Solvent-Free Condensation Reactions to Synthesize Five-Membered Heterocycles Containing the Sulfamide Fragment

Article abstract of DOI:10.1055/s-0035-1561371

We report a study of the solvent-free condensation reaction of 1,2-dicarbonyl compounds with sulfamide catalyzed by a Keggin-type acid (H₃PMo₁₂O₄₀·nH₂O, MPA) to obtain 3,4-disubstituted 1,2,5-thiadiazole 1,1-dioxide derivatives. Some reactions were also performed in solution or using nano-sized silica-supported MPA catalyst in order to compare the results under different experimental conditions. Effects of the temperature used for the thermal pretreatment of the catalyst, the reaction temperature, the molar ratios sulfamide/1,2-dicarbonyl compound and MPA/1,2-dicarbonyl compound, and alternative experimental procedures on the yield of the reaction product were investigated. Under suitable experimental conditions eight compounds were obtained in good yields. The catalyst was recycled and reused, but with some loss of its catalytic activity. The presented synthetic method is a simple, clean, and environmentally friendly alternative for synthesizing different 1,2,5-thiadiazole 1,1-dioxide derivatives.

Full text of DOI:10.1055/s-0035-1561371

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
N. R. Arroyo et al.
Paper
Synthesis
Solvent-Free Condensation Reactions To Synthesize Five-
Membered Heterocycles Containing the Sulfamide Fragment
Nelson Rodríguez Arroyoa
María F. Rozasa
Patricia Vázquezb
Gustavo P. Romanellib,c
María V. Mirífico*a,d
solvent-free
condensation
H3PMo12O40·nH2O
Recycled and reused up to 70% yield
R1
R2
R1
R2
O
O
25–150 °C
N
O
S
H2N
H2N
O
O
S
+
+
2 H2O
O
N
a Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA,
CCT La Plata-CONICET), Facultad de Ciencias Exactas, Departamento de
Química, Universidad Nacional de La Plata, Casilla de Correo 16, Sucursal
4, 1900 La Plata, Argentina
8 examples
up to 93% yield
R1, R2 = Alk, Ar
b Centro de Investigación y Desarrollo en Ciencias Aplicadas ‘Dr. J. J. Ronco’
(CINDECA), Departamento de Química, Facultad de Ciencias Exactas,
UNLP-CCT-CONICET, Calle 47 No 257, 1900 La Plata, Argentina
c Cátedra de Química Orgánica, Facultad de Ciencias Agrarias y Forestales,
UNLP, Calles 60 y 119, 1900 La Plata, Argentina
d Departamento de Ingeniería Química, Facultad de Ingeniería,
Universidad Nacional de La Plata, Calle 47 y 1, 1900 La Plata, Argentina
mirifi@inifta.unlp.edu.ar
Received: 08.09.2015
Accepted after revision: 14.01.2016
Published online: 09.03.2016
copper and mild steel in acid medium,6,7 and on the ability
of some other derivatives as acceptor molecules that give
stable radical anions.8,9
DOI: 10.1055/s-0035-1561371; Art ID: ss-2015-m0477-op
One of the most general procedures for the synthesis of
heterocyclic compounds based on sulfamides involves their
condensation with carbonyl compounds.10–12 For the prepa-
ration of 3,4-disubstituted 1,2,5-thiadiazole 1,1-dioxide de-
rivatives, the more general reaction is the condensation of
Abstract We report a study of the solvent-free condensation reaction
of 1,2-dicarbonyl compounds with sulfamide catalyzed by a Keggin-
type acid (H3PMo12O40·nH2O, MPA) to obtain 3,4-disubstituted 1,2,5-
thiadiazole 1,1-dioxide derivatives. Some reactions were also per-
formed in solution or using nano-sized silica-supported MPA catalyst in
order to compare the results under different experimental conditions.
Effects of the temperature used for the thermal pretreatment of the
catalyst, the reaction temperature, the molar ratios sulfamide/1,2-di-
carbonyl compound and MPA/1,2-dicarbonyl compound, and alterna-
tive experimental procedures on the yield of the reaction product were
investigated. Under suitable experimental conditions eight compounds
were obtained in good yields. The catalyst was recycled and reused, but
with some loss of its catalytic activity. The presented synthetic method
is a simple, clean, and environmentally friendly alternative for synthesiz-
ing different 1,2,5-thiadiazole 1,1-dioxide derivatives.
the 1,2-dicarbonyl compounds
1 with sulfamide (2)
(Scheme 1) in solution catalyzed by strong mineral acids.13–15
To overcome the use of strong acids, an efficient and mild
access to these 1,2,5-thiadiazole heterocycles using N,N′-
bis(trimethylsilyl)sulfamide and 1 promoted by BF3·OEt2
was recently reported by Zezschwitz et al.16 Also, Erturk
and Bekdemir17 performed a microwave-assisted synthesis
for the condensation reaction of 1 with 2 in absolute EtOH.
It is well known that conventional strong mineral acids
are corrosive and pose risks in handling, disposal, and re-
generation due to their corrosive and toxic nature. A major
source of waste in the fine chemicals industry is derived
from the widespread use of liquid mineral acids and a vari-
ety of Lewis acids. They cannot easily be recycled and gen-
erally end up, via a hydrolytic workup, as waste streams
containing large amounts of inorganic salts. Their replace-
ment by recyclable solid acids would afford a significant re-
duction in waste. Waste prevention and environmental pro-
tection are imperative requirements in an overcrowded
world of increasing demands. Synthetic chemistry contin-
ues to develop chemical procedures for obtaining products
with less environmental impact. One of the more promising
approaches is solvent-free organic synthesis.
