Microwave-assisted reactions of nitroheterocycles with dienes. Diels-Alder and tandem hetero Diels-Alder/[3,3] sigmatropic shift

Article abstract of DOI:10.1016/j.tet.2009.04.065

Diels-Alder cycloaddition of 3-nitro-1-(p-toluenesulfonyl)indole 1 with dienes 2-6 under microwave irradiation in solvent-free conditions gave carbazole derivatives after elimination of the nitro group and in situ aromatization. While 3-nitro-1-(p-toluene

Full text of DOI:10.1016/j.tet.2009.04.065

Tetrahedron 65 (2009) 5328–5336
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Microwave-assisted reactions of nitroheterocycles with dienes. Diels–Alder
and tandem hetero Diels–Alder/[3,3] sigmatropic shift
a
a
a
,
b
,
z
a
*
´
´
´
´
M. Victoria Gomez , Ana I. Aranda , Andres Moreno , Fernando P. Cossıo , Abel de Cozar ,
Angel Dıaz-Ortiz , Antonio de la Hoz y, Pilar Prieto a
a
a,
´
´
a
´
´
Departamento de Quımica Organica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain
b
´
Kimika Organikoa Saila, Kimika Fakultatea, Universidad del Pa´ıs Vasco-Euskal Herriko Unibertsitatea, P.K. 1071, 20080 San Sebastian-Donostia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Diels–Alder cycloaddition of 3-nitro-1-(p-toluenesulfonyl)indole 1 with dienes 2–6 under microwave
irradiation in solvent-free conditions gave carbazole derivatives after elimination of the nitro group and
in situ aromatization. While 3-nitro-1-(p-toluenesulfonyl)pyrrole 11 afforded indole derivatives, 4-nitro-
1-(p-toluenesulfonyl)pyrazole 13 with cyclohexadiene 2 did not afford the expected cycloadduct but
instead gave 1-cyclohexen-2-ylpyrazole 16. This process occurred by hydrolysis of the 1-(p-toluene-
sulfonyl) group, protonation of the diene and nucleophilic addition of the pyrazolate ion, as elucidated by
computational studies. Reaction of nitroindole 1 with cyclohexadiene 2 afforded exclusively the endo
stereoisomer (10endo) in a tandem hetero Diels–Alder/[3,3] sigmatropic shift, as determined by com-
putational calculations.
Received 26 March 2009
Received in revised form 17 April 2009
Accepted 20 April 2009
Available online 24 April 2009
Keywords:
Microwave irradiation
Diels–Alder
Diels–Alder/[3,3] sigmatropic shift
Computational studies
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
electron-withdrawing groups in positions 1 and 3, high tempera-
tures or pressures8 and long reaction times.1
Since the first original paper from Wenkert,1 indole derivatives
have attracted attention as dienophiles for the preparation of car-
bazoles, because its structure is related to several natural products
such as (ꢀ)-aspidospermine2 or plumerene-type alkaloids.3 Al-
though indoles participate as dienophiles in inverse-demand Diels–
Alder reactions, only a few examples of cycloaddition reactions
with electron-rich dienes have been described.4 These reactions
require electron-withdrawing groups both in positions 1 and 3 of
the indole,1,2 high temperatures (150–200 ꢁC),1 long reaction times
(26 h to 4 days) and the use of electron-rich and reactive dienes
such as 1-(N-acetyl-N-propylamino)-1,3-butadiene3 or Dani-
shefsky5 and Rawal dienes.5,6
The long reaction times and high temperatures can be some-
what reduced by applying high pressure (10–11.5 kbar) due to the
negative activation volume of Diels–Alder reactions.7 In a similar
way to indoles, Diels–Alder reactions of pyrrole derivatives as
dienophiles in normal-demand cycloaddition reactions require
Microwave irradiation has been successfully applied in
chemistry since 1975 and a large number of examples have been
described in organic synthesis.9,10 With the aid of microwave irra-
diation, cycloaddition reactions have been performed with great
success11 because they otherwise require the use of harsh condi-
tions that are not compatible with sensitive compounds.
Moreover, the applicability of Diels–Alder reactions is limited by
the reversibility of the reaction in cases where a long reaction time
is required. All of these problems can be conveniently solved by the
rapid heating produced by microwave irradiation, a situation not
accessible by classical methods.
Some results obtained cannot be explained by the effect of rapid
heating alone, and this has led various authors to postulate the
existence of a so-called ‘microwave effect’12 Hence, acceleration or
changes in reactivity and selectivity could be explained by a specific
radiation effect and not merely by a thermal effect. This is still
a controversial matter and several reports show that thermal ef-
fects can explain most reported improvements found on using
microwaves.13 However, in several reports the selectivity (chemo-,
regio- and stereoselectivity) of a reaction has been modified in
relation to that obtained with conventional heating.14,15 These re-
sults show that microwave irradiation can be used as an alternative
to conventional heating to obtain different results to those afforded
by classical methods.
* Corresponding author. Tel.: þ34 926 29 5300; fax: þ34 926 29 5318.
E-mail addresses: fp.cossio@ehu.es (F.P. Cossı´o), antonio.hoz@uclm.es (A. de la
Hoz).
y
Tel.: þ34 926 29 5300x3463; fax: þ34 926 29 5318.
z
Tel.: þ34 943 01 5442.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.065

M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
5329
Table 1
2. Discussion
Reaction of 3-nitro-1-(p-toluenesulfonyl)indole 1 with dienes 2–6
Reactions were performed under solvent-free conditions in
a monomode reactor and in closed vessels in order to avoid the
evaporation of low boiling dienes. Indole, pyrrole, pyrazole and
imidazole derivatives were chosen as dienophiles because of the
importance of their benzoderivatives. Firstly, we chose 3-nitro-1-
(p-toluenesulfonyl)indole 1 as a substrate because the nitro group
may enhance the cycloaddition by favouring aromatization, thus
preventing the retrocycloaddition. We performed the cycloaddition
with a variety of dienes including cyclohexadiene 2, 1-methoxy-
and 2-methoxycyclohexadienes 3 and 4, cyclopentadiene 5 and 1-
(N-acetyl-N-isopropylamino)-1,3-butadiene 6 (Scheme 1 and Table 1).
The series of dienes (2–4, 6) can, through in situ elimination or
retro-Diels–Alder reaction, produce the aromatic benzene ring
easily. Finally, we studied the reaction with cyclopentadiene 5 in
order to elucidate the mechanism of the cycloaddition and the
stereochemical outcome of this process. An excess of diene was
used in order to minimize the effect of its evaporation and poly-
merization. A 1:12 molar ratio of indole to diene was found to give
the best results.
