. Soc. Chim. Fr. 1971, 1103–1104.
a) G. Vernin, R. Jauffred, C. Ricard, H. J. M. Dou, J. Metzger,
J. Chem. Soc. Perkin Trans. 2 1972, 1145–1150; b) C. Riou, G.
Vernin, H. J. M. Dou, J. Metzger, Bull. Soc. Chim. Fr. 1972,
2673–2678; c) J. W. Pavlik, P. Tongcharoensirikul, N. P. Bird,
A. C. Day, J. A. Barltrop, J. Am. Chem. Soc. 1994, 116, 2292–
2300.
Supporting Information (see also the footnote on the first page of
this article): GC–MS, 1H and 13C NMR, DEPT and computational
details.
Acknowledgments
[15]
[16]
[17]
C. Vernin, C. Riou, H. J. M. Dou, L. Bouscasse, J. Metzger, G.
Loridan, Bull. Soc. Chim. Fr. 1973, 1743–1751.
We thank the Italian Ministry of University and Research (MUR)
(Project no. PRIN 2007) and the University of Basilicata for finan-
cial support.
C. Riou, J. C. Poite, G. Vernin, J. Metzger, Tetrahedron 1974,
30, 879–898.
a) M. Kojima, M. Maeda, J. Chem. Soc. C 1970, 386–387; b)
M. Maeda, M. Kojima, J. Chem. Soc. Perkin Trans. 1 1978,
685–692.
[1] a) R. Antonioletti, M. D’Auria, A. De Mico, G. Piancatelli, A.
Scettri, Tetrahedron 1985, 41, 3441–3446; b) R. Antonioletti,
M. D’Auria, A. De Mico, G. Piancatelli, A. Scettri, J. Chem.
Soc. Perkin Trans. 1 1985, 1285–1288; c) M. D’Auria, R. Anto-
nioletti, A. De Mico, G. Piancatelli, Heterocycles 1986, 24,
1575–1578; d) R. Antonioletti, M. D’Auria, F. D’Onofrio, G.
Piancatelli, A. Scettri, J. Chem. Soc. Perkin Trans. 1 1986,
1755–1758; e) M. D’Auria, A. De Mico, F. D’Onofrio, G. Pian-
catelli, J. Chem. Soc. Perkin Trans. 1 1987, 1777–1780; f) M.
D’Auria, A. De Mico, F. D’Onofrio, D. Mendola, G. Piancat-
elli, J. Photochem. Photobiol. A: Chem. 1989, 47, 191–201; g)
M. D’Auria, Gazz. Chim. Ital. 1994, 124, 195–197; h) M. D’Au-
ria, in: Targets in Heterocyclic Systems, Chemistry and Proper-
ties (Eds.: O. A. Attanasi, D. Spinelli), Italian Society of Chem-
istry, Rome, 1997, vol. 1, pp. 277–302; i) M. D’Auria, E.
De Luca, G. Mauriello, R. Racioppi, G. Sleiter, J. Chem. Soc.
Perkin Trans. 1 1997, 2369–2373; j) M. D’Auria, E. De Luca,
G. Mauriello, R. Racioppi, J. Chem. Soc. Perkin Trans. 1 1998,
271–273.
[18]
[19]
[20]
I. Saito, T. Morii, Y. Okamura, S. Mori, K. Yamaguchi, T.
Matsuura, Tetrahedron Lett. 1986, 27, 6385–6388.
I. Saito, T. Morii, S. Mori, K. Yamaguchi, T. Matsuura, Tetra-
hedron Lett. 1988, 29, 3963–3966.
a) M. D’Auria, in: Targets in Heterocyclic Systems, Chemistry
and Properties, (Eds: O. A. Attanasi, D. Spinelli), Italian Soci-
ety of Chemistry, Rome, 1999, vol. 2, pp. 233–279; b) M. D’Au-
ria, Heterocyles 1999, 50, 1115–1136; c) M. D’Auria, J. Org.
Chem. 2000, 65, 2494–2498; d) M. D’Auria, Adv. Heterocycl.
Chem. 2001, 79, 41–88; e) M. D’Auria, J. Photochem. Pho-
tobiol. A: Chem. 2002, 149, 31–37; f) M. D’Auria, Tetrahedron
2002, 58, 8037–8042; g) M. D’Auria, R. Racioppi, Lett. Org.
Chem. 2004, 1, 12–19; h) S. Buscemi, M. D’Auria, A. Pace, I.
Pibiri, N. Vivona, Tetrahedron 2004, 60, 3243–3249.
a) M. La Deda, I. Aiello, A. Grisolia, M. Ghedini, M. Amati,
F. Lelj, Dalton Trans. 2006, 390–399; b) A. Crispini, I. Aiello,
M. La Deda, I. De Franco, M. Amati, F. Lelj, M. Ghedini,
Dalton Trans. 2006, 5124–5134; c) M. Amati, S. Belviso, P. L.
