Synthesis of isoindoles by one-electron reductions of dibenzo[1,4]diazocines

Article abstract of DOI:10.1002/ejoc.201403315

A synthetic protocol to isoindoles is reported through one-electron reductions of dibenzo[1,4]diazocines. The utility of the approach has been demonstrated through the synthesis of six novel isoindole derivatives. Photophysical measurements revealed emissions between 440 and 460 nm. A reaction mechanism, supported by experimental results and quantum chemical calculations, is postulated.

Full text of DOI:10.1002/ejoc.201403315

Job/Unit: O43315
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Date: 15-12-14 12:37:05
Pages: 12
FULL PAPER
DOI: 10.1002/ejoc.201403315
Synthesis of Isoindoles by One-Electron Reductions of Dibenzo[1,4]diazocines
Marcel Bovenkerk[a] and Birgit Esser*[a]
Keywords: Synthetic methods / Electrochemistry / Electron transfer / Reduction / Heterocycles
A synthetic protocol to isoindoles is reported through one-
electron reductions of dibenzo[1,4]diazocines. The utility of
the approach has been demonstrated through the synthesis
of six novel isoindole derivatives. Photophysical measure-
ments revealed emissions between 440 and 460 nm. A reac-
tion mechanism, supported by experimental results and
quantum chemical calculations, is postulated.
Introduction
Isoindoles have been known since 1951 when Wittig et
al. isolated the derivative N-methylisoindole.[1] The parent
compound, however, was not isolated until 1972 due to its
instability at room temperature.[2] Since then, the chemistry
of isoindoles has expanded rapidly.[3] Derivatives of isoin-
dole have applications in medicinal chemistry,[3b] namely as
potential antitumor agents due to their antiproliferative ac-
tivity,[4] and in materials science, due to their luminescent
properties.[3b,5] In addition, the oxidized and reduced iso-
indole skeletons are found in many natural products.[6] Iso-
indoles are prone to oxidation due to their o-quinoid struc-
ture, and direct functionalization is generally only possible
through electrophilic aromatic substitution,[3a] although
some cases of functionalization have been achieved through
nucleophilic substitution reactions.[7] Therefore synthetic
methods are required to access differently substituted iso-
indoles from stable starting materials. Existing methods[3]
include cycloaddition reactions, oxidative processes starting
from isoindolines,[5b,8] reductive transformations of phthal-
imides, and condensation reactions of diketones with pri-
mary amines.
Figure 1. Isoindole derivatives 1 accessible through one-electron re-
ductions of dibenzo[1,4]diazocines 2.
Results and Discussion
We discovered this one-electron reaction during our in-
vestigations of organic redox-active polymers. It has been
postulated that the diazocine core should show reversible
reduction behavior due to the formation of a planar, aro-
matic dianion with 10π electrons upon two-electron re-
duction (Scheme 1),[9] making it a potential side-group for
redox-active polymers.
In this paper we describe a new synthetic pathway to
isoindole derivatives 1 through one-electron reductions of
dibenzo[1,4]diazocines 2 (Figure 1). The transformation,
starting from stable and easily accessible diazocines 2, yields
aniline-substituted isoindoles 1 in good to excellent yields.
Scheme 1. Predicted boat-to-planar conformational change of
[1,5]diazocine through two-electron reduction.
Based on this prediction, dibenzo[1,5]diazocine was in-
corporated as a redox-active side-group into an aliphatic
polymer (P1; Scheme 2). The synthesis of P1 started from
the brominated derivative 3.[10] Reaction with 1 equiv. of
nBuLi followed by quenching with MeOH led to the mono-
bromo derivative 30, which was subjected to Suzuki–
Miyaura coupling with pinacol vinylboronate leading to 4.
[a] Kekulé-Institut für Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
E-mail: birgitesser@uni-bonn.de
http://www.esser-lab.uni-bonn.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403315.
Free-radical polymerization of
4
gave P1 (Mw
=
2.5؋105 a.u., Mw/Mn = 2.05).[11]
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M. Bovenkerk, B. Esser
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ducing conditions, such as zinc/acetic acid or platinum/di-
hydrogen, can also induce transannular ring closure to 6.[14]
Due to the irreversibility of the redox processes of 5, we
turned our attention to the 1,4-derivative 2a (for its synthe-
sis, see Scheme 4). As shown in the CV in Figure 2, how-
ever, the electrochemical behavior of 2a is similar to that of
5, displaying one irreversible reduction wave at –2.6 V (vs.
Fc/Fc+).
Upon reduction of 2a using sodium metal, in analogy to
Eisch et al.,[13a] isoindole 1a was isolated as the only prod-
uct in good yield as an air-sensitive, yellow, fluorescent
compound (Scheme 3).[15] Ollièro et al. reported the forma-
tion of 1a through the reaction of 2a with diborane, how-
ever, no yields were given for this transformation.[16] Trans-
annular ring closure also occurred upon sodium reduction
of the isomeric 6,7-diphenyldibenzo[e,g][1,4]diazocine to
give a carbazole derivative.[17]
Considering the significance of isoindoles in medicinal
chemistry as well as in materials science,[3] the conditions
for the reduction of 2a to 1a were optimized (Table 1). All
of the one-electron reduction agents tested (lithium
naphthalenide, sodium naphthalenide, and magnesium an-
thracene[18]) yielded isoindole 1a in good to excellent yields
within 10 min. The best yield of 1a (96%, Table 1, entry 4)
was obtained by using an excess (8 equiv.) of sodium naph-
thalenide.
Scheme 2. Synthesis of P1 as a potential redox-active polymer.
The cyclic voltammogram (CV) of P1 in solution, how-
ever, showed irreversible redox processes, that is, two
irreversible reductions at –2.5 and –3.1 V (vs. Fc/Fc+, see
Figure S2 in the Supporting Information). To gain a clearer
picture of the redox processes that occur in P1, model com-
pound 5 (Scheme 3), which was isolated as a byproduct in
the synthesis of 4, was studied by CV. Compound 5 shows
a strong and electrochemically irreversible reduction wave
at –2.5 V (vs. Fc/Fc+; Figure 2). Similar irreversible behav-
ior was observed by Koch and Dessy,[12] who described the
formation of the tetrahydroindoloindole 6 (Scheme 3) from
a transannular ring closure upon preparative-scale electrol-
ysis of 5. Eisch et al. recently demonstrated a chemical re-
duction of 5 to give 6 by using sodium metal.[13] Other re-
Table 1. Optimization of the reaction conditions for the one-elec-
tron reduction of dibenzo[1,4]diazocine 2a to isoindole 1a.
Entry [Red]
T [°C] Time [min] Yield [%][a]
1
2
3
4
5
6
LiNaph[b] (8 equiv.)
40[e]
40[e]
r.t.[e]
r.t.[e]
r.t.[e]
70
10
10
10
10
10
30
77
54
77
96
85
NaNaph[c] (2 equiv.)
NaNaph[c] (4 equiv.)
NaNaph[c] (8 equiv.)
[MgAnth(thf)3][d] (4 equiv.)
Mg (8 equiv.), anthracene
(10 mol-%), EtBr (10 mol-%)
Ͻ10
Scheme 3. Products of the sodium reduction of dibenzo[1,5]di-
azocine 5[13] and dibenzo[1,4]diazocine 2a.
