Photochemistry of 3- and 5-phenylisothiazoles. Competing phototransposition pathways

Article abstract of DOI:10.1021/jo991785y

5-Phenylisothiazole undergoes phototransposition via the electrocyclic ring closure-heteroatom migration pathway and by the N₂-C₃ interchange reaction pathway. The latter route is enhanced by the addition of triethylamine (TEA) to the reaction medium and by increasing the polarity of the solvent. In addition to phototransposition, 5-phenylisothiazole also undergoes photocleavage to 2-cyano-1-phenylethenethiol which was trapped by reaction with benzyl bromide to yield 2-cyano-1-phenylethen-1-ylbenzyl thioether. 3-Phenylisothiazole also phototransposes by both reaction pathways, but the product distribution is not affected by the addition of TEA or by changing the solvent polarity.

Full text of DOI:10.1021/jo991785y

3626
J . Org. Chem. 2000, 65, 3626-3632
P h otoch em istr y of 3- a n d 5-P h en ylisoth ia zoles. Com p etin g
P h ototr a n sp osition P a th w a ys
J ames W. Pavlik* and Pakamas Tongcharoensirikul
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute,
Worcester, Massachusetts 01609
Received November 16, 1999
5-Phenylisothiazole undergoes phototransposition via the electrocyclic ring closure-heteroatom
migration pathway and by the N2-C3 interchange reaction pathway. The latter route is enhanced
by the addition of triethylamine (TEA) to the reaction medium and by increasing the polarity of
the solvent. In addition to phototransposition, 5-phenylisothiazole also undergoes photocleavage
to 2-cyano-1-phenylethenethiol which was trapped by reaction with benzyl bromide to yield 2-cyano-
1-phenylethen-1-ylbenzyl thioether. 3-Phenylisothiazole also phototransposes by both reaction
pathways, but the product distribution is not affected by the addition of TEA or by changing the
solvent polarity.
Sch em e 1
In tr od u ction
Work in this laboratory has recently shown (Scheme
1) that 4-substituted isothiazoles undergo photocleavage
in benzene solvent to yield cyanothiols which can be
trapped as their benzyl thioether derivatives.1 The ad-
dition of a small amount of a base such as triethylamine
(TEA) to the reaction media has a profound effect on the
photoreaction. Under these conditions 4-substituted thia-
zoles, the expected P4 phototransposition products, are
also formed.2,3 This work also revealed that the 4-sub-
stituted isothiazole f 4-substituted thiazole P4 transpo-
sition occurs by way of isocyanosulfide intermediates
which in some cases can be observed spectroscopically
and can be trapped as their N-formylaminobenzyl thio-
ether derivatives. In the absence of trapping agents, these
isocyanosulfides can also cyclize to 4-substituted thia-
zoles, the observed P4 transposition product.1
consumed and that 3-phenylisothiazole (4), 2-phenyl-
thiazole (3), and 4-phenylthiazole (2) were formed in
yields of 5%, 2%, and 15%, respectively. Whereas these
are the products anticipated via the P5, P6, and P7
permutation pathways, GLC analysis did not reveal the
formation of any 5-phenylthiazole (5), the product ex-
pected by the P4 pathway which involves interchange of
the N2-C3 atoms.
In the present work we have explored the effects of
TEA and solvent polarity on the photochemistry of 3- and
5-phenylisothiazoles and have searched for the isocyano
intermediates in the photorearrangements of these com-
pounds.
Resu lts a n d Discu ssion
To determine the effect of TEA on the photochemistry
of 5-phenylisothiazole (1), two solutions of 1 in benzene
(3.0 mL, 2.2 × 10-2 M), without and with TEA (1.4 ×
10-2 M), were simultaneously irradiated on a merry-go-
round apparatus for 30 min. Gas liquid chromatographic
(GLC) analysis of the resulting solutions showed that in
the absence of TEA 32% of the reactant had been
(1) Pavlik, J . W.; Tongcharoensirikul, P.; French, K. M. J . Org.
Chem. 1998, 63, 5592.
(2) For a discussion of permutation pattern analysis in aromatic
phototransposition chemistry, see: (a) Barltrop, J . A.; Day, A. C. J .
Chem. Soc., Chem. Commun. 1975, 177. (b) Barltrop, J . A.; Day, A.
C.; Moxon, P. D.; Ward, R. W. J . Chem. Soc., Chem. Commun. 1975,
786. (c) Barltrop, J . A.; Day, A. C.; Ward, R. W. J . Chem. Soc., Chem.
Commun. 1978, 131.
(3) For five-membered heterocycles containing two heteroatoms,
there are 12 different ways of transposing the five ring atoms resulting
in 12 permutation patterns identified P1-P12. For a table showing these
permutation patterns, see: Pavlik, J . W.; Kurzweil, E. M. J . Org. Chem.
1991, 56, 6313.
GLC analysis revealed that addition of TEA to the
solution resulted in several changes to the reaction. First,
in the presence of TEA, the consumption of 1 increased
from 32% to 44%. Second, although 5-phenylthiazole (5)
was not observed as a product in the absence of TEA, in
10.1021/jo991785y CCC: $19.00 © 2000 American Chemical Society
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Photochemistry of 3- and 5-Phenylisothiazoles
J . Org. Chem., Vol. 65, No. 12, 2000 3627
the presence of TEA it is the major product formed in
14% yield. In addition, although TEA had no effect on
the yield of 3-phenylisothiazole (4), the yields of 4-phen-
ylthiazole (2) and 2-phenylthiazole (3) decreased from
15% and 2% to 4% and 0%, respectively. Finally, GLC
analysis showed that TEA was not consumed during the
photolysis.
