Synthesis of Hydrazinylpyridines via Nucleophilic Aromatic Substitution and Further Transformation to Bicyclo[22.2]octenes Fused with Two N -Aminosuccinimide Moieties

Article abstract of DOI:10.1055/s-0040-1706481

Efficient and reliable synthesis of substituted hydrazinylpyridines in thick-wall ACE tubes via nucleophilic substitution of a chlorine substituent in different chloropyridines is presented. Hydrazine hydrate and alkylhydrazines were used as nucleophiles and simple alcohols and diethyl ether were the only organic solvents necessary, making the process environmentally and user friendly, potentially reaching 100% atomic efficiency. In the next step, transformations of succinic anhydride moieties fused to the bicyclo[2.2.2]octene framework into succinimide moieties via nucleophilic substitution of oxygens were conducted. As nucleophiles two of the synthesized hydrazinylpyridines (2-hydrazinyl-3-nitropyridine and 2-hydrazinyl-5-nitropyridine) and also hydrazine hydrate, phenylhydrazine, and 4-nitrophenylhydrazine were used. Reactions were again carried out in ACE tubes and only simple alcohols, diethyl ether, and acetone were needed as solvents. One of the prepared bicyclo[2.2.2]octene adducts displayed water solubility thus being a promising candidate for future studies as a novel bidentate ligand for various metal cations in aqueous solutions or acting as an unprecedented halogen bond acceptor.

Full text of DOI:10.1055/s-0040-1706481

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–I
paper
A
en
J. Ekar, K. Kranjc
Paper
Synthesis
Synthesis of Hydrazinylpyridines via Nucleophilic Aromatic Substi-
tution and Further Transformation to Bicyclo[2.2.2]octenes Fused
with Two N-Aminosuccinimide Moieties
Jernej Ekar1
Krištof Kranjc*
Faculty of Chemistry and Chemical Technology, University of
Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
kristof.kranjc@fkkt.uni-lj.si
eKFaMrcišautilColtofykrKrorirsefatsCnophfjo.ceknmrdaiinsntjgcry@Aafukntkhdto.Curhnei-mlj.iscial Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
Received: 21.07.2020
Accepted after revision: 04.09.2020
Published online: 12.10.2020
metallic complexes applied as antibiotics,13,14 as a complex-
ing site for technetium in molecules used in radioactive im-
aging in medicine,15 and as a precursor in the synthesis of
some pesticides.5,16 Both 2- and 4-hydrazinylpyridines can
be used in the synthesis of compounds that exhibit anti-
tumor activity17,18 and antidepressant characteristics.19
Hydrazide derivatives of pyrimidine are used as precursors
for the synthesis of various compounds of pharmacological
interest.20
DOI: 10.1055/s-0040-1706481; Art ID: ss-2020-t0393-op
Abstract Efficient and reliable synthesis of substituted hydrazinylpyr-
idines in thick-wall ACE tubes via nucleophilic substitution of a chlorine
substituent in different chloropyridines is presented. Hydrazine hydrate
and alkylhydrazines were used as nucleophiles and simple alcohols and
diethyl ether were the only organic solvents necessary, making the pro-
cess environmentally and user friendly, potentially reaching 100%
atomic efficiency. In the next step, transformations of succinic anhy-
dride moieties fused to the bicyclo[2.2.2]octene framework into succin-
imide moieties via nucleophilic substitution of oxygens were conduct-
ed. As nucleophiles two of the synthesized hydrazinylpyridines (2-
hydrazinyl-3-nitropyridine and 2-hydrazinyl-5-nitropyridine) and also
hydrazine hydrate, phenylhydrazine, and 4-nitrophenylhydrazine were
used. Reactions were again carried out in ACE tubes and only simple al-
cohols, diethyl ether, and acetone were needed as solvents. One of the
prepared bicyclo[2.2.2]octene adducts displayed water solubility thus
being a promising candidate for future studies as a novel bidentate li-
gand for various metal cations in aqueous solutions or acting as an un-
precedented halogen bond acceptor.
There are different options for the synthesis of hydraz-
inylpyridines. They (as well as the other aromatic hydra-
zines) can be prepared via formation of diazonium salts
from aromatic amines, followed by reduction of the diazo-
nium group using SnCl2 and HCl,5,21,22 PPh3 and HCl23 or
24–26
Na2SO3
in combination with H2SO4,24,25 HCl,27 Zn dust
and acetic acid24 or NaOH and SO2.24 The main problem
with this type of synthesis is an excessive amount of toxic
waste generated in the form of inorganic salts.
Hydrazinylpyridines can be also prepared via nucleo-
philic aromatic substitution of a halogen in halopyridines
with hydrazine (Scheme 1),5 appropriate halogens being
fluorine, chlorine, and bromine.5 Besides hydrazine hydrate,
substituted hydrazines can also be used, for example, meth-
ylhydrazine28 and 4-tolylhydrazine.29 Substitution most
easily occurs on activated ortho- and para-positions regard-
ing the nitrogen of pyridine ring, but can be in some cases
achieved even on meta-position.5
Key words green chemistry, chloropyridine, bicyclo[2.2.2]octene,
water-soluble ligand, succinimide, nucleophilic substitution
Hydrazinylpyridines and their substituted analogues are
simple organic molecules that can be used for many further
transformations: acting as nucleophiles,2–5 for the synthesis
of more complex nitrogen heterocyclic compounds, mainly
various [1,2,3]triazolopyridines5–7 and azaindazoles,8 or for
hydrazone formation.5 Hydrazine and its substituted ana-
logues can be furthermore used for the synthesis of pyra-
zole and its derivatives.9–12 Hydrazinyl group in hydrazinyl-
pyridines can be substituted with a hydrogen, halogen,
hydroxy, or phenyl group or reduced to an amine group.5 2-
Hydrazinylpyridine can be used for the synthesis of organo-
N
N
N2H4•H2O
R
X
NH
NH2
R
– HX
X = F, Cl, Br
Scheme 1 General reaction pathway of nucleophilic substitution of a
halogen in halopyridine with hydrazine hydrate
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Ekar, K. Kranjc
Paper
Synthesis
Nucleophilic substitution with hydrazine hydrate en-
abled preparation of many hydrazinylpyridines, for exam-
ple, 4-hydrazinylpyridine from 4-chloropyridine,30 3-
chloro-2-hydrazinylpyridine from 2,3-dichloropyridine,31
and 3-chloro-2-fluoropyridine,32 and 3,5-dichloro-2-hydra-
zinylpyridine from 2,3,5-trichloropyridine.5 Appropriate re-
action conditions can result even in substitution of two hal-
ogens as in the case of the synthesis of 2,6-dihydrazinyl-
pyridine from 2,6-difluoropyridine.33
With perfluoro- and perchloropyridine substitution
mainly takes place on para-position.34 If perbromopyridine
is used, para-product is still predominant, but the amount
of ortho-product increases as a consequence of steric hin-
drance caused by the larger bromine substituents.34,35 Pyri-
dine ring is activated for the nucleophilic substitution if
other electron-withdrawing substituents (nitro, cyano
group) are present.5 Examples of such compounds are 2-
chloro-3-nitropyridine,28 2-bromo-5-chloro-3-nitropyri-
dine,28 and 3-carbonitrile-2,4,5,6-tetrachloropyridine.5
Substitution of a halogen at meta-position was successful in
the cases of 3-fluoro- and 3-chloro-2-nitropyridines6 and
also 3-fluoro- and 3-bromo-4-nitropyridine N-oxides.29
Most of the hydrazinylpyridine syntheses via nucleo-
philic substitution of a halogen are conducted in solvents
such as simple alcohols (methanol, ethanol, n-propyl alco-
hol), THF, DMF, acetonitrile, dichloromethane, pyridine, or
1,4-dioxane,5 under reflux,30,34 at room temperature,28 or at
0 °C34 depending on the type and reactivity of starting ha-
lopyridines. Products are generally isolated by extraction
into chloroform28,34 followed by recrystallization30,34 in
some cases.