[a] Isolated yields. [b] Lithium naphthalenide. [c] Sodium
naphthalenide. [d] Magnesium anthracene. [e] Ultrasound.
Substituted dibenzo[1,4]diazocines 2 were then synthe-
sized to test the scope of the reduction to the corresponding
isoindoles 1. Me, OMe, Cl, and Br were chosen as substitu-
ents on either side of the diazocine core. The derivatives 2b–
i were synthesized by condensation of the corresponding
1,2-phenylenediamines with the respective diketones follow-
ing a modified procedure of Ollièro and Solladié[19]
(Scheme 4).
The substituted diketones 7–11 were accessed either
through the oxidation of the corresponding isobenzofurans
(diketones 7, 8, and 11 from 12–14), nucleophilic replace-
ment of carbothioates (diketone 10), or oxidation of a
Figure 2. CVs of 5 and 2a in THF (glassy carbon electrode, 1 mm
solutions with 0.1 m nBu4PF6, scan rate = 0.2 V/s).
2
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Isoindoles by One-Electron Reductions of Dibenzodiazocines
Dibenzo[1,4]diazocines 2b–i were then submitted to the
previously optimized reduction conditions (Table 2). In
those cases in which the substituent is on the diketone side
of the dibenzodiazocine core (R1), only one isomeric prod-
uct can be formed (entries 2 and 3, products 1b,c); however,
if the diamine side is substituted (R2), two regioisomeric
products are possible (entries 6 and 7; products 1f,g and
1j,k).
By means of this simple protocol, six as yet unknown
isoindole derivatives were synthesized with a methyl or
methoxy substituent on the isoindole core (1b,c) or on the
attached aniline moiety (1f,g and 1j,k). The yields of the
transformations were good in all cases; however, when R2
was varied, one of the regioisomeric products (1f,g) was
clearly preferred over the other (1j,k). This regioselectivity
can be rationalized through the proposed mechanism (see
below and Scheme 7). Halogen substituents did not with-
stand the reduction conditions and led to the unsubstituted
Scheme 4. Synthesis of dibenzo[1,4]diazocines 2a–i.
benzohydrazide (diketone 9, Scheme 5). The substituted
isobenzofurans 13 and 14 were synthesized as shown in
Scheme 6.
Scheme 5. Synthesis of diketones 7–11.
Scheme 6. Synthesis of isobenzofurans 13 and 14.
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M. Bovenkerk, B. Esser
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Table 2. Sodium naphthalenide reduction of dibenzo[1,4]diazocines
2a–i to isoindoles 1a–k.
Several experiments were performed to elucidate the re-
action mechanism for isoindole formation. A plausible
mechanism is postulated in Scheme 7. An initial electron
transfer to dibenzo[1,4]diazocine 2a leads to radical anion
25, which then undergoes transannular ring closure to 26
through attack of the negatively charged nitrogen center on
the imine carbon. Transfer of a second electron to 26 leads
to the tetracyclic dianion 27, which can rearrange to form
the isoindole core in 28. Hydrolysis of 28 furnishes 1a.
A one-electron transfer process is supported by two facts:
When the reduction of 2a was performed with 1 equiv. of
sodium naphthalenide, no isoindole was formed, instead
99% of 2a was recovered. This observation is in line with an
initial quantitative formation of radical anion 25 by a one-
electron transfer mechanism. Secondly, the observed regio-
selectivities in the reductions of 2f and 2g can be explained
by assuming the corresponding derivatives of 25 as interme-
diates. The isomer in which the negatively charged nitrogen
is located at the meta position with respect to the methyl or
methoxy substituent is preferred over a para substitution.
Several NMR experiments were conducted to shed light
on which dianionic intermediate 27 or 28 is present before
the reaction is quenched with water. First, 2a was reduced
with sodium in [D8]THF and the reaction was followed by
1H NMR spectroscopy. The 1H NMR spectrum of the
dark-red solution (see Figure S7 in the Supporting Infor-
mation) indicates the presence of more than one species;
however, the most pronounced signals show a pattern con-
sistent with dianion 28. The observed coupling patterns of
four protons resemble that of the aniline ring in 1a, but the
resonances are shifted upfield by 0.7–0.8 ppm, as expected
upon deprotonation of the amino group.
In a second experiment, 1H NMR spectra were recorded
after the addition of 1 equiv., 2 equiv., and an excess of
nBuLi to a solution of 1a in [D8]THF (see Figures S6 and
S7 in the Supporting Information). For comparison, 2a was
reduced with lithium in [D8]THF and the reaction followed
1
by H NMR spectroscopy, as described above for sodium.
The spectra after the addition of 2 or more equivalents of
nBuLi appear similar to the in situ spectra recorded during
lithium or sodium reduction, namely an upfield shift of the
aniline ring protons of 0.3–0.8 ppm is observed. In ad-
dition, the resonance of the ortho protons of the phenyl
substituents on the isoindole core experiences a downfield
shift of 0.17 ppm and is found at the same chemical shift
1
as in the H NMR spectra recorded in situ during the re-
duction of 2a. These observations support our postulated
mechanism with 28 as an intermediate before quenching of
the reaction.
[a] Dehalogenation occurred. [b] Ratio determined by 1H NMR
spectroscopy. [c] Compound isolated as a mixture with the other
isomer.
To further elucidate the reaction mechanism, quantum
chemical calculations were performed.[20] Of particular
interest was the transformation of 27 into 28; hence, these
structures as well as transition state 29 were optimized[21]
derivative 1a (entries 4, 5, 8, and 9 in Table 2). When the at the TPSS[22]-D3[23]/def2-TZVP[24] level of theory and in-
bromo-substituted 2i was reduced by using 1.9 equiv. of so- cluding the COSMO[25] model to account for solvation. To
dium naphthalenide, 2a was isolated as the main product, find the transition state, constrained optimizations were
which demonstrates that dehalogenation is faster than iso- performed with fixed lengths of the breaking C–N bond
indole formation.
(Figure 3).
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Isoindoles by One-Electron Reductions of Dibenzodiazocines
Scheme 7. Postulated mechanism for the formation of isoindole 1a through the reduction of 2a (NaNaph = sodium naphthalenide; Naph
= naphthalene).
Figure 4. Optimized structures [TPSS-D3/def2-TZVP (COSMO)]
and relative energies of the proposed intermediates 27 and 28 and
Figure 3. Energy profiles for the reaction of 27 to 28.
transition state 29. [a] TPSS-D3/def2-TZVP. [b] TPSS-D3/def2-
TZVP (COSMO)).
At the TPSS-D3/def2-TZVP level of theory, the reaction
from 27 to 28 is exothermic by 3.2 kcal/mol with an acti-
vation energy of 8.7 kcal/mol (Figure 3 and Figure 4).
When the COSMO model is included to simulate the effect
of bulk solvent, the reaction becomes endothermic by
2.7 kcal/mol with a higher barrier of 13.4 kcal/mol. These
results show that the intermediates 27 and 28 have similar
energies, and rearrangement of 27 to 28 is feasible.