Yields of carbazole 7 were improved to 71% by using a more
reactive diene, N-acetyl-N-isopropylamine-1,3-butadiene 6 (Table
1, entry 4). This result represents a clear improvement on those
previously obtained under thermal conditions, where a yield of 11%
was achieved when the reaction was performed at 90 ꢁC for 7 days,
with an increase to a maximum of 55% at 200 ꢁC for 24 h. Reaction
with a 65:35 mixture of 1-methoxy-1,3-cyclohexadiene 3 and 2-
methoxy-1,3-cyclohexadiene 4 showed that the cycloaddition is
regioselective, producing exclusively carbazoles 8 and 9, re-
spectively, in a global yield of 61% (Table 1, entry 2). Aromatization
is not possible in the cycloaddition with cyclopentadiene 5 and, as
a consequence, cycloadduct 10 was obtained in 29% yield (entry 3)
without loss of the nitro group. The reaction is stereoselective and
produces exclusively the endo stereoisomer. The stereochemistry of
this product was inferred by NOE difference experiments. The
spectroscopic data for 10 include a broad signal (3.51–3.50 ppm) for
the bridgehead methines (H-1, H-4). Addition of methanol as
a solvent that can form hydrogen bonds with the nitro group en-
abled the differentiation of the two bridgehead protons and the
assignment of the stereochemistry. In an attempt to explain the
preference for the endo stereoisomer, we performed theoretical
calculations for this reaction and the results confirmed the
Entry
Diene
Molar ratioa
Time (min)
Yield (%) (product)
1
2
3
4
2
1:12
1:12
1:12
1:12
45
30
30
30
44 (7)
3þ4
25 (8)þ36 (9)
5
29 (10)
6
71 (7)
a
Indole:diene molar ratio. Power 50 W, temperature 100 ꢁC.
differences observed in the reaction with indole 1 and in the
stereoselectivity.
It should be noted that the reaction did not occur when per-
formed with conventional heating under comparable conditions
(45 min, 100 ꢁC) to microwave irradiation. These results again
demonstrate the utility of the microwave methodology.
We extended these conditions to other nitroheterocycles. Re-
action of 3-nitro-1-(p-toluenesulfonyl)pyrrole 11 with diene 6 in
a 1:6 molar ratio under microwave irradiation afforded the
expected indole 12 in 79% yield in only 5 min (Scheme 2).
Once again this reaction does not occur with conventional
heating under similar conditions (5 min, 100 ꢁC) and the reaction at
120 ꢁC for 72 h gave only 53% of the aromatic product 12.16 Reaction
of 4-nitro-1-(p-toluenesulfonyl)pyrazole 13 with N-acetyl-N-iso-
propyl-1,3-butadiene 6 under several sets of reaction conditions
produced only traces of the expected indazole 14 (Scheme 3).
(H3C)2HC
COCH3
N
NO2
MW, 50W
100 °C, 5 min
+
N
N
SO2C6H4CH3
SO2C6H4CH3
6
12
11
79 %
Scheme 2.
NO2
(H3C)2HC
+
COCH3
N
N
MW, 50W
100 °C, 15 min
N
N
N
SO2C6H4CH3
SO2C6H4CH3
14, traces
13
6
Scheme 3.
(H3C)2HC
COCH3
N
NO2
NO2
or
N
5
6
2
N
N
SO2C6H4CH3
SO2C6H4CH3
1
SO2C6H4CH3
10
7
OCH3
OCH3
+
3
4
OCH3
N
OCH3
N
SO2C6H4CH3
SO2C6H4CH3
9
8
Scheme 1.

5330
M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
The use of cyclohexadiene 2 as the diene in a 1:3 ratio produced
mechanism that explains the different reactivity observed in the
reaction between 4-nitro-1-(p-toluenesulfonyl)pyrazole 13 and
cyclohexadiene 2 (Scheme 4).
In order to reproduce the reaction conditions and geometric
features of the substituents, structural simplifications were not
introduced. Experimentally, significant excesses of dienes (cyclo-
pentadiene and cyclohexadiene) were used and the dienes can
therefore act as solvents. We chose benzene as the solvent for
computational studies because of its similarity with our dienes and
the fact that it is also conveniently parameterized.
an unexpected result, with 1-cyclohexen-3-ylpyrazole 16 obtained
in 72% yield (Scheme 4). This yield was improved to 80% on using
a 1:1 molar ratio. This reaction involves removal of the p-toluene-
sulfonyl group and addition of the nitropyrazole to the diene. As
a consequence, the reaction is even more favourable on using 4-
nitropyrazole 15 (Scheme 4). The reaction under conventional
heating at 100 ꢁC produced only 5% of the addition product. How-
ever, the reaction did not occur with 1-(p-toluenesulfonyl)pyrazole
17 or pyrazole 18, both of which are better nucleophiles than 4-
nitropyrazole 15. A more strongly acidic azole, such as 4-nitro-
imidazole 19, and a better nucleophile, such as imidazole 20, did
not react. As a consequence, we performed computational studies
in order to elucidate the mechanism for the formation of 1-cyclo-
hexen-3-ylpyrazole 16.
3.1. Reaction of 3-nitro-1-(p-toluenesulfonyl)indole 1 and
cyclopentadiene 5
We initially studied the stereocontrol observed in the reaction
between 1 and 5. In this case two possible reaction paths are
therefore possible and these correspond to a normal [4þ2] cyclo-
addition and a tandem hetero Diels–Alder cycloaddition/[3,3]
sigmatropic shift (Scheme 5). They represent an example of cross-
[4þ2] cycloaddition reactions.
3. Computational studies
All calculations included in this paper were carried out using
the Gaussian 0317 series of programs, with the standard 6-31G
*
In the literature some examples of this kind of reaction are
collected. Yamabe et al.26 studied the reaction of butadiene with
acrolein in the presence of Lewis acids by using ab initio calcula-
tions. They demonstrated that the reaction leads to a vinyl-
dihydropyran, but not through the expected Diels–Alder
cycloaddition. The transition state corresponded to an inverse-de-
mand [4þ2] cycloadduct where butadiene acts as a dienophile and
acrolein as a 1-azadiene. This adduct was transformed to a normal-
electron-demand [4þ2] product through a Claisen rearrangement.
Other cross-Diels–Alder reactions were studied in the reaction
of phenylsulfonyl-1,3-dienes and pyridones with dienes.27 The
basis set.18 In order to include electron correlation at a reasonable
computational cost, Density Functional Theory (DFT)19 was used.