Key words heterocycles, solvent-free reaction, condensation, acid ca-
talysis, heteropolyacids, 1,2-dicarbonyl compounds, sulfamide
Numerous and varied heterocyclic compounds that con-
tain the sulfamide fragment (>NSO2N<) exhibit a broad
spectrum of physiological activities and they are also used
as components of fungicide and insecticide mixtures, as de-
tergents, and in photography.1 In particular five-membered
thiadiazole heterocyclic compounds have been used in or-
ganic synthesis,2 in medicine,3 in agrochemistry as potent
pesticides,4 and the high value of these building blocks for
the generation of n-type conjugated organic materials has
been emphasized.5 Recently, our group reported for the
first time on the capacity of two 3,4-disubstituted 1,2,5-
thiadiazole 1,1-dioxide derivatives as corrosion inhibitor for
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
N. R. Arroyo et al.
Paper
Synthesis
conventional procedure:13
solvent, catalyst, reflux
this work:
HPA, solvent-free reaction
R1
R2
R1
R2
O
N
N
H2N
H2N
O
O
O
O
S
S
+
+
2 H2O
O
3
1
2
1a, 3a R1 = R2 = Ph
1b, 3b R1,R2
1c, 3c R1,R2
=
1e, 3e R1 = R2
=
=
1f, 3f R1 = R2 = 4-ClC6H4
1g, 3g R1 = Me; R2 = Ph
1h, 3h R1 = R2 = Me
1d, 3d R1 = R2 = 2-Naph
Scheme 1 Synthesis of 3 by condensation reaction of 1 with 2, catalyzed by HPA under solvent-free conditions
Catalysis by heteropolyacids (HPAs) is a field of increas-
ing importance worldwide.18 Advances are being carried
out both in basic investigation and in fine chemicals pro-
cesses.19,20 HPAs are good acid catalysts in homogeneous
and heterogeneous media.21 These solid catalysts have
many advantages over liquid acid catalysts. The Brønsted
acidity of HPAs compared to mineral acids leads to rates per
proton that are usually significantly higher for HPAs. They
are non-corrosive and are environmentally benign, present-
ing fewer disposal problems. Solid HPAs have attracted
much attention in organic synthesis owing to easy workup
procedures, easy filtration, and minimization of cost and
waste generation due to reuse and the possibility of catalyst
recycling.22 Reactions catalyzed both in homogeneous or
heterogeneous systems have been reviewed by many re-
searchers.23,24 There are various different structural types of
HPAs, but for acid catalysts in common catalytic applica-
tions the commercial Keggin-type HPAs are often used, es-
pecially owing to their availability, and chemical and ther-
mal stability.25,26
used for the thermal pretreatment of the catalyst, the reac-
tion temperature, the molar ratios 2/1 and MPA/1, the time
of contact between 1 and MPA previous to the addition of 2,
and the different experimental procedures, on the yield of
the reaction product were investigated with the aim of ob-
taining 3 with the best yields. Suitable experimental condi-
tions to prepare 3a–h (Scheme 1) generally in good yields
were found.
The scope, generality of the method, and molar yields
for the products 3a–h are illustrated with several examples
in Table 1. The experimental conditions are also shown in
Table 1 and in its footnotes. For comparison, data from the
literature13,28 (entries 1 and 14) are also included in this ta-
ble. In this work, yields of 3 are similar to or improved com-
pared to those reported in the literature. The reaction times
shown in Table 1 should be considered with caution, be-
cause the initial mass of 1 employed in the assays and the
reactors were not the same for all experiments. Three ex-
perimental procedures were assayed for solvent-free reac-
tions (procedures A–C).
Supported HPA catalysts are important for applications
because bulk HPAs have a low specific surface. The acidity
and catalytic activity of supported HPAs depend on the
type of the carrier, the HPA loading, pretreatment condi-
tions, etc., the most frequently used carrier being silica. Sili-
ca is relatively inert towards HPAs, the thermal stability of
HPA on silica seems to be comparable to or slightly lower
than that of the parent HPA.27
To the best of our knowledge, in the literature there is
no information on synthetic procedures for the preparation
of 3 (Scheme 1) using HPAs as strong acid catalysts or the
use of solvent-free reactions for the synthesis of such deriv-
atives. The present work focuses on the study of the con-
densation reaction of 1a–h (Scheme 1) with 2 catalyzed by
a Keggin-type HPA, molybdophosphoric acid (H3PMo12O40·nH2O,
MPA), in the absence of solvent (solvent-free reaction, Table
1, entries 2–5, 7–10, 12, 13, and 15–23), to obtain deriva-
tives 3a–h (Scheme 1). Some reactions were also performed
in absolute EtOH solution (entry 11) in order to compare
the results under both different experimental conditions.
Effects of the process variables, such as the temperature
Results shown in Table 1 indicate that the appropriate
MPA/1 and 2/1 molar ratios and reaction temperature to
obtain a better yield of 3 depend on the chemical structure
of 1 and on the previous thermal treatment of the catalyst.
When the isolation of 3 from the solid reaction mixture
(solvent-free reaction) was carried out by extraction with
CH2Cl2, the practical molar yield was similar to that ob-
tained when water was used. The use of water for the isola-
tion is recommended because it is chemically sustainable.
When water is used, MPA and 2 are soluble in the aqueous
phase, while if CH2Cl2 is employed, they remain as an insol-
uble solid residue.