Owing to their luminescent properties, isoindoles are at-
tractive compounds for materials science. The synthesized
isoindole derivatives 1a–c and 1f,g were characterized
through their UV/Vis absorption and emission spectra (Fig-
ure 5). The UV/Vis spectra show several absorption max-
ima with the most intense peak below 200 nm and the long-
Figure 5. UV/Vis absorption (solid lines) and emission (dashed
lines; excitation at 375 nm) spectra of isoindoles 1a–c and 1f–g in
CH3CN.
est wavelength absorption at 374 nm. All the derivatives
show one emission maximum, which is found between 443
and 447 nm for 1a,b,f,g and is slightly redshifted to 457 nm
for the methoxy derivative 1c. Thus, the emissions of
isoindoles such as 1b and 1c can be shifted to longer wave-
lengths by substitution with electron-donating groups.
Conclusions
A unique and efficient route to 2-aniline-substituted iso-
indoles has been established through one-electron re-
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alene (216 mg, 1.69 mmol), and (5Z,11Z)-6,11-diphenyldi-
benzo[b,f][1,4]diazocine (2a; 75.0 mg, 209 μmol) and yielded 73 mg
(96%) of 1a. Rf = 0.81 (CH2Cl2/NEt3, 100:1). 1H NMR (400 MHz,
[D6]DMSO): δ = 7.60 (dd, J = 6.6, 3.0 Hz, 2 H), 7.37–7.34 (m, 4
H), 7.31–7.26 (m, 4 H), 7.22–7.17 (m, 2 H), 7.06–6.98 (m, 3 H),
6.91 (dd, J = 7.8, 1.6 Hz, 1 H), 6.66 (dd, J = 8.2, 1.4 Hz, 1 H), 6.47
(ddd, J = 7.6, 1.4 Hz, 1 H), 4.84 (s, 2 H) ppm. 1H NMR (400 MHz,
[D8]THF): δ = 7.66 (dd, J = 6.7, 3.0 Hz, 2 H), 7.36 (d, J = 7.1 Hz,
4 H), 7.22 (dd, J = 7.2 Hz, 4 H), 7.12 (dd, J = 7.6 Hz, 2 H), 7.03–
6.99 (m, 1 H), 6.95 (dd, J = 6.7, 3.0 Hz, 2 H), 6.87 (dd, J = 7.9,
1.6 Hz, 1 H), 6.59 (dd, J = 8.2, 1.4 Hz, 1 H), 6.47 (ddd, J = 7.5,
1.4 Hz, 1 H), 4.37 (s, 2 H) ppm. 13C NMR (100 MHz [D6]DMSO):
δ = 145.1, 131.6, 129.9, 129.5, 129.3, 128.0, 126.3, 123.9, 122.8,
122.7, 122.1, 119.6, 115.8, 115.2 ppm. MS (EI+): m/z = 360 [M]+,
283 [M – Ph]+. HRMS (EI+): calcd. for C26H19N2 359.1543 [M –
H]+; found 359.1549. UV/Vis (MeCN): λmax [log(ε/m–1 cm–1)] = 200,
233 [4.5], 272 [4.1], 305 [4.0], 372 nm [4.2]; emission (MeCN): λ =
445 nm.
ductions of dibenzo[1,4]diazocines using sodium
naphthalenide. Six as yet unknown isoindole derivatives
were synthesized by using this procedure, four of them in
good yield, and further characterized through photophysi-
cal measurements. A mechanism for the formation of iso-
indoles has been proposed and underlined experimentally
and through quantum chemical calculations.
Experimental Section
General: Commercially available chemicals were obtained from
Sigma–Aldrich, Acros-Organics, TCI-Europe, and Alfa Aesar, and
used without further purification. Experiments with water- or oxy-
gen-sensitive substances were carried out under argon using glass-
ware dried by heating under vacuum and standard Schlenk tech-
niques. Anhydrous solvents were obtained from an M-Braun sol-
vent purification system (MB-SPS), and stored under argon over
molecular sieves (3 or 4 Å) for a minimum duration of 48 h. All
other solvents were distilled prior to use. 1H and 13C{1H}NMR
spectra were recorded with Bruker Avance dpx 300 and 400 MHz
spectrometers at room temperature unless stated otherwise and ref-
erenced to the residual proton or carbon resonance of the deuter-
iated solvent.[32] The NMR spectra were analyzed by using the
MestReNova software.[33] Electrospray ionization mass spectra
(ESI-MS) were recorded with a Bruker micrOTOF-Q time-of-flight
spectrometer, and electron-impact ionization mass spectra(EI-MS)
were recorded with a Thermo Finnigan (Bremen) MAT 90 or MAT
95 XL sector field device. The most abundant masses are reported.
Silica gel layered alumina plates (Merck, Silica Gel 60 F254) were
used for TLC, and compounds were detected by using UV light (λ
= 366 and 254 nm). For flash column chromatography silica gel
(Merck 60, 40–63 μm) was used as the stationary phase. Eluents are
described in the respective synthetic procedures. Polymer molecular
weights were determined by using a GPC unit composed of an
IsoPump G1310A, an ALS G1329A auto sampler, a VWD G1314B
UV detector, and a RID G1362A RI detector by Agilent Technol-
ogies using a set of three columns (PSS Polymer Standard Service
GmbH, polystyrene, 8 mmϫ300 mm with a porosity of 102, 103,
and 105 Å with an integrated precolumn). THF stabilized with
2.5 ppm BHT (p.a., Fisher) was used as eluent at a flow rate of
1 mL/min, and measurements were calibrated against polystyrene
standards by PSS Polymer Standard Service GmbH. For thermal
gravimetric analysis (TGA) a Mettler Toledo TGA/STAA851 in-
strument (SF 1100 °C, MT 1, N2 atmosphere) was used with an
Alox 40 μL melting pot. For differential scanning calorimetry
(DSC) a Mettler Toledo DSC823e instrument (HSS7, N2 atmo-
sphere, liquid N2 cooling) was used with a standard aluminium
40 μL melting pot.
2-(5-Methyl-1,3-diphenyl-2H-isoindol-2-yl)aniline (1b): The general
procedure was followed by using Na (31.0 mg, 1.34 mmol),
naphthalene (137 mg, 1.07 mmol), and (5Z,11Z)-8-methyl-6,11-di-
phenyldibenzo[b,f][1,4]diazocine (2b; 50.0 mg, 134 μmol). Column
chromatography (silica gel, cyclohexane/CH2Cl2/NEt3, 2:1:0.01)
yielded 37 mg (74%) of 1b. Rf = 0.76 (cyclohexane/CH2Cl2/NEt3,
1:1:0.01). 1H NMR (400 MHz, [D6]DMSO): δ = 7.52 (d, J =
8.7 Hz, 1 H), 7.36–7.32 (m, 5 H), 7.30–7.26 (m, 4 H), 7.20–7.16 (m,
2 H), 7.05–7.01 (m, 1 H), 6.91 (dd, J = 7.8, 1.5 Hz, 1 H), 6.86 (dd,
J = 8.8, 1.4 Hz, 1 H), 6.65 (dd, J = 8.1, 1.3 Hz, 1 H), 6.46 (ddd, J
= 7.5, 1.4 Hz, 1 H), 4.77 (s, 2 H), 2.34 (s, 3 H) ppm. 13C NMR
(100 MHz [D6]DMSO): δ = 145.1, 131.8, 131.7, 130.8, 129.9, 129.4,
129.2, 129.1, 128.0, 128.0, 126.2, 126.1, 125.0, 123.8, 123.0, 123.0,
122.9, 121.5, 119.5, 117.4, 115.8, 115.2, 21.7 ppm. MS (EI+):
m/z = 374 [M]+, 297 [M – Ph]+. HRMS (EI+): calcd. for
C27H22N2 374.1778 [M]+; found 374.1779. UV/Vis (MeCN): λmax
[log(ε/m–1 cm–1)] = 200, 230 [4.4], 278 [3.9], 303 [3.8], 326 [3.8],
372 nm (4.0]; emission (MeCN): λ = 447 nm.
