Recyclable supported catalysts in microwave-assisted reactions: first Diels-Alder cycloaddition of a triazole ring

Article abstract of DOI:10.1016/j.tetlet.2006.10.006

We describe here the first example in which a 1,2,3-triazole ring acts as a diene towards DMAD in microwave-assisted solvent-free Diels-Alder cycloadditions. The extrusion of a molecule of a nitrile affords pyrazole derivatives as the products. The yields

Full text of DOI:10.1016/j.tetlet.2006.10.006

Tetrahedron Letters 47 (2006) 8761–8764
Recyclable supported catalysts in microwave-assisted reactions:
first Diels–Alder cycloaddition of a triazole ring
´
*
*
Angel D ´ı az-Ortiz, Abel de C o´ zar, Pilar Prieto, Antonio de la Hoz and Andr e´ s Moreno
Dpto. Q. Inorg a´ nica, Q. Org a´ nica y Bioqu ı´ mica, Facultad de Qu ı´ mica, Universidad de Castilla-La Mancha,
E-13071 Ciudad Real, Spain
Received 23 August 2006; revised 29 September 2006; accepted 2 October 2006
Available online 20 October 2006
Abstract—We describe here the first example in which a 1,2,3-triazole ring acts as a diene towards DMAD in microwave-assisted
solvent-free Diels–Alder cycloadditions. The extrusion of a molecule of a nitrile affords pyrazole derivatives as the products. The
yields can be markedly increased by using a recyclable supported Lewis acid catalyst, which can be reused at least five times without
a decrease in the yield.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The intermolecular Diels–Alder reactions of heterocyclic
compounds are the basis for the synthesis of a wide
range of target molecules.
Typically, a Lewis acid catalyst such as aluminium chlo-
ride is used in Diels–Alder reactions. However, in recent
years, following a drive for simplified work-ups, solid
acids have become increasingly considered for these
reactions, albeit with limited success. These solid acids
were shown to be capable of facilitating the same reac-
tions as the unsupported reagents, with the advantage
of recovery by filtration for a subsequent reuse.1
1
Dimethyl acetylenedicarboxylate (DMAD) undergoes
Diels–Alder cycloaddition reactions with several hetero-
cyclic systems with subsequent extrusion of a small
molecule (through retro-Diels–Alder cleavage). DMAD
3
reacts with: (i) 3-arylsydnones to afford pyrazole-3,4-
2
dicarboxylates and CO ; (ii) oxazoles leading to furans
In the last decade, we have often demonstrated the
utility of microwave irradiation in cycloaddition reac-
2
4
3
5
and a nitrile; (iii) furan and pyrrole derivatives to give
furan- or pyrrole-3,4-dicarboxylates and ethylene or an
alkyne, respectively; (iv) methoxythiophenes to yield di-
methyl phthalates and sulfur; (v) dimesityl-1,2,4-oxadi-
phosphole to give a 1,2-oxaphosphole and mesitylphos-
1
4
tions. The combination of supported reagents and
microwave irradiation can be used to carry out a wide
range of Diels–Alder reactions in short times and with
high conversions and selectivity, without the need for
solvents.
6
7
phaacetylene; (vi) 2-(1H)-pyrazinones to afford 2-(1H)-
pyridinone-4,5-dicarboxylates and cyanogen chloride or
8
pyridine-3,4-dicarboxylates and an isocyanate.
As a continuation of our studies, we report here that
1,2,3-triazoles undergo a Diels–Alder cycloaddition with
1
,2,3-Triazole is the essential structural unit in a number
DMAD under solvent-free conditions and microwave
irradiation within 20 min to afford pyrazole-3,4-dicarb-
oxylates with extrusion of the substituent on position 4
of the triazole as a nitrile (Scheme 1). Yields can be
of drugs and some of these materials are also potent
HIV-1 inhibitors, antimicrobial agents or selective
b3-adrenergic receptor agonists. 1,2,3-Triazole can be
9
10
1
1
easily built by a 1,3-dipolar cycloaddition using an azide
increased significantly by using silica-bound AlCl as a
catalyst (0.1 mol %) (Table 1).
