C-C coupling reactions between benzofurazan derivatives and 1,3-diaminobenzenes

Article abstract of DOI:10.3390/molecules22050684

Aromatic substitution reactions between 1,3-diaminobenzene and chloronitrobenzofurazan derivatives have never been reported so far. The aim of the current study was to synthesize novel electron-donor and -acceptor architectures of interest in applied fields and to provide new insights on the nucleophilic behavior of 1,3-diaminobenzenes. The reaction of 1,3-dipiperidinyl-, 1,3-dimorpholinyl-, 1,3-dipyrrolidinyl-, or 1,3-dimethylamino-benzene with 7-chloro-4,6-dinitrobenzofuroxan or with a series of chloro-nitrobenzofurazans has been carried out in mild conditions. The partners reactivity has been investigated by monitoring the reaction course through ¹H-NMR spectroscopy. The reaction occurred in a regioselective way, providing in good yields the novel C-C coupling compounds. Indications on the reactivity behavior for the studied nucleophiles have been relieved.

Full text of DOI:10.3390/molecules22050684

molecules
Article
C-C Coupling Reactions between Benzofurazan
Derivatives and 1,3-Diaminobenzenes
Gabriele Micheletti 1,*, Silvia Bordoni 1, Elena Chugunova 2 and Carla Boga 1,
*
1
Department of Industrial Chemistry ‘Toso Montanari’, Alma Mater Studiorum Università di Bologna
Viale Del Risorgimento, Bologna 4402136, Italy; Silvia.bordoni@unibo.it
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center,
Russian Academy of Sciences, Akad. Arbuzov st. 8, Kazan, Tatarstan 420088, Russia;
chugunova.e.a@gmail.com
2
*
Correspondence: gabriele.micheletti3@unibo.it (G.M.); carla.boga@unibo.it (C.B.);
Tel.: +39-051-209-3616 (C.B.)
Academic Editor: Margaret A. Brimble
Received: 23 February 2017; Accepted: 20 April 2017; Published: 26 April 2017
Abstract: Aromatic substitution reactions between 1,3-diaminobenzene and chloronitrobenzofurazan
derivatives have never been reported so far. The aim of the current study was to synthesize novel
electron-donor and -acceptor architectures of interest in applied fields and to provide new insights on
the nucleophilic behavior of 1,3-diaminobenzenes. The reaction of 1,3-dipiperidinyl-, 1,3-dimorpholinyl-
,
1,3-dipyrrolidinyl-, or 1,3-dimethylamino-benzene with 7-chloro-4,6-dinitrobenzofuroxan or with a
series of chloro-nitrobenzofurazans has been carried out in mild conditions. The partners reactivity
has been investigated by monitoring the reaction course through 1H-NMR spectroscopy. The reaction
occurred in a regioselective way, providing in good yields the novel C-C coupling compounds.
Indications on the reactivity behavior for the studied nucleophiles have been relieved.
Keywords: benzofurazans; aromatic substitution; 1,3-diaminobenzenes
1. Introduction
The aromatic substitution is one of the most exploited reactions in organic chemistry. The reaction
can simply be indicated as aromatic substitution if both the reagents are aromatic, whereas the
distinction into SEAr and SNAr has been invoked when only one reagent is aromatic. The case
of C-C coupling between neutral aromatic substrates requires opposite features in the reagents
(i.e., electron-rich vs. electron-poor). The 1,3,5-triaminobenzene derivatives—first studied by the
pioneer work of Effenberger [
to react at the neutral carbon atom [
with a plethora of electrophiles, such as proton [1–10], halogens [11,12], acyl- [13–15], alkyl- [16], and
aryl-halides [17]. The coupling between 1,3,5-triaminobenzene of types and and aryl diazonium
salts gave stable Wheland intermediates ( ) by the azo-coupling reaction [18] (Scheme 1), conversely
1
]—belong to neutral electron-rich aromatic substrates and are able
1,2
]. (These kinds of nucleophiles have been reported to react
A
B
W
to what is usually reported in the textbooks. They provided evidence of the reversibility [19], and the
proton departure from Wheland intermediate as the rate-determining step [20].
The coupling of 1,3,5-triaminobenzenes
A–C (Scheme 2) with 4,6-dinitrobenzofuroxan (DNBF)
provided the first example of characterized Wheland-Meisenheimer (WM) intermediate. The
zwitterionic nature is generated by the contemporary presence of Wheland on the nucleophilic
fragment and Meisenheimer on the electrophilic one. Further, WM intermediates have been identified
by the sym-triaminobenzenes with 4,6-dinitrotetrazolopyridine (DNTP) or 2,3,4-trinitrothiophene [21].
4,6-Dinitrobenzofuroxan (DNBF) and 4,6-dinitrotetrazolopyridine (DNTP) are 10π electron-deficient
Molecules 2017, 22, 684; doi:10.3390/molecules22050684
www.mdpi.com/journal/molecules

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heteroaromatics exhibiting reactivity behavior to be ranked as “superelectrophilic heteroaromatics” [22,23]
.