In this study, these calculations were carried out by means of the
three-parameter functional developed by Becke et al.,20 which is
usually denoted as B3LYP. This method has been shown to pro-
duce reliable results in pericyclic reactions and, in particular, in
[4þ2] cycloadditions.21 Zero-point vibrational energies (ZPVEs)
were computed at the B3LYP/6-31G level and were not scaled. All
*
transition structures and minima were fully characterized by
harmonic analysis. For each located transition structure, only one
imaginary frequency was obtained in the diagonalized Hessian
matrix, and the corresponding vibration was found to be associ-
ated with nuclear motion along the reaction coordinate. Reaction
paths were checked by Intrinsic Reaction Coordinate (IRC)
calculations.22
NO2
+
N
The molecular hardness (h) of each of the species was computed
Tos
according to the following approximate expression (Eq. 1).23
5
1
1
2
h
¼
ð
3L
ꢀ
3H
Þ
(1)
O-
N
NO2
H
NO2
H
Where 3L and 3H are the energies of the LUMO and HOMO,
respectively.
O
N
Tos
N
Tos
N
Tos
The solvent effect in DFT calculations was introduced by means
of the Polarizable Continuum Model (PCM).24 In all cases included
in this study the model solvent was benzene (
3
¼2.25).
TS 1
TS 3
TS 2
We have been interested in the theoretical study of cycloaddi-
tion reactions for a long time.25 In this context, the aim of the
present study was (a) to elucidate the exo/endo stereocontrol of the
Diels–Alder reaction between 3-nitro-1-(p-toluenesulfonyl)indole
1 and cyclopentadiene 5 (Scheme 1) and (b) to find a possible
O
NO2
H
O2N
N
O
H
N
Tos
N
Tos
N
Tos
NO2
H
H
H
NO2
or
NO2
+
N
10endo
10exo
Int 1
N
MW, 50W
N
2
N
N
N
100 °C, 15 min
N
H
SO2C6H4CH3
13
O
N
15
16
O
NO2
H
N
MW, 50W
100 °C, 15 min
or
N
SO2C6H4CH3
or
N
Tos
N
+
2
No reaction
H
N
H
N
H
H
TS 4
17
18
19
Scheme 4.
Scheme 5. Possible mechanisms for the reaction between 3-nitro-1-(p-toluenesulfo-
nyl)indole 1 and cyclopentadiene 5.

M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
5331
Table 2
Activation energies (
the B3LYP/6-31G
use of electron-rich dienes produced the normal Diels–Alder cy-
cloaddition, whereas the use of the more restricted cyclo-
pentadiene yielded an inverse Diels–Alder product.
D
D
Ea, kcal/mol), reaction energies (
DErxn, kcal/mol) computed at
*
þ
ZPVE level and at B3LYP(PCM)/6-31G
*
using benzene as solvent
Denmark et al.28 have shown that reactions of nitroalkenes
with cyclopentadiene can lead to mixtures of Diels–Alder and
hetero-Diels–Alder cycloadducts. In the thermal reaction cyclo-
Reaction
D
Ea
D
Ea
D
Erxn
1
2
1þ5/endo (10endo)
1þ5/exo (10exo)
Gas phase (1 atm)
Benzene (1 mol/l)
22.90
22.35
25.38
24.30
1.85
ꢀ0.95
pentadiene acts as a 4
p component, but the presence of a Lewis
Gas phase (1 atm)
Benzene (1 mol/l)
25.74
25.35
d
d
0.86
0.19
acid reverse the periselectivity. A computational study by Houk
et al.29 on this reaction showed that in the thermal conditions
reaction proceeded by an endo Diels–Alder transition state and
a Claisen rearrangement of the endo adduct accounts for the
formation of the hetero-Diels–Alder cycloadduct. However, no
Claisen rearrangement transition state could be found in acid
catalyzed conditions.
the [3,3] sigmatropic shift would lead not to the experimentally
observed 10endo product, but to a highly hindered trans-fused
indolizine system.
The results shown in Table 2 indicate that activation barriers are
lower for the formation of the endo cycloadduct 10endo than for the
exo cycloadduct 10exo (22.35 and 24.30 kcal/mol vs. 25.35 kcal/
mol).
Similar results were described by Domingo et al.30 in the re-
action of 4-aza-6-nitrobenzofuroxan with cyclopentadiene. At
ꢀ20 ꢁC the inverse electron demand Diels–Alder reaction was ob-
served while at 0 ꢁC the normal-electron-demand Diels–Alder re-
action occurs. Conversion of the [2þ4] cycloadduct to the endo
[4þ2] cycloadduct is associated to a Claisen rearrangement, a [3,3]
sigmatropic shift.
Moreover, similarly to that found by Domingo et al.30 theoretical
values in solution showed that formation of the 10endo cyclo-
adduct is exothermic (0.95 kcal/mol), while formation of the 10exo
cycloadduct is endothermic (ꢀ0.19 kcal/mol). These outcomes in-
dicate that the 10endo cycloadduct is the kinetic and the thermo-
dynamic product.
In this context, we performed a computational study of our
reaction. The two possible reaction paths mentioned above were
located at the B3LYP/6-31G
*
and B3LYP(PCM)/6-31G levels using
*
Differences in the activation barriers are not sufficient to explain
the stereochemical outcome of the cycloaddition, so kinetic anal-
yses of the computed activation energies were therefore carried
out. The rate constants given in Table 3 were calculated using the
benzene as the solvent. The most important stationary points of
both reaction profiles are shown in Figure 1 and the activation and
reaction energies in the gas phase and in solution are shown in
Table 2.
Experimentally, only the 10endo stereoisomer was observed.
Our calculations show that the endo approach (TS 3) always leads to
a nitronate intermediate (Int 1), which corresponds to a [2þ4]
cycloadduct, and there was no evidence for the corresponding
[4þ2] transition state (TS 1).
Eyring equation (Eq. 2), where
culated at B3LYP(PCM)/6-31G
Boltzmann and Planck constants, respectively.
D
þ
Gsn is the activation barrier cal-
DZPVE and KB and h are the
*
ꢀ
ꢁ
kBT
h
D
Gns
kn
¼
exp
ꢀ
(2)
RT
This study also shows that the endo approach corresponds to
a tandem reaction as it was previously reported by other authors.
