Intriguing enigma of nitrobenzofuroxan's ‘Sphinx’: Boulton-Katritzky rearrangement or unusual evidence of theN-1/N-3-oxide rearrangement?

Article abstract of DOI:10.1039/d0ra05249c

The S_EAr/S_NAr reaction between 7-chloro-4,6-dinitrobenzofuroxan (ClDNBF) and 2-morpholinyl-, 2-piperidinyl-, or 2-pyrrolidinylthiazole afforded unexpectedly two isomeric products, bearing the benzofuroxanyl moiety bound to the C-5 carbon atom of the thiazole ring. The relative ratio for the two isomers was dependent on temperature and solvent, suggesting the occurrence of an equilibrium between the two novel species. In order to investigate their structure and to design a plausible mechanistic pathway, a series of synthetic and spectroscopic experiments was planned. The isomer's structure was unambigously assigned when the reduction of furoxanyl to the furazanyl ring of the products gave exclusively a single species whose NMR data were coincident with those obtained by reacting the starting 2-aminothiazole derivatives with the 7-chloro-4,6-dinitrobenzofurazan (ClDNBZ). Possible mechanistic pathways might involveN-1-/N-3 oxide tautomerism or Boulton-Katritzky rearrangement and the current study is the first attempt to compare these two reactions. The data collected agree with the first one and DFT calculations permitted also a significant correlation with¹³C NMR experimental data and the assignment of the structure of each isomer. Finally, only one Meisenheimer intermediate for each electrophile/nucleophile combination was isolated by coupling the 2-aminothiazole derivatives with 4,6-dinitrobenzofuroxan (DNBF).

Full text of DOI:10.1039/d0ra05249c

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Intriguing enigma of nitrobenzofuroxan's ‘Sphinx’:
Boulton–Katritzky rearrangement or unusual
evidence of the N-1/N-3-oxide rearrangement?†
Cite this: RSC Adv., 2020, 10, 34670
a
b
Leonardo Iannuzzo,a Matteo Calvaresi,
Silvia Bordoni,a
*
Gabriele Micheletti,
Dario Telese,a Elena Chugunova
cd
a
*
and Carla Boga
The SEAr/SNAr reaction between 7-chloro-4,6-dinitrobenzofuroxan (ClDNBF) and 2-morpholinyl-, 2-
piperidinyl-, or 2-pyrrolidinylthiazole afforded unexpectedly two isomeric products, bearing the
benzofuroxanyl moiety bound to the C-5 carbon atom of the thiazole ring. The relative ratio for the two
isomers was dependent on temperature and solvent, suggesting the occurrence of an equilibrium
between the two novel species. In order to investigate their structure and to design a plausible
mechanistic pathway, a series of synthetic and spectroscopic experiments was planned. The isomer's
structure was unambigously assigned when the reduction of furoxanyl to the furazanyl ring of the
products gave exclusively a single species whose NMR data were coincident with those obtained by
reacting the starting 2-aminothiazole derivatives with the 7-chloro-4,6-dinitrobenzofurazan (ClDNBZ).
Possible mechanistic pathways might involve N-1-/N-3 oxide tautomerism or Boulton–Katritzky
rearrangement and the current study is the first attempt to compare these two reactions. The data
collected agree with the first one and DFT calculations permitted also a significant correlation with 13C
NMR experimental data and the assignment of the structure of each isomer. Finally, only one
Meisenheimer intermediate for each electrophile/nucleophile combination was isolated by coupling the
2-aminothiazole derivatives with 4,6-dinitrobenzofuroxan (DNBF).
Received 15th June 2020
Accepted 28th August 2020
DOI: 10.1039/d0ra05249c
rsc.li/rsc-advances
benzofuroxans were proposed to exhibit a dioxime peroxide or
o-dinitroso skeleton conguration, until 1912 when the current
Introduction
benzo[1,2-c]1,2,5-oxadiazole N-oxide formulation was sug-
gested,12 which was unequivocally conrmed only 50 years later
through NMR and X-ray crystal structure determinations.13,14
Benzofuroxan derivatives are still an interesting source of
peculiar structural features. The rst one is the possibility to
undergo isomerisation between the N-1-oxide and N-3-oxide
form, a transformation that is believed to occur via 1,2-dini-
trosoarene as transient intermediate (Scheme 1).
Since the N-1-oxide/N-3-oxide tautomerism is a fast equili-
brating system at room temperature, the 1,2-dinitrosoarene
constitutes a fugitive species. The existence of this elusive
species has been supported by both kinetic studies15,16 and
theoretical calculations.17,18 Spectroscopic indications (IR and
Benzofuroxan and its derivatives belong to a class of heterocy-
cles of wide and growing interest both in mechanistic and
applied elds.1–4 They can be exploited for many applications,
ranging from energetic materials5,6 to biologically active
compounds, depending on the type of substituents. As bioactive
compounds, they can behave as anti-parasitic, anti-microbial,
anti-fungal, immunosuppressive and anticancer agents, and
have anti-aggregating and vasorelaxant activity owing to their
ability to release NO under physiological conditions.7,8
Since its discovery,9 the benzofuroxanyl ring has been
a considerable challenge to structure attribution.10,11 First,
aDepartment of Industrial Chemistry ‘Toso Montanari’, Alma Mater Studiorum –
`
Universita di Bologna Viale Del Risorgimento, 4 402136 Bologna, Italy. E-mail:
gabriele.micheletti3@unibo.it; carla.boga@unibo.it
bDepartment of Chemistry ‘G. Ciamician’, Alma Mater Studiorum-Universita di
`
Bologna, Via F. Selmi 2, Bologna 40126, Italy
cArbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientic Center,
Russian Academy of Sciences, Akad. Arbuzov st. 8, Kazan, Tatarstan 420088, Russia
dLaboratory of Plant Infectious Diseases, FRC Kazan Scientic Center of Russian
Academy of Sciences, Lobachevskogo st. 2/31, Kazan, Tatarstan 420111, Russia
† Electronic supplementary information (ESI) available: 1H NMR, 13C NMR, mass
spectra of new compounds and cartesian coordinates for A and A0. See DOI:
10.1039/d0ra05249c
Scheme 1 N-1-Oxide/N-3-oxide tautomerism in benzofuroxan (and
its derivatives).
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Scheme 2 BKR rearrangement of 4-nitrobenzofuroxan.
Scheme 4 Synthesis of 2-aminothiazole derivatives 3a–c from 2-
bromothiazole (1) and amines 2a–c.
UV/Vis spectra) of its presence were obtained by photolysis of
benzofuroxan in argon matrices at 14 K.19 Further, the reaction
products recovered when benzofuroxan was reacted with ace-
tonylmethyl sulde,20 p-anisyl azide and diphenyldiazo-
methane21 were explained invoking the intermediacy of 1,2-
dinitrosoarene species. A similar dinitroso derivative was also
substantiated in the work of Terrier et al., that reported the
recovery and characterization of a diadduct from a Diels–Alder
cycloaddition as result of the reaction with a o-dinitroso
species.22 Recently, a ruthenium complex of the 1,2-dini-
trosoarene intermediate derived from the opening of the pen-
tatomic ring of benzofuroxan has been reported.23
The second characteristic feature of substituted benzofur-
oxans is their susceptibility to undergo Boulton–Katritsky
rearrangement (BKR)24,25 (Scheme 2). The BKR of 4-nitro-
benzofuroxan can be considered as a prototype reaction for
a class of molecular rearrangements and can compete with the
N-1-oxide/N-3-oxide tautomerization; the direction of this rear-
rangement depends on the substituent in 5 or 7 position.26,27
A third peculiar aspect of benzofuroxans resides into their
10p-electron structure which is able to confer electrophilic
properties.
In particular, when two nitro substituents are bound to the
carbocyclic ring of the benzofuroxan (or benzofurazan) or their
derivatives, these compounds are so much electrophilic to be
dened (labeled) as superelectrophiles.28,29 Actually, it is well-
known4,30–35 that the reaction of 4,6-dinitrobenzofuroxan
(DNBF) produces stable Meisenheimer intermediates, as well as
4,6-dinitrobenzofurazan (DNBZ), with a series of charged or
neutral nucleophiles. Recently, the coupling of 1,3,5-tri-
aminobenzene derivatives (TABa-c) or 2-aminothiazoles with
a series of electrophiles,35–38 including DNBF or DNBZ, gave
evidence of the zwitterionic intermediate – contemporaneously
Wheland and Meisenheimer – formed in these SEAr/SNAr
aromatic substitution reactions (e.g. WMa-h in Scheme 3). In
Scheme 3 we represented the N–O position of WM intermedi-
ates on the basis of X-ray diffraction analysis on WMh.
In the thiazole series in particular, the coupling between 2,4-
dipyrrolidinylthiazole and DNBF produced the intermediate
WMh (Scheme 3, bottom), which was stable enough to provide
the rst X-ray crystal structure along the class of zwitterionic
intermediates, likely due to the high stabilization of the positive
charge conferred to the Wheland moiety by both the
Scheme 3 Examples of WM intermediates detected and characterized using DNBF or DNBZ as electrophiles.
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pyrrolidinyl groups.38 On the other hand, 2,4-dipyrrolidinyl atom, endocyclic nitrogen atom, and C-5. However, the selected
thiazole is such an activated nucleophile that gives a very substrates 3a–c bear a secondary amino group in position 2 that
complicated mixture of products when reacted with electro- prevents the tautomeric equilibrium occurring when a –NH2 or
philes such as aryldiazonium salts.39
–NHR group is present in that position. Thus, only the products
On the contrary, when 2-pyrrolidinylthiazole reacted with 5a–c derived from the nucleophilic attack at C-5 were expected
aryldiazonium salts, the corresponding azo derivatives bound to be formed (Scheme 5), as previously found for aryldiazonium
in position 5 (ref. 39) of the thiazole ring were formed in good salts.39
yields.
As soon as the reaction between 3a–c and 7-chloro-4,6-
A literature survey revealed that both the 2-pyrrolidinylth- dinitrobenzofuroxan (4, or ClDNBF), run at room temperature
iazole and the analogous 2-piperidinyl- and 2-morpholinyl- in acetonitrile with 2 : 1 molar ratio, started, the color of the
derivatives (3a–c in Scheme 4) have been poorly studied so far. mixture turned from pale yellow to deep blue.
Since it is well known that chloronitro- or chlorodinitro-
The reaction was monitored by TLC, showing the spot rela-
benzofuroxans and -benzofurazans easily give C–C coupling tive to novel blue species at RF higher than those related to the
with many nucleophiles30,31,36,40–42 producing a plethora of starting reactants. Aer 24 h (for the combination 3a/4), 12 h
compounds of interest in applied elds (e.g. pharmaceutical, (for 3b/4), or 4 h (for 3c/4), the crude product obtained was
energetic, optoelectronic), we designed to carry out the reaction subjected to column chromatography on silica gel (FC) leading
of the 2-aminothiazole derivatives with 7-chloro-4,6- to isolation of the novel species.
dinitrobenzofuroxan
(ClDNBF)
or
7-chloro-4,6-
The ESI-MS spectrum of the blue solid isolated by FC was in
dinitrobenzofurazan (ClDNBZ) to obtain novel hybrids bearing agreement with that of a product derived from the aromatic
two moieties, the thiazolyl- and the benzofuroxanyl (or benzo- substitution between 3a–c and 4, but the 1H- and 13C-NMR
furazanyl-) one.43
spectrum showed a number of signals higher with respect to
Inspired by these considerations, we focused our investiga- those expected for species 5a–c. In particular, the 1H NMR
tions on the above reactions to obtain novel highly conjugated spectrum in CD3CN of the solid derived from the reaction
systems and to exploit new insights on their mechanistic between 3c and 4 exhibited four singlets in the aromatic region
behavior.
(Fig. S30, in ESI†). The signal multiplicity and the relative
integration suggested the presence of two isomers in 62/38
relative molar ratio bearing the benzofuroxanyl moiety bound
to the C-5 of the thiazole moiety, labeled as 5c and 50c in Scheme
5. Aer many attempts, the separation of two blue spots was
achieved on preparative TLC plate by eluting with a mixture of
diethyl ether: light petroleum (7 : 3 v/v). Then, each spot was
scraped and worked-up (see Experimental), and the organic
residues were dissolved in CD3CN and analyzed by NMR spec-
troscopy. Surprisingly, each spectrum showed presence of two
compounds, as previously observed aer FC, thus suggesting
the occurrence of a re-equilibration phenomenon.
Results and discussion
2-Morpholinylthiazole (3a), 2-piperidinylthiazole (3b) and 2-
pyrrolidinylthiazole (3c) have been synthesized at room
temperature and under solvent-free conditions by reacting 2-
bromothiazole (1) with morpholine (2a), piperidine (2b), or
pyrrolidine (2c), respectively (Scheme 4).
Compounds 3a–c have been synthesized within 24, 4 and 2 h
reaction time affording 90, 95 and 98% yield respectively; the
different reaction time required to reach the above indicated
yields is likely due to the different nucleophilicity of the starting
amines whose values, according to the nucleophilicity scale
This prompted us to plan further experiments to shed some
light on this behavior and, for the sake of clarity, below we
report in sub-headings the results obtained.
developed by Mayr,44–47 are, in acetonitrile at 20 ꢀC, NMayr
15.65, 17.35, and 18.64 for morpholine, piperidine, and pyrro-
lidine, respectively.48
¼
Is the isomeric ratio affected by solvent nature or
It is known that 2-aminothiazoles can behave as nucleo-
philes at three distinct positions, namely, exocyclic nitrogen
temperature?
First, we investigated whether the relative ratio between the two
isomers 5 and 50 could be inuenced by the reaction conditions
such as the solvent or the temperature. For this purpose, we
planned to investigate the behavior of the isomeric mixture 5c +
50c derived from the combination of 3c and 4, since in case c the
reaction occurs in a considerably shorter time.
A rst series of experiments has been run by recording the 1H
NMR spectrum of the isomeric mixture, aer its isolation by FC,
in different solvents at 25 ꢀC. We attributed the two set of
signals to the isomers labelled as A and A0 without direct rela-
tion to the structure 5c or 50c of Scheme 5. The results are re-
ported in Table 1.
Scheme 5 C–C coupling reaction between 3a–c and 4 with forma-
tion of the expected products 5a–c together with unexpected
isomers.
From the relative integration of the signals of the two
species, and by supposing the same trend of related chemical
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Table 1 Relative ratio of the isomersa derived from the reaction between 3c and 4 in different solvents
c
Entry
Solvent polarityb
Solvent
Isomerc A (%)
Isomer A0 (%)
1
2
3
4
5
6
7
Benzene 0.111
THF 0.207
Benzene-d6
53
50
55
57
60
67
59
47
50
45
43
40
33
41
Tetrahydrofuran-d8
Chloroform-d1
Acetone-d6
Acetonitrile-d3
DMSO-d6
CHCl3 0.259
Acetone 0.355
CH3CN 0.460
DMSO 0.444
CH3OH 0.762
Methanol-d4
a
1
Aer isolation by FC. b Data from ref. 49. c Calculated from the H NMR spectrum recorded at 25 ꢀC.
1
shi along the solvents, it can be evinced that their relative ratio the H NMR spectra recorded in the rst two solvents showed
is always in favor of the same isomer (except in THF-d8, entry 2 that the A/A0 ratio was the same to what reported in entries 3
of Table 1). The most relevant difference was observed in and 5 of Table 1, respectively. Surprisingly, no product was
DMSO-d6 (entry 6 of Table 1). On going from THF to acetonitrile formed when the reagents were mixed in DMSO-d6.
(entries 2–5 of Table 1) it emerge that the relative ratio is slightly
In Table 3 are reported the results obtained by 1H NMR
dependent from the solvent even if, from the data obtained, spectroscopy, from the reaction between 3c and 4 carried out at
a clear correlation with the solvent polarity cannot be advanced.
1
In a second series of experiments we analyzed the H NMR
spectrum of the mixture A + A0, isolated by FC, at variable
temperature and in different solvents; the results are reported
in Table 2.
Table
reaction between 3c and 4 in different solventsb
3
Variable temperaturea experiments by monitoringa the
c
Temp (ꢀC)
Conversion
A/A0
In DMSO-d6 the spectrum of the mixture was recorded from
25 ꢀC to 80 ꢀC (Table 2, entries 1–5): on raising the temperature,
a gradual increase (until 15%) of the minor isomer was
observed. On the contrary, no signicant variation of the
Solvent
CDCl3
ꢁ48
32
40
50
58
71
90
93
36
42
45
66
74
84
91
99
7
43/57
36/64
34/66
31/69
41/59
55/45
56/44
75/25
80/20
85/15
78/22
73/27
72/28
62/38
62/38
95/5
93/7
92/8
95/5
96/4
96/4
96/4
93/7
ꢁ37
ꢁ26
ꢀ
isomeric ratio was observed both in acetonitrile (from 25 C to
ꢁ15
40 ꢀC, Table 2, entries 6–10) and in acetone (from +25 ꢀC to
ꢁ4
ꢀ
+30
ꢁ90 C, Table 2, entries 11–15).
+40
In a third series of experiments, the reaction was carried out
by mixing the reagents directly in the NMR spectroscopy tube
and monitoring it with time. When reagents 3c and 4 (in 2 : 1
molar ratio) were mixed at 25 ꢀC in CDCl3, CD3CN, or DMSO-d6,
CD3CN
ꢁ43
ꢁ32
ꢁ21
ꢁ9
+6
+13
+24
Table 2 Isomeric ratio of the productsa derived from 3c and 4 in
different solvents at different temperatures
+24 aer 1 day
CD3COCD3
ꢁ93d
ꢁ82d
7
8
8
ꢁ71d
Entry Solvent
Temperature (ꢀC) Isomer Ab (%) IsomerA0b (%)
ꢁ59d
ꢁ48d
11
22
35
51
61
71
78
86
94
1
2
3
4
5
6
7
8
DMSO-d6
CD3CN
25
35
50
70
80
25
35
45
55
65
67
65
64
60
57
62
61
59
58
58
57
60
60
60
60
33
35
36
40
43
38
39
41
42
42
43
40
40
40
40
ꢁ37d
ꢁ26d
ꢁ15
ꢁ15 aer 10 min.
87/13
72/28
63/37
59/41
58/42
ꢁ4
ꢁ4 aer 10 min.
+8d
+25d
9
a
10
11
12
13
14
15
Reaction carried out directly in the NMR spectroscopy tube by mixing,
at the lowest temperature indicated in the Table 3, 3c and 4 in 2 : 1
CD3COCD3 25
0
b
molar ratio. Monitoring of the reaction conversion and isomeric
ꢁ20
ratio of the products through 1H NMR spectroscopy at variable
c
temperature. The % molar ratio was calculated from the NMR
spectrum of the crude reaction mixture. The conversion and relative
ratio values remained unchanged within 10 min aer varying the
ꢁ50
d
ꢁ90
a
1
Aer isolation by FC. b Calculated from the H NMR spectrum.
temperature.
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temperatures), but limited conversion at lower temperatures
and trend of the isomer ratio and conversion on raising the
temperature (see data of Table 3) do not permit to infer if the
formation of A and A0 is ruled by kinetics or thermodynamic
control (or by both).
Moreover, it is worth note that, in the 1H NMR spectra
recorded when the conversion was not complete, the signals
belonging to the unreacted starting aminothiazole result coin-
cident to the salied one. This observation indicates that the
two species (i.e. protonated and not-protonated 2-amino-
thiazole) are in equilibrium, as we already reported in analo-
gous protonation reactions.39,50
Finally, we want to point out the peculiarity of the behavior
showed by the herein reported coupling between 4 and 2-ami-
nothiazole derivatives 3a–c; actually, in our previous studies on
the C–C coupling between ClDNBF and diamino-, triamino- or
trihydroxybenzene derivatives, solely one product was always
isolated.35,42
Scheme 6 Possible rearrangements of the product derived from the
reaction between ClDNBF and 3a–c. via (i): N-1/N-3-oxide equilibrium
forming two structural isomers B1 and B2; via (ii): BKR from B1 to B3.
1H NMR experiments of ClDNBF from +25 to ꢁ93 ꢀC in
acetone-d6 were also carried out to test the opportunity to detect
the presence of two species or to trap the suggested dinitroso
intermediate, but no variation was detected.
low temperature directly in the NMR tube inserted in a cryo-
probe. The reaction was monitored with time and at different
temperatures.
The reaction was carried out in acetone-d6 at ꢁ93 ꢀC, in
CDCl3 at ꢁ48 ꢀC, and in CD3CN at ꢁ43 ꢀC. In all cases, the
1
conversion was low and the H NMR spectrum showed preva-
What about the structure of the two isomers?
lence of signals for one isomer. On raising the temperature, the
conversion gradually increased. At +25 ꢀC the conversion was
complete and the relative isomeric ratio was in all cases about 6/
4, in agreement with results obtained from reaction carried out
at room temperature (Table 1). It has to be noted that, in CDCl3,
once the reaction was complete, the major isomer was the
opposite with respect to that formed at low temperature.
In acetone-d6 the conversion and the isomeric ratio (ꢂ95/5)
remained almost unchanged from ꢁ93 ꢀC to ꢁ60 ꢀC, then
The unexpected nding for the reaction between ClDNBF and
aminothiazoles 3a–c related to the formation of two isomers
(5a–c and 50a–c) give rise to questions on their structure and
mechanism of formation.
From the mechanistic point of view, it has to be considered
that, in principle, the products from the reaction between 3a–c
and ClDNBF might undergo structural rearrangement through
two main pathways: (i) N-1-oxide/N-3-oxide tautomerism (via (i)
in Scheme 6) or Boulton-Katritzky rearrangement (BKR, via (ii),
red arrows in Scheme 6). The rst equilibrium is a ring open-
closure via the 1,2-dinitroso intermediate which, in the
current case, might produce species B1 and B2 (Scheme 6), with
a formal shi of oxygen atom from N-1 to N-3.
ꢀ
they gradually changed. At 25 C, the reaction goes to comple-
tion and the isomeric ratio gradually was 58/42.
The behavior in acetone may suggest that isomer A could be
kinetic product (A is almost the exclusive species at lower
Scheme 7 Synthetic routes designed to obtain 8c.
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The second reaction pathway, i.e. BKR, occurs when the ascertain the structure of the product derived from the reduc-
benzofuroxan moiety bears a nitro group bound to the carbon tion of the mixture A + A0. For this purpose, we planned to
atom belonging to the carbocyclic ring and adjacent to the prepare an authentic sample of the product that might derive
fusion carbon, as occurs in current case. In Scheme 6 we indi- from the reduction of B1 and B2, namely 8c, in order to compare
cated the occurrence of BKR on the reaction product B1, since it the spectroscopic data with those of the product obtained by
has been reported that
rearrangement.51
4
does not undergo BKR reduction of the mixture 5c + 50c. As our rst approach, we
designed to obtain 8c by nitration of 7c, in turn obtained from 4-
Although both the mechanisms might simultaneously occur, chloro-7-nitrobenzofurazan (6, ClNBZ) and 3c (via a in Scheme
the presence in the 1H NMR spectrum of the crude reaction 7) but the SNAr with ClNBZ did not occur, likely due to the poor
mixture of signals ascribable to two novel species prevents this electrophilicity of 6 with respect to 4.
hypothesis. Actually, in case of occurrence of both the rear-
Therefore we used via b as alternative procedure (Scheme 7).
ragements, the signals of three products, namely B1, B2, and B3 4-Chloro-5,7-dinitrobenzofurazan (9) was prepared by nitration
must be expected in the spectrum. Therefore, we planned of ClNBZ and reacted with 3c to give 8c, whose chemico-physical
further experiments to discriminate between the two pathways. data were in agreement with the unique compound obtained by
Focusing attention to the possible N-1/N-3 oxide interconver- reduction of the two isomers 5c and 50c. Moreover, by adding
sion, we realized that the reduction of B1 and B2 from furoxan a little amount of 8c to the product obtained by reduction of the
1
derivatives to furazans would produce the same product. Thus, mixture A + A0, increasing of the related H NMR signals was
the isomeric mixture 5c/50c (also indicated as A and A0 in Tables signicantly observed. Through an analogous procedure we
1–3, without correspondence of the structure of A or A0 with 5c synthesized also 8a and 8b. Compounds 8a–c are novel and
in Scheme 5) derived from the reaction between 3c and 4 was might be of interest in applied eld, since they bear contem-
subjected to reduction with triphenylphosphine in xylene. Since porarily an electron-donor and an electron-withdrawing moiety.
only one compound has been recovered, the occurrence of the 1-
oxide/3-oxide tautomerism sketched in Scheme 6 is therefore B3 in favor of 1/3-oxide rearrangement, by considering that
strongly supported.
upon reduction of the furoxan ring of A + A0 to furazan one, only
Summarizing, the above ndings bring to exclude structure
However, it is not possible to exclude, ‘a priori’, the occur- product 8c was formed. One plausible explanation for the not
rence of the preferential reduction of one of the two species formation of B3 might be ascribed to the steric hindrance of the
involved in the BKR rearrangement; in this case, due to the two nitro substituents in ortho position with respect to the
equilibrium, only one isomer might be recovered aer reduc- thiazole moiety in the BKR product.
tion. To shed light on this aspect, it has been necessary to
Table 4 Calculated energies for A and A0 tautomers. Experimental and calculated 13C chemical shiftsa
Energy (kcal molꢁ1
)
0.0
0.23
13C chem. shis
Calc.
Exp.a (A, major isomer)
Calc.
Exp.a (A0, minor isomer)
C3a
C4
C5
C6
C7
C7a
C8
C9
C10
C11
C12
106.12
127.03
125.03
138.13
127.38
151.20
115.67
157.53
171.60
50.64
105.95
124.97
127.87
137.95
128.04
151.26
113.83
156.57
172.54
50.76
144.84
126.21
128.71
137.51
129.73
114.73
110.92
156.59
173.37
50.97
144.89
125.38
128.53
138.93
130.72
113.43
109.06
153.85
172.38
50.76
27.23
25.61
27.21
25.55
a
Data from spectra recorded at T ¼ 25 ꢀC in CDCl3.
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chemical shis was used for the assignment of the 13C chemical
shis of the two tautomers. The 13C theoretical chemical shis
(Table 4) correlate very well with the experimental data, with
correlation coefficients of least-squares linear ts (R2) close to
unity (0.9995 and 0.9992 respectively for A and A0).
Theoretical calculations allowed also the determination of
the energy of the tautomers A and A0. In agreement with the
assignment of the 13C chemical shis of the two tautomers, the
most abundant tautomer A (N-3-oxide) is also energetically
more stable than A0 (N-1-oxide). The energetic difference
between the two tautomers is very small (0.23 kcal molꢁ1),
explaining their presence in a isomeric mixture (Table 1).
The two tautomers show a similar structure (Fig. 1), the main
factor that control their relative stability is (i) the presence of an
non-standard intramolecular hydrogen bond between C9–H9 and
N-1 in tautomer A and N-1-oxide in tautomer A0, (ii) the steric/
electrostatic repulsions between the N-oxide moieties with the
nitro-group in tautomer A or C9–H9 bond in tautomer A0.
Fig. 1 Molecular structure of (a) N-3-oxide, (b) N-1-oxide tautomers.
These ndings are in agreement with those previously re-
ported by Chistyakov et al. on the reaction between 4 and N-
methylpyrrole that gave two 1,3-N-oxide tautomers.52
Further mechanistic insights: reaction of 3a–c with 4,6-
dinitrobenzofuroxan
DFT calculations
The above nding of two isomeric species derived from the
The relative 13C NMR signals of A and A0, owing to their different aromatic substitution reaction involving ClDNBF has never re-
relative ratio were attributed by g-HSQC NMR experiments ported before.
(Table 4). However, the tautomeric structure of A and A0 (due to
By using nucleophilic species such as diamino- or triamino-
the 1/3-oxide rearrangement) in solution cannot be unambi- benzenes, only one substituted product has been recovered
gously assigned by NMR experiments solely. from the reaction with ClDNBF. Further, no evidence of
One of the main difficulties in studying these compounds isomeric intermediates such as Meisenheimer (M) or Wheland-
spectrometrically resides mainly in the lack of spin markers Meisenheimer (WM) species was so far reported from C–C
(protons). The g-HSQC experiments allowed to assign with coupling reactions of 4,6-dinitrobenzofuroxan (10, DNBF) either
condence only correlations with the H5 and H9 signals while with amino- (or hydroxy)-benzenes or 2,4-dipyrrolidinylthiazole
other correlations are usually too weak to be used in structural (11 in Scheme 8). In the latter case, the isomeric structure of the
elucidation. Quantum mechanical calculations of 13C NMR isolated intermediate (WM in Scheme 8) was ascertained by X-
chemical shis are widely used to make easier signal assignment. ray diffraction analysis. The particular behavior found by
Thus, a joint analysis of experimental and calculated NMR 13C coupling 2-aminothiazoles 3a–c with ClDNBF suggested us to
Scheme 8 Formation of stable intermediates of reactions between DNBF and 2,4-dipyrrolidinylthiazole (11) or 2-aminothiazoles 3a–c.
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investigate the reaction with DNBF. Equimolar amount of DNBF
and 3a (or 3b, 3c) were mixed in acetone-d6 at ꢁ93 ꢀC in a NMR
spectroscopy tube and the mixture was analyzed by NMR at
Experimental
General
1
The 1H and 13C NMR spectra were recorded at 300, 400, or 600
MHz (1H NMR) and 75.46, 100.56, or 150.80 MHz (13C NMR),
respectively. J values are given in Hz. Signal multiplicities were
established by DEPT-135 experiments. Chemical shis were
referenced to the solvent [d ¼ 7.27 and 77.0 ppm for CDCl3), (d ¼
1.96 and 118.26 ppm for CD3CN), (d ¼ 2.05 and 30.2 ppm for
ꢀ
ꢁ93 C. Immediately aer mixing, new born H NMR signals
appeared in the spectrum, compatible with those of the s-
anionic intermediate Ma (or Mb, Mc) (Scheme 8). In particular,
diagnostic was the signal at high eld (5–6 ppm) and ascribable
to the sp3 hybridized carbon atom bound to H-7, which is
involved in the newly formed C–C bond. Moreover, two singlets
belonging to H-5 and H-40 were present in the 5–10 ppm region
(see Spectra in ESI†).
1
CD3COCD3), (d ¼ 2.50 and 39.5 ppm for DMSO-d6) for H and
13C NMR, respectively]. ESI-MS spectra were recorded using
a Waters 2Q 4000 instrument. Chromatographic purications
(FC) were carried out on silica gel columns at medium pressure.
TLC was carried out on aluminum coated silica gel with 254 nm
uorescence indicator (Fluka, DC-Alufolien-Kieselgel).
ClNBZ was commercially available, whereas 2-pyrrolidi-
nylthiazole (3c),39 7-Chloro-4,6-dinitrobenzofurazan (ClDNBZ,
9),35 7-Chloro-4,6-dinitrobenzofuroxan (ClDNBF, 4),43 and 4,6-
dinitrobenzofuroxan (DNBF, 10),34 were synthesized and puri-
ed as previously described. All novel solid compounds
decomposed when heated in melting point apparatus. Although
the reactions carried out in NMR spectroscopy tube showed
conversion almost quantitative, the yields in isolated products
were lower, likely due to purication methods, but we did not
focus our efforts on yield optimization. Computational and
variable temperature NMR experimental details are reported in
ESI.†
On gradually raising the temperature, the intensity of signals
of Ma–Mc increased, whereas those of reactants gradually
disappear (at 25 ꢀC and 0 ꢀC completely for cases b and c,
respectively; whereas, in case of a traces of reagents were
ꢀ
present at 25 C).
Once the conversion has been complete, a red solid appeared
at the bottom of the tube extracted from the NMR probe. The
solid was collected, then dissolved in DMSO-d6 for 1H NMR, 13
C
NMR and g-HSQC experiments that conrmed the Mei-
senheimer structure. The solid was stable enough to be
analyzed also through ESI mass spectrometry (negative ion
mode).
In principle, in the reactions between 3a–c and 10 the species
WMa-WMc (Scheme 8) are the rst covalent intermediates but
only M species were spectroscopically detected.
Conversely, the presence of two amino groups on the thia-
zole moiety (as in compound 11), stabilizes so strongly the
corresponding zwitterionic WM intermediate to allow its
isolation and the rst example of X-ray structural determination
in such elusive species38 (WM in Scheme 8). This indicates that
the lack of the second amino group give rise to zwitterionic
fugitive species WMa-WMc undetectable on the NMR time
scale. Further, as a matter of facts, only one M species has been
detected and isolated for each electrophile/nucleophile combi-
nation by coupling 3a–c with 10. In Scheme 8 (as well as in
Scheme 3) we have represented the structure of WMa-WMc and
Ma-Mc intermediates as N-1 oxides by analogy with the struc-
ture of WM, and also in agreement with literature data from
which it emerges that the N-oxide in ClDNBF and DNBF is sit-
uated on the nitrogen farthest from the nitro group in peri
position (and adjacent to the junction carbon). Moreover, in
current case, as well as in those represented in Scheme 3, in
which DNBF is used (and chlorine is absent), the experimental
nding of only one intermediate might be explained taking into
consideration that the formation of the two isomers (N-1-oxide
and N-3-oxide) through the passage to dinitrosobenzene is
disadvantaged or impeded as the tautomeric process involves
rearomatization of the carbocyclic ring which is unlikely when
a negative charge still exists on the latter as in M or WM and the
departure of the hydride ion is generally difficult. On the
Synthesis of compounds 3a–c
General procedure. 2-Bromothiazole (0.56 mL, 6.22 mmol)
was added to 5 mL of amine (morpholine, piperidine, pyrroli-
dine) and the mixture was kept at reux under magnetic stir-
ring. The conversion of 2-bromothiazole was monitored
through TLC (eluent: diethyl ether/petroleum light 8/2; RF
¼
0.45) and GC-MS. Aer 24 h, 4 h and 2 h in case of use of
morpholine, piperidine or pyrrolidine, respectively, the excess
of amine was removed under vacuum in a rotavapor then the
product was puried through column chromatography on silica
gel (eluent: diethyl ether/petroleum light 8/2; RF ¼ 0.45). The
product obtained aer FC sometimes appeared as viscous
liquid; in this case, the residual solvent was removed by adding
little amount of chloroform or dichloromethane then ltering
off the liquid. Compounds 3a–c were obtained in yield of 90
(3a), 95 (3b), and 98% (3c), respectively, and their data agreed
with those reported in the literature (ref. 53, 54 and 39 for 3a,
3b, and 3c, respectively). They were stored in freezer and in the
dark.
Reaction between 3a–c and ClDNBF
General procedure. To a solution of ClDNBF (0.023 g, 0.088
contrary, in the case in which the starting electrophile is mmol) in acetonitrile (7 mL), 0.030 g of 3a, 3b or 0.028 g for 3c
ClDNBF, as in current case, likely the isomerization occurs (0.177, 0.179, or 0.181 mmol, respectively) were added at room
immediately aer the departure of the chloride, which would temperature. Immediately, the solution turned blue and was
make stable, even if for a very short life time, the dini- monitored by TLC (eluent: CH2Cl2/ethyl acetate 9/1) under
trosobenzene, thus making possible the formation of the two magnetic stirring. Aer 24, 12 and 4 h, respectively, the solvent
isomers A and A0.
was removed in vacuo and the residue subjected to FC eluting
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with CH2Cl2 until the rst blue eluate was obtained, then with Maj/Min ratio ¼ 56 : 44) d (ppm): 8.73 (s, 1H, Maj), 8.66 (s, 1H,
the CH2Cl2 : ethyl acetate 9 : 1. The collected fractions were Min), 8.35 (s, 1H, Min), 7.90 (s, 1H, Maj), 3.72–3.33 (m, 8H, Maj
1
concentrated in vacuo and analyzed through H NMR and 13C + Min), 2.14–1.94 (m, 8H, Maj + Min); 13C NMR: (150.8 MHz,
NMR, and mass spectrometry. The NMR analysis indicated CDCl3, 25 ꢀC) d (ppm): 172.8, 172.7, 156.8 (CH), 154.9 (CH),
presence of two species. Many attempts to obtain crystals suit- 151.3, 145.0, 138.6, 137.9, 130.3, 128.6 (CH), 127.9, 125.6, 125.0,
able for X-ray diffraction analysis failed. The mixture was sub- 124.9 (CH), 113.9, 113.3, 109.2, 106.0, 50.6 (NCH2, 2 broad
jected to preparative TLC and the two separated spot were signals overlapped), 29.7 (NCH2CH2), 25.6 (NCH2CH2); HRMS
scraped but, once each was dissolved in CD3CN to be analyzed, (ESI+) m/z: [M + H]+ calcd for C13H11N6O6S+: 379.0455; found:
the 1H NMR revealed presence of a mixture of two compounds 379.0466.
in relative ratio equal to that found prior to separation. Thus,
below we report the physico-chemical data of the mixture of
isomers and, due to the presence of two isomers, we considered
Synthesis of 7-(2-dialkylaminothiazol)-4,6-dinitrobenzo[c]
[1,2,5]oxadiazoles
sufficient to record ESI-MS data. In particular, when, from the
1H NMR spectrum, it was evident that the two species were
General procedure. To a solution of ClDNBZ (0.018 g, 0.074
present in different amount, we indicated as Maj or Min the mmol) in acetonitrile (9 mL) 0.028 g of 3a (or 3b, or 3c) (0.165,
signals of the isomer present in major or minor amount, 0.167, 0.182 mmol, respectively) were added. Immediately aer
respectively. On the basis of the analysis derived from experi- the reagents mixture, the colour of the solution turned blue.
mental data/DFT calculations, below we report the names of the The reaction was carried out at room temperature and under
isomers attributing structure A0 to 5c and A to 50c, and assuming magnetic stirring, and the conversion was monitored through
analogous behaviour also for cases a and b.
TLC analysis (eluent: CH2Cl2). Aer 4 h, 3 h and 2 h, for the
reaction with 3a, 3b, or 3c, respectively, the solvent was removed
7-(2-Morpholinothiazol-5-yl)-4,6-dinitrobenzo[c][1,2,5]oxa-
diazole 1-oxide (5a) and 4-(2-morpholinothiazol-5-yl)-5,7-dini- in vacuo and the crude residue was chromatographed on silica
trobenzo[c][1,2,5]oxadiazole 1-oxide (50a). Dark blue solid, gel column eluting with CH2Cl2 giving pure substitution
0.008 g, 24% yield; 1H NMR (300 MHz, CD3CN, 25 ꢀC, isomeric compounds 8a–c. Compound 8c was obtained also from
Maj (50a)/Min (5a) ratio ¼ 67 : 33) d (ppm): 8.73 (s, 1H, Maj), 8.47 reduction of the isomeric mixture 5c/5c0 with P(Ph)3 in xylene
(s, 1H, Min), 8.32 (s, 1H, Min), 7.71 (s, 1H, Maj), 3.85–3.75 (m, using the procedure already reported of reduction of benzo-
1
8H, Maj + Min), 3.67–3.59 (m, 8H, Maj + Min); H NMR (399.9 furoxans to benzofurazans.55
ꢀ
MHz, CDCl3, 25 C, isomeric Maj/Min ratio ¼ 50 : 50) d (ppm):
4-(2-Morpholinothiazol-5-yl)-5,7-dinitrobenzo[c][1,2,5]oxa-
8.69 (s, 1H), 8.65 (s, 1H), 8.24 (s, 1H), 7.79 (s, 1H), 3.89–3.84 (m, diazole (8a). Dark blue solid, 0.007 g, 25% yield. 1H NMR: (599.7
8H), 3.78–3.74 (m, 4H), 3.71–3.67 (m, 4H); 13C NMR: (150.8 MHz, CD3CN, 25 ꢀC) d (ppm): 8.80 (s, 1H), 8.78 (s, 1H), 3.83–3.80
MHz, CDCl3, 25 C) d (ppm, selected data): 176.0, 175.9, 154.9 (m, 4H), 3.77–3.73 (m, 4H); 13C NMR: (150.8 MHz, CD3CN, 25
ꢀ
(CH), 152.1 (CH), 151.1, 144.6, 139.5, 132.4, 127.9 (CH), 125.0, ꢀC) d (ppm): 177.4, 157.1 (CH), 151.4, 144.3, 130.1, 130.0, 127.7
124.6, 124.2 (CH), 113.5, 113.3, 108.6, 105.8, 66.0 (OCH2), 65.9 (CH), 126.1, 116.3, 66.5 (OCH2), 49.8 (NCH2); HRMS (ESI+) m/z:
(OCH2), 48.9 (NCH2), 48.8 (NCH2); ESI-MS (m/z): 393 (M ꢁ H)ꢁ; [M + H]+ calcd for C13H11N6O6S+: 379.0455; found: 379.0466.
HRMS (ESI+) m/z: [M + H]+ calcd for C13H11N6O7S+: 395.0404;
found: 393.0412.
5,7-Dinitro-4-(2-(piperidin-1-yl)thiazol-5-yl)benzo[c][1,2,5]
1
oxadiazole (8b). Green-blue solid, 0.006 g, 22% yield. H NMR
ꢀ
4,6-Dinitro-7-(2-(piperidin-1-yl)thiazol-5-yl)benzo[c][1,2,5]
(300.0 MHz, CD3CN, 25 C) d, ppm: 8.90 (s, 1H), 8.79 (s, 1H),
oxadiazole 1-oxide (5b) and 5,7-dinitro-4-(2-(piperidin-1-yl) 3.83–3.73 (m, 4H), 1.80–1.70 (m, 6H); 1H NMR (599.7 MHz,
thiazol-5-yl)benzo[c][1,2,5]oxadiazole 1-oxide (50b). Night blue CDCl3, 25 ꢀC) d, ppm: 9.06 (s, 1H), 8.79 (s, 1H), 3.79 (br. s, 4H),
1
13
ꢀ
ꢀ
solid, 0.010 g, 29% yield. H NMR: (599.7 MHz, CDCl3, 25 C, 1.79 (br. s, 6H); C NMR: (150.8 MHz, CDCl3, 25 C) d, ppm:
isomeric Maj (50b)/Min (5b) ratio ¼ 56 : 44) d (ppm): 8.79 (s, 1H, 176.1, 159.3 (CH), 149.9, 142.9, 136.7, 129.1 (CH), 128.3, 125.4,
Maj), 8.71 (s, 1H, Min), 8.29 (s, 1H, Maj), 7.94 (s, 1H, Min), 3.80– 116.3, 50.7 (br. s. NCH2), 25.5 (NCH2CH2), 23.8 (NCH2CH2CH2);
3.73 (m, 4H, Min), 3.73–3.68 (m, 4H, Maj), 1.83–1.73 (m, 12H, HRMS (ESI+) m/z: [M + H]+ calcd for C14H13N6O5S+: 377.0663;
Maj + Min); 13C NMR: (150.8 MHz, CDCl3, 25 ꢀC) d (ppm): 176.1, found: 377.0680.
175.8, 157.1 (CH), 155.1 (CH), 151.3, 145.0, 138.6, 138.0, 130.4,
128.7 (CH), 127.9, 125.4, 125.0, 124.9 (CH), 113.8, 113.3, 109.4, oxadiazole (8c). Dark blue solid, 0.004 g, 15% yield. H NMR:
5,7-Dinitro-4-(2-(pyrrolidin-1-yl)thiazol-5-yl)benzo[c][1,2,5]
1
ꢀ
105.9, 50.5 (NCH2, 2 signals overlapped), 25.4 (NCH2CH2), 23.8 (599.7 MHz, CD3CN, 25 C) d (ppm): 8.94 (s, 1H), 8.80 (s, 1H),
(NCH2CH2CH2), 23.7 (NCH2CH2CH2); HRMS (ESI+) m/z: [M + 4.00–3.33 (br. m, 4H), 2.15–2.10 (br. m, 4H); 13C NMR: (150.8
H]+ calcd for C14H13N6O6S+: 393.0612; found: 393.0632.
MHz, CD3CN, 25 C) d (ppm): 174.0, 159.4 (CH), 151.4, 144.4,
ꢀ
4,6-Dinitro-7-(2-(pyrrolidin-1-yl)thiazol-5-yl)benzo[c][1,2,5]
138.1, 130.5 (CH), 129.4, 126.4, 116.8, 51.8 (br. s. NCH2), 26.1
oxadiazole 1-oxide (5c) and 4-(2-morpholinothiazol-5-yl)-5,7- (br. s, NCH2CH2); HRMS (ESI+) m/z: [M + H]+ calcd for
dinitrobenzo[c][1,2,5]oxadiazole 1-oxide (50c). Brilliant dark
C
13H11N6O5S+: 363.0506; found: 363.0513.
green shiny, 0.019 g, 57% yield. 1H NMR: (400 MHz, CDCl3,
Reactions between 1–3 and DNBF (10). Formation of Ma–Mc
ꢀ
25 C, isomeric Maj (50c, or A)/Min (5c, or A0) ratio ¼ 59 : 41) (experimental details on variable temperature NMR reactions
d (ppm): 8.81 (s, 1H, Maj), 8.71 (s, 1H, Min), 8.28 (s, 1H, Maj), are reported in ESI†).
7.96 (s, 1H, Min), 4.00–3.35 (m, 8H, Maj + Min), 2.27–2.03 (m,
(7-(2-Morpholinothiazol-5-yl)-6-nitro-1-oxidobenzo[c][1,2,5]
1
8H, Maj + Min); H NMR: (300 MHz, CD3CN, 25 C, isomeric oxadiazol-4(7H)-ylidene)azinate (Ma). 1H NMR: (399.9 MHz,
ꢀ
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acetone-d6, ꢁ48 ꢀC, conversion: 53%) d (ppm): 8.73 (s, 1H, H-5), compare N-1/N-3-oxide and BKR isomerizations. Finally,
7.29 (s, 1H, H-40), 5.63 (d, J ¼ 0.53 Hz, 1H, H-7), 3.77 (br. t, J ¼ a unique Meisenheimer intermediate Ma, Mb, or Mc, were
5.3 Hz, 4H, OCH2), 3.48 (br. t, J ¼ 5.5 Hz, 4H, NCH2). Aer isolated by coupling the 2-aminothiazole derivative 3a, 3b, or 3c
heating until +25 ꢀC Ma was recovered as red solid, 0.018 g, with 4,6-dinitrobenzofuroxan (DNBF).
1
ꢀ
94%, H NMR: (599.7 MHz, DMSO-d6, 25 C) d (ppm): 8.64 (s,
1H, H-5), 7.34 (s, 1H, H-40), 5.64 (s, 1H, H-7), 3.69 (br. t, J ¼
Conflicts of interest
4.8 Hz, 4H, OCH2), 3.44 (br. t, J ¼ 4.8 Hz, 4H, NCH2); 13C NMR:
(150.8 MHz, DMSO-d6, 25 ꢀC) d (ppm): 169.3, 147.9, 131.1 (br. s, There are no conicts to declare.
CH, C-40), 130.9 (CH), 124.5, 120.8, 112.1, 109.7, 64.9, (OCH2),
48.6 (NCH2), 32.1 (C-7); ESI-MS: 395 (M ꢁ H)ꢁ.
Acknowledgements
(6-Nitro-1-oxido-7-(2-(piperidin-1-yl)thiazol-5-yl)benzo[c]
[1,2,5]oxadiazol-4(7H)-ylidene)azinate (Mb). 1H NMR: (399.9 The authors are grateful, for the nancial support, to Alma
MHz, acetone-d6, ꢁ93 ꢀC, conversion: 67%) d (ppm): 8.71 (s, 1H, Mater Studiorum – Universita di Bologna (RFO funds). E. Chu-
`
H-5), 7.38 (s, 1H, H-40), 5.64 (s, 1H, H-7), 3.58–3.46 (m, 4H, gunova is grateful for the nancial support to the Ministry of
NCH2), 1.72–1.55 (m, 6H, NCH2CH2 + NCH2CH2CH2). Aer Science and Higher Education of the Russian Federation (grant
heating until +25 ꢀC Mb was recovered as red solid, 0.018 g, No. 075-15-2019-1881). The authors thank Dr Daniele Padovan
1
ꢀ
94%; H NMR: (300.0 MHz, DMSO-d6, 25 C) d (ppm): 8.65 (s, and Mr Luca Zuppiroli for mass spectra.
1H, H-5), 7.40 (s, 1H, H-40), 5.64 (s, 1H, H-7), 3.55–3.45 (m, 4H,
NCH2), 1.69–1.51 (m, 6H, NCH2CH2 + NCH2CH2CH2); 13C NMR:
Notes and references
ꢀ
(75.4 MHz, DMSO-d6, 25 C) d (ppm): 168.2, 148.2, 131.5 (CH),
127.0 (br. s, CH, C-40), 124.2, 120.1, 112.3, 110.3, 50.7, (NCH2),
32.5 (C-7), 24.7 (NCH2CH2), 22.9 (NCH2CH2CH2); ESI-MS: 393
(M ꢁ H)ꢁ.
1 A. J. Boulton and P. B. Ghosh, Advances in Heterocyclic
Chemistry, ed. A. R. Katritzky and A. J. Boulton, Academic
Press, New York, 1969, vol. 10, pp. 1–41.
2 A. Gasco and A. J. Boulton, Furoxans and Benzofuroxans in
Advances in Heterocyclic Chemistry, ed. A. R. Katritzky and
A. J. Boulton, Academic Press, New York, 1981, vol. 29,
pp.251–340.
3 G. N. Nikonov and S. Bobrov, 1,2,5-Oxadiazoles, in
Comprehensive Heterocyclic Chemistry III, Five-membered
Rings: Triazoles, Oxadiazoles, Thiadiazoles and Their Fused
Carbocyclic Derivatives, ed. A. R. Katritzky, C. A. Ramsden,
E. F. V. Scriven and R. J. K. Taylor, Elsevier, 2008, vol. 5,
pp. 315–395.
(6-Nitro-1-oxido-7-(2-(pyrrolidin-1-yl)thiazol-5-yl)benzo[c]
[1,2,5]oxadiazol-4(7H)-ylidene)azinate (Mc). 1H NMR: (399.9
MHz, acetone-d6, ꢁ93 ꢀC, conversion: 81%) d (ppm): 8.71 (s, 1H,
H-5), 7.52 (s, 1H, H-40), 5.65 (s, 1H, H-7), 3.77–3.32 (m, 4H,
NCH2), 2.20–1.98 (m, 4H, NCH2CH2). Aer heating until +25 ꢀC
1
Mc was recovered as red solid, 0.016 g, 87%; H NMR: (399.9
MHz, DMSO-d6, 25 ꢀC) d (ppm): 8.66 (s, 1H, H-5), 7.51 (br. s., 1H,
H-40), 5.67 (d, J ¼ 0.6 Hz, 1H, H-7), 3.47 (t, J ¼ 7.4 Hz, 4H, NCH2),
2.03–1.98 (m, 4H, NCH2CH2); 13C NMR: (100.6 MHz, DMSO-d6,
ꢀ
25 C) d, ppm: 164.3, 147.8, 131.2 (CH), 127.1 (br. s, CH, C-40),
123.6, 119.7, 111.8, 109.9, 51.3, (NCH2), 32.1 (C-7), 25.3
4 F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley
VCH, Weinheim, 2013.
5 J. W. Fronabarger, M. D. Williams, W. B. Sanborn,
D. A. Parrish and M. Bichay, Propellants, Explos., Pyrotech.,
2011, 36, 459–470.
(NCH2CH2), ESI-MS: 379 (M ꢁ H)ꢁ.
Conclusions
ˇ
ˇ
ˇ
¯
The SEAr/SNAr reaction by combination of Cl-DNBF and 2-ami-
nothiazole derivatives 3a–c gave two isomeric products, bearing
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