spectrum which exhibited a singlet at δ 8.73 due to the
H-2 proton of 5-phenylthiazole (5) but no signal at δ 8.05
where the H-4 proton is known to absorb. This confirms
that 4-deuterio-5-phenylisothiazole (1-4d1) has phototrans-
posed to 4-deuterio-5-phenylthiazole (5-4d1) by the N2-
C3 interchange mechanism which is consistent with the
P4 permutation pathway. The second band at Rf ) 0.75
The permutation patterns2,3 for these transpositions
were unambiguously determined by synthesizing and
studying the photochemistry of 4-deuterio-5-phenyliso-
thiazole (1-4d1), a molecule in which each isothiazole ring
position is uniquely labeled. This was prepared by
lithium-halogen exchange of 4-bromo-5-phenylisothia-
zole 6 using tert-butyllithium and quenching 4-lithio-5-
provided a yellow oil that was identified by H NMR as
1
a mixture of 4-deuterio-3-phenylisothiazole (4-4d1) and
1
undeuterated 3-phenylisothiazole (4). Thus, the H NMR
spectrum of this material exhibited a singlet at δ 8.69
due to H-5 of 4-4d1 and a doublet of low intensity at δ
7.61 (J ) 4.71 Hz) due to H-4 coupled with H-5 of
undeuterated 3-phenylisothiazole (4). Integration of these
signals and analysis of the m/z 162 and 161 peaks in the
mass spectrum indicates that the isolated product is a
mixture of 4-deuterio-3-phenylisothiazole (4-4d1), de-
manded by the P5 permutation pathway, and undeuter-
ated 3-phenylisothiazole (4) in a ratio of 57:43. Interest-
ingly, when 1-4d1 was irradiated in benzene without
TEA, the ratio of 4-4d1:4 was 10.1. Thus, in the presence
of TEA, considerably more deuterium-hydrogen ex-
change occurs during the phototransposition reaction.
The residues remaining after evaporation of the solvent
from the irradiated solutions of 5-phenylisothiazole (1)
were also examined by infrared spectroscopy in order to
detect the formation of photocleavage products. These
spectra showed a weak absorption at 2209 cm-1, char-
acteristic of a nitrile functional group, but no absorption
in the 2100 cm-1 region where an isocyanide would be
expected to absorb. This suggests that 5-phenylisothia-
zole (1) has undergone photocleavage leading presumably
to 2-cyano-1-phenylethenethiol (8), the expected photo-
cleavage product of 1.
phenylisothiazole 7 with CH3OD. The mass spectrum of
the resulting product exhibited a molecular ion at m/z
162 but no signal at m/z 161, confirming complete
deuteration and an intense peak at m/z 135 due to loss
of H-C(3)tN indicating that the deuterium is located
at position 4 of the isothiazole ring.5,6 This was confirmed
1
by the H NMR spectrum which exhibited a singlet at δ
8.45 due to the H-3 proton but no signal at δ 7.40 where
the C-4 proton of 1 is known to absorb.7
A benzene solution of 4-deuterio-5-phenylisothiazole (1-
4d1) (50 mL, 2.0 × 10-2 M) containing TEA (7.5 × 10-2
M) was irradiated for 30 min after which GLC analysis
showed that 49% of the reactant was consumed and that
5-phenylthiazole (5), 3-phenylisothiazole (4), and 4-phen-
ylthiazole (2) were formed in yields of 19%, 9%, and 8%,
respectively.
The photolysate was also examined by GC-MS. The
mass spectrum of the unconverted 4-deuterio-5-phenyl-
isothiazole (1-4d1) was identical to the spectrum before
photolysis, showing that no deuterium was lost or
scrambled in the reactant during the irradiation. The
mass spectrum of deuterated 4-phenylthiazole (2) exhib-
ited a molecular ion at m/z 162 and an intense peak at
m/z 135 due to loss of H-C(2)tN. This shows that the
deuterium is located at position 5 of the 4-phenylthiazole
(2) ring and that the product is 5-deuterio-4-phenyl-
thiazole (2-5d1) formed from 4-deuterio-5-phenylisothia-
zole (1-4d1) by a mechanism consistent with the P7
permutation.
In an attempt to trap 8 as its benzyl thioether deriva-
tive, a solution of 1 in diethyl ether was irradiated until
after 30 min GLC analysis showed that greater than 90%
of the reactant had been consumed. TEA and then benzyl
bromide were added to the solution. After standing
overnight, preparative layer chromatography allowed
isolation of 2-cyano-1-phenylethen-1-ylbenzyl thioether
(9) as a yellow oil in 10.3% yield.
As required by this structural assignment, the mass
spectrum of this product exhibited a molecular ion at m/z
251, consistent with a molecular formula of C16H13NS,
and a base peak at m/z 91, as expected for a benzyl
derivative. Furthermore, the infrared spectrum exhibited
a sharp absorption at 2210 cm-1 for the nitrile functional
1
group. The H NMR spectrum showed a singlet at δ 3.88
assigned to the benzyl protons and a singlet due to the
vinyl proton at δ 5.44 with an integrated ratio of 2:1. In
addition to signals for the phenyl carbons, the 13C NMR
spectrum exhibited absorptions due to the benzyl, cyano,
and vinyl carbons at δ 37.7, 116.6, and 162.1, respec-
tively. These spectral properties are consistent with the
assigned structure.
Preparative layer chromatography of the photolysate
residue provided two major products. The band at Rf )
0.3 provided a yellow oil which was identified as 4-deu-
terio-5-phenylthiazole (5-4d1) on the basis of the 1H NMR
(4) All reported yields are absolute yields and are based on the
quantity of reactant consumed.
(5) Salmona, G.; Vincent, E.-J . Org. Mass. Spectrum 1978, 13, 119.
(6) Clarke, G. M.; Grigg, R.; Williams, D. H. J . Chem. Soc. B 1966,
339.