TS 3 is formed by a [4þ2] cycloaddition with the nitrovinylindole 1
system acting as the diene and cyclopentadiene 5 as the dienophile,
a situation that leads to a nitronate intermediate (Int 1). A [3,3]
sigmatropic shift produces TS 4 and this finally gives the 10endo
stereoisomer (Scheme 5 and Fig. 1). In contrast, the exo approach of
cyclopentadiene 5 to the nitro group is a concerted process and
corresponds to a normal [4þ2] cycloaddition. The exploration of
this energy hypersurface yields TS 2 as the only saddle point con-
necting reactant and products. This transition state is asynchro-
nous; the two critical distances are 1.85 and 2.85 Å (Fig. 1). The exo
approach in the [2þ4] heterocycloaddition would lead to an in-
termediate in which the reactive centres for the [3,3] sigmatropic
shift are at very long distance (4.5 Å) from one another. Moreover,
Numerical simulations were performed as the calculated kinetic
constants are of the same order (Table 3). Integration of the con-
centration versus time curve yields the almost exclusive formation
Table 3
Calculated kinetic constants (kn, mol/s) associated with the reaction between 3-
nitro-1-(p-toluenesulfonyl)indole
1
and cyclopentadiene
5
computed at the
B3LYP(PCM)/6-31G
*
þDZPVE level according to Eq. 2
ki
k
ꢀi
10endo
10exo
Step 1
Step 2
2.56 E-4
9.54 E-6
1.62 E-6
1.78 E-5
2.71 E-5
2.23 E-6
Figure 1. Fully optimized B3LYP(PCM)/6-31G
and cyclopentadiene 5.
*
(using benzene as solvent) structures of the different transition states for the reaction between 3-nitro-1-(p-toluenesulfonyl)indole 1

5332
M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
Table 5
Energy barriers (
D
Ea, kcal/mol) computed at the B3LYP(PCM)/6-31G
*
DZPVE level
þ
for all possible mechanisms of the reaction between 4-nitropyrazole 15 and cyclo-
hexadiene 2
Mechanism
DEa
Addition mechanism 1
Diels–Alder (endo)
Diels–Alder (exo)
Hetero [2þ4]
29.5
33.5
35.9
34.5
sigmatropic shift, changes in polarity are not expected from ground
to transition states. Therefore, all outcomes indicate that micro-
wave irradiation led to the thermodynamic product.
3.2. Reaction of 4-nitropyrazoles 13, 15 and 4-nitroimidazole
19 with cyclohexadiene 2
Figure 2. Simulated stereochemical outcome associated with the reaction between 3-
nitro-1-(p-toluenesulfonyl)indole 1 and cyclopentadiene 5.
We performed a computational study aimed at explaining the
different reactivities of 3-nitro-1-(p-toluenesulfonyl)indole 1, 4-
nitropyrazoles 13, 15 and 4-nitroimidazole 19 with cyclohexadiene
2. As stated above, 4-nitro-1-(p-toluenesulfonyl)pyrazole 13 and 4-
nitropyrazole 15 react with cyclohexadiene 2 to give 1-cyclohexen-
3-ylpyrazole 16 and the expected cycloadduct is not observed
(Scheme 4). Furthermore, pyrazoles 17 and 18 and 4-nitroimidazole
19 do not react under similar conditions.
Formation of compound 16 from 13 implies a previous hydro-
lysis of the tosyl group; this is not surprising since acyl pyrazoles
are used as acylation agents in mild and neutral conditions because
pyrazole is a good leaving group. The mechanism may involve the
protonation of cyclohexadiene and subsequent nucleophilic attack
of the pyrazolate anion (Scheme 6, mechanism 1).
Table 4
Di0pole moments
(m, D), hardnesses (h, eV), average polarizability volumes
(
a av, Bohr3) of ground and transition structures for the reaction between 1 and 5
m
a0av
h
1
5
TS 2
TS 3
TS 4
8.869
226.73
51.88
309.63
311.34
311.26
0.0732
0.1009
0.0507
0.0516
0.0485
0.4892
11.741
11.042
11.006
of 10endo (Fig. 2), a situation in excellent agreement with the ex-
perimental evidence.
It has also been reported that the modification of selectivity
under microwave irradiation depends on the hardness and polar-
izability of the transition state, with the harder and less polarizable
transition state favoured under microwaves.31 As a result, we cal-
culated the polarity, hardness and polarizability of all saddle points
and the results are collected in Table 4.
The polarity values of all transition states are of the same order,
although TS 2 (corresponding to a [4þ2] cycloaddition) is more
polar (11.74 D) and less polarizable than TS 3 (11.04 D) and TS 4
(11.06 D), both of which correspond to hetero Diels–Alder re-
actions. In pericyclic reactions such as Diels–Alder or [3,3]
Experimentally only compound 16 was observed and the
product of a Diels–Alder or hetero [4þ2] cycloaddition was not
detected. In order to justify this result, all possible reaction paths at
the B3LYP(PCM)/6-31 G
level were computed using benzene as
*
solvent. The activation energies are given in Table 5.
The activation energy for mechanism 1 is 4 kcal/mol lower than
that of the Diels–Alder cycloaddition and 5 kcal/mol lower than
that of the possible hetero [4þ2] process.
The main features of the transition structures in the reaction
between 4-nitropyrazole 15 and cyclohexadiene 2 are shown in
Figure 3.
Mechanism 1
R
R
R
NO2
N
N
N
H
+
H
N
H
N
H
N
H
N
N
H
H
H
H
H
H
H
H
15 R = NO2
2
H
18 R = H
H
TS 6
16
TS 5 R = NO2
TS 7 R = H
Mechanism 2
NO2
NO2
N
N
N
N
NO2
O2N
O2N
N
N
H
N
N
N
+
H
H
H
N
H
19
20
2
H
H
TS 8
TS 9
Scheme 6.

M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
5333
Table 7
Dipole moments (
(
m
, D), hardnesses (
h
, eV) and average polarizability volumes
a0av, Bohr3) of ground and transition structures. Polarity increases from ground to
transition states (Dm, D)
Entry
m
a0av
65.38
60.80
41.60
h
Dm
1
2
3
4
5
6
7
8
9
2
15
18
19
TS 5
TS 6
TS 7
TS 8
TS 9
1.003
5.472
2.626
0.1017
0.1460
0.1090
0.0926
0.0563
0.0834
0.0524
0.0317
0.0385
8.647
61.26
14.967
10.396
4.711
15.245
10.310
169.86
148.34
132.98
173.14
157.20
8.49
1.08
5.59
pKa values (pKa¼14.21 and 14.4, respectively) than 4-nitropyrazole
15 (pKa¼9.64). The main features of the transition structures for
these reactions are shown in Figure 4 and the activation energies in
solution are given in Table 6.
