Photocyclization reaction of some 2-methyl-4-phenyl- substituted aldehyde thiosemicarbazones. Mechanistic aspects

Article abstract of DOI:10.1016/S0040-4020(00)00012-0

Irradiation of 2-methyl-4-phenyl- substituted benzaldehyde thiosemicarbazones led with good yields to the corresponding ?²1,2,4- triazoline-5-thione derivatives through the formation of stable 1,2,4- triazolidine-5-thione intermediates. The relative quantum yields of photocyclization at 313 nm were analysed by means of the Hammett equation and p values determined: We interpreted the results in terms of the mechanism of photocyclization of 2-methyl-4-phenyl-substituted benzaldehyde thiosemicarbazones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00012-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 999–1004
Photocyclization Reaction of some
2-Methyl-4-phenyl- Substituted Aldehyde Thiosemicarbazones.
Mechanistic Aspects
*
Silvestre Buscemi and Michelangelo Gruttadauria
`
Dipartimento di Chimica Organica ‘E. Paterno’, Viale delle Scienze, Parco d’Orleans II, 90128 Palermo, Italy
Received 4 October 1999; revised 26 November 1999; accepted 16 December 1999
Abstract—Irradiation of 2-methyl-4-phenyl- substituted benzaldehyde thiosemicarbazones led with good yields to the corresponding D2-
1,2,4-triazoline-5-thione derivatives through the formation of stable 1,2,4-triazolidine-5-thione intermediates. The relative quantum yields of
photocyclization at 313 nm were analysed by means of the Hammett equation and r values determined. We interpreted the results in terms of
the mechanism of photocyclization of 2-methyl-4-phenyl-substituted benzaldehyde thiosemicarbazones. ᭧ 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
thiadiazoline 3 heterocycles, the second being favoured by
electron-withdrawing groups linked to the –CHyN–NϽ
hydrazone moiety (Scheme 1).6,9
Semi- and thiosemi-carbazones as well as 1,2,4-triazole,
1,3,4-oxadiazole and 1,3,4-thiadiazole rings, which can be
obtained by oxidative cyclization, have received attention
by pharmacologists. Semicarbazones have been considered
as peptide isosteres and as possible urea peptide mimetics,1
while thiosemicarbazones and their copper complexes have
been used as antimalarial agents.2,3 Further, 1,2,4-triazoline-
5-ones and 1,2,4-triazoline-5-thiones have shown biological
activity and have been used as anti-inflammatories, cardio-
tonics, or dopamine b-hydroxilase inhibitors,4 as well as
fungicides and herbicides.5
In contrast, only the 1,2,4-triazolines 2 were obtained when
cupric perchlorate in methanol was used as oxidizing agent,
but low concentrations of both the reagents (Ͻ0.01 M) had
to be used in order to avoid the formation of stable
complexes.10
Recently11 we have investigated the photochemical
behaviour of some substituted aldehyde thiosemicarbazones
in methanol at 254 nm. We have found that the aldehyde
residue influences the photoheterocyclization. In fact,
thiosemicarbazones of glyoxyl methyl ester 4 cyclized to
furnish the 3-thioxo-1,2,4-triazin-5-one 5 while, but when
the group bonded to the –CHyN–NϽ hydrazone moiety was
a methyl or phenyl group, only the 1,2,4-triazoline 2 was
obtained. For comparison, the oxidative cyclization with
ferric chloride solutions gave, in the former case only the
1,3,4-thiadiazolinic product 6 while, in the latter case,
Several oxidizing agents can be used for the cyclization of
semi- and thiosemi-carbazones and the regiochemistry of
the cyclization reaction depends on conditions adopted for
the reaction as well as the structure of the starting
substrate.6–11 For example, we have found that the oxidation
of 2-methyl-4-phenyl thiosemicarbazones 1 with ferric
chloride solutions gave 1,2,4-triazoline 2 and/or 1,3,4-
Scheme 1.
Keywords: photocyclization; benzaldehyde thiosemicarbazones; Hammett equation; 1,2,4-triazoles.
* Corresponding author. E-mail: sbuscemi@unipa.it
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00012-0

1000
S. Buscemi, M. Gruttadauria / Tetrahedron 56 (2000) 999–1004
Scheme 2.
usually a mixture of 1,2,4-triazoline and 1,3,4-thiadiazoline
rings (Scheme 2).6
reported data obtained for the irradiation at 313 nm for
compounds 1a–i. These results confirmed an excellent
efficiency, leading to an almost quantitative formation of
the D2-1,2,4-triazoline-5-thione derivatives 1a–i. Irradia-
tion at 254 nm of compound 1c gave 2c in lower yield
(53%).11 Some quenching experiments were carried out
in the presence of a large excess of penta-1,3-diene
(piperylene) as a triplet quencher. The disappearance of
compounds 1a–i was not quenched (both at 254 and
313 nm). This result suggested that, in the primary
photochemical process, singlet excited states should be
involved.
