Unexpected formation of N-(1-(2-aryl-hydrazono)isoindolin-2-yl)benzamides and their conversion into 1,2-(bis-1,3,4-oxadiazol-2-yl)benzenes

Article abstract of DOI:10.1021/jo400023z

Reaction between ortho-phthalaldehyde and various aroylhydrazines unexpectedly yields N-(1-(2-aryl-hydrazono)isoindolin-2-yl)benzamides as major products along with the predictable 1,2-bis-aroylhydrazones. NMR investigation of the major reaction products indicate the presence of a mixture of geometrical isomers, in various ratios. Single crystal X-ray diffraction confirms the proposed structure and indicates a Z configuration of the C=N double bond substitutents. Optimization of the condensation reaction conditions enabled quantitative isolation of the cyclic isomer. Oxidation of the isomers with bis(trifluoroacetoxy)iodobenzene (PIFA) leads to rapid formation of new highly fluorescent 1,2-bis(5-aryl-1,3,4-oxadiazol-2-yl)benzenes.

Full text of DOI:10.1021/jo400023z

Article
pubs.acs.org/joc
Unexpected Formation of N‑(1-(2-Aryl-hydrazono)isoindolin-2-
yl)benzamides and Their Conversion into 1,2-(Bis-1,3,4-oxadiazol-2-
yl)benzenes
Codruta
̧
C. Paraschivescu,† Mihaela Matache,*,† Cristian Dobrota,†,⊗ Alina Nicolescu,‡,§ Catalin Maxim,∥
̆
̆
̆
Calin Deleanu,‡,§ Ileana C. Farcasa
̧
nu,† and Niculina D. Hadade*,⊥
̆
̆
̆
̆
†University of Bucharest, Faculty of Chemistry, 90-92 Panduri Street, RO-050663-Bucharest, Romania
‡
̣
“Petru Poni” Institute of Macromolecular Chemistry of the Romanian Academy, Aleea Grigore Ghica Voda 41-A, RO-0700487-Iasi,
Romania
§Centre of Organic Chemistry of the Romanian Academy, Spl. Independentei 202-B, RO-0060023-Bucharest, Romania
∥Inorganic Chemistry Laboratory, Faculty of Chemistry, University of Bucharest, 23 Dumbrava Rosie Str., RO-020464-Bucharest,
Romania
⊥
̣
Faculty of Chemistry and Chemical Engineering, “Babes-Bolyai” University, 11 Arany Janos Str., RO-400028-Cluj-Napoca, Romania
S
* Supporting Information
ABSTRACT: Reaction between ortho-phthalaldehyde and various aroylhydrazines unexpectedly yields N-(1-(2-aryl-
hydrazono)isoindolin-2-yl)benzamides as major products along with the predictable 1,2-bis-aroylhydrazones. NMR investigation
of the major reaction products indicate the presence of a mixture of geometrical isomers, in various ratios. Single crystal X-ray
diffraction confirms the proposed structure and indicates a Z configuration of the CN double bond substitutents. Optimization
of the condensation reaction conditions enabled quantitative isolation of the cyclic isomer. Oxidation of the isomers with
bis(trifluoroacetoxy)iodobenzene (PIFA) leads to rapid formation of new highly fluorescent 1,2-bis(5-aryl-1,3,4-oxadiazol-2-
yl)benzenes.
17
[Et2NSF2]BF4 have been mostly used for dehydration,
while cerium ammonium nitrate (CAN),18 lead(IV) tetrace-
tate,19−21 or hypervalent iodine reagents22−25 were reported for
the oxidative cyclization. Mixtures of acetic anhydride and
acetic acid were also used for the synthesis of dihydroox-
adiazoles.26
Bis-1,3,4-oxadiazoles could be easily prepared using both
synthetic strategies, starting from a wide variety of scaffolds.
Most commonly, the heterocycles are generated on different
aromatic rings such as in compounds 127 and 25 or as 1,3- or
1,4-subtituted compounds of type 3 or 4 (Scheme 1).21,26 Early
research21 describes preparation of bis-1,3,4-oxadiazoles of type
3 (Scheme 1) by cyclization with lead(IV) acetate of the
corresponding bis-aroylhydrazones derived from 1,3- and 1,4-
INTRODUCTION
■
The increasing interest in the synthesis of 2,5-substituted-1,3,4-
oxadiazoles can be attributed to their remarkable photophysical
properties1,2 but also because they have been evaluated as
promising antiviral,3,4 antibacterial, anti-inflammatory/analgesic
or antifungal agents, as well as inhibitors of various enzymes.4
Bis-1,3,4-oxadiazoles have emerged as important targets for
development of organic light emitting diodes (OLEDs)5−10 as a
consequence of their improved optoelectronic properties with
an increasing number of the heterocyclic rings.
Generally, closure of the 1,3,4-oxadiazole ring has been
described4,11 either through intramolecular dehydration1,12−17
of diacylhydrazines or oxidative cyclization18−24 of N-acyl-N′-
arylidene-hydrazines. Numerous dehydrating and oxidative
reagents were reported to be very effective for this purpose
including phosphorus oxychloride1,12,15 and thionyl chloride.13
Recently, triflic anhydride,16 zirconium(IV) chloride,14 or
Received: January 6, 2013
© XXXX American Chemical Society
A
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Scheme 1. Examples of Bis-(1,3,4-oxadiazoles) Grafted on Different Aromatic Rings or on the Same Ring As 1,3- or 1,4-
Disubstituents
phthalaldehydes, respectively. The attempt to obtain the 1,2-
(bis-oxadiazolyl)benzenes derived from ortho-bis-aroylhydra-
zones was reported to fail under the same conditions.20 Later,26
only preparation of 1,3- and 1,4-bis(dihydrooxadiazolyl)-
benzenes 4 (Scheme 1) was successfully reported starting
from the corresponding 1,3- and 1,4-bis-aroylhydrazones.
In this context, preparation of 1,2-bis(1,3,4-oxadiazol-2-
yl)benzenes 5 (Scheme 2) looked challenging and therefore
hydrazide of ortho-phthalic acid and 4-pyridylaldehyde gave a
mixture of phthalazine-1,4-dione 7 and pyridylmethylenehy-
drazine 8 (Scheme 3) instead of the expected aroylhydrazone.
However, the reaction between ortho-phthalaldehyde and
pyridin-4-yl-hydrazide was found to yield the corresponding
bis-aroylhydrazone in such a low yield that the compound
could not be isolated.26
It became clear that in order to prepare the target bis-1,3,4-
oxadiazoles 5, the synthesis of their precursors was the key step.
Indeed, this proved to be the most challenging step. Between
the two available methods for their synthesis,4,11 the
condensation of ortho-phthalaldehyde with various aroylhy-
drazines 9 (Scheme 4) was the most attractive and procedurally
simple.
Scheme 2. Structure of the Target 1,2-Bis(1,3,4-oxadiazol-2-
yl)benzenes
The condensation reactions were initially performed using a
modified version of a previously reported procedure,20 yielding,
with no exception, a mixture of products, in which the target
aroylhydrazones 10A (Scheme 4) could be identified as minor
products, along with a major compound 10C that is different
from all the structures previously described.26
we focused on finding a new strategy to synthesize them. We
describe here the synthesis of 5 via oxidative cyclization with
bis(trifluoroacetoxy)iodobenzene (PIFA) of the condensation
products between ortho-phthalaldehyde and various aroylhy-
drazines.
Numerous attempts to separate these compounds always led
to isolation of the major compounds 10C as mixtures of Z/E
isomers, while the minor aroylhydrazone 10A could not be
isolated in pure form.
