Dual synthesis of 1H-[1,2,4]triazolo[3,4-a]isoindoles and new 1H-[1,2,4]triazolo[5,1-a]isoindoles - Experimental and theoretical approaches

Article abstract of DOI:10.1002/1099-0690(200104)2001:7<1407::aid-ejoc1407>3.0.co;2-n

The syntheses and characterization of 4-substituted 4H-[1,2,4]triazol-1-ium phenylmethylides 8c-e and the new 5-aryl-1-phenacyl-1H-[1,2,4]triazolo[5,1-a]isoindole core 13 are reported for the first time. Treatment of triazolium salts 6c-e with triethylami

Full text of DOI:10.1002/1099-0690(200104)2001:7<1407::aid-ejoc1407>3.0.co;2-n

FULL PAPER
Dual Synthesis of 1H-[1,2,4]Triazolo[3,4-a]isoindoles and New 1H-
[1,2,4]Triazolo[5,1-a]isoindoles ؊ Experimental and Theoretical Approaches
Patrice Woisel,*[a] Gheorghe Surpateanu,[a] Franc¸ois Delattre,[a] and Marc Bria[b]
Keywords: Cyclizations / Isoindoles / Salts / Semiempirical calculations / Ylides
The syntheses and characterization of 4-substituted 4H-
[1,2,4]triazol-1-ium phenylmethylides 8c−e and the new 5-
aryl-1-phenacyl-1H-[1,2,4]triazolo[5,1-a]isoindole core 13
are reported for the first time. Treatment of triazolium salts
and 8c−e. Intramolecular annulation of the latter in DMSO
resulted in the formation of 1H-[1,2,4]triazolo[3,4-a]isoindole
and 1H-[1,2,4]triazolo[5,1-a]isoindole derivatives, respect-
ively . In order to explain this unusual chemical behavior, a
6c−e with triethylamine in the presence of picryl chloride re- theoretical approach, using AM1 and PM3 procedure
sulted in a regioselective mixture of disubstituted ylides 7c−e
methods, is also presented.
Introduction
[1,2,4]-triazolo[5,1-a]isoindole (4) and 1H-[1,2,4]-tria-
zolo[3,4-a]isoindole (5) derivatives, respectively.
The synthetic utility of heterocyclic mesomeric betaine 1
is widely recognized[1Ϫ3] For example, it is well known that
the monosubstituted ylide 1 is able to take part in 1,3-di-
polar cycloadditions with a large variety of dipolarophile
compounds, which is a traditional way to form five-mem-
bered fused heterocycles 2 (Scheme 1). The reaction of this
class of compounds with strong electrophiles such as picryl
chloride[4Ϫ11] has also been described and used in particular
to trap the reactive species 1.
This procedure provided a good method for preparation
of these unusual frameworks. However, when this experi-
ment was carried out with different substitution patterns
(6cϪe) with R2 ϭ Br, OCH3 and NO2 in the 1,2,4-triazole
series, the course of the reaction changed slightly. Surpris-
ingly, two isomeric forms of disubstituted ylides 7 and 8
were detected (Scheme 2).
Thus, in the light of the experimental findings described
above, it was possible to envisage two concomitant ways by
which isomeric isoindole cores might be synthesized. In this
paper, the synthesis of triazolium salts 6cϪe and their
chemical behavior under basic conditions are reported. The
synthesis of triazol-1-ium phenylmethylides 8cϪe and 1-
substituted 5-aryl-1H-[1,2,4]triazolo[5,1-a]isoindoles is also
described for the first time. Additionally, in order to explain
the observed regioselectivities, a theoretical approach using
AM1 and PM3 calculations is reported.
Scheme 1. Reactivity of the monosubstituted ylides
As a part of our research program on the reactivity of
disubstituted ylides 3 and their application in the synthesis
of aza-fused heterocycles, we have recently reported the syn-
thesis of 4-subsituted 4H-[1,2,4]triazol-1-ium[12] and 1 sub-
stituted-1H-[1,2,4]triazol-4-ium 2,4,6-trinitrophenylmethyl-
ide[13] derivatives. These species underwent intramolecular
annulation in moderate to good yields to form the 1H-
Results and Discussion
[a]
`
Laboratoire de Synthese Organique et Environnement, EA
2599, MREID,
The required salts 6cϪe were easily prepared in two steps
from the available 1H-[1,2,4]triazole 9 (Scheme 3). Treat-
ment of 1H-[1,2,4]triazole 9 with sodium in ethanol, fol-
lowed by the addition of benzyl bromide, produced a separ-
able 90:10 mixture of 1-benzyl[1,2,4]triazole and 1-benzyl-
[1,3,4]triazole.[14] The 1-benzyl[1,2,4]triazole derivative 10
145 rue Maurice Schumann, 59140 Dunkerque, France
Fax: (internat.) ϩ 33-3/28658254
E-mail: woisel@univ-littoral.fr
Laboratoire de Chimie Oganique Physique, URA CNRS No.
351, USTL,
59655 Villeneuve d’Ascq Cedex
E-mail: bria@pop.univ-lille1.fr
[b]
´
Eur. J. Org. Chem. 2001, 1407Ϫ1412
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0407Ϫ1407 $ 17.50ϩ.50/0
1407

P. Woisel, G. Surpateanu, F. Delattre, M. Bria
FULL PAPER
ylides 6 and 7 were unambiguously established by 1H NMR
1
spectroscopy of the crude product. The H NMR spectro-
scopic data clearly indicate the disappearance of one
methylene group in each isomer compound and the pres-
ence of two downfield singlets, appearing at δ ഠ 8.6, corres-
ponding to the two magnetically equivalent CH units in the
nitroaromatic moiety.