Moreover the yields of the photoreactions strongly depend
on the nature of the group bonded to the N(4) atom, being
better when it is an aryl group; in fact the photocyclization
of 1c gave 2 in 70% yield after 8 h, while the 2,4-dimethyl-
thiosemicarbazone of benzaldehyde did not react after 40 h
of irradiation.11
In order to gain more information about the photochemical
behaviour of thiosemicarbazones, we have studied the
photocyclization reaction at various wavelengths (254,
313 and 366 nm) of some 2-methyl-4-phenyl benzaldehyde
thiosemicarbazones 1a–i. Compounds 1a–i were chosen in
such a way as to have a change of electronic density on both
the carbon–nitrogen double bond and the N(4). Further-
more, the effect of substituents on cyclization at 313 nm
has been also investigated.
Monitoring the reaction solution of 1c at 313 nm by HPLC
or TLC, we observed an intermediate species, the con-
centration of which at first increased to a maximum and
then decreased while the concentration of 2c increased.
Differently from what was observed at 313 nm, the reaction
of 1c at 254 nm proceeded without formation of the inter-
mediate species, but the photoproduct 2c was formed
directly. However, when the solution of 1c was degassed
by argon bubbling (15 min) and then irradiated at 254 nm, a
small amount of the intermediate species was detected (by
HPLC). We were able to isolate the intermediate species
7c in good yield (80%) by irradiation of a diluted solution
of 1c (100 mg in 200 mL of MeOH) degassed by argon
bubbling and then irradiated at 313 nm for 60 min. The
structure of compound 7c was proved by the usual
1
Ar1
Ar2
a
b
c
d
e
f
g
h
i
4-MeOC6H4
4-MeC6H4
C6H5
4-ClC6H4
4-BrC6H4
4-CF3C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Table 1. lmax and e values at lmax, 254, 313 and 366 nm for 1a–i
Compound
lmax
emax
e254
e313
e366
1a
1b
1c
1d
1e
1f
1g
1h
1I
328
321
318
323
325
326
317
317
318
37 900
38 100
35 300
36 400
40 400
35 900
36 900
36 700
33 200
8100
5700
5400
6300
7200
6500
8300
7100
8400
27 500
32 900
32 800
29 600
31 600
29 400
35 200
34 600
31 100
2300
800
900
1600
1000
2300
1400
1100
900
C6H5
C6H5
Results and Discussion
Table 2. Yields and reaction time for the photochemical cyclization of 1a–i
UV spectra of compounds 1a–i showed an absorption maxi-
mum around 300 nm and a minimum around 250 nm. In
Table 1 are reported lmax and e values at lmax, 254, 313
and 366 nm.
Compound
2 (%)
Irradiation time (h)
1a
1b
1c
1d
1e
1f
1g
1h
1I
95
95
95
95
95
85
95
95
95
14
16
16
19
20
40
16
21
30
Preparative Photolysis
Since all the compounds 1a–i showed an adsorption maxi-
mum around 300 nm, we have irradiated at 313 nm in order
to improve the yields of the reactions. In Table 2 are

S. Buscemi, M. Gruttadauria / Tetrahedron 56 (2000) 999–1004
1001
Scheme 3.
Table 3. lmax and e values at lmax, 254, 313 and 366 nm for 7b–c,e
depicted as the cyclization to the 1,2,4-triazolidine-5-thione
derivatives 7, the second step as the photooxidation of 7 to
give the D2-1,2,4-triazoline-5-thione derivatives 2. The first
step takes place faster at 313 nm in comparison with the
irradiation at 254 nm (higher absorption of compounds 1),
whereas the second step takes place faster at 254 nm (higher
absorption of compounds 7). For the photocyclization at
254 nm of the thiosemicarbazones 1, it was noted11 that
the photochemically active chromophore was the phenyl-
amino group, i.e. the activation of N(4) nitrogen atom is
the main factor affecting the photocyclization of thiosemi-
carbazones. By contrast the presence of a phenyl group
linked on the –CHyN–NϽ hydrazone moiety does not
seem to be essential.