3
1
2
15
16
derivative. However, its reactivity, particularly in
Diels–Alder reactions, has barely been studied in com-
parison with other heterocyclic systems.
The silica-bound Lewis acid catalyst could be reused five
times in the cycloaddition of 1f under microwaves with-
out a decrease in the product yield. This result shows the
utility and enhances the environmentally benign applica-
*
Corresponding authors. Tel.: +34 926 295300; fax: +34 926 295318
´
1
7
(
A.D.-O.); e-mail: Angel.Diaz@uclm.es
tions of this catalyst.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.006

´
A. D ı´ az-Ortiz et al. / Tetrahedron Letters 47 (2006) 8761–8764
8762
Ph
N
MeO2C
N
CO Me
R1
2
CO Me
N
2
silica-bound AlCl3
R1
R2
_
R1
N
N
+
CO Me
2
N
MW / 80 - 130 °C
N
R2
N
R2
N
Ph
CO2Me
20 min
Ph
CO Me
2
1
a-h
2
3a-e
Scheme 1. Reaction of 1,2,3-triazoles 1a–h with DMAD under microwave irradiation.
Table 1. Product yield obtained in the reaction of 1,2,3-triazoles 1a–h with DMAD by classical heating or under microwaves
c
a,b
Product yield (%)
Entry
Substrate
R
1
R
2
Product
Power (W)
Temperature (ꢁC)
d
Classical heating
Microwaves
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
H
H
H
H
CH
CH
CH
CH
3a
3a
3a
3a
3b
3c
3d
3e
60
80
80
80
60
40
60
80
120
120
130
120
120
80
15 (8)
34 (5)
7 (4)
12 (5)
30 (11)
46 (25)
62 (12)
48 (21)
40 (14)
58 (18)
35 (15)
38 (12)
57 (20)
89 (56)
94 (20)
86 (34)
C
6
H
5
CHO
CO Me
2
C
6
H
5
3
3
3
3
CH
CH
CH
3
3
3
CH
OCH
(CH
2
CH
OCH
(CH
2
1g
1h
2
2
100
100
2
)
3
2
)
3
a
b
c
Isolated products.
Yields of uncatalyzed reactions are given in brackets.
Starting power in the microwave-assisted reactions.
d
No significative increase of the yields is observed at higher reaction times.
To the best of our knowledge, this reaction represents
the first example of a Diels–Alder cycloaddition involv-
ing a 1,2,3-triazole ring. The importance of these results
particularly relates to: (i) the transformation of a very
unreactive and scarcely studied heterocyclic system,
which extends the scope of its reactivity and (ii) the envi-
ronmentally friendly and sustainable reaction conditions
used, that is, absence of solvent, microwave irradiation
and recyclable supported catalyst.
act as dienes and these, in principle, should be more
reactive than 1-substituted 1,2,3-triazoles.
In the absence of microwaves and catalyst, and under
similar reaction conditions (time and temperature), the
yields of the products decrease dramatically (4–25%).
This fact explains why 1,2,3-triazole and/or its cyclo-
addition reactions have not been studied previously.
5
-Phenyl-1,2,3-triazoles, such as 1,5-diphenyl- and 1,4,5-
The reactivity of heterocyclic compounds as dienes in
Diels–Alder reactions is a subject of extensive study
from two points of view: (i) in terms of synthetic appli-
cations leading to valuable compounds and (ii) from a
theoretical point of view because, as aromatic com-
pounds, these are at the limit of reactivity as dienes.