Our goal was to develop a simple, one-step synthesis of
a set of hydrazinylpyridines 3a–g starting from various
chloro-substituted pyridines 1a–e and hydrazines 2a–c,
where the desired aromatic nucleophilic substitution of the
chloro substituent would take place under environmentally
friendly conditions, including the consideration of the type
and amount of waste. We decided to conduct all reactions
in high-pressure ACE tubes, except in the case of the syn-
thesis of 2-(1-methylhydrazinyl)-3-nitropyridine (3f),
where room temperature turned out to be sufficient. n-Pro-
pyl alcohol was used as the solvent, except again in the case
of 3f, where methanol was selected. Closed high-pressure
ACE tubes offer many advantages: reactions can be con-
ducted at higher temperatures than the boiling point of the
reaction mixture; any loss of reactants, products, and sol-
vents can be prevented; pressure resistant (glass) equip-
ment are available in a range of sizes (offering the possibili-
ty of scale-up). According to the reactivity of chloropyri-
dines 1a–e and the type of hydrazine 2a–c used, the
reaction temperature, time, and excess of hydrazines were
adjusted (Table 1), enabling the synthesis of hydrazinylpyri-
dines 3a–g in excellent yields (60–93%, with the exception
of 3g).
In the cases when pyridine ring is inactivated (1a,b) or
weakly activated (1c) for nucleophilic substitution, large
excesses of hydrazine hydrate (2a) are needed for the com-
plete transformation to 3a–c (Table 1). When smaller
amounts of hydrazine hydrate (2–3-fold excess) are used,
the yields of 3a,b decrease substantially to only 10–30%, but
still depend upon the reaction temperature and time. In our
cases, we were unable to replicate the results of a previous
study stating that 1.1-fold excess of hydrazine hydrate is
Table 1 General Reaction Scheme for the Synthesis of Hydrazinylpyridines 3a–g
R
NH2
H2N NH
R1
R2
N
R1
R2
N
N
N
2a–c
R
or
R2
R4
R4
– HCl
R4
R3
R3
HN
NH2
1a–e
3b
3a,c–g
Entry
Chloropyridine 1
R1 R2
Hydrazine 2
Molar ratio Temp (°C) Time
of 1:2
Product
Yield (%)
R3
R4
R
1
2
3
4
5
6
7
Cl
H
H
H
H
H
H
1a
1b
1c
1d
1e
1d
1e
H
2a
2a
2a
2a
2a
2b
2c
1:6
1:8
1:7
1:3
1:4
1:4
1:3
150
150
140
60
20 h
3aa
93
60
90
79
74
72
32
H
H
Cl
H
H
H
H
H
H
20 h
3b·HCla
3ca
Cl
Cl
Cl
Cl
Cl
Cl
H
4 h
NO2
H
H
30 min
1 h
3da
NO2
H
80
3ea
NO2
H
H
Me
r.t.
30 min
45 min
3fb
NO2
CH2CH2OH
100
3ga
a Reaction was conducted in a high pressure ACE tube, PrOH was used as the solvent.
b Reaction was conducted in an open vessel, MeOH was used as the solvent.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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J. Ekar, K. Kranjc
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Synthesis
sufficient for the reaction with 4-chloropyridine (1b).30 Ob-
viously, at least 2-fold excess of hydrazine 2 is needed in all
cases, because one equivalent of 2 is consumed for the neu-
tralization of hydrogen chloride liberated as the side prod-
uct of the nucleophilic substitution yielding 3. In all cases,
except for 4-hydrazinylpyridine hydrochloride (3b·HCl),
pure hydrazinylpyridines 3 and not their salts were isolated
demonstrating that products 3 are less basic (have lower
pKb values) than starting hydrazines 2. On the other hand,
as 3b is more basic than hydrazine, a decreased amount of
hydrazine is enough for the complete reaction (HCl formed
does not decrease the nucleophilicity of the starting hydra-
zine 2). Nevertheless, the use of 4-chloropyridine hydro-
chloride (1b·HCl) still requires an excess of hydrazine (2a),
because in the first step an equivalent of 2a is consumed for
the neutralization of 1b·HCl to form its free base 1b.
Figure 1 Assigned 1H NMR spectra of 2-hydrazinyl-5-nitropyridine (3e)
measured at 29 °C (red line) and 59 °C (blue line)
The choice of the solvent (alcohol) also effects the over-
all yield. It turned out that all compounds 3, including those
containing nitro group (3d–g), are very polar. When the last
step of isolation is filtration (for 3c–e,g), application of
higher alcohols such as n-propyl, isobutyl, and n-butyl alco-
hols improves the yield. In the cases of 3a,b, the solvents are
removed by vacuum distillation before the isolation, there-
fore the solubility of 3 in the solvents applied for the reac-
tions does not affect the final yield. Alcohols with lower
boiling points, such as ethyl, isopropyl and n-propyl alco-
hols are therefore favored.
oxygens from NO2 group. A long chain of molecules can
form sufficiently small energy gap between HOMO and
LUMO orbitals for coloration to appear. This could be sup-
ported by a previous report, that describes a derivative of
hydrazinylpyridine already successfully implemented as a
colorimetric sensor for carbonate ions due to its color
changes upon the formation of hydrogen bonds with car-
bonate ion in an aqueous solution.36
Use of N-alkyl-substituted hydrazines, such as methyl-
hydrazine (2b) and 2-hydrazinylethanol (2c), led, in accor-
dance with the previous results,6 to the substitution taking
place on the secondary nitrogen as shown by the exclusive
formation of products 3f,g. Nucleophilicity of the secondary
nitrogen in substituted hydrazines is increased (in compari-
son with the primary one) by the electron-donating prop-
erties of the additional alkyl substituent, as evident in the
cases of 2b,c, where electronic effects override the steric
hindrance. These observations possibly explain the unsuc-
cessful reaction of N,N-dimethylhydrazine.
