Thiazolo[3,4- b ]indazole-2,2-dioxides as masked extended dipoles: Pericyclic reactions of benzodiazafulvenium methides

Article abstract of DOI:10.1021/jo302463q

Herein we report the first examples of 1,3-dipolar cycloadditions of thiazolidine-derived sydnones with benzyne leading to 1,3-dihydrothiazolo[3,4-b] indazoles. These heterocycles were converted into the corresponding sulfones which were used as precursor

Full text of DOI:10.1021/jo302463q

Article
pubs.acs.org/joc
Thiazolo[3,4‑b]indazole-2,2-dioxides as Masked Extended Dipoles:
Pericyclic Reactions of Benzodiazafulvenium Methides
Maria I. L. Soares,† Claudio M. Nunes,† Clara S. B. Gomes,‡ and Teresa M. V. D. Pinho e Melo*,†
́
†Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
‡Centro de Química Estrutural, Instituto Superior Tec
́
nico, Technical University of Lisbon, Av. Rovisco Pais, 1049-001 Lisboa,
Portugal
S
* Supporting Information
ABSTRACT: Herein we report the first examples of 1,3-
dipolar cycloadditions of thiazolidine-derived sydnones with
benzyne leading to 1,3-dihydrothiazolo[3,4-b]indazoles. These
heterocycles were converted into the corresponding sulfones
which were used as precursors of novel benzo-2,3-diazafulve-
nium methides. These reactive intermediates reacted with N-
substituted maleimides affording new 1H-indazoles charac-
terized by an intense yellow color, a property that gives them a
potential application as dyes. The synthesis of these hetero-
cycles was rationalized considering the initial 1,3-cycloaddition
of benzodiazafulvenium methides to maleimides. This chemical behavior is in contrast with the previously observed reactivity for
4,5-(methoxycarbonyl)diazafulvenium methides, which participate exclusively in [8π + 2π] cycloadditions to give 1,7-
cycloadducts. Quantum chemical calculations, carried out at the DFT level of theory, were in agreement with the rationalization
of the observed reactivity. Under flash vacuum pyrolysis or under microwave irradiation, 1-methyl- and 7,7-dimethylbenzo-2,3-
diazafulvenium methides undergo sigmatropic [1,8]H shifts allowing the efficient synthesis of N-vinyl- and C-vinyl-2H-indazoles.
Our goal is to broaden the study to new extended dipolar
systems capable of participating in pericyclic reactions, as a way
of developing new synthetic routes to heterocycles. Indazoles
were selected as our target scaffold, a class of compounds
displaying a wide variety of biological activities but rare in
nature, making the chemistry of indazoles of considerable
interest.3 In recent years, significant efforts have been made to
find synthetic strategies to avoid harsh reaction conditions of
some of the known methods and to widen the diversity of
substituted indazole derivatives. Several synthetic approaches
involve the construction of the pyrazole ring from suitable 1,2-
substitued benzene derivatives.3a,b More recently, the syntheses
of indazoles based on addition reactions to arynes have been
reported.4 These include [3 + 2] cycloaddition of arynes with
diazo compounds,4a−c with nitrile imines,4d and with
sydnones4e,f and [3 + 2] annulation of arynes with N-
tosylhydrazones.4g,h The synthesis of pyridino[1,2-b]indazoles
via 1,3-dipolar cycloaddition of arynes has also been described.5
In this context, we envisaged that thiazolo[3,4-b]indazoles 13
could be obtained by the cycloaddition of benzyne with
sydnones 12 and converted into the corresponding sulfones 14.
Pericyclic reactions of the novel reactive species derived from
thiazolo[3,4-b]indazole-2,2-dioxides 14 and benzo-2,3-diazaful-
venium methides 15 would give access to functionalized
indazoles (Scheme 3).
1. INTRODUCTION
The study of pericyclic reactions of aza- and diazafulvenium
methide systems 1 and 2 is one of our current research
interests.1 After the pioneering work of Storr and co-workers2
describing the first evidence for trapping of these transient
dipolar systems in pericyclic reactions, we further explored this
chemistry and demonstrated their versatility as building blocks
for the synthesis of heterocyclic compounds. Aza- and
diazafulvenium methides are generated from 1H,3H-pyrrolo-
[1,2-c]thiazole-2,2-dioxides and 1H,3H-pyrazolo[1,5-c]thiazole-
2,2-dioxides, respectively, by thermal extrusion of sulfur dioxide.
These “higher-order” azomethine ylides and azomethine imines
can act as 4π 1,3-dipoles or as 8π 1,7-dipoles although the
typical reactivity pattern is that expected for 1,7-dipoles. In fact,
only with 5-(trifluoromethyl)azafulvenium methides did we
observe evidence of azafulvenium methides acting as a 1,3-
dipole.1f Thus, 1,7-dipoles 3-6 participate in sigmatropic [1,8]H
shifts giving vinylpyrroles and vinylpyrazoles (Scheme 1).
Azafulvenium methides 7 can be intercepted in microwave-
induced [8π + 2π] cycloadditions affording 1,7-cycloadducts.1e
Diazafulvenium methides 8 also behave as 8π 1,7-dipoles either
under microwave irradiation or conventional heating giving
pyrazolo-annulated heterocycles.1g−j This synthetic method-
ology was used to obtain a new type of stable 4,5,6,7-
tetrahydropyrazolo[1,5-a]pyridine-fused chlorines 10 and
bacteriochlorins 11, macrocycles with potential for various
biomedical applications (Scheme 2).1i,j
Received: November 9, 2012
Published: December 7, 2012
© 2012 American Chemical Society
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Scheme 1. Pericyclic Reactions of Aza- and Diazafulvenium
Methides
Scheme 3. Synthetic Strategy for the Generation of Benzo-
2,3-diazafulvenium Methides
of fluoride ion (method A and B) or from the reaction of
anthranilic acid with isoamyl nitrite (method C) (Table 1).
Dihydrothiazolo[3,4-b]indazole 13a was obtained in moderate
yield from the fluoride-induced 1,2-elimination of o-trimethyl-
silyltriflate using CsF in acetonitrile (method A, entry 1).
Attempts to improve the efficiency of this synthesis, either by
increasing the number of equivalents of the benzyne precursor
or by carrying out the reaction at various reaction temperatures,
were unsuccessful. Changing the fluoride source from CsF to
tetra-n-butylamonium fluoride (TBAF) also did not lead to any
improvement (method B, entry 2). When benzyne was
generated from anthranilic acid in the presence of isoamyl
nitrite, by decomposition of the internal benzenediazonium-2-
carboxylate, the target compound 13a was obtained in 31%
yield (method C, entry 3). Dihydrothiazolo[3,4-b]indazole 13b
was obtained in moderate yields by using either o-
(trimethylsilyl)phenyl triflate or anthranilic acid as benzyne
precursor (entries 4 and 5). Since compounds 13a and 13b
were obtained in moderate yields regardless of the method-
ology used to generate benzyne and considering that anthranilic
acid is an easily available reagent, the synthesis of
dihydrothiazolo[3,4-b]indazoles 13c and 13d was carried out
using only method C. We were pleased to observed that
starting from sydnones 12c and 12d the corresponding 1,1-
dimethyl-dihydrothiazolo[3,4-b]indazoles 13c and 13d could
be obtained in 66% and 62% yield, respectively (entries 6 and
7). It is worth noting that the synthesis of this new type of
indazole-annulated system represents the first examples of 1,3-
dipolar cycloaddition of thiazolidine-derived sydnones with
benzyne acting as dipolarophile.
Scheme 2. [8π + 2π] Cycloaddition of Aza- and
Diazafulvenium Methides
1,3-Dihydrothiazolo[3,4-b]indazole-2,2-dioxides 14 were ob-
tained in good yield from the oxidation of thiazolo[3,4-
b]indazole derivatives 13 with m-chloroperoxybenzoic acid
(MCPBA) (Scheme 4, Table 2).
Generation and Reactivity of Benzo-2,3-diazafulve-
nium Methides. The first evidence for the generation of
benzo-2,3-diazafulvenium methides 15 came from the extrusion
of SO2 from sulfones 14 in presence of maleimides under
conventional thermolysis or under microwave irradiation
(Table 3). The expected 1,7-cycloadducts were not formed,
and 4-(1H-indazol-1-yl)-1H-pyrrole-2,5-dione derivatives 18
were isolated instead.
2. RESULTS AND DISCUSSION
Synthesis of Thiazolo[3,4-b]indazole-2,2-dioxides.
The approach for the synthesis of thiazolo[3,4-b]indazole-2,2-
dioxides is outlined in Scheme 4. Thiazolidine-derived
sydnones 12 are stable mesoionic species which can be isolated
and undergo 1,3-dipolar cycloaddition with dipolarophiles such
as acetylene dicarboxylates giving 1H,3H-pyrazolo[1,5-c]-
thiazole derivatives.1,6 On the other hand, arynes have
demonstrated good reactivity as dipolarophiles in several 1,3-
dipolar cycloaddition reactions leading to 2H-indazole,
including in the reaction with a proline-derived sydnone.4e,f
Thus, dihydrothiazolo[3,4-b]indazoles 13a and 13b were
prepared by 1,3-dipolar cycloaddition of the corresponding
thiazolidine-derived sydnones 12 with benzyne, generated
either from o-(trimethylsilyl)phenyl triflate7 in the presence
In fact, the reaction of unsubstituted 1,3-dihydrothiazolo[3,4-
b]indazole-2,2-dioxide (14a) and N-methylmaleimide (NMM)
in boiling 1,2,4-trichlorobenzene (1,2,4-TCB) afforded one
product in 27% yield isolated as a solid (Table 3, entry 1). The
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Scheme 4. Synthesis of 1,3-Dihydrothiazolo[3,4-b]indazoles 13 and 1,3-Dihydrothiazolo[3,4-b]indazole-2,2-dioxides 14
are characterized by an intense yellow color, a property that
gives them a potential application as dyes.
Table 1. Synthesis of 1,3-Dihydrothiazolo[3,4-b]indazoles
13
We have previously observed that diazafulvenium methides
with the general structure 8 participate in [8π + 2π]
cycloadditions, and addition to 1,3-positions was never
observed.1g,h,e The [8π + 2π] cycloadditions of dipole 8 (R =
H) was observed to occur with both electron-rich and electron-
deficient dipolarophiles, whereas 1,7-dipole 8 (R = Me) only
reacts with electron-deficient dipolarophiles. An illustrative
example of the typical reactivity of diazafulvenium methides 8 is
shown in Scheme 5. The thermolysis of 1H,3H-pyrazolo[1,5-
c][1,3]thiazole-2,2-dioxide 19 in refluxing 1,2,4-trichloroben-
zene for 7 h in the presence of N-phenylmaleimide gives
hexahydro-5H-pyrrolo[3′,4′:5,6]pyrazolo[1,5-a]pyridine 20 in
high yield via [8π + 2π] cycloaddition of diazafulvenium
methide 8a.1h Carrying out the microwave irradiation of sulfone
19 at 260 °C for 20 min in the presence of N-phenylmaleimide
affords heterocycle 20 in 44% yield.
13, isolated yield
entry sydnone method
reaction conditions
(%)
1
2
3
4
5
6
7
12a
12a
12a
12b
12b
12c
12d
A
B
CsF, CH3CN, 80 °C, 24 h
13a, 29
13a, 28
13a, 31
13b, 26
13b, 40
13c, 66
13d, 62
TBAF, THF, r.t., 19 h
a
C
B
DCM, reflux
TBAF, THF, r.t., 12 h
a
C
C
C
DCM, reflux
DCM, reflux, 1 h
a
DCM, reflux
a
The reaction was complete after finishing the addition of the
anthranilic acid solution.
Table 2. Synthesis of 1,3-Dihydrothiazolo[3,4-b]indazole-
2,2-dioxides 14
entry
substrate
reaction time (h)
14, isolated yield (%)
In contrast with these observations, here it was reported that
benzodiazafulvenium methides 15 behave as 1,3-dipoles on
reacting with maleimides. On the other hand, attempts to
intercept dipole 15 by carrying out thermolysis (MW, 230 °C,
10 min) in the presence of bis(trimethylsilyl)acetylene, furan-
2,5-dione, and 2,3-dihydrofuran were unsuccessful. Thus, the
reactivity of benzodiazafulvenium methides 15 toward dipolar-
ophiles is quite distinct from diazafulvenium methides 8, since
they could only be intercepted with N-substituted maleimides
via [4π + 2π] cycloaddition.
In order to be able to rationalize the different chemical
behavior of benzodiazafulvenium methides 15 and diazafulve-
nium methides 8 toward dipolarophiles, quantum chemical
calculations were carried out at the DFT level of theory (see
Supporting Information). The B3LYP functional, selected for
this task, has been shown to be an effective method for
modeling dipolar cycloadditions.8 Cycloadditions of benzodia-
zafulvenium methide 15a and diazafulvenium methide 8a with
N-phenylmaleimide (NPM) were selected as the model
reactions. Full geometry optimizations were performed,
followed by harmonic frequency calculations, at the same
level of theory, which also allowed characterization of the
nature of the stationary points. For the dipole diazafulvenium
8a, four different conformers were found by performing a
systematic variation of the two relevant torsion angles [τCC−
CO) and τNC−CO)], from 0° to 360°, with increments
of 90° (Figure S49). Nonetheless, only the two lower energy
conformers 8aC1 and 8aC2 were used in the cycloaddition
reaction modeling studies. The dipole benzodiazafulvenium
methide 15a was found to be planar, and only this structure was
used in the cycloaddition calculations (Figure S50). For the
dipolarophile N-phenylmaleimide, it was found that the phenyl
1
2
3
4
13a
13b
13c
13d
1.5
2
14a, 74
14b, 53
14c, 66
14d, 74
4
2
same product was obtained in 35% yield when the reaction was
carried out under microwave irradiation (MW) at 230 °C for
10 min (Table 3, entry 2). The structure of this heterocycle
could only be unambiguously established by X-ray crystallog-
raphy as being 4-(1H-indazol-1-yl)-1H-pyrrole-2,5-dione 18a
(Figure S52).
The reaction of 14a and N-phenylmaleimide (NPM) under
conventional thermolysis or under microwave irradiation also
afforded the corresponding indazole derivative 18b in yields
ranging from 20% to 40% (Table 3, entries 3−10).
The chemical behavior of 1,3-dihydrothiazolo[3,4-b]-
indazole-2,2-dioxides 14b−d under microwave-induced ther-
molysis in 1,2,4-trichlorobenzene in the presence of N-
substituted maleimides was similar to the one observed for
sulfone 14a, giving the corresponding indazole derivatives 18 in
moderate yield (Table 3, entries 11−16). However, in the case
of the reaction of maleimides with benzo-2,3-diazafulvenium
methide 15b, the indazoles 18c and 18d could only be obtained
in low yield (Table 3, entries 11 and 12).
The synthesis of 1H-indazoles 18 can be rationalized
considering that initially benzodiazafulvenium methides 15
react with maleimides affording cycloadducts 16, resulting from
the addition across the 1,3-position. Cycloadducts 16 undergo
pyrazolidine ring-opening, followed by a sigmatropic H-shift
giving the more stable 1H-indazoles 18. It is noteworthy that
the new 1H-indazoles 18, with an unusual substitution pattern,
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Table 3. Reaction of Benzo-2,3-diazafulvenium Methides 15
with N-Substituted Maleimides
Scheme 5. Cycloadddition of Diazafulvenium Methide 8a
with N-Phenylmaleimide
were considered: (i) exo-1,3-cycloaddition; (ii) endo-1,3-
cycloaddition; (iii) exo-1,7-cycloaddition, and (iv) endo-1,7-
cycloaddition. The activation energies corresponding to these
transitions states are reported in Tables 4 and 5. The results
Table 4. Relative Energy of the Transition States for the
Cycloaddition of Diazafulvenium 8a with NPM, Calculated
at the B3LYP/6-31G* Level of Theory
18, isolated
entry substrate dipolarophile
reaction conditions
yield (%)
relative energy (kJ mol−1
)
1
2
14a
14a
NMM
NMM
Δ, 1,2,4-TCB, reflux, 2 h
MW, 1,2,4-TCB, 230 °C,
10 min
18a, 27
18a, 35
transition state
B3LYP/6-31G*
TS[Exo-1,3-(8aC1-NPMC1)]
TS[Exo-1,3-(8aC1-NPMC2)]
TS[Exo-1,3-(8aC2-NPMC1)]
TS[Exo-1,3-(8aC2-NPMC2)]
TS[Endo-1,3-(8aC1-NPMC1)]
TS[Endo-1,3-(8aC1-NPMC2)]
TS[Endo-1,3-(8aC2-NPMC1)]
TS[Endo-1,3-(8aC2-NPMC2)]
TS[Exo-1,7-(8aC1-NPMC1)]
TS[Exo-1,7-(8aC1-NPMC2)]
TS[Exo-1,7-(8aC2-NPMC1)]
TS[Exo-1,7-(8aC2-NPMC2)]
TS[Endo-1,7-(8aC1-NPMC1)]
TS[Endo-1,7-(8aC1-NPMC2)]
TS[Endo-1,7-(8aC2-NPMC1)]
TS[Endo-1,7-(8aC2-NPMC2)]
22.1
24.3
23.3
24.7
23.2
20.6
26.7
22.7
8.8
3
4
5
14a
14a
14a
NPM
NPM
NPM
Δ, 1,2,4-TCB, reflux, 2 h
Δ, 1,2,4-TCB, reflux, 6 h
MW, 1,2,4-TCB, 150 °C,
10 min
18b, 36
18b, 23
18b, 30
6
14a
14a
14a
14a
14a
14b
14b
14c
14c
14d
14d
NPM
NPM
NPM
NPM
NPM
NMM
NPM
NMM
NPM
NMM
NPM
MW, 1,2,4-TCB, 200 °C,
5 min
18b, 39
18b, 40
18b, 20
18b, 31
18b, 27
18c, 8
7
MW, 1,2,4-TCB, 200 °C,
10 min
8
MW, 1,2,4-TCB, 200 °C,
20 min
8.5
9
MW, 1,2,4-TCB, 230 °C,
10 min
8.4
8.2
10
11
12
13
14
15
16
MW, 1,2,4-TCB, 250 °C,
20 min
13.5
12.4
12.2
9.3
MW, 1,2,4-TCB, 230 °C,
15 min
MW, 1,2,4-TCB, 230 °C,
15 min
18d, 13
18e, 38
18f, 45
18g, 22
18h, 30
MW, 1,2,4-TCB, 230 °C,
10 min
Table 5. Relative Energy of the Transition States for the
Cycloaddition of Benzodiazafulvenium Methide 15a with
NPM, Calculated at the B3LYP/6-31G* Level of Theory
MW, 1,2,4-TCB, 230 °C,
10 min
MW, 1,2,4-TCB, 230 °C,
15 min
MW, 1,2,4-TCB, 230 °C,
15 min
relative energy (kJ mol−1
)
transition state
B3LYP/6-31G*
TS[Exo-1,3-(15a-NPMC1)]
TS[Exo-1,3-(15a-NPMC2)]
TS[Endo-1,3-(15a-NPMC1)]
TS[Endo-1,3(15a-NPMC2)]
TS[Exo-1,7-(15a-NPMC1)]
TS[Exo-1,7-(15a-NPMC2)]
TS[Endo-1,7-(15a-NPMC1)]
TS[Endo-1,7-(15a-NPMC2)]
5.9
8.1
ring rotation leads to four symmetric minor-image equivalent
forms. Nevertheless, two of these forms were not equivalent in
the transition states of the cycloaddition reactions, and for this
reason the two forms NPMC1 and NPMC2 were used in the
modeling studies (Figure S51).
In the study of cycloaddition reactions of diazafulvenium 8a
and benzodiazafulvenium methide 15a with N-phenylmalei-
mide, transition states resulting from the following reactions
4.4
2.4
12.3
12.0
17.4
16.1
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include zero-point-energy (ZPE) correction, but no thermal
correction; they are ΔH(0K). The optimized geometries of the
more relevant transition structures for the cycloaddition of
diazafulvenium 8a and benzodiazafulvenium methide 15a with
N-phenylmaleimide are presented in Figures 1 and 2,
respectively.
The results of the quantum chemical calculations demon-
strate that transition states of the addition of N-phenyl-
maleimide to the 1,7-positions of diazafulvenium methide 8a
are significantly more stable than transition states resulting
from the addition across the 1,3-positions, which is consistent
with the experimentally observed exclusive formation of the
corresponding [8π + 2π] cycloadduct. Furthermore, the exo-
addition is predicted to be favored over the endo-approach of
this 1,7-dipole and N-phenylmaleimide (Table 4 and Figure 1).
Interestingly, the computational results on the cycloaddition
reaction of benzodiazafulvenium methide 15a with N-phenyl-
maleimide indicate that this reactive intermediate should react
as a 1,3-dipole, which corroborates the rationalization of the
synthesis of 1H-indazoles 18 from 1,3-dihydrothiazolo[3,4-
b]indazole-2,2-dioxides 14 via the initial 1,3-cycloaddition of
benzodiazafulvenium methides 15 to maleimides (Table 3).
The endo-[4π + 2π] cycloaddition of benzodiazafulvenium
methide 15a with N-phenylmaleimide is predicted to be
favored (Table 5 and Figure 2).
Sigmatropic [1,8]H shifts of the new benzo-2,3-diazafulve-
nium methide derivatives were also explored (Scheme 6, Table
6). 1,3-Dihydrothiazolo[3,4-b]indazole-2,2-dioxides 14b−14d,
Table 6. Sigmatropic [1,8]H Shift of Benzo-2,3-
diazafulvenium Methides 15c and 15d
Figure 1. Geometries of transition states for the cycloaddition of
diazafulvenium 8a with N-phenylmaleimide, TS[Exo-1,7-(8aC2-
NPMC2)] and TS[Exo-1,3-(8aC2-NPMC2)], calculated at the
B3LYP/6-31G* level of theory.
23, isolated yield
entry substrate
reaction conditions
(%)
1
2
3
4
5
14c
14c
14c
14d
14d
FVP (600 °C, 2.0 × 10−5 mbar)
FVP (500 °C, 2.0 × 10−5 mbar)
MW (1,2,4-TCB, 230 °C, 10 min)
FVP (500 °C, 2.0 × 10−5 mbar)
MW (1,2,4-TCB, 230 °C, 10 min)
23a, 61
23a, 73
23a, 58
23b, 92
a
23b, 71
a
Compound 24 was also isolated in 23% yield.
having hydrogen atoms in the appropriate position to undergo
sigmatropic shifts, were selected for this study. As expected,
when carrying out the flash vacuum pyrolysis (FVP), at 500 °C,
of the unsubstituted 1,3-dihydrothiazolo[3,4-b]indazole-2,2-
dioxide 14a, no products could be detected. However, under
FVP reaction conditions (500 °C, 2.0 × 10−5 mbar), compound
14b, bearing one methyl group at C-3, afforded 3-methyl-2-
vinyl-2H-indazole (21) in 69% yield (Scheme 6). The structural
assignment of 2-vinyl-2H-indazole 21 was based on a NOESY
experiment. In the NOESY spectrum, methyl protons at C-3
Figure 2. Geometries of transition states for the cycloaddition of
benzodiazafulvenium methide 15a with N-phenylmaleimide, TS[Endo-
1,7-(15a-NPMC2)] and TS[Endo-1,3(15a-NPMC2)], calculated at
the B3LYP/6-31G* level of theory.
Scheme 6. Chemical Behavior of Benzo-2,3-diazafulvenium Methide 15b under Thermolysis
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tubes. The reaction temperatures were measured by infrared surface
detector during microwave heating. Thin-layer chromatography
(TLC) analyses were performed using precoated silica gel plates.
Flash column chromatography was performed with silica gel 60 as the
show connectivity with the vinyl proton at C-8 and with the
aromatic proton at C-4, thus confirming that the vinyl group is
attached to the nitrogen in position 2. Under microwave
irradiation (230 °C, 15 min) sulfone 14b affords the expected
N-vinyl-indazole 21 (32%) together with the formation of 3-
methyl-1H-indazole (22) (16%).
1
stationary phase. H NMR spectra were recorded on an instrument
operating at 400 MHz. 13C NMR spectra were recorded on an
instrument operating at 100 MHz. Chemical shifts are expressed in
parts per million relatively to internal tetramethylsilane (TMS), and
coupling constants (J) are in hertz. Infrared spectra (IR) were
recorded on a Fourier transform spectrometer. Mass spectra were
recorded under electron impact (EI) or electrospray ionization (ESI).
High-resolution mass spectra (HRMS) spectra were obtained on an
electron impact (EI) or electrospray (ESI) TOF mass spectrometer.
Melting points were determined in open glass capillaries and are
uncorrected. 4H,6H-Thiazolo[3,4-c][1,2,3]oxadiazol-7-ium-3-oxides
1a6 and 1b−d1h were prepared as described in the literature.
General Procedure for the Synthesis of 1,3-Dihydrothiazolo-
[3,4-b]indazoles. Method A. To a mixture of the appropriate
sydnone 12 (4.50 mmol) and the benzyne precursor (5.40 mmol) in
acetonitrile (38 mL) was added cesium fluoride (11.25 mmol). The
resulting mixture was stirred at 80 °C under N2 over a period of 24 h.
After cooling to room temperature the reaction mixture was quenched
with saturated NaHCO3 solution (20 mL), the organic fraction was
extracted with ethyl actetate and dried over anhydrous Na2SO4, and
the solvent was evaporated off. The products were isolated by flash
chromatography.
Flash vacuum pyrolysis of 1,1-dimethyl-1,3-dihydrothiazolo-
[3,4-b]indazole-2,2-dioxide (14c) carried out at 600 °C gave 3-
vinyl-2H-indazole 23a exclusively in 61% yield (Table 6, entry
1). Decreasing the temperature to 500 °C allowed the isolation
of vinylindazole 23a in higher yield (73%) (Table 6, entry 2).
The same indazole 23a was also obtained from sulfone 14c
under MW irradiation in 58% yield (Table 6, entry 3). The
structural assignment of 2H-indazole 23a was supported by a
NOESY experiment, since connectivity was observed between
methyl protons at N-2 and the two vinyl proton at position 3.
Under FVP conditions (500 °C, 2.0 × 10−5 mbar), 1,1,3-
trimethyl-1,3-dihydrothiazolo[3,4-b]indazole-2,2-dioxide (14d)
was converted exclusively into 3-vinyl-2H-indazole 23b in high
yield (92%) (Table 6, entry 4). It is worth noticing that in this
particular case, the SO2 extrusion from indazole 14d leads to
benzodiazafulvenium methide 15d where two potential
sigmatropic [1,8]H shifts could in principle take place. In
fact, microwave-induced thermolysis of sulfone 14d afforded C-
vinyl-2H-indazole 23b in 71% yield together with N-vinyl-2H-
indazole 24 in 23% yield (Table 6, Entry 5).
Method B. To a mixture of the appropriate sydnone 12 (1.00
mmol) and the benzyne precursor (1.60 mmol) in tetrahydrofuran (10
mL) was added TBAF, 1 M in THF solution (1.6 mmol, 1.6 mL). The
resulting mixture was stirred under N2 at room temperature for the
time indicated in each case. After cooling to room temperature the
reaction mixture was treated with saturated aqueous sodium
bicarbonate solution (20 mL), the organic fraction was extracted
with ethyl actetate and dried over anhydrous Na2SO4, and the solvent
was evaporated off. The products were isolated by flash chromatog-
raphy.
These results have shown that 1,3-dihydrothiazolo[3,4-
b]indazole-2,2-dioxides 14b−14d are efficiently converted
into vinyl-2H-indazoles via sigmatropic [1,8]H shifts of the in
situ generated benzo-2,3-diazafulvenium methides. Moreover,
when flash vacuum pyrolysis was used, higher yields and higher
selectivity were observed than in the microwave-induced
thermolysis due to the milder gas-phase thermolysis conditions.
Method C. A solution of anthranilic acid (5.50 mmol) in acetone
(25 mL) was added dropwise over 45−60 min to a refluxing mixture of
the appropriate sydnone 12 (5.00 mmol) and isoamyl nitrite (10.00
mmol) in dichloromethane (50 mL) under N2. The resulting solution
was isolated immediately after finishing the addition of the solution of
anthranilic acid or refluxed for an additional time. After cooling to
room temperature the reaction mixture was quenched with 3 M KOH
(20 mL), the organic fraction was extracted with ethyl actetate and
dried over anhydrous Na2SO4, and the solvent was evaporated off. The
residue was purified by flash chromatography.
3. CONCLUSION
The generation and reactivity of benzo-2,3-diazafulvenium
methides derived from thiazolo[3,4-b]indazole-2,2-dioxides are
described for the first time. The new dipoles could be trapped
in the presence of N-substituted maleimides, giving new
indazole derivatives characterized by an intense yellow color, a
property that gives them a potential application as dyes.
The reported results gave an insight into the chemistry of a
new type of extended dipolar systems. The studied
benzodiazafulvenium methides participated in 1,3-cycloaddition
with maleimides in contrast with the previously observed
reactivity for 4,5-(methoxycarbonyl)diazafulvenium methides,
which participate exclusively in 1,7-cycloadditions. Quantum
chemical calculations were in agreement with this finding.
Furthermore, 1-methyl- and 7,7-dimethylbenzo-2,3-diazaful-
venium methides undergo sigmatropic [1,8]H shifts under flash
vacuum pyrolysis or under microwave irradiation allowing the
efficient synthesis of N-vinyl- and C-vinyl-2H-indazoles,
respectively.
1,3-Dihydrothiazolo[3,4-b]indazole (13a). Method A. Ob-
tained from compound 12a6 (650 mg, 4.50 mmol) as described in
the general procedure. Purification of the crude product by flash
chromatography [hexanes/EtOAc (2:1)] gave compound 13a as a
solid (230 mg, 29%).
Method B. Obtained from compound 12a6 (148 mg, 1.03 mmol) as
described in the general procedure (reaction time: 19 h). Purification
by flash chromatography [hexanes/EtOAc (2:1)] gave compound 13a
(50 mg, 28%).
Method C. Obtained from compound 12a6 (288 mg, 1.03 mmol) as
described in the general procedure (the reaction was complete after
finishing the addition of the solution of anthranilic acid). Purification
by flash chromatography [hexanes/EtOAc (2:1)] gave compound 13a
(108 mg, 31%).
White needles; mp 134−136 °C (from hexanes/diethyl ether); IR
(KBr) 1627, 1376, 1275, 1222, 1160 cm−1; 1H NMR (400 MHz,
CDCl3) δ 4.40 (s, 2H), 5.50 (s, 2H), 7.09 (pseudo-t, J = 7.4 Hz, 1H),
7.30 (pseudo-t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.65 (d, J =
8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 27.2, 50.9, 116.2, 118.0,
119.4, 121.5, 126.4, 135.9, 154.5; MS (EI) m/z: 176 (100) [M]+, 148
(5), 131 (31), 102 (38); HRMS (EI) m/z: calcd for C9H8N2S [M]+
176.0408, found 176.0412.
4. EXPERIMENTAL SECTION
Microwave reactions were carried out in a microwave reactor CEM
Focused Synthesis System Discover S-Class using 10 mL microwave
3-Methyl-1,3-dihydrothiazolo[3,4-b]indazole (13b). Method
B. Obtained from compound 12b1h (108 mg, 0.68 mmol) as described
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Article
in the general procedure (reaction time: 12 h). Purification by flash
chromatography [hexanes/EtOAc (2:1)] gave compound 13b as a low
melting solid (35 mg, 26%).
53%). mp 158−160 °C; IR (KBr) 1630, 1400, 1326, 1133, 1108 cm−1;
1H NMR (400 MHz, CDCl3) δ 2.02 (d, J = 6.6 Hz, 3H), 4.73 (s, 2H),
5.44 (q, J = 6.6 Hz, 1H), 7.12 (pseudo-t, J = 7.6 Hz, 1H), 7.38
(pseudo-t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 50.9, 73.6, 118.2,
118.3, 119.0, 123.2, 124.4, 127.5, 150.3; MS (EI) m/z: 222 (13) [M]+,
158 (100), 130 (38), 102 (11); HRMS (EI) m/z: calc for
C10H10N2SO2 [M]+ 222.0463, found 222.0465.
Method C. Obtained from compound 12b1h (1.16 g, 7.34 mmol) as
described in the general procedure (the reaction was completed after
finishing the addition of the solution of anthranilic acid). Purification
by flash chromatography [hexanes/EtOAc (2:1)] gave compound 13b
as a low melting solid (0.56 g, 40%).
IR (film) 1742, 1629, 1400, 1333, 1270, 1211, 1092 cm−1; 1H NMR
(400 MHz, CDCl3) δ 1.98 (d, J = 6.2 Hz, 3H), 4.35−4.44 (m, 2H),
5.85−5.89 (m, 1H), 7.09 (pseudo-t, J = 7.6 Hz, 1H), 7.30 (pseudo-t, J
= 7.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 23.6, 26.3, 61.4, 116.3, 118.1, 119.4, 121.4,
126.3, 135.1, 154.2; MS (EI) m/z: 190 (100) [M]+, 178 (26), 158
(26), 145 (21), 131 (82), 102 (37); HRMS (EI) m/z: calcd for
C10H10N2S [M]+ 190.0565, found 190.0571.
1,1-Dimethyl-1,3-dihydrothiazolo[3,4-b]indazole-2,2-diox-
ide (14c). Obtained from compound 13c (0.77 g, 3.77 mmol) as
described in the general procedure (reaction time: 4 h). The crude
product was triturated with diethyl ether to give 14c as a pale yellow
solid (0.59 g, 66%). mp 169−171 °C; IR (KBr) 1402, 1387, 1330,
1
1320, 1180, 1132, 1117, 1080 cm−1; H NMR (400 MHz, CDCl3) δ
1.92 (s, 6H), 5.48 (s, 2H), 7.17 (pseudo-t, J = 7.4 Hz, 1H), 7.37
(pseudo-t, J = 7.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.0, 63.4, 65.9, 117.0,
118.3, 118.3, 123.0, 127.4, 136.4, 150.7; MS (EI) m/z: 236 (5) [M]+,
172 (100), 157 (38), 128 (7); HRMS (EI) m/z: calcd for
C11H12N2SO2 [M]+ 236.0619, found 236.0627.
1,1,3-Trimethyl-1,3-dihydrothiazolo[3,4-b]indazole-2,2-di-
oxide (14d). Obtained from compound 13d (0.65 g, 2.98 mmol) as
described in the general procedure (reaction time: 2 h). After
purification by flash chromatography [hexanes/EtOAc (2:1)],
compound 14d was obtained as a pale yellow solid (0.55 g, 74%).
mp 136−138 °C (from diethyl ether); IR (KBr) 1628, 1460, 1439,
1385, 1322, 1284, 1161, 1123, 1105 cm−1; 1H NMR (400 MHz,
CDCl3) δ 1.88 (s, 3H), 1.95 (s, 3H), 2.04 (d, J = 6.6 Hz, 3H), 5.41 (q,
J = 6.6 Hz, 1H), 7.16 (pseudo-t, J = 7.4 Hz, 1H), 7.37 (pseudo-t, J =
7.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.5, 21.2, 23.7, 62.0, 71.7, 116.9, 118.3,
118.5, 122.8, 127.2, 135.1, 150.3; MS (EI) m/z: 250 (12) [M]+, 186
(100), 171 (86), 158 (38), 144 (25), 115 (16); HRMS (EI) m/z: calcd
for C12H14N2SO2 [M]+ 250.0776, found 250.0775.
General Procedures for Generation and Trapping of Benzo-
2,3-diazafulvenium Methides. Method A. A suspension of the
appropriate 1,3-dihydrothiazolo[3,4-b]indazole-2,2-dioxide 14 (0.40
mmol) and N-substituted maleimide (2 equiv, 0.80 mmol) in 1,2,4-
trichlorobenzene (3 mL) was heated at 230 °C under dry nitrogren for
2 h. After cooling to room temperature the product was isolated by
flash chromatography.
Method B. A suspension of the appropriate 1,3-dihydrothiazolo[3,4-
b]indazole-2,2-dioxide 14 (0.40 mmol) and N-substituted maleimide
(2 equiv, 0.80 mmol) in 1,2,4-trichlorobenzene (1 mL) was irradiated
in the microwave reactor at 230 °C for the time indicated in each case.
After cooling to room temperature the product was isolated by flash
chromatography.
1,3-Dimethyl-4-(3-methyl-1H-indazol-1-yl)-1H-pyrrole-2,5-
dione (18a). Method A. Obtained from compound 14a (49 mg, 0.24
mmol) as described in the general procedure. After purification of the
crude product by flash chromatography [hexanes, then hexanes/
EtOAc (2:1)], compound 18a was obtained as an intense yellow solid
(16 mg, 27%).
Method B. Obtained from compound 14a (60 mg, 0.29 mmol) as
described in the general procedure (reaction time: 10 min).
Purification by flash chromatography [hexanes, then hexanes/EtOAc
(2:1)] gave compound 18a (26 mg, 35%).
mp 157−159 °C (from hexanes/DCM); IR (KBr) 1708, 1677,
1445, 1388, 1091, 1016 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.23 (s,
3H), 2.62 (s, 3H), 3.13 (s, 3H), 7.27 (pseudo-t, J = 7.4 Hz, 1H), 7.46
(pseudo-t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 9.5, 12.1, 24.1, 112.2, 120.3,
122.3, 125.1, 127.7, 127.8, 135.9, 140.6, 147.7, 166.8, 171.0; MS (ESI)
m/z: 278 (100) [M + Na]+, 256 (8); HRMS (ESI) m/z: calcd for
C14H13N3O2Na [M + Na]+ 278.0906, found 278.0908; UV−vis
(CH2Cl2) λ/nm (ε/M−1 cm−1) = 387 (5348).
1,1-Dimethyl-1,3-dihydrothiazolo[3,4-b]indazole (13c). Ob-
tained from compound 12c1h (0.99 g, 5.76 mmol) as described in the
general procedure for method C (reaction time: 1 h). Purification by
flash chromatography [hexanes/EtOAc (3:1), then hexanes/EtOAc
(2:1)] gave compound 13c as a yellowish solid (0.77 g, 66%). mp 93−
95 °C (from hexanes/diethyl ether); IR (KBr) 1398, 1367, 1317, 1245,
1
1123, 1075 cm−1; H NMR (400 MHz, CDCl3) δ 1.95 (s, 6H), 5.57
(s, 2H), 7.07 (pseudo-t, J = 7.4 Hz, 1H), 7.29 (pseudo-t, J = 7.8 Hz,
1H), 7.61 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 31.2, 51.0, 51.2, 114.5, 118.2, 118.6, 121.2,
126.3, 143.9, 154.2; MS (EI) m/z: 204 (41) [M]+, 189 (100), 158
(29), 128 (11), 115 (16); HRMS (EI) m/z: calcd for C11H12N2S [M]+
204.0721, found 204.0724.
1,1,3-Trimethyl-1,3-dihydrothiazolo[3,4-b]indazole (13d).
Obtained from compound 12d1h (0.64 g, 3.44 mmol) as described
in the general procedure for method C (the reaction was completed
after finishing the addition of the solution of anthranilic acid).
Purification by flash chromatography [hexanes/EtOAc (3:1)] gave
compound 13d as a yellowish oil (0.47 g, 62%); IR (film) 1627, 1456,
1
1384, 1334, 1270, 1214, 1123 cm−1; H NMR (400 MHz, CDCl3) δ
1.92 (s, 3H), 1.98 (s, 3H), 1.99 (d, J = 6.4 Hz, 3H), 5.93 (q, J = 6.4
Hz, 1H), 7.07 (pseudo-t, J = 7.6 Hz, 1H), 7.29 (pseudo-t, J = 7.6 Hz,
1H), 7.61 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 24.1, 31.8, 32.0, 49.8, 61.8, 114.6, 118.2, 118.8,
121.1, 126.2, 143.2, 154.1; MS (EI) m/z: 218 (41) [M]+, 203 (100),
188 (17), 159 (16), 129 (10), 115 (15); HRMS (EI) m/z: calcd for
C12H14N2S [M]+ 218.0878, found 218.0880.
General Procedure for the Synthesis of 1,3-Dihydrothiazolo-
[3,4-b]indazole-2,2-dioxides. To a stirred ice-cold solution of the
appropriate 1,3-dihydrothiazolo[3,4-b]indazole 13 (1.00 mmol) in dry
dichloromethane (8 mL) was added portionwise 3-chloroperoxyben-
zoic acid (3.00 mmol) under N2 atmosphere. The cooling bath was
removed, and the reaction mixture was allowed to warm to room
temperature. After stirring at room temperature for the time indicated
in each case, the reaction mixture was washed twice with 10% (w/v)
aqueous sodium bisulfite solution (2 × 20 mL) and twice with 10%
(w/v) aqueous sodium bicarbonate solution (2 × 20 mL). The organic
fraction was then dried over anhydrous Na2SO4 and the solvent
evaporated off.
1,3-Dihydrothiazolo[3,4-b]indazole-2,2-dioxide (14a). Ob-
tained from compound 13a (227 mg, 1.29 mmol) as described in
the general procedure (reaction time: 1.5 h). The crude product was
triturated with diethyl ether to give 14a as a white solid (198 mg,
74%). mp 204−206 °C; IR (KBr) 1630, 1407, 1339, 1292, 1228, 1139
1
cm−1; H NMR (400 MHz, DMSO-d6) δ 5.13 (s, 2H), 5.86 (s, 2H),
7.16 (pseudo-t, J = 7.4 Hz, 1H), 7.36 (pseudo-t, J = 7.6 Hz, 1H),
7.68−7.73 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 51.7, 67.2,
117.3, 117.7, 120.0, 122.0, 126.8, 128.1, 149.3; MS (EI) m/z: 208 (11)
[M]+, 144 (100), 115 (28), 89 (14); HRMS (EI) m/z: calcd for
C9H8N2SO2 [M]+ 208.0306, found 208.0310.
3-Methyl-1,3-dihydrothiazolo[3,4-b]indazole-2,2-dioxide
(14b). Obtained from compound 13b (0.73 g, 3.84 mmol) as
described in the general procedure (reaction time: 2 h). The crude
product was triturated with diethyl ether to give 14b as a solid (0.45 g,
3-Methyl-4-(3-methyl-1H-indazol-1-yl)-1-phenyl-1H-pyrrole-
2,5-dione (18b). Method A. Obtained from compound 14a (83 mg,
0.40 mmol) as described in the general procedure. After purification by
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flash chromatography [hexanes, then hexanes/EtOAc (2:1)], com-
pound 18b was obtained as an intense yellow solid (36%).
Method B. Obtained from compound 14a (40 mg, 0.19 mmol) as
described in the general procedure (reaction time: 10 min).
Purification by flash chromatography [hexanes, then hexanes/EtOAc
(2:1)] gave compound 18b (19 mg, 31%).
9.6, 21.5, 27.5, 112.7, 120.4, 122.2, 123.7, 126.0, 127.3, 127.6, 127.7,
129.0, 131.3, 136.0, 140.8, 156.5, 165.4, 169.6; MS (EI) m/z: 345 (24)
[M]+, 186 (51), 172 (100), 157 (82), 130 (32), 102 (19), 77 (18);
HRMS (EI) m/z: calcd for C21H19N3O2 [M]+ 345.1477, found
345.1477; UV−vis (CH2Cl2) λ/nm (ε/M−1 cm−1) = 393 (5960).
3-Ethyl-4-(3-isopropyl-1H-indazol-1-yl)-1-methyl-1H-pyr-
role-2,5-dione (18g). Obtained from compound 14d (66 mg, 0.26
mmol) as described in the general procedure for method B (reaction
time: 15 min). Purification by flash chromatography [hexanes, then
hexanes/EtOAc (3:1)] gave compound 18g as a yellow oil (17 mg,
mp 193−195 °C (from hexanes/DCM) ; IR (KBr) 1714, 1679,
1
1495, 1449, 1382, 1348, 1120 cm−1; H NMR (400 MHz, CDCl3) δ
2.34 (s, 3H), 2.64 (s, 3H), 7.29 (pseudo-t, J = 7.6 Hz, 1H), 7.38
(pseudo-t, J = 7.0 Hz, 1H), 7.46−7.51 (m, 5H), 7.69−7.73 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 9.8, 12.1, 112.5, 120.4, 122.5, 125.2,
1
22%). IR (film) 1713, 1653, 1434, 1402, 1018 cm−1; H NMR (400
MHz, CDCl3) δ 1.20 (t, J = 7.4 Hz, 3H), 1.46 (d, J = 6.8 Hz, 6H), 2.71
(q, J = 7.4 Hz, 2H), 3.12 (s, 3H), 3.42 (h, J = 6.8 Hz, 1H), 7.23−7.27
(m, 1H), 7.44 (pseudo-t, J = 7.8 Hz, 1H), 7.73−7.76 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 11.9, 16.3, 20.6, 23.0, 26.5, 111.6, 119.4,
121.1, 122.8, 126.6, 131.8, 134.7, 139.9, 155.3, 165.9, 169.8; MS (EI)
m/z: 297 (10) [M]+, 282 (100), 210 (13), 197 (17); HRMS (EI) m/z:
calcd for C17H19N3O2 [M]+ 297.1477, found 297.1479; UV−vis
(CH2Cl2) λ/nm (ε/M−1 cm−1) = 390 (5538).
126.1, 127.5, 127.8, 127.9, 129.1, 131.5, 135.8, 140.7, 148.0, 165.5,
169.7; MS (EI) m/z: 317 (39) [M]+, 288 (16), 260 (10), 197 (34),
169 (100), 102 (13); HRMS (EI) m/z: calcd for C19H15N3O2 [M]+
317.1164, found 317.1163; UV−vis (CH2Cl2) λ/nm (ε/M−1 cm−1) =
390 (5331).
3-Ethyl-1-methyl-4-(3-methyl-1H-indazol-1-yl)-1H-pyrrole-
2,5-dione (18c). Obtained from compound 14b (123 mg, 0.55
mmol) as described in the general procedure for method B (reaction
time: 15 min). Purification by flash chromatography [hexanes, then
hexanes/EtOAc (3:1)] gave compound 18c as a yellow oil (12 mg,
3-Ethyl-4-(3-isopropyl-1H-indazol-1-yl)-1-phenyl-1H-pyr-
role-2,5-dione (18h). Obtained from compound 14d (41 mg, 0.16
mmol) as described in the general procedure for method B (reaction
time: 15 min). Purification by flash chromatography [hexanes, then
hexanes/EtOAc (3:1)] gave compound 18h as a yellow oil (18 mg,
1
8%). IR (film) 1709, 1654, 1443, 1386, 1074 cm−1; H NMR (400
MHz, CDCl3) δ 1.17 (t, J = 7.6 Hz, 3H), 2.62 (s, 3H), 2.71 (q, J = 7.6
Hz, 2H), 3.12 (s, 3H), 7.25−7.28 (m, 1H), 7.46 (pseudo-t, J = 7.6 Hz,
1H), 7.65−7.69 (m 2H); 13C NMR (100 MHz, CDCl3) δ 12.1, 12.8,
17.3, 24.0, 112.2, 120.3, 122.2, 125.1, 127.8, 133.3, 135.3, 140.7, 147.6,
166.9, 170.7; MS (EI) m/z: 269 (10) [M]+, 254 (100), 182 (28), 169
(24), 143 (5); HRMS (EI) m/z: calcd for C15H15N3O2 [M]+
269.1164, found 269.1165; UV−vis (CH2Cl2) λ/nm (ε/M−1 cm−1)
= 386 (4329).
1
30%). IR (film) 1716, 1656, 1502, 1386 cm−1; H NMR (400 MHz,
CDCl3) δ 1.26 (t, J = 7.4 Hz, 3H), 1.49 (d, J = 6.9 Hz, 6H), 2.81 (q, J
= 7.4 Hz, 2H), 3.45 (h, J = 6.9 Hz, 1H), 7.24−7.28 (m, 1H), 7.38
(pseudo-t, J = 7.0 Hz, 1H), 7.42−7.51 (m, 5H), 7.75 (d, J = 8.0 Hz,
1H), 7.81 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.0,
17.6, 21.6, 27.6, 112.9, 120.5, 122.3, 124.0, 126.1, 127.7, 127.8, 129.1,
131.5, 132.6, 135.7, 141.0, 156.7, 165.7, 169.5; MS (EI) m/z: 359 (27)
[M]+, 344 (100), 239 (51), 210 (36), 197 (31); HRMS (EI) m/z:
calcd for C22H21N3O2 [M]+ 359.1634, found 359.1630; UV−vis
(CH2Cl2) λ/nm (ε/M−1 cm−1) = 395 (5391).
General Procedure for Generation and Pericyclic Reactions
of Benzo-2,3-diazafulvenium Methides under MW. A suspen-
sion of the appropriate 1,3-dihydrothiazolo[3,4-b]indazole-2,2-dioxide
14 (0.20 mmol) in 1,2,4-trichlorobenzene (0.5 mL) was irradiated in
the microwave reactor at 230 °C for the time indicated in each case.
After cooling to room temperature the product was isolated by flash
chromatography.
3-Methyl-2-vinyl-2H-indazole (21) and 3-methyl-1H-inda-
zole (22). Obtained from compound 14b (62 mg, 0.28 mmol) as
described in the general procedure (reaction time: 15 min).
Purification of the crude product by flash chromatography [hexanes,
then hexanes/EtOAc (2:1)] gave, in order of elution, 3-methyl-2-vinyl-
2H-indazole 21 as a colorless oil (14 mg, 32%) and 3-methyl-1H-
indazole 22 as a yellowish solid (6 mg, 16%).
3-Methyl-2-vinyl-2H-indazole (21). IR (film) 1645, 1627, 1358,
1284 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.66 (s, 3H), 5.18 (d, J =
8.8 Hz, 1H), 6.14 (d, J = 15.2 Hz, 1H), 7.04 (pseudo-t, J = 7.6 Hz,
1H), 7.26−7.31 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 9.8, 105.8, 117.4, 119.9, 121.1,
121.5, 127.5, 130.0, 131.4, 148.8; MS (EI) m/z: 158 (100) [M]+, 131
(32), 102 (11), 84 (14); HRMS (EI) m/z: calcd for C10H10N2 [M]+
158.0844, found 158.0849.
3-Ethyl-4-(3-methyl-1H-indazol-1-yl)-1-phenyl-1H-pyrrole-
2,5-dione (18d). Obtained from compound 14b (53 mg, 0.24 mmol)
as described in the general procedure for method B (reaction time: 15
min). Purification by flash chromatography [hexanes, then hexanes/
EtOAc (3:1)] gave compound 18d as an intense yellow solid (10 mg,
1
13%). mp 118−120 °C; IR (KBr) 1714, 1670, 1503, 1374 cm−1; H
NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.4 Hz, 3H), 2.64 (s, 3H), 2.81
(q, J = 7.4 Hz, 2H), 7.26−7.30 (m, 1H), 7.38 (pseudo-t, J = 6.8 Hz,
1H), 7.44−7.51 (m, 5H), 7.69 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 11.1, 11.8, 16.5, 111.5, 119.3,
121.4, 124.2, 125.0, 126.8, 126.8, 128.1, 130.4, 131.9, 134.3, 139.7,
146.9, 164.6, 168.4; MS (EI) m/z: 331 (30) [M]+, 316 (100), 211
(65), 183 (67), 169 (50), 143 (15), 102 (10); HRMS (EI) m/z: calcd
for C20H17N3O2 [M]+ 331.1321, found 331.1322; UV−vis (CH2Cl2)
λ/nm (ε/M−1 cm−1) = 393 (4953).
3-(3-Isopropyl-1H-indazol-1-yl)-1,4-dimethyl-1H-pyrrole-
2,5-dione (18e). Obtained from compound 14c (80 mg, 0.34 mmol)
as described in the general procedure for method B (reaction time: 10
min). After purification by flash chromatography [hexanes, then
hexanes/EtOAc (3:1)], compound 18e was obtained as an intense
yellow solid (38 mg, 38%). mp 97−99 °C (from diethyl ether/
1
hexanes); IR (KBr) 1705, 1651, 1387, 1074 cm−1; H NMR (400
MHz, CDCl3) δ 1.47 (d, J = 7.0 Hz, 6H), 2.26 (s, 3H), 3.13 (s, 3H),
3.43 (h, J = 7.0 Hz, 1H), 7.24−7.27 (m, 1H), 7.45 (pseudo-t, J = 7.6
Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 9.5, 21.7, 24.1, 27.6, 112.6, 120.5, 122.2, 123.7,
127.6, 127.7, 136.2, 140.9, 156.3, 166.8, 171.1; MS (EI) m/z: 283
(100) [M]+, 268 (56), 252 (36), 198 (75), 183 (49), 155 (28), 102
(26); HRMS (EI) m/z: calcd for C16H17N3O2 [M]+ 283.1321, found
283.1319; UV−vis (CH2Cl2) λ/nm (ε/M−1 cm−1) = 388 (5845).
3-(3-Isopropyl-1H-indazol-1-yl)-4-methyl-1-phenyl-1H-pyr-
role-2,5-dione (18f). Obtained from compound 14c (74 mg, 0.31
mmol) as described in the general procedure for method B (reaction
time: 10 min). After purification by flash chromatography [hexanes,
then hexanes/EtOAc (2:1)], compound 18f was obtained as an
intense yellow solid (48 mg, 45%). mp 145−146 °C (from diethyl
3-Methyl-1H-indazole (22). The indazole 22 was identified by
comparison with a specimen previously described in the literature.9 mp
102−103 °C (from hexanes/diethyl ether), lit.9 113 °C. 1H NMR (400
MHz, CDCl3) δ 2.60 (s, 3H), 7.15 (pseudo-t, J = 7.4 Hz, 1H), 7.36−
7.44 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H).
2-Methyl-3-(prop-1-en-2-yl)-2H-indazole (23a). Obtained
from compound 14c (50 mg, 0.21 mmol) as described in the general
procedure (reaction time: 10 min). After purification by flash
chromatography [hexanes, then hexanes/EtOAc (1:1)], compound
23a was obtained as an oil (21 mg, 58%). IR (film) 1622, 1486, 1357,
1
1286, 1040 cm−1; H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 4.16
1
ether); IR (KBr) 1712, 1673, 1506, 1382, 1120 cm−1; H NMR (400
(s, 3H), 5.26 (s, 1H), 5.60 (s, 1H), 7.06 (pseudo-t, J = 7.4 Hz, 1H),
7.25−7.27 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 23.1, 38.6, 116.9, 120.3, 120.5, 121.3,
MHz, CDCl3) δ 1.50 (d, J = 6.9 Hz, 6H), 2.36 (s, 3H), 3.46 (h, J = 6.9
Hz, 1H), 7.26−7.29 (m, 1H), 7.40 (pseudo-t, J = 7.2 Hz, 1H), 7.43−
7.52 (m, 5H), 7.76−7.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
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dx.doi.org/10.1021/jo302463q | J. Org. Chem. 2013, 78, 628−637

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Article
126.0, 134.0, 137.2, 147.9; MS (EI) m/z: 172 (100) [M]+, 157 (54),
128 (14), 114 (10), 103 (6), 77 (6); HRMS (EI) m/z: calcd for
C11H12N2 [M]+ 172.1000, found 172.1001.
2-Ethyl-3-(prop-1-en-2-yl)-2H-indazole (23b) and 3-Isoprop-
yl-2-vinyl-2H-indazole (24). Obtained from compound 14d (39 mg,
0.16 mmol) as described in the general procedure (reaction time: 10
min). Purification of the crude product by flash chromatography
[hexanes, then hexanes/EtOAc (3:1)] gave, in order of elution, 3-
isopropyl-2-vinyl-2H-indazole 24 as a yellowish oil (7 mg, 23%) and 2-
ethyl-3-(prop-1-en-2-yl)-2H-indazole 23b as a colorless oil (20 mg,
71%).
2-Ethyl-3-(prop-1-en-2-yl)-2H-indazole (23b). IR (film) 1621,
1400, 1362, 1279, 1056 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.57 (t,
J = 7.2 Hz, 3H), 2.24 (s, 3H), 4.45 (q, J = 7.2 Hz, 2H), 5.25 (s, 1H),
5.59 (s, 1H), 7.04 (pseudo-t, J = 7.4 Hz, 1H), 7.25−7.28 (m, 1H), 7.58
(d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 16.2, 23.4, 45.9, 117.1, 120.2, 120.3, 120.4, 121.1, 125.9,
134.2, 136.6, 147.9; MS (EI) m/z: 186 (100) [M]+, 171 (66), 158
(36), 144 (21), 128 (24), 115 (14); HRMS (EI) m/z: calcd for
C12H14N2 [M]+ 186.1157, found 186.1157.
3-Isopropyl-2-vinyl-2H-indazole (24). IR (film) 1400, 1261,
1096, 1017 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.53 (d, J = 7.0 Hz,
6H), 3.54 (h, J = 7.0 Hz, 1H), 5.19 (d, J = 8.6 Hz, 1H), 6.16 (d, J =
15.2 Hz, 1H), 6.97 (pseudo-t, J = 7.6 Hz, 1H), 7.23−7.27 (m, 1H),
7.34 (dd, J = 8.6 and 15.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.73 (d, J
= 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.2, 26.6, 106.7,
117.7, 119.6, 120.9, 121.1, 127.0, 130.1, 140.6, 149.0; MS (EI) m/z:
186 (53) [M]+, 171 (100), 156 (16), 131 (12), 115 (13); HRMS (EI)
m/z: calcd for C12H14N2 [M]+ 186.1157, found 186.1155.
General Procedure for Generation and Pericyclic Reactions
of Benzo-2,3-diazafulvenium Methides under FVP. Pyrolysis of
the appropriate 1,3-dihydrothiazolo[3,4-b]indazole-2,2-dioxide (0.40
mmol) at 500 °C/2 × 10−5 mbar onto a surface cooled at −196 °C
over a period of 1 h gave a yellowish pyrolysate (the rate of
volatilization of the starting material was controlled by the use of a
Kugelrohr oven which heated the sample at 100−250 °C). After
cooling to room temperature the pyrolysate was removed from the
coldfinger with dichloromethane, and the solvent was removed in
vacuo. The products were isolated by flash chromatography.
3-Methyl-2-vinyl-2H-indazole (21). Obtained from compound
14b (47 mg, 0.21 mmol) as described in the general procedure.
Purification by flash chromatography [hexanes/EtOAc (2:1)] gave
compound 21 (23 mg, 69%), which was identified by comparison with
the specimen previously prepared.
2-Methyl-3-(prop-1-en-2-yl)-2H-indazole (23a). Obtained
from compound 14c (70 mg, 0.27 mmol) as described in the general
procedure. Purification by flash chromatography [hexanes/EtOAc
(2:1), then hexanes/EtOAc (1:1)] gave indazole 23a (34 mg, 73%),
which was identified by comparison with the specimen previously
prepared. Compound 23a was also obtained, although in lower yield
(61%), when FVP was carried out at 600 °C.
correction,12 the Lee, Young, Parr,13 and the Vosko, Wilk,
Nusair correlation functionals.14 For more details see the
Supporting Information.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for all new compounds, UV−vis
spectra of compounds 18, ORTEP, bond lengths and angles of
compound 18a determined by X-ray crystallography, and
theoretical calculation results; Cartesian Coordinates (Å)
obtained from the B3LYP/6-31G* calculations. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tmelo@ci.uc.pt
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Thanks are due to FCT (PEst-C/QUI/UI0313/2011 and
SFRH/BPD/64423/2009), FEDER, COMPETE, and QREN
for financial support. We acknowledge the Nuclear Magnetic
Resonance Laboratory of the Coimbra Chemistry Center
(www.nmrccc.uc.pt), University of Coimbra for obtaining the
NMR data. C.S.B.G. thanks Prof. M. Teresa Duarte for valuable
discussions on X-ray crystallography.
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