Photochemistry of phenyl-substituted 1,2,4-thiadiazoles. 15N-labeling studies

Article abstract of DOI:10.1021/jo0340915

Irradiation of 5-phenyl-1,2,4-thiadiazole (6) resulted in the formation of benzonitrile (5), 3-phenyl-1,2,4-thiadiazole (4), phenyl- and diphenyl-1,3,5-triazines (7 and 8), and a trace quantity of diphenyl-1,2,4-thiadiazole (9). The formation of 4, 5, 7, and 8 can be explained in terms of photoinduced electrocyclic ring closure resulting in the formation of an intermediate 4-phenyl-1,3-diaza-5-thiabicyclo[2.1.0]pentene. ¹⁵N-labeling experiments revealed that sulfur can undergo sigmatropic shifts around all four sides of the diazetine ring. Thus, irradiation of 6-4-¹⁵N led to the formation of 6-2-¹⁵N and an equimolar mixture of 4-2-¹⁵N and 4-4-¹⁵N. The thiabicyclo[2.1.0]pentene intermediate is also suggested to undergo sulfur elimination resulting in the formation of phenyldiazacyclobutadiene, which can undergo complete fragmentation to benzonitrile or [4+2] cycloaddition leading to unstable tricyclic adducts, the suggested precursors of the 1,3,5-triazine products 7 and 8. The observed ¹⁵N distribution in 7 and 8 is consistent with this mechanism. Irradiation of 4 led only to the formation of 5. ¹⁵N-labeling experiments show that 4 does not undergo electrocyclic ring closure but reacts exclusively by photofragmentation of the thiadiazole ring.

Full text of DOI:10.1021/jo0340915

P h otoch em istr y of P h en yl-Su bstitu ted 1,2,4-Th ia d ia zoles.
15N-La belin g Stu d ies‡
J ames W. Pavlik,* Chuchawin Changtong, and Vikki M. Tsefrikas
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute,
Worcester, Massachusetts 01609
jwpavlik@wpi.edu
Received J anuary 24, 2003
Irradiation of 5-phenyl-1,2,4-thiadiazole (6) resulted in the formation of benzonitrile (5), 3-phenyl-
1,2,4-thiadiazole (4), phenyl- and diphenyl-1,3,5-triazines (7 and 8), and a trace quantity of diphenyl-
1,2,4-thiadiazole (9). The formation of 4 ,5, 7, and 8 can be explained in terms of photoinduced
electrocyclic ring closure resulting in the formation of an intermediate 4-phenyl-1,3-diaza-5-
thiabicyclo[2.1.0]pentene. 15N-labeling experiments revealed that sulfur can undergo sigmatropic
shifts around all four sides of the diazetine ring. Thus, irradiation of 6-4-15N led to the formation
of 6-2-15N and an equimolar mixture of 4-2-15N and 4-4-15N. The thiabicyclo[2.1.0]pentene
intermediate is also suggested to undergo sulfur elimination resulting in the formation of
phenyldiazacyclobutadiene, which can undergo complete fragmentation to benzonitrile or [4+2]
cycloaddition leading to unstable tricyclic adducts, the suggested precursors of the 1,3,5-triazine
products 7 and 8. The observed 15N distribution in 7 and 8 is consistent with this mechanism.
Irradiation of 4 led only to the formation of 5. 15N-labeling experiments show that 4 does not undergo
electrocyclic ring closure but reacts exclusively by photofragmentation of the thiadiazole ring.
In tr od u ction
The photochemical properties of 1,2,4-thiadiazoles 1
are intriguing because the ring can be viewed as a
combination of an isothiazole 2 and a thiazole 3. Although
the photochemistry of isothiazoles and thiazoles has been
extensively studied,2-16 no accounts of the photochemistry
of 1,2,4-thiadiazoles have appeared in the literature. We
now report that phenyl-substituted 1,2,4-thiadiazoles
undergo photofragmentation, phototransposition, and an
unusual reaction leading to the formation of 1,3,5-
triazines. Product distributions in these reactions depend
on the position of the phenyl substituent on the thiadia-
zole ring.
‡ This paper is dedicated to Dr. A. Colin Day (1934-2001), friend
and colleague, in recognition of his many contributions to the photo-
chemistry of heteroaromatic compounds.
(1) Presented in part at the 222nd National Meeting of the American
Chemical Society, Chicago, IL, August 30, 2001.
(2) Kojima, M.; Maeda, M. J . Chem. Soc., Chem. Commun. 1970,
386-387.
Resu lts a n d Discu ssion
Not all phenyl-substituted 1,2,4-thiadiazoles react by
all three pathways. Irradiation of a solution of 3-phenyl-
1,2,4-thiadiazole (4) in acetonitrile, for example, was
accompanied by the formation of a finely divided suspen-
sion of what was presumed to be elemental sulfur. Gas-
liquid chromatographic (GLC) analysis as a function of
irradiation time showed the gradual consumption of the
reactant and the formation of a GLC-volatile product,
which was identified by its retention time and mass
spectrum as benzonitrile (5). After a total of 120 min of
irradiation, quantitative GLC showed that 82% of 4 was
(3) Vernin, G.; Poite, J .-C.; Metzger, J .; Aune, J .-P.; Dou, J . M. Bull.
Soc. Chim. Fr. 1971, 1103-1104.
(4) Vernin, G.; J auffred, R.; Richard, C.; Dou, H. J . M.; Metzger, J .
J . Chem. Soc., Perkin Trans. 2 1972, 1145-1150.
(5) Riou, C.; Vernin, G.; Dou, H. J . M.; Metzger, J . Bull. Soc. Chim.
Fr. 1972, 2673-2678.
(6) Vernin, G.; Poite, J .-C.; Dou, H. J . M.; Metzger, J . Bull. Soc.
Chem. Fr. 1972, 3157-3167.
(7) Vernin. G.; Riou, C.; Dou, H. J . M.; Bouscasse, L.; Metzeter, J .;
Loridan, G. Bull. Soc. Chim. Fr. 1973, 1743-1751.
(8) Maeda, M.; Kojima, M. Tetrahedron Lett. 1973, 3523-3526.
(9) Riou, C.; Poite, J .-C.; Vernin, G.; Metzger, J . Tetrahedron 1974,
30, 879-898.