Their Mayr electrophilicity values [24–28] are −5.06 [29] and −4.67, [22], respectively.
Scheme 1. Simplified reaction pathway of the azo coupling reaction.
Scheme 2. The first examples of detection and characterization of Wheland-Meisenheimer (WM
)
intermediates. DNBF: 4,6-dinitrobenzofuroxan; DNTP: 4,6-dinitrotetrazolopyridine.
Finally, DNBF and DNTP gave WM intermediates by C-C coupling with other nucleophilic
substrates, such as 2-aminothiazole [30] or 2,4-di(pyrrolidinyl)thiazole [31]. Further, the C-C coupling
between a series of chloro-nitrobenzofurazans and sym-triaminobenzenes gave access to highly
conjugated structures of interest in the material field [32]. In the study, the first Wheland intermediate
in benzofurazan series was isolated and fully characterized [32]. Among the mechanistic studies here
described, it is noteworthy that benzofuroxans and benzofurazans are interesting reagents from a
biological point of view—for example, as fluorescent probes [33
constitutes a biologically important molecule of the endothelium-derived relaxing factor, and the
benzofuroxan moiety is well known for its ability to release NO under physiological conditions [36 37].
,34] or fungicides [35]. Nitric oxide
,
Several derivatives obtained from the combination of a benzofuroxanyl moiety with distinct bioactive
substructure have recently received particular attention as anti-inflammatory [38] or antimicrobial
agents [39]. Moreover, nitrobenzofurazans and nitrobenzofuroxans are also recognized to be versatile
compounds in optoelectronic, agrochemical, or material fields [40,41].
Contrarily to the case of 1,3,5-triaminobenzenes, few examples of C-C coupling involving
diaminobenzene derivatives [17,42–44] are present in the literature, likely due to their minor carbon
nucleophilicity with respect to 1,3,5-triaminobenzenes.
Scarce literature reports on the reactivity of 1,3-diaminobenzenes suggested that we react them
with 7-chloro-4,6-dinitrobenzofuroxan and chloro-nitrobenzofurazan derivatives. We investigated
the reactivity of these nucleophiles to achieve compounds of interest for applications related to the
simultaneous presence of electron-poor and electron-rich functions on the same scaffold.

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2. Results and Discussion
The reaction between 1,3-bis(N,N-dialkylamino)benzenes
1–
4
(indicated thereafter by the
acronyms shown in Scheme 3) and the chloro-nitrobenzofurazans
room temperature with an equimolar amount of reagents.
5–7 was carried out in acetonitrile at
a
◦
Reaction run at 80 C also
Scheme 3. Combination between nucleophiles
1
–4
and electrophiles
5
–7.
b
with no conversion improving. In the presence of alumina, the yield became 60%. DPBH: 1,3-bis(N-
piperidinyl)benzene, DMBH: 1,3-bis(N-morpholinyl)benzene, DPyBH: 1,3-bis(N-pyrrolidinyl)benzene,
DNMeBH: 1,3-bis(dimethylamino)benzene; DPB: 1,3-bis(N-piperidinyl)phenyl; DMB: 1,3-bis(N-
morpholinyl)phenyl; DPyB: 1,3-bis(N-pyrrolidinyl)phenyl; DNMeB: 1,3-bis(dimethylamino)phenyl.
Two distinct isomers (
bis(dialkyl)aminobenzene (Scheme 4) at the carbon atom in position 2 or 4. As a matter of fact, the
isomer has solely been formed. By preventing the nucleophilic attack in position 2, steric hindrance
A and B in Scheme 4) might be expected from the attack of the
B
did not likely permit the formation of isomer A.
E
2
R2N
NR2
R2N
NR2
R2N
NR2
E
1
6
3
4
CH3CN, r.t.
E
+
+
5
A
B
Scheme 4. Possible reaction products derived from the reaction of 1,3-diaminobenzene derivatives
with electrophilic reagents.
The C-C coupling products were purified by flash chromatography (FC) on silica gel column
and were fully characterized. In the cases of the reactions involving 1,3-bis(N-morpholinyl)benzene
(DMBH, 2
), no product was formed, even by increasing the reaction temperature within 80 ◦C. Yields
shown in Scheme 3 were calculated without considering that a half equivalent of the nucleophile
might react with the hydrochloric acid formed as reaction co-product. This salification may be
responsible for decreasing the nucleophilic efficiency so that a 50% row-yield was the maximum
expected. Conversely, the achieved 54%/53% yields after work-up process for compounds 11
respectively, suggests that protonation on the reaction products might occur, as previously observed in
the case of triaminobenzenes with benzofurazans 32]. Occasionally, to remove the formed HCl
/13,
5–7 [
from the reaction mixture, some experiments were run in the presence of basic alumina. Neutralization
procedure increased the yield in few cases, probably ascribed to the disrupting interactions with the
Al2O3 stationary phase.

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By testing the reactivity of
1–
4
with the purpose of using more efficient electrophiles, we decided
to use 7-chloro-4,6-dinitrobenzofuroxan (18), the electrophilicity of which is enhanced by introducing
a further nitro and an N-oxide function in the oxadiazole ring (Scheme 5). In the latter case, the
conversion was consistently getting raised so that the reaction on 1,3-di(morpholinyl)benzene (2)
afforded derivative 20.
Scheme 5. Reaction between 18 and 1,3-diaminobenzene derivatives 1–4.
Once the products between 1–4 and 5–8 were isolated and fully characterized, we planned to
investigate the reaction course. For this purpose, an equimolar amount of each electrophile/nucleophile
couple—dissolved in CDCl3 or CD3CN—was added, and the reaction was monitored within 72 h into
the NMR tube. The results are reported in Table 1.
Table 1. Electrophile/nucleophile combinations 1 monitored via 1H-NMR 2.
Entry
Electrophile
Nucleophile
Solvent
Product
10 min
2 h
24 h 48 h
72 h
26 3
1
2
3
4
5
6
7
8
9
5
5
5
5
5
7
7
7
18
18
18
18
DPBH (1)
DPBH (1)
DNMeBH (4)
DNMeBH (4)
DPyBH (3)
DPBH (1)
DNMeBH (4)
DPyBH (3)
DPBH (1)
DMBH (2)
DNMeBH (4)
DPyBH (3)
CDCl3
CD3CN
CDCl3
8
8
-
9
4
4
12
21
65
53
40
40
55
>98
87
32
/
21
48
40
73
53
55
55
63
/
26
50
40
76
56
n.c.
n.c.
70
52 4
5
11
11
10
14
17
16
19
20
22
21
n.c.
n.c.
n.c.
60
55
n.c.
/
5
5
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
25
42
15
16
35
27
25
3
5
/
10
11
12
1
95
87
/
>98
>98
/
/
/
/
>97 6
Reaction between equimolar amounts of the (N,N-dialkyl)-diaminobenzene (0.05 mmol) and benzofurazan- (or
benzofuroxan-)derivative (0.05 mmol). The reagents were mixed in a vial and dissolved in 0.7 mL of deuterated
2
1
solvent.
Relative % conversion was calculated from the H-NMR spectrum with respect to the remained
3
4
electrophile signals. The conversion became 55% after 24 h from the addition of triethylamine. After 24 h
from the addition of triethylamine, the conversion became nearly quantitative. n.c. means not calculated. The
spectrum showed the presence of other unidentified products.
5
6
To analyze the solvent influence, we investigated reactions of
5 with nucleophiles 1 and 4 both in
CDCl3 and CD3CN (Table 1, entries 1–4). Noticeably, the yields of the expected products raised up to
50% by using CD3CN solvent in all the reactions monitored. Quantitative yield was afforded in the
case of electrophile 18. The behavior is ascribed to the salification of the final product, as reported
above for compounds 11 and 13.
The conversion consistently increases by using dinitrobenzofuroxan as reagent. The data inferred
by comparing (Table 1) the reaction of substrate
18 with nucleophile or (entries 9, 12) were expected on the basis of electrophilicity increasing due
to the introduction of a further nitro group in the substrate. It has been reported that upon going from
5 with nucleophile 1 or 3 (entries 2, 5) and reaction of
1
3

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benzofurazan to benzofuroxan, the influence of the N-oxide in the pentatomic heteroaromatic ring was
almost negligible [45,46].
By comparing the reaction data between
5 and the nucleophiles 1, 3, and 4 after 10 min (time
within the salification process of the starting nucleophile and/or the reaction product can be considered
negligible), the conversion relative on the nucleophilic species is DPBH < DNMeBH < DPyBH. Since
the nucleophilicity of compounds 1–4 have not been reported so far, the above trend can be correlated
to the nucleophilicity values of the substituent, in agreement with the equation developed by Mayr:
NMayr = 15.65, 17.35, and 18.64 for morpholine, piperidine, and pyrrolidine [47], and 17.96 for
dimethylamine [48], respectively. Similar considerations can be made by analyzing the reactions
of
conversions of
; this observation might be explained by considering two distinct factors: steric hindrance due to both
1
and
3
with
7
(entries 6, 8) and reactions of
1,
2
, and
3
with 18 (entries 9, 10, 12). The reaction
7
,
18 with substrate resulted lower or comparable with respect to the reaction with
4
1
or
2
the proximity (ortho-position) of the nitro groups in the electrophile, and that of the dimethylamino
group on the incoming nucleophile.
To confirm this hypothesis and also to extend the study to the reactivity of monoaminobenzene
derivatives, we reacted the chloro-nitrobenzofurazan
5 and the chlorodinitrobenzofuroxan 18 with
N-pyrrolidinylbenzene (23) and N,N-dimethylaminobenzene (24) (Scheme 6) in equimolar amounts,
and monitored the reaction course via by 1H-NMR spectroscopy.
Scheme 6. Reaction between 5 and 18 and monoaminobenzenes 23–24.
We found that
5 did not react with either 23 or 24, whereas the reactions with 18 occurred at
room temperature to afford the C-C coupling in para-position with respect to the amino group of the
nucleophile. Specifically, the 1H-NMR spectrum showed a 44% and 23% conversion, respectively, for
23 and 24 after 10 min. These findings are in agreement with the nucleophilicity values of the amino
substituent reported above, and support the occurrence of steric hindrance to explain the unexpected
very low conversion to 22 (Table 1, entry 11). The absence of the crowding in monoaminobenzenes
permitted the formation of products 25 (from 18 and 23) and 26 (from 18 and 24), and thus gave a
further confirmation of the increase in the reactivity of the electrophile ascribed to the presence of an
additional nitro group.
Finally, the proposed mechanism for the current SEAr/SNAr reactions (shown in Scheme 7
for compound
evolve into a cationic Wheland-like intermediate (
anionic Meisenheimer like ( ) intermediate via proton expulsion. The final substitution product
can be generated from both intermediates. Due to presence of a chloride leaving group, the
-anionic intermediate (as well as WM) is an elusive species, which to the best of our knowledge
has never been detected. The presence of electron-donor groups on the nucleophilic fragment
might be responsible for the stabilization of intermediate to let it be detectable. In the case of
reaction between and 1,3,5-tris(pyrrolidinyl)benzene [32], we already reported the isolation and
characterization of -type intermediate. The efforts to analogously trap elusive species in the NMR
5) implies the formation of WM zwitterionic intermediate. The intermediate might
W
) through the chloride displacement or to an
M
σ
M
W
5
W

Molecules 2017, 22, 684
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tube at low temperature for the reactions reported in Scheme 7 did not afford analogous results,
indicating that the electronic features of two amino groups are not sufficient requisites to stabilize the
σ-cationic intermediate.
Scheme 7. Possible intermediates in the SEAr/SNAr reaction between chloro-nitrobenzofurazans and
1,3-diaminobenzene derivatives.
3. Materials and Methods
3.1. General Methods
The 1H spectra were recorded with a Mercury 400 (Varian, Palo Alto, CA, USA) spectrometer
1
operating at 400 MHz for H-NMR and 100.56 MHz for 13C-NMR. Signal multiplicities were
established by Distortioless Enhanced by Polarization Transfer (DEPT) experiments. Chemical shifts
were measured in δ (ppm) with reference to the solvent (δ = 7.26 ppm and 77.00 ppm for CDCl3, for
1H-, and 13C-NMR, respectively). J values are given in Hz. Electron spray ionization mass spectra
(ESI-MS) were recorded with a WATERS 2Q 4000 instrument (Waters Corporation, Milford, MA, USA).
IR spectra were recorded on a Perkin Elmer FT-IR spectrometer (Perkin Elmer, Waltham, MA, USA)
Spectrum Two equipped with a UATR TWO ATR accessory (diamond crystal, DTGS detector; spectral
resolution 4 cm−1). Chromatographic purifications (FC) were carried out on glass columns packed
with silica gel (Merck grade 9385, 230–400 mesh particle size, 60 Å pore size) at medium pressure.
Thin layer chromatography (TLC) was performed on silica gel 60 F254 coated aluminum foils (Fluka
Chemie GmbH, Buchs, Switzerland).
3.2. Synthesis of 1,3-Di(piperidin-1-yl)benzene (1) and N1,N1,N3,N3-Tetramethylbenzene-1,3-diamine (4)
To a solution of 1,3-dichlorobenzene (0.85 mL, 7.45
×
10−3 mol) and amine (piperidine or
dimethylamine 0.06 mol) in 50 mL of anhydrous THF, under nitrogen atmosphere, phenyl lithium
(30 mL, 0.06 mol) was added dropwise. The mixture was stirred for 24 h at room temperature, then
was quenched with water (50 mL). The organic layer was separated, and the aqueous fraction was
extracted with diethyl ether (3
and filtered. The product was purified by column chromatography on silica gel (n-hexane/ethyl acetate
×
30 mL). The organic layer was anhydrified over magnesium sulfate
2:1). The chemico-physical data of
the literature.
1 [49,50] and 4 [51] are in good agreement with those reported in
3.3. Synthesis of 1,3-Dimorpholinobenzene (2) and 1,3-Di(pyrrolidin-1-yl)benzene (3)
The reaction was carried out in autoclave. Amine (morpholine or pyrrolidine, 0.07 mol) and
potassium tert-butylate (5.4 g, 0.048 mol) were added to the solution of 1,3-dichlorobenzene (1.37 mL,
◦
0.011 mol) in toluene (10 mL). The reaction was left at 160 C for 4 days under magnetic stirring,
then it was allowed to stand at room temperature and quenched with water (50 mL). The organic

Molecules 2017, 22, 684
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layer was separated, and the aqueous fraction was extracted with dichloromethane (3
The organic layer was dried over anhydrous magnesium sulfate. The product was purified by column
×
30 mL).
chromatography on silica gel. The chemico-physical data of
with those reported in the literature.