Close inspection of the 1H NMR spectrum also revealed
weak absorptions at δ 4.00 and 5.23 which may be due
to the benzyl and vinyl protons of a second stereoisomer
of the benzyl thioether 9. The vinyl protons of the (Z)-
(7) Staab, A.; Mannschreck, A. Chem. Ber. 1965, 98, 1111.

3628 J . Org. Chem., Vol. 65, No. 12, 2000
Pavlik and Tongcharoensirikul
and (E)-isomers of 9 are estimated to absorb at δ 5.75
and δ 5.16, respectively.8 Since the vinyl protons of the
major and minor stereoisomers of 9 were observed at δ
5.44 and upfield at δ 5.23, the major isomer was assigned
the (Z)-configuration. Isolation of 9 provides excellent
evidence that 5-phenylisothiazole (1) has undergone
photocleavage to yield cyanothiol 8.
The photochemistry of 5-phenylisothiazole (1) was also
investigated in methanol and 2,2,2-trifluoroethanol (TFE)
solvents with and without added TEA. Solutions of 1 in
methanol (3.0 mL, 2.1 × 10-2 M) without and with TEA
(1.5 × 10-2 M) were irradiated simultaneously on a
merry-go-round apparatus for 30 min. GLC analysis
showed that in the absence of TEA 33% of 1 had been
consumed and that 5-phenylthiazole (5), 4-phenylthiazole
(2), and 3-phenylisothiazole (4) had been formed in yields
of 23%, 6%, and 2%, respectively.9 GLC analysis also
revealed that in the presence of TEA the consumption of
1 increased to 51% and that the only photoproducts
observed are 5-phenylthiazole (5) and 4-phenylthiazole
(2) in yields of 34% and 2%, respectively. Interestingly,
an isocyanothiol in the phototransposition of 5-phenyl-
isothiazole (1).
Vernin and Maeda previously reported that 3-phenyl-
isothiazole (4) phototransposes to 4-phenylthiazole (2),
the expected P6 permutation product, in ether or benzene
solvent but not to 2-phenylthiazole (3), the expected P4
permutation product.11-14 In our laboratory, two solutions
of 3-phenylisothiazole (4) (3.0 mL, 2.0 × 10-2 M) in
benzene in the absence or presence of TEA (1.5 × 10-2
M) were irradiated simultaneously for 3.0 h on a merry-
go-round apparatus. GLC analysis showed that in the
absence of TEA 34% of 3-phenylisothiazole (4) was
consumed and that 4-phenylthiazole (2) and 2-phenylthi-
azole (3) were formed in 42.1% and 2.6% yields, respec-
tively. When the irradiation was carried out in the
presence of TEA, GLC analysis showed that the con-
sumption of 3-phenylisothiazole (4) was increased to 51%
and that 4-phenylthiazole (2) and 2-phenylthiazole (3)
were formed in 12.9% and 2.4% yields, respectively. The
decrease in the yield of 4-phenylthiazole (2) from 42.1%
to 12.9% was found to be due to the instability of 2 upon
prolonged irradiation in the presence of TEA.15,16 The
yields of 2-phenylthiazole (3) in the two reactions show
that TEA has little affect on the formation of this
compound. Finally, the infrared spectra of the residues
left after evaporation of the solvent from these reactions
did not show absorptions that would suggest the forma-
tion of products containing cyano or isocyano functional
groups.
this shows that the phototransposition becomes more
regioselective with increasing polarity of the solvent.
Indeed, when 1 was irradiated in the more polar TFE
solvent (3.0 mL, 2.0 × 10-2 M), 5-phenylthiazole (5) was
the only product observed. Thus, GLC analysis showed
that in the absence of TEA 5-phenylthiazole (5) was
formed in 32% yield while in the presence of TEA (1.5 ×
10-2 M) the yield of 5 was increased to 42%. Again, TEA
was not consumed during these irradiations. Finally, in
either methanol or TFE solvent, 4-deuterio-5-phenyl-
isothiazole (1-4d1) was converted to 4-deuterio-5-phen-
ylthiazole (5-4d1), showing that the increased solvent
polarity has not changed the permutation pathway for
the phototransposition reaction.
3-Phenylisothiazole (4) was also irradiated in methanol
solvent under the conditions described above. GLC
analysis showed that in the absence of TEA 36% of
3-phenylisothiazole (4) had been consumed while 4-
phenylthiazole (2) and 2-phenylthiazole (3) were formed
in yields of 16.8% and 4.9%, respectively. In the same
manner as for the reaction carried out in benzene, when
3-phenylisothiazole (4) was irradiated in methanol con-
taining TEA, the consumption of 4 was increased to 56%
whereas 4-phenylthiazole (2) and 2-phenylthiazole (3)
were formed in yields of 8.7% and 3.3%, respectively.
4-Phenylthiazole (2) is the product expected if 3-
phenylisothiazole (4) transposes via a P6 permutation
pathway. This permutation was confirmed by studying
the phototransposition of 5-deuterio-3-phenylisothiazole
(4-5d1) synthesized from 3-phenylisothiazole (4) by base-
(10) Ohashi, M.; Iio, A.; Ezaki, A.; Yonezawa, T. Heterocycles 1975,
1, 69.
(11) Maeda, M.; Kojima, M. J . Chem. Soc., Perkin Trans 1 1977,
239.
(12) Maeda, M.; Kawahara, A.; Kai, M.; Kojima, M. Heterocycles
1975, 5, 389.
(13) Vernin, G.; Poite, J . C.; Metzger, J .; Aune, J . P.; Dou, H. J . M.
Bull. Soc. Chim. Fr. 1971, 1103.