Structural investigation of the isolated product by NMR (1H,
13C, 15N, and 2D correlations), high-resolution-mass spectrom-
etry (HR-MS), and X-ray diffraction in the particular case of
compound 10a led to identification of the cyclic compound
10Ca (Scheme 4). This compound is present in solution as
mixture of Z/E isomers in a 1:0.6 molar ratio, as inferred from
RESULTS AND DISCUSSION
■
To the best of our knowledge, except for the preparation of 1,2-
bis(5-phenyl-1,3,4-oxadiazol-2-yl)benzene starting from 1,2-
bis(5-tetrazolyl)benzene and acyl chlorides,10,28 all previous
results were negative in attempting to obtain aryl-substituted-
bis-1,3,4-oxadiazoles from aroylhydrazones.20,26 Oxidative
cyclization of ortho-bis-aroylhydrazones with lead(IV) tetrace-
tate was reported to yield phthalazine derivative 620 (Scheme
3). In addition, in the attempt to prepare the N-acyl-N′-
arylidene-hydrazines26 precursors, the reaction between the
1
the H NMR integration of the corresponding signals of the
CH2 protons in Z and E diastereoisomers, respectively. Similar
results were observed for all the condensation reactions. The
isomeric ratios for all compounds 10C were calculated from 1H
NMR (Scheme 4).
Structural Aspects in Solid State. The single crystal X-ray
diffraction confirmed the structure of compound 10Ca. It
contains an isoindolinyl ring in which the nitrogen is provided
by an aroylhydrazone group, while the second aroylhydrazone
group yields an exocyclic double bond with Z configuration
(Figure 1). The analysis of the bond lengths between the atoms
of the five membered ring as well as of the exocyclic C−N and
N−N bonds indicates a series of interesting features. Thus, the
C2−N4 interatomic distance, which is equal to 1.379(4) Å, is
an intermediary value between the length of a C−N bond in an
aliphatic chain [usually between 1.472(5) and 1.479(5) Å] and
in pyrrol [1.372(12) Å].29 The length of the C2−N3 exocyclic
bond, equal to 1.287(4) Å, is much smaller than the previous
Scheme 3. Products Resulted from Oxidative Cyclization of
ortho-Bis-aroylhydrazone Derived from Phthalaldehyde and
Hydrazide of the Benzoic Acid (6) and Products Resulted
from Condensation Reaction between ortho-Phthalic Acid
and 4-Pyridylaldehyde (7 and 8)
B
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Scheme 4. Structure of the Products Resulted from the Condensation between ortho-Phthalaldehyde and the Aroylhydrazines 9
As Well As the Molar Ratio of Z/E of 10C Determined by 1H NMR Spectroscopy through Integration of the CH2 Resonances
Figure 1. Molecular structure of compound 10Ca-Z, showing the atom numbering scheme. Selected bonds lengths (Å): C2−N4, 1.379(4); C2−N3,
1.287(4); C1−N4, 1.471(4); C1−C8, 1.497(5); N4−N2, 1.390(4); C10−O1, 1.213(4); N1−N3, 1.414(4); C9−O2, 1.245(4).
one and corresponds to a double bond length, comparable to a
bond of azomethines30−33 or oxadiazoles.10 The C1−N4
[1.471(4) Å] and C1−C8 [1.497(5) Å] bonds have typical
lengths for simple covalent bonds. In addition, it was noticed
that the N4−N2 [1.390(4) Å] and C10−O1 [1.213(4) Å]
bond lengths are slightly smaller than the N1−N3 [1.414(4)]
and C9−O2 [1.245(4) Å)].
The crystal structure of 10C-Z comprises supramolecular
chains of molecules associated through hydrogen bonding
(Figure 2). The molecules within the same chain adopt a zigzag
arrangement. The dihedral angle between the isoindolinyl
benzene rings of two neighboring molecules is 45.763°.
The supramolecular chains are built up by intermolecular
association of molecules via four hydrogen bonds: two NH---O
hydrogen bonds (dH‑‑‑O equal to 2.136 Å and 2.248 Å, with N−
H−O angles equal to 167.704° and 125.449°, respectively)
between the N−H groups of one molecule and the O2 oxygen
of another molecule; two CH---O hydrogen bonds between (i)
an aromatic CH group and the same O2 oxygen atom (dH‑‑‑O
equal to 2.506 Å and C−H−O angle 159.382°) and (ii) a
hydrogen atom of the CH2 group with the O1 atom of a second
molecule (dH‑‑‑O equal to 2.326 Å and C−H−O angle equal to
140.791°) as well as a CH−π interaction between a hydrogen
atom of a methoxy group and the benzene ring of the
isoindolinyl from the neighboring molecule (the distance of this
hydrogen atom to the benzene ring centroid is 2.794 Å and the
angle between the C−H bond axis and the plane of the benzene
ring is 155.056°), (Figure 2). In addition, the supramolecular
chains in the lattice of 10C-Z are associated by hydrogen
bonding between the H atoms of the methoxy groups
belonging to molecules of one chain and the O atoms of
methoxy groups from molecules of another chain (dH‑‑‑O equal
C
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Figure 2. Fragment of the lattice of 10C-Z: a perspective view (along the a axis) reveals the association of molecules through hydrogen bonds and
CH−π interaction to form supramolecular chain associations. Hydrogen atoms (except the ones involved in different interactions) are omitted for
clarity.
to 2.615, 2.784, 2.823, or 2.878 Å and C−H−O angles of
157.617°, 123.737°, 115.860°, and 115.881° respectively; see
Figure S2 in the Supporting Information).
Structural Aspects in Solution. The presence in solution
of the two diastereomers could be due either to the existence of
geometrical isomers at the exocyclic CN double bond or as a
result of the hindered rotation of the C−N amide bond, the
latter situation having been previously reported for related
N′,N′′-1H-isoindole-1,3-diylidenedicarbohydrazides.34 To es-
tablish the stereochemistry of the two detected diaster-
eoisomers, nuclear Overhauser effects (NOE) have been used
(see the Supporting Information). The results clearly indicated
the geometrical isomerism at the exocyclic CN bond. Thus,
in the rotating frame Overhause effect spectroscopy (ROESY)
spectrum (Figure 3), a correlation peak between the NH signal
at 10.84 ppm (assigned to the NH-1′) and CH signal at 7.93
ppm (CH-4) could be observed, both signals corresponding to
the minor isomer. For the major isomer no such correlation
peak could be observed. This indicated that the major isomer
has the Z configuration while the minor isomer has the E
configuration, relative to the exocyclic CN double bond.
Moreover, in the ROESY spectrum correlation peaks between
the NH signals with CH signals belonging to the aromatic rings
(NH-1′ with CH-21/CH-25 and NH-2′ with CH-12/CH-16,
respectively) could be observed, for both major and minor
isomers.
Dynamic NMR studies conducted up to 393 K in DMSO-d6
as solvent did not reveal any coalescence of resonances. This
suggests a free rotation around the amide (C−N) bond at room
temperature and above. This conclusion is also supported by
the presence of a single set of signals (one for each Z or E
diastereoisomer) in the 1H and 13C- NMR spectra. Around 373
K, the spectra indicate decomposition of the product (see the
Supporting Information).
Figure 3. ROESY spectrum (selection) for compound 10Ca in
DMSO-d6 (400 MHz).
D
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Scheme 5. Proposed Reaction Mechanism for the Oxadiazole Ring Closure
Optimization of the Condensation Reaction. As already
stated, under reaction conditions previously reported, we
obtained mixtures of aroylhydrazones 10A and the isoindolin
derivatives 10C that cannot be separated without complete loss
of the acyclic hydrazones. However, we performed a series of
preliminary tests which showed that both the crude reaction
(containing cyclic isomers 10C-Z, 10C-E and aroylhydrazones
10A) and the isolated cyclic isomers 10C conveniently convert
into the target oxadiazole when subjected to an oxidizing agent
such as bis(trifluoroacetoxi)iodobenzene, as it will be further
described. This suggests that the two compounds are present in
solution in equilibrium and the cyclization reaction probably
occurs through an identical intermediate. A proposed reaction
mechanism involving the acyclic isomer is depicted in Scheme
5, following the suggested mechanism of oxadiazoles formation
by Shang.24
forms 10C. Therefore, on the basis of this hypothesis, we
focused on optimizing the reaction conditions to provide a
mixture of the two forms, so that we obtain the greatest amount
of the acyclic compound. We used as a model compound the
corresponding hydrazide of 3,4,5-trimethoxybenzoic acid 9a.