3,4-Diphenyl-1,2,5-thiadiazole 1,1-dioxide (3a) was
synthesized following procedure A. The condensation reac-
tion took place at an appreciable rate when MPA70 °C was
used as the catalyst (MPA70 °C/1a: 0.02; 2/1a: 1.2) at 70 °C,
but the reaction remained incomplete even after a pro-
longed reaction time (908 h). Increasing the excess of 2, us-
ing ca. three times the stoichiometric amount, and the mo-
lar ratio MPA70 °C/1a: 0.43 (entry 2) the reaction went to
completion and the yield of 3a was slightly higher (53%)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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N. R. Arroyo et al.
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Synthesis
Table 1 Condensation of 1,2-Dicarbonyl Compounds 1 with Sulfamide 2 Catalyzed by MPA, under Various Conditions
Entry
1
1 (mmol)
1a (50)
Conditionsa
EtOH
Temp (°C)
reflux
70
Time (h)
2
Ratiob 2/1
1.0
Ratioc MPAT °C/1
3
Yieldd (%)
HCl(g)
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3c
3c
3d
3d
3e
3e
3f
5113
53f
2
1a (0.25)
1a (0.50)
1a (0.52)
1a (0.50)
1b (10)
–e (A)
29
96
100
144
1
3.1
0.43 (MPA70 °C
0.23 (MPA150 °C
0.23 (MPA150 °C
0.11 (MPA300 °C
HCl(g)
)
3
–e(A/B)
–e (B/C)
–e (B/C)
EtOH
70
6.6
)
)
)
91f (75)f
91f (83)f
93f (82)f
8228
64f,g
85f
4
70
2.3
5
70
1.3
6
reflux
120
150
150
150
reflux
150
150
reflux
150
150
150
150
r.t.
1.0
7
1b (0.27)
1b (0.48)
1b (0.48)
1b (0.52)
1b (0.33)
1c (0.13)
1c (0.17)
1d (5.4)
–e (A)
31
7
9.0
0.064 (MPA150 °C
0.062 (MPA150 °C
0.062 (MPA150 °C
)
)
)
8
–e (A)
9.0
9
–e (A)
7
9.0
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
–e (A)
3.5
10
28
15
15
94
97
8
9.0
0.04 (MPA300 °C
0.06 (MPA150 °C
0.18 (MPA150 °C
0.011 (MPAsupp
HCl(g)
)
)
)
86f
abs. EtOHh
–e (A)
7.8
84
14.6
14.6
5.4
37f,g
70f
–e (A)
)
150 °C
i
EtOH
7029
71f
1d (0.066)
1e (0.28)
1e (0.14)
1f (0.39)
1g (1.68)
1h (2.36)
1b (0.48)
1b (0.49)
1a (0.13)
–e (A)
10.4
9.0
0.080 (MPA150 °C
0.074 (MPA150 °C
0.069 (MPA300 °C
0.025 (MPA150 °C
0.008 (MPA150 °C
0.008 (MPA150 °C
0.062 (MPA150 °C
)
)
)
)
)
)
)
)
–e (A)
58f
–e (C)
9.0
60f
–e (A/B)
–e (A)
95
70
52
68
7.5
530
9.0
49f (40)f
86f
1.2
3g
3h
3b
3b
3a
–e (A)
r.t.
1.2
83f
–e (A, a)
–e (A, b)
–e (B/C, b)
150
150
70
13.0
9.2
15f
0.060 (MPA300 °C
70f
j
j
5.1
0.21 (MPA150 °C
)
42f
a Procedure is in parentheses.
b Ratio 2/1 mmol/mmol.
c Ratio MPAT °C/1 mmol/mmol
d Yield of 3 calculated recovered 1 (yield based on initial amount of 1).
e Solvent-free reaction.
f Reaction product extracted with CH2Cl2.
g Incomplete reaction.
h Homogeneous catalysis.
i Nano-sized silica-supported MPA150 °C
j Recycled catalyst.
.
than that published in the literature (51%,13 entry 1), but in-
creasing the excess of 2 (2/1a: 6.6, result not shown) did
not improve the yield. Similar yields resulted when 3a was
isolated by procedures (i, with water) or (ii, with CH2Cl2).
The low yield of 3a and the weight loss of the solid reaction
mixture observed during the experiments were assumed as
a result of evaporation of 1a and 2. Then we decided to use
a sublimator as the reactor (procedure B). Using it both
compounds were recovered from the cold finger.
An increase in the temperature of the thermal pre-treat-
ment of MPA to 300 °C (MPA300 °C) slightly improved the
yield for 3a: 93%, still using low MPA300 °C/1a (0.11) and 2/1a
(1.3) molar ratios following procedure B/C (entry 5 vs. 4).
An increase in the reaction temperature to reduce reaction
time is not convenient (results not shown) because of the
evaporation of 1a and 2.
It can be concluded that the best procedure to synthe-
size 3a is procedure B/C, MPA300 °C, 2/1a and MPA/1a molar
ratios 1.3 and 0.11, respectively, at 70 °C (entry 5). This
work resulted in an improved yield of 3a compared to that
reported in the literature (51%,13 87%,16 or 66%17). The reac-
tion times in solvent-free reactions catalyzed by MPA are
longer than those measured following the guidelines in refs.
13 and 17, and we are currently investigating improve-
ments to the technique that would shorten the reaction
Using MPA150 °C as the catalyst and working as in proce-
dure A/B, the yield of 3a was 91% based on recovered 1a or
75% based on 1a initially added (entry 3). Following proce-
dure B/C, to get the same yield for 3a (entry 4) it was neces-
sary to use a smaller amount of 2 than that used in proce-
dure A/B.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
N. R. Arroyo et al.
Paper
Synthesis
times. We are using a nano-sized silica-supported MPA cat-
alyst (MPAsupp) to obtaining a high specific surface. The re-
sults so far obtained are very encouraging, e.g. 3a was pre-
pared in 90% yield with MPAsupp150 °C/1a: 0.1, 2/1a: 6.6, 48 h,
at 70 °C (results not shown).