Figure 3. Main features of transition structures calculated at the B3LYP(PCM)/6-
31G ZPVE level of theory for the reaction between 4-nitropyrazole 15 and cyclo-
hexadiene 2.
*
þD
Reaction with pyrazole 18 is again concerted. However, only
one asynchronous TS was detected (TS 7)din contrast to 4-
nitropyrazole 15, where two synchronous and product-like TSs
were detected. The reaction with 4-nitroimidazole 19 again has
two TSs, one for the protonation of cyclohexadiene 2 (TS 8) and
a second for the nucleophilic attack of the imidazole anion (TS 9).
However, the 1,3-disposition of the nitrogen atoms in the imid-
azole ring prevents the occurrence of a concerted mechanism and
a stepwise mechanism is detected in the reaction with 4-nitro-
imidazole 19.
The calculated values of the activation barriers (Table 6) are very
high in both cases (40.4 and 35.3 kcal/mol), in contrast to those
calculated for the reaction of 4-nitropyrazole (29.5 kcal/mol).
The polarity, hardness and polarizability of all saddle points
were calculated and compared with those of the starting materials.
The results are collected in Table 7.
As expected for the proposed mechanism, there is an in-
crease in the polarity from the starting material to the TS.
Considering the polarities of transition structures, TS 7 (which
corresponds to a concerted mechanism) is less polar (4.7 D)
(Table 7, entry 7) than transition structures that correspond to
stepwise mechanisms (TS 5, TS 6, TS 8 and TS 9) (Table 7, en-
tries 5, 6, 8 and 9).
However, regardless of the polarity of the TS, only the reaction of
4-nitropyrazole 15 actually occurs. These results are in agreement
with a thermal effect and with our calculations,33 showing that
under microwave heating reactions with high activation energies
(29.5 kcal/mol) can be successfully performed. However, when the
activation energies are above 30 kcal/mol the processes do not
occur.
It is remarkable that the reaction between 4-nitropyrazole 15
and cyclohexadiene 2 afforded 80% of 16 under microwave irradi-
ation while only 5% of the addition product was obtained under
conventional heating.
The theoretical results are therefore in good agreement with the
experimental ones and they are compatible with the exclusive
formation of 16.
Figure 4. Main features of transition structures calculated at the B3LYP(PCM)/6-
31G
*
DZPVE level for the reactions of pyrazole 18 and 4-nitroimidazole 19 with
cyclohexadiene 2.
þ
Transition structures TS 5 and TS 6 are highly organized, with
both nitrogen atoms involved in the proton transfer and identical
N/H distances in TS 5 and N/C distances in TS 6. In the same way,
the imaginary frequency of TS 6 corresponds to the nucleophilic
attack of both nitrogen atoms to the allyl system of the cyclo-
hexadienyl fragment. Once again, both critical distances are equal
(2.31 Å). Recently, Dalko et al.32 described how the exceptional
enantioselectivity of proline-mediated reactions can be rational-
ized by the capacity of this molecule to promote the formation of
highly organized transition states.
A product was not observed when pyrazole 18 or 4-nitro-
imidazole 19 were used (Scheme 4), despite these having higher
4. Conclusion
Table 6
In conclusion, we have shown that under microwave irradiation
the cycloaddition reactions of nitroindoles and nitropyrroles in
solvent-free conditions give good yields of the aromatic carbazoles
and indoles, respectively, through elimination of the nitro group
and subsequent aromatization. The mechanism and stereo-
selectivity of the cycloaddition of indole 1 with cyclopentadiene 5
were determined by computational methods and these indicate
Energy barriers (DEa, kcal/mol) of transition structures indicated in Figures 3 and 4
computed at the B3LYP(PCM)/6-31G
*
þDZPVE level
Compound
D
Ea (kcal/mol)
Pyrazole 18
4-Nitroimidazole 19
4-Nitropyrazole 15
40.4
35.3
29.5

5334
M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
that the reaction takes place through a tandem hetero [4þ2] cy-
cloaddition/[3,3] sigmatropic shift. This mechanism gives the endo
stereoisomer.
The reaction of 4-nitropyrazole 15 with cyclohexadiene 2 gave
1-cyclohexen-2-ylpyrazole 16 as the product. The mechanism of
this reaction was also elucidated by computational methods. In this
case, after hydrolysis of the tosyl group, the mechanism involves
protonation of cyclohexadiene 5, followed by nucleophilic attack of
the anionic pyrazolyl group through a concerted mechanism.
Reactions were greatly improved under microwave irradiation.
5.1.2. Diels–Alder reactions of N-substituted indoles as dienophiles:
general procedure
A mixture of 3-nitro-1-(p-toluenesulfonyl)indole 1 and the di-
ene was submitted to microwave irradiation in a closed flask (for
reaction conditions see Table 1). Crude products were purified by
column chromatography on silica gel and analyzed by 1H NMR
spectroscopy.
5.1.2.1. Reaction of 3-nitro-1-(p-toluenesulfonyl)indole 1 with 1,3-
cyclohexadiene 2. In the absence of catalyst. In a similar way to the
general procedure, a mixture of indole 1 (0.16 g, 0.5 mmol) and 1,3-
cyclohexadiene 2 (0.48 g, 6 mmol) was submitted to microwave
irradiation. The pure product was obtained as a white solid by
column chromatography on silica gel using hexane/ethyl acetate
(13:1) as the eluent. Yields were determined by 1H NMR by in-
5. Experimental section
5.1. General
Microwave irradiations were performed in a CEM Discover mi-
crowave reactor in standard closed vessels. Temperature was
monitored during the reaction by the standard IR pyrometer in-
cluded in the microwave reactor. Analysis by thin layer chroma-
tography was performed on aluminium oxide 60 F254 and
separations by column chromatography were carried out on silica
gel type 60 (0.040–0.063 mm).
tegration of the 1-H signal of 9-p-toluenesulfonylcarbazole 7 (d
4.93 ppm) and using CH2Br2 as internal standard. Mp 129–129.5 ꢁC
(ethanol/water) (lit. 130–133 ꢁC).46 dH (500 MHz, CDCl3) 8.33 (2H, d,
J 8.3, H1, H8), 7.9 (2H, d, J 7.1, H4, H5), 7.7 (2H, d, J 8.3, H20, H60), 7.47
(2H, dd, J 8.3, 7.1, H2, H7), 7.35 (2H, t, J 7.1, H3, H6), 7.08 (2H, d, J 8.3,
H30, H50), 2.25 (s, 3H, CH3). dC (125 MHz, CDCl3) 144.9, 138.4, 135.07,
126.5 (C40, C10, C1a, C8a, C4a, C5a), 129.81 (C30, C50), 127.5 (C2, C7),
126.6 (C20, C60), 123.9 (C4, C5), 120.1 (C3, C6), 115.3 (C1, C8), 21.7
(CH3). HRMS (EI, Mþ) (m/z) calcd for C19H15NSO2: 321.0823. Found:
321.0585.