Compound
lmax
emax
e254
e313
e366
7b
7c
7e
259
259
254
13 000
13 000
10 100
12 500
12 500
10 100
2700
2500
3600
60
40
200
spectroscopic techniques, in particular the signal at d 5.96 in
1
the H NMR spectrum and that at d 79.7 in the 13C NMR
spectrum were attributed to the C–H of the heterocycle. In
order to distinguish photochemical and thermal processes, a
sample of 7c was irradiated in methanol at 313 nm giving
directly the corresponding D2-1,2,4-triazoline-5-thione 2c,
showing that the formation of 2c was the final result of two
consecutive photochemical reactions. In fact, compound 1c
was thermally stable at 40ЊC and compound 7c was
converted into 2c at 40ЊC after 50 h (Scheme 3).
This result was also confirmed by irradiation at 313 nm of
compound 8a that gave the corresponding D2-1,2,4-triazo-
line-5-thione 9 in good yield (90%), in fact this leaves out a
meaningful contribution of the aldehydic residue chromo-
phore to the primary photochemical process. Compound 8b
did not show photochemical reactivity at 254 or 313 nm.
Moreover, the influence of the sulphur atom on photo-
chemical process was ascertained by irradiation of
compound 8c at 254 and 313 nm. Both the reactions did
not take place (Scheme 4).
In the irradiation at 254 nm we did not isolate compound 7c
because of the high ratio e7c/e1c (12 500/5400), whereas we
were able to do so at 313 nm (e7c/e1cˆ2500/32 800) (see
Table 3).
In order to realize a method for the synthesis of compounds
7 we have carried out photochemical reactions at 366 nm (at
this wavelength compounds 7 do not have appreciable
absorption) in anhydrous methanol, degassing the solutions
by argon bubbling. Irradiation of compounds 1b,c,e gave
compounds 7b,c,e in high yields (90%).
These results clearly indicate that the photochemically
active chromophore should be the CSNHPh group that can
undergo three different types of transitions based on the
presence of the three donor centres, p–pء of the aryl
group, n–pء of the nitrogen atom and n–pء of the sulphur
atom. Moreover it is well known that thiosemicarbazones
can undergo an enolization reaction as depicted in Scheme
5.12
Also compounds 7b,e showed absorption maxima around
254 nm and low absorption at 366 nm (see Table 3).
In order to gain deeper insight into the photochemical
processes we have analysed the rate of reaction on irradia-
tion of compounds 1a–d,f–i at 313 nm. In Table 4 are
Mechanistic Consideration
The first step of the photoreaction of compounds 1 could be
Scheme 4.

1002
S. Buscemi, M. Gruttadauria / Tetrahedron 56 (2000) 999–1004
Scheme 5.
Table 4. Disappearance (%) and relative quantum yields (FS/FH) for the photochemical cyclization of 1a–d,f–i
Compound
Disappearance of 1 (%)
FS/FH
Compound
Disappearance of 1 (%)
FS/FH
1a
1b
1c
1d
34
26
16
8.5
2.125
1.625
1.000
0.431
1g
1h
1c
1i
5.6
8.8
16
0.350
0.550
1.000
2.906
47
reported the relative quantum yields [FS/FH; FS indicates
the quantum yield for compounds with substituted phenyl
ring, FH indicates the quantum yield for compound with
unsubstituted phenyl ring (1c)].
non-linear trend was observed when cupric perchlorate was
used as oxidizing agent.10 So the positive value calculated
for susceptibility constant r in the present study represents a
further and different substituent effect.
In order to quantify the above substituent effects we have
attempted to correlate the data reported in Table 4 with s
substituent constant13 in terms of Hammett’s equation and
obtained the following good correlations:
This is not surprising, indeed it is plausible that the sub-
stituent effects on the N-phenyl thioamide moiety can be
different according to reaction conditions. In the case of
oxidation induced by metallic salts the relative importance
of various steps determines the observed substituent effects.
In the photochemical cyclization reaction, the collected data
seem to suggest that the primary photochemical process
involves a n–pء transition of the N(4) nitrogen atom that
leads to an electrophilic N(4) nitrogen atom in its singlet
state responsible for the cyclization to give the dihydro
1. log FS=FHˆϪ0:01ꢀ0:01†Ϫ1:32ꢀ0:05†s (rˆ0.998) for
substitution on the phenyl ring bonded to –CHyN–NϽ
hydrazone moiety;
2. log FS=FHˆ0:03ꢀ0:02†ϩ1:86ꢀ0:11†s (rˆ0.996) for
substitution on the phenyl ring bonded to N(4) atom
(Fig. 1).