1c was still present in the reaction mixture, and for this rea-
son the reaction was considered finished. With the aim of
150 °C
decreasing the reaction time, we worked with MPAsupp
with a low MPAsupp150 °C/1c molar ratio (0.011) at the same
reaction temperature. By using MPAsupp150 °C, the yield ob-
tained (70%, entry 13) was twice as high as that obtained
using unsupported MPA150 °C, the reaction time decreased,
and moreover, the formation of the byproduct was only ob-
served at the end of the reaction time.
Phenanthro[9,10-c][1,2,5]thiadiazole 2,2-dioxide (3b);
Table 1 (entry 6) shows the published results for the tradi-
tional synthesis of 3b.28 In solvent-free reactions using
MPA150 °C (MPA150 °C/1b: 0.06) and a high 2/1b molar ratio: 9,
at 120 °C, the reaction was not complete after 31 h (entry
7). However, the yield for 3b was 85% at a reaction tempera-
ture of 150 °C and under other similar experimental condi-
tions (entry 8). The same yields resulted from isolating 3b
by procedures (i) or (ii) (entries 8 and 9). Using pretreat-
ment of the heteropolyacid at higher temperature (MPA300
°C) and with a lower MPA300 °C/1b molar ratio: 0.04 gave 3b
in 86% yield in a lower reaction time (3.5 h) (entry 10). Re-
sults from experiments performed to compare procedures
A and C shown that for the synthesis of 3b both procedures
give similar yields. A similar yield for 3b (84%, entry 11)
was reached in a longer reaction time when the reaction
was performed in EtOH solution (homogeneous catalysis)
by heating to mild reflux, and using a high MPA150 °C/1b:
0.060 and a lower 2/1b: 7.8 molar ratio. The results show
that the catalyst in EtOH solution is not as effective as in
solvent-free reactions.
It can be concluded that the best results are obtained for
solvent-free reactions with the following experimental
conditions: MPA300 °C, with molar ratios MPA300 °C/1b: 0.04
and 2/1b: 9.0 and 150 °C as reaction temperature. The best
yield for 3b (86%, entry 10) and the reaction time obtained
in this work are somewhat higher that published in the lit-
erature28 (82%, entry 6). The reaction times for the synthe-
sis of 3b performed in solution of EtOH/MPA are higher
than under solvent-free reactions, but product yields are
similar. The higher concentration of reactants in the ab-
sence of solvents usually leads to more favorable kinetics
than in solution. Protons in the surface layer of acidic MPA
were much more active than protons from MPA in homoge-
neous solution. The very large excess of 2 necessary for the
synthesis of 3b be complete is rationalized by evaporation
of 2 at 150 °C. As discussed, the large excess of 2 required
for the reaction to go to completion can be recovered and
reused if the reaction is performed in a sublimator (proce-
dure B).
3,4-Di(2-naphthyl)-1,2,5-thiadiazole 1,1-dioxide (3d)
and 3,4-di(biphenyl-4-yl)-1,2,5-thiadiazole 1,1-dioxide
(3e); compound 3d was previously synthesized in our labo-
ratory29 in 70% yield (entry 14) following the general proce-
dure reported by Wright.13 Now 3d was prepared from 1d
in a solvent-free reaction catalyzed by MPA150 °C (entry 15)
following procedure A. The molar yield for 3d (71%) was
marginally higher and the reaction time was ca. six times
longer than the published one.29 Similar experimental con-
ditions were employed for the synthesis of 3e, but the com-
pound was obtained in 58% yield (entry 16), lower than that
for 3d. The reaction was also performed using MPA300 °C fol-
lowing procedure C and although the yield of 3e (entry 17)
was improved only slightly, the reaction time was shorter.
3,4-Bis(4-chlorophenyl)-1,2,5-thiadiazole 1,1-dioxide
(3f); experiments were carried out without solvent, follow-
ing procedure A/B using MPA150 °C. For the assays performed
with 2/1f: 9.9, and MPA150 °C/1f: 0.083–0.17 at 70–100 °C,
the condensation reaction did not take place even over an
extended period (193 h). With molar ratio 2/1f: 9.0 and
MPA150 °C/1f: 0.025, but increasing the reaction temperature
to 150 °C, the reaction product 3f was obtained in a 49%
yield (based on recovered 1f) (entry 18). Compounds 1f and
2 were recovered from the cold finger of the sublimator.
For the synthesis of 3-methyl-4-phenyl-1,2,5-thiadi-
azole 1,1-dioxide (3g) and 3,4-dimethyl-1,2,5-thiadiazole
1,1-dioxide (3h), only procedure A was assayed using
MPA150 °C. Reaction products 3g,h were obtained in good
yields [86% (3g) and 83% (3h)] (entries 19 and 20) using the
ratios MPA150 °C/1g,h: 0.008 and 2/1g,h: 1.2, at ca. 25 °C.
Should be observed that as 1g,h are liquids at room tem-
perature and their boiling points are ca. 100 °C, it is not
possible work at a higher reaction temperature. Yields for
both compounds are higher than that reported in the litera-
ture (29%13 and 74%6 for 3g and 3h, respectively).
Compounds 3a–d,g,h were synthesized in good yields,
but yields were only moderate for 3e,f. Reaction times were
in general long, particularly for 3a,d–h, while for 3b,c the
reaction times were shorter. Compounds 3a,d–f are 3,4-
disubstituted with the substituents containing separated π-
electronic systems, and while 3b,c are derivatives that are
3,4-disubstituted where the substituents have a connected
π-electronic system.30 Compounds 3g,h are alkyl-aryl and
alkyl-alkyl 3,4-disubstituted 1,2,5-thiadiazole 1,1-dioxide
derivatives and are not included in the above classification.