Figure 2 Color variability of synthesized hydrazinylpyridines 3 (top
row: 3a–c, bottom row: 3d–g) in their crystalline form
Free rotation of 2-hydrazinyl-5-nitropyridine (3e) in
DMSO-d6 solution seems to be heavily hindered, as seen
from the lack of fine structure in its 1H NMR spectrum mea-
sured at 29 °C (Figure 1, red line). Furthermore, at 29 °C
only two 13C NMR signals were observed. Increasing the
measurement temperature to 59 °C caused a drastic change
in 1H NMR spectrum, with nicely resolved fine structure
observed (Figure 1, blue line), whereas in 13C NMR spec-
trum five signals for five chemically inequivalent carbon
nuclei were detected. This observation, unusual for a com-
pound with so small molecular mass, could be due to strong
intermolecular (hydrogen) bonds.
An unexpected wide variability was noted in the colors
of compounds 3 in their pure crystalline forms (Figure 2).
This observation might be as well explained with intermo-
lecular (hydrogen) bonds forming in the solid state between
hydrogens of NH2 (or NH) groups and pyridine nitrogen or
By optimizing synthetic procedures only small amounts
of solvents (simple alcohols and diethyl ether) are needed;
furthermore, they can be easily recycled. Products 3 are ob-
tained pure even without recrystallization, the only by-
product being hydrazine hydrochloride or the correspond-
ing salt of alkylhydrazines 2b,c, which are removed togeth-
er with the aqueous phase (when extraction is used in the
cases of 3a–c) or washed away during the filtration of the
final products (in the cases of 3d–g). Hydrazine hydrochlo-
ride can be isolated from the aqueous phases; 1H NMR anal-
ysis showed its purity to be around 90% and with further
purification (or neutralization to regain hydrazine as a free
base) can be efficiently reused. Consequently, the described
synthetic process has 100% atomic efficiency if water, com-
ing from the hydrazine hydrate, is not considered as a
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D
J. Ekar, K. Kranjc
Paper
Synthesis
waste. The presence of water in the reaction mixture shifts
the chemical equilibrium away from the products 3. To low-
er the amount of hydrazine needed, from the two-phase
system that appears during the synthesis of 3a–c, continu-
ous removal of water layer (containing mainly hydrazine
hydrochloride) and continuous addition of fresh hydrazine
hydrate is feasible. Such approach becomes attractive when
the preparation of hydrazinylpyridines is taking place on a
larger scale.
In the next step, hydrazine hydrate, two commercially
available derivatives [phenyl- (2d) and 4-nitrophenylhydra-
zine (2e)] as well as two of the above prepared hydrazinyl-
pyridines (i.e., 3d,e) were selected for the transformation of
succinic anhydride rings fused to the bicyclo[2.2.2]octene
core of the compounds 4a–d into corresponding N-substi-
tuted succinimides 5a–i. These products contain N-amino
(5a,b), N-phenylamino groups (5c,d), or its nitro analogue
(5e,f) as well as N-nitropyridylamino groups (5g–i) that
represent potential bidentate ligands for metal cations as
demonstrated in similar, albeit more complex com-
pounds.37 Especially pyridine-containing derivatives 5g–i
are of great interest, as their heterocyclic nitrogen, having
increased electron density, displays high affinity for coordi-
nation with various metal cations. Furthermore, such ad-
ducts can act as unprecedented double halogen bond accep-
tors with potential applicability in crystal engineering.38,39
Adducts with free N-amino groups, on the other hand, are
of interest as they offer easy entry into -aminophosphine
ligands showing a plethora of possible coordination modes
as demonstrated recently for Pd(II) and Pt(II) complexes.40
The most straightforward approach towards the re-
quired symmetric exo,exo-bicyclo[2.2.2]octenes 4a–d pos-
sessing two succinic anhydride moieties starts from the ap-
propriate 2H-pyran-2-ones and maleic anhydride via dou-
ble stereospecific thermal Diels–Alder cycloaddition.41,42
Adducts 4 were in the next step transformed into succin-
imide derivatives 5 via nucleophilic attack of NH2 group of
amines, hydrazines, or hydrazides. Reactions with amines
generally require harsh conditions; ethanamine, as an ex-
ample, required 5 days (in water at 75 °C), whereas (pyri-
din-3-yl)methanamine required only 5 hours (in DMF at ca.
150 °C).2 Reactions could be in some cases greatly accelerat-
ed by microwave heating (2 h at 160 °C in water was suffi-
cient in most cases).2,43 With hydrazine and its alkyl and
aryl derivatives, being better nucleophiles than amines,
transformations can be conducted more easily but micro-
wave conditions still show good potential.2–4 Reactions de-
scribed in the literature were completed under microwave
irradiation in 90 minutes or less (at 100–160 °C),2,4 or with
conventional heating in n-butyl alcohol in 3 hours (at 160
°C).44
For the transformations of 4a–d, unsubstituted hydra-
zine (2a) and its aryl derivatives (2d,e and 3d,e) were used
as nucleophiles. Reactions were again conducted in high-
Table 2 Substituted Bicyclo[2.2.2]octenes 5a–i Synthesized from 4a–d and Substituted Hydrazines 2 or 3 via Nucleophilic Substitution of Oxygen with
Nitrogen
R
R2
R2
R1
H2N NH
O
R
R1
O
O
2a,d,e or 3d,e
O
R
O
HN
N
O
O
NH
N
O
n-BuOH or i-BuOH
160–175 °C
O
O
R3COHN
R3COHN
4a–d
5a–i
Entry
Bicyclo[2.2.2]octene 4
R1 R2
Hydrazines 2 or 3
Molar ratio of Temp (°C) Time (h) Product Yield (%)
4:hydrazine
R3
Me
R
1
2
3
4
5
6
7
8
9
Me
H
4a
H
2a
1:20a
1:12
1:2.5
1:2.2
1:2.5
1:3.6
1:4
170
160
160
160
160
170
175
175
175
1.5
3
5ab
5bc
5cc
5dc
5ec
5fc
80
38
72
69
51
56
65
69
52
Et
Me
H
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
4b
4a
4b
4c
4d
4b
4c
4c
H
2a
2d
2d
2e
2e
3d
3d
3e
Me
Ph
3
Et
Me
H
Ph
3
4-MeC6H4
Me
4-NO2C6H4
4-NO2C6H4
3-NO2-pyridin-2-yl
3-NO2-pyridin-2-yl
5-NO2-pyridin-2-yl
2.5
2.5
5
CO2Me
Me
H
Et
5gb
5hb
5ib
4-MeC6H4
4-MeC6H4
1:4
4
H
1:4
3
a For the reaction with 1 mol of bicyclo[2.2.2]octene, 2 mol of hydrazine were needed, so the ratio of 1:20 accounts for the 10-fold molar excess of hydrazine;
analogously in the other cases as well.
b i-BuOH was used as the solvent.
c n-BuOH was used as the solvent.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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J. Ekar, K. Kranjc
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Synthesis
pressure ACE tubes at 160–175 °C using n-butyl or isobutyl
alcohol as the solvent yielding products 5a–i in medium
yields (Table 2). The main goal was to fine tune the substit-
uent patterns of the products 5 to increase their solubility
in aqueous media as this property plays an important role
in the applicability as ligands for metal cations and inhibi-
tors of various physiologically important enzymes. The aim
was to prepare at least one water-soluble product; indeed,
5a turned out to be soluble in water and partially in metha-
nol, while insoluble in higher alcohols such as n-butyl or
isobutyl alcohol. On the other hand, products 5b–i, as well
as their analogues previously reported in the literature, are
completely insoluble in water and well soluble only in
DMSO and DMF, greatly diminishing their potential appli-
cability.