In the mass spectra, moreover, a unique molecular peak
was detected in each mixture of disubstituted ylides. The
ratios of the N1 and N4 isomer ylides in the isomeric mix-
tures were estimated from the relative intensities of the re-
maining methylenic protons. The data are reported in
Table 1.
Table 1. Salts 6cϪe, disubstituted ylides 7cϪe and 8cϪe and isoin-
dole derivatives 12cϪe and 13c-e
Compound
Yield [%]
Ratio[a] of crude
mixture 7/8 [%]
6c
6d
76
47
75
80
61
78
76
68
54
82
78
67
Ϫ
Ϫ
Ϫ
72:28
73:27
87:13
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
6e
7c, 8c
7d, 8d
7e, 8e
12c
Scheme 2. Reaction between the 1,2,4-triazolium salts and picryl
chloride
12d
12e
was then treated with commercial 4-substituted 2-bro-
moacetophenones 11cϪe to produce the corresponding 1-
benzyl-2-(4-substituted phenacyl)[1,2,4]triazolium bromides
6cϪe exclusively. This synthesis is also known as the ‘‘salt
method’’.[15,16]
13c
13d
13e
Ϫ
[a]
1
Isomer ratio based on H NMR analysis of product mixture.
Next, each mixture of ylides 7 and 8 was dissolved in
dimethyl sulfoxide (DMSO) and treated with piperidine at
room temperature to afford, as expected, a mixture of the
cycloadducts 12cϪe and 13cϪe. Every compound of type
12cϪe and 13cϪe was separated by flash chromatography
(Scheme 4).
Scheme 3. Preparation of the disubstituted ylides
1
All quaternized products were characterized by H and
13C NMR spectroscopy. In all cases, N1ϪCH2Ph and
ϩN4ϪCH2C(O) signals were observed as a singlet in the
chemical shift range from δ ϭ 4.5 to 6.13, while 13C NMR
spectra showed the CϭO resonance at δ ഠ 188.
When the unsymmetrical triazolium salts 6cϪe, dissolved
in chloroform at room temperature, were treated with trie-
thylamine (2 equiv.) as base in the presence of picryl chlor-
Scheme 4. Isoindole derivatives
In the intramolecular condensation of species 7 and 8,
ide, a mixture of two isomeric ylides 7cϪe and 8cϪe was the primary cycloadducts 14cϪe and 15cϪe were not usu-
obtained. Experimentally, in order to avoid the decomposi- ally isolable, because nitrous acid was easily eliminated, giv-
tion of the ylides by cleavage of the NϩϪCϪ bond, all ylide ing the corresponding, highly conjugated products 12cϪe
syntheses were performed in the absence of light. Disap- and 13cϪe. The structures of compounds 12cϪe and 13cϪe
pointingly, all attempts to isolate isomers 7 and 8 failed. were supported by NMR spectroscopic (1H, 13C), and
Nevertheless, the structure assignments of the disubstituted CHN elemental analysis. The signals of the methylene pro-
1408
Eur. J. Org. Chem. 2001, 1407Ϫ1412

1H-[1,2,4]Triazolo[3,4-a]isoindoles and 1H-[1,2,4]Triazolo[5,1-a]isoindoles
FULL PAPER
tons of compounds 12 and 13 appeared in the region δ ϭ most stable conformer, a multi-pass sequential search, in-
5.82Ϫ6.10 (and 9.20Ϫ9.70 for the remaining proton in the volving all five single bonds in the backbone, was de-
triazole ring) and, in the 13C NMR spectra the correspond- veloped. The energy minimization techniques employed
ing methylene carbon resonated in the region δ ϭ 49Ϫ54 were (i) the steepest descent for the initial minimization and
(and between δ ϭ 182.4 and 180.2 for the CϭO group) . for the relaxation of the starting geometry (maximum 300
Nevertheless, there were no large chemical shift differences steps), (ii) the conjugate gradient technique for the final re-
between compounds 12 and 13. Thus, in order to confirm fined minimization. Each structure was optimized until the
the assignment of the signals of each compound, we de- energy change was less than 0.001 kcal/mol. The rotational
veloped a GATEDEC[17,18] sequence. The result of this ex- increment was 15°. Finally, every most stable conformer ob-
periment clearly showed a singlet and a triplet (J ϭ 4.2 Hz) tained by the MM3 method was subjected to a new geo-
for the CϭO group, and these were attributed to 12 and metry optimization by AM1 and PM3 procedures. The se-
13, respectively.
lection of the most stable conformer was performed by ∆H
(heat of formation, kcal/mol) in MM3 and by ET (Total
Energy) in the AM1 and PM3 procedure methods. The nu-
merical data in the AM1 and PM3 methods were recorded
by single point calculations.
Theoretical Study
As regards the chemical mechanism of the synthesis of
the isoindole derivatives 12cϪe and 13cϪe, only the forma-
tion of two tautomeric or isomeric ylides 16cϪe and 17cϪe
as intermediate products can explain this conversion
(Scheme 5).
Theoretical Results
Table 2 lists some representative geometrical data of the
monosubstituted triazolium ylides 16aϪe and 17aϪe, ob-
tained by the AM1 and PM3 methods. Triazolium salts are
normally considered as flexible molecules as regards the
single bonds in the backbone.