(10) Maeda, M.; Kawahara, A.; Kai, M.; Kojima, M. Heterocycles
1978, 3, 389-393.
(16) For reviews see: (a) Lablache-Combier, A. In Photochemistry
of Heterocyclic Compounds; Buchardt, O., Ed.; Wiley: New York, 1976.
(b) Padwa, A. In Rearrangements in Ground and Excited States; de
Mayo, P., Ed.; Academic Press: New York, 1980; Vol. III, p 501. (c)
Lablache-Combier, A. In CRC Handbook of Organic Photochemistry
and Photobiology; Horspool, W., Ed.; CRC Press: Boca Raton, FL, 1995;
p 1063. (d) Pavlik, J . W. In Molecular and Supramolecular Photo-
chemistry; Ramamurthy, V., Schanze, K. S., Eds.; Marcel Dekker: New
York, 1997; p 57.
(11) Maeda, M.; Kojima, M. J . Chem. Soc., Perkin Trans. 1 1978,
685-692.
(12) Pavlik, J . W.; Pandit, C. R.; Samuel, C. J .; Day, A. C. J . Org.
Chem. 1993, 58, 3407-3410.
(13) Pavlik, J . W.; Tongcharoensirikul, P.; Bird, N. P.; Day, A. C.;
Barltrop, J . A. J . Am. Chem. Soc. 1994, 116, 2292-2300.
(14) Pavlik, J . W.; Tongcharoensirikul, P.; French, K. M. J . Org.
Chem. 1998, 63, 5592-5603.
(15) Pavlik, J . W.; Tongcharoensirikul, P. J . Org. Chem. 2000, 65,
3626-3632.
(17) All yields reported are percent yields determined by quantita-
tive GLC and based on the number of moles of reactant consumed.
10.1021/jo0340915 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/14/2003
J . Org. Chem. 2003, 68, 4855-4861
4855

Pavlik et al.
SCHEME 1
consumed and that benzonitrile (5) was formed in 74%
yield.17 These results show that 3-phenyl-1,2,4-thiadia-
zole (4) undergoes only photofragmentation of the thia-
diazole ring to yield benzonitrile (5).
SCHEME 2
The photochemistry of 5-phenyl-1,2,4-thiadiazole (6) is
more complicated. Irradiation of a solution of 6 in
acetonitrile for 150 min was accompanied by the con-
sumption of 53% of the reactant and the formation of
eight GLC-volatile products. Although three of the most
minor products could not be identified, comparison of the
GLC retention times and mass spectra with authentic
samples allowed the remaining five products to be
identified as benzonitrile (5), the photofragmentation
product, 3-phenyl-1,2,4-thiadiazole (4), a phototranspo-
sition product, phenyl-1,3,5-triazine (7), diphenyl-1,3,5-
triazine (8), and diphenyl-1,2,4-thiadiazole (9). These
products were formed in yields of 58%, 18%, 4%, 2%, and
trace, respectively.
P h ototr an sposition . The phototransposition of 5-phen-
yl-1,2,4-thiadiazole (6) to 3-phenyl-1,2,4-thiadiazole (4)
can be rationalized by a mechanism that has been used
to explain the phototransposition reactions of other five-
membered heteroaromatic compounds.16d Thus, as shown
in Scheme 1, upon photochemical excitation 6 is predicted
to undergo electrocyclic ring closure leading to the
formation of bicyclic intermediate, BC-6. Because it is
not possible to distinguish between the two nitrogen
atoms in BC-6, one or two sigmatropic shifts of sulfur
would lead to the same bicyclic species, BC-4. Rearoma-
tization of this species would lead to the observed
phototransposition product, 4. In addition, sulfur migra-
tion in the opposite direction would lead to a bicyclic
species identical with BC-6 except for the interchange
of the two ring nitrogens. Rearomatization of this species
would lead back to the reactant 6.
3-Methyl-5-phenyl-1,2,4-thiadiazole (10) reacted simi-
larly. Thus, irradiation of a solution of 10 in acetonitrile
for 150 min was accompanied by the consumption of 76%
of the reactant and the formation of benzonitrile (5) in
50% yield, 5-methyl-3-phenyl-1,2,4-thiadiazole (11) in
Since it is not possible to distinguish between the two
nitrogen atoms in the 1,2,4-thiadiazole ring, it is not
possible to distinguish between formation of 3-phenyl-
1,2,4-thiadiazole (4) by one or two sulfur migrations.
Similarly, it is not possible to detect sulfur migration in
the opposite direction since that pathway leads back to
5-phenyl-1,2,4-thiadiazole (6).
approximately 10% yield, and dimethylphenyl-1,3,5-
triazine (12) and methyldiphenyl-1,3,5-triazine (13) in
yields of 33% and 5% respectively. These products were
identified by comparison of their GLC-retention times
and mass spectra with authentic samples of each com-
pound.
This ambiguity was resolved by studying the photo-
chemistry of 5-phenyl-1,2,4-thiadiazole-4-15N, 6-415N.
Scheme 2 confirms that if the 14N atom at ring position
4 is replaced by 15N, then the one- and two-step sulfur
migrations lead to an equilibrium mixture of BC-4 and
BC-4′. Rearomatization of these bicyclic species would
result in the formation of 3-phenyl-1,2,4-thiadiazole-4-
15N (4-4-15N) and 3-phenyl-1,2,4-thiadiazole-2-15N (4-2-
15N), respectively. Furthermore, sulfur migration in the
opposite direction and rearomatization would result in
the formation of 5-phenyl-1,2,4-thiadiazole-2-15N (6-2-15N)
via BC-6′.
Diphenyl-1,2,4-thiadiazole (9) was also observed to
undergo photofragmentation and triazine formation.
Thus, irradiation of a solution of diphenyl-1,2,4-thiadia-
zole (9) in cyclohexane resulted in the formation of
benzonitrile (5) and triphenyl-1,3,5-triazine (14) in yields
of 26% and 52%, respectively.
5-Phenyl-1,2,4-thiadiazole-4-15N (6-4-15N) was synthe-
4856 J . Org. Chem., Vol. 68, No. 12, 2003

Photochemistry of Phenyl-Substituted 1,2,4-Thiadiazoles
sized from commercially available benzamide-15N.18 The
mass spectrum of 6-4-15N exhibited a molecular ion at
m/z 163, and a base peak at m/z 136, which would result
from loss of HC14N, but no signal at m/z 135, which would
result from loss of HC15N.