Cristinziano, C. Minichino, F. Lelj, J. Phys. Chem. A 2007, 111,
13403–13414; d) M. Ghedini, T. Pugliese, M. La Deda, N.
Godbert, I. Aiello, M. Amati, S. Belviso, F. Lelj, G. Accorsi,
F. Barigelletti, Dalton Trans. 2008, 4303–4318; e) T. Pugliese,
N. Godbert, I. Aiello, M. La Deda, M. Ghedini, M. Amati, S.
Belviso, F. Lelj, Dalton Trans. 2008, 6563–6572.
[21]
[2] M. DЈAuria, C. Distefano, F. D’Onofrio, G. Mauriello, R. Ra-
cioppi, J. Chem. Soc. Perkin Trans. 1 2000, 3513–3518.
[3] M. A. Ciufolini, Y.-C. Shen, Org. Lett. 1999, 1, 1843–1846.
[4] a) M. D’Auria, A. De Mico, F. D’Onofrio, G. Piancatelli, Gazz.
Chim. Ital. 1986, 116, 747–748; b) M. D’Auria, A. De Mico, F.
D’Onofrio, G. Piancatelli, Synth. Commun. 1987, 17, 491–497;
c) M. D’Auria, A. De Mico, F. D’Onofrio, G. Piancatelli, J.
Org. Chem. 1987, 52, 5243–5247; d) M. D’Auria, F. D’Onofrio,
Gazz. Chim. Ital. 1988, 118, 633–635; e) M. D’Auria, A.
De Mico, F. D’Onofrio, G. Piancatelli, Gazz. Chim. Ital. 1989,
119, 201–202; f) M. D’Auria, A. Vantaggi, Photochem. Pho-
tobiol. 1991, 53, 181–184; g) M. D’Auria, D. Tofani, Tetrahe-
[22]
N. J. Turro, Modern Molecular Photophysics, University Sci-
ence Books, 1991.
C. F. Foote, Photochem. Photobiol. 1991, 54, 659.
K. Gollnick, A. Schnatterer, Photochem. Photobiol. 1986, 43,
365–378.
[23]
[24]
3426
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3416–3427

Tandem Photoarylation–Photoisomerization of Halothiazoles
[25] a) K. Gollnick, S. Held, J. Photochem. Photobiol. B: Biology
1990, 5, 85–93; b) W. Adam, M. Bran, A. Griesbeck, V. Lucch-
ini, E. Stabb, B. Will, J. Am. Chem. Soc. 1989, 111, 203–212.
[26] a) R. Akaba, K. Ohshima, Y. Kawai, Y. Obuchi, A. Negishi,
H. Sakuragi, K. Tokumaru, Tetrahedron Lett. 1991, 32, 109–
112; b) M. D’Auria, F. D’Onofrio, J. Suwinski, K. Swierczek,
Tetrahedron 1993, 49, 3899–3906.
[27] K. Gollnick, S. Held, J. Photochem. Photobiol. A: Chem. 1993,
70, 135–145.
[28] R. S. Becker, J. Seixas de Melo, A. Maçanita, F. Elisei, J. Phys.
Chem. 1996, 100, 18683.
[29] D. Lenoir, Synthesis 1977, 553–554.
[30] J. N. Demas, G. A. Crosby, J. Phys. Chem. 1971, 75, 991–1024.
[31] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M.Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok-
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Re-
vision D.02, Gaussian, Inc., Wallingford, CT, 2004.
R. Ahlrichs, M. Bär, M. Häser, H. Horn, C. Kölmel, Chem.
Phys. Lett. 1989, 162, 165–169.
R. G. Parr, W. Yang, Density Functional Theory of Atoms and
Molecules, Oxford University Press, New York, and Clarendon
Press, Oxford, 1989.
[32]
[33]
[34]
a) M. E. Casida, in: Recent Advances in Density Functional
Methods (Ed.: D. P. Chong), World Scientific, Singapore, 1995,
vol. 1, pp. 155–192; b) M. E. Casida, C. Jamorski, K. C. Cas-
ida, D. R. Salahub, J. Chem. Phys. 1998, 108, 4439–4449.
[35] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[36] a) P. Fluckiger, H. P. Luthi, S. Portmann, J. Weber, Molekel 4.3,
Swiss Center for Scientific Computing, Manno (Switzerland),
2000–2002; b) S. Portmann, H. P. Luthi, Chimia 2000, 54, 766.
Received: January 23, 2010
Published Online: May 11, 2010
Eur. J. Org. Chem. 2010, 3416–3427
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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