In every pair of tautomeric ylides, the calculated ylide
bond NϩϪCϪ, calculated by either of the AM1 and PM3
methods, is longer for 16 than for 17. Taking into account
the values of valence carbon atoms C6 and C14
(N4ϪC6ϪC7, N4ϪC6ϪH21 and H21ϪC6ϪC7 in ylides 16
and N1ϪC14ϪC15, N1ϪC14ϪH22 and H22ϪC14ϪC15
in ylides 17), we may suppose that the configuration of all
the ylidic carbon atoms is close to an sp2 hybridization. The
values of the dihedral angles N4ϪC6ϪC7ϪC8 in ylides 16
and N2ϪN1ϪC14ϪC15 in ylides 17 suggest a planar struc-
ture for the triazolium ring and the carbanion as the most
stable conformer. Indeed, this theoretical result is in a good
agreement with other previously published data[24] con-
cerning the structure of monosubstituted cycloimmonium
ylides.
The atomic charges of the hydrogen atoms in both
methylenic groups of the salts 6aϪe are depicted in Table 3.
In fact, no significant difference in the charges calculated
by the same method could be observed. From the theoret-
ical point of view, this would mean that the two tautomeric
ylides 16 and 17 should be obtained with the same degree
of probability. At first sight, such a result may appear ex-
tremely surprising, taking the nature of the two methylenic
groups into consideration: One is a benzylic type, while the
other is bonded to a benzoyl group. On the other hand, the
presence of a second nitrogen atom in position β to the
benzylic methylene group may be considered as a good ex-
Scheme 5. Reactivity of the triazolium salts
Thus, from a theoretical point of view, in order to explain
the regioselectivity observed, it is very important to estim-
ate the difference in mobilities of the corresponding two
types of protons; that is, those bonded to C6 and C14 in
salts 6aϪe. Afterwards, each monosubstituted triazolium
ylide can react independently with picryl chloride to form
the corresponding disubstituted triazolium ylides 6cϪe and
7cϪe. This was the reason for extending our theoretical
study on the reactivity of the two types of ylidic carbon
atoms C6 and C14.
Materials and Methods
Our study was based on molecular mechanics, the MM3 planation of this theoretical result. This is why a theoretical
and semiemperical, AM1[19] and PM3[20Ϫ22] procedure treatment of the monosubstituted triazolium ylides 16 and
methods, using Cache on a Power PC 9600/200 and a PC 17 may produce some supplementary knowledge on the re-
Computer. In this paper, we focused on the 1,2,4-triazolium activity of these molecular systems.
salts 6aϪe and the corresponding monosubstituted 1,2,4-
triazol-1-ium ylides 16aϪe and 17aϪe.
The values of the total energies given in Table 4 show
that, thermodynamically, the formation of the phenacylyl-
Firstly, all structures were subjected to geometry optim- ides 16 is preferred over that of the corresponding benzylyl-
ization by the MM3[23] method. Then, in order to find the ides 17. The reaction of ylides 16 or 17 with picryl chloride
Eur. J. Org. Chem. 2001, 1407Ϫ1412
1409

P. Woisel, G. Surpateanu, F. Delattre, M. Bria
Dihedral angles[b]
FULL PAPER
Table 2. Structural data of the most stable conformers of ylides 16 and 17
Ylide
Method
Distance[a]
Bond angles[b]
NϩϪCϪ
N4ϪC6ϪC7
N4ϪC6ϪH21
N1ϪC14ϪH15
N1ϪC14ϪH22
N2ϪN1ϪC4ϪC5
C5ϪN4ϪC6ϪC7
16a
16b
16c
16d
16e
17a
17b
17c
17d
17e
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
1.358
1.362
1.359
1.361
1.362
1.360
1.360
1.360
1.363
1.365
1.347
1.331
1.347
1.335
1.348
1.334
1.347
1.335
1.334
1.333
122.02
123.16
122.11
123.08
122.31
123.24
122.28
123.02
122.06
122.84
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
115.91
117.25
115.72
117.54
115.68
117.20
116.45
117.33
115.66
117.23
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ0.97
Ϫ0.38
0.47
0.45
0.04
3.82
2.19
Ϫ0.79
1.02
Ϫ3.80
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
126.02
123.89
123.76
122.42
126.17
123.61
125.70
123.71
124.13
121.66
116.38
118.62
117.18
119.67
116.39
118.73
116.50
118.69
117.49
119.81
175.91
178.96
176.83
178.27
175.89
178.40
175.41
177.51
176.94
178.49
Ϫ
Ϫ
Ϫ
[a]
[b]
˚
Distances are expressed in A. Ϫ Angles are expressed in °.