A solution of 6-4-15N in acetonitrile was irradiated for
180 min. GLC analysis showed that 70% of the reactant
had been consumed. The mass spectrum of the recovered
15N-labeled reactant again exhibited an intense signal at
m/z 136 due to the loss of HC14N from 5-phenyl-1,2,4-
thiadiazole-4-15N (6-4-15N). In addition, the spectrum also
showed a prominent signal at m/z 135 due to the loss of
HC15N. This signal at m/z 135 was not present in the
mass spectrum of the reactant before irradiation. Its
appearance after irradiation indicates that a portion of
5-phenyl-1,2,4-thiadiazole-4-15N (6-4-15N) has transposed
to 5-phenyl-1,2,4-thiadiazole-2-15N (6-2-15N). The m/z 135/
136 ratio of 0.40 indicates that the recovered 15N-labeled
reactant consists of 71% of the 4-15N isomer 6-4-15N and
29% of the 2-N15 isomer 6-2-15N.
HC14N from a molecule of 3-phenyl-1,2,4-thiadiazole with
an 15N atom at ring position 2, as in 4-2-15N. After 12.0
and 16.0 min of irradiation the m/z 135/136 ratio was
also determined to be 1.07 ( 0.08 and 1.12 ( 0.02,
respectively. These ratios show that after 8.0 min of
irradiation the 15N-labeled 3-phenyl-1,2,4-thiadiazole
product consists of a 50:50 mixture of 3-phenyl-1,2,4-
thiadiazole-4-15N (4-4-15N) and 3-phenyl-1,2,4-thiadiaz-
ole-2-15N (4-2-15N) and that the composition of this
mixture remained constant during the entire 16.0 min
irradiation period.
The 15N-labeling results are consistent with the elec-
trocyclic ring closure-sulfur migration mechanism shown
in Scheme 2. Thus, formation of a 1:1 mixture of 4-2-15N
and 4-4-15N is consistent with the formation of a 1:1
equilibrium mixture of BC-4 and BC-4′. The observed
phototransposition of 5-phenyl-1,2,4-thiadiazole-4-15N (6-
4-15N) to 5-phenyl-1,2,4-thiadiazole-2-15N (6-2-15N) also
confirms that sulfur must also shift in the opposite
direction to yield 15N-labeled BC-6′.
Although 5-phenyl-1,2,4-thiadiazole (6) undergoes pho-
totransposition to 3-phenyl-1,2,4-thiadiazole (4), the re-
verse photoisomerization was not observed. As shown in
Scheme 1, however, the phototransposition of 6 f 4
involves rearrangement of the initially formed, less-stable
bicyclic species BC-6, in which the phenyl is substituted
at the bridgehead position, to the more stable bicyclic
species, BC-4, in which the phenyl is in conjugation with
the C-N double bond. Thus, conversion of BC-6 to BC-4
should compete with the rearomatization of BC-6 to 6.
The reverse transposition of 3-phenyl-1,2,4-thiadiazole
(4) to 5-phenyl-1,2,4-thiadiazole (6), however, would
require that the more stable BC-4 be converted to the
less stable BC-6. This reaction is expected to be slow and
presumably would not compete with the rearomatization
of BC-4 back to 4. If formed, however, BC-4 would be
expected to be in equilibrium with BC-4′, since these
bicyclic species are of equal energy. Indeed, since 15N-
substituted-3-phenyl-1,2,4-thiadiazole (4-15N) was formed
as a 1:1 mixture of 4-2-15N and 4-4-15N, this indicates
that BC-4 and BC-4′ are in equilibrium when formed by
rearrangement of BC-6. This equilibrium mixture should
also result if the 15N-labeled BC-4′ is formed directly by
irradiation of 4-2-15N. Rearomatization of the equilibrium
mixture of BC-4 and BC-4′ would result in the reforma-
tion of 3-phenyl-1,2,4-thiadiazole (4) with interchange of
the two ring nitrogen atoms.
Mass spectral analysis of the 15N-labeled 3-phenyl-
1,2,4-thiadiazole (4-15N) and phenyl- and diphenyl-1,3,5-
triazine photoproducts obtained after this prolonged
irradiation also exhibited 15N scrambling. The origin of
this scrambling is unclear, however, due to the extensive
scrambling in the reactant.
To minimize the extent of 15N-scrambling in the
reactant and to preclude the possibility of secondary
photolysis of the primary products, the irradiation was
carried out for a shorter period of time. In this experiment
a solution of 5-phenyl-1,2,4-thiadiazole-4-15N (6-4-15N) in
acetonitrile (4.0 mL, 2.0 × 10-2M) was irradiated and
analyzed by GLC and mass spectroscopy after each 4.0
min of irradiation.
After 8.0, 12.0, and 16.0 min of irradiation the m/z 135/
136 ratio in the mass spectrum of the 15N-labeled
reactant increased from 0.02 at 8.0 min to 0.06 at 12.0
min and 0.080 ( 0.005 at 16.0 min of irradiation. This
illustrates the slow phototransposition of 5-phenyl-1,2,4-
thiadiazole-4-15N (6-4-15N) to 5-phenyl-1,2,4-thiadiazole-
2-15N (6-2-15N) until after 16.0 min of irradiation the m/z
ratio of 0.080 ( 0.005 indicates that the remaining 15N-
labeled reactant consists of 93% 6-4-15N and 7% 6-2-15N.
The 15N-labeled 3-phenyl-1,2,4-thiadiazole (4-15N) pho-
totransposition product could be unambiguously detected
by GLC of the reaction mixture after 8.0 min of irradia-
tion. The mass spectrum of this product at that time
exhibited a molecular ion at m/z 163 and two intense
signals of almost equal intensity at m/z 135 and 136 with
a 135/136 ratio of 1.11 ( 0.08. The signal at m/z 135 must
be due to loss of HC15N from a molecule of 3-phenyl-1,2,4-
thiadiazole with the 15N atom at ring position 4, 4-4-15N,
whereas the peak at m/z 136 must originate by loss of
To investigate this possible pathway, 3-phenyl-1,2,4-
thiadiazole-2-15N (4-2-15N) was synthesized from benza-
mide-15N by the procedure shown in Scheme 3 developed
to synthesize unlabeled 4.19 The mass spectrum of 4-2-
15N exhibited a molecular ion at m/z 163 and a base peak
at m/z 136 due to loss of H-C14N, but no signal at m/z
135 which would result from loss of H-C15N. This
confirms that before irradiation all of the 15N-label is at
ring position 2 of the 1,2,4-thiadiazole ring.