(14) Vernin, G.; Riou, C.; Dou, H. J . M.; Bouscasse, L.; Metzger, J .;
Loridan, G. Bull. Soc. Chim. Fr. 1973, 1743.
(15) Although irradiation of 4-phenylisothiazole 10 in the presence
of TEA for 30 min results in the formation of 4-phenylthiazole 2 in
70% yield,16 independent experiments show that prolonged irradiation
of 2 in the presence of TEA results in substantial loss of the heterocycle.
When the irradiated solution of 1 in TFE containing
TEA was allowed to react with benzyl bromide, the
infrared spectrum of the residue left after evaporation
of the solvent showed weak absorptions at 2211 and at
2099 cm-1, suggesting the presence of both cyano- and
isocyanobenzyl thioethers. These results again implicate
(8) Frieboln, H. Basic One- and Two-Dimensional NMR Spectros-
copy, 2nd; Ed.; VCH Publishers: New York, 1993; pp 139-143.
(9) Ohashi10 also reported that 5-phenylisothiazole (1) phototrans-
poses to 5-phenylthiazole (5) but made no mention of the formation of
4-phenylthiazole (2) or 3-phenylisothiazole (4).
(16) The acidity of the C-2 hydrogen of 4-phenylthiazole
2 is
enhanced upon photochemical excitation.17 In the presence of TEA,
excited 2 is no doubt efficiently deprotonated which may enhance its
reactivity.

Photochemistry of 3- and 5-Phenylisothiazoles
J . Org. Chem., Vol. 65, No. 12, 2000 3629
Ta ble 1. Qu a n tu m Yield Resu lts
Sch em e 2
reactant (solvent)
1 (C6H12
1 (C6H12/TEA)
4 (C6H12
Φ (consumption)
)
0.24 ( 0.01
0.24 ( 0.01
0.20 ( 0.03
)
Ta ble 2. Sp ectr oscop ic a n d P h otop h ysica l P r op er ties
λmax (nm) log ꢀ Φf (×104) τf (ps) τp (ms)
E
E
T1
S1
4
1
271
265
4.24
4.18
100
4.2
68
2.4
215
45
97
98
66
64
catalyzed hydrogen-deuterium exchange.17 A solution of
5-deuterio-3-phenylisothiazole (4-5d1) in benzene (3.0 mL,
2.0 × 10-2 M) was irradiated, and the deuterated 4-phen-
ylthiazole formed was analyzed by mass spectroscopy.
The major mass spectral fragmentation pathway for
4-phenylthiazole (2) involves loss of H-C(2)tN, resulting
in the formation of an m/z 134 fragment. In the mass
spectrum of deuterated 4-phenylthiazole formed from
5-deuterio-3-phenylisothiazole (4-5d1), the spectrum ex-
hibited a molecular ion at m/z 162 and a base peak at
m/z 134 showing that fragmentation has resulted in the
loss of D-C(2)tN. This shows that the C-5-deuterium
of 4-5d1 has transposed to position 2 of the 4-phenylthi-
azole ring to yield 2-deuterio-4-phenylthiazole (2-2d1) as
isothiazole (1) (ET ) 64 kcal mol-1) could not be sensitized
in cyclohexane by butyrophenone (ET ) 74.7 kcal mol-1
)
despite the observation that both 4 and 1 efficiently
quench the Norrish type II reaction of the sensitizer with
rate constants (kq) of 3.88 × 109 and 5.00 × 109 M-1 s-1
,
respectively.
Mech a n istic Discu ssion . Deuterium labeling shows
that the phototransposition of 5-phenylisothiazole (1) and
3-phenylisothiazole (4) involves competition between
electrocyclic ring closure-sulfur migration and the P4
interchange of N2 and C3 of the isothiazole ring.
As shown in Scheme 2, 5-phenylisothiazole (1) can be
converted to 3-phenylisothiazole (4), the P5 permutation
product, via a single sulfur walk, 1 + hν f BC-1 f BC-4
f 4, whereas 4-phenylthiazole (2), the P7 permutation
product, is formed via a double walk, process 1 + hν f
BC-1 f BC-4 f BC-2 f 2 and/or 1 + hν f BC-1 f
BC-3 f BC-2 f 2. Although BC-1 is expected to
rearrange mainly to BC-4, which is more stable than BC-
3, the latter pathway via BC-3 must account for at least
a portion of the transposition since the formation of
2-phenylthiazole (3), the P6 permutation product, impli-
cates the existence of BC-3 on the transposition pathway.
The formation of 4-phenylthiazole (2) as the major
product most likely reflects the fact that BC-2 is the most
stable bicyclic intermediate.
4-Deuterio-5-phenylisothiazole (1-4d1) was observed to
phototranspose in benzene to 4-deuterio-3-phenylisothia-
zole (4-4d1) with approximately 10% H-D exchange, and
a much greater amount of exchange was observed when
the irradiation was carried out in benzene-TEA.
Previous work in this laboratory has shown that
5-phenylisothiazole (1) undergoes phototransposition in
benzene-D2O to yield a mixture of 3-phenylisothiazole
(4) and 4-deuterio-3-phenylisothiazole (4-4d1).17 Mecha-
nistically, we suggested that the initially formed BC-1
undergoes deuterium incorporation and simultaneous
sigmatropic shift of sulfur to yield 4-4d1 via (4D-4-H-BC-
demanded by the P6 permutation pathway. Deuterated
2-phenylthiazole was also formed in this reaction, but the
yield was too low to allow determination of the position
of the deuterium.
Qu a n tu m Yield s. The quantum yields for the con-
sumption of isothiazoles 1 and 4 were determined in
triplicate in cyclohexane solutions. In the case of 1, the
quantum yield for consumption was also measured in
cyclohexane containing TEA. These values are shown in
Table 1. 1,3-Cycloheptadiene was used as the actinom-
eter.18
Sp ectr oscop ic P r op er ties. 3-Phenylisothiazole (4)
and 5-phenylisothiazole (1) exhibit structureless absorp-
tion spectra in methylcyclohexane solvent (Table 2) with
extinction coefficients consistent with π f π* transitions.