Pyreno[4,5-c][1,2,5]thiadiazole 10,10-dioxide (3c);
qualitative assay shows that in a solvent-free reaction using
MPA70 °C with MPA70 °C/1c: 0.10 and 2/1c: 10.3, for 23 h at
70 °C, the formation of 3c and the disappearance of 1c were
not observed (TLC). MPA150 °C was tested with MPA150 °C/1c:
0.18 at a higher reaction temperature (150 °C). Even using a
high 2/1c ratio (14.6) for 28 h, the reaction did not go to
completion and 3c was obtained in low yield (37%, entry
12). The formation of a byproduct was observed (TLC) when
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N. R. Arroyo et al.
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Synthesis
The condensation reaction involves an addition of the
nucleophile to the carbonyl groups and then elimination of
two molecules of water to yield the five-membered hetero-
cycle 3. Acids catalyze the addition of weak nucleophiles,
such as 2, to carbonyl compounds by protonating the car-
bonyl oxygen atoms. This makes the carbonyl carbon more
electrophilic and reactive thereby enhancing its susceptibil-
ity to attack by nucleophiles. The dicarbonyl compound
precursors of 3b,c can better stabilize the positive charge by
resonance in the conjugated acid than in dicarbonyl com-
pound precursors of 3a,d–h, hence the protonation equilib-
rium (Scheme 2) for 1b,c is more shifted to the right than
for 1a,d–h, and the concentration of the reactive conjugated
acid is higher for 1b,c. The elimination reactions may also
be catalyzed by acids, but the effect of the aromatic substit-
uent on the positive charge will be minor (only inductive
effect).
Following procedure (a). A fine powdered solid mixture
of thermally pretreated residual solid (150 °C, 24 h) and 1a
in the same ratio as the original experiment (entry 3) was
heated at the reaction temperature (70 °C) for 262 h, but
the reaction to give 3a did not occur. No reaction occurred
after further addition of 2 (2/1a: 9.0) after 528 h, at the
same reaction temperature. For compound 3b the residual
solid from assay entry 8 was thermally pretreated at 150 °C,
for 24 h and 1b was added in the same ratio as the original
experiment. After 48 h at 150 °C the reaction did not occur,
but after further addition of 2 (2/1b: 13.0) the reaction take
place (entry 21), but 3b was isolated in a low yield.
The catalyst recycled by the above procedure (a)
showed substantial loss in its catalytic activity, but when
recycled by procedure (b), it showed a better catalytic activ-
ity although the yields of 3 were lower and reaction times
were longer than in the original reactions. As typical exam-
ples, 3a in 42% yield for the reused catalyst (entry 23) vs.
91% (entry 4) for the original experiment; 3b in 70% yield
for the reused catalyst (entry 22) vs. 86% for the original ex-
periment (entry 10).
H+
O
O
H
O
O
Scheme 2
The above results suggest that 2 deactivates the catalyst
and it is necessary to remove 2 from the catalyst to be re-
used. Procedure C is recommended to reuse the catalyst
with a minimal loss of MPA during the washing with water.
As a typical example compare entries 3–5 in Table 1 (for
3a). When the reaction is complete, the small excess of 2 is
removed with a minimum volume of water and thus the
minimum quantity of MPA is lost. When isolation of 3 was
performed using water, the catalyst and 2 were soluble in
the aqueous phase. After evaporation of the water solvent,
the residual solid was treated as described above.
This work provides a new alternative of low ecological
demand for the synthesis of 3,4-disubstituted 1,2,5-thiadi-
azole 1,1-dioxides that restricts the use of solvent and elim-
inates the employment of strong mineral acids that are cor-
rosive and harmful to the environment. The reaction prod-
ucts are obtained in good yield, they are easy to isolate, and
the crude product only contains traces of impurities. The
catalyst is recovered and reused though with some loss of
its catalytic activity. To recover the catalyst it is necessary to
eliminate sulfamide (2) that remains together with the het-
eropolyacid after the isolation of the reaction product. The
thermal pretreatment of the catalyst has a marked effect on
the rate of the reaction, as well as on the ratio MPA/1. Re-
sults show that the best experimental conditions depend
on the structure of the dicarbonyl compound. However, a
general tendency is observed in the examples of the reac-
tion scope. Procedure C in which the dicarbonyl compound
and the solid catalyst in a fine powdered mixture (or a
paste for liquid dicarbonyl compounds) is left in contact for
a time before an excess of sulfamide is added is, in general,
preferred, although in some examples similar results are
obtained following the procedure A (both reagents and the
catalyst are mixed together). The use of a conventional sub-
In a previous paper29 we reported the efficient forma-
tion of a 9,10-dihydrophenanthrene polycyclic system
fused to a 1,2,5-thiadiazole 1,1-dioxide via the formation of
an aryl–aryl bond using strong Brønsted and Lewis acids, at
different temperatures (–80 to 25 °C). The syntheses of 3b
and the novel asymmetric naphtho[2′,1′:3,4]anthra[1,2-
c][1,2,5]thiadiazole 8,8-dioxide from 3a and 3d, respective-
ly, employing concentrated sulfuric or chlorosulfonic acids,
or AlCl3 as catalysts, were compared.29 We also looked29 at
the synthesis of 3b in a domino-type reaction directly from
1a and 2, the same reagents employed in the traditional
synthesis of 3a.13 In concentrated sulfuric acid we obtained
3b in 55% yield. The reaction rate was low at room tempera-
ture, but increased at higher temperatures (<100 °C). As it is
reported than HPAs present an acid force stronger than the
strong mineral acids used conventionally,31 we considered
the possibility of preparing 3b by cyclization of 3a using
150 °C
MPAsupp
as catalyst (molar ratio MPAsupp150 °C/3a: 0.2 at
150 °C). After a reaction time of 171 h, the original mass of
3a was recovered unchanged. The formation of 3b as a by-
product was also not observed (TLC) under the conditions
shown in entries 2–5. Under the experimental conditions
investigated in this work, the carbonyl compounds are pro-
tonated by the MPA, but the thiadiazole products are not,
and thus the intramolecular cyclization is not possible (see
proposed reaction mechanism29).