(18) Pavlik, J . W.; Changtong, C.; Tantayanon, S. J . Heterocycl.
Chem. 2002, 39, 237-239.
(19) Howe, R. K.; Franz, J . E. J . Org. Chem. 1974, 39, 962-964.
J . Org. Chem, Vol. 68, No. 12, 2003 4857

Pavlik et al.
isothiazole photochemistry,2-16 photocleavage of the S-N
bond22 (Path B, Scheme 4) would lead to diradical 16-
15N, which would undergo cleavage to provide 5-15N and
ultimately sulfur and hydrogen cyanide. Either pathway
is consistent with the observation that photofragmenta-
tion of 4-2-15N yields only 5-15N.
SCHEME 3
The photofragmentation of 5-phenyl-1,2,4-thiadiazole-
4-15N (6-4-15N) is more complicated. The 15N-labeled
photofragmentation product could be detected after 6-4-
15N was irradiated in acetonitrile for 4 min. The mass
spectrum of this product exhibited molecular ions at m/z
103 and 104, due to the formation of benzonitrile-14N (5-
14N) and benzonitrile-15N (5-15N) in a ratio of 0.17. After
8.0, 12.0, and 16.0 min of irradiation this ratio gradually
increased to 0.24, 0.27, and 0.32, respectively. Thus, after
16.0 min of irradiation, when the reactant consisted of
93% 5-phenyl-1,2,4-thiadiazole-4-15N (6-4-15N) and 7%
5-phenyl-1,2,4-thiadiazole-2-15N (6-2-15N), the photofrag-
mentation product was a mixture of 76% benzonitrile-
15N (5-15N) and 24% benzonitrile-14N (5-14N). This shows
that there is more 15N scrambling in the photofragmen-
tation product than in the 15N-labeled reactant. Forma-
tion of benzonitrile (5), therefore, cannot occur only by
direct photofragmentation of the 1,2,4-thiadiazole ring
but requires another pathway, or pathways, that allow
for a greater amount of 15N-scrambling.
Tr ia zin e F or m a tion . Irradiation of 5-phenyl-1,2,4-
thiadiazole-4-15N (6-4-15N) in acetonitrile also led to the
formation of the 15N-labeled triazine products. After 8.0
min of irradiation the mass spectrum of the 15N-labeled
phenyl-1,3,5-triazine (7) exhibited molecular ions at m/z
158 and 159 in a ratio of 0.84 ( 0.02. After 12.0 and 16.0
min of irradiation this ratio remained unchanged and
was determined to be 0.80 ( 0.04 and 0.85 ( 0.01,
respectively. These ratios show that phenyl-1,3,5-triazine
was formed with 46% of the molecules containing one 15N
atom and 54% containing two 15N atoms.
After 8.0 min of irradiation GLC analysis of the same
irradiated solution also revealed the formation of diphe-
nyl-1,3,5-triazine (8). After 8.0, 12.0, and 16.0 min of
irradiation the mass spectrum of this product exhibited
molecular ions at m/z 234 and 235 with almost equal
intensities. The ratio could be measured accurately after
16.0 min of irradiation and was found to have a value of
1.14 ( 0.03. This shows that 53% of the diphenyl-1,3,5-
triazine molecules contained one 15N atom while 47%
were formed with two 15N atoms. These results show that
the 15N-labeled phenyl and diphenyl-1,3,5-triazines are
each formed with essentially equal amounts of mono- and
di-15N-labeled molecules.
SCHEME 4
A solution of 3-phenyl-1,2,4-thiadiazole-2-15N (4-2-15N)
in acetonitrile was irradiated for a total of 150 min. GLC
analysis of the resulting solution showed that 46% of the
reactant had been consumed. The mass spectrum of the
recovered 15N-labeled reactant was identical with the
spectrum obtained before irradiation. Thus, after irradia-
tion the mass spectrum again exhibited a molecular ion
at m/z 163 and a base peak at m/z 136 due to loss of
HC14N from 3-phenyl-1,2,4-thiadiazole with the 15N-label
still in ring position 2. No signal, however, could be
detected in the mass spectrum at m/z 135, which would
be observed if the molecular ion eliminated H-C15N. This
shows that 3-phenyl-1,2,4-thiadiazole-2-15N (4-2-15N) had
not transposed to 3-phenyl-1,2,4-thiadiazole-4-15N (4-4-
15N) during irradiation. This reveals that photochemical
excitation of 3-phenyl-1,2,4-thiadiazole (4) is not ac-
companied by electrocyclic ring closure to yield BC-4.
This pathway apparently cannot compete with the direct
photofragmentation pathway leading to benzonitrile (5).
P h otofr a gm en ta tion . Irradiation of 3-phenyl-1,2,4-
thiadiazole-2-15N (4-2-15N) led to the formation of ben-
zonitrile (5). The mass spectrum of this product exhibited
a molecular ion at m/z 104 with no signal detectable at
m/z 103. This shows that the photofragmentation product
is exclusively benzonitrile-15N (5-15N). This could result
from direct fragmentation of the 3-phenyl-1,2,4-thiadia-
zole-2-15N (4-2-15N) ring (Path A, Scheme 4) leading to
hydrogen cyanide and 15N-labeled benzonitrile sulfide
(15-15N),20 which is known to eliminate sulfur to provide
benzonitrile-15N (5-15N).21 Alternately, by analogy with
It is plausible that triazines 7 and 8 can also arise from
bicyclic species BC-6. Thus, in addition to heteroatom
migration leading to transposition (Scheme 1), BC-6
(23) (a) Kurtz, D. W.; Schechter, H. J . J . Chem. Soc., Chem.
Commun. 1966, 689-690. (b) Ullman, E. G.; Singh, B. J . Am. Chem.
Soc. 1966, 88, 1844-1845. (c) Ullman, E. G.; Singh, B. J . Am. Chem.
Soc. 1967, 89, 6911-6916. (d) Singh, B.; Zweig, A.; Gallivan, J . B. J .
