Microwave irradiation as an efficient tool for the generation of N-heterocyclic o-quinodimethanes: Synthesis of polyheterocyclic compounds by Diels-Alder reactions

Article abstract of DOI:10.1055/s-2006-932460

Microwave irradiation provides a general methodology for the generation of o-quinodimethanes derived from 1,2,4-triazine, pyrazole and 1,2,3-triazole. The cycloaddition reactions of such compounds with electron-deficient dienophiles allow the correspondin

Full text of DOI:10.1055/s-2006-932460

LETTER
579
Microwave Irradiation as an Efficient Tool for the Generation of N-Hetero-
cyclic o-Quinodimethanes: Synthesis of Polyheterocyclic Compounds by
Diels–Alder Reactions
M
icrowaves in the
n
G
eneration
g
of
N
-Heteroc
e
yclic
o
-Qu
l
inodimethane
D
s
íaz-Ortiz,* María A. Herrero, Antonio de la Hoz, Andrés Moreno, José R. Carrillo
Departamento de Química Orgánica, Facultad de Química, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain
Fax +34(926)295318; E-mail: Angel.Diaz@uclm.es
Received 13 December 2005
We wish to report here a microwave-assisted approach for
Abstract: Microwave irradiation provides a general methodology
the generation and Diels–Alder reactions of o-quinodi-
for the generation of o-quinodimethanes derived from 1,2,4-tri-
methane derivatives of 1,2,4-triazine, pyrazole and 1,2,3-
triazoles. These heterocyclic systems have not been as
azine, pyrazole and 1,2,3-triazole. The cycloaddition reactions of
such compounds with electron-deficient dienophiles allow the
corresponding heteropolycyclic adducts to be obtained within 15 widely studied as other systems (e.g., indole) and a gener-
minutes in 51–87% yield.
al synthetic application of o-quinodimethanes derived
from these nitrogen-bearing heterocycles is lacking – per-
haps owing to the modest results achieved by classical
methods.
Key words: Diels–Alder reactions, microwaves, heterocycles, o-
quinodimethanes
The 1,2,4-triazine ring system is a key component of com-
mercial dyes, herbicides and insecticides.6 In addition,
some derivatives have shown wide antibiotic and antitu-
mor activities.7 Pyrazoles have long been of pharmacolog-
ical interest as antianxiety,8 antipyretic, analgesic and
antiinflammatory drugs9 as well as antimicrobials.10
1,2,3-Triazole is the essential structural unit in a number
of drugs and some of these materials are also potent
HIV-1 inhibitors,11 antimicrobial agents,12 or selective b3-
adrenergic receptor agonists.13
Heterocyclic o-quinodimethanes are unstable and reactive
dienes that must be generated in situ.1 In solution and in
the presence of a dienophile the o-quinodimethanes can be
intercepted in a Diels–Alder reaction.2 This is the basis for
the synthesis of a wide range of polycyclic natural prod-
ucts.3 Most of the papers in this area describe the genera-
tion of o-quinodimethanes in situ and trapping with
dienophiles to obtain the Diels–Alder adduct. In this re-
gard, the general application of these reactions has not
been fully explored.
In the last decade, Stephanidou-Stephanatou and co-
workers have studied the generation of o-quin-
odimethanes derived from pyrazole and 1,2,3-triazole.14
The Diels–Alder reactions with electron-deficient dieno-
philes afforded the corresponding adducts in 11–52%
yield.
The generation of o-quinodimethane derivatives generally
involves harsh reaction conditions under which the
reagents are heated to very high temperatures (frequently
up to 200 °C). Moreover, o-quinodimethanes rapidly
decompose or undergo intramolecular reactions in the
absence of an activated dienophile.
We report here a general microwave-assisted synthetic
methodology to prepare, in good yields and within a few
minutes, heteropolycyclic compounds derived from 1,2,4-
triazine, pyrazole and 1,2,3-triazole.
In the last decade, microwave irradiation under solvent-
free conditions has been shown to be a useful energy
source in a wide range of synthetic reactions. The rapid
heating induced by the radiation avoids decomposition of
reagents and/or products, reactions are cleaner and yields
are in many cases higher than those obtained by classical
heating.4 For these reasons, the microwave approach
represents a very promising methodology to generate o-
quinodimethane derivatives.
Irradiation of bromoderivatives 1, 2 or 3 under solvent-
free conditions in the presence of NaI and a small amount
of DMF (0.1 mL, the presence of a small amount of DMF
is necessary to dissolve the sodium salt) gave the corre-
sponding o-quinodimethane. Subsequent cycloadditon
with electron-deficient dienophiles afforded the corre-
sponding cycloadducts within 15 minutes in 51–87%
yield (Figure 1 and Scheme 1).15 The results are given in
Table 1.
Recently, we studied the microwave-enhanced reactivity
of non-activated dienophiles (aromatic alkynes and en-
amines) towards a pyrazine o-quinodimethane. This
methodology allowed the corresponding quinoxalines to
be obtained in 33–43% yield.5
These findings clearly demonstrate that microwave irradi-
ation provides an excellent way to induce the generation
and Diels–Alder cycloaddition of heterocyclic o-quino-
dimethane derivatives.
SYNLETT 2006, No. 4, pp 0579–0582
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932460; Art ID: G38205ST
© Georg Thieme Verlag Stuttgart · New York
0
2.
0
3.
2
0
0
6
All of the products were characterised on the basis of their
spectroscopic and analytical data. Reactions were con-
ducted until the starting bromoderivative had completely