Various conditions were assessed, including previously
reported ones20,36 in terms of solvent, reaction time, temper-
ature, and catalyst (see the Supporting Information). As
expected, each of the reactions yielded a different ratio of
acyclic/cyclic form, as the 1H NMR spectra of the crude
products indicated. The reactions that were performed in
ethanol displayed either a very complex mixture of products or
the cyclic isomers accompanied by considerable amounts of
unreacted raw materials. When chloroform was used for the
condensation reaction, the resulting products ratio varied
according to the presence of the acid catalyst. Thus, if the
condensation was run without any acid catalyst, at room
The presumed reaction mechanism for the reversible
transformation of the acyclic forms 10A to cyclic isomers
10C is presented in Scheme 6. Thus, we presume that the
1
temperature, the H NMR spectrum of the crude reaction
indicated the formation of the cyclic isomers as major products.
In the presence of acetic acid as a catalyst and a reflux
temperature for a certain time, the H NMR spectra indicated
1
Scheme 6. Proposed Reaction Mechanism for the
Transformation 10A to 10C
the presence of both cyclic and acyclic isomers, the former
being the major ones. Finally, when the reaction was run in
toluene, the 1H NMR spectrum of the crude reaction indicated
the formation almost exclusively of the cyclic forms with a very
high degree of purity, after minimum workup (see the
Supporting Information).
Taking into account that (i) the greatest amount of the
acyclic compound was provided from the reaction run in
chloroform, in the presence of acetic acid, at reflux for a few
hours, then at room temperature, (ii) the condensation in
toluene provided almost exclusively the cyclic isomers, and (iii)
the cyclization reactions for the preparation of the target 1,3,4-
oxadiazoles occurred similarly when performed on mixture of
compounds and on the cyclic isomers (see the Supporting
Information), it follows that the cyclization reaction occurs
efficiently no matter the resulting ratio of the cyclic and acyclic
isomers, probably through the same intermediate species. In
this context, we decided to use the following reaction
conditions for all condensation reactions: chloroform and
catalytic amounts of acetic acid, 4 h at reflux and then stirred
overnight at room temperature.
formation of the five member ring takes place in the canonical
form I of the acyclic isomer 10A by the nucleophilic attack of a
negatively charged nitrogen to the electrophilic double bonded
CH. Next, the azo form III undergoes an azo-hydrazone
tautomerism35 reaction with the formation of the isolated cyclic
isomer 10C.
Since the cyclization reaction is presumed to occur through
the same intermediate species, it follows that the reaction
performed on the mixture of 10A and 10C isomers should
occur better than the reaction performed on the pure cyclic
Synthesis of Bis-1,3,4-oxadiazoles. Among the multitude
of possible oxidative agents, we have chosen the hypervalent
iodine reagents37 since their use is very efficient in preparation
of such compounds.25 Bis(trifluoroacetoxy)iodobenzene
(PIFA) requires very mild reaction conditions and is
commercially available, inexpensive, stable to air and humidity,
E
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Table 1. Formation of the Target Oxadiazoles 5 through Oxidation with PIFA of the Acyclic and Cyclic Isomers 10 and the
Overall Isolated Yields
entry
compound
Ar
overall isolated yield (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
3,4,5-triMeO−C6H2
4-Br−C6H4
4-Cl−C6H4
3-Cl−C6H4
4-Me−C6H4
4-OMe−C6H4
4-NO2−C6H4
Ph
43
39
47
37
42
43
32
46
36
5g
5h
5i
4-Py
and well-known as an effective oxidative agent for preparation
of 1,3,4-oxadiazoles.22,23,38
iently performed both starting from mixtures of isomers and
pure cyclic forms, under the action of the hypervalent iodine
reagent bis(trifluoroacetoxy)iodobenzene. This indicates that
the cyclization reaction occurs through the acyclic form, which
is in equilibrium with and is less stable than the cyclic isomer.
Current efforts are focused on the study of the photophysical
properties of the oxadiazoles, especially their fluorescent
properties.
Therefore, the products of condensation were treated with
PIFA in dichloromethane and left to react overnight at room
temperature. The successful formation of the bis-1,3,4-
oxadiazoles (Table 1) could be monitored by TLC and
visualization under UV irradiation since the resulting
compounds were displayed as fluorescent spots. Unlike their
precursors, the heterocyclic compounds are very soluble in
organic solvents and can be easily purified by column
EXPERIMENTAL SECTION
■
1
chromatography. The H NMR spectra display fewer signals,
General Experimental Information. The air and water sensitive
reactions were performed in anhydrous solvents and under a positive
pressure of argon. Dry dichloromethane was distilled over CaH2. All
other solvents and reagents were purchased from commercial suppliers
and used without further purification.
in agreement with the symmetrical structures, which can be
easily assigned to each structure.
Preliminary investigation of the photophysical properties of
the newly synthesized 2,5-substituted bis-1,3,4-oxadiazoles
indicated a strong absorption between 262 and 301 nm,
when UV−vis spectra were recorded as well as fluorescence
emission between 360 and 384 nm (see Supporting
Information).10
The NMR spectra have been fully assigned based on spectra
recorded on a spectrometer equipped with a 5 mm multinuclear
inverse detection probe, operating at 400.1, 100.6, and 40.6 MHz for
1H, 13C, and 15N nuclei, respectively. The 1D and 2D experiments
(H−H correlation spectroscopy (COSY), ROESY, H−C hetero-
nuclear multiple bond correlation (HMBC), H−C heteronuclear
single quantum correlation (HSQC), H−N heteronuclear multiple-
quantum correlation (HMQC), and H−N HMBC) were recorded
using standard pulse sequences in the version with z-gradients, as
delivered by the spectrometer manufacturer operating software. The
15N chemical shifts were indirectly detected as projections from the 2D
H−N HMBC spectra and are referred to external liquid ammonia (0.0
ppm) using nitromethane (380.2 ppm) as an external standard. For
the major isomers (Z configuration) all 15N signals have been detected,
whereas for minor isomers, due to the smaller concentration in the
mixture, often two out of the four 15N signals have not been detected.
For reaction control, various NMR spectrometers operating at 400,
500, 360, 300, and 250 MHz have been used. Chemical shifts (δ) are
reported in parts per million (ppm) using the residual solvent peak as
CONCLUSIONS
■
In this work, we described the unexpected formation of N-(1-
(2-aryl-hydrazono)isoindolin-2-yl)benzamides 10C from ortho-
phthalaldehyde and carboxylic acid hydrazides, as mixtures of
geometrical isomers due to the exocyclic CN double bond
(as inferred from the X-ray molecular structure and NMR
studies), along with their acyclic isomeric aroylhydrazones 10A
as nonseparable minor products. The single crystal X-ray
analysis of 10Ca indicates a Z configuration of the CN
double bond substituents. Variation of the conditions for the
condensation reaction led to preparation of pure cyclic isomers.
Synthesis of 1,2-(1,3,4-oxadiazol-2-yl)benzenes was conven-
F
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an internal reference. High-resolution mass spectra were recorded
using the positive mode atmospheric pressure chemical ionization
(APCI) technique on a spectrometer equipped with an Orbital Ion
Trap mass analyzer. Thin layer chromatography (TLC) was performed
on silica gel coated aluminum F254 plates. All plates were visualized by
UV irradiation at 254 nm. Preparative column chromatography was
performed on silica. Melting points were determined in open capillary
tubes using an electric melting point apparatus and are uncorrected.
Single Crystal X-ray Diffraction. X-ray diffraction measurements
were performed using an Ag−Kα (λ = 0.5608 Å) X-ray tube with a
graphite monochromator. The hydrogen atoms were introduced at
calculated positions and not refined (riding model).39 The structure
was solved by direct methods and refined with full-matrix least-squares
technique on F2 using the SHELXS-97 and SHELXL-97 programs
within the WINGX interface. The CCDC number is 912069. A
summary of the crystallographic data is listed in the Supporting
Information (Table S1).