Am. Chem. Soc. 1972, 94, 1199-1206. (e) Nishiwaki, T.; Nakano, A.;
Matsuoka, J . J . Chem. Soc. C 1970, 1825-1829. (f) Nishiwaki, T.;
Fujiyama, F. J . Chem. Soc., Perkin Trans. 1972, 1456-1459. (g)
Wamhoff, H. Chem. Ber. 1972, 105, 748-752. (h) Good, R. H.; J ones,
G. J . Chem. Soc. C 1971, 1196-1198. (i) Goeth, H.; Gagneux, A. R.;
Eugster, C. H.; Schmid, H. Helv. Chim. Acta 1967, 50, 137-142. (j)
Padwa, A.; Chen, E.; Ku, A. J . Am. Chem. Soc. 1975, 97, 6484-6491.
(k) Dietliker, K.; Gilgen, P.; Heimgartner, H.; Schmid, H. Helv. Chim.
Acta 1976, 59, 2074-2099.
(20) It is interesting to note that the base peak in the mass spectrum
of 3-phenyl-1,2,4-thiadiazole-2-15N (4-2-15N) is observed at m/z 136,
consistent with the elimination of HCN and the formation of benzoni-
trile sulfide-15N (15-15N).
(21) Paton, R. M. Chem. Soc. Rev. 1989, 18, 33-52.
(22) Photocleavage of the bond between the two heteroatoms is a
major pathway for five-membered heteroaromatic compounds contain-
ing two adjacent heteroatoms and initiates the N2-C3 interchange
pathway by which isoxazoles,23a-k pyrazoles,24-27 and isothiazoles are14
converted to oxazoles, imidazoles, and thiazoles. This pathway would
result in the conversion of 1,2,4-thiadiazoles to 1,3,4-thiadiazoles which
were not among the products observed in this study.
4858 J . Org. Chem., Vol. 68, No. 12, 2003

Photochemistry of Phenyl-Substituted 1,2,4-Thiadiazoles
SCHEME 5
SCHEME 6
example, the tricyclic adduct 19 would be expected to
eliminate HC-15N or HC-14N resulting in the formation
of mono- or di-15N-labeled diphenyl-1,3,5-triazine, respec-
tively. This mechanistic pathway predicts that the tri-
azines would be formed as a 1:1 mixture of mono- and
di-15N-labeled compounds, which is very close to the
observed ratio.
would also be expected to undergo thermal and/or pho-
tochemical elimination of sulfur.28-35 Starting with 15N-
labeled 6-4-15N, electrocyclic ring closure and sulfur
elimination would lead to 15N-labeled phenyldiazacyclo-
butadiene, which presumably would exist as an equilib-
rium mixture of 17a -15N and 17b-15N. Several reaction
Tr a p p in g Exp er im en ts. Direct photofragmentation
of 3-phenyl-1,2,4-thiadiazole (4) and 5-phenyl-1,2,4-thia-
diazole (6) could lead to the formation of benzonitrile (5)
via the intermediacy of benzonitrile sulfide (15). Indeed,
formation of diphenyl-1,2,4-thiadiazole (9) as a product
from irradiation of 5-phenyl-1,2,4-thiadiazole (6) seems
to suggest a mechanism involving trapping of photo-
chemically generated benzonitrile sulfide (15) by ben-
zonitrile (5). Similarly, Howe and Franz have shown that
thermally generated benzonitrile sulfide 15 can be ef-
pathways can be envisioned for this species. First, as
shown in Scheme 5, complete fragmentation of 17a -15N
and 17b-15N would yield benzonitrile-14N (5-14N) and
benzonitrile-15N (5-15N) in a 1:1 ratio. This constitutes a
second photofragmentation pathway which, moreover,
leads to more 15N-scrambling in benzonitrile formation
than is predicted by the direct fragmentation pathway.
This would be consistent with the observed 15N-labeling
distribution in benzonitrile (5).
Second, by analogy with cyclobutadiene, 17a and 17b
would also be expected to undergo [4+2] cycloaddition
leading to the formation of unstable tricyclic adducts.36,37
Although there are numerous orientations for this [4+2]
cycloaddition, two examples are shown in Scheme 6. In
the first case, tricyclic species 18 could eliminate ben-
zonitrile-15N (5-15N) or benzonitrile-14N (5-14N) to form
phenyl-1,3,5-triazines with either one or two 15N atoms
per molecule. Alternatively, as shown in the second
fectively trapped in 1,3-dipolar cycloaddition reactions
with acetylenes38 or by reaction with ethyl cyanoformate
20 to yield ethyl 3-phenyl-1,2,4-thiadiazole-5-carboxylate
(21).19
(24) Pavlik, J . W.; Kurzweil, E. M. J . Org. Chem. 1991, 56, 6313-
6302.
To test for the intermediacy of benzonitrile sulfide 15
in these reactions, solutions of thiadiazoles 4 and 6 in
acetonitrile solvent containing 5.0 equiv of ethyl cyano-
formate 20 were irradiated for 210 or 300 min, respec-
tively. GLC analysis showed the consumption of 78% of
4 and 74% of 6. In each case, in addition to the expected
products observed after irradiation of 4 or 6 in the
absence of ethyl cyanoformate 20, GLC analysis showed
the formation of a new product with a retention time of
approximately 19 min. The mass spectrum of this new
product exhibited a molecular ion at m/z 234 and a
fragmentation pattern identical with the fragmentation
pattern of an authentic sample of ethyl 3-phenyl-1,2,4-
thiadiazole-5-carboxylate (21).19 The formation of this
product is convincing evidence that irradiation of 4 or 6
results in the formation of benzonitrile sulfide (15), which
is captured by cycloaddition with ethyl cyanoformate (20).
(25) Pavlik, J . W.; Connors, R. E.; Burns, D. S.; Kurzweil, E. M. J .
Am. Chem. Soc. 1993, 115, 7645-7652.
(26) Pavlik, J . W.; Kebede, N.; Bird, N. P.; Day, A. C.; Barltrop, J .
A. J . Org. Chem. 1995, 60, 8138-8139.
(27) Pavlik, J . W.; Kebede, N. J . Org. Chem. 1997, 62, 8325-8334.
(28) Coffen, D. L.; Poon, Y. C.; Lee, M. L. J . Am. Chem. Soc. 1971,
93, 4627-4628.