triphenyl-1,2,3-triazoles 1i and 1j, respectively, do not
react with DMAD under prolonged irradiation at high
temperatures and in these cases only decomposition of
the reagents was observed. In order to have a higher
knowledge on the mechanism of this reaction, we
decided to compute the structure of the 4-phenyl- and
*
5
-phenyl-1,2,3-triazoles at the B3LYP/6-31G level of
Five-membered heterocyclic systems with one hetero-
atom have been reacted as dienes, with furan being the
most reactive and thiophene the least. The introduction
of a second heteroatom decreases the reactivity of these
systems as dienes. In azoles only 1,3-diazoles and—
almost exclusively—oxazoles (2-azadienes) show reac-
tivity as dienes, whereas 1,2-azoles (1-azadienes) do
not react at all.
theory (Fig. 1). These structures show that the steric
hindrance is crucial in this reaction. Thus, the 4-phenyl
group is coplanar with the triazole ring. The driedral an-
gle between the 4-phenyl and the triazole is ꢀ2.89ꢁ in
compound 1b and ꢀ26.86ꢁ in compound 1e. In contrast,
the 5-phenyl substituent is more perpendicular to the
triazole (43.66ꢁ in the case of 1i and ꢀ57.31 in 1j) and,
for this reason, the approach of DMAD is unfavoured
on both sides of the triazole ring.
In this regard, of the five-membered heterocyclic com-
pounds with three heteroatoms only 1,3,4-oxadiazole
On the other hand, the reaction of (1H)-1,2,3-triazole (4)
and DMAD under microwave irradiation in the absence
of catalyst led to a mixture of products 5 (as the E ste-
reoisomer) and 6 (as a E/Z mixture, 7:3 ratio) through
a Michael addition (Scheme 2). The overall yield in-
creased from 57% to 91% in the presence of silica-bound
(
2,3-diazadiene) reacts as a diene and a large number
of papers have been published in this area. In contrast,
-substituted 1,2,3-triazole is one of the least reactive
heterocyclic systems (1,2-diazadiene) and reports on its
1
1
9
1
8
use as a diene have not been published.
AlCl without modification of the isomer ratio. Tenta-
3
As a consequence, our methodology opens new possibil-
ities for a large number of heterocyclic compounds to
tively, in the absence of a protic solvent, protonation
of the Michael intermediate must occur mainly from

´
A. D ı´ az-Ortiz et al. / Tetrahedron Letters 47 (2006) 8761–8764
8763
Figure 1. Fully optimized [B3LYP/6-31G+d level of theory] structures of 1,2,3-triazoles 1b,e,i,j.
N
K. T.; Marshall, J. J. Chem. Soc., Chem. Commun. 1972,
1000.
. (a) Cook, M. J.; Forbes, E. J. Tetrahedron 1968, 24, 4501;
(b) Mavoungon-Gom e` s, L.; Bruneton, J.; Aicart, M. J.
Heterocycl. Chem. 1985, 22, 1233.
N
MeO C
N
N
N
2
DMAD
N
N
N
+
4
MW / 120 °C
MeO C
2
N
H
H
8
0 W
CO Me
2
H
2
0 min
CO Me
2
4
5
. Noland, W. E.; Lee, C. K. J. Org. Chem. 1980, 45,
6
5
4
573.
. (a) Corral, C.; Lissavetzky, J.; Manzanares, I. Synthesis
997, 29; (b) Loupy, A.; Maurel, F.; Sabati e´ -Gogov a´ , A.
without catalyst
44%
13%
32%
6
with silica-bound AlCl3 59%
1
Tetrahedron 2004, 60, 1683.
. Mack, A.; Bergstr a¨ ßer, U.; Reiß, G. J.; Regitz, M. Eur. J.
Org. Chem. 1999, 587.
Scheme 2. Reaction between (1H)-1,2,3-triazole (4) and DMAD.
7
8
. (a) Kaval, N.; Van der Eycken, J.; Caroen, J.; Kappe, C.
O.; Dehaen, W.; Strohmeier, G. A.; Van der Eycken, E.