The exo,exo arrangement of the five-membered rings
fused to the bicyclo[2.2.2]octene framework is conserved
during the transformations 4 → 5. This is confirmed by the
value of the coupling constants in 1H NMR spectra of prod-
ucts 5 for the doublets belonging to 3a-H and 4a-H (and
also 7a-H and 8a-H) being around 8 Hz, consistent with the
literature data (on the other hand, for endo arrangement
these coupling constants are known to be around 10 Hz).45
1H NMR spectrum of compound 5i measured at 29 °C
(Figure 3, red line) was again lacking any fine structure (ex-
cept for the phenyl and p-tolyl group signals). Analogously,
at 29 °C there were also signals missing in 13C NMR spec-
trum. Increasing the measurement temperature to 59 °C
Figure 3 Assigned 1H NMR spectra of compound 5i measured at 29 °C
(red line) and 59 °C (blue line)
lected hydrazine derivatives, including some hydrazinyl-
pyridines 3 that we prepared, a set of nine bicyclo-
[2.2.2]octenes 5a–i fused with two N-substituted succinim-
ide moieties was obtained via nucleophilic substitution of
the oxygen in succinic anhydride moieties. We managed to
exchange the traditionally used solvents, such as decalin or
tetralin (both of them classified as toxic to aquatic life with
long-lasting effects and possibly fatal if swallowed, tetralin
additionally causing skin and eye irritation and suspected
of causing cancer, decalin being flammable) with environ-
mentally friendly alcohols (isobutyl alcohol, n-butyl alco-
hol). Furthermore, our important goal of obtaining a water-
soluble derivative was reached (i.e., product 5a is very solu-
ble in water and partially soluble in methanol), thus open-
ing potential applications of such adducts as bidentate li-
gands for metal cations in aqueous solutions or as highly
modular halogen bond acceptors, in both cases acting as
unprecedented building blocks in crystal engineering capa-
ble of forming 1D molecular architectures. We also found
that 2-hydrazinyl-5-nitropyridine (3e) displays heavily hin-
dered rotation in a DMSO-d6 solution at room temperature,
this being unexpected for a molecule as small as 3e. This
behavior was observed in its adduct 5i as well.
1
caused the fine structure of H NMR spectrum to appear,
with better resolved and narrower signals (Figure 3, blue
line). Additionally, in 13C NMR spectrum at 59 °C signals for
all chemically inequivalent carbons were observed. This be-
havior could again be explained by the heavily restricted
free rotation in DMSO-d6 solution as a consequence of
strong intermolecular bonds.
Worth noting is that the hydrazine used in the prepara-
tion of 5i was 3e, the one for which restricted rotation was
already demonstrated. It is interesting that molecules of 3e
do not show restricted free rotation in solution only, but
also when representing a part (covalently bound fragment)
of a larger organic molecule such as 5i, when they affect bi-
cyclo[2.2.2]octene skeleton as well (with only remote side
groups staying unaffected).
Observation that methoxycarbonyl group of compound
5f does not react with 4-nitrophenylhydrazine (2e), leads to
the conclusion that the reaction conditions applied are not
harsh enough for the ester groups to be transformed to cor-
responding hydrazides.
In conclusion, seven substituted hydrazinylpyridines
3a–g were synthesized in very good yields (60–93%, with
the exception of 3g), starting from chloropyridines 1a–e
and hydrazines 2a–c via nucleophilic substitution of chlo-
rine. Simple isolation via filtration or vacuum distillation
was sufficient, so no purifying of the products was needed,
rendering the process environmentally friendly. Using se-
Melting points were determined using an automatic OptiMelt
MPA100 (Stanford Research System) instrument and are uncorrected.
1H and 13C NMR spectra were recorded with a Bruker Avance III spec-
trometer at 29 °C (unless stated otherwise) using Me4Si as the inter-
nal standard at 300 MHz or 75.5 MHz, respectively. 13C NMR spectra
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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J. Ekar, K. Kranjc
Paper
Synthesis
are referenced against the central line of the solvent signal (DMSO-d6
at 39.5 ppm). Mass spectra were recorded using an Agilent 6624 Ac-
curate Mass TOF LC/MS spectrometer via ESI ionization. IR spectra of
compounds as powders were recorded on a Bruker Alpha Platinum
ATR FT-IR spectrophotometer. Elemental analyses were performed on
a PerkinElmer 2400 Series II CHNS/O analyzer.
2-(1-Methylhydrazinyl)-3-nitropyridine (3f)
2-Chloro-3-nitropyridine (1d; 1.59 g, 10.0 mmol) was suspended in
MeOH (5 mL). While stirring, methylhydrazine (2b; 2.11 mL, 1.84 g,
40.0 mmol) was slowly added. Caution: The reaction was heavily
exothermic and the addition had to be slow. A red solution was
formed and left stirring for 30 min at r.t. Distilled H2O (15 mL) was
added whereupon a red oil was formed. The mixture of MeOH and
H2O was removed with a syringe and the red oil was cooled in an ice-
salt bath. The orange precipitate obtained was filtered and washed
with distilled H2O (10 mL).
Reagents and solvents were used as received from commercial suppli-
ers with purity of 98% or more. Bicyclo[2.2.2]octenes 4a–d were pre-
pared from appropriately substituted 2H-pyran-2-ones and maleic
anhydride under reflux in tetralin according to the published proce-
dure.41 Commercially available thick-walled ACE glass tubes closed by
a Teflon screw-plug were used.
Bicyclo[2.2.2]octene Derivatives 5a–d
Succinic anhydride adduct 4a,b (1.0 mmol) was suspended in i-BuOH
(6 mL, for 5a) or BuOH (12 mL, for 5b–d) inside a 15 mL ACE tube.
While stirring, hydrazine hydrate (2a; 972 L, 1.00 g, 20.0 mmol for
5a and 583 L, 0.601 g, 12.0 mmol for 5b) and phenylhydrazine (2d;
246 L, 0.270 g, 2.50 mmol for 5c and 217 L, 0.238 g, 2.20 mmol for
5d), respectively, was added. The respective reaction mixture was
stirred for 1.5 h at 170 °C (for 5a) or for 3 h at 160 °C (for 5b–d) and
then cooled to 4 °C. The resulting precipitate was filtered and washed
with MeOH (5 mL) and Et2O (10 mL).