Both compounds exhibit very weak fluorescence and
phosphorescence in methylcyclohexane. Discernible O,O
bands in the fluorescence and phosphorescence spectra
of 4 and 1 indicate that ES values are 97 and 98 kcal
1
mol-1 while ET values are 66 and 64 kcal mol-1
,
1
respectively. The quantum yields of fluorescence at room
temperature were measured relative to hexaphenylben-
zene19 and are shown in Table 2. The measured fluores-
cence and phosphorescence lifetimes at room temperature
and at 77 K, respectively, are also shown in Table 2. The
lifetimes of S1 and T1 and the energy gaps are consistent
with π,π* configurations.
Sen sit ized Ir r a d ia t ion s. The photoreactions of 3-
phenylisothiazole (4) (ET ) 66 kcal mol-1) and 5-phenyl-
(17) Pavlik, J . W. Tongcharoensirikul, P.; Bird, N. P.; Day, A. C.;
Barltrop, J . A. J . Am. Chem. Soc. 1994, 116, 2292.
(18) Numao, N.; Hamada, T.; Yonemitsu, O. Tetrahedron Lett. 1997,
1661.
(19) Berlman, I. B. Handbook of Fluorescence Spectra of Aromatic
Molecules, 2nd ed.; Academic Press: New York, 1971; p 237.
4)+. In the present case, 4-deuterio-5-phenylisothiazole
(1-4d1) phototransposed to 4-deuterio-3-phenylisothiazole
(4-4d1) with exchange of a small quantity of deuterium

3630 J . Org. Chem., Vol. 65, No. 12, 2000
Pavlik and Tongcharoensirikul
Sch em e 4
Sch em e 3
for hydrogen at position 4. This must be due to a small
quantity of H2O in the benzene solvent. The extent of
H-D exchange was substantially enhanced when the
photolysis of 1-4d1 was carried out in the presence of
TEA. In this case TEA presumably deprotonates (4D-4H-
BC-4)+ to yield 4 and H-TEA+ which is a better proton
donor in the exchange reaction.
As shown in Scheme 3, 3-phenylisothiazole (4) can be
converted to 4-phenylthiazole (2) via a single sulfur walk,
4 + hν f BC-4 f BC-2 f 2. This is consistent with
deuterium labeling which shows that 3-phenylisothiazole
(4) transposes to 4-phenylthiazole (2) by way of a P6
permutation pathway. Failure to observe 5-phenylthia-
zole (1) as a product in this reaction indicates that BC-4
partitions only between 4 and BC-2 and not the signifi-
cantly less stable bicyclic species BC-1.
Although the conversion of 5-deuterio-3-phenylisothia-
zole (4-5d1) to 2-deuterio-4-phenylthiazole (2-2d1) con-
firmed that the transposition occurs via the P6 permu-
tation pathway, deuterated 2-phenylthiazole was not
formed in sufficient quantity to allow determination of
the position of the deuterium. Accordingly, in this reac-
tion it is not possible to unambiguously determine the
permutation pattern since both the P4 N2-C3 interchange
and the double sulfur walk P7 pathways lead coinciden-
tally to the same product, 2-phenylthiazole (3).
The conversion of 3-phenylisothiazole (4) to 2-phen-
ylthiazole (3) via the P7 pathway is unlikely, however,
since it would require a pathway (Scheme 2) involving 4
+ hν f BC-4 f BC-2 f BC-3 f 3. 4-Phenylthiazole (2),
however, phototransposes only to 3-phenylisothiazole (4)
and not to 2-phenylthiazole (3). This reveals that BC-2
partitions only between 2 and BC-4 and not to the
significantly less stable bicyclic species BC-3. The ab-
sence of the formation of 5-phenylisothiazole (1) from
3-phenylisothiazole (4) makes walk in the opposite
direction, i.e., 4 + hν f BC-4 f BC-1 f BC-3 f 3, also
unlikely. In view of these arguments, it is more likely
that 2-phenylthiazole (3) is formed from 3-phenylisothia-
zole (4) via the P4 permutation pathway.
4-Phenylisothiazole (10) undergoes photocleavage and
phototransposition exclusively by the P4 N2-C3 inter-
change pathway. Both of these reactions are initiated by
photochemically breaking of the S-N bond, resulting in
the formation of a species that can be viewed as diradical
11a or as â-thioformylvinyl nitrene 11b. This species, as
well as the transition state leading to it, is appreciably
stabilized by the â-phenyl group. This stabilization thus
assists photocleavage of the S-N bond relative to other
possible reactions. As a result, 4-phenylisothiazole (10),
which has a quantum yield of consumption of 0.41, is the
most reactive of the phenylisothiazole isomers. 5-Phen-
ylisothiazole (1) and 3-phenylisothiazole (4) react less
efficiently and have quantum yields of consumption of
0.20 and 0.13, respectively, reflecting the lack of stabi-
lization exerted by the phenyl group from the 3 and 5
positions. Moving the phenyl group from C4 to C5 or C3
not only decreases reactivity of the P4 N2-N3 interchange
pathway but also allows the slower electrocyclic ring
closure to compete with breaking of the S-N bond. Thus,
both 3-phenyl- and 5-phenylisothiazoles (4 and 1) react
by both the P4 N2-C3 interchange pathway and the
electrocyclic ring closure-heteroatom migration pathway
leading to P5, P6, and P7 phototransposition products.