580
Á. Díaz-Ortiz et al.
LETTER
CH2Br
CH2Br
Bromoderivatives 2 and 3 were prepared from the corre-
sponding diols 17 and 18, respectively, through a nucleo-
philic substitution reaction. In order to increase the
sustainability of the methodology, we performed these
transformations using an ionic liquid under microwave ir-
radiation.
N
N
CHBr2
N
N
CH2Br
CH2Br
N
N
N
N
CHBr2
Ph
Ph
1
2
3
Figure 1 Bromoderivatives 1–3 used as precursors in the generation
of o-quinodimethanes
In accordance with a recent study by Leadbeater,17 we
prepared and used the ionic liquid 19 to obtain 2 and 3. Ir-
radiation of a mixture of the diol, TsOH, the ionic liquid
and xylene (1 mL) at 150 °C for 3.5 minutes afforded the
bromoderivatives 2 and 3 in 66 and 61% yield, respective-
ly (Scheme 2).18 In the classical procedure, treatment of
the diol with PBr3/DMAP in CH2Cl2 at room temperature
for 24 hours gave compounds 2 and 3 in 51% and 40%
yield, respectively. These results again demonstrate the
synergy between ionic liquids and microwave irradiation
to accelerate reactions and increase product yields. This
work also constitutes the first application of this reaction
in heterocyclic compounds.
Het
CHXBr
CHX
NaI, DMF
Het
Het
MW
CHX
CHXBr
X = H or Br
Br
N
N
Het = 1,2,4-triazine,
pyrazole or
CH2OH
CH2Br
Y
Y
19
1,2,3-triazole
N
N
CH2OH
CH2Br
N
N
PTSA, xylene
MW
Ph
Ph
17 Y = CH
18 Y = N
2 Y = CH
3 Y = N
Het
Scheme 2
Scheme 1
In conclusion, in this work we have applied microwave
irradiation in the generation and Diels–Alder cycloaddi-
tion of several heterocyclic o-quinodimethanes. The re-
sults represent a general synthetic procedure to prepare,
within a few minutes, a wide range of heterocyclic com-
pounds in good yields. The novelty of this work is not the
synthetic approach employed but the application of
microwave heating in the development of a general syn-
thetic procedure to prepare interesting heteropolycyclic
products in good yields.
disappeared. It should be noted, however, that reaction
conditions have not been optimised.
The use of precursor 1 and subsequent elimination of two
equivalents of HBr allowed aromatic products to be ob-
tained.16 Precursors 2 and 3 afforded aromatic cyclo-
adducts with triple-bonded dienophiles (such as DMAD)
and p-benzoquinone. However, other double-bonded
dienophiles (N-methylmaleimide and DEAD) led to non-
aromatic adducts.
Table 1 Cycloaddition Reactions between Bromoderivatives 1–3 and Electron-Deficient Dienophiles 4–7 under Microwave Irradiation
Entry
1
Substrate
Dienophile
Temp (°C)
90
Product
Yield (%)
68
O
N
O
O
N
N
Me
N
Me
1
N
O
8
9
4
N
CO2Me
CO2Me
MeO2C
CO2Me
2
1
90
55
N
5
N
Synlett 2006, No. 4, 579–582 © Thieme Stuttgart · New York