2-Hydrazinylpyridine (3a) and 4-Hydrazinylpyridine Hydrochlo-
ride (3b·HCl)
For the synthesis of 3a, hydrazine hydrate (2a; 2.92 mL, 3.00 g, 60.0
mmol) and PrOH (3 mL) were mixed in a 15 mL ACE tube. While stir-
ring, 2-chloropyrdine (1a; 938 μL, 1.14 g, 10.0 mmol) was added.
For the synthesis of 3b, hydrazine hydrate (2a; 972 L, 1.00 g, 20.0
mmol) and PrOH (5 mL) were mixed in a 15 mL ACE tube. While stir-
ring, 4-chloropyrdine hydrochloride (1b·HCl; 1.50 g, 10.0 mmol) was
added. Two-phase system appeared and the bottom aqueous layer
with hydrazine hydrochloride was removed with a syringe. Addition-
al hydrazine hydrate (2a; 2.92 mL, 3.00 g, 60.0 mmol) was added.
Bicyclo[2.2.2]octene Derivatives 5e–i
4-Nitrophenylhydrazine (2e; 0.383 g, 2.50 mmol for 5e and 0.551 g,
3.60 mmol for 5f), 2-hydrazinyl-3-nitropyridine (3d; 0.308 g, 2.00
mmol for 5g,h), and 2-hydrazinyl-5-nitropyridine (3e; 0.308 g, 2.00
mmol for 5i), respectively, was dissolved in the solvent (15 mL) given
in Table 2 while heating in an open 25 mL ACE tube. While stirring, 4c
(0.457 g, 1.0 mmol for 5e), 4d (0.439 g, 1.0 mmol for 5f), 4b (0.205 g,
0.5 mmol for 5g), and 4c (0.229 g, 0.5 mmol for 5h,i) was added, re-
spectively. The respective reaction mixture was stirred at the specific
temperature and time (Table 2). Thereafter, it was cooled to 10 °C, the
resulting precipitate was filtered, and suspended in a mixture of
MeOH (10 mL) and acetone (5 mL) for 5e and 5f and EtOH (10 mL) and
acetone (10 mL) for 5g–i. The precipitate formed was filtered again
and washed with Et2O (10 mL).
Both the reaction mixtures were stirred for 20 h at 150 °C giving a
two-phase system. The bottom aqueous layer, containing hydrazine
hydrochloride, was removed and the upper layer evaporated under
vacuum, yielding an orange oil that solidified at 4 °C (3a), or a white
precipitate (3b·HCl). The latter was suspended in Et2O (20 mL) and fil-
tered.
3-Chloro-2-hydrazinylpyridine (3c)
2,3-Dichloropyridine (1c; 1.48 g, 10.0 mmol) was dissolved in PrOH
(6 mL) in a 15 mL ACE tube. While stirring, hydrazine hydrate (2a;
3.40 mL, 3.51 g, 70.0 mmol) was added and the reaction mixture was
stirred for 4 h at 140 °C giving a two-phase system. The bottom aque-
ous layer was removed and the upper layer was cooled to around
10 °C until white crystals were formed. This suspension was poured
into distilled H2O (6 mL). Crystals of 3c were filtered and washed with
Et2O (6 mL).
CAUTION! Care should be taken regarding boiling point of the alco-
hol, reaction temperature, and ACE tube strength to avoid an acciden-
tal explosion.
2-Hydrazinylpyridine (3a)
Yield: 1.01 g (93%); red solid; mp 44–46 °C (PrOH–EtOH–MeOH).
2-Hydrazinyl-3-nitropyridine (3d), 2-Hydrazinyl-5-nitropyridine
(3e), and 2-[1-(5-Nitropyridin-2-yl)hydrazinyl]ethanol (3g)
IR (neat): 3254, 3009, 1595, 1570 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 7.97 (ddd, J1 = 5 Hz, J2 = 2 Hz, J3 = 1
Hz, 1 H, 6-H), 7.43 (ddd, J1 = 8.5 Hz, J2 = 7 Hz, J3 = 2 Hz, 1 H, 4-H), 7.32
(s, 1 H, NH), 6.67 (dt, J1 = 8.5 Hz, J2 = 1 Hz, 1 H, 3-H), 6.53 (ddd, J1 = 7
Hz, J2 = 5 Hz, J3 = 1 Hz, 1 H, 5-H), 4.07 (br s, 2 H, NH2).
13C NMR (75.5 MHz, DMSO-d6):  = 162.3, 147.7, 137.3, 113.0, 106.9.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C5H8N3: 110.0713; found:
For the preparation of 3d, 2-chloro-3-nitropyridine (1d; 0.793 g, 5.0
mmol) and for the preparation of 3e,g, the same amount of 2-chloro-
5-nitropyridine (1e; 0.793 g, 5.0 mmol) was suspended in PrOH (20
mL) in a 25 mL ACE tube, respectively. While stirring, hydrazine hy-
drate (2a; 729 L, 0.751 g, 15.0 mmol for 3d and 972 L, 1.00 g, 20.0
mmol for 3e) and 2-hydrazinylethanol (2c; 1.02 mL, 1.14 g, 15.0
mmol for 3g) was added, respectively, and the respective reaction
mixture was stirred at the specific temperature and time (Table 1). Af-
ter reaction completion, in the case of 3d,e, the resulting mixture was
cooled to 4 °C, the precipitate filtered, suspended in distilled H2O (15
mL), filtered again, then suspended in Et2O (15 mL) and filtered once
more. In the case of 3g, the mixture was vacuum evaporated, the re-
maining red oil cooled in an ice-salt bath. After around 30 min, a yel-
low precipitate was formed, which was suspended in distilled H2O (20
mL), filtered, then suspended in Et2O (20 mL) and filtered again.
110.0708.
4-Hydrazinylpyridine Hydrochloride (3b·HCl)
Yield: 0.875 g (60%); brown solid; mp 235–238 °C (MeOH–EtOH–
Et2O) [Lit.30 mp 242–243 °C (MeOH)].
IR (neat): 3300, 3187, 2905, 2871, 2813, 1654, 1595, 1533 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 9.98 (s, 1 H, NH), 8.06 (d, J = 6.5 Hz,
2 H, 2-H, 6-H), 6.96 (d, J = 6.5 Hz, 2 H, 3-H, 5-H), 4.93 (br s, 2 H, NH2).
13C NMR (75.5 MHz, DMSO-d6):  = 158.4, 144.7, 106.1.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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J. Ekar, K. Kranjc
Paper
Synthesis
HRMS (ESI, TOF): m/z [M – Cl]+ calcd for C5H8N3: 110.0713; found:
2-[1-(5-Nitropyridine-2-yl)hydrazinyl]ethanol (3g)
110.0711.
Yield: 0.320 g (32%); yellow solid; mp 97.5–100 °C (PrOH).
IR (neat): 3302, 3182, 2862, 1591, 1567, 1485 cm–1
.
Anal. Calcd for C5H8ClN3: C, 41.24; H, 5.54; N, 28.87; Cl, 24.35. Found:
C, 41.54; H, 5.53; N, 28.76; Cl, 24.17.