2-(5-Methoxy-1,3-diphenyl-2H-isoindol-2-yl)aniline (1c): The gene-
ral procedure was followed by using Na (24.0 mg, 1.03 mmol),
naphthalene (106 mg, 1.03 mmol), and (5Z,11Z)-8-methoxy-6,11-
diphenyldibenzo[b,f][1,4]diazocine (2c; 40.0 mg, 103 μmol). Col-
umn chromatography (silica gel cyclohexane/CH2Cl2/NEt3,
2:1:0.01) yielded 27 mg (67%) of 1c. Rf = 0.48 (CH2Cl2/NEt3,
100:1). 1H NMR (300 MHz, [D6]DMSO): δ = 7.50 (dd, J = 9.2,
0.7 Hz, 1 H), 7.36–7.25 (m, 8 H), 7.22–7.14 (m, 2 H), 7.02 (ddd, J
= 8.1, 7.3, 1.6 Hz, 1 H), 6.90 (dd, J = 7.8, 1.5 Hz, 1 H), 6.86 (m, 1
H), 6.70 (dd, J = 9.2, 2.2 Hz, 1 H), 6.64 (dd, J = 8.1, 1.3 Hz, 1 H),
6.45 (ddd, J = 7.5, 1.4 Hz, 1 H), 4.78 (s, 2 H), 3.75 (s, 3 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 155.6, 145.2, 131.9, 131.5,
130.0, 129.4, 129.1, 129.0, 128.1, 128.0, 126.4, 126.0, 124.4, 123.0,
122.7, 122.5, 121.2, 119.3, 117.1, 115.8, 115.1, 95.5, 54.8 ppm. MS
(EI+): m/z = 390 [M]+, 313 [M – Ph]+. HRMS (EI+): calcd. for
C27H22N2O 390.1727 [M]+; found 390.1735. UV/Vis (MeCN): λmax
[log(ε/m–1 cm–1)] = 200, 228 [4.4], 285 [4.0], 372 nm (3.9]; emission
(MeCN): λ = 457 nm.
General Procedure for the Preparation of Isoindoles 1a–1c, 1f/1j, and
1g/1k: Na pieces were added to dry, degassed THF (4 mL), and the
mixture sonicated for 20 min at room temp. Naphthalene was
added, and the mixture sonicated for 20 min. Residual Na pieces
were removed by using tweezers. The corresponding [1,4]diazocine
2 was added, and the mixture sonicated for 10 min. Water (1 mL)
was added, and the solution was filtered through a pad of alumin-
ium oxide. The mixture was purified by Kugelrohr distillation
(100 °C, 10–2 mbar) and column chromatography (silica gel, cyclo-
hexane/CH2Cl2/NEt3) afforded isoindoles 1a–1c, 1f/1j, and 1g/1k
as slightly yellow, fluorescent solids.
2-(1,3-Diphenyl-2H-isoindol-2-yl)-4-methylaniline (1f) and 2-(1,3-
Diphenyl-2H-isoindol-2-yl)-5-methylaniline (1j): The general pro-
cedure was followed by using Na (31.0 mg, 1.34 mmol), naphth-
alene (137 mg, 1.07 mmol), and (5Z,11Z)-2-methyl-6,11-diphenyld-
ibenzo[b,f][1,4]diazocine (2f; 75.0 mg, 201 μmol). Column
chromatography (silica gel, cyclohexane/CH2Cl2/NEt3, 2:1:0.01) af-
forded a mixture of 1f and 1j (58 mg, 77%) in a ratio of 78:22.
2-(1,3-Diphenyl-2H-isoindol-2-yl)aniline (1a): The general pro-
cedure was followed by using Na (48.0 mg, 2.09 mmol), naphth-
Analytical Data for 2-(1,3-Diphenyl-2H-isoindol-2-yl)-4-methylanil-
ine (1f): Rf = 0.56 (CH2Cl2/NEt3, 100:1). 1H NMR (400 MHz, [D6]-
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43315
/KAP1
Date: 15-12-14 12:37:05
Pages: 12
Isoindoles by One-Electron Reductions of Dibenzodiazocines
DMSO): δ = 7.58 (dd, J = 6.7, 3.0 Hz, 2 H), 7.39–7.34 (m, 4 H),
7.31–7.28 (m, 4 H), 7.22–7.18 (m, 2 H), 6.99 (dd, J = 6.7, 3.0 Hz,
2 H), 6.79 (d, J = 7.8 Hz, 1 H), 6.46 (br. s, 1 H), 6.28 (dd, J = 8.1,
1.9 Hz, 1 H), 4.74 (s, 2 H), 2.14 (s, 3 H) ppm. 13C NMR (100 MHz
[D6]DMSO): δ = 144.7, 138.5, 131.7, 129.6, 129.3, 128.1, 126.3,
124.0, 122.6, 122.0, 120.6, 119.5, 116.8, 115.5, 21.0 ppm. MS (EI+):
m/z = 374 [M]+, 297 [M – Ph]+. HRMS (EI+): calcd. for C27H22N2
359.1699 [M – H]+; found 359.1703. UV/Vis (MeCN): λmax
[log(ε/m–1 cm–1)] = 200, 232 [4.6], 272 [4.1], 305 [4.0], 372 nm [4.2];
emission (MeCN): λ = 443 nm.
131.8, 129.9, 129.7, 129.1, 128.1, 124.7, 122.0 ppm. MS (EI+): m/z
= 358 [M]+, 281 [M – Ph]+. Diazocine 2a was further characterized
by X-ray crystallography (see the Supporting Information).[26]
(5Z,11Z)-8-Methyl-6,11-diphenyldibenzo[b,f][1,4]diazocine (2b): The
general procedure was followed by using 1,2-dibenzoyl-4-methyl-
benzene (8; 1.20 g, 4.00 mmol), AcOH (50 mL), and o-phenylene-
diamine (portion 1: 475 mg, 4.40 mmol; portion 2: 560 mg,
5.18 mmol). Column chromatography (silica gel, cyclohexane/
1
EtOAc, 20:1) yielded 694 mg (47%) of 2b. Rf = 0.10 (CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.83–7.80 (m, 4 H), 7.44–7.33 (m, 6
H), 7.18 (ddd, J = 7.9, 1.7, 0.8 Hz, 1 H), 7.04 (d, J = 7.9 Hz, 1 H),
7.02–6.96 (m, 4 H), 6.95 (ddd, J = 1.5, 0.8 Hz, 1 H), 2.32 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1, 170.0, 142.2,
139.0, 138.2, 136.6, 133.7, 131.0, 129.8, 129.1, 128.4, 128.3, 127.7,
127.2, 124.1, 124.1, 121.4, 21.5 ppm. MS (ESI+): m/z = 767 [2M +
Na]+, 745 [2M + H]+, 395 [M + Na]+, 373 [M + H]+. HRMS
(ESI+): calcd. for C27H20N2Na 395.1519 [M + Na]+; found
359.1521.