The negative value calculated for susceptibility constant r
of the former correlation shows that the above substituents
influence the cyclization reaction of thiosemicarbazones 1
in a similar manner irrespective of the fact that the reaction
is carried out with a metallic salt as oxidizing agent or under
photochemical conditions.
Such substituent effects are rationalized assuming that the
–CHyN–NϽ hydrazone moiety acts as an internal nucleo-
phile. On the contrary, the effect of a substituent bonded to
phenyl group linked to N(4) nitrogen atom depends on the
conditions adopted for the cyclization reactions. In fact, a
negative value for susceptibility constant r was calculated
for the oxidative reaction induced by ferric chloride9 while a
Figure 1. Plots of log FS=FH versus sp for the photochemical cyclization
of 1a–f (squares) and 1c,g–i (circles).

S. Buscemi, M. Gruttadauria / Tetrahedron 56 (2000) 999–1004
1003
derivatives 7.14,15 The electron-withdrawing substituents
support the formation of the above singlet excited state
and consequently favour the electrophilic attack delocaliz-
ing the increase of the electron density on the aromatic ring
as a consequence of n–pء transition.
methanol (100 mL) was degassed by argon bubbling
(15 min) and then irradiated for 90 min (for 1b,c) or
210 min (for 1e) at 366 nm. Removal of the solvent under
reduced pressure gave the triazolidines 7b,c and 7e (Ͼ90%)
that were not purified (less than 5% of the corresponding
1
thiosemicarbazones and triazolines were detected by H
NMR).
Conclusions
Compound 7c: 1H NMR (250 MHz) (CDCl3) d: 3.47 (s, 3H,
NCH3), 4.50 (s br, 1H, NH), 5.96 (s, 1H, CH), 7.20–7.50 (m,
10H, ArH); 13C NMR d: 36.1, 79.7, 126.0, 126.1, 127.0,
127.4, 127.7, 128.3, 129.1, 130.0, 130.4, 135.3, 138.7,
180.5.
Our study has clarified the photochemical processes
involved in the cyclization of some thiosemicarbazones
derivatives, showing that this reaction is the result of two
consecutive photochemical processes and how the sub-
stituents bonded to the two phenyl rings can affect the
cyclization. We have also realized an interesting method
for the synthesis of the 1,2,4-triazolidine-5-thiones 7.
Some 3-monosubstituted 1,2,4-triazolidine-5-thiones were
observed during the recording of mass-spectra of thiosemi-
carbazones.16 They may be produced in the gas phase after
multiple collisions of the vaporized sample molecules with
hot surfaces of the ion source prior to the ionization. Our
method allows us to prepare these compounds in a very
simple way.
Compound 7b: 1H NMR (250 MHz) (CDCl3) d: 2.30 (s, 3H,
CH3), 3.44 (s, 3H, NCH3), 4.55 (s br, 1H, NH), 5.89 (s, 1H,
CH), 7.12 (d, Jˆ7.8 Hz, 2H, p-MeC6H4), 7.15–7.29 (m, 7H,
ArH).
Compound 7e: 1H NMR (250 MHz) (CDCl3) d: 3.26 (s, 3H,
NCH3), 4.43 (s br, 1H, NH), 5.74 (s, 1H, CH), 6.97–7.22 (m,
7H, ArH), 7.29 (d, Jˆ8.8 Hz, 2H, p-BrC6H4).
Acknowledgements
Experimental
This investigation has been supported by the University of
Palermo (funds for selected research topics). We also wish
Materials and methods
`
to thank Prof. Renato Noto and Prof. Nicolo Vivona for their
Photochemical reactions were carried out in anhydrous
methanol by using a Rayonet RPR-100 photoreactor fitted
with 16 lamps irradiating at lˆ254 nm (in quartz vessels),
lˆ313 and 366 nm (in pyrex vessels) and a merry-go-round
apparatus. HPLC analyses were performed by using a C-18
SIL-X-10 Perkin–Elmer column (25 cm×4.6 mm diameter)
eluting with water/acetonitrile 20:80, flow 1 mL/min at
lˆ280 nm. UV spectra were recorded with a Jasco 7800
spectrophotometer. 1H and 13C NMR spectra were recorded
on a Bruker AC-E series 250 MHz spectrometer with TMS
as internal standard. Photoproducts 2a–i9 and 9a6 were
compared with authentic samples. Compounds 1a–i,9
8a,b6 and 8c8 were prepared as reported.
valuable suggestions and helpful discussion.