1H NMR (300 MHz, DMSO-d6):  = 8.88 (d, J = 3 Hz, 1 H, 6-H), 8.15 (dd,
J1 = 10 Hz, J2 = 3 Hz, 1 H, 4-H), 7.18 (d, J = 10 Hz, 1 H, 3-H), 4.98 (s, 2 H,
NH2), 4.83 (br s, 1 H, OH), 3.91 (t, J = 6 Hz, 2 H, CH2), 3.65 (t, J = 6 Hz, 2
H, CH2).
3-Chloro-2-hydrazinylpyridine (3c)
Yield: 1.29 g (90%); white solid; mp 164–166.5 °C (PrOH) [Lit.31 mp
169 °C (EtOH)].
IR (neat): 3284, 3195, 1917, 1890, 1865, 1622, 1592 cm–1
13C NMR (75.5 MHz, DMSO-d6):  = 163.0, 146.5, 134.2, 132.5, 106.6,
58.3, 53.8.
.
1H NMR (300 MHz, DMSO-d6):  = 8.05 (dd, J1 = 5 Hz, J2 = 1.5 Hz, 1 H,
6-H), 7.57 (dd, J1 = 8 Hz, J2 = 1.5 Hz, 1 H, 4-H), 7.56 (br s, 1 H, NH), 6.62
(dd, J1 = 8 Hz, J2 = 5 Hz, 1 H, 5-H), 4.22 (br s, 2 H, NH2).
HRMS (ESI, TOF): m/z [M + H]+ calcd for C7H11N4O3: 199.0826; found:
199.0824.
Anal. Calcd for C7H10N4O3: C, 42.42; H, 5.09; N, 28.27. Found: C, 42.21;
H, 4.97; N, 28.18.
13C NMR (75.5 MHz, DMSO-d6):  = 156.2, 146.1, 136.7, 114.1, 113.7.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C5H7ClN3: 144.0323; found:
144.0318.
N-(2,6-Diamino-8-methyl-1,3,5,7-tetraoxo-
1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo-
[3,4-f]isoindol-4-yl)acetamide (5a)
2-Hydrazinyl-3-nitropyridine (3d)
Yield: 0.612 g (79%); orange solid; mp 166–167.5 °C (PrOH) [Lit.28 mp
171–172 °C (EtOH)].
Yield: 0.277 g (80%); grey solid; mp 267.5–269.5 °C (i-BuOH).
IR (neat): 3349, 3281, 2980, 2929, 1772, 1690, 1670, 1535 cm–1
.
IR (neat): 3296, 3086, 1600, 1562 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 8.35 (s, 1 H, CONH), 5.96 (d, J = 9
Hz, 1 H, CH=CH), 5.80 (d, J = 9 Hz, 1 H, CH=CH), 4.88 (s, 4 H, 2 × NH2),
4.02 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 2.94 (d, J = 8 Hz, 2 H, 3a-H, 4a-H),
1.94 (s, 3 H, COCH3), 1.72 (s, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6):  = 173.7, 172.3, 170.9, 134.7, 131.3,
57.5, 46.8, 42.3, 39.6, 24.0, 19.6.
1H NMR (300 MHz, DMSO-d6):  = 9.34 (s, 1 H, NH), 8.51 (dd, J1 = 4 Hz,
J2 = 2 Hz, 1 H, 6-H), 8.39 (dd, J1 = 8 Hz, J2 = 2 Hz, 1 H, 4-H), 6.74 (dd, J1 =
8 Hz, J2 = 4 Hz, 1 H, 5-H), 4.88 (s, 2 H, NH2).
13C NMR (75.5 MHz, DMSO-d6):  = 156.5, 152.5, 135.8, 127.0, 112.1.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C5H7N4O2: 155.0564; found:
HRMS (ESI, TOF): m/z [M + H]+ calcd for C15H18N5O5: 348.1302; found:
348.1308.
155.0562.
Anal. Calcd for C5H6N4O2: C, 38.96; H, 3.93; N, 36.35. Found: C, 39.32;
H, 3.48; N, 35.95.
N-(2,6-Diamino-8-ethyl-9-methyl-1,3,5,7-tetraoxo-
1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo-
[3,4-f]isoindol-4-yl)benzamide (5b)
2-Hydrazinyl-5-nitropyridine (3e)
Yield: 0.569 g (74%); green solid; mp 200–201.5 °C (PrOH).
IR (neat): 3334, 3215, 2974, 1665, 1606 cm–1
1H NMR (300 MHz (59 °C, DMSO-d6):  = 8.93 (br s, 1 H, NH), 8.85 (d,
J = 3 Hz, 1 H, 6-H), 8.13 (dd, J1 = 9 Hz, J2 = 3 Hz, 1 H, 4-H), 6.76 (d, J = 9
Hz, 1 H, 3-H), 4.59 (br s, 2 H, NH2).
13C NMR (75.5 MHz (59 °C, DMSO-d6):  = 163.9, 147.0, 134.9, 132.6,
105.3.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C5H7N4O2: 155.0564; found:
155.0563.
Yield: 0.166 g (38%); white solid; mp 302.5–304 °C (dec.) (BuOH).
.
IR (neat): 3338, 3286, 3074, 2968, 2950, 1772, 1690, 1635, 1551 cm–1
1H NMR (300 MHz, DMSO-d6):  = 8.55 (s, 1 H, CONH), 7.88 (m, 2 Harom
.
,
C6H5, 2-H, 6-H), 7.54 (m, 3 Harom, C6H5, 3-H, 4-H, 5-H), 6.04 (s, 1 H,
C=CH), 4.90 (s, 4 H, 2 × NH2), 4.15 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 3.27 (d,
J = 8 Hz, 2 H, 3a-H, 4a-H), 2.35 (q, J = 7 Hz, 2 H, CH2), 1.55 (s, 3 H, CH3),
1.18 (t, J = 7 Hz, 3 H, CH2CH3).
13C NMR (75.5 MHz, DMSO-d6):  = 173.6, 172.6, 168.4, 141.4, 136.3,
131.4, 128.4, 128.2, 124.7, 58.1, 44.7, 42.1, 41.8, 20.7, 18.6, 8.5.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C22H24N5O5: 438.1772; found:
438.1772.
Anal. Calcd for C5H6N4O2: C, 38.96; H, 3.93; N, 36.35. Found: C, 39.11;
H, 3.52; N, 36.34.
2-(1-Methylhydrazinyl)-3-nitropyridine (3f)
Yield: 1.21 g (72%); yellow solid; mp 59–60.5 °C (MeOH–H2O) [Lit.28
mp 60–61 °C (EtOH)].
N-[8-Methyl-1,3,5,7-tetraoxo-2,6-bis(phenylamino)-
1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo-
[3,4-f]isoindol-4-yl]acetamide (5c)
IR (neat): 3338, 2976, 2884, 1636, 1591, 1553, 1514, 1487 cm–1
.
Yield: 0.360 g (72%); beige solid; mp 210.5–214.5 °C (BuOH).