J. Comb. Chem. 2003, 5, 560; (b) Kaval, N.; Ermolat’es,
D.; Appukkuttan, P.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. J. Comb. Chem. 2005, 7, 490.
the triazole side leading to the E stereoisomer as the only
or main product. This stereochemical assignment was
confirmed by comparison of the olefinic proton chemical
2
0
shifts in 5 and 6 with its pyrazole analogue.
¨
9
. Olgen, S.; Chung, K. C. Z. Naturforsch., B: Chem. Sci.
001, 56, 804.
In conclusion, we have described the first microwave-
assisted Diels–Alder reaction in which a 1,2,3-triazole
ring acts as a diene. The use of a recyclable silica gel
functionalized Lewis acid in the absence of solvent not
only improves the product yields dramatically but
makes this reaction into an environmentally friendly
process. Further studies to expand the scope of this
reaction to other uninvestigated heterocyclic systems
will be the subject of future publications.
2
10. Genin, M. J.; Alwine, D. A.; Anderson, D. J.; Barbachyn,
M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.;
Grega, K. C.; Hester, J. B.; Hutchison, D. K.; Morris, J.;
Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J.
C.; Schaadt, R. D.; Staper, D.; Yagi, B. H. J. Med. Chem.
2
000, 43, 953.
1
1. Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore,
M. R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney,
W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Tota,
L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg.
Med. Chem. Lett. 2000, 10, 2111.
Acknowledgements
12. (a) Huisgen, R. Proc. Chem. Soc. 1961, 357; (b) Rostovt-
sev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. 2002, 114, 2708; (c) Amantini, D.; Fringu-
elli, F.; Piermatti, O.; Pizzo, F.; Zunino, E.; Vaccaro, L.
J. Org. Chem. 2005, 70, 6526.
Financial support from the Spanish DGCyT (Project
CTQ2004-01177/BQU) and Junta de Comunidades de
Castilla-La Mancha (Projects PAI05-019 and PBI06-
020) is gratefully acknowledged. We would like to
thank Juan de M. Mu n˜ oz for technical support.
1
3. (a) McKillop, A.; Young, K. W. Synthesis 1979, 401 and
81; (b) Laszlo, P. Preparative Chemistry using Supported
0
4
Reagents; Academic Press: San Diego, USA, 1987; (c)
Smith, K. Solid Supports and Catalyst in Organic Synthe-
sis; Ellis Horwood: Chichester, 1992; (d) Clark, J. H.;
Rhodes, C. N. Clean Synthesis using Porous Inorganic
Solid Acid Catalysts and Supported Reagents; RSC Clean
Technology Monographs: Cambrigde, UK, 2000.
References and notes
1
. Carruthers, W. Cycloaddition Reactions in Organic Syn-
thesis; Pergamon Press: Oxford, UK, 1990.
. (a) Gottardt, H.; Reiter, F. Chem. Ber. 1979, 112, 1206; (b)
Hunnur, R. K.; Latthe, P. R.; Badami, B. V. J. Chem. Res.
14. See, for example: (a) D ´ı az-Ortiz, A.; D ´ı ez-Barra, E.; de la
Hoz, A.; Prieto, P.; Moreno, A.; Langa, F.; Prang e´ , T.;
Neuman, A. J. Org. Chem. 1995, 60, 4160; (b) D ´ı az-Ortiz,
A.; Langa, F.; de la Hoz, A.; Moreno, A. Eur. J. Org.
Chem. 2000, 4, 3659; (c) De la Hoz, A.; D ´ı az-Ortiz, A.;
Langa, F. In Microwaves in Organic Synthesis; Loupy, A.,
2
2
005, 592.
3
. See, for example: (a) Grigg, R.; Hayes, R.; Jackson, J. L.
J. Chem. Soc., Chem. Commun. 1969, 1167; (b) Potts,

´
A. D ı´ az-Ortiz et al. / Tetrahedron Letters 47 (2006) 8761–8764
8764
+
Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 295–
(COOCH
3 16 2 5
). ESI-HRMS C15H N O (M+H) : calcd:
344.
