Microwave-enhanced reactivity of non-activated dienophiles towards pyrazine o-quinodimethanes

Article abstract of DOI:10.1055/s-2002-35593

Microwave irradiation in solvent-free conditions induces cycloaddition reactions of pyrazine o-quinodimethane intermediates with electron-rich dienophiles within 10-15 min to afford quinoxaline derivatives in acceptable yields.

Full text of DOI:10.1055/s-2002-35593

LETTER
2037
Microwave-Enhanced Reactivity of Non-Activated Dienophiles Towards
Pyrazine o-Quinodimethanes
M
icrowave-Enhan
n
c
ed
R
eactivit
g
yof
D
ienoph
e
iles l Díaz-Ortiz,* Antonio de la Hoz, Andrés Moreno, Pilar Prieto, Rafael León, María A. Herrero
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 4 September 2002
Pyrazine o-quinodimethane derivatives can be generated
from 2,3-bis(dibromomethyl)pyrazine (1) by a 1,4-
elimination reaction.5 These intermediates react under
classical heating with N-phenylmaleimide or cyclohexa-
2,5-diene-1,4-dione to give good yields of products.5
However, the reactivity of pyrazine o-quinodimethanes
with electron-rich dienophiles has not been reported. As
Lewis stated: ‘poorer reacting systems tend to show a
greater effect under microwave irradiation than reacting
systems’.6 For this reason, we studied the Diels–Alder re-
action of pyrazine o-quinodimethanes with non-activated
dienophiles under microwave irradiation.
Abstract: Microwave irradiation in solvent-free conditions induces
cycloaddition reactions of pyrazine o-quinodimethane intermedi-
ates with electron-rich dienophiles within 10–15 min to afford qui-
noxaline derivatives in acceptable yields.
Key words: alkynes, heterocycles, Diels–Alder reactions, micro-
waves, o-quinodimethanes
o-Quinodimethane derivatives are reactive dienes and can
be generated in situ by a number of methods. The inter-
and intramolecular Diels–Alder reactions of these com-
pounds form the basis of the synthesis of a wide range of
target molecules.1
Thus, when 2,3-bis(dibromomethyl)pyrazine (1) is irradi-
ated in 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),
the o-quinodimethane 2 is generated. Subsequent cy-
cloadditions with aromatic alkynes 3–5 or enamines 6–7
afford the corresponding cycloadducts 9-13 within 10–15
minutes in 33–43% yield (see Scheme 1 and Table 1).7
Traditionally, heterocyclic o-quinodimethanes have re-
ceived much less attention. However, the generation and
synthetic applications of these materials have been recent-
ly reviewed2 and interest in them is growing rapidly. Gen-
eration of o-quinodimethane derivatives involves harsh
reaction conditions under which the reagents are heated to
very high temperatures (frequently up to 200 ºC). More-
over, o-quinodimethanes are very reactive and unstable
intermediates that rapidly decompose or undergo intramo-
lecular reactions in the absence of an activated dienophile.
The rate of disappearance of tetrabromide 1 is greater un-
der microwave irradiation than by classical heating. How-
ever, at this moment, we cannot affirm if the microwave
induced elimination of 1 lead to an ‘activated’ o-quin-
odimethane which is more reactive in cycloaddition or the
microwaves affect the reactivity of the dienophile.
Microwave irradiation in solvent-free conditions has been
widely demonstrated as a useful energy source in synthet-
ic reactions. The rapid heating induced by the radiation
avoids the decomposition of the reagents and/or products,
reactions are cleaner and yields are in many cases higher
than those obtained by classical heating.3 For these rea-
sons, microwave technology is a very promising tech-
nique to generate o-quinodimethane derivatives. These
reactive intermediates react under classical heating condi-
tions, with activated electron-poor dienophiles in Diels–
Alder cycloadditions and, in many cases, good yields are
obtained. However, their reactivity towards non-activated
dienophiles has received much less attention, perhaps be-