All NMR spectra were recorded on a 500 MHz spectrometer in
CDCl3 at 298 K and at 499.769 MHz and 125.678 MHz for 1H and 13
C
NMR, respectively. Chemical shifts were referenced to internal TMS
at 0 ppm. Assignment of spectra was carried out using NOESY-1D,
g-COSY and g-HSQC experiments. The NOESY-1D spectra were
recorded with the following acquisition parameters: mixing time
800 ms and number of scans 256. Two-dimensional NMR spectra
were acquired using 4 scans and 128 increments. The pulse pro-
grams were taken from the standard Varian pulse sequence library.
All spectra were Fourier transformed with MestReNova 5.1.0
software.
1,3-Cyclohexadiene 2, 1-methoxy-1,3-cyclohexadiene 3, dicy-
clopentadiene, 4-nitroimidazole 19, pyrazole 18, indole and pyrrole
are commercially available. Commercial 1-methoxy-1,3-cyclo-
hexadiene 3 contains 35% of the isomeric 2-methoxy-1,3-cyclo-
hexadiene 4.
The following compounds were prepared by previously reported
procedures: 1-(p-toluenesulfonyl)indole,4 1-(p-toluenesulfonyl)-3-
nitroindole 1,1 1-(p-toluenesulfonyl) pyrrole,34 3-nitro-1-(p-tolue-
nesulfonyl)pyrrole 11,35 2-nitropyrrole,36 3-nitropyrrole,36 2-nitro-
1-(p-toluenesulfonyl)pyrrole,37 4-nitropyrazole 15,38 4-nitro-1-(p-
toluenesulfonyl)imidazole,39 N-2-butenylideneisopropylamine,40
1-(N-acetyl-N-isopropylamino)-1,3-butadiene 6.41 Cyclopentadiene
5 was prepared from dicyclopentadiene by cracking. In a round-
bottomed flask dicyclopentadiene was heated and fractionally dis-
tilled. The fraction boiling at 39 ꢁC was collected and used fresh.
Silica-supported Lewis acids [Si(Al), Si(Ti) and Si(Zn)]. The cat-
alysts were obtained by treatment of silica with ZnCl2 [Si(Zn)],42
Et2AlCl [Si(Al)],43 or TiCl4 [Si(Ti)].44
In the presence of catalyst. In a similar way to the general pro-
cedure, 3-nitro-1-(p-toluenesulfonyl)indole 1 (0.126 g, 0.39 mmol),
cyclohexadiene 2 (0.38 g, 4.74 mmol) and silica-supported Lewis
acid [Si (Ti) and Si (Zn)] (0.25 g) were used. The crude product was
extracted with CH2Cl2 and the catalyst was separated by filtration.
5.1.2.2. Reaction of 3-nitro-1-(p-toluenesulfonyl)indole 1 with 1-
methoxy-1,3-cyclohexadiene
4. In the absence of catalyst. In a similar way to the general pro-
cedure using 3-nitro-1-(p-toluenesulfonyl)indole (0.158 g,
3 and 2-methoxy-1,3-cyclohexadiene
1
0.5 mmol) and a 65:35 mixture of 1-methoxy-1,3-cyclohexadiene 3
and 2-methoxy-1,3-cyclohexadiene 4 (0.66 g, 6 mmol). The crude
product was purified by column chromatography on silica gel using
hexane/ethyl acetate (9:1) as the eluent to give an inseparable
mixture of 4-methoxy-9-p-toluenesulfonylcarbazole
8 and 2-
methoxy-9-p-toluenesulfonylcarbazole 9 as an oil. Yields were
determined by 1H NMR by integration of the –OCH3 signal (
d
3.99 ppm) and using CH2Br2 as internal standard. HRMS (EI, Mþ)
(m/z) calcd for C20H17NSO3: 351.0929. Found: 351.0946.
Data for 8: dH (500 MHz, CDCl3) 8.32 (1H, d, J 8.3, H8), 8.22 (1H,
d, J 7.8, H5), 7.95 (1H, d, J 7.8, H1), 7.68 (2H, d, J 8.3, H20, H60), 7.46–
7.43 (1H, m, H7), 7.42–7.40 (1H, m, H2), 7.38–7.36 (1H, m, H6), 7.06
(2H, d, J 7.8, H30, H50), 6.8 (1H, d, J 8.3, H3), 4.00 (3H, s, OCH3), 2.23
(3H, s, CH3). dC (125 MHz, CDCl3) 155.7, 144.7, 139.5, 137.6, 134.9,
125.6, 115.4 (C1a, C4a, C5a, C8a, C4, C10, C40), 129.7 (C30, C50), 128.0
(C2), 126.9 (C20, C60), 126.5 (C6), 126.5 (C7), 123.5 (C5), 114.9 (C8),
108.0 (C1), 106.0 (C3), 55.5 (OCH3), 22.0 (CH3).
5.1.1. 4-Nitro-1-(p-toluenesulfonyl)pyrazole 13
Data for 9: dH (500 MHz, CDCl3) 8.26 (1H, d, J 8.3, H8), 7.88 (1H,
d, J 2.4, H1), 7.78 (1H, d, J 7.8, H5), 7.74 (1H, d, J 8.8, H4), 7.68 (2H, d, J
8.3, H20, H60), 7.39–7.37 (1H, m, H7), 7.31–7.29 (1H, m, H6), 7.08 (2H,
d, J 8.3, H30, H50), 6.94 (1H, dd, J 2.4, 8.8, H3), 3.95 (3H, s, OCH3), 2.25
(3H, s, CH3). dC (125 MHz, CDCl3) 159.7, 144.8, 139.6, 138.3, 134.8,
126.4, 120.5, (C1a, C4a, C5a, C8a, C2, C10, C40), 129.7 (C30, C50), 126.9
(C20, C60, C7), 124.8 (C6), 121.0 (4C), 119.7 (C5), 114.8 (C8), 112.9 (C3),
100.0 (C1), 56.0 (OCH3), 22.0 (CH3).