Table 3. The Mulliken atomic charge of hydrogen atoms in methyl-
ene groups of salts 6aϪe
Table 4. Total energy and dipole values of ylides 16 and 17; atomic
orbital coefficient and net atomic charge of C6 (16aϪe) and C14
(17aϪe)
Salt
Method
Charge [ua]
H21
H22
Ylide Method ET [eV] HOMO (Pz) Charge [ua] Dipole [D]
6a
6b
6c
6d
6e
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
AM1
PM3
0.160
0.121
0.163
0.123
0.163
0.122
0.163
0.122
0.169
0.125
0.166
0.120
0.167
0.122
0.167
0.122
0.166
0.121
0.169
0.123
16a
17a
16b
17b
16c
17c
16d
17d
16e
17e
AM1 Ϫ3319.57
PM3 Ϫ3022.53
AM1 Ϫ3318.90
PM3 Ϫ3022.17
AM1 Ϫ3475.40
PM3 Ϫ3172.20
AM1 Ϫ3473.80
PM3 Ϫ3171.90
AM1 Ϫ3659.20
PM3 Ϫ3360.60
AM1 Ϫ3658.50
PM3 Ϫ3360.10
AM1 Ϫ3795.40
PM3 Ϫ3465.40
AM1 Ϫ3794.80
PM3 Ϫ4149.70
AM1 Ϫ4150.50
PM3 Ϫ3753.90
AM1 Ϫ4149.70
PM3 Ϫ3753.40
Ϫ0.730
ϩ0.720
ϩ0.630
ϩ0.616
ϩ0.734
Ϫ0.721
ϩ0.640
ϩ0.628
Ϫ0.740
ϩ0.721
Ϫ0.625
Ϫ0.618
ϩ0.734
Ϫ0.721
ϩ0.628
Ϫ0.618
Ϫ0.739
ϩ0.726
Ϫ0.637
ϩ0.628
Ϫ0.46
Ϫ0.73
Ϫ0.31
Ϫ0.53
Ϫ0.46
Ϫ0.73
Ϫ0.31
Ϫ0.54
Ϫ0.46
Ϫ0.73
Ϫ0.30
Ϫ0.53
Ϫ0.46
Ϫ0.73
Ϫ0.31
Ϫ0.53
Ϫ0.46
Ϫ0.73
Ϫ0.30
Ϫ0.52
4.35
3.77
4.33
4.43
3.99
3.37
5.14
5.30
6.07
5.19
4.11
4.37
3.75
3.25
5.28
5.33
10.41
9.82
4.72
4.99
could be considered as a donor (ylide)Ϫacceptor (picryl
chloride) interaction. Moreover, the total atomic charges
and the absolute atomic coefficient values of the HOMO of
ylidic carbon atoms C6 and C14 point to the phenacylylides
(NϩϪC6Ϫ) as the more reactive species (see data in
Table 4).
Indeed, in all the experiments, the disubstituted triazol-
ium ylides 7 were obtained in larger quantities than the yl-
ides 8. Experimentally, two disubstituted triazolium ylides
6 and 7 have been characterized only in the cases when R ϭ
Br, OCH3, and NO2.
knowledge, the synthesis of 4-substituted-4H-[1,2,4]triazol-
1-ium phenylmethylides 8cϪe and of the 5-aryl-1-benzyl-
1H-[1,2,4]triazolo[5,1-a]isoindole core 13 is announced for
the first time in this paper.
Furthermore, the presence of these disubstituted car-
banion ylides 7 and 8 must unambiguously involve the
formation of the corresponding monosubstituted ylides 16
Conclusion
In this paper we have described the interesting chemical and 17 as intermediates. If we take the experimental data
behavior of salts 6cϪe under basic conditions. After and the theoretical results (charges, net atomic coefficient)
quenching with picric chloride, these furnished an unexpec- into consideration together, we can explain the formation
ted mixture of disubstituted ylides: phenacylylides 7 and and the ratios of the two disubstituted ylides when R ϭ Br,
benzylylides 8. These disubstituted carbanion ylides 7 and OCH3 and NO2. However, no simple explanation could be
8 were then converted into the corresponding triazoloisoin- given for the lack of benzylylide derivatives 8a and 8b when
dole derivatives 12 and 13 in DMSO. To the best of our Rϭ H and CH3. In theory, the site of deprotonation can
1410
Eur. J. Org. Chem. 2001, 1407Ϫ1412

1H-[1,2,4]Triazolo[3,4-a]isoindoles and 1H-[1,2,4]Triazolo[5,1-a]isoindoles
FULL PAPER
(s, 1 aromatic H). Ϫ 13C NMR (CDCl3/TMS): δ ϭ 54.4, 54.8,
124.2, 128.8, 129.0, 129.2, 129.8, 133.3, 138.1, 142.6, 146.1, 150.7,
189.8. Ϫ IR (KBr): ν˜ ϭ 3102 cmϪ1, 3042, 2905, 1696, 1524, 1347,
1228, 1000, 857. Ϫ MS (ESϩ, cone 21); m/z (%): 323 (100) [M Ϫ
Br], 341 (10) [M ϩ H2O], 355 (40) [M ϩ CH3OH], 91 (15) [PhCH2].
Ϫ C17H16BrN3O2 (403.2): calcd. C 50.64, H 3.75, N 13.89; found
C 50.39, H 3.78, N 13.71.
be estimated by quantum chemical calculation. Moreover,
the presence of the solvent can interfere with and affect (i)
the geometry of the salts, and (ii) the relative stability of
the conjugated base, and these also have an influence on
the experimental data obtained in solution. Accordingly, a
more thorough theoretical calculation, taking into account
the nature of the solvent, is in progress in our laboratory.
General Procedure for the Synthesis of (1-Benzyl-1H-[1,2,4]triazol-
4-io)(4-substituted benzoyl)(2,4,6-trinitrophenyl)methanides 7c؊e
and {4-[2-Oxo-2-(4-substituted phenyl)ethyl]-4H-[1,2,4]triazol-1-
Experimental Section
io}(phenyl)(2,4,6-trinitrophenyl)methanides 8c؊e:
A solution of
freshly distilled Et3N (5.6 mmol) in dry CHCl3 (5 mL) was added
to a stirred suspension of 6 (2.8 mmol) and picryl chloride
(2.8 mmol) in dry CHCl3 (30 mL) at O °C under Ar. The mixture
was allowed to warm to room temperature, in the absence of light,
over three hours. The solvent was evaporated and the deep purple
crude product was chromatographed on SiO2, using acetone-hex-
ane (40:60) as eluent.