Hydrazides 9c and 9i were commercially available and used as
purchased, while the rest of them were synthesized from the
corresponding carboxylic acids, as previously described.15 NMR signal
assignments for compounds 5 and 10C were made according to the
numbering schemes shown in the Supporting Information for each of
them, which do not correspond to IUPAC numbering rules.
General Experimental Procedure for the Synthesis of the
Compounds 10: ortho-Phthalaldehyde (1.5 mmol, 0.201 g) and the
corresponding hydrazide 9 (3 mmol) were dissolved in chloroform
(50 mL). Acetic acid (a few drops) was added into the resulted
solution and heated to reflux for 4 h. The mixture was stirred overnight
at room temperature, then the solvent was removed under vacuum,
and the residue was washed with cold diethyl ether. The product was
further used without any other purification, except for the NMR
spectra recording, when it was recrystallized from methanol.
3,4,5-Trimethoxy-N-(1-(2-(3,4,5-trimethoxybenzoyl)hydrazono)-
isoindolin-2-yl)benzamide 10Ca. White solid, mp 162−164 °C.
Major isomer: 1H NMR (400.1 MHz, DMSO-d6), δ (ppm): 3.58
(12H, s, OCH3-17, 19, 26, 28), 3.66 (3H, s, OCH3-27), 3.67 (3H, s,
OCH3-18), 4.73 (2H, s, H-1), 6.93 (2H, s, H-21, 25), 7.02 (2H, s, H-
12, 16), 7.51 (1H, t, 8.0 Hz, H-5), 7.54 (1H, d, 7.5 Hz, H-7), 7.59 (1H,
t, 8.0 Hz, H-6), 7.79 (1H, d, 7.5 Hz, H-4), 10.32 (1H, br, NH-1),
10.84 (1H, br, NH-2). 13C NMR (100.6 MHz, DMSO-d6), δ (ppm):
55.5 (OCH3-17, 19 or OCH3-26, 28), 55.6 (OCH3-17, 19 or OCH3-
26, 28), 57.4 (C-1), 59.8 (OCH3-27), 59.9 (OCH3-18), 104.7 (C-21,
25), 105.1 (C-12, 16), 121.9 (C-4), 122.9 (C-7), 126.3 (C-11), 127.9
(C-5), 128.9 (C-20), 130.6 (C-6), 133.0 (C-3), 138.7 (C-10), 139.5
(C-23), 140.5 (C-14), 152.2 (C-22, 24), 152.4 (C-13, 15), 152.4 (C-
2), 161.1 (C-9), 164.3 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ
(ppm): 111.60 (N-4′), 134.12 (N-2′), 146.98 (N-1′), 223.97 (N-3′).
Minor isomer: 1H NMR (400.1 MHz, DMSO-d6), δ (ppm): 3.73 (3H,
s, OCH3-27), 3.75 (3H, s, OCH3-18), 3.84 (6H, s, OCH3-17, 19 or
OCH3-26, 28), 3.86 (6H, s, OCH3-17, 19 or OCH3-26, 28), 4.78 (2H,
s, H-1), 7.31 (2H, s, H-21, 25), 7.33 (2H, s, H-12, 16), 7.40−7.50 (1H,
m, H-5), 7.60 (1H, t, 7.6 Hz, H-6), 7.62 (1H, d, 8.1 Hz, H-7), 7.93
(1H, d, 7.8 Hz, H-4), 10.84 (1H, br, NH-1), 11.04 (1H, br, NH-2).
13C NMR (100.6 MHz, DMSO-d6), δ (ppm): 55.9 (OCH3-17, 19 or
7), 124.4 (C-20), 126.1 (C-14), 127.9 (C-5), 128.9 (C-18, 22), 129.4
(C-12, 16), 130.3 (C-11), 130.7 (C-6), 130.9 (C-19, 21), 131.4 (C-
13,15), 132.7 (C-3), 132.9 (C-17), 138.71 (C-8), 152.0 (C-2), 160.9
(C-9), 164.1 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm):
1
134.50 (N-2′), 147.40 (N-1′). Minor isomer: H NMR (400.1 MHz,
DMSO-d6), δ (ppm): 4.78 (2H, s, H-1), 7.40−7.50 (1H, m, H-5), 7.60
(1H, d, 7.9 Hz, H-7), 7.60 (1H, t, 7.8 Hz, H-6), 7.72 (2H, d, 8.1 Hz,
H-19, 21), 7.77 (2H, d, 8.4 Hz, H-13, 15), 7.90 (2H, d, 8.0 Hz, H-18,
22), 7.92 (2H, d, 8.6 Hz, H-12, 16), 7.93 (1H, d, 8.5 Hz, H-4), 10.98
(1H, br, NH-1), 11.14 (1H, br, NH-2). 13C NMR (100.6 MHz,
DMSO-d6), δ (ppm): 53.6 (C-1), 123.4 (C-7), 123.4 (C-20), 125.9
(C-14), 125.9 (C-4), 127.8 (C-5), 128.9 (C-3), 129.0 (C-18, 22),
129.6 (C-12, 16), 131.1 (C-6), 131.4 (C-11), 131.4 (C-19, 21), 131.6
(C-13, 15), 132.9 (C-17), 140.1 (C-8), 160.6 (C-2), 162.4 (C-9),
164.6 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm): 132.70 (N-
2′), 148.00 (N-1′). HRMS (APCI-Orbit trap) m/z calcd for
C22H17Br2N4O2 [M + H]+, 528.9692; found, 528.9695.
4-Chloro-N-(1-(2-(4-chlorobenzoyl)hydrazono)isoindolin-2-yl)-
1
benzamide 10Cc. White solid, mp 182−185 °C. Major isomer: H
NMR (400.1 MHz, DMSO-d6), δ (ppm): 4.76 (2H, s, H-1), 7.34 (2H,
d, 8.4 Hz, H-19, 21), 7.46 (2H, t, 8.4 Hz, H-13, 15), 7.52 (1H, t, 7.6
Hz, H-5), 7.54 (1H, d, 7.9 Hz, H-7), 7.59 (2H, d, 8.8 Hz, H-18, 22),
7.60 (1H, t, 8.0 Hz, H-6), 7.78 (2H, d, 8.2 Hz, H-12, 16), 7.80 (1H, d,
7.5 Hz, H-4), 10.44 (1H, br, NH-1), 10.96 (1H, br, NH-2). 13C NMR
(100.6 MHz, DMSO-d6), δ (ppm): 57.3 (C-1), 121.9 (C-4), 122.9 (C-
7), 127.9 (C-5), 127.9 (C-19, 21), 128.4 (C-13, 15), 128.5 (C-18, 22),
129.3 (C-12, 16), 129.9 (C-11), 130.7 (C-6), 132.6 (C-17), 132.7 (C-
3), 135.6 (C-20), 137.1 (C-14), 138.7 (C-8), 152.1 (C-2), 160.9 (C-
9), 163.9 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm): 135.42
(N-2′), 148.58 (N-1′), 224.30 (N-3′). Minor isomer: 1H NMR (400.1
MHz, DMSO-d6), δ (ppm): 4.79 (2H, s, H-1), 7.44−7.50 (1H, m, H-
5), 7.60 (2H, d, 8.2 Hz, H-19, 21), 7.61 (1H, t, 8.1 Hz, H-6), 7.62 (1H,
d, 7.8 Hz, H-7), 7.64 (2H, d, 8.6 Hz, H-13, 15), 7.94 (1H, d, 8.0 Hz,
H-4), 7.97 (2H, d, 8.4 Hz, H-18, 22), 8.00 (2H, d, 8.4 Hz, H-12, 16),
10.99 (1H, br, NH-1), 11.16 (1H, br, NH-2). 13C NMR (100.6 MHz,
DMSO-d6), δ (ppm): 53.6 (C-1), 123.4 (C-7), 126.1 (C-4), 127.8 (C-
5), 128.6 (C-13, 15), 128.8 (C-19, 21), 128.9 (C-3), 129.1 (C-18, 22),
129.5 (C-12, 16), 130.9 (C-11), 131.1 (C-6), 132.6 (C-17), 135.8 (C-
20), 136.9 (C-14), 140.1 (C-8), 160.6 (C-2), 162.3 (C-9), 164.5 (C-
10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm): 133.41 (N-2′),
149.15 (N-1′), 228.0 (N-3′). HR-MS (APCI-Orbit trap) m/z calcd for
C22H17Cl2N4O2 [M + H]+, 439.0723; found, 439.0728.