Interestingly, the same structure-reactivity trends were
observed in the three isomeric phenyl-substituted 1-me-
thylpyrazoles.20
In addition to recyclizing to isothiazole reactant 1,
â-thiocarbonyl vinyl nitrene 12 (Scheme 4) would be
expected to rearrange to cyanothiol 8, possibly by way of
thiocarbonylketene 13. Isomerization to nitriles is a well-
documented reaction of terminal vinyl nitrenes.21 In
addition, 12 would also be expected to be in equilibrium
with thiocarbonylazirine 14.22 Two reaction pathways can
be envisioned for this azirine. First, on the basis of the
known photochemistry of azirines,23,24 14 would be ex-
pected to undergo photochemical opening of the C-C
bond resulting in the formation of nitrile ylide 15, a likely
(20) Pavlik, J . W.; Kebede, N. J . Org. Chem. 1997, 62, 8325.
(21) See: Hassner, A. In Azides and Nitrenes. Reactivity and Utility;
Scriven, E. F. V., Ed.; Academic Press: Orlando, 1984; pp 35-94, and
references therein.
(22) Hassner, A.; Wiegand, N. H.; Gottlieb, H. E. J . Org. Chem. 1986,
51, 3176.
(23) Padwa, A.; Smolanoff, J .; Tremper, A. Tetrahedron Lett. 1974,
29; J . Am. Chem. Soc. 1975, 97, 4682.
(24) (a) Padwa, A. Acc. Chem. Res. 1976, 9, 371. (b) Griffin, G. W.;
Padwa, A. In Photochemistry of Heterocyclic Compounds; Buchardt,
O., Ed.; J ohn Wiley and Sons: New York, 1976.

Photochemistry of 3- and 5-Phenylisothiazoles
J . Org. Chem., Vol. 65, No. 12, 2000 3631
Sch em e 5
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
recorded at 200 and 50.3 MHz, respectively. GLC was per-
formed using a 30 m × 0.25 µm Supelcowax 10 bonded phase
column. Preparative layer chromatography was carried out on
20 cm × 20 cm glass plates coated with 2 mm Kieselgel 60254
(Merck).
Ma ter ia ls. Benzene was purified by being refluxed over
calcium hydride followed by fractional distillation. Diethyl
ether was purified by being refluxed over a 40% dispersion of
sodium in paraffin containing benzophenone until the benzo-
phenone ketyl radical was bright blue followed by fractional
distillation. Methanol was purified by being refluxed over
magnesium methoxide followed by fractional distillation. 2,2,2-
Trifluoroethanol (NMR grade) and triethylamine (99.5%) were
obtained from Aldrich Chemical Co. and used as received.
Syn t h esis of R ea ct a n t s a n d P r od u ct s. Phenylisothia-
zoles and phenylthiazoles 1-5 were synthesized by procedures
previously described.17
5-Deu t er io-3-P h en ylisot h ia zole (4-5d 1). 3-Phenyliso-
thiazole (4) (0.25 g, 1.44 mmol) was added to CH3OD (10 mL)
containing sodium metal (0.13 g, 5.4 mmol), and the flask was
tightly closed and allowed to stand at room temperature in
the dark for 5 days. The resulting solution was added to
aqueous HCl (5 M, 50 mL), and the mixture was extracted
with dichloromethane (3 × 100 mL). The extract was dried
(Na2SO4) and concentrated to yield a colorless oil (0.25 g) which
was distilled (Kugelrohr) to give 5-deuterio-3-phenylisothiazole
(4-5d1) as a colorless oil: bp (oven temperature) 120 °C (1.5
Torr); 0.22 g (1.36 mmol, 88% yield); 1H NMR (CDCl3) δ 7.35-
7.50 (m, 3H), 7.55 (s, 1H), 7.85-8.05 (2H, m); MS m/z (%), 162
(100).
precursor of the P4 thiazole transposition product 5. The
concentration of 14, however, would be expected to be
low. This pathway would therefore be expected to be of
limited efficiency since azirine 14 would not be able to
compete with isothiazole 1 for the incident light. In the
absence of other ring expansion pathways, the yield of
5-phenylthiazole (5) would be low. In the presence of a
suitable base such as TEA, the base would be expected
to deprotonate azirine 14, resulting in its conversion to
isocyanide 16.25 Reprotonation of 16 at carbon also leads
to nitrile ylide 15 and, after cyclization, 5-phenylthiazole
5, the P4 phototransposition product. This mechanistic
pathway thus explains the observed increase in the yield
of thiazole 5 upon addition of TEA to the reaction
mixture.
This mechanistic pathway is also consistent with the
observed photochemistry of 3-phenylisothiazole (4). Thus,
in the absence of an R-H, thioformylvinyl nitrene 17
(Scheme 5), derived from 4, cannot rearrange to a nitrile.
This accounts for our inability to observe a nitrile
absorption band in the crude product mixtures. In
addition, in the absence of a hydrogen at C3, the depro-
tonation-ring opening-cyclization pathway for the for-
mation of the P4 transposition product, which was
available for the conversion of azirine 14 to 5-phenyl-
thiazole 5, is not available for the conversion of azirine
18 to 2-phenylthiazole 2. In the case of 4, the addition of
TEA is not expected to enhance the yield of the P4
phototransposition product. The only phototransposition
pathway thus must involve the less efficient photochemi-
cal ring opening of azirine 18, accounting for the low yield
of 2.