1
General Remarks: H and 13C NMR spectra were recorded with a
Bruker AM 250 spectrometer with trimethylsilane as internal
standard. The abbreviations used are: s (singlet), d (doublet), t
(triplet) and m (multiplet). Ϫ Mass spectra were measured using a
Platform II Micromass Apparatus. Ϫ IR spectra were recorded us-
ing a PerkinϪElmer instrument. Ϫ Melting points were obtained
with a Reichert Thermopan apparatus and are uncorrected. Ϫ
Chromatographic separations were carried out on SDS silica gel 60
(70Ϫ200 µm). All reagents were used as purchased unless otherwise
stated. Solvents were dried according to standard procedures. All
reactions were performed under dry argon. The reagents were
transferred by syringe.
(1-Benzyl-1H-[1,2,4]triazol-4-io)(4-bromobenzoyl)(2,4,6-
trinitrophenyl)methanide (7c) and {4-[2-(4-Bromophenyl)-2-oxoe-
thyl]-4H-[1,2,4]triazol-1-io}(phenyl)(2,4,6-trinitrophenyl)methanide
1
(8c): Yield 1.27 g (80%). Ϫ H NMR (CDCl3/TMS): δ ϭ 5.32 (7c)
and 5.40 (8c) (s, 2 H, CH2), 7.02Ϫ7.43 (m, 9 aromatic H), 8.03 (8c)
and 8.14 (7c) (s, 1 aromatic H), 8.46 (7c) and 8.68 (8c) (s, 2 aromatic
H), 9.60 (7c) and 10.61 (8c) (s, 1 aromatic H). Ϫ IR (KBr): ν˜ ϭ
3084 cmϪ1, 1700, 1598, 1527, 1448, 1305. Ϫ MS (ESϩ, cone 32);
m/z (%): 569 (100) [M ϩ H], 567 (100) [M ϩ H].
General Procedure for the Synthesis of 1-Benzyl-1H-[1,2,4]triazol-4-
ium Bromides 6c؊e: The ω-bromoacetophenone compounds 11cϪe
are commercially available. Ϫ A solution of ω-bromoacetophenone
11cϪe in anhydrous acetone (30 mL) was added at room temper-
ature under argon to a solution of 1-benzyl-1H-[1,2,4]triazol (10,
10 mmol) in dry acetone (80 mL). The solution was warmed to
reflux for 8 h. The crude product precipitated was filtered off and
recrystallized from EtOH.
(1-Benzyl-1H-[1,2,4]triazol-4-io)(4-methoxybenzoyl)(2,4,6-
trinitrophenyl)methanide (7d) and {4-[2-(4-Methoxyphenyl)-2-oxoe-
thyl]-4H-[1,2,4]triazol-1-io}(phenyl)(2,4,6-trinitrophenyl)methanide
(8d): Yield 0.88 g (61%). Ϫ 1H NMR (CDCl3/TMS): δ ϭ 3.76 (8d)
and 3.78 (7d) (s, 3 H, OCH3), 5.30 (8d) and 5.42 (7d) (s, 2 H,
CH2), 6.65Ϫ6.72 (m, 2 aromatic H), 7.16Ϫ7.31 (m, 4 aromatic H),
7.44Ϫ7.47 (m, 3 aromatic H), 7.91 (8d) and 8.17 (7d) (s, 1 aromatic
H), 8.47 (7d) and 8.63 (8d) (s, 2 aromatic H), 9.49 (7d) and 10.45
(8d) (s, 1 aromatic H). Ϫ IR (KBr): ν˜ ϭ 3089 cmϪ1, 1703, 1603,
1520, 1454, 1299, 1250. Ϫ MS (ESϩ, cone 63); m/z (%): 519 (30)
[M ϩ H], 472 (100) [M Ϫ NO2], 91 (100) [PhCH2].
1-Benzyl-4-[2-(4-bromophenyl)oxoethyl]-1H-[1,2,4]triazol-4-ium
Bromide (6c): Yield 3.32 g (76%), m.p. 200Ϫ201 °C. Ϫ 1H NMR
(CDCl3/TMS): δ ϭ 5.79 (s, 2 H, CH2), 6.15 (s, 2 H, CH2),
7.42Ϫ7.52 (m, 5 aromatic H), 7.89 (d, J ϭ 8.5 Hz, 2 aromatic H),
8.00 (d, J ϭ 8.5 Hz, 2 aromatic H), 9.18 (s, 1 aromatic H), 10.25
(s, 1 aromatic H). Ϫ 13C NMR (CDCl3/TMS): δ ϭ 54.0, 54.8,
128.8, 128.8, 129.0, 130.2, 132.3, 132.5, 133.3, 143.6, 146.1, 189.8.
Ϫ IR (KBr): ν˜ ϭ 3110 cmϪ1, 2972, 1700, 1583, 1396, 1340, 1225,
1149, 992, 823. Ϫ MS (ESϩ, cone 24); m/z (%): 356 (100) [M Ϫ
Br], 358 (100) [M Ϫ Br], 91 (20) [PhCH2]. Ϫ C17H15Br2N3O
(437.1): calcd. C 46.71, H 3.46, N 9.61; found C 46.92, H 3.44,
N 9.52.