In the purification process 1f could be obtained in pure form; how-
ever, 1j could only be obtained in a mixture with 1f.
Analytical Data for 2-(1,3-Diphenyl-2H-isoindol-2-yl)-5-methylanil-
ine (1j): Rf = 0.54 (CH2Cl2/NEt3, 100:1). 1H NMR (400 MHz, [D6]-
DMSO): δ = 7.60 (dd, J = 6.5, 3.0 Hz, 2 H), 7.38–7.35 (m, 4 H),
7.31–7.28 (m, 4 H), 7.22–7.18 (m, 2 H), 7.00 (dd, J = 6.5, 3.3 Hz,
2 H), 6.87 (dd, J = 8.4, 2.1 Hz, 1 H), 6.72 (d, J = 2.0 Hz, 1 H),
6.59 (d, J = 8.2 Hz, 1 H), 4.64 (s, 2 H), 2.02 (s, 3 H) ppm.
(5Z,11Z)-8-Methoxy-6,11-diphenyldibenzo[b,f][1,4]diazocine (2c):
The general procedure was followed by using 1,2-dibenzoyl-4-
methoxybenzene (9; 180 mg, 569 μmol), AcOH (9 mL), and o-
phenylenediamine (portion 1: 61.5 mg, 569 μmol; portion 2:
61.5 mg, 569 μmol). Column chromatography (silica gel, cyclohex-
ane/EtOAc, 20:1) yielded 171 mg (77%) of 2c. Rf = 0.33 (cyclohex-
2-(1,3-Diphenyl-2H-isoindol-2-yl)-4-methoxyaniline (1g) and 2-(1,3-
Diphenyl-2H-isoindol-2-yl)-5-methoxyaniline (1k): The general
procedure was followed by using Na (29.0 mg, 1.28 mmol), naphth-
alene (130 mg, 1.02 mmol), and (5Z,11Z)-2-methoxy-6,11-diphen-
yldibenzo[b,f][1,4]diazocine (2g; 40.0 mg, 102 μmol). Column
chromatography (silica gel, cyclohexane/CH2Cl2/NEt3, 2:1:0.01) af-
forded a mixture of 1g and 1k (24 mg, 62%) in a ratio of 96:4.
1
ane/EtOAc, 10:1). H NMR (400 MHz, CDCl3): δ = 7.83–7.79 (m,
4 H), 7.44–7.39 (m, 2 H), 7.38–7.33 (m, 4 H), 7.06 (d, J = 8.5 Hz,
1 H), 7.01–6.94 (m, 4 H), 6.90 (dd, J = 8.6, 2.6 Hz, 1 H), 6.63 (d,
J = 2.5 Hz, 1 H), 3.74 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 169.9, 169.5, 159.7, 142.2, 142.1, 138.4, 138.1, 137.9, 131.1,
131.0, 129.2, 129.1, 128.8, 128.8, 128.4, 128.3, 124.2, 124.1, 121.4,
115.0, 112.1, 77.2, 55.5 ppm. MS (EI+): m/z = 388 [M]+, 373 [M –
Me]+ 311 [M – Ph]+. HRMS (EI+): calcd. for C27H20N2O+
388.1570 [M]+; found 388.1573.
Analytical Data for 2-(1,3-Diphenyl-2H-isoindol-2-yl)-4-methoxy-
1
aniline (1g): Rf = 0.43 (CH2Cl2/NEt3, 100:1). H NMR (400 MHz,
[D6]DMSO): δ = 7.59 (dd, J = 6.7, 3.0 Hz, 2 H), 7.38–7.28 (m, 8
H), 7.23–7.18 (m, 2 H), 6.99 (dd, J = 6.6, 3.0 Hz, 2 H), 6.82 (d, J
= 8.6 Hz, 1 H), 6.21 (d, J = 2.7 Hz, 1 H), 6.05 (dd, J = 8.6, 2.7 Hz,
1 H), 4.84 (s, 2 H), 3.64 (s, 3 H) ppm. 13C NMR (75 MHz [D6]
DMSO): δ = 159.8, 146.1, 131.7, 130.7, 129.3, 128.1, 126.3, 124.1,
122.6, 122.0, 119.5, 116.4, 102.1, 99.3, 54.7 ppm. MS (EI+): m/z =
390 [M]+, 313 [M – Ph]+. HRMS (EI+): calcd. for C27H22N2O
390.1727 [M]+; found 390.1730. UV/Vis (MeCN): λmax
[log(ε/m–1 cm–1)] = 197, 231 [4.6], 272 [4.1], 300 [4.1], 372 nm [4.2];
emission (MeCN): λ = 445 nm.
(5Z,11Z)-8-Chloro-6,11-diphenyldibenzo[b,f][1,4]diazocine (2d): The
general procedure was followed by using 4-chloro-1,2-dibenzo-
ylbenzene (10; 350 mg, 1.09 mmol), AcOH (15 mL), and o-phen-
ylenediamine (portion 1: 130 mg, 1.20 mmol; portion 2: 130 mg,
1.20 mmol). Column chromatography (silica gel, cyclohexane/
1
General Procedure for the Preparation of [1,4]diazocines 2a–2i: Ac-
cording to a modified literature method,[19] the respective 1,2-di-
benzoylbenzene was dissolved in AcOH. The respective o-phen-
ylenediamine was added, and the reaction mixture was stirred at
60–80 °C for 5 h. A further 1–4 portions of the respective o-phen-
ylenediamine were added, and the solution was stirred at 50–80 °C
for 9–65 h. The mixture was neutralized with satd. aq. Na2CO3,
extracted with CH2Cl2, washed with brine, and dried (Na2SO4).
The solvent was then removed under reduced pressure. Column
chromatography (silica gel, CH2Cl2 and/or cyclohexane/EtOAc) af-
forded [1,4]diazocines 2a–2i as yellow solids.
CH2Cl2, 1:1) yielded 304 mg (72%) of 2d. Rf = 0.26 (CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.79–7.77 (m, 4 H), 7.46–7.41 (m, 2
H), 7.39–7.35 (m, 5 H), 7.15 (d, J = 2.1 Hz, 1 H), 7.09 (d, J =
8.3 Hz, 1 H), 7.04–6.95 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.4, 168.6, 141.4, 141.0, 138.1, 137.1, 137.1, 135.4,
134.7, 131.7, 131.7, 129.5, 129.3, 129.2, 128.8, 128.6, 128.6, 127.3,
124.8, 124.7, 121.6, 121.6 ppm. MS (EI+): m/z = 392 [M]+, 359 [M –
Ph]+. HRMS (EI+): calcd. for C26H17ClN2 392.1075 [M]+; found
392.1086.