304.1059. Found: 304.1053.
1
1
5. Aluminium chloride functionalized silica gel (particle size
Dimethyl 5-butyl-1-phenylpyrazole-3,4-dicarboxylate (3e):
yellow oil. H NMR d (ppm) 7.46 (m, 3H, H Ph); 7.37 (m,
1
70–120 mesh, extent of labeling: 1.5 mmol/g) was supplied
by Sigma–Aldrich Co.
2H, H Ph); 3.91 and 3.84 (2 · s, 6H, 2 · CH
3
); 2.82 (m,
0
0
0
6. Experimental procedure:
A
mixture of 1,2,3-triazole
2H, H-1 butyl); 1.43 (m, 2H, H-2 butyl); 1.2 (m, 2H, H-3
1
3
(
1 equiv), DMAD (3 equiv) and silica-bound aluminium
butyl); 0.76 (t, J = 7.2 Hz, 3H, CH butyl). C NMR d
3
chloride (0.1 mol %) in an open vessel was irradiated in a
Discover microwave reactor (CEM) at the power and
temperature indicated in Table 1 for 20 min. The crude
reaction mixture was extracted with dichloromethane
(ppm) 163.5 and 163.1 (CO); 149.1 (ipso-C); 144.4 (C-3);
ꢂ
138.5 (C-4); 129.7 (p-C Ph); 129.5 (o-C Ph); 126.5 (m-C
0
Ph); 112.5 (C-5); 52.7 and 52.0 (OCH ); 31.3 (C-2 butyl);
3
0
0
25.0 (C-1 butyl); 22.5 (C-3 butyl); 13.7 (CH
3
butyl). ESI-
H N O (M+H) : calcd: 316.1423. Found:
20 2 4
+
(
2 · 25 mL) and the product was purified by flash column
HRMS C17
316.1429.
chromatography (silica gel) using hexane/ethyl acetate as
the eluent.
17. Silica-bound AlCl was recovered by filtration and drying
3
Dimethyl 1-phenylpyrazole-3,4-dicarboxylate (3a): mp 76–
at 80 ꢁC under reduced pressure for 2 h. The use of this
recycled catalyst for five consecutive experiments in the
cycloaddition of 1f with DMAD afforded 3c in 89%, 89%,
88%, 88% and 89% yield, respectively.
7
7 ꢁC (lit. 75–76 ꢁC, Claisen L. Liebigs Ann. Chem. 1897,
1
295, 311). H NMR d (ppm) 8.4 (s, 1H, H-5); 7.72–7.52
(
m, 2H, H Ph); 7.5–7.48 (m, 2H, H Ph); 7.46–7.31 (m, 1H,
H Ph); 4.0 and 3.9 (2 · s, 6H, 2 · CH
3
).
18. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: Lon-
don, UK, 1987; (b) Tietze, L. F.; Kettschau, G. Hetero
Diels–Alder Reactions in Organic Chemistry. In Topics in
Current Chemistry, 1998; 190, 1–121.
Dimethyl 5-methyl-1-phenylpyrazole-3,4-dicarboxylate (3b):
1
colorless oil. H NMR d (ppm) 7.52–7.47 (m, 3H, H Ph);
7
.42–7.4 (m, 2H, H Ph); 3.95 and 3.88 (2 · s, 6H, 2 ·
13
3 3
OCH ); 2.49 (s, 3H, CH ). C NMR d (ppm) 163.3 and
1
62.7 (CO); 144.18; 144.13; 138.11 (ipso-C Ph); 129.3 (o-C
Ph); 129.2 (m-C Ph); 125 (p-C Ph); 112.0 (C-5); 52.5 and
1.8 (OCH ); 11.9 (CH ). ESI-HRMS
M+H) : calcd: 274.0954. Found: 274.0949.