LETTER
Microwaves in the Generation of N-Heterocyclic o-Quinodimethanes
581
Table 1 Cycloaddition Reactions between Bromoderivatives 1–3 and Electron-Deficient Dienophiles 4–7 under Microwave Irradiation
(continued)
Entry
Substrate
Dienophile
Temp (°C)
150
Product
Yield (%)
80
O
O
N
O
N
Me
N
Me
3
2
N
O
Ph
4
10
11
CO2Me
CO2Me
N
MeO2C
CO2Me
4
5
2
2
110
110
51
62
N
5
Ph
CO2Et
CO2Et
EtO2C
N
N
N
N
N
N
CO2Et
Ph
6
12
13
O
O
N
6
2
115
58
N
Ph
O
7
O
O
O
N
N
N
O
Me
N
Me
7
8
3
3
3
150
140
120
87
68
66
N
O
Ph
4
14
15
CO2Me
CO2Me
N
N
MeO2C
CO2Me
N
5
Ph
EtO2C
CO2Et
CO2Et
N
N
N
N
N
N
9
N
CO2Et
Ph
6
16
(3) For instance: (a) Nicolaou, K. C.; Gray, D. L. F. J. Am.
Acknowledgment
Chem. Soc. 2004, 126, 607. (b) Nicolaou, K. C.; Gray, D. L.
F.; Tae, J. S. J. Am. Chem. Soc. 2004, 126, 613.
Financial support from the Spanish DGCyT (Project CTQ2004-
01177/BQU) and Junta de Comunidades de Castilla-La Mancha
(Project PAI05-019) is gratefully acknowledged. One of us
(M.A.H.) wishes to acknowledge a grant from JJCC.
(4) (a) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48,
1665. (b) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet,
F.; Jacquault, P.; Mathé, D. Synthesis 1998, 1213.
(c) Microwaves in Organic Synthesis; Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2002. (d) Varma, R. S. Microwave
Technology – Chemical Synthesis Applications, In Kirk-
Othmer Encyclopedia of Chemical Technology; John Wiley
and Sons Inc.: New York, 2003. (e) Kappe, C. O. Angew.
Chem. Int. Ed. 2004, 43, 6250. (f) De la Hoz, A.; Díaz-
Ortiz, A.; Moreno, A. In Advances in Organic Synthesis,
Vol. 1; Atta-ur-Rahman, Ed.; Bentham Science Publishers
Ltd.: Hilversum, 2005, 119.
References and Notes
(1) Segura, J. L.; Martín, N. Chem. Rev. 1999, 99, 3199.
(2) (a) Chou, T.-S. Rev. Heteroat. Chem. 1993, 8, 65.
(b) Collier, S. J.; Storr, R. C. Prog. Heterocycl. Chem. 1999,
10, 25. (c) Wojciechowski, K. Eur. J. Org. Chem. 2001,
3587. (d) Ando, K.; Takayama, H. Heterocycles 1994, 37,
1417. (e) Van de Water, R. W.; Pettus, T. R. R. Tetrahedron
2002, 58, 5367.
(5) Díaz-Ortiz, A.; de la Hoz, A.; Moreno, A.; Prieto, P.; León,
R.; Herrero, M. A. Synlett 2002, 2037.
Synlett 2006, No. 4, 579–582 © Thieme Stuttgart · New York