(5Z,11Z)-8-Bromo-6,11-diphenyldibenzo[b,f][1,4]diazocine (2e): The
general procedure was followed by using 4-bromo-1,2-dibenzo-
(5Z,11Z)-6,11-Diphenyldibenzo[b,f][1,4]diazocine (2a): The general ylbenzene (11; 198 mg, 542 μmol), AcOH (9 mL), and o-phenylene-
procedure was followed by using 1,2-dibenzoylbenzene (7; 2.67 g, diamine (portion 1: 61.0 mg, 564 μmol; portion 2: 61.0 mg,
9.32 mmol), AcOH (120 mL), and o-phenylenediamine (portion 1: 564 μmol; portion 3: 50.0 mg, 462 μmol; portion 4: 61.0 mg,
1.01 g, 9.32 mmol; portion 2: 0.76 g, 6.99 mmol). Column 564 μmol). Column chromatography (silica gel, cyclohexane/
chromatography (silica gel, cyclohexane/EtOAc, 15:1) yielded
EtOAc, 20:1) yielded 181 mg (76%) of 2e. Rf = 0.50 (cyclohexane/
2.83 g (84%) of 2a. Rf = 0.27 (cyclohexane/EtOAc, 15:1). 1H NMR EtOAc, 10:1). 1H NMR (400 MHz, CDCl3): δ = 7.80–7.77 (m, 4
(400 MHz, CDCl3): δ = 7.81 (dd, J = 8.3, 1.5 Hz, 4 H), 7.44–7.34
(m, 8 H), 7.15 (dd, J = 5.7, 3.3 Hz, 2 H), 7.01–6.95 (m, 4 H) ppm.
H), 7.52 (dd, J = 8.2, 2.0 Hz, 1 H), 7.46–7.41 (m, 2 H), 7.40–7.33
(m, 4 H), 7.30 (d, J = 2.0 Hz, 1 H), 7.07–6.95 (m, 5 H) ppm. 13C
1H NMR (400 MHz, [D8]THF): δ = 7.82–7.78 (m, 4 H), 7.41–7.36 NMR (100 MHz, CDCl3): δ = 169.0, 168.3, 141.5, 141.4, 138.4,
(m, 4 H), 7.35–7.30 (m, 4 H), 7.14 (dd, J = 5.7, 3.3 Hz, 2 H), 6.93–
6.84 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9, 142.1, 124.6, 124.5, 123.3, 121.5, 121.5 ppm. MS (EI+): m/z = 436 [M]+,
137.9, 136.6, 131.1, 129.1, 128.9, 128.4, 127.2, 124.2, 121.3 ppm.
359 [M – Ph]+. HRMS (EI+): calcd. for C26H17BrN2 436.0570
13C NMR (100 MHz, [D8]THF): δ = 170.3, 143.2, 139.1, 137.7, [M]+; found 436.0573.
137.4, 137.3, 135.4, 132.3, 131.5, 130.1, 129.1, 128.9, 128.6, 128.5,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O43315
/KAP1
Date: 15-12-14 12:37:05
Pages: 12
M. Bovenkerk, B. Esser
(5Z,11Z)-2-Methyl-6,11-diphenyldibenzo[b,f][1,4]diazocine (2f): The (26 mg, 22.8 μmol, 2 mol-%) were added to the reaction mixture,
FULL PAPER
general procedure was followed by using 1,2-dibenzoylbenzene (7;
500 mg, 1.75 mmol), AcOH (25 mL), and 1,2-diamino-4-methyl-
benzene (portion 1: 214 mg, 1.75 mmol; portion 2: 214 mg,
1.75 mmol). Two consecutive column chromatography steps (silica
gel, CH2Cl2 and cyclohexane/EtOAc, 20:1) yielded 507 mg of 2f
which was stirred at 80 °C for 3 h. Water (5 mL) was added, and
the mixture was extracted with CH2Cl2 (3ϫ 40 mL). The organic
layer was washed with brine (50 mL), dried with Na2SO4, and the
solvent evaporated under reduced pressure resulting in a yellow
foam. The crude product was purified by flash column chromatog-
(78%). Rf = 0.15 (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.81– raphy (silica gel, cyclohexane/CH2Cl2, 1:1) to give 396 mg (90%)
7.78 (m, 4 H), 7.43–7.33 (m, 8 H), 7.17–7.12 (m, 2 H), 6.88–6.86
of 4 as a yellow solid. Rf = 0.74 (CH2Cl2). 1H NMR (300 MHz,
(m, 1 H), 6.81–6.79 (m, 2 H), 2.25 (s, 3 H) ppm. 13C NMR CDCl3): δ = 7.79–7.76 (m, 2 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.44–
(100 MHz, CDCl3): δ = 169.7, 169.6, 141.7, 139.3, 138.1, 138.0, 7.30 (m, 7 H), 7.05–7.01 (m, 3 H), 7.00–6.96 (m, 2 H), 6.71 (dd, J
136.7, 136.6, 133.8, 131.1, 131.0, 129.1, 128.9, 128.8, 128.4, 128.4,
= 17.6, 10.9 Hz, 1 H), 5.79 (dd, J = 17.6, 0.9 Hz, 1 H), 5.30 (dd, J
127.3, 127.3, 125.1, 121.8, 121.3, 21.0 ppm. MS (ESI+): m/z = 395
= 10.9, 0.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.7,
[M + Na]+, 373 [M + H]+. HRMS (ESI+): calcd. for C27H21N2 169.2, 152.1, 152.0, 140.3, 138.1, 137.5, 136.3, 131.2, 129.8, 129.8,
373.1699 [M + H]+; found 373.1698.
129.7, 129.5, 128.3, 127.7, 127.6, 127.1, 127.0, 126.1, 123.5, 123.5,
121.1, 121.0, 115.7 ppm. MS (EI+): m/z = 384 [M]+. HRMS (ESI+):
calcd. for C28H21N2 385.1699 [M + H]+; found 385.1693.
(5Z,11Z)-2-Methoxy-6,11-diphenyldibenzo[b,f][1,4]diazocine (2g):
The general procedure was followed by using 1,2-dibenzoylbenzene
(7; 500 mg, 1.75 mmol), AcOH (25 mL), and 1,2-diamino-4-
methoxybenzene (portion 1: 242 mg, 1.75 mmol; portion 2: 214 mg,
1.75 mmol). Two consecutive column chromatography steps (silica
gel, CH2Cl2 and cyclohexane/EtOAc, 20:1) yielded 92 mg (14%) of
2g. Rf = 0.08 (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.82–
7.77 (m, 4 H), 7.44–7.32 (m, 8 H), 7.18–7.11 (m, 2 H), 6.90 (d, J
= 8.7 Hz, 1 H), 6.59 (dd, J = 8.7, 2.8 Hz, 1 H), 6.53 (d, J = 2.7 Hz,
1 H), 3.74 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.8,
156.6, 142.9, 138.1, 137.8, 136.7, 136.5, 135.2, 131.2, 131.0, 129.1,
129.0, 128.9, 128.8, 128.4, 128.4, 127.4, 127.3, 122.6, 110.8, 106.0,
55.5 ppm. MS (ESI+): m/z = 411 [M + Na]+, 389 [M + H]+. HRMS
(ESI+): calcd. for C27H21N2O 389.1648 [M + H]+; found 389.1635.
1,2-Dibenzoylbenzene (7): Compound 7 was prepared according to
a modified literature method.[27] 1,3-Diphenylisobenzofuran (12;
5.74 g, 21.2 mmol) was dissolved in CH2Cl2 (150 mL). mCPBA
(70–75%, 5.50 g, 31.9 mmol) was added, and the reaction mixture
was stirred at room temp. for 5 min. The solution was poured into
satd. aq. NaHCO3 (100 mL) and the mixture extracted with
CH2Cl2 (3ϫ 100 mL), washed with water and brine, and dried
(Na2SO4). The solvent was removed under reduced pressure. Col-
umn chromatography (silica gel, cyclohexane/CH2Cl2, 1:2) afforded
1
7 (5.76 g, 95%) as a colorless solid. Rf = 0.61 (CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 7.71–7.69 (m, 4 H), 7.62 (s, 4 H), 7.54–7.49
(m, 2 H), 7.40–7.35 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 196.7, 140.2, 137.3, 133.1, 130.5, 130.0, 129.8, 128.5 ppm. MS
(EI+): m/z = 286 [M]+, 209 [M – Ph]+, 181 [M – Ph – CO]+, 105
[M – 2Ph – CO]+.