3-Chloro-N-(1-(2-(3-chlorobenzoyl)hydrazono)isoindolin-2-yl)-
1
benzamide 10Cd: White solid, mp 193−197 °C. Major isomer: H
NMR (400.1 MHz, DMSO-d6), δ (ppm): 4.76 (2H, s, H-1), 7.33 (1H,
t, 8.0 Hz, H-21), 7.42 (1H, t, 8.0 Hz, H-15), 7.50 (1H, d, 7.6 Hz, H-
20), 7.53 (1H, t, 7.7 Hz, H-5), 7.55 (1H, d, 8.0 Hz, H-7), 7.55 (1H, s,
H-18), 7.60 (2H, m, H-14 and H-22), 7.61 (1H, t, 8.2 Hz, H-6), 7.75
(1H, d, 8.1 Hz, H-16), 7.76 (1H, s, H-12), 7.80 (1H, d, 7.3 Hz, H-4),
10.51 (1H, br, NH-1), 11.01 (1H, br, NH-2). 13C NMR (100.6 MHz,
DMSO-d6), δ (ppm): 57.2 (C-1), 121.9 (C-4), 122.9 (C-7), 125.7 (C-
22), 126.2 (C-16), 126.8 (C-18), 127.2 (C-12), 127.9 (C-5), 129.9 (C-
21), 130.3 (C-15), 130.6 (C-20), 130.7 (C-6), 131.9 (C-14), 132.7 (C-
3), 132.9 (C-17), 133.3 (C-11 and C-13), 135.8 (C-19), 138.7 (C-8),
152.4 (C-2), 160.6 (C-9), 163.6 (C-10). 15N NMR (40.6 MHz,
DMSO-d6), δ (ppm): 111.01 (N-4′), 135.73 (N-2′), 148.79 (N-1′),
OCH3-26, 28), 56.0 (OCH3-17, 19 or OCH3-26, 28), 53.6 (C-1), 60.0
(OCH3-27), 60.1 (OCH3-17), 104.6 (C-21, 25), 105.1 (C-12, 16),
123.4 (C-7), 126.3 (C-4), 127.1 (C-11), 127.8 (C-5), 128.9 (C-20),
131.1 (C-6), 133.0 (C-3), 139.7 (C-23), 140.2 (C-8), 140.6 (C-14),
152.6 (C-22, 24), 152.7 (C-13, 15), 160.8 (C-2), 162.6 (C-9), 164.7
(C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm): 132.15 (N-2′),
147.71 (N-1′). HRMS (APCI-Orbit trap) m/z calcd for C28H31N4O8
[M + H]+, 551.2136; found, 551.2143.
1
224.43 (N-3′). Minor isomer: H NMR (400.1 MHz, DMSO-d6), δ
(ppm): 4.80 (2H, s, H-1), 7.50−7.60 (1H, m, H-5), 7.56 (1H, t, 8.3
Hz, H-21), 7.61 (1H, t, 7.8 Hz, H-15), 7.62 (1H, t, 7.5 Hz, H-6), 7.63
(1H, d, 8.0 Hz, H-7), 7.64 (1H, d, 9.1 Hz, H-20), 7.72 (1H, d, 8.1 Hz,
H-14), 7.55 (1H, s, H-18), 7.94 (1H, d, 7.7 Hz, H-22), 7.95 (1H, d, 6.1
Hz, H-4), 7.96 (1H, d, 7.8 Hz, H-16), 8.04 (1H, s, H-12), 11.05 (1H,
br, NH-1), 11.21 (1H, br, NH-2). 13C NMR (100.6 MHz, DMSO-d6),
δ (ppm): 53.7 (C-1), 126.1 (C-4), 123.5 (C-7), 125.8 (C-22), 126.3
(C-16), 127.0 (C-18), 127.4 (C-12), 127.9 (C-5), 128.7 (C-3), 130.4
(C-21), 130.7 (C-15), 130.9 (C-20), 131.2 (C-6), 131.9 (C-14), 133.2
(C-17), 133.3 (C-11), 134.1 (C-13), 135.8 (C-19), 140.1 (C-8), 160.6
(C-2), 161.1 (C-9), 164.1 (C-10). 15N NMR (40.6 MHz, DMSO-d6),
δ (ppm): 149.39 (N-1′). HR-MS (APCI-Orbit trap) m/z calcd for
C22H17Cl2N4O2 [M + H]+, 439.0723; found, 439.0728.
4-Bromo-N-(1-(2-(4-bromobenzoyl)hydrazono)isoindolin-2-yl)-
1
benzamide 10Cb. White solid, mp 211−212 °C. Major isomer: H
NMR (400.1 MHz, DMSO-d6), δ (ppm): 4.76 (2H, s, H-1), 7.47 (2H,
d, 9.0 Hz, H-19, 21), 7.49 (2H, d, 8.6 Hz, H-18, 22), 7.51 (1H, t, 7.6
Hz, H-5), 7.53 (1H, d, 8.1 Hz, H-7), 7.59 (1H, t, 7.4 Hz, H-6), 7.61
(2H, d, 9.6 Hz, H-13, 15), 7.68 (2H, d, 8.4 Hz, H-12, 16), 7.78 (1H, d,
7.4 Hz, H-4), 10.43 (1H, br, NH-1), 10.94 (1H, br, NH-2). 13C NMR
(100.6 MHz, DMSO-d6), δ (ppm): 57.2 (C-1), 121.9 (C-4), 122.9 (C-
G
dx.doi.org/10.1021/jo400023z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4-Methyl-N-(1-(2-(4-methylbenzoyl)hydrazono)isoindolin-2-yl)-
(2H, d, 8.0 Hz, H-18, 22), 8.21 (2H, d, 8.8 Hz, H-12, 16), 8.34 (2H, d,
9.6 Hz, H-19, 21), 8.40 (2H, d, 8.8 Hz, H-13, 15), 11.29 (1H, br, NH-
1), 11.44 (1H, br, NH-2). 13C NMR (100.6 MHz, DMSO-d6), δ
(ppm): 53.7 (C-1), 123.5 (C-7), 123.6 (C-19, 21), 123.8 (C-13, 15),
126.1 (C-4), 127.9 (C-5), 128.7 (C-18, 22), 129.1 (C-12, 16), 131.3
(C-6), 139.5 (C-17), 140.2 (C-8), 148.9 (C-20), 149.5 (C-14), 160.6
(C-2), 161.6 (C-9), 164.0 (C-10). HR-MS (APCI-Orbit trap) m/z
calcd for C22H17N6O6 [M + H]+, 461.1204; found, 461.1210.
1
benzamide 10Ce. White solid, mp 225−228 °C. Major isomer: H
NMR (400.1 MHz, DMSO-d6), δ (ppm): 2.31 (3H, s, H-24), 2.37
(3H, s, H-17), 4.76 (2H, s, H-1), 7.07 (2H, d, 7.6 Hz, H-20, 22), 7.25
(2H, d, 7.6 Hz, H-13, 15), 7.44 (2H, d, 7.6 Hz, H-19, 23), 7.52 (1H, t,
7.3 Hz, H-5), 7.53 (1H, d, 7.6 Hz, H-7), 7.59 (1H, t, 8.1 Hz, H-6),
7.73 (2H, d, 8.8 Hz, H-12, 16), 7.78 (1H, d, 7.1 Hz, H-4), 10.29 (1H,
br, NH-1), 10.91 (1H, br, NH-2). 13C NMR (100.6 MHz, DMSO-d6),
δ (ppm): 20.9 (C-24), 21.0 (C-17), 57.4 (C-1), 121.7 (C-4), 122.9
(C-7), 126.9 (C-19, 23), 127.5 (C-12, 16), 127.9 (C-5), 128.4 (C-11),
128.6 (C-20, 22), 129.0 (C-13, 15), 130.5 (C-6), 131.1 (C-18), 132.8
(C-3), 138.8 (C-8), 140.1 (C-21), 142.5 (C-14), 150.2 (C-2), 161.9
(C-9), 165.1 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm):
108.4 (N-4′), 135.18 (N-2′), 148.47 (N-1′), 227.62 (N-3′). Minor
N-(1-(2-Benzoyl)hydrazono)isoindolin-2-yl)benzamide 10Ch.