cause these reactions fail under classical conditions.
NaI (5 equiv)
DMF (0.1 mL)
N
N
CHBr
CHBr
N
N
CHBr2
CHBr2
MW, 60 W
90 ºC, 10-15 min
1
2
Ar
R
N
N
N
Ar
N
As a continuation of our previous studies on microwave-
induced cycloaddition reactions,4 we report here the Di-
els–Alder reaction of pyrazine o-quinodimethane deriva-
tive 2 with non-activated dienophiles, such as aromatic
alkynes or enamines, under microwave irradiation in sol-
vent-free conditions.
R
N
9-11 (38-43%)
12, 13 (33-41%)
Scheme 1
All the quinoxaline derivatives – prepared in acceptable
yields via this microwave technology reported here for
the first time – were characterised on the basis of their
spectroscopic and analytical data. Reaction conditions
have not been optimised, although a higher reaction
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2037,2038,ftx,en;G25702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2038
A. Díaz-Ortiz et al.
LETTER
Table 1 Diels–Alder Cycloadditions between Pyrazine o-Quin-
odimethane 2 and Dienophiles 3–8 under Microwave Irradiation
In conclusion, Diels–Alder cycloadditions of pyrazine
o-quinodimethanes with electron-poor dienophiles can
proceed in good yields either under microwave irradiation
or by classical heating. However, with electron-rich di-
enophiles these reactions can only be successfully per-
formed under microwave irradiation providing the
corresponding quinoxaline compounds to be obtained in
acceptable yields.
En- Dienophile
try
Time Producta
(min)
Yield
(%)
Ph
N
Ph
3
1
2
13
38
43
N
9
N
Ph
Acknowledgement
Ph
Me
CH
15
4
Financial support from the Spanish DGESIC (Project BQU2001-
1095) and Junta de Comunidades de Castilla-La Mancha (Project
PAI-02-019) is gratefully acknowledged. One of us (M. A. H.)
wishes to acknowledge a grant from Fondo Social Europeo.
N
Me
10
11
N
Naph
C
3
4
15
41
41
N
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5
N
15
N
N
12
13
6
N
5
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69
N
N
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8
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(7) Experimental procedure: A mixture of 2,3-
Ph
N
Ph
10
NO2
N
9
bis(dibromomethyl)pyrazine5(1) (150 mg, 0.35 mmol), NaI
(265 mg, 1.77 mmol), DMF (0.1 mL) and the corresponding
dienophile (1.25 mmol) was placed in an open vessel and
irradiated at 60 W in a focused microwave reactor (CixMO
model RF46280)8 for 10–15 min (final temperature 90 ºC).
The crude reaction product was purified by flash column
chromatography (silica gel, Merck type 60 230–400 mesh)
using hexane/ethyl acetate as the eluent to obtain the adduct.
For example:
a Naph = 1-naphthyl
temperature (up to 100 ºC) leads to decomposition of the
o-quinodimethane intermediate 2 before reaction with the
dienophile and a corresponding decrease in the yield is
observed.
Data for 13: yellow oil; IR (film, cm–1) 2950, 2850, 1580,
1490, 1460; 1H NMR (CDCl3, 300 MHz) (ppm) 1.90 (m, 4
H, H-7 and -8), 3.06 (m, 4 H, H-6 and -9), 7.79 (s, 2 H, H-5
and -10), 8.73 (s, 2 H, H-2 and -3); 13C NMR (CDCl3, 75
MHz) (ppm) 22.7 (C-7 and -8), 29.8 (C-6 and -9), 127.8
(C-5 and -10), 141.3 and 141.5 (C-4a, -5a, -9a and -10a),
144.1 (C-2 and -3); EM (EI) m/z 184 (M+).
Logically, when a reactive electron-poor dienophile –
such as -nitrostyrene (8) – is employed, the cycloaddi-
tion is much easier and the yield of the corresponding ad-
duct increases to near 70% (entry 6). On the other hand, as
one would predict, classical heating using an oil bath in
conjunction with similar reaction conditions (time and
temperature) gives only traces of the cycloadducts 9–13
(less than 3%) in all cases. This fact provides further evi-
dence for the efficiency of microwave radiation.
(8) Focused microwave reactor model RF46280 has total
control of the power and temperature by an infrared sensor
and has been developed by CixMO (www.cixmo.com).
Synlett 2002, No. 12, 2037–2038 ISSN 0936-5214 © Thieme Stuttgart · New York