4-Br om o-5-p h en ylisot h ia zole (6). Bromine (4.5 g, 28.2
mmol) was added dropwise over a period of 30 min to a stirred
mixture of 5-phenylisothiazole (1), (1.41 g, 8.8 mmol) anhy-
drous potassium acetate (1.34 g, 14.0 mmol), and glacial acetic
acid (30 mL). The reaction mixture was stirred at room
temperature overnight and then refluxed for 2 h. The reaction
mixture was cooled to room temperature and treated with
aqueous sodium bisulfite (33%, 10 mL). The solution was made
basic with aqueous sodium hydroxide (20%), extracted with
dichloromethane (3 × 80 mL), dried (anhydrous Na2SO4), and
evaporated to dryness to a yellow solid (2.1 g). The crude
product was distilled (Kugelrohr, 130 °C, 0.5 Torr) to yield a
colorless liquid that solidified to give 4-bromo-5-phenylisothia-
zole (6) as a white solid (1.9 g, 7.9 mmol, 89.8% yield): mp
1
50-52 °C; H NMR (200 MHz), CDCl3) δ 8.36 (s, 1H), 7.66-
7.58 (m, 2H), 7.52-7.43 (m, 3H); 13C NMR (50.3 MHz, CDCl3)
δ 161.0, 159.5, 129.8, 129.2, 129.0, 128.4, 106.0; MS m/z (%)
243(4.8), 242(10.4), 241(100). Anal. Calcd for C9H6NSBr: C,
45.02; H, 2.52, N, 5.83; Br, 33.28. Found: C, 45.03, H, 2.47;
N, 5.79; Br, 33.19.
Con clu sion . Phenylisothiazoles undergo phototrans-
position via their S1(π,π*) states. Unlike 4-phenylisothia-
zole (10), which transposes exclusively via the N2-C3
interchange pathway, 3- and 5-phenylisothiazoles (4 and
1) transpose by both the N2-C3 interchange pathway and
the electrocyclic ring closure-heteroatom migration path-
way. In the case of 5-phenylisothiazole (1), the N2-C3
interchange pathway is affected by the presence of TEA
in the reaction medium and by the solvent polarity. For
example, although upon irradiation in benzene 1 trans-
poses only by the electrocyclic ring closure-heteroatom
migration pathway, when the photoreaction is carried out
in TFE solvent containing TEA 1 transposes regiospe-
cifically by the N2-C3 interchange pathway. 3-Phenyl-
isothiazole (4) also phototransposes by both transposition
pathways, but in this case the product distribution is not
affected by the solvent polarity or the presence of TEA.
4-Deu ter io-5-P h en ylisoth ia zole (1-4d 1). tert-Butyllith-
ium (1.7 M in pentane, 4.0 mL, 6.8 mmol) was added dropwise
to a stirred solution of 4-bromo-5-phenylisothiazole (6) (1.44
g, 6.0 mmol) in anhydrous ether (30 mL) at -110 °C (ethanol/
liquid N2) under argon. After addition was complete, the
solution was stirred at -110 °C for 1 h, quenched by the
addition of CH3OD (4.0 mL), and allowed to warm to room
temperature. The suspension was filtered, and the filtrate was
concentrated. Distillation of the residue (Kugelrohr, 120 °C,
0.5 Torr) gave a colorless liquid that solidified to give 4-deu-
terio-5-phenylisothiazole (1-4d1) as a white solid (0.90 g, 5.56
1
mmol, 93% yield): mp 47-48 °C; H NMR (200 MHz, CDCl3
δ 8.45 (s, 1H), 7.62-7.57 (m, 2H), 7.46-7.38 (m, 3H); MS m/z
(%), 164 (5), 163 (11), 162 (100), 135 (36).
Ir r a d ia tion a n d An a lysis P r oced u r es. Photoreactions of
phenylisothiazoles 1 and
4 on an analytical scale were
monitored by GLC and by IR spectroscopy. To determine the
effect of TEA on the photoreactions of 1 and 4 in a particular
solvent, two solutions of 1 or 4 (3.0 mL, 2.0 × 10-2 M) in
benzene, methanol, or TFE in the absence or presence of TEA
(1.5 × 10-2 M) were placed in quartz tubes (0.7 cm inside
diameter × 12 cm long) which were sealed with rubber septae,
(25) Isomura, K.; Hirose, Y.; Shuyama, H.; Abe, S.; Ayabe, G.;
Taniguchi, H. Heterocycles 1978, 1207.

3632 J . Org. Chem., Vol. 65, No. 12, 2000
Pavlik and Tongcharoensirikul
purged with argon for 30 min, and irradiated simultaneously
in a Rayonet photochemical reactor equipped with a merry-
go-round and eight low-pressure Hg lamps.
irradiated as above until GLC analysis showed that 49% of
1-4d1 was consumed.
An aliquot (0.5 mL) of the resulting solution was treated
and analyzed as above. 4-Deuterio-5-phenylisothiazole (1-4d1)
exhibited signals m/z (%), 164 (5.2), 163 (11.4), 162 (100), and
135 (35.8). Deuterated 4-phenylthiazole (2-5d1) exhibited
signals at m/z (%), 162 (100), 161 (3.8), 135 (91.6), and 134
(12.9).
GLC An a lysis. Quantitative GLC analysis of reactant
consumption and product formation was accomplished using
calibration curves constructed for 1-5 by plotting detector
responses versus 10 standards of known concentrations.
Correlation coefficients ranged from 0.995 to 0.999. At 190 °C
1-5 elute in the order 2-phenylthiazole (3), 5-phenylisothiazole
(1), 5-phenylthiazole (5), 3-phenylisothiazole (4), and 4-phe-
nylthiazole (2) with retentions [relative to 5-phenylisothiazole
(1)] of 0.92, 1.0, 1.14, 1.16, and 1.30, respectively.
IR An a lysis. An aliquot (2.0 mL) of the irradiated solution
was evaporated under reduced pressure. The residue was
dissolved in methylene chloride (0.1 mL), and this solution was
allowed to evaporate on a sodium chloride disk. The residual
oil was covered with a second disk and the infrared spectrum
recorded.