(29) Kellogg, R. M. J . Am. Chem. Soc. 1971, 93, 2344-2346.
(30) Padwa, A.; Au, A.; Lee, G. A.; Owens, W. J . Org. Chem. 1975,
40, 1142-1149.
(31) Umemoto, T.; Otsubo, T.; Misumi, S. Tetrahedron Lett. 1974,
1573-1576.
(32) Kellogg, R. M.; Prins, J . Org. Chem. 1974, 39, 2366-2374.
Block, E.; Page, J .; Toscano, J . P.; Wang, C.-W.; Zhang, X.; DeOrazio,
R.; Guo, C.; Sheridan, R. S.; Towers, G. H. N. J . Am. Chem. Soc. 1996,
118, 4719-4720.
(33) Padwa, A.; Au, A.; Lee, G. A.; Owens, W. J . Org. Chem. 1945,
40, 1142-1149.
(34) Nakayama, J .; Shimomura, M.; Iwamoto, M.; Hoshino, M.
Heterocycles 1985, 23, 1907-1910.
(35) Block, E.; Page, J .; Toscano, J . P.; Wang, C.-W.; Zhang, X.;
DeOrazio, R.; Guo, C.; Sheridan R. S.; Towers, G. H. N. J . Am. Chem.
Soc. 1996, 118, 4719-4720.
(36) Masamune, S.; Suda, M.; Ona, H.; Leichter, L. M. J . Chem. Soc.,
Chem. Commun. 1972, 1268-1269.
(38) Howe, R. K.; Franz, J . E. J . Chem. Soc., Chem. Commun. 1973,
524-525.
(37) Li, Y.; Houk, K. N. J . Am. Chem. Soc. 1996, 118, 880-885.
J . Org. Chem, Vol. 68, No. 12, 2003 4859

Pavlik et al.
benzonitrile sulfide (15) with ethyl cyanoformate followed by
saponification and decarboxylation of the ethyl ester;19 15 by
decarboxylation of 5-phenyl-1,3,4-oxathiazole-2-one prepared
by condensation of chlorocarbonylsulfenyl choride with ben-
zamide;40 5-phenyl-1,2,4-thiadiazole (6) and 3-methyl-5-phenyl-
1,2,4-thiadiazole (10) by condensing thiobenzamide with N,N-
dimethylformamide dimethylacetal or N,N-dimethylacetamide
dimethylacetal followed by cyclization of the resulting amidines
with hydroxylamine-O-sulfonic acid;41 diphenyl-1,2,4-thiadia-
zole (9) by reaction of thiobenzamide with nitrous acid;42
phenyl-1,3,5-triazine (7) and diphenyl-1,3,5-triazine (8) as a
mixture by condensing formamidine hydrochloride and ben-
zamidine hydrochloride followed by separation by steam
distillation;43 and 2,4-dimethyl-6-phenyl-1,3,5-triazine (12) and
2-methyl-4,6-diphenyl-1,3,5-triazine (13) by condensation of
N-[(dimethylamino)ethylidene]benzamide and either acetami-
dine or benzamidine in refluxing THF.44 Benzonitrile (5) and
triphenyl-1,3,5-triazine (14) were commercially available.
3-P h en yl-1,2,4-th ia d ia zole-2-15N (4-2-15N): Prepared from
benzamide-15N by the procedure developed to synthesize the
unlabeled compound;41 1H NMR (CDCl3) δ 7.51-7.56 (m, 3H),
The yields of the cycloaddition product 21 were small,
however, ranging from ∼0.1% in the case of 4 to ∼0.5%
upon irradiation of 6. These low yields suggest that either
a photofragmentation pathway involving the interme-
diacy of benzonitrile sulfide (15) is a very minor reaction
pathway or photochemically generated benzonitrile sul-
fide (15) is less efficiently trapped than the thermally
generated species. Some evidence suggests that this may
be the case. Thus, although thermal decarboxyation of
5-phenyl-1,3,4-oxathiazol-2-one (22) in one molar excess
of dimethyl acetylenedicarboxylate (DMAD) led to the
formation of dimethyl 3-phenylisothiazole-4,5-dicarboxy-
late (23) in 90% yield, the corresponding irradiation of
22 in the presence of the same trapping agent led only
to the formation of benzonitrile (5) and sulfur.39
) 1.5 Hz); 13C NMR
1
15
8.37-8.39 (m, 2H), 9.90 (d, 1H, J
,
H
N
(CDCl3) δ (DEPT-135) 128.7 (+), 129.2 (+), 131.0 (+), 132.8
(0), 173.1 (+) 174.5 (0) (d, J
) 3.0 Hz); 15N NMR (CDCl3)
13 15
C,
N
δ 258.4; MS m/z (%) 163 (80), 136 (100), 104 (23), 77 (26), 51,
(14).
Con clu sion
5-P h en yl-1,2,4-th ia d ia zole-4-15N (6-4-15N): Prepared by
converting benzamide-15N to thiobenzamide-15N,45 and pro-
ceeding according to the method developed to synthesize the
unlabeled compound;19 1H NMR (acetone-d6) δ 7.58-7.61 (m,
Photofragmentation leading to benzonitrile (5) forma-
tion is a major reaction pathway for phenyl-1,2,4-thia-
diazoles. 3-Phenyl-1,2,4-thiadiazole (4) reacts only by this
pathway and 15N-labeling experiments suggest that 5 is
formed either by direct fragmentation of the thiadiazole
ring or from the 1,5-diradical formed by photocleavage
of the S-N bond. In addition to fragmentation, 5-phenyl-
1,2,4-thiadiazole (6) also undergoes phototransposition
to 3-phenyl-1,2,4-thiadiazole (4) and photoconversion to
phenyl- and diphenyl-1,3,5-triazines (7 and 8). These
reactions are suggested to originate in electrocyclic ring
closure in 6 leading to 4-phenyl-1,3-diaza-5-thiabicyclo-
[2.1.0]pent-2-ene (BC-6). Sulfur migration and rearoma-
tization would account for the observed phototrans-
position while sulfur elimination would lead to phenyl-
diazacyclobutadiene 17. This species could undergo com-
plete fragmentation to benzonitrile (5) or [4+2] cycload-
dition leading to unstable tricyclic adducts, the suggested
precursors of the 1,3,5-triazine products 7 and 8. The
distribution of 15N in the phototransposition and triazines
products is consistent with this mechanistic interpreta-
tion.