Reusability of MPA. The MPA was recovered after the
synthesis and reused as a catalyst in the condensation reac-
tions. Two procedures (a) and (b) were tested. The best re-
sults were obtained by procedure (b).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
N. R. Arroyo et al.
Paper
Synthesis
limator as reactor may be considered as suitable because
the excess sulfamide and some dicarbonyl compounds (e.g.,
benzyl in this work) may be deposited on the cold finger
and may be recovered and reused. The highest yields of the
products were obtained using catalyst pretreated at 300 °C.
A lower temperature (150 °C) may be used without signifi-
cant loss of the yields, but a higher catalyst/dicarbonyl
compound molar ratio is necessary. The optimal general re-
action temperature is 150 °C, but for some products a lower
temperature (70 °C or room temperature) is sufficient. Un-
der the experimental conditions investigated, the dicarbon-
yl compounds are protonated by the MPA, but the thiadi-
azole products are not.
MPA300 °C, respectively), for 24 h and was maintained in a vacuum des-
iccator at r.t., immediately before use.
The nano-sized, silica-supported MPA catalyst (MPAsupp) was pre-
pared by wet impregnation. Nanosilica was added to a solution of
MPA in acetone solvent in order to obtain a catalyst containing 40 g
MPA/140 g catalyst. The suspension was allowed to stand with mag-
netic stirring for 15 min, and then the solvent was evaporated. The
yellow solid obtained was dried under reduced pressure at r.t. for 8 h.
Before use, MPAsupp was pre-treated at 150 °C (MPAsupp150 °C), for 24 h
and maintained in a vacuum desiccator at r.t., immediately before
performing the experiments.
General Synthetic Procedure
Condensation reactions were carried out in the temperature range
25–150 °C. The used molar ratios of reactants and catalyst were: 2/1
1.0–14.6; MPA/1 0.008–0.43. The course of the reactions was routine-
ly monitored by TLC. A small sample of the reaction mixture (solvent-
free reactions: ca. 0.2 mg; reactions in solution: ca. 0.1 mL) was treat-
ed with CH2Cl2 (ca. 1 mL), sonicated and the supernatant was ana-
lyzed by TLC. Completion of the reaction was judged by the disap-
pearance of the TLC spot of the reagent 1a–h. A few experiments were
stopped before the complete disappearance of 1 (Table 1, entries 7
and 12). Longer heating did not lead to decomposition of the reaction
products 3.
All the chemicals were of analytical grade. Abs. EtOH, CH2Cl2, anhyd
Na2SO4, benzil (1a), phenanthrene-9,10-dione (1b), 1-phenylpro-
pane-1,2-dione (1g), biacetyl (1h), and 2 were purified by standard
methods.32 Pyrene-4,5-dione (1c) was synthesized in our laboratory
by a literature procedure33 with modification (exclusion of light and
under N2 atmosphere) that gave a better yield (60%) than the pub-
lished one (46%).33 1,2-Di(2-naphthyl)ethane-1,2-dione (1d), 1,2-
di(biphenyl-4-yl)ethane-1,2-dione (1e), and 1,2-bis(4-chlorophe-
nyl)ethane-1,2-dione (1f) were synthesized from the corresponding
benzoin by CuSO4 oxidation,34 and the benzoin was obtained by the
reaction known as benzoin condensation from the corresponding ar-
omatic aldehyde.35 MPA (99.9%, from Aldrich) was thermally pre-
treated immediately before use (vide infra), nano-sized silica (from
Sigma-Aldrich), particle size 7 nm, surface area 390 ± 40 m2 g–1, was
employed to support MPA, and distilled water deionized by the sys-
tem Milli Pore-MilliQ was used for all the procedures.
Solvent-Free Reaction; Procedure A
A fine powdered mixture (or a paste for liquids 2) of 1, MPA, and 2
placed in a Pyrex glass centrifuge tube (size: 107–109 mm, diameter:
16–17 mm, style type: rimless) was kept at 25–150 °C until the reac-
tion was complete. Occasionally the mixture was allowed to cool to
r.t. in a desiccator and then was again finely pulverized.
Solvent-Free Reaction; Procedure B
Compounds 3a–d,f–h (see Scheme 1) are known compounds.5,8,9,13,29
They were synthesized by our research group using the conventional
technique13 suitably modified for better yields and/or by procedures
designed by our working group.29 Physical properties, spectroscopic
data, and X-ray crystal structure analysis measured for compounds 3
synthesized in this work were compared with those of the authentic
samples and with data previously published by us or by other au-
thors, except for 3e, and found to be identical. Synthesis, physical
properties, spectroscopic data (FT-IR, 1H and 13C NMR, and UV-vis)
and X-ray crystal structure analysis for 3e have not been previously
published. For TLC, Silica gel 60 F254 plates from Merck were used
and examined under UV light irradiation (254, 365, and 200–800
nm). Melting points were determined using the capillary tube meth-
od by a Melting Point Apparatus B-545 (Büchi, Flawil, Switzerland)
and are uncorrected. FT-IR spectra were recorded in KBr pellets on a
Perkin Elmer FTIR spectrophotometer or a FTIR Thermo Scientific Ni-
colet 8700, and the UV-vis spectral measurements were made with a
Shimadzu-1800 spectrophotometer equipped with a thermostatic
cell holder. Teflon-stoppered quartz cells with a 1-cm optical path
were used. 1H and 13C NMR spectra were recorded on Bruker 200 or
400 MHz spectrometers. Elemental analysis were performed by the
Unidad de Microanálisis y Métodos Físicos Aplicados a Química
Orgánica (UMYMFOR), Facultad de Ciencias Exactas, UBA using an El-
emental Analyzer CE440.