(1-Benzyl-1H-[1,2,4]triazol-4-io)(4-nitrobenzoyl)(2,4,6-
trinitrophenyl)methanide (7e) and {4-[2-(4-Nitrophenyl)-2-oxoethyl]-
4H-[1,2,4]triazol-1-io}(phenyl)(2,4,6-trinitrophenyl)methanide (8e):
1
Yield 1.16 g (78%). Ϫ H NMR (CDCl3/TMS): δ ϭ 5.36 (8d) and
5.50 (7d) (s, 2 H, CH2), 7.34Ϫ7.48 (m, 7 aromatic H), 7.95Ϫ8.04
(m, 2 aromatic H), 7.93 (8d) and 8.17 (7d) (s, 1 aromatic H), 8.55
(7d) and 8.70 (8d) (s, 2 aromatic H), 9.51 (7d) and 10.83 (8d) (s, 1
aromatic H). Ϫ IR (KBr): ν˜ ϭ 3050 cmϪ1, 1705, 1607, 1525, 1453,
1307, 1309. Ϫ MS (ESϩ, cone 35); m/z (%): 534 (100) [M ϩ H],
487 (100) [M Ϫ NO2], 91 (50) [PhCH2].
1-Benzyl-4-[2-(4-methoxyphenyl)oxoethyl]-1H-[1,2,4]triazol-4-ium
Bromide (6d): Yield 1.82 g (47%), m.p. 160Ϫ165 °C. Ϫ 1H NMR
(CDCl3/TMS): δ ϭ 3.89 (s, 3 H, OCH3), 5.79 (s, 2 H, CH2), 6.12
(s, 2 H, CH2), 7.17 (d, J ϭ 8.9 Hz, 2 aromatic H), 7.44Ϫ7.48 (m,
5 aromatic H), 8.05 (d, J ϭ 8.9 Hz, 2 aromatic H), 9.21 (s, 1 aro-
matic H), 10.28 (s, 1 aromatic H) Ϫ 13C NMR (CDCl3/TMS): δ ϭ
53.7, 54.8, 55.8, 114.4, 128.8, 129.0, 130.2, 130.7, 133.3, 143.7,
146.1, 164.3, 188.6. Ϫ IR (KBr): ν˜ ϭ 3062 cmϪ1, 2972, 1672, 1595,
1562, 1156, 1322, 1269, 1249, 1177, 1010, 828. Ϫ MS (ESϩ, cone
General Procedure for the Synthesis of 1-Benzyl-6,8-dinitro-5-(4-sub-
stituted benzoyl)-1H-[1,2,4]triazolo[3,4-a]isoindoles 12c؊e and 1-[2-
Oxo-2-(4-substituted phenyl)ethyl]-5-phenyl-1H-[1,2,4]triazolo[5,1-
a]isoindoles 13c؊e: A solution of 7 and 8 (1.5 mmol) in DMSO
(20 mL) was stirred under Ar in darkness at room temperature in
the presence of piperidine (3 mmol) for 5 h. Initially, the solution
had a deep purple color, which progressively turned to red. The
solution was acidified with 3  acetic acid and washed with water
to obtain a red precipitate, which was filtered. The crude mixture
was then separated by chromatography on SiO2 using acetone/hex-
35); m/z (%): 308 (100) [M
C18H18BrN3O2 (388.3): calcd. C 55.68, H 4.67, N 10.82; found C
55.54, H 4.62, N 10.69
Ϫ Br], 91 (15) [PhCH2]. Ϫ
1-Benzyl-4-[2-(4-nitrophenyl)oxoethyl]-1H-[1,2,4]triazol-4-ium
Bromide (6e): Yield 3.02 g (75%), m.p. 211Ϫ212 °C. Ϫ 1H NMR
(CDCl3/TMS): δ ϭ 5.80 (s, 2 H, CH2), 6.21 (s, 2 H, CH2),
7.43Ϫ7.52 (m, 5 aromatic H), 8.30 (d, J ϭ 8.5 Hz, 2 aromatic H), ane (50:50) as eluent. Finally, each compound 12cϪe and 13cϪe
8.47 (d, J ϭ 8.5 Hz, 2 aromatic H), 9.18 (s, 1 aromatic H), 10.24
Eur. J. Org. Chem. 2001, 1407Ϫ1412
was washed with boiling EtOH.
1411

P. Woisel, G. Surpateanu, F. Delattre, M. Bria
FULL PAPER
1-Benzyl-5-(4-bromobenzoyl)-6,8-dinitro-1H-[1,2,4]triazolo[3,4-a]-
isoindole (12c): Yield 0.64 g (76%), m.p. 256Ϫ257 °C. Ϫ H NMR
123.4, 125.2, 128.0, 128.5, 128.9, 129.5, 132.7, 133.3, 134.4, 136.0,
137.8, 162.1, 182.4. Ϫ IR (KBr): ν
˜ ϭ 3154 cm
1
Ϫ1, 2924, 2853, 1729,
(DMSO/TMS): δ ϭ 5.96 (s, 2 H, CH2), 7.45Ϫ7.74 (m, 9 aromatic 1623, 1595, 1576, 1526, 1501, 1455, 1360, 1304, 1254, 1152, 1059,
H), 8.62 (s, 1 aromatic H), 8.74 (s, 1 aromatic H), 9.19 (s, 1 aromatic
H). Ϫ 13C NMR (DMSO/TMS): δ ϭ 46.7, 106.1, 109.4, 118.1,
120.9, 122.9, 126.3, 127.7, 128.7, 129.1, 131.2, 131.4, 131.9, 134.1,
856. Ϫ MS (ESϩ, cone 36); m/z (%): 472 (30) [M ϩ H], 412 (100).