P r ep a r a tive Sca le Ir r a d ia tion s. A solution of the reac-
tant was dissolved in the appropriate solvent and the mixture
placed in a quartz tube [1.45 cm inside diameter × 13 cm long
(for 10.0 mL) or 2.5 cm inside diameter × 30 cm long (for 50.0
or 90.0 mL)] which was closed with a rubber septum, purged
with argon for 30 min, and irradiated in a Rayonet reactor
while the solution was continuously purged with a fine stream
of argon.
Ir r a d ia tion of 4-Deu ter io-5-p h en ylisoth ia zole (1-4d 1)
in Ben zen e. 4-Deuterio-5-phenylisothiazole (1-4d1) (0.14 g,
0.86 mmol) was dissolved in benzene (50.0 mL) and irradiated
in a Rayonet reactor equipped with 16 low-pressure Hg lamps
until GLC analysis showed that 97% of 1-4d was consumed.
An aliquot (0.5 mL) of the resulting solution was evaporated
to dryness, redissolved in benzene (0.020 mL), and analyzed
by GLC-MS. 4-Deuterio-5- phenylisothiazole (1-4d1) exhibited
a base peak due to the molecular ion at m/z ) 162 and a strong
signal at m/z ) 135. 5-Deuterio-4-phenylthiazole (2-5d1)
exhibited a base peak due to the molecular ion at m/z ) 162
and an intense signal at m/z ) 135.
The remaining solution (49.5 mL) was evaporated, and the
residue (0.16 g) was subjected to preparative layer chroma-
tography (silica gel, CH2Cl2). The band at Rf ) 0.32 gave
4-deuterio-5-phenylthiazole (5-4d1) as a yellow oil (0.012 g):
1H NMR (200 MHz, CDCl3), δ 8.73 (s, 1H), 7.59-7.29 (m, 5H);
MS m/z (%), 164 (4.9), 163 (11.6), 162 (100), 135 (85.7), 134
(27.4). The band at Rf ) 0.75 gave a mixture of 3-phenyl-
isothiazole (4) and 4-deuterio-3-phenylisothiazole (4-4d1) as a
yellow oil (0.006 g): 1H NMR (200 MHz, CDCl3), δ 8.71-8.69
(brs, 1.4H), 7.98-7.90 (m, 2H), 7.61 (d, J ) 4.17 Hz, 0.6H),
7.50-7.39 (m, 3H); MS m/z (%), 164 (4.6), 163 (12.9), 162 (100).
Ir r a d ia tion of 4-Deu ter io-5-p h en ylisoth ia zole (1-4d 1)
in TF E. 4-Deuterio-5-Phenylisothiazole (1-4d1) (0.032 g, 0.2
mmol) was dissolved in freshly distilled TFE (10.0 mL) and
irradiated in a Rayonet reactor equipped with eight low-
pressure Hg lamps for 30 min. An aliquot (0.5 mL) of the
irradiated solution was evaporated to dryness, redissolved in
CH2Cl2 (0.02 mL), and analyzed by GLC-MS. The peak due to
4-deuterio-5-phenylisothiazole (1-4d1) exhibited signals at m/z
(%), 164 (5.1), 163 (11.2), 162 (100), 135 (36.2). The peak due
to 4-deuterio-5-phenylthiazole (5-4d1) exhibited signals at m/z
(%), 164 (5.2), 163 (11.4), and 162 (100).
Ir r adiation of 5-P h en ylisoth iazole (1) in Dieth yl Eth er .
Tr a p p in g of Cya n osu lfid e 8. 5-Phenylisothiazole (1) (0.050
g, 0.31 mmol) was dissolved in freshly distilled diethyl ether
(90 mL) and irradiated in a Rayonet reactor equipped with
eight low-pressure Hg lamps. TEA (5.0 mL) was added
followed by benzyl bromide (0.10 mL, 0.14 g 0.84 mmol). The
reaction mixture was allowed to stand overnight at room
temperature and filtered, and the filtrate was evaporated to
dryness to leave a yellow oil. The combined residue (0.38 g)
from two such reactions was subjected to preparative layer
chromatography (silica gel, CH2Cl2:hexane 6:4). The band at
Rf ) 0.35 gave 2-cyano-1-phenylethen-1-ylbenzyl thioether (9)
as a slightly unstable yellow oil (0.016 g, 0.064 mmol, 10.3%
yield): 1H NMR (200 MHz, CDCl3), δ 7.43-6.00 (m, 5H, 5.44
(s, 1H), 3.88 (s, 2H); 13C NMR (50.3 MHz, CDCl3) δ 162.1,
136.4, 136.2, 130.7, 128.9, 128.8, 128.5, 128.1, 127.5, 116.6,
97.1, 37.7; MS m/z (%), 253 (1.0), 252 (2.9), 251 (15.5), 91 (100).
The remaining solution (49.5 mL) was evaporated to dry-
ness, and the residue (0.12 g) was subjected to preparative
layer chromatography (silica gel, CH2Cl2). The band at Rf 0.75
gave deuterated 3-phenylisothiazole (4) as a yellow oil (0.005
g): 1H NMR (200 MHz, CDCl3), δ 8.69 (brs, 1.0H), 7.98-0.790
(m, 2H), 7.61 (d, J ) 4.71 Hz, 0.1H), 7.50-7.39 (m, 3H); MS
m/z (%), 164 (5.1), 163 (12.2), 162 (100), 61 (26.4), 135 (24.0).
Ir r a d ia tion of 4-Deu ter io-5-p h en ylisoth ia zole (1-4d 1)
in Ben zen e Con ta in in g TEA. 4-Deuterio-5-phenylisothiazole
(1-4d1) (0.16 g, 0.99 mmol) and TEA 0.5 mL) were dissolved
in benzene (50.0 mL) in a quartz tube and treated and
J O991785Y