19. Dimethyl (1,2,3-triazol-1-yl)maleate (5): mp 84–84.5 ꢁC.
1
H NMR d (ppm) 7.85 and 7.8 (2 · d, J = 0.9 Hz, 2H, H-4
5
(
3
3
C
14
H
14
2
N O
4
and -5); 6.79 (s, 1H, @CH); 4.0 and 3.8 (2 · s, 6H,
+
13
3
2 · CH ). C NMR d (ppm) 165.0 and 162.6 (CO); 138.0
Dimethyl 5-ethyl-1-phenylpyrazole-3,4-dicarboxylate (3c):
colorless oil. H NMR d (ppm) 7.5–7.48 (m, 3H, H Ph);
and 134.6 (C maleate); 123.0 and 122.5 (C-4 and -5): 55.0
1
+
and 53.0 (CH ). ESI-HRMS C H N O (M+H) : calcd:
3
8
9
3
4
7
2
3
1
.3 (m, 2H, H Ph); 3.93 and 3.87 (2 · s, 6H, 2 · OCH
3
);
211.0593. Found: 211.0590.
.86 (q, J = 7.3 Hz, 2H, CH ); 1.12 (t, J = 7.4 Hz,
2
Dimethyl (1,2,3-triazol-2-yl)maleate (E-6): mp 76–77 ꢁC.
13
1
H, CH3). C NMR d (ppm) 163.25 and 162.89 (CO);
49.89 (ipso-C Ph); 144.2 (C-3); 138.3 (C-4); 129.6
H NMR d (ppm) 7.85 (s, 2H, H-4 and -5); 6.77 (s, 1H,
1
3
@CH); 4.0 and 3.8 (2 · s, 6H, 2 · CH ). C NMR d (ppm)
165.1 and 162.2 (CO); 143.1 and 137.9 (C fumarate); 107.4
3
(
o-C Ph); 129.4 (p-C Ph); 126.29 (m-C Ph); 112.09 (C-5);
2.7 and 52.0 (OCH ); 19.06 (CH ); 13.89 (CH ). ESI-
HRMS C H N O (M+H) : calcd: 288.1110. Found:
5
3
2
3
(C-4 and -5): 53.0 and 52.0 (CH
3
). ESI-HRMS C
8 9 3 4
H N O
+
+
(M+H) : calcd: 211.0593. Found: 211.0600.
15
16
2
4
2
88.1118.
Dimethyl (1,2,3-triazol-2-yl)fumarate (Z-6): Colorless oil.
1
Dimethyl 5-methoxymethyl-1-phenylpyrazole-3,4-dicarb-
oxylate (3d): colorless oil. H NMR d (ppm) 7.7–7.6 (m,
H NMR d (ppm) 7.76 (s, 2H, H-4 and -5); 7.01 (s, 1H,
1
13
3
@CH); 3.8 and 3.6 (2 · s, 6H, 2 · CH ). C NMR d (ppm)
2
CH
CH
H, oꢀH Ph); 7.5–7.48 (m, 3H, m- and p-H Ph); 4.5 (s, 2H,
163.5 and 162 (CO); 137.0 and 136.4 (C maleate); 126.7
(C-4 and -5); 54.0 and 52.0 (CH ). ESI-HRMS C
(M+H) : calcd 211.0593. Found: 211.0601.
2
); 3.96 and 3.9 (2 · s, 6H, 2 · COOCH
3
); 3.4 (s, 3H,
3
8 9 3 4
H N O
13
+
3
). C MR d (ppm) 162.8 and 162.6 (CO); 145; 143.2;
1
38.4 (ipso-C Ph); 129.6 (o-C Ph); 129.5 (m-C Ph); 125.6
20. Elguero, J.; de la Hoz, A.; Pardo, C. J. Chem. Soc., Perkin
Trans 2 1985, 427.
(p-C Ph); 115.2 ; 62.3 (CH ); 59.2 (OCH ); 52 and 52.8
2
3