Ϫ C24H17N5O6 (471.4): calcd. C 61.15, H 3.63, N 14.86; found C
61.15, H 3.58, N 14.89.
137.1, 137.6, 139.3, 146.4, 180.5. Ϫ IR (KBr): ν˜ ϭ 3118 cmϪ1
,
6,8-Dinitro-1-[2-(4-nitrophenyl)-2-oxoethyl]-5-phenyl-1H-
[1,2,4]triazolo[5,1-a]isoindole (13e): Yield 0.09 g (67%), m.p.
2927, 1732, 1604, 1551, 1524, 1502, 1291, 1252, 1171, 839. Ϫ MS
(ESϩ, cone 40); m/z (%): 520 (100) [M ϩ H], 522 (100) [M ϩ H]Ϫ
C23H14BrN5O5 (520.3): calcd. C 53.18, H 2.71, N 13.46; found C
53.41, H 2.75, N 13.62.
1
278Ϫ279 °C. Ϫ H NMR (DMSO/TMS): δ ϭ 6.17 (s, 2 H, CH2),
7.42Ϫ7.49 (m, 5 aromatic H), 7.79 (d, J ϭ 8.0 Hz, 2 aromatic H),
8.31 (d, J ϭ 8.0 Hz, 2 aromatic H), 8.73 (s, 1 aromatic H), 9.24 (s,
1 aromatic H), 9.64 (s, 1 aromatic H). Ϫ 13C NMR (DMSO/TMS):
δ ϭ 54.1, 107.5, 107.9, 121.4, 124.2, 125.0, 128.0, 128.4, 128.6,
128.9, 133.3, 134.3, 137.0, 138.1, 140.7, 147.2, 148.8, 180.9. Ϫ IR
(KBr): ν˜ ϭ 3148 cmϪ1, 2924, 1725, 1598, 1549, 1524, 1515, 1499,
1301, 1251, 1159, 835. Ϫ MS (ESϩ, cone 57); m/z (%): 525 (100)
[M ϩ Kϩ], 487 (80) [M ϩ Naϩ]. Ϫ C24H14N5O6 (486.4): calcd. C
56.80, H 2.90, N 17.28; found C 56.69, H 3.11, N 17.05.
1-Benzyl-5-(4-methoxybenzoyl)-6,8-dinitro-1H-[1,2,4]triazolo[3,4-a]-
1
isoindole (12d): Yield 0.40 g (68%), m.p. 248Ϫ249 °C. Ϫ H NMR
(DMSO/TMS): δ ϭ 3.87 (s, 3 H, OCH3), 5.95 (s, 2 H, CH2), 7.05
(d, J ϭ 8.7 Hz, 2 aromatic H), 7.37Ϫ7.55 (m, 5 aromatic H), 7.82
(d, J ϭ 8.7 Hz, 2 aromatic H), 8.62 (s, 1 aromatic H), 8.77 (s, 1
aromatic H), 9.19 (s, 1 aromatic H). Ϫ 13C NMR (DMSO/TMS):
δ ϭ 49.7, 55.5, 105.3, 109.6, 113.7, 117.8, 119.8, 123.3, 127.7, 128.7,
129.1, 131.6, 133.5, 133.5, 134.1, 136.4, 138.8, 146.4, 162.8, 181.1.
Ϫ IR (KBr): ν˜ ϭ 3119 cmϪ1, 2925, 1731, 1607, 1553, 1527, 1504,
1311, 1252, 1172, 839. Ϫ MS (ESϩ, cone 40); m/z (%): 472 (100)
[M ϩ H]. Ϫ C24H17N5O6 (471.4): calcd. C 61.13, H 3.64, N 14.86;
found C 61.20, H 3.55, N 14.82.
[1]
K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863Ϫ909.
[2]
X. Wei, Y. Hu, T. Li, H. Hu, J. Chem. Soc., Perkin Trans. 1
1993, 2487Ϫ2489.
[3]
X-C. Zhang, W-Y. Huang, Synthesis 1999, 51Ϫ54.
[4]
F. Kröhnke, H. Schmeiss, Chem. Ber. 1937, 70, 1728Ϫ1732.
[5]
1-Benzyl-6,8-dinitro-5-(4-nitrobenzoyl)-1H-[1,2,4]triazolo[3,4-a]-
D. B Reusching, F Kröhnke, Chem. Ber. 1971, 104, 2103Ϫ2109.
[6]
1
G. Surpateanu, A. Lablache-Combier, Heterocycles 1984, 22,
isoindole (12e): Yield 0.50 g (54%), m.p. 249Ϫ250 °C. Ϫ H NMR
2079Ϫ2128.
(DMSO/TMS): δ ϭ 5.96 (s, 2 H, CH2), 7.33Ϫ7.53 (m, 5 aromatic
H), 8.04 (d, J ϭ 8.7 Hz, 2 aromatic H), 8.34 (d, J ϭ 8.7 Hz, 2
aromatic H), 8.68 (s, 1 aromatic H), 8.79 (s, 1 aromatic H), 9.18 (s,
1 H). Ϫ 13C NMR (DMSO/TMS): δ ϭ 50.6, 107.8, 110.3, 119.2,
122.7, 123.5, 124.4, 129.6, 130.0, 131.3, 135.0, 135.5, 138.6, 140.5,
144.9, 147.4, 150.2, 180.2. Ϫ IR (KBr): ν˜ ϭ 3120 cmϪ1, 2927, 1729,
1608, 1553, 1527.1520, 1502, 1307, 1254, 1169, 840. Ϫ MS (ESϩ,
cone 35); m/z (%): 487 (100) [M ϩ H]Ϫ C24H17N5O6 (486.4): calcd.