In some experiments for the preparation of 3a and 3f the centrifuge
tube was replaced by a conventional sublimator at atmospheric pres-
sure. When the reaction was performed according to this procedure
some of the initial 1a,f and 2 mass were deposited on the cold finger
of the sublimator and were recovered, recrystallized and reused in
other experiments. The solid removed from the cold finger of the sub-
limator was washed with water or CH2Cl2 (with water: 2 was soluble
and 1 was insoluble; with CH2Cl2: 2 was insoluble and 1 was soluble).
Solvent-Free Reaction; Procedure C
A procedure slightly different than procedure A was also tested (as
examples, Table 1 entries 5, 17, and 23). A homogeneous fine pow-
dered mixture of 1 and MPA was left at the reaction temperature for
ca. 18 h, then the mixture was allowed to cool to r.t. in the desiccator,
2 was added and the solid mixture was again pulverized and heated
at the reaction temperature.
At the end of the reaction for the three above procedures, the solid
mixture was allowed to cool to r.t. in the desiccator. Two procedures
for the isolation of the reaction product were tested: (i) ice water
(200–500 mL) was added or (ii) the solid reaction mixture was ex-
tracted with CH2Cl2 (total volume 150–250 mL: 10 × 15–25 mL). The
residual solid after the extractions was reserved and reutilized. (i) Ad-
dition of ice water: the insoluble solid was filtered, washed with copi-
ous amounts of cold H2O, and dried under reduced pressure at 40 °C
to constant weight. (ii) Extraction with CH2Cl2: the combined organic
extracts were washed with H2O, dried (anhyd Na2SO4) and then the
solvent was evaporated under reduced pressure at r.t. yielding a solid
Preparation of MPA Catalyst
Commercial MPA was treated at different temperatures in order to
enhance the acid strength: 70, 150, or 300 °C (MPA70 °C, MPA150 °C, and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
N. R. Arroyo et al.
Paper
Synthesis
that was dried under reduced pressure at 40 °C to constant weight.
Using both procedures (i) and (ii) crude 3a was obtained as a chro-
matographically (TLC) pure product, but in crude 3b–h products trac-
es (TLC) of unknown by products were present. Pure 3b–f were ob-
tained by the following procedures: 3b, recrystallization (boiling ace-
tone); 3c, repeated washing with warm EtOH; 3d, recrystallization
(boiling CH2Cl2); 3e, repeated washing with EtOH; 3f, repeated wash-
ing with n-hexane, and 3g,h, recrystallization (boiling benzene with
drops of TFA). When MPAsupp was used for 3c preparation, the isola-
tion of the reaction product was performed by extraction with CH2Cl2
to not destroy the supported catalyst.
Phenanthro[9,10-c][1,2,5]thiadiazole 2,2-Dioxide (3b) (Table 1, En-
try 10)
Following procedure A, a fine powered mixture of 1b (108.2 mg, 0.52
mmol), MPA300 °C (37.0 mg, 0.020 mmol), and 2 (445.2 mg, 4.64 mmol)
was kept at 150 °C until the reaction was complete (3.5 h). At the end
of the reaction the solid mixture was allow to cool to r.t. in a desicca-
tor. The solid mixture was treated with water or extracted with
CH2Cl2 following procedures (i) or (ii) yielding 3b (120.2 mg, 0.48
mmol, 86%).
Pyreno[4,5-c][1,2,5]thiadiazole 10,10-Dioxide (3c) Using
MPAsupp150 °C (Table 1, Entry 13)
Reactions in EtOH Solution
Following procedure A, a fine powered mixture of 1c (50.0 mg, 0.17
mmol), MPAsupp150 °C (15.4 mg, 0.0024 mmol of MPA), and 2 (403.1 mg,
4.19 mmol) was kept at 150 °C until the reaction was complete (15 h).
At the end of the reaction, the solid mixture was allow to cool to r.t. in
a desiccator. The solid mixture was extracted with CH2Cl2 following
procedure (ii) yielding 3c (44.1 mg, 0.15 mmol, 70%).
A fine powdered solid mixture of 1b (60 mg, 0.33 mmol) and
MPA150 °C (36 mg, 0.02 mmol) was added to abs EtOH (45–50 mL) con-
tained in a Pyrex glass round-bottom flask (100-mL volume). The ini-
tial yellow homogeneous solution turned green after 45 min of heat-
ing to mild reflux. Then, excess of 2 (250 mg, 2.6 mmol) was added,
and the solution was allowed to stand with magnetic stirring under
heating to mild reflux. When the reaction was complete (TLC), the
heterogeneous solution (MPA was soluble in EtOH) was allowed to
cool to r.t., and then was left in a refrigerator overnight. The solid (3b)
was filtered, washed with cold water, then with cold EtOH, dried to
constant weight and was recrystallized from boiling acetone.