582
Á. Díaz-Ortiz et al.
LETTER
(6) (a) Hurst, D. T. Prog. Heterocycl. Chem. 1995, 7, 244.
(b) Groger, H.; Sans, J.; Gunther, T. Chim. Oggi 2000, 18,
12. (c) Neunhoffer, H. In Comprehensive Heterocyclic
Chemistry, Vol. 3; Katrizky, A. R.; Rees, C. W.; Boulton, A.
J.; McKilop, A., Eds.; Pergamon: Oxford, 1984.
(7) (a) Hirata, K.; Nakagami, H.; Takashina, J.; Miyamoto, K.
Heterocycles 1996, 43, 1513. (b) Abdel-Rahman, R. M.;
Seada, M.; Fawly, M.; El-Baz, I. Farmaco 1993, 48, 397.
(8) (a) Häufel, J.; Breitmaier, E. Angew. Chem., Int. Ed. Engl.
1974, 13, 604. (b) Wustrow, D. J.; Capiris, T.; Rubin, R.;
Knobelsdorf, J. A.; Akunne, H.; Davis, M. D.; MacKenzie,
R.; Pugsley, T. A.; Zoski, K. T.; Heffner, T. G.; Wise, D. L.
Bioorg. Med. Chem. Lett. 1998, 8, 2067.
(9) (a) Menozzi, G.; Mestri, L.; Fossa, P.; Mattioli, F.; Ghia, M.
J. Heterocycl. Chem. 1997, 34, 963. (b) Penning, T. D.;
Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.;
Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, G. D.; Cogburn, J. N.; Gregory, S.
A.; Kobodt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40,
1347.
(10) (a) Habib, N. S.; Tawil, G. G. Sci. Pharm. 1981, 49, 42.
(b) Devi, S.; Mitro, P.; Mishra, S. B.; Mittra, A. S. J. Indian
Chem. Soc. 1983, 60, 679. (c) Daidone, G.; Maggio, B.;
Plescia, S.; Raffa, D.; Musiu, C.; Milia, C.; Perra, G.;
Marongiu, M. E. Eur. J. Med. Chem. 1998, 33, 375. (d) El-
Emary, T. I.; Bakhite, E. A. Pharmazie 1999, 54, 106.
(11) (a) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De
Clercq, E.; Perno, C.-F.; Karlsson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4185. (b) Ölgen,
S.; Chung, K. C. Z. Naturforsch., B: Chem. Sci. 2001, 56,
804.
(15) Experimental Procedure.
A mixture of bromoderivative (1 equiv), NaI (5 equiv if 1 is
employed or 3 equiv in the case of 2 and 3), DMF (0.1 mL)
and the corresponding dienophile (2 equiv) was placed in an
open vessel and irradiated at 10 W in a focused microwave
reactor (Discover®, CEM) for 15 min. The crude product
was purified by flash column chromatography (silica gel,
Merck type 60, 230–400 mesh) using hexane–EtOAc as the
eluent to obtain the adduct.
Data for 8: mp 204–205 °C. 1H NMR (500 MHz, CDCl3):
d = 3.35 (s, 3 H, CH3), 8.60 (s, 1 H, H-5), 9.05 (s, 1 H, H-9),
10.14 (s, 1 H, H-3) ppm. 13C NMR (125 MHz, CDCl3):
d = 25.0 (CH3), 126.0 (C-5), 126.3 (C-9), 132.2, 135.7 (C-9a
and -4a), 143.9, 149.6 (C-8a and -5a), 165.6 (C=O). MS (EI):
m/z = 214 [M+].
Data for 10: mp 165.5–166.5 °C. 1H NMR (500 MHz,
CDCl3): d = 2.86 (dd, 1 H, J = 7.3, 15.4 Hz, H-4), 2.90 (s, 3
H, CH3), 2.93 (dd, 1 H, J = 7.3, 16.1 Hz, H-10), 3.23 (dd, 1
H, J = 1.6, 15.4 Hz, H-4), 3.34 (dd, 1 H, J = 1.6, 7.3 Hz, H-
5), 3.36 (dd, 1 H, J = 1.8, 7.3 Hz, H-9), 3.55 (dd, 1 H, J = 1.8,
16.1 Hz, H-10), 7.37 (t, 1 H, J = 6.3 Hz, p-H Ph), 7.44 (t, 2
H, J = 6.3 Hz, m-H Ph), 7.46 (t, 2 H, J = 6.3 Hz, o-H Ph),
7.47 (s, 1 H, H-3) ppm. 13C NMR (125 MHz, CDCl3): d =
21.1 (C-4), 21.7 (C-10), 25.3 (CH3), 39.6, 39.9 (C-5 and -9),
123.5 (m-C), 127.5 (p-C), 129.3 (o-C), 137.7 (C-3), 179.0,
179.4 (C=O), 115.2, 135.9, 139.1 ppm. MS (EI): m/z 281
[M+].
Data for 16: yellow oil. 1H NMR (500 MHz, CDCl3): d =
1.26 (m, 6 H, 2 × CH3), 4.21 (m, 4 H, 2 × CH2), 4.51 (br s, 2
H, H-4a and -7a), 5.30 (br s, 2 H, H-4b and -7b), 7.54 (m, 5
H, Ph) ppm. 13C NMR (125 MHz, CDCl3): d = 14.4 (CH3),
42.0, 44.3 (C-4 and -7), 63.2 (COOCH2), 122.3 (p-C), 129.3
(m-C), 129.9 (o-C), 140.7 (ipso-C), 155.3, 155.6 (COO),
136.3 ppm. MS (EI): m/z = 345 [M+].
(12) Genin, M. J.; Alwine, D. A.; Anderson, D. J.; Barbachyn, M.
R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; G rega, 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.;
Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
(13) 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.
(16) Shepherd, M. K. J. Chem. Soc., Perkin Trans. 1 1986, 1495.
(17) Leadbeater, N. E.; Torenius, H. M.; Tye, H. Tetrahedron
2003, 59, 2253.
(18) Experimental Procedure.
A mixture of hydroxyderivative 17 or 18 (1 equiv), ionic
liquid 19 (2.8 equiv), PTSA (2 equiv) and xylene (1 mL) was
placed in an closed vessel and irradiated at 15 W in a focused
microwave reactor (Discover®, CEM) for 3.5 min (final
temperature 150 °C). The organic layer was separated from
this two-phase system. The ionic liquid was washed with
xylene (2 × 1 mL). The combined organic layers were dried
with MgSO4 and the solvent removed at reduced pressure.
The resulting bromoderivatives, 2 or 3, can be directly
employed or purified by flash column chromatography
(silica gel, Merck type 60, 230–400 mesh) using hexane–
EtOAc 2:1 as the eluent.
(14) (a) Mitkidou, S.; Stephanidou-Stephanatou, J. Tetrahedron
Lett. 1990, 31, 5197. (b) Mertzanos, G. E.; Stephanidou-
Stephanatou, J.; Tsoleridis, C. A.; Alexandrou, N. E.
Tetrahedron Lett. 1992, 33, 4499.
Synlett 2006, No. 4, 579–582 © Thieme Stuttgart · New York