C 56.80, H 2.90, N 17.28; found C 56.54, H 3.01 N, 16.98.
[7]
C. Luchian, V. Barboiu, G. Surpateanu, M. Petrovanu, Bul.
Inst. Politeh. Iasi 1983, 29, 77Ϫ81. ((AUTHOR: Please check
this reference!))
[8]
A. Couture, A. Lablache-Combier, P. Grandclaudon, G. Surpa-
teanu, Heterocycles 1990, 31, 2111Ϫ2114.
[9]
G. Surpateanu, A. Lablache-Combier, P. Grandclaudon, A.
Couture, B. Mouchel, Rev. Roum. Chim. 1993, 38, 671Ϫ681.
[10]
Y. Karzazi, G. Surpateanu, Heterocycles 1999, 51, 863Ϫ925.
[11]
G. Surpateanu, N. C. Lungu, N. Avarvari, A. Lablache-Com-
bier, P. Grandclaudon, A. Couture, J. Chim. Phys. 1994, 91,
1648Ϫ1657.
[12]
1-[2-(4-Bromophenyl)-2-oxoethyl]-6,8-dinitro-5-phenyl-1H-
[1,2,4]triazolo[5,1-a]isoindole (13c): Yield 0.27 g (82%), m.p.
G. G. Surpateanu, G. Vergoten, A. Elass, G. Surpateanu, Het-
erocycles 1999, 51, 2213Ϫ2220.
[13]
1
P. Woisel, M.-L. Lehaire, G. Surpateanu, Tetrahedron 2000,
236Ϫ237 °C. Ϫ H NMR (DMSO/TMS): δ ϭ 6.15 (s, 2 H, CH2),
56, 377Ϫ380.
7.37Ϫ7.51 (m, 7 aromatic H), 7.67 (d, J ϭ 8.5 Hz, 2 aromatic H),
8.71 (s, 1 aromatic H), 9.20 (s, 1 aromatic H), 9.59 (s, 1 aromatic
H). Ϫ 13C NMR (DMSO/TMS): δ ϭ 54.1, 107.3, 121.2, 124.3,
125.1, 125.4, 128.0, 128.5, 128.9, 129.1, 131.9, 133.0, 134.4, 136.6,
138.0, 139.9, 140.4, 182.0. Ϫ IR (KBr): ν˜ ϭ 3152 cmϪ1, 2925, 2954,
1706, 1623, 1571, 1526, 1446, 1357, 1308, 1251, 1148, 1074, 913,
734. Ϫ MS (ESϩ, cone 35); m/z (%): 520 (100) [M ϩ H], 522 (100)
[M ϩ H]. Ϫ C23H14BrN5O5 (520.3): calcd. C 53.18, H 2.71, N
13.46; found C 53.35, H 2.59, N 13.54.
[14]
A. R. Katritzky, W. Kuzmierkiewicz, J. V. Greenhill, Recl. Trav.
Chim. Pays-Bas 1991, 110, 369Ϫ373.
[15]
F. Kroehnke, K. Gerlach, Chem. Ber. 1962, 95, 1124Ϫ1127.
[16]
G. Surpateanu, J. P. Catteau, P. Karafiloglou, A. Lablache-
Combier, Tetrahedron 1976, 32, 2647Ϫ2663.
[17]
Heteronuclear gated decoupling sequence.
[18]
E. Fukushima, B. W. Stephen, Experimental pulse NMR, a nuts
and bolts approach, Addison-Wesley, Massachusetts, USA,
1981, pp. 101Ϫ103.
[19]
M. J. S. Dewar, E. G. Zoebish, E. F. Healy, J. J. P. Stewart, J.
Am. Chem. Soc. 1985, 107, 3902Ϫ3909.
[20]
1-[2-(4-Methoxyphenyl)-2-oxoethyl]-6,8-dinitro-5-phenyl-1H-
[1,2,4]triazolo[5,1-a]isoindole (13d): Yield 0.17 g (78%), m.p.
229Ϫ230 °C. Ϫ 1H NMR (DMSO/TMS): δ ϭ 3.83 (s, 3 H, OCH3),
6.14 (s, 2 H, CH2), 7.00 (d, J ϭ 8.8 Hz, 2 aromatic H), 7.37Ϫ7.50
(m, 5 aromatic H), 7.59 (d, J ϭ 8.8 Hz, 2 aromatic H), 8.72 (s, 1
aromatic H), 9.19 (s, 1 aromatic H), 9.51 (s, 1 aromatic H). Ϫ 13C
NMR (DMSO/TMS): δ ϭ 54.1, 55.4, 106.6, 107.2, 114.2, 120.9,
J. J. P. Stewart, J. Comput. Chem. 1988, 13, 157.
[21]
J. J. P. Stewart, J. Comput. Chem. 1989, 10, 209Ϫ220.
[22]
J. J. P. Stewart, J. Comput. Chem. 1989, 10, 221Ϫ264.
[23]
N. L. Allinger, Y. H Lii, J. Am. Chem. Soc. 1989, 111,
8551Ϫ8576.
[24]
G. Surpateanu, Y. Karzazi, Heterocycles 1999, 51, 863Ϫ925.
Received July 18, 2000
[O00380]
1412
Eur. J. Org. Chem. 2001, 1407Ϫ1412