In a round-bottomed flask potassium tert-butoxide (0.79 g,
7.0 mmol), 4-nitropyrazole (0.8 g, 7.0 mmol) and two drops of
water were stirred at 20 ꢁC for 45 min. Tetrabutylammonium bro-
mide (TBAB) (0.23 g, 0.7 mmol) and p-toluenesulfonyl chloride
(1.3 g, 7.0 mmol) were added and stirring was continued at 20 ꢁC
for 24 h. Chloroform (50 ml) was added and the mixture was fil-
tered. The filtrate was purified by column chromatography on silica
gel using hexane/ethyl acetate (5:1) as the eluent to give 1.31 g of 13
(70%) as a white solid. Mp 116–117 ꢁC (ethanol).45 dH (500 MHz,
DMSO-d6) 7.93 (2H, s, H3, H5), 7.5 (2H, d, J 7.8, H20, H60), 7.1 (2H, d, J
7.8, 30-H, 50-H), 2.49 (s, 3H, CH3). dC (125 MHz, DMSO-d6) 147.5 (C40),
139.6 (C3), 136.8 (C10), 136.7 (C4), 131.5 (C5), 130.5 (C30, C50), 128.5
(C20, C60), 21.1 (CH3).
5.1.2.3. Reaction of 3-nitro-1-(p-toluenesulfonyl)indole
1
with
cyclopentadiene 5. Following the general procedure from indole 1
(0.16 g, 0.5 mmol) and cyclopentadiene 5 (0.5 ml, 6 mmol). The
crude product was purified by column chromatography on silica
gel using hexane/ethyl acetate (9:1) as the eluent. Yields of

M.V. Go´mez et al. / Tetrahedron 65 (2009) 5328–5336
5335
carbazole 10 were determined by 1H NMR by integration of the 2-
H signal ( 6.4 ppm) using CH2Br2 as internal standard. Mp 141–
Supplementary data
d
143 ꢁC (hexane/ethyl acetate). dH (500 MHz, CDCl3) 7.73–7.68 (1H,
m, H5), 7.70 (2H, d, J 8.5, H20, H60), 7.41–7.38 (1H, m, H6), 7.37–7.34
(1H, m, H8), 7.2 (2H, d, J 8.5, H30, H50), 7.1 (1H, pseudo t, J 7.55, H7),
6.42–6.39 (1H, m, H2), 6.22–6.19 (1H, m, H3), 4.77–4.76 (1H, m,
H9a), 3.50 (2H, br s, H1, H4), 2.35 (3H, s, CH3), 1.75–1.72 (1H, m,
H10b), 1.50 (1H, d, J 10, H10a). dC (125 MHz, CDCl3) 145.0, 144.7,
133.4, 127.1, 102.7 (C4a, C5a, C8a, C10, C40), 138.0 (C2), 136.0 (C3),
132.2 (C8), 129.8 (C30, C50), 127.6 (C20, C60), 124.4 (C7), 123.8 (C6),
115.8 (C5), 72.0 (C9a), 52.0 (C1), 51.0 (C4), 44.0 (C10), 22.0 (CH3).
HRMS (EI, Mþ) (m/z) calcd for C20H18N2SO4: 382.0987. Found:
382.1077.
NMR spectra of compounds 7, 8, 9, 10, 12 and 16. Total electronic
energies, zero-point correction of energies and number of imagi-
nary frequencies of all stationary points. Cartesian coordinates of all
the stationary points. Supplementary data associated with this ar-
ticle can be found in the online version, at doi:10.1016/
j.tet.2009.04.065.
References and notes
1. Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc. 1988, 110, 7188–7194.
2. Biolatto, B.; Kneeteman, M.; Mancini, P. Tetrahedron Lett. 1999, 40, 3343–3346.
3. Biolatto, B.; Kneeteman, M.; Mancini, P. M. Molecules 2000, 5, 393–395.
4. (a) Lee, L.; Snyder, J. K. Adv. Cycloaddit. 1999, 6, 119–171; (b) Hsieh, M.-F.; Rao, P.
D.; Liao, C.-C. Chem. Commun. 1999, 1441–1442; (c) Benson, S. C.; Lee, L.; Yang,
L.; Snyder, J. K. Tetrahedron 2000, 56, 1165–1180; (d) Padwa, A.; Brodney, M. A.;
Dimitroff, M. J. Org. Chem. 1998, 63, 5304–5305.
5. (a) Kraus, G. A.; Zhang, N.; Melekhow, A.; Jensen, J. H. Synlett 2001, 521–522; (b)
Kishbaugh, T. L. S.; Gribble, G. W. Tetrahedron Lett. 2001, 42, 4783–4795.
6. (a) Pelkey, E. T.; Gribble, G. W. Chem. Commun. 1997, 1873–1874; (b) Gribble,
G. W.; Pelkey, E. T.; Simon, W. M.; Trujillo, H. A. Tetrahedron 2000, 56,
10133–10140.
5.1.2.4. Reaction of 3-nitro-1-(p-toluenesulfonyl)indole 1 with N-
acetyl-N-isopropyl-1,3-butadiene 6. Indole 1 (0.237 g, 0.75 mmol)
and diene 6 (1.376 g, 9 mmol) were submitted to microwave irra-
diation in a closed vessel at 100 ꢁC for 5 min. The crude product was
purified by column chromatography on silica gel using hexane/
ethyl acetate (13:1) as the eluent, to give carbazole 7 in 71% yield.
7. (a) Le Noble, W.; Kelm, H. Angew. Chem. 1980, 19, 841–856; (b) Matsumoto, K.;
Sera, A.; Uchida, T. Synthesis 1985, 1–26; (c) Isaacs, N. Tetrahedron 1991, 47,
8463–8497; (d) Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P. M. E. J. Org.
Chem. 2001, 66, 3906–3912; (e) Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R.
Org. Lett. 2001, 3, 515–518.
5.1.3. Diels–Alder reactions of other N-substituted heterocycles as
dienophiles: general procedure
A mixture of the corresponding N-substituted heterocycle and
the appropriate diene was submitted to microwave irradiation for
the appropriate time.
´
8. (a) Chretien, A.; Chataigner, I.; Piettre, S. R. Chem. Commun. 2005, 1351–1353;
(b) Chre´tien, A.; Chataigner, I.; Piettre, S. R. Tetrahedron 2005, 61, 7907–7915.
9. (a) Bose, A. K.; Manhas, M. J.; Banik, B. K.; Robb, E. W. Res. Chem. Intermed. 1994,
20, 1–11; (b) Caddick, S. Tetrahedron 1995, 52, 10403–10432; (c) Galema, S. A.