1
White solid, mp 221−224 °C. Major isomer: H NMR (400.1 MHz,
DMSO-d6), δ (ppm): 4.78 (2H, s, H-1), 7.25 (2H, t, 7.2 Hz, H-19,
21), 7.44 (2H, t, 7.6 Hz, H-13, 15), 7.45 (1H, t, 7.5 Hz, H-20), 7.53
(1H, d, 7.9 Hz, H-7), 7.53 (1H, t, 7.4 Hz, H-5), 7.54 (2H, d, 7.5 Hz,
H-18, 22), 7.59 (1H, t, 8.1 Hz, H-14), 7.59 (1H, t, 7.4 Hz, H-6), 7.78
(1H, d, 7.2 Hz, H-4), 7.82 (2H, d, 7.6 Hz, H-12, 16), 10.38 (1H, br,
NH-1), 10.97 (1H, br, NH-2). 13C NMR (100.6 MHz, DMSO-d6), δ
(ppm): 57.3 (C-1), 121.8 (C-4), 122.9 (C-7), 126.9 (C-18, 22), 127.5
(C-12, 16), 127.9 (C-5), 127.9 (C-19, 21), 128.4 (C-13, 15), 130.5 (C-
6), 130.8 (C-20), 131.1 (C-11), 132.3 (C-14), 132.8 (C-3), 133.9 (C-
17), 138.8 (C-8), 150.7 (C-2), 161.9 (C-9), 165.1 (C-10). 15N NMR
(40.6 MHz, DMSO-d6), δ (ppm): 108.6 (N-4′), 134.5 (N-2′), 149.0
1
isomer: H NMR (400.1 MHz, DMSO-d6), δ (ppm): 2.37 (3H, s, H-
24), 2.39 (3H, s, H-17), 4.76 (2H, s, H-1), 7.30 (2H, d, 8.0 Hz, H-20,
22), 7.34 (2H, d, 8.0 Hz, H-13, 15), 7.40−7.50 (1H, m, H-5), 7.60
(1H, t, 8.9 Hz, H-6), 7.61 (1H, d, 7.8 Hz, H-7), 7.84 (2H, d, 8.0 Hz,
H-19, 23), 7.89 (2H, d, 8.0 Hz, H-12, 16), 7.92 (1H, d, 7.6 Hz, H-4),
10.78 (1H, br, NH-1), 10.91 (1H, br, NH-2). 13C NMR (100.6 MHz,
DMSO-d6), δ (ppm): 20.9 (C-24), 21.0 (C-17), 53.6 (C-1), 123.4 (C-
7), 126.1 (C-4), 127.2 (C-19, 23), 127.6 (C-12, 16), 127.7 (C-5),
128.9 (C-20, 22), 129.0 (C-13, 15), 129.2 (C-3), 129.5 (C-11), 130.9
(C-6), 131.1 (C-18), 140.1 (C-8), 140.8 (C-21), 142.1 (C-14), 160.7
(C-2), 163.3 (C-9), 165.3 (C-10). 15N NMR (40.6 MHz, DMSO-d6),
δ (ppm): 132.12 (N-2′), 148.06 (N-1′), 230.05 (N-3′). HR-MS
(APCI-Orbit trap) m/z calcd for C24H23N4O2 [M + H]+, 399.1815;
found, 399.1823.
1
(N-1′), 226.7 (N-3′). Minor isomer: H NMR (400.1 MHz, DMSO-
d6), δ (ppm): 4.80 (2H, s, H-1), 7.40−7.50 (1H, m, H-5), 7.52 (2H, t,
7.1 Hz, H-19, 21), 7.56 (2H, t, 7.6 Hz, H-13, 15), 7.56 (1H, t, 7.2 Hz,
H-6), 7.60 (1H, d, 8.6 Hz, H-7), 7.61 (1H, t, 9.1 Hz, H-20), 7.64 (1H,
t, 7.1 Hz, H-14), 7.95 (2H, d, 7.3 Hz, H-18, 22), 7.96 (1H, d, 8.3 Hz,
H-4), 8.00 (2H, d, 7.6 Hz, H-12, 16), 10.89 (1H, br, NH-1), 11.04
(1H, br, NH-2).13C NMR (100.6 MHz, DMSO-d6), δ (ppm): 53.6 (C-
1), 123.4 (C-7), 126.1 (C-4), 127.1 (C-18, 22), 127.6 (C-12, 16),
127.7 (C-5), 128.4 (C-19, 21), 128.5 (C-13, 15), 129.1 (C-3), 130.9
(C-6), 130.9 (C-20), 132.0 (C-14), 132.2 (C-11), 133.9 (C-17), 140.1
(C-8), 160.6 (C-2), 163.3 (C-9), 165.4 (C-10). 15N NMR (40.6 MHz,
DMSO-d6), δ (ppm): 102.60 (N-4′), 132.99 (N-2′), 148.82 (N-1′),
229.90 (N-3′) HRMS (APCI-Orbit trap) m/z calcd for C22H19N4O2
[M + H]+, 371.1503; found, 371.1508.
4-Methoxy-N-(1-(2-(4-methoxybenzoyl)hydrazono)isoindolin-2-
1
yl)benzamide 10Cf. White solid, mp 204−206 °C. Major isomer: H
NMR (400.1 MHz, DMSO-d6), δ (ppm): 3.78 (3H, s, H-24), 3.82
(3H, s, H-17), 4.75 (2H, s, H-1), 6.80 (2H, d, 8.4 Hz, H-20, 22), 6.99
(2H, d, 8.4 Hz, H-13, 15), 7.49 (1H, t, 7.3 Hz, H-5), 7.51 (1H, d, 8.1
Hz, H-7), 7.53 (2H, d, 8.8 Hz, H-19, 23), 7.56 (1H, t, 7.9 Hz, H-6),
7.76 (1H, d, 7.6 Hz, H-4), 7.82 (2H, d, 8.8 Hz, H-12, 16), 10.27 (1H,
br, NH-1), 10.85 (1H, br, NH-2). 13C NMR (100.6 MHz, DMSO-d6),
δ (ppm): 55.3 (C-24), 55.5 (C-17), 57.4 (C-1), 113.3 (C-20, 22),
113.8 (C-13, 15), 121.7 (C-4), 122.9 (C-7), 123.2 (C-11), 126.0 (C-
18), 127.9 (C-5), 128.7 (C-19, 23), 129.5 (C-12, 16), 130.4 (C-6),
132.8 (C-3), 138.8 (C-8), 150.0 (C-2), 161.3 (C-21), 161.4 (C-9),
162.4 (C-14), 164.8 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ
(ppm): 103.5 (N-4′), 132.90 (N-2′), 146.3 (N-1′), 226.3 (N-3′).
Minor isomer: 1H NMR (400.1 MHz, DMSO-d6), δ (ppm): 3.83 (3H,
s, H-24), 3.84 (3H, s, H-17), 4.75 (2H, s, H-1), 7.03 (2H, d, 8.8 Hz,
H-20, 22), 7.07 (2H, d, 8.8 Hz, H-13, 15), 7.40−7.50 (1H, m, H-5),
7.57 (1H, t, 6.6 Hz, H-6), 7.58 (1H, d, 8.1 Hz, H-7), 7.92 (1H, d, 8.8
Hz, H-4), 7.92 (2H, d, 8.8 Hz, H-19, 23), 7.97 (2H, d, 8.8 Hz, H-12,
16), 10.71 (1H, br, NH-1), 10.85 (1H, br, NH-2).13C NMR (100.6
MHz, DMSO-d6), δ (ppm): 53.7 (C-1), 55.3 (C-24), 55.4 (C-17),
113.7 (C-20, 22), 113.7 (C-13, 15), 123.35 (C-7), 124.4 (C-11), 126.1
(C-4), 126.1 (C-18), 127.7 (C-5), 128.9 (C-19, 23), 129.2 (C-3),
129.5 (C-12, 16), 130.9 (C-6), 140.1 (C-8), 160.7 (C-2), 161.5 (C-
21), 162.2 (C-14), 163.0 (C-9), 164.9 (C-10). 15N NMR (40.6 MHz,
DMSO-d6), δ (ppm): 132.90 (N-2′), 145.05 (N-1′), 229.40 (N-3′).
HR-MS (APCI-Orbit trap) m/z calcd for C24H23N4O4 [M + H]+,
431.1714; found, 431.1722.
4-Pyridyl-N-(1-(2-(3,4,5-trimethoxybenzoyl)hydrazono)-
isoindolin-2-yl)benzamide 10 Ci. White solid, mp 291−293 °C.
Major isomer: 1H NMR (400.1 MHz, DMSO-d6), δ (ppm): 4.79 (2H,
s, H-1), 7.50 (2H, d, 6 Hz, H-17, 20), 7.55 (1H, t, 7.6 Hz, H-5), 7.57
(1H, d, 8.2 Hz, H-7), 7.63 (1H, t, 7.8 Hz, H-6), 7.63 (2H, d, 5.2 Hz,
H-12, 15), 7.81 (1H, d, 7.6 Hz, H-4), 8.52 (2H, d, 5.6 Hz, H-18, 19),
8.61 (2H, d, 5.6 Hz, H-13, 14), 10.72 (1H, br, NH-1), 11.21 (1H, br,
NH-2). 13C NMR (100.6 MHz, DMSO-d6), δ (ppm): 57.3 (C-1),
120.9 (C-17, 20), 121.1 (C-12, 15), 122.1 (C-4), 123.0 (C-7), 128.1
(C-5), 130.9 (C-6), 132.5 (C-3), 138.3 (C-11), 138.7 (C-8), 140.7 (C-
16), 149.7 (C-18, 19), 150.2 (C-13, 14), 153.3 (C-2), 160.0 (C-9),
163.3 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm): 111.3 (N-
4′), 136.9 (N-2′), 150.1 (N-1′), 223.7 (N-3′), 321.6 (N-6′), 325.5 (N-
1
5′). Minor isomer: H NMR (400.1 MHz, DMSO-d6), δ (ppm): 4.82
(2H, s, H-1), 7.40−7.50 (1H, m, H-5), 7.64 (1H, d, 7.6 Hz, H-7), 7.64
(1H, t, 7.6 Hz, H-6), 7.86 (2H, d, 6.0 Hz, H-17, 20), 7.89 (2H, d, 6.0
Hz, H-12, 15), 7.95 (1H, d, 7.6 Hz, H-4), 8.76 (2H, d, 5.6 Hz, H-18,
19), 8.82 (2H, d, 5.6 Hz, H-13, 14), 11.25 (1H, br, NH-1), 11.42 (1H,
br, NH-2). 13C NMR (100.6 MHz, DMSO-d6), δ (ppm): 53.6 (C-1),
121.2 (C-17, 20), 121.3 (C-12, 15), 123.5 (C-7), 126.1 (C-4), 127.9
(C-5), 128.6 (C-3), 131.3 (C-6), 139.1 (C-11), 140.1 (C-8), 140.7 (C-
16), 150.3 (C-18, 19), 150.5 (C-13, 14), 160.6 (C-2), 161.6 (C-9),
164.0 (C-10). 15N NMR (40.6 MHz, DMSO-d6), δ (ppm): 150.9 (N-
1′), 228.5 (N-3′), 322.8 (N-6′), 325.4 (N-5′). HR-MS (APCI-Orbit
trap) m/z calcd for C20H17N6O2 [M + H]+, 373.1408; found,
373.1414.
4-Nitro-N-(1-(2-(4-nitrobenzoyl)hydrazono)isoindolin-2-yl)-
1
benzamide 10Cg. Yellow solid, mp 213−215 °C. Major isomer: H
NMR (400.1 MHz, DMSO-d6), δ (ppm): 4.80 (2H, s, H-1), 7.53 (1H,
t, 7.4 Hz, H-5), 7.56 (1H, d, 7.9 Hz, H-7), 7.61 (1H, t, 7.9 Hz, H-6),
7.79 (2H, d, 8.8 Hz, H-18, 22), 7.81 (1H, d, 7.5 Hz, H-4), 7.93 (2H, d,
8.7 Hz, H-12, 16), 8.09 (2H, d, 9.2 Hz, H-19, 21), 8.17 (2H, d, 8.4 Hz,
H-13, 15), 10.74 (1H, br, NH-1), 11.21 (1H, br, NH-2). 13C NMR
(100.6 MHz, DMSO-d6), δ (ppm): 57.3 (C-1), 122.1 (C-4), 123.0 (C-
7), 123.1 (C-19, 21), 123.4 (C-13, 15), 128.1 (C-5), 128.4 (C-18, 22),
128.9 (C-12, 16), 130.9 (C-6), 132.6 (C-3), 136.8 (C-11), 138.8 (C-
8), 139.4 (C-17), 148.5 (C-20), 149.4 (C-14), 153.2 (C-2), 160.4 (C-
9), 163.2 (C-10). Minor isomer: 1H NMR (400.1 MHz, DMSO-d6), δ
(ppm): 4.83 (2H, s, H-1), 7.40−7.50 (1H, m, H-5), 7.62 (1H, t, 8.1
Hz, H-6), 7.63 (1H, d, 8.3 Hz, H-7), 7.96 (1H, d, 10.8 Hz, H-4), 8.18
General Experimental Procedure for the Synthesis of Bis-
1,3,4-oxadiazoles 5. An oven-dried flask was charged with 10 (0.50
mmol) and PIFA (3 equiv, 1.5 mmol, 0.64 g) and filled with argon.
Dry dichloromehane (10 mL) was added through the septum, and the
mixture was stirred overnight at room temperature. The solvent was
removed in vacuo, and the residue was treated with ethyl acetate (30
mL) and neutralized with a solution of 5% sodium bicarbonate (3 × 20
mL). The organic layers were then washed with water and brine and
dried over anhydrous magnesium sulfate, and the solvent was removed
H
dx.doi.org/10.1021/jo400023z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
in vacuo. The residue was chromatographed using as eluent various
mixtures of solvents to afford the pure product.
gel, EtOAc/petroleum ether = 1:1). 1H NMR (400.1 MHz, CDCl3), δ
(ppm): 7.39 (4H, t, 7.2 Hz, H-8), 7.47 (2H, t, 7.2 Hz, H-9), 7.75−7.79
(2H, m, H-3), 7.92 (4H, d, 6.8 Hz, H-7), 8.14−8.18 (2H, m, H-2). 13C
NMR (100.6 MHz, CDCl3), δ (ppm): 123.4 (C-1), 123.6 (C-6), 126.9
(C-7), 129.1 (C-8), 130.8 (C-2), 131.8 (C-9), 131.9 (C-3), 163.3 (C-
4), 165.3 (C-5). HR-MS (APCI-Orbit trap) m/z calcd for C22H15N4O2
[M + H]+, 367.1190; found, 367.1195.