3,4-Di(2-naphthyl)-1,2,5-thiadiazole 1,1-Dioxide (3d) (Table 1, En-
try 15)
Following procedure A, a fine powered mixture of 1d (20.4 mg, 0.066
mmol), MPA150 °C (9.7 mg, 0.0053 mmol), and 2 (65.5 mg, 0.688 mmol)
was kept at 150 °C until the reaction was complete (94 h). At the end
of the reaction, the solid mixture was allow to cool to r.t. The solid
mixture was extracted with CH2Cl2 following procedure (ii) yielding a
solid (17.3 mg, 0.047 mmol, 71%).
Reusability of MPA
The catalyst was assayed to be recovered and to be reused in the reac-
tions for 3. After the extraction of 3 from the solid reaction mixture
with CH2Cl2, the residual solid contains MPA and the excess of 2. The
residual solid was treated by the following two different procedures:
(a) The residual solid was dried and thermally pre-treated under the
same conditions as for the original reaction. (b) The residual solid was
washed with a small volume of water [MPA solubility in water:
0.0169 g/mL at r.t. (ratio: 5 mL water/g residual solid) and 2 is freely
water soluble]. 2 passed to the aqueous phase, and a small amount
(8%) of MPA was lost in water during the washing. A suitable volume
of water was added to the residual solid and then it was centrifuged
for 20 min at 4300 rpm (ROLCO I-2036 centrifuge), the aqueous phase
was separated and the washed residual solid was dried for 48 h at 70
°C in an oven at reduced pressure at r.t. up to constant weight. Finally,
the catalyst thus recovered was thermally pretreated under the same
experimental conditions as the original test and was reused.
3,4-Di(biphenyl-4-yl)-1,2,5-thiadiazole 1,1-Dioxide (3e) (Table 1,
Entry 17)
Following procedure C, a fine powered mixture of 1e (50.1 mg, 0.14
mmol), MPA300 °C (17.8 mg, 0.0097 mmol) and 2 (129.1 mg, 1.34
mmol) was kept at 150 °C until the reaction was complete (8 h). At
the end of the reaction, the solid mixture was allow to cool to r.t. in a
desiccator. The solid mixture was extracted with CH2Cl2 following
procedure (ii) yielding 3e (35.3 mg, 0.084 mmol, 60%) as a bright yel-
low crystalline solid; mp 270.5–271.0 °C.
FT-IR (KBr): 3070–3010, 1600, 1580, 1570, 1540, 1380, 1270, 1190,
1180, 1000, 980, 850, 790, 765, 740, 690, 640, 560, 530, 515 cm–1
.
1H NMR (200 MHz, DMSO-d6): δ = 8.54–7.44 (complex multiplet, CAr–H).
13C NMR (50 MHz, DMSO-d6): δ = 167.2 (heterocyclic sp2 C-atoms),
The synthetic procedures that gave the best results are detailed be-
low; physical and spectroscopic data for all known compounds are
given in the Supporting Information.
144.5–125.9 (several signals CAr).
UV-vis (MeCN): λ (ε, L mol–1 cm–1) = 261 (3.2 × 104), 369 nm (2.02 ×
104).
UV-vis (EtOH): λ (ε, L mol–1 cm–1) = 258 (2.5 × 104), 316 nm (2.6 × 104).
3,4-Diphenyl-1,2,5-thiadiazole 1,1-Dioxide (3a) (Table 1, Entry 5)
Anal. Calcd for C26H18N2O2S: C, 73.93; H, 4.27; N, 6.64; S, 7.58. Found:
C, 74.75; H, 4.33; N, 6.75; S, 7.65.
Following procedure B/C, a fine powered mixture of 1a (105.2 mg,
0.50 mmol), MPA300 °C (91.3 mg, 0.05 mmol), and 2 (60.6 mg, 0.60
mmol) was kept in a conventional sublimator at atmospheric pres-
sure and 70 °C until the reaction was complete (144 h). At the end of
the reaction the solid mixture was allow to cool to r.t. The solid mix-
ture was extracted with water or CH2Cl2 following procedures (i) or
(ii). The solid removed from the cold finger of the sublimator with
CH2Cl2 was 1a (7.9 mg, 0.04 mmol). The crude 3a [116.3 mg, 0.43
mmol, 93% (based on recovered 1a)] was a pure product (TLC).
Crystal Structure for 3e
Single crystals of 3e were obtained from MeCN solutions by slow
evaporation of the solvent. Single crystal X-ray data were obtained
with a KappaCCD diffractometer, using ϕ and ω scans and graphite
monochromated MoKα radiation (λ = 0.71073 Å) in the θ range from
3.33 to 25.00°. The structure was solved by direct and Fourier meth-
ods and the final molecular model obtained by full-matrix least-
squares refinement on F2 of the non-hydrogen atoms employing the
SHELXS-9736 and SHELXL-9737 programs. An ORTEP diagram of 3e is
presented in Figure 1. Detailed X-ray crystal structure data are avail-
able in the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
N. R. Arroyo et al.
Paper
Synthesis
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561371.
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try 19)
Following procedure A, a fine powered mixture of 2 (195.7 mg, 2.040
mmol), MPA150 °C (22.4 mg, 0.0122 mmol), and 1g (248.1 mg, 0.2 mL,
1.676 mmol) was kept at r.t. until the reaction was complete (70 h). At
the end of the reaction the solid mixture was extracted with CH2Cl2
and procedure (ii) was followed. Solid 3g (301.4 mg, 1.449 mmol, 86%;
Lit.13 29%).
3,4-Dimethyl-1,2,5-thiadiazole 1,1-Dioxide (3h) (Table 1, Entry 20)
Following procedure A, a fine powered mixture of MPA150 °C (38.9 mg,
0.021 mmol), 2 (301.3 mg, 3.13 mmol), and 1h (203.6 mg, 0.2 mL,
2.358 mmol), was kept at r.t. until the reaction was complete (52 h).
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I