Chem. Soc. Rev. 1997, 25, 233–238; (d) Lidstro¨m, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225–9283; (e) Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250–6284; (f) Hayes, B. L. Aldrichimica Acta 2004, 37, 66–77.
10. (a) Microwaves in Organic Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley-VCH:
Weinheim, 2006; (b) Hayes, B. L. In Microwave Synthesis: Chemistry at the Speed
of Light; CEM: Matthews, NC, 2002; (c) Microwave-Assisted Organic Synthesis;
Lidsto¨m, P., Tierney, J. P., Eds.; Blackwell Scientific: Oxford, 2005; (d) Kappe, C.
O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry. In Methods and
Principles in Medicinal Chemistry; Mannhold, R., Kubinyi, H., Folkers, G., Eds.;
Wiley: Weinheim, 2005; Vol. 25.
5.1.3.1. Reaction of 3-nitro-1-(p-toluenesulfonyl)pyrrole 11 with N-
acetyl-N-isopropylamine-1,3-butadiene 6. Pyrrole 11 (0.199 g,
0.75 mmol) and diene 6 (0.688 g, 4.5 mmol) were submitted to
microwave irradiation (50 W) in a closed vessel at 100 ꢁC for 5 min.
The crude product was purified by column chromatography using
hexane/ethyl acetate (25:1) as the eluent to give N-(p-toluene-
sulfonyl)indole 12 as a white solid. Yields were determined by 1H
NMR by integration of the 3-H signal (d 6.65 ppm) using CH2Br2 as
´
11. (a) de la Hoz, A.; Dıaz-Ortiz, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem. 2000,
internal standard. Mp 78–80 ꢁC (dichloromethane/hexane). dH
(500 MHz, CDCl3) 7.99 (1H, d, J 8.3, H7), 7.75 (2H, d, J 8.5, H20, H60),
7.56 (1H, d, J 0.7, H2), 7.52 (1H, d, J 7.8, H4), 7.30 (1H, dd, J 7.4, 8.3,
H6), 7.25 (1H, dd, J 7.8, 7.4, H5), 7.20 (1H, d, J 8.5, H30, H50), 6.65 (1H,
d, J 0.7, H3), 2.33 (3H, s, CH3). dC (125 MHz, CDCl3) 145.0, 135.3,
134.7, 130.7 (C40, C10, C3a, C8a), 129.8 (C30, C50), 126.7 (C20, C60),
126.2 (C2), 124.6 (C6), 123.2 (C4), 121.3 (C5), 113.9 (C7), 108.9 (C3),
21.5 (CH3). MS (EI) m/z: 271 (Mþ).
3659–3673; (b) de la Hoz, A.; Dı´az-Ortiz, A.; Moreno, A.; Langa, F. In Microwaves
in Cycloadditions in Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, 2002; Chapter 9; (c) Bougrin, K.; Soufiaoui, M.; Bashiardes, G. In
Microwaves in Cycloadditions in Microwaves in Organic Synthesis, 2nd ed.; Loupy,
A., Ed.; Wiley-VCH: Weinheim, 2006, Chapter 11.
12. (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223; (b) de la Hoz, A.;
Dı´az-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 168–178.
13. (a) Raner, K. D.; Strauss, C. R.; Vyskoc, F.; Mokbel, L. J. Org. Chem. 1993, 58, 950–
953; (b) Stuerga, D. In Microwave-Material Interactions and Dielectric Properties,
Key Ingredients for Mastery of Chemical Processes in Microwaves in Organic
Synthesis, 2nd ed.; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2006; Chapter 1; (c)
Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 36–47.
14. Dı´az-Ortiz, A.; de la Hoz, A.; Moreno, A. Curr. Org. Chem. 2004, 8, 903–918;
Langa, F.; de la Cruz, P.; de la Hoz, A.; Dı´az-Ortiz, A.; Dı´ez-Barra, E. Contemp. Org.
Synth. 1997, 4, 373–386.
5.1.3.2. Reaction of 4-nitropyrazole 15 and 4-nitro-1-(p-toluene-
sulfonyl)pyrazole 13 with 1,3-cyclohexadiene 2. Pyrazole 13 or 15
(0.88 mmol) and 1,3-cyclohexadiene 2 (0.07 g, 0.88 mmol) were
submitted to microwave irradiation (50 W) in a closed vessel at
15. (a) de la Hoz, A.; Dı´az-Ortiz, A.; Fraile, J. M.; Go´mez, M. V.; Mayoral, J. A.;
´
´
Moreno, A.; Saiz, A.; Vazquez, E. Synlett 2001, 753–757; (b) Dıaz-Ortiz, A.; Fraile,
J. M.; de la Hoz, A.; Go´ mez, M. A.; Mayoral, J. A.; Moreno, A.; Prieto, P.; Salva-
tella, L.; Saiz, A.; Va´zquez, E. Eur. J. Org. Chem. 2001, 2891–2899; (c) Moreno, A.;
Go´ mez, M. V.; Va´zquez, E.; de la Hoz, A.; Dı´az-Ortiz, A.; Prieto, P.; Mayoral, J. A.;
Pires, E. Synlett 2004, 1259–1263.
100 ꢁC for 15 min. Yields of 1-cyclohexen-3-ylpyrazole 16 were
1
determined by H NMR by integration of the H10 signal (
d
4.91 ppm) using CH3NO2 as internal standard. Mp 57.5–59.8 ꢁC
(hexane). dH (500 MHz, CDCl3) 8.19 (1H, s, H3), 8.10 (1H, s, H5),
6.25–6.22 (1H, m, H30), 5.83–5.80 (1H, m, H20), 4.91 (1H, br s, H10),
2.26–2.17 (2H, m, CH240), 2.15–1.99 (2H, m, CH260), 1.77–1.55 (2H,
m, CH250). dC (125 MHz, CDCl3) 135.9 (C3), 135.3 (C5), 127.4 (C30),
124.0 (C4), 122.9 (C20), 58.2 (C10), 29.7 (C40), 24.7 (C60), 18.5 (C50).
HRMS (EI, Mþ) (m/z) calcd for C9H11N3O2: 193.0851. Found:
193.0703.
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Acknowledgements
Financial support from the DGICYT of Spain through project
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CTQ2007-60037/BQU and from the Consejerıa de Ciencia y Tecno-
´
logıa JCCM through projects PBI-06-0020 and PCI-08-0040 is
gratefully acknowledged. M.V.G. acknowledges the Ministerio de
Educacion y Ciencia for financial support.
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