1,2-Bis[5-(3′,4′,5′-trimetoxiphenyl)-1,3,4-oxadiazol-2-yl]benzene
5a. White solid, mp 212−213 °C, overall isolated yield 117 mg (43%),
Rf = 0.45 (silica gel, EtOAc/DCM = 1:2). 1H NMR (400 MHz,
CDCl3): δ (ppm): 3.84 (12H, s, OCH3), 3.87 (s, 6H, OCH3), 7.11 (s,
4H, H-7), 7.76−7.80 (2H, m, H-3), 8.15−8.20 (2H, m, H-2). 13C
NMR (100.6 MHz, CDCl3), δ (ppm): 56.2 (CH3-8), 61.0 (CH3-9),
104.0 (C-7), 118.2 (C-6), 123.4 (C-1), 130.8 (C-2), 131.9 (C-3),
141.3 (C-9), 153.6 (C-8), 163.3 (C-4), 165.2 (C-5). MS (ES+): m/z,
547.2 [M + H]+; 569.2 [M + Na]+; 813.4 [3M + H + Na]2+; 839.4
[3M + H + K]2+. HR-MS (APCI-Orbit trap) m/z calcd for
C28H27N4O8 [M + H]+, 547.1823; found, 547.1829.
1,2-Bis[5-(4-piridyl)-1,3,4-oxadiazol-2-yl]benzene 5i. White solid,
mp 210−212 °C, overall isolated yield 66 mg (36%), Rf = 0.50 (alox,
1
EtOAc/DCM = 3:1). H NMR (400.1 MHz, CDCl3), δ (ppm): 7.83
(4H, d, 6.0 Hz, H-7), 7.82−7.84 (2H, m, H-3), 8.14−8.16 (2H, m, H-
2), 8.77 (4H, d, 5.6 Hz, H-8). 13C NMR (100.6 MHz, CDCl3), δ
(ppm): 120.2 (C-7), 123.3 (C-1), 130.5 (C-6), 130.9 (C-2), 132.3 (C-
3), 151.0 (C-8), 163.4 (C-4), 163.9 (C-5). HR-MS (APCI-Orbit trap)
m/z calcd for C20H13N6O2 [M + H]+, 369.1100; found, 369.1095.
1,2-Bis[5-(4′-bromophenyl)-1,3,4-oxadiazol-2-yl]benzene 5b.
White solid, mp 249−250 °C, overall isolated yield 102 mg (39%),
1
Rf = 0.46 (silica gel, EtOAc/petroleum ether = 1:3). H NMR (400.1
MHz, CDCl3), δ (ppm): 7.57 (4H, d, 8.8 Hz, H-8), 7.75−7.79 (2H, m,
H-3), 7.80 (4H, d, 8.8 Hz, H-7), 8.11−8.15 (2H, m, H-2).13C NMR
(100.6 MHz, CDCl3), δ (ppm): 122.3 (C-6), 123.4 (C-1), 126.8 (C-
9), 128.2 (C-7), 130.8 (C-2), 131.9 (C-3), 132.5 (C-8), 163.4 (C-4),
164.5 (C-5). HR-MS (APCI-Orbit trap) m/z calcd for C22H13Br2N4O2
[M + H]+, 524.9379; found, 524.9385.
ASSOCIATED CONTENT
* Supporting Information
Details about synthesis, X-ray diffraction, NMR and HR-MS
spectra of the new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
1,2-Bis[5-(4′-clorophenyl)-1,3,4-oxadiazol-2-yl]benzene 5c. White
solid, mp 212−214 °C, overall isolated yield 102 mg (47%), Rf = 0.75
AUTHOR INFORMATION
Corresponding Author
*E-mail: nbogdan@chem.ubbcluj.ro (N.D.H.); mihaela.
matache@g.unibuc.ro (M.M.).
1
■
(silica gel, EtOAc/DCM = 1:2). H NMR (400.1 MHz, CDCl3), δ
(ppm): 7.41 (4H, d, 8.8 Hz, H-8), 7.77−7.79 (2H, m, H-3), 7.87 (4H,
d, 8.4 Hz, H-7), 8.12−8.15 (2H, m, H-2). 13C NMR (100.6 MHz,
CDCl3), δ (ppm): 121.8 (C-6), 123.4 (C-1), 128.1 (C-7), 129.5 (C-
8), 130.8 (C-2), 131.9 (C-3), 138.4 (C-9), 163.4 (C-5), 164.4 (C-4).
HR-MS (APCI-Orbit trap) m/z calcd for C22H13Cl2N4O2 [M + H]+,
435.0410; found, 435.0421.
Present Address
⊗Toronto Research Chemicals, 2 Brisbane Rd., Toronto,
Ontario, Canada M3J 2J8.
1,2-Bis[5-(3′-clorophenyl)-1,3,4-oxadiazol-2-yl]benzene 5d.
White solid, mp 133−136 °C, overall isolated yield 80 mg (37%), Rf
Notes
1
= 0.41 (silica gel, EtOAc/petroleum ether = 0.5:1). H NMR (400.1
The authors declare no competing financial interest.
MHz, CDCl3), δ (ppm): 7.37 (2H, t, 8.0 Hz, H-10), 7.47 (2H, d, 8.4
Hz, H-9), 7.77−7.81 (2H, m, H-3), 7.85 (2H, d, 7.6 Hz, H-11), 7.93
(2H, s, H-7), 8.13−8.16 (2H, m, H-2). 13C NMR (100.6 MHz,
CDCl3), δ (ppm): 123.4 (C-1), 124.9 (C-6 and C-11), 126.9 (C-7),
130.5 (C-10), 130.8 (C-2), 132.0 (C-3 and C-9), 135.3 (C-8), 163.5
(C-4), 164.1 (C-5). HR-MS (APCI-Orbit trap) m/z calcd for
C22H13Cl2N4O2 [M + H]+, 435.0410; found, 435.0421.
ACKNOWLEDGMENTS
■
Financial support by the National Research Council (CNCS)
of Romania, Project PNII-TE-314/2010 as well as Postdoctoral
Programme POSDRU/89/1.5/S/60746 of the European Social
Fund are gratefully acknowledged. We also thank Alina Jurca
for performing the preliminary fluorescence assays.
1,2-Bis[5-(4′-methylphenyl)-1,3,4-oxadiazol-2-yl]benzene 5e.
White solid, mp 175−176 °C, overall isolated yield 82 mg (42%), Rf
= 0.57 (silica gel, EtOAc/DCM = 0.5:1). 1H NMR (400.1 MHz,
CDCl3), δ (ppm): 2.37 (6H, s, CH3), 7.19 (4H, d, 8.0 Hz, H-8), 7.73−
7.76 (2H, m, H-3), 7.80 (4H, d, 8.0 Hz, H-7), 8.12−8.15 (2H, m, H-
2). 13C NMR (100.6 MHz, CDCl3), δ (ppm): 21.6 (CH3), 120.6 (C-
6), 123.6 (C-1), 126.8 (C-7), 129.7 (C-8), 130.8 (C-2), 131.7 (C-3),
142.4 (C-9), 163.1 (C-4), 165.4 (C-5). HR-MS (APCI-Orbit trap) m/
z calcd for C24H19N4O2 [M + H]+, 395.1503; found, 395.1514.
1,2-Bis[5-(4-metoxiphenyl)-1,3,4-oxadiazol-2-yl]benzene 5f.
White solid, mp 165−166 °C, overall isolated yield 92 mg (43%), Rf
= 0.44 (silica gel, EtOAc/DCM = 1:4). 1H NMR (400.1 MHz,
CDCl3), δ (ppm): 3.83 (6H, s, CH3), 6.88 (4H, d, 8.8 Hz, H-8), 7.73−
7.75 (2H, m, H-3), 7.84 (4H, d, 8.8 Hz, H-7), 8.13−8.15 (2H, m, H-
2). 13C NMR (100.6 MHz, CDCl3), δ (ppm): 55.4 (CH3), 114.5 (C-
8), 115.9 (C-6), 123.6 (C-1), 128.7 (C-7), 130.8 (C-2), 131.7 (C-3),
162.4 (C-9), 162.9 (C-4), 165.2 (C-5). HR-MS (APCI-Orbit trap) m/
z calcd for C24H19N4O4 [M + H]+, 427.1401; found, 427.1404.
1,2-Bis[5-(4′-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzene 5g. White
solid, mp 246−248 °C, overall isolated yield 73 mg (32%), Rf = 0.26
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