IR (neat): 3296, 1779, 1718, 1662, 1602, 1539, 1496 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 8.22 (dd, J1 = 5 Hz, J2 = 2 Hz, 1 H, 6-
H), 7.88 (dd, J1 = 8 Hz, J2 = 2 Hz, 1 H, 4-H), 6.73 (dd, J1 = 8 Hz, J2 = 5 Hz,
1 H, 5-H), 4.77 (s, 2 H, NH2), 3.26 (s, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6):  = 153.8, 150.2, 134.6, 133.9, 112.3,
41.0.
1H NMR (300 MHz, DMSO-d6):  = 8.50 (s, 1 H, CONH), 8.32 (s, 2 H, 2 ×
NH), 7.18 (t, J = 7.5 Hz, 4 Harom, 2 × C6H5, 3-H, 5-H), 6.80 (t, J = 7.5 Hz, 2
Harom, 2 × C6H5, 4-H), 6.63 (d, J = 7.5 Hz, 4 Harom, 2 × C6H5, 2-H, 6-H),
6.32 (d, J = 9 Hz, 1 H, CH=CH), 6.21 (d, J = 9 Hz, 1 H, CH=CH), 4.31 (d,
J = 8 Hz, 2 H, 7a-H, 8a-H), 3.21 (d, J = 8 Hz, 2 H, 3a-H, 4a-H), 1.94 (s, 3
H, COCH3), 1.78 (s, 3 H, CH3).
HRMS (ESI, TOF): m/z [M + H]+ calcd for C6H9N4O2: 169.0720; found:
169.0721.
13C NMR (75.5 MHz, DMSO-d6):  = 174.4, 173.1, 171.1, 146.6, 135.9,
132.4, 129.3, 120.2, 113.1, 57.5, 47.1, 42.6, 39.8, 23.9, 19.5.
Anal. Calcd for C6H8N4O2: C, 42.85; H, 4.80; N, 33.32. Found: C, 42.76;
H, 4.78; N, 33.20.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
J. Ekar, K. Kranjc
Paper
Synthesis
HRMS (ESI, TOF): m/z [M + H]+ calcd for C27H26N5O5: 500.1928; found:
N-{8-Ethyl-9-methyl-2,6-bis[(3-nitropyridine-2-yl)amino]-
500.1926.
1,3,5,7-tetraoxo-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-
ethenopyrrolo[3,4-f]isoindol-4-yl}benzamide (5g)
N-[8-Ethyl-9-methyl-1,3,5,7-tetraoxo-2,6-bis(phenylamino)-
1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo-
[3,4-f]isoindol-4-yl]benzamide (5d)
Yield: 0.444 g (65%); yellow solid; mp >330 °C (dec.) (i-BuOH).
IR (neat): 3365, 3247, 2969, 2955, 1782, 1723, 1665, 1602, 1539, 1483
cm–1
.
Yield: 0.409 g (69%); white solid; mp 321.5–323.5 °C (BuOH).
1H NMR (300 MHz, DMSO-d6):  = 10.16 (br s, 2 H, 2 × NH), 8.76 (s, 1
H, CONH), 8.54 (dd, J1 = 8 Hz, J2 = 2 Hz, 2 H, 2 × Py, 4-H), 8.44 (dd, J1 = 5
Hz, J2 = 2 Hz, 2 H, 2 × Py, 6-H), 7.85 (m, 2 Harom, C6H5, 2-H, 6-H), 7.49
(m, 3 Harom, C6H5, 3-H, 4-H, 5-H), 7.08 (dd, J1 = 8 Hz, J2 = 5 Hz, 2 H, 2 ×
Py, 5-H), 6.31 (s, 1 H, C=CH), 4.43 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 3.60 (d,
J = 8 Hz, 2 H, 3a-H, 4a-H), 2.32 (q, J = 7 Hz, 2 H, CH2), 1.76 (s, 3 H, CH3),
1.21 (t, J = 7 Hz, 3 H, CH2CH3).
13C NMR (75.5 MHz, DMSO-d6):  = 173.0, 172.3, 168.8, 155.4, 149.7,
141.5, 136.2, 136.0, 131.4, 129.5, 128.4, 128.2, 125.5, 116.5, 57.8, 45.0,
42.1, 20.9, 19.3, 8.5; one aliphatic signal is hidden.
IR (neat): 3296, 2960, 1775, 1705, 1661, 1601, 1495 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 8.79 (s, 1 H, CONH), 8.35 (s, 2 H, 2 ×
NH), 7.87 (m, 2 Harom, C6H5, 2-H, 6-H), 7.52 (m, 3 Harom, C6H5, 3-H, 4-H,
5-H), 7.19 (t, J = 7.5 Hz, 4 Harom, 2 × NC6H5, 3-H, 5-H), 6.81 (t, J = 7.5 Hz,
2 Harom, 2 × NC6H5, 4-H), 6.62 (d, J = 7.5 Hz, 4 Harom, 2 × NC6H5, 2-H, 6-
H), 6.47 (s, 1 H, C=CH), 4.45 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 3.54 (d, J = 8
Hz, 2 H, 3a-H, 4a-H), 2.37 (q, J = 7 Hz, 2 H, CH2), 1.76 (s, 3 H, CH3), 1.22
(t, J = 7 Hz, 3 H, CH2CH3).
13C NMR (75.5 MHz, DMSO-d6):  = 174.3, 173.4, 168.8, 146.6, 142.5,
136.3, 131.5, 129.3, 128.5, 128.1, 126.5, 120.3, 112.9, 58.1, 45.0, 42.2,
42.1, 20.7, 19.3, 8.4.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C32H28N9O9: 682.2004; found:
682.1999.
HRMS (ESI, TOF): m/z [M + H]+ calcd for C34H32N5O5: 590.2398; found:
590.2392.
N-{2,6-Bis[(3-nitropyridine-2-yl)amino]-1,3,5,7-tetraoxo-8-
(p-tolyl)-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-etheno-
pyrrolo[3,4-f]isoindol-4-yl}benzamide (5h)
N-{2,6-Bis[(4-nitrophenyl)amino]-1,3,5,7-tetraoxo-8-(p-tolyl)-
1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-ethenopyrrolo-
[3,4-f]isoindol-4-yl}benzamide (5e)
Yield: 0.500 g (69%); brown solid; mp >200 °C (dec.) (i-BuOH).
IR (neat): 3349, 3322, 1790, 1731, 1653, 1602, 1573, 1526, 1476 cm–1
.
Yield: 0.373 g (51%); orange solid; mp >320 °C (dec.) (BuOH).
IR (neat): 3318, 3263, 1790, 1721, 1661, 1599, 1500, 1483 cm–1
1H NMR (300 MHz, DMSO-d6):  = 10.06 (br s, 2 H, 2 × NH), 8.99 (s, 1
H, CONH), – 8.49 (m, 4 H), 7.88 (d, J = 9 Hz, 2 H), 7.76 (d, J = 8 Hz, 1 H),
7.52 (m, 3 H), 7.33 (d, J = 8 Hz, 1 H), 7.23 (d, J = 8 Hz, 1 H), 7.07 (m, 3
H), 6.94 (dd, J1 = 8 Hz, J2 = 4 Hz, 1 H), 6.80 (m, 1 H): (CH=CH, C6H5, 4-
MeC6H4, 2 × Py) – 4.65 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 4.06 (d, J = 8 Hz, 2
H, 3a-H, 4a-H), 2.31 (s, 3 H, CH3).