(5Z,11Z)-2-Chloro-6,11-diphenyldibenzo[b,f][1,4]diazocine (2h): The
general procedure was followed by using 1,2-dibenzoylbenzene (7;
500 mg, 1.75 mmol), AcOH (25 mL), and 1,2-diamino-4-chloro-
benzene (portion 1: 249 mg, 1.75 mmol; portion 2: 249 mg,
1.75 mmol). Column chromatography (silica gel, cyclohexane/
1,2-Dibenzoyl-4-methylbenzene (8): A mixture of lactones 23a and
23b (1.00 g, 4.46 mmol) was dissolved in dry THF (20 mL).
PhMgBr (3 m in Et2O, 1.78 mL, 5.35 mmol) was added dropwise at
0 °C during 15 min. The reaction mixture was warmed to room
temp. and stirred for 20 h. The solution was cooled to 0 °C, acidi-
fied with 5.8 m aq. HCl (20 mL) and stirred for 30 min. The solu-
tion was warmed to room temp. and extracted with CH2Cl2 (3ϫ
50 mL). The organic layer was washed with brine and 10% aq.
Na2CO3 and dried (Na2SO4). The solvent was removed under re-
duced pressure to afford 5-methyl-1,3-diphenylisobenzofuran (13;
1.30 g, quant.) as a yellow, fluorescent solid, which was used in the
next step without further purification. Isobenzofuran 13 (1.30 g,
4.57 mmol) was dissolved in CH2Cl2 (20 mL), mCPBA (70–75%,
1.69 g, 6.86 mmol) was added, and the reaction mixture was stirred
at room temp. for 5 min. The solution was poured into satd. aq.
NaHCO3 (100 mL) and the mixture extracted with CH2Cl2 (3ϫ
50 mL), washed with water and brine, and dried (Na2SO4). The
solvent was removed under reduced pressure. Column chromatog-
raphy (silica gel, cyclohexane/EtOAc, 5:1) afforded 8 (1.20 g, 87%)
1
EtOAc, 20:1) yielded 517 mg (75%) of 2h. Rf = 0.38 (CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.79–7.76 (m, 4 H), 7.45–7.39 (m, 4
H), 7.38–7.33 (m, 4 H), 7.19–7.12 (m, 2 H), 6.98 (d, J = 2.2 Hz, 1
H), 6.95 (dd, J = 8.3, 2.3 Hz, 1 H), 6.89 (d, J = 8.3 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 170.7, 170.5, 143.2, 140.7, 137.7,
137.6, 136.2, 136.2, 131.5, 131.4, 129.3, 129.2, 129.2, 129.1, 128.5,
128.5, 127.3, 127.3, 124.2, 122.6, 121.3 ppm. MS (ESI+): m/z = 807
[2M + Na]+, 415 [M + Na]+, 393 [M + H]+. HRMS (EI+): calcd.
for C26H17ClN2Na 415.0972 [M + Na]+; found 415.0986.
(5Z,11Z)-2-Bromo-6,11-diphenyldibenzo[b,f][1,4]diazocine (2i): The
general procedure was followed by using 1,2-dibenzoylbenzene (7;
500 mg, 1.75 mmol), AcOH (25 mL), and 1,2-diamino-4-bromo-
benzene (portion 1: 325 mg, 1.75 mmol; portion 2: 195 mg,
1.05 mmol; portion 3: 260 mg, 1.40 mmol). Column chromatog-
raphy (silica gel, cyclohexane/EtOAc, 20:1) yielded 568 mg (74%)
of 2i. Rf = 0.56 (cyclohexane/EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3): δ = 7.79–7.75 (m, 4 H), 7.46–7.32 (m, 8 H), 7.19–7.13 (m,
2 H), 7.12 (d, J = 2.0 Hz, 1 H), 7.09 (dd, J = 8.3, 2.2 Hz, 1 H),
6.84 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.8, 170.5, 143.5, 141.1, 137.6, 137.5, 136.2, 136.1, 131.5, 131.5,
129.2, 129.2, 129.2, 129.2, 128.5, 127.4, 127.3, 127.1, 124.2, 122.9,
117.0 ppm. MS (EI+): m/z = 436 [M]+, 359 [M – Ph]+. HRMS
(EI+): calcd. for C26H17BrN2 436.0570 [M]+; found 436.0573.
1
as a colorless solid. Rf = 0.69 (cyclohexane/EtOAc, 2:1). H NMR
(400 MHz, CDCl3): δ = 7.70–7.65 (m, 4 H), 7.55–7.53 (m, 1 H),
7.52–7.47 (m, 2 H), 7.41–7.34 (m, 6 H), 2.48 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 197.1, 196.4, 141.6, 140.8, 137.6,
137.5, 136.9, 133.0, 132.9, 130.8, 130.3, 130.2, 129.9, 129.8, 128.4,
128.4, 21.6 ppm. MS (EI+): m/z = 300 [M]+, 223 [M – Ph]+, 195
[M – Ph – CO]+. HRMS (EI+): calcd. for C21H16O2 300.1145
[M]+; found 300.1148.
(5Z,11Z)-6-Phenyl-12-(4-vinylphenyl)dibenzo[b,f][1,5]diazocine (4):
(5Z,11Z)-6-(4-Bromophenyl)-12-phenyldibenzo[b,f][1,5]diazocine
(30; 500 mg, 1.14 mmol) was dissolved in THF (30 mL). A solution
of NaOH (140 mg, 3.5 mmol in 2 mL of water) was poured into
the reaction flask, and the mixture was degassed with argon. Allyl-
boronic acid pinacol ester (249 mg, 1.72 mmol) and [Pd(PPh3)4]
1,2-Dibenzoyl-4-methoxybenzene (9): Compound 9 was prepared in
analogy to a published procedure.[30] Pb(OAc)4 (399 mg, 900 μmol)
was added to a suspension of (Z)-NЈ-[(2-hydroxy-4-methoxyphen-
yl)(phenyl)methylene]benzohydrazide (18; 295 mg, 852 μmol) in
8
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Job/Unit: O43315
/KAP1
Date: 15-12-14 12:37:05
Pages: 12
Isoindoles by One-Electron Reductions of Dibenzodiazocines
THF (4 mL) at 0 °C. The mixture was warmed to room temp. and
stirred for 5 h. The solvent was removed under reduced pressure
and the resulting solid suspended in EtOAc and filtered through a
pad of Celite. The filtrate was washed with satd. aq. NaHCO3 and
brine, the solution was dried (Na2SO4), and the solvent removed
under reduced pressure. Column chromatography (silica gel, cyclo-
hexane/EtOAc, 20:1) afforded 9 (218 mg, 81%) as a colorless solid.