2 [49,50] and 3 [52] are in good agreement
3.4. Reactions between (N,N-Dialkyl)-diaminobenzenes (1–4) and Compounds 5–7—General Procedure
To a stirred solution of (N,N-dialkyl)-diaminobenzene (0.1 mmol) in acetonitrile (5 mL), an
equimolar amount of electrophile was added. The reaction was left at room temperature under
magnetic stirring for about 12 h. The product was purified by column chromatography on silica gel.
An analogous procedure but with a 2/1 nucleophile/electrophile relative molar ratio was used for the
reactions of 18 with 5–7, 23, 24; reactions of 5 with 23 and 24 did not work.
4-(2,4-Di(piperidin-1-yl)phenyl)-7-nitrobenzo[c][1,2,5]oxadiazole (8): eluent: n-hexane/ethyl acetate 8/2;
yield 27%; brown solid, m.p.: >200 ◦C (dec); IR (v, cm−1): 1601, 1503, 1299, 1235; 1H-NMR (CDCl3,
◦
400 MHz, 25 C):
δ (ppm): 8.52 (d, J = 8.1 Hz, 1H); 8.26 (br.s, 1H); 7.66 (d, J = 8.1 Hz, 1H); 6.64 (br.s, 2H);
3.35 (br.s, 4H); 2.85 (br.s, 4H); 1.85–1.60 (m, 6H); 1.46 (br.s, 6H); 13C-NMR (CDCl3: 100.56 MHz, 25 ◦C):
δ
(ppm): 154.5; 154.0; 150.1; 143.5; 139.5; 133.7; 131.3; 125.8; 116.8; 109.0; 105.8; 53.4; 49.1; 25.9; 25.5; 23.9;
ESI-MS (m/z): 408 [M + H]+, 430 [M + Na]+, 446 [M + K]+; HRMS (ES+) m/z: [M + H]+ calculated for
C22H26N5O3 408.2036 found 408.2038.
4-(2,4-Di(pyrrolidin-1-yl)phenyl)-7-nitrobenzo[c][1,2,5]oxadiazole (10): eluent: petroleum light/diethyl
ether 1/1; yield 40%; brown solid, m.p.: >280 ◦C (dec); IR (v, cm−1): 1605, 1499, 1288, 1235; 1H-NMR
(CDCl3, 400 MHz, 25 ◦C):
δ
(ppm): 8.49 (d, J = 8.2 Hz, 1H); 7.72 (d, J = 8.9 Hz, 1H); 7.25 (d, J = 8.3 Hz,
1H); 6.27 (dd, J1 = 9.0 Hz, J2 = 2.2 Hz, 1H); 6.10 (s, 1H), 3.41 (t, J = 6.7 Hz, 4H), 3.06 (t, J = 6.7 Hz, 4H);
2.10–2.03 (m, 4H); 1.89–1.81 (m, 4H); 13C-NMR (CDCl3: 100.56 MHz, 25 ◦C):
(ppm): 150.4; 150.1;
δ
149.9; 143.6; 140.5; 134.7; 132.0; 130.9; 124.1; 111.3; 104.7; 97.3; 52.2; 48.0; 25.7; 25.4; ESI-MS (m/z): 380
+
[M + H]+, 402 [M + Na] , 418 [M + K]+; HRMS (ES+) m/z: [M + H]+ calculated for C20H22N5O3
380.1723 found 380.1724.
N1,N1,N3,N3-Tetramethyl-4-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)benzene-1,3diamine (11): eluent: petroleum
light/diethyl ether 4/6; yield 54%; brown solid, m.p.: >280 ◦C (dec); IR (v, cm−1): 1600, 1478, 1297,
◦
1235; 1H-NMR (CDCl3, 400 MHz, 25 C):
δ
(ppm): 8.51 (d, J = 8.0 Hz, 1H); 8.01 (d, J = 7.6 Hz, 1H); 7.73
(d, J = 8.6 Hz, 1H); 6.49 (d, J = 8.6 Hz, 1H); 6.43 (s, 1H); 3.09 (s, 6H); 2.68 (s, 3H); 13C-NMR (CDCl3:
δ (ppm): 153.6; 152.2; 150.1; 143.7; 139.6; 134.4; 132.5; 131.8; 125.2; 114.9; 106.6;
102.6; 43.9; 40.7; ESI-MS (m/z): 328 [M + H]+, 350 [M + Na]+, 366 [M + K]+; HRMS (ES+) m/z: [M + H]+
100.56 MHz, 25 ◦C):
calculated for C16H18N5O3 328.1410 found 328.1413.
4-(2,4-Di(piperidin-1-yl)phenyl)-5-nitrobenzo[c][1,2,5]oxadiazole (12): eluent: petroleum light/diethyl ether
1
9/1; yield 23%; dark blue solid, m.p.: >80 ◦C (dec.); IR (v, cm−1): 1598, 1502, 1285, 1234; H-NMR
(CDCl3, 400 MHz, 25 ◦C):
δ
(ppm): 7.91 (d, J = 9.5 Hz, 1H); 7.82 (d, J = 9.5 Hz, 1H); 7.42 (d, J = 8.4 Hz,
1H); 6.85–6.54 (m, 2H); 3.31 (br.s, 4H); 2.70–2.53 (m, 4H); 1.9–1.59 (m, 8H); 1.35 (m, 4H); 13C-NMR
(CDCl3: 100.56 MHz, 25 ◦C):
δ (ppm): 153.9; 150.7; 149.2; 146.3; 131.7; 128.0; 126.7; 114.5; 109.7; 107.4;
53.6; 49.4; 25.8; 25.5; 24.8; ESI-MS (m/z): 408 [M + H]+, 430 [M + Na]+, 446 [M + K]+; HRMS (ES+) m/z:
[M + H]+ calculated for C22H26N5O3 408.2036 found 408.2037.
N1,N1,N3,N3-Tetramethyl-4-(5-nitrobenzo[c][1,2,5]oxadiazol-4-yl)benzene-1,3diamine (13): eluent: ethyl
acetate/dichloromethane 8/2; yield 53%;◦brown solid, m.p.: >155 ◦C (dec); IR (v, cm−1): 1602, 1490,
δ (ppm): 7.81 (d, J = 9.4 Hz, 1H); 7.77 (d, J = 9.4 Hz, 1H);
1289, 1236; 1H-NMR (CDCl3, 400 MHz, 25 C):
7.46 (d, J = 9.0 Hz, 1H); 6.52 (d, J = 9.0 Hz, 1H); 6.41 (br.s, 1H); 3.06 (s, 6H); 2.45 (br.s, 6H); 13C-NMR
(CDCl3: 100.56 MHz, 25 ◦C):
δ (ppm): 153.4; 152.5; 150.6; 149.2; 145.9; 132.1; 128.2; 126.4; 113.9; 112.3;
106.5; 103.1; 42.0; 40.3; ESI-MS (m/z): 328 [M + H]+, 350 [M + Na]+, 366 [M + K]+; HRMS (ES+) m/z:
[M + H]+ calculated for C16H18N5O3 328.1410 found 328.1411.

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5-(2,4-Di(piperidin-1-yl)phenyl)-4-nitrobenzo[c][1,2,5]oxadiazole (14): eluent: ethyl acetate/dichloromethane
1
2/8; 38%; brown solid, m.p.: >120 ◦C (dec); IR (v, cm−1): 1598, 1506, 1319, 1235; H-NMR (CDCl3,
400 MHz, 25 ◦C):
δ
(ppm): 7.96 (d, J = 9.0 Hz, 1H); 7.67 (d, J = 9.0 Hz, 1H); 7.10 (br.s, 1H); 6.63 (br.s,
2H); 3.30 (br.s, 4H); 2.84 (br.s, 4H); 1.73 (br.s, 4H); 1.64 (br.s, 4H); 1.43 (br.s, 4H); 13C-NMR (CDCl3:
100.56 MHz, 25 ◦C):
δ (ppm): 154.2; 153.5; 149.0; 144.2; 140.9; 137.2; 130.8; 122.5; 121.3; 118.7; 110.0;
106.1; 53.5; 49.3; 29.7; 25.9 (two signals overlapped); 24.1; ESI-MS (m/z): 408 [M + H]+, 430 [M + Na]+,
446 [M + K]+ HRMS (ES+) m/z: [M + H]+ calculated for C22H26N5O3 408.2036 found 408.2033.
5-(2,4-Di(pyrrolidin-1-yl)phenyl)-4-nitrobenzo[c][1,2,5]oxadiazole (16): eluent: ethyl ether/petroleum light
◦
1
7/3; yield 50%; orange solid, m.p.: >115 C (dec); IR (v, cm−1): 1601, 1503, 1321, 1233; H-NMR
(CDCl3, 400 MHz, 25 ◦C):
J = 8.6 Hz, 1H); 6.34–6.25 (m; 2 H, two signals overlapped); 3.42 (t, J = 6.5 Hz, 4H), 3.16 (s; 2H); 3.04 (s,
2H) 2.08 (t, J = 6.48 Hz, 4H); 1.83 (t, J = 6.33 Hz, 4H); 13C-NMR (CDCl3: 100.56 MHz, 25 ◦C):
(ppm):
δ (ppm): δ, ppm: 7.89 (d, J = 9.4 Hz, 1H); 7.62 (d, J = 9.4 Hz, 1H); 7.05 (d,
δ
149.4; 148.9; 144.3; 142.2; 136.5; 132.1; 118.9; 105.8; 100.8; 51.7; 50.0; 25.6; 25.2; (selected data); ESI-MS
(m/z): 380 [M + H]+, 402 [M + Na]+; HRMS (ES+) m/z: [M + H]+ calculated for C20H22N5O3 380.1723
found 380.1723.
N1,N1,N3,N3-Tetramethyl-4-(4-nitrobenzo[c][1,2,5]oxadiazol-5-yl)benzene-1,3diamine (17): eluent: ethyl
ether/petroleum light 3/7;yield 36%; brown solid, m.p.: >130 ◦C (dec); IR (v, cm−1): 1604, 1498, 1315,
◦
1237;1H-NMR (CDCl3, 400 MHz, 25 C):
δ
(ppm): 77.94 (d, J = 9.4 Hz, 1H); 7.64 (d, J = 9.4 Hz, 1H), 7.11
(d, J = 8.6 Hz, 1H); 6.50 (br.s, 2H, two signals overlapped); 3.07 (s, 6H), 2.65 (s, 6H); 13C-NMR (CDCl3:
100.56 MHz, 25 ◦C):
δ (ppm): 152.9; 152.1; 149.0; 148.9; 144.3; 140.8; 136.4; 132.8; 131.4; 127.5; 119.1;
107.7; 103.5; 43.3; 41.2; ESI-MS (m/z): 328 [M + H]+, 350 [M + Na]+, 366 [M + K]+; HRMS (ES+) m/z:
[M + H]+ calculated for C16H18N5O3 328.1410 found 328.1413.
7-(2,4-Di(piperidin-1-yl)phenyl)-4,6-nitrobenzo[c][1,2,5]oxadiazole-1-oxide (19): eluent: ethyl ether/petroleum
light 1/1; yield 80%; brown solid, m.p.: >280 ◦C (dec); IR (v, cm−1): 1610, 1554, 1520, 1312;1H-NMR
(CDCl3, 400 MHz, 25 ◦C):
δ (ppm): 8.80 (s, 1H); 7.66 (d, J = 9.7 Hz, 2 H, two signals overlapped); 6.66
(br.s, 1H); 3.43–3.30 (m, 4H); 2.91–2.75 (m, 4H); 1.77 (br.s, 2H); 1.69 (s, 2H); 1.49 (br.s, 4H); ESI-MS (m/z):
469 [M + H]+, 491 [M + Na]+, 507 [M + K]+; HRMS (ES+) m/z: [M + H]+ calculated for C22H25N6O6
469.1836 found 469.1838.
7-(2,4-Di(morpholin-1-yl)phenyl)-4,6-nitrobenzo[c][1,2,5]oxadiazole-1-oxide (20): eluent: ethyl acetate/n-hexane
◦
7/3; yield 80%; brown solid, m.p.: >280 C (dec); IR (v, cm−1): 1607, 1549, 1515, 1313; 1H-NMR (CDCl3,
400 MHz, 25 ◦C):
δ (ppm): 8.77 (s, 1H); 7.00 (d, J = 9.0 Hz, 1H); 6.67 (dd, J1 = 8.5 Hz, J2 = 1.8 Hz, 1H);
6.62 (d, J = 1.85 Hz, 1H); 3.87 (t, J = 4.6 Hz, 4H); 3.50–3.39 (m, 4H); 3.35 (t, J = 4.6 Hz, 4H); 2.97–2.78
(m, 4H); 13C-NMR (CDCl3: 100.56 MHz, 25 ◦C):
δ (ppm): 154.3; 153.9; 144.3; 142.1; 134.1; 133.9; 131.1;
127.7; 113.7; 111.8; 110.3; 105.5; 67.0; 66.3; 52.8; 47.8. ESI-MS (m/z): 473 [M + H]+, 495 [M + Na]+, 511
[M + K]+; HRMS (ES+) m/z: [M + H]+ calculated for C20H21N6O8 473.1421 found 473.1423.
7-(2,4-Di(pyrrolidin-1-yl)phenyl)-4,6-nitrobenzo[c][1,2,5]oxadiazole-1-ozide (21): eluent: ethyl ether/petroleum
light 1/1; yield 65%; brown solid, m.p.: >250 ◦C (dec); IR (v, cm−1): 1609, 1546, 1516, 1313; 1H-NMR
(CDCl3, 400 MHz, 25 ◦C):
δ (ppm): 8.85 (s, 1H); 7.01 (d, J = 8.7 Hz, 1H); 6.75 (d, J = 8.7 Hz, 1H); 6.72
(br.s, 1H); 3.68–3.59 (m, 4H); 4.48–3.41 (m, 4H); 2.17–2.05 (m, 8H); ESI-MS (m/z): 441 [M + H]+, 463
[M + Na]+; HRMS (ES+) m/z: [M + H]+ calculated for C20H21N6O6 441.1523 found 441.1526.
7-(2,4-Bis(dimethylamino)phenyl)-4,6-nitrobenzo[c][1,2,5]oxadiazole-1-ozide (22): eluent: ethyl ether/petroleum
light 8/2; yield 65% (70% in presence of Al2O3); brown solid, m.p.: >130 ◦C (dec); IR (v, cm−1): 1612,
◦
1545, 1510, 1314; 1H-NMR (CDCl3, 400 MHz, 25 C):
δ (ppm): 8.88 (s, 1H); 7.66 (d, J = 8.9 Hz, 1H); 6.56
(dd, J1 = 8.8 Hz, J2 = 2.1 Hz, 1H); 6.35 (s, 1H); 3.14 (s, 6H), 2.54 (s, 6H); 13C-NMR (CDCl3: 100.56 MHz,
(ppm): 154.1; 151.8; 143.2; 142.3; 134.2; 133.5; 131.4; 128.2; 111.3; 107.2; 102.4; 43.2; 40.2; ESI-MS
(m/z): 389 [M + H]+, 411 [M + Na]+; HRMS (ES+) m/z: [M + H]+ calculated for C16H17N6O6 389.1210
◦
25 C):
δ
found 389.1211.

Molecules 2017, 22, 684
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4,6-Dinitro-7-(4-(pyrrolidin-1-yl)phenyl)benzo[c][1,2,5]oxadiazole 1-oxide (25): eluent: petroleum light/diethyl
◦
ether 6/4; yield 66%, dark blue solid; m.p. > 280 C (dec); IR (v, cm−1): 1614, 1556, 1522, 1312; 1H-NMR
(CDCl3, 400 MHz, 25 ◦C):
(ppm): 8.68 (s, 1H), 7.23 (d, J = 8.71 Hz, 2H), 6.63 (d, J = 8.71 Hz, 2H), 3.43
(t, J = 6.37 Hz, 4H), 2.08 (t, J = 6.37 Hz, 4H); 13C-NMR (CDCl3, 100.56 MHz)
(ppm): 150.4, 147.7,
δ
δ
141.4, 134.6, 131.5 (CH), 127.9 (CH), 113.5, 112.3, 111.8 (CH), 110.9, 47.7 (CH2), 25.4 (CH2); ESI-MS
(m/z): 372 [M + H]+, 394 [M + Na]+; HRMS (ES+) m/z: (M + H)+ calculated for C16H14N5O6 372.0944
found 372.0946.
7-(4-(Dimethylamino)phenyl)-4,6-dinitrobenzo[c][◦1,2,5]oxadiazole 1-oxide (26): petroleum light/diethyl
ether 4/6; yield 62% dark blue solid; m.p.: >145 C (dec); IR (v, cm−1): 1610, 1554, 1521, 1309; 1H-NMR
(CDCl3, 400 MHz, 25 ◦C):
δ (ppm): 8.69 (s, 1H), 7.24 (d, J = 9.10 Hz, 2H), 6.76 (d, J = 9.10 Hz, 2H), 3.12
(s, 1H); 13C-NMR (CDCl3, 100.56 MHz) (selected data)
δ (ppm): 152.7, 144.6, 131.2 (CH), 127.8 (CH),
111.5 (CH), 40.0 (CH3); ESI-MS (m/z): 346 [M + H]+, 368 [M + Na]+, 384 [M + K]+; HRMS (ES+) m/z:
[M + H]+ calculated for C14H12N5O6 346.0788 found 346.0790.
4. Conclusions
The nucleophile/electrophile combinations between 1,3-dialkylaminobenzene derivatives
1–4
and the chloro-nitrobenzofurazan derivatives or the chloro-dinitrobenzofuroxan 18 occurred
5–7
regioselectively, yielding the product from the attack in the less-hindered ortho-position to the amino
groups located on the aromatic ring of the nucleophile. The novel synthesized compounds are
highly conjugated systems contemporarily bearing an electron-rich and an electron-poor moiety. This
characteristic feature makes them interesting candidates for eventual future applications in applied
fields, such as solar cells, optoelectronic, and chromogenic materials. In the case of benzofuroxan
derivatives, in the pharmaceutical field as NO release agents.
Further, the extension to some monoaminobenzene derivatives as nucleophiles permits to
highlight the effect of steric encumbrance of the amino substituents on the reactivity of the considered
systems on going from mono- to towards polysubstituted species.
Acknowledgments: Work supported by Alma Mater Studiorum–Università di Bologna (RFO funds).
E. Chugunova is grateful for the financial support of the Russian Science Foundation (grant 14-50-00014). Authors
thank Matteo Verdolini, Silvia Cino, and Luca Zuppiroli for running the mass spectra. Authors dedicate this
paper in memory of the 100th anniversary of the death of Ludwik Lejzer Zamenhof (Białystok, 15 December
1859—Warsaw, 14 April 1917), founder of the Esperanto language.
Author Contributions: C.B. conceived, designed the experiments and analyzed the data; G.M. and E.C. performed
the experiments and analyzed the data; C.B. and S.B. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).