3H), 8.06-8.08 (m, 2H), 8.84 (d, 1H, J
) 13.9 Hz); 13C
1
15
H,
N
NMR (acetone-d6) δ (Dept-135) 128.2 (+), 130.3 (+), 131.1 (0)
(d, J
(d, J
) 3.8 Hz), 188.6 (+); 15N NMR (acetone-d6) δ 302.2
) 13.9 Hz); MS m/z (%) 163 (88), 136 (100), 105 (92),
13 15
C,
N
1
15
H,
N
104 (24), 77 (59), 59 (64).
Ir r a d ia tion a n d An a lysis P r oced u r es. To monitor reac-
tions on an analytical scale, a solution of the reactant (4.0 mL,
2.0 × 10-2M) in the appropriate solvent was placed in a Pyrex
tube (7.0 mm inside diameter × 13.0 cm long), sealed with a
rubber septum, purged with argon for 10 min, and irradiated
in a Rayonet reactor equipped with 16 3000-Å lamps for the
appropriate length of time. Preparative-scale reactions were
carried out as indicated.
Reaction progress was monitored by removing aliquots at
specified times for GLC analysis. Retentions of all products
are given relative to the appropriate reactant. Quantitative
GLC analysis of reactant consumption and product formation
was accomplished by using calibration curves constructed for
the reactants and products by plotting detector responses
versus five standards of known concentrations. Correlation
coefficients ranged from 0.991 to 0.998. After irradiation, the
resulting solutions were concentrated to ∼0.1 mL and analyzed
by GC-MS. Retention times and fragmentation patterns were
compared with those of authentic samples of products.
All of the following irradiation are on an analytical-scale
unless otherwise indicated.
Exp er im en ta l Section
1
Gen er a l P r oced u r es. H, 13C, and 15N NMR spectra were
recorded at 400.1, 100.6, and 40.5 MHz, respectively. 15N
chemical shifts are reported in ppm downfield from NH3(l) and
were measured relative to aqueous Na15NO3, which was used
as an external standard and taken to absorb at 378.4 ppm
downfield from NH3(l). Mass spectra were recorded with an HP
5970B mass selective detector interfaced to an HP588 capillary
gas chromatograph. GLC was performed with use of a 15-m
× 3-µm Carbowax-20M bonded phase column employing the
following temperature program: 140 °C (4 min), 20 °C/min to
180 °C (14 min), 20 °C/min to 240 °C (30 min). Preparative
layer chromatography was carried out on 20-cm × 20-cm glass
plates coated with 2 mm Kieselgel 60 F254 (Merck).
3-P h en yl-1,2,4-th ia d ia zole (4). GLC analysis after 120
min of irradiation showed the consumption of 4 (81.6%) and
the formation of benzonitrile (5) (74.1%) with a relative
retention of 0.22. MS m/z (%) 103 (100), 77 (11), 76 (66), 75
(34), 74 (18), 73 (11), 653 (11), 52 (11), 51 (23).
(40) Muhlbauer, E.; Weiss, W. British Patent 1,079,348, 1967; Chem.
Abstr. 1968, 68, 69000W.
(41) Lin, Y.-I.; Lang, S. A., J r.; Petty, S. R. J . Org. Chem. 1980, 45,
3750-3753.
(42) Bahadir, M.; Siegfried, N.; Harun, P.; Korte, F. J . Agric. Food
Chem. 1979, 24, 815-818.
P r ep a r a tion of Sta r tin g Ma ter ia ls a n d P r od u cts. Com-
pounds previously described in the literature were prepared
as follows: 3-phenyl-1,2,4-thiadiazole (4) by cycloaddition of
(43) Schaefer, F.; Hechenbleikner, I.; Peters, G.; Wystrach, V. P. J .
Am. Chem. Soc. 1959, 81, 1466-1470.
(44) Chen, C.; Dagnino, R.; McCarthy, J . J . Org. Chem. 1995, 60,
8428-8430.
(45) King, L. C.; Miller, F. M. J . Am. Chem. Soc. 1949, 71, 367-
368.
(39) Franz, J . E.; Black, L. L. Tetrahedron Lett. 1970, 1381-1384.
4860 J . Org. Chem., Vol. 68, No. 12, 2003

Photochemistry of Phenyl-Substituted 1,2,4-Thiadiazoles
5-P h en yl-1,2,4-th ia d ia zole (6). GLC analysis after 150
min of irradiation showed the consumption of 6 (53%) and the
formation of benzonitrile (5) (58%), relative retention 0.38 [MS
m/z (%) 103 (100), 77 (11), 76 (66), 75 (34), 74 (18), 73 (11), 63
(11), 52 (11), 51 (23)], phenyl-1,3,5-triazine (7) (4%), relative
retention 0.94 [MS m/z (%) 157 (75), 104 (100), 103 (29), 75
(18), 76 (24), 51 (13), 50 (13)], 3-phenyl-1,2,4-thiadiazole (4)
(18%), relative retention 1.14 [MS m/z (%) 162 (75), 135 (100),
103 (25), 91 (10), 77 (32), 76 (20), 51 (18), 50 (15)], diphenyl-
1,3,5-triazine (8) (2%), relative retention 3.77 [MS m/z (%) 233
(57), 130 (17), 103 (100), 76 (26)], and diphenyl-1,2,4-thiadiaole
(9) (trace), relative retention 4.0 [MS m/z (%) 238 (35), 135
(100), 103 (19), 77 (22), 76 (12), 51 (12)].
3-Meth yl-5-p h en yl,1,2,4-th ia d ia zole (10). GLC analysis
after 150 min of irradiation showed the consumption of 10
(76%) and the formation of benzonitrile (5) (56%), relative
retention 0.42 [MS m/z (%) as above], 2,4-dimethyl-6-phenyl-
1,3,5-triazine (12) (33%), relative retention 0.96 [MS m/z (%)
185 (55), 103 (100), 82 (33), 76 (28)], 5-methyl-3-phenyl-1,2,4-
thiadiazole (11) (∼10%), relative retention 1.13 [MS m/z (%)
176 (54), 135 (100), 103 (19), 77 (39)], and 2-methyl-4,6-
diphenyl-1,3,5-triazine (13) (7%), relative retention 2.33 [MS
m/z (%) 247 (31), 103 (100), 76 (19)].
lamps until GLC analysis showed 40% consumption of the
reactant. The resulting solution was concentrated under
reduced pressure and the residue was subjected to preparative
layer chromatography (silica gel, CH2Cl2-hexane, 4:1). After
4 elutions, the band at Rf 0.69 gave unconsumed 5-phenyl-
1,2,4-thiadiazole-15N: 1H NMR (400 MHz, CDCl3) δ 7.28-7.53
(m, 3H), 7.95-7.98 (M, 2H), 8.69 (d, 1H, J ) 13.9 Hz). The
band at Rf 0.39 gave 3-phenyl-1,2,4-thiadiazole-15N: 1H NMR
(400 MHz, CDCl3) δ 7.23-7.50 (m, 3H), 8.32-8.34 (m, 2H),
9.87 (d, J ) 11.1 Hz); 9.87 (d, J ) 1.5 Hz).
P r ep a r a tive-Sca le Ir r a d ia tion of Dip h en yl-1,2,4-Th ia -
d ia zole (9). A solution of diphenyl-1,2,4-thiadiazole (9) in
cyclohexane was placed in a Pyrex tube (2.5 cm inside diameter
× 30 cm long), sealed with a rubber septum, purged with argon
for 30 min, and irradiated in a Rayonet reactor equipped with
16 3000-Å lamps until GLC analysis showed complete con-
sumption of the reactant. The resulting solution was concen-
trated and the residue subjected to silica gel (100 g) flash
column chromatography. The column (68 cm long × 3.5 cm
diameter) was eluted with hexane:dichloromethane (1:1) and
fractions (15 mL) were collected and analyzed by thin-layer
chromatography. Fractions 13-16 were concentrated to yield
triphenyl-1,3-5-triazine (14) as a while solid: mp 235-237
1
°C (lit.46 mp 237-238 °C); 0.169 (0.52 mmol, 52% yield); H
Dip h en yl-1,2,4-Th ia d ia zole (9). GLC analysis after 5 min
of irradiation showed the consumption of 9 (12.9%) and the
formation of benzonitrile (5) (35%), relative retention (0.11)
[MS m/z (%) as above]. At a higher oven temperature a second
product eluted showing the formation of triphenyl-1,3,5-
triazine (14), relative retention 3.5 [MS m/z (%) 309 (64), 103
(100), 76 (14)].
NMR (400 MHz, CDCl3) δ 129.0, 129.3, 132.9, 136.6, 172.0;
MS m/z (%) 309 (10), 104 (13), 103 (100), 77 (12), 76 (19), 51
(8).
Ir r adiation of 3-P h en yl-1,2,4-Th iadiazole (4) or 5-P h en -
yl-1,2,4-Th ia d ia zole (6) in th e P r esen ce of Eth yl Cya n o-
for m a te. Tr a p p in g of Ben zon itr ile Su lfid e (15). Solutions
of 3-phenyl-1,2,4-thiadiazole (4) and 5-phenyl-1,2,4-thiadiazole
(6) in acetonitrile (4.0 mL, 2.0 × 10-2M) each containing ethyl
cyanoformate (0.1 mL, 1 × 10-1 M) in Pyrex tubes were sealed
with a rubber septa, purged with argon for 30 min, and
irradiated in a Rayonet Reactor equipped with 16 3000-Å
lamps for 210 or 300 min, respectively. GLC analysis showed
the consumption of 4 (-78%) and 6 (-74%). In addition to the
products observed in the absence of ethyl cyanoformate, GLC
analysis showed the formation of ethyl 3-phenyl-1,2,4-thia-
diazole-5-carboxylate 21 (∼0.1% from 4 and ∼0.5% from 6),
MS m/z (%) 234 (50), 162 (14), 135 (100), 103 (21), 77 (19), 41
(12).
5-P h en yl-1,2,4-th iadiazole-4-15N (6-4-15N). GLC-MS analy-
sis after the specified irradiation time showed the following
ratios: for unconsumed 6-4-15N, m/z 135:136 0.02 (8.0 min),
0.06 (12.0 min), 0.080 ( 0.005 (16.0 min), 0.40 (180 min); for
benzonitrile (5), m/z 103:104, 0.17 (4.0 min), 0.24 (8.0 min),
0.27 (12.0 min), 0.32 (16.0 min); for 3-phenyl-1,2,4-thiadiazole
(4), m/z 135:136, 1.11( 0.08 (8 min), 1.07 ( 0.08 (12.0 min),
1.12 ( 0.02 (16 min); for phenyl-1,3,5-triazine (7), m/z 158:
159, 0.84 ( 0.02 (8.0 min), 0.80 ( 0.04 (12. min), 0.85 ( 0.01
(16.0 min); and for diphenyl-1,3,5-triazine (8), m/z 234:235,
1.14 ( 0.03 (16.0 min).
3-P h en yl-1,2,4-th iadiazole-2-15N (4-2-15N). GLC and GLC-
MS analysis after 150 min of irradiation showed consumption
of 4-2-15N (46%) but no change in the mass spectrum of the
unconsumed reactant and the formation of benzonitrile-15N (5-
N15) (71%) with a relative retention of 0.27. MS m/z (%) 104
(100), 76 (70), 50 (15).
P r ep a r a tive-Sca le Ir r a d ia tion of 5-P h en yl-1,2,4-Th ia -
d ia zole-4-15N (6-4-15N). A solution of 5-phenyl-1,2,4-thiadia-
zole-4-15N (6-4-15N) in acetonitrile (8.0 mL, 2.0 × 10-2M) was
placed in a Pyrex tube (7.0 mm inside diameter × 20 cm long),
sealed with a rubber septum, purged with argon for 30 min,
and irradiated in a Rayonet reactor equipped with 16 3000-Å
Ack n ow led gm en t. We are grateful to Dr. Lawrence
Scott, Department of Chemistry, Boston College, for an
insightful discussion regarding the mechanistic under-
standing of triazines formation.
J O0340915
(46) Forsberg, J . H.; Spaziano, V. T.; Klump, S. P.; Sanders, K. M.
J . Heterocycl. Chem. 1988, 25, 767-770.
J . Org. Chem, Vol. 68, No. 12, 2003 4861