References
1. Limal, D.; Grand, V.; Vanderesse, R.; Marraud, M.; Aubry, A.
Tetrahedron Lett. 1995, 35, 3711.
2. West, D. X.; Liberta, A. E.; Padhye, S. B.; Chikate, R. C.;
Sonawane, P. B.; Kumbhar, A. S.; Yerand, R. G. Coord. Chem.
Rev. 1993, 123, 49.
3. Offiong, O. E.; Martelli, S. Farmaco 1993, 48, 777.
4. Connor, D. T.; Kolstan, C. R.; Mullican, M. D.; Wilson, M. W.;
Flynn, D. L.; Shrum, G. P.; Unagst, P. C. Eur. Pat. Appl. EP
371483, 1990; Chem. Abstr. 1990, 113, 231381t; Murai, T.;
Kuriyiama, K.; Hyama, Y.; Nagatahira, R.; Ito, K. Jpn. Kokai
Tokkyo Koho JP 02 15,069 [90,15,069], 1990; Chem. Abstr.
1990, 113, 23929a; Nomoto, Y.; Takai, H.; Ono, T.; Kubo, K.
Jpn. Kokai Tokkyo Koho JP 02,167,277 [90,167,277], 1990;
Chem. Abstr. 1990, 113, 212010e; Kruse, L. I.; Finkelstein, J. A.
Eur. Pat. Appl. EP 395,505, 1990; Chem. Abstr., 1990, 113,
115311w.
General procedure for photochemical reactions
A sample of the thiosemicarbazones 1a–i and 8a (250 mg;
0.7–0.9 mmol) in methanol (150–200 mL) was apportioned
into three or four pyrex tubes and then irradiated
(lˆ313 nm) for the time indicated. Removal of the solvent
under reduced pressure gave the triazolines 2a–i and 9a.
5. Reddy, K. R.; Mogilaiah, K.; Swamy, B.; Sreenisvasulu, B.
Acta Chim. Hung. 1990, 127, 45; Theodoridis, G. U.S. Pat. US
4,906,284, 1990; Chem. Abstr. 1990, 113, 23931v.
6. Noto, R.; Buccheri, F.; Cusmano, G.; Gruttadauria, M.; Werber,
G. J. Heterocycl. Chem. 1991, 28, 1421.
7. Gruttadauria, M.; Buccheri, F.; Cusmano, G.; Lo Meo, P.; Noto,
R.; Werber, G. J. Heterocycl. Chem. 1993, 30, 765.
8. Noto, R.; Gruttadauria, M.; Lo Meo, P.; Frenna, V.; Werber, G.
J. Heterocycl. Chem. 1995, 32, 1277.
Analytical photoreactions
On the basis of e values at lˆ313 nm (see Table 1), solu-
tions of substrates 1a–d,f–i were made to have the same
absorbance. Solutions of each thiosemicarbazone 1a–d,f–i
in 10 mL of methanol were irradiated simultaneously for
45 min in a merry-go-round apparatus and the resulting
photolysates were analysed quantitatively by HPLC in
order to determine the disappearance of compounds 1.
9. Noto, R.; Gruttadauria, M.; Lo Meo, P.; Werber, G. J. Hetero-
cycl. Chem. 1996, 33, 863.
Synthesis of 1,2,4-triazolidine-5-thiones
10. Gruttadauria, M.; Lo Meo, P.; Noto, R.; Werber, G. Gazz.
Chim. It. 1997, 127, 277.
A sample (100 mg) of 1b, 1c or 1e, respectively, in

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S. Buscemi, M. Gruttadauria / Tetrahedron 56 (2000) 999–1004
11. Gruttadauria, M.; Buccheri, F.; Buscemi, S.; Cusmano, G.;
Noto, R.; Werber, G. J. Heterocycl. Chem. 1992, 29, 233.
12. Hassan, A. A.; Ibrahim, Y. R.; Semida, A. A.; Mourad, A. E.
Liebigs Ann. Chem. 1994, 989.
14. Barltrop, J. A.; Coyle, J. D. Excited States in Organic
Chemistry, Wiley: London, 1975.
15. Cowan, D. O.; Drisko, R. L. Elements of Organic Photo-
chemistry, Plenum: New York, 1976.
13. Exner, O. Correlation Analysis in Chemistry, Recent
Advances; Chapman, N. B., Shorter, J. Eds.; Plenum: New York,
1978.
16. Zelenin, K. N.; Kuznetsova, O. B.; Alekseyev, V. V.;
Terentyev, P. B.; Torocheshnikov, V. N.; Ovcharenko, V. V.
Tetrahedron 1993, 49, 1257.