.
1H NMR (300 MHz, DMSO-d6):  = 9.44 (br s, 2 H, 2 × NH), 8.99 (s, 1 H,
CONH), 8.12 (d, J = 9 Hz, 4 Harom, 2 × 4-NO2C6H4, 3-H, 5-H), 7.89 (d, J =
8 Hz, 2 H), 7.78 (d, J = 8 Hz, 1 H), 7.52 (m, 3 H), 7.37 (br s, 1 H), 7.36 (d,
J = 8 Hz, 1 H), 7.26 (d, J = 8 Hz, 1 H), 7.10 (d, J = 8 Hz, 1 H), 6.99 (br s, 1
H): (CH=CH, C6H5, 4-MeC6H4), – 6.75 (d, J = 9 Hz, 4 Harom, 2 × 4-
NO2C6H4, 2-H, 6-H), 4.72 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 4.07 (d, J = 8 Hz,
2 H, 3a-H, 4a-H), 2.31 (s, 3 H, CH3).
HRMS (ESI, TOF): m/z [M + H]+ calcd for C36H28N9O9: 730.2004; found:
730.1995.
13C NMR (75.5 MHz, DMSO-d6):  = 172.4, 172.3, 168.9, 152.4, 139.9,
136.1, 136.0, 135.3, 131.7, 129.5, 128.6, 128.5, 128.1, 127.9, 127.7,
126.2, 112.0, 58.7, 48.1, 46.3, 43.0, 21.1.
N-{2,6-Bis[(5-nitropyridine-2-yl)amino]-1,3,5,7-tetraoxo-8-
(p-tolyl)-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-etheno-
pyrrolo[3,4-f]isoindol-4-yl}benzamide (5i)
HRMS (ESI, TOF): m/z [M + H]+ calcd for C38H30N7O9: 728.2100; found:
Yield: 0.383 g (52%); beige solid; mp >300 °C (dec.) (i-BuOH).
IR (neat): 3411, 3308, 1790, 1723, 1653, 1601, 1585, 1507, 1485 cm–1
.
728.2098.
1H NMR (300 MHz (59 °C, DMSO-d6):  = 10.12 (br s, 2 H, 2 × NH), 8.97
(s, 2 H, 2 × Py, 6-H), 8.82 (s, 1 H, CONH), 8.33 (d, J = 9 Hz, 2 H, 2 × Py, 4-
Methyl 4-Benzamido-8-methyl-2,6-bis[(4-nitrophenyl)amino]-
1,3,5,7-tetraoxo-1,2,3,3a,4,4a,5,6,7,7a,8,8a-dodecahydro-4,8-
ethenopyrrolo[3,4-f]isoindole-9-carboxylate (5f)
H), 7.91 (d, J = 7 Hz, 2 Harom, C6H5, 2-H, 6-H), 7.76 (d, J = 8 Hz, 1 Harom
,
4-MeC6H4), 7.52 (m, 3 Harom, C6H5, 3-H, 4-H, 5-H), 7.36 (d, J = 8 Hz, 1
Harom, 4-MeC6H4), 7.25 (d, J = 8 Hz, 1 Harom, 4-MeC6H4), 7.11 (br s, 2 H,
CH=CH, 4-MeC6H4), 6.89 (d, J = 9 Hz, 1 H, CH=CH), 6.74 (d, J = 9 Hz, 2
H, 2 × Py, 3-H), 4.72 (d, J = 8 Hz, 2 H, 7a-H, 8a-H), 4.07 (d, J = 8 Hz, 2 H,
3a-H, 4a-H), 2.32 (s, 3 H, CH3).
13C NMR (75.5 MHz (59 °C, DMSO-d6):  = 171.8, 171.7, 168.9, 160.2,
145.9, 138.3, 136.2, 136.0, 135.4, 133.8, 132.9, 131.5, 131.1, 129.3,
128.5, 128.1, 127.9, 107.0, 58.7, 48.0, 46.3, 43.0, 21.0.
Yield: 0.400 g (56%); brown solid; mp >325 °C (dec.) (BuOH).
IR (neat): 3413, 3304, 2936, 1788, 1737, 1703, 1662, 1599, 1497 cm–1
1H NMR (300 MHz, DMSO-d6):  = 9.53 (s, 2 H, 2 × NH), 9.08 (s, 1 H,
CONH), 8.06 (d, J = 9 Hz, 4 Harom, 2 × 4-NO2C6H4, 3-H, 5-H), 7.88 (d, J =
8 Hz, 2 Harom, C6H5, 2-H, 6-H), 7.79 (s, 1 H, C=CH), 7.53 (m, 3 Harom
C6H5, 3-H, 4-H, 5-H), 6.75 (br s, 4 Harom, 2 × 4-NO2C6H4, 2-H, 6-H), 4.69
(d, J = 8 Hz, 2 H, 7a-H, 8a-H), 3.78 (s, 3 H, OCH3), 3.52 (d, J = 8 Hz, 2 H,
3a-H, 4a-H), 2.05 (s, 3 H, CH3).
.
,
HRMS (ESI, TOF): m/z [M + H]+ calcd for C36H28N9O9: 730.2004; found:
13C NMR (75.5 MHz, DMSO-d6):  = 173.2, 172.0, 168.7, 163.8, 152.3,
141.9, 140.1, 135.7, 131.8, 128.6, 128.0, 125.9, 112.0, 58.6, 52.9, 48.1,
42.3, 41.7, 18.6; one aromatic signal is hidden.
730.2004.
Funding Information
HRMS (ESI, TOF): m/z [M + H]+ calcd for C34H28N7O11: 710.1841;
found: 710.1839.
Ministry of Education, Science and Sport of the Republic of Slovenia
(Ministrstvo za izobraževanje, znanost in šport RS) and the Slovenian
Research agency (Javna Agencija za raziskovalno dejavnost RS); grant
No. P1-0230-0103.Jav
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J. Ekar, K. Kranjc
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Synthesis
Supporting Information
(20) Camargo, A. F.; Marangoni, M. A.; de Moraes, P. A.; Nogara, P. A.;
Afolabi, B. A.; Bencke, C. E.; Rocha, J. B. T.; Bonacorso, H. G.;
Martins, M. A. P.; Zanatta, N. Synthesis 2020, 52, 2347.
(21) Frahn, J. L.; Illman, R. J. Aust. J. Chem. 1974, 27, 1361.
(22) Baker, R.; Matassa, V. G.; Street, L. J. Patent US 5298520 A, 1994.
(23) Ray, P. C.; Medikonduri, S.; Ramanjaneyulu, G. S. Patent EP
1981860 B1, 2007.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706481. Su
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I