Rf = = 0.41 (cyclohexane/EtOAc, 4:1). 1H NMR (400 MHz,
dissolved in a mixture of THF (30 mL) and NEt3 (3 mL) at 0 °C
and stirred at 0 °C for 15 min. Dichloride 31 (2.10 g, 8.84 mmol)
in THF (30 mL) was then added in one portion. The mixture was
stirred for 1 min and quenched with 1% aq. HCl (120 mL). The
solution was extracted with CH2Cl2 (3ϫ 5 mL) and washed with
10% aq. NaOH, 1 m aq. NaHCO3, and water. The mixture was
dried (Na2SO4), and the solvents removed under reduced pressure.
The resulting oil was recrystallized from CH2Cl2/Et2O to afford 16
CDCl3): δ = 7.72–7.69 (m, 2 H), 7.66–7.63 (m, 3 H), 7.52–7.47 (m, (1.72 g, 50%) as a colorless solid. Rf = 0.32 (cyclohexane/EtOAc,
2 H), 7.39–7.33 (m, 4 H), 7.08 (d, J = 2.5 Hz, 1 H), 7.05 (dd, J = 1:1). 1H NMR (400 MHz, CDCl3): δ = 8.31–8.30 (m, 1 H), 7.67
8.5, 2.6 Hz, 1 H), 3.90 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 196.8, 195.3, 162.0, 143.5, 137.9, 137.3, 133.1, 132.8, 132.6,
131.2, 129.9, 129.6, 128.5, 128.4, 114.9, 114.9, 55.9 ppm.
(dd, J = 1.8, 0.6 Hz, 1 H), 7.64 (dd, J = 8.2, 0.6 Hz, 1 H), 7.56 (dd,
J = 8.0, 1.8 Hz, 1 H), 7.55–7.51 (m, 3 H), 7.40 (dd, J = 8.1, 1.7 Hz,
1 H), 7.09 (dd, J = 4.8, 2.0 Hz, 1 H), 7.08 (dd, J = 4.7, 2.0 Hz, 1
H) ppm. MS (ESI+): m/z = 795 [2M + Na]+, 716 [2M – Py +
Na]+, 562 [2M – 3Py + Na]+, 409 [M + Na]+, 387 [M + H]+, 330
[M – Py + Na]+.
4-Chloro-1,2-dibenzoylbenzene (10): Compound 10 was prepared in
analogy to a published procedure.[28] PhMgBr (3 m, 2.38 mL,
7.14 mmol) was added dropwise to a solution of S,SЈ-dipyridin-
2-yl 4-chlorobenzene-1,2-dicarbothioate (16; 1.25 g, 3.25 mmol) in
THF (30 mL) at 0 °C. The solution was stirred for 15 min at 0 °C
and quenched with 2 m HCl (65 mL). The solution was extracted
(Z)-NЈ-[(2-Hydroxy-4-methoxyphenyl)(phenyl)methylene]benzo-
hydrazide (18): Compound 18 was prepared in analogy to a pub-
lished procedure.[30] 2-Hydroxy-4-methoxybenzophenone (17; 1.0 g,
with CH2Cl2 (3ϫ 50 mL), and washed with 1 m aq. NaOH and 4.38 mmol) and benzoylhydrazine (596 mg, 4.38 mmol) were dis-
satd. aq. NaHCO3. The organic layer was dried (Na2SO4), and the solved in 1-propanol (25 mL) and heated at 110 °C for 48 h. The
solvent removed under reduced pressure. Column chromatography
suspension was cooled to room temp., and the resulting colorless
precipitate was filtered, washed with cold 1-propanol, and dried
(silica gel, cyclohexane/CH2Cl2, 2:1) afforded 10 (360 mg, 34%) as
a bright-yellow solid. Rf = 0.53 (CH2Cl2). 1H NMR (400 MHz, under high vacuum at 80 °C to afford 18 as a white solid (312 mg,
1
CDCl3): δ = 7.70–7.65 (m, 4 H), 7.59–7.58 (m, 3 H), 7.56–7.51 (m, 21%). H NMR (400 MHz, CDCl3): δ = 12.61 (s, 1 H), 8.82 (s, 1
2 H), 7.41–7.36 (m, 4 H) ppm. 13C NMR (75 MHz [D6]DMSO): δ
= 195.5, 195.3, 142.1, 138.1, 137.2, 137.0, 136.8, 133.5, 133.4, 131.3,
130.3, 129.9, 129.9, 129.6, 128.6, 128.6 ppm. MS (EI+): m/z = 320
[M]+, 285 [M – Cl]+, 243 [M – Ph]+, 215 [M – PhCO]+.
H), 7.67–7.59 (m, 3 H), 7.55–7.47 (m, 3 H), 7.40–7.36 (m, 4 H),
6.69 (d, J = 8.8 Hz, 1 H), 6.61 (s, 1 H), 6.30 (dd, J = 8.8, 2.6 Hz,
1 H), 3.81 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.7,
161.7, 132.3, 131.8, 130.6, 130.3, 130.1, 128.9, 128.1, 127.1, 112.5,
106.6, 101.9, 55.5 ppm.
4-Bromo-1,2-dibenzoylbenzene (11): A mixture of lactones 24a and
24b (399 mg, 1.38 mmol) was dissolved in dry THF (8 mL) and
PhMgBr (3 m in Et2O, 553 μL, 1.66 mmol) was added dropwise at
0 °C during 15 min. The reaction mixture was then warmed to
room temp. and stirred for 20 h. The solution was cooled to 0 °C,
acidified with 5.8 m aq. HCl (6 mL), and stirred for 30 min. The
solution was again warmed to room temp., and extracted with
2-Benzoyl-5-methylbenzoic Acid (21a) and 2-Benzoyl-4-methyl-
benzoic Acid (21b): 4-Methylphthalic anhydride (19; 1.29 g,
7.96 mmol) was added to benzene (10 mL). Anhydrous AlCl3
(2.12 g, 15.9 mmol) was added, and the reaction mixture was
stirred at 90 °C for 3 h. After cooling to room temp., ice was added
to the reaction mixture, which was then extracted with CH2Cl2 (3ϫ
CH2Cl2 (3ϫ 20 mL). The organic layer was washed with brine and 75 mL). The organic layer was extracted with 10% aq. Na2CO3,
10% aq. Na2CO3 and dried (Na2SO4). The solvent was removed
under reduced pressure to afford crude 5-bromo-1,3-diphenyliso-
benzofuran (14; 506 mg, quant.) as a yellow, fluorescent solid,
which was used in the next step without further purification. Iso-
benzofuran 14 (468 mg, 1.34 mmol) was dissolved in CH2Cl2
and the aqueous layer was acidified with HCl (conc.) and stored at
4 °C for 15 h. The resulting precipitate was filtered and dried to
afford a mixture of 21a and 21b in a ratio of 38:62 (1.82 g, 95%)
as a light-beige solid. H NMR (400 MHz, [D6]DMSO): δ = 13.07
(s, 1 H), 7.89 (d, J = 7.9 Hz, 0.62 H), 7.80 (d, J = 1.8 Hz, 0.38 H),
1
(6 mL), mCPBA (70–75%, 347 mg, 2.01 mmol) was added, and the 7.65–7.21 (m, 6 H), 7.29 (d, J = 7.7 Hz, 0.38 H), 7.21 (s, 0.62 H),
reaction mixture was stirred at room temp. for 5 min. The solution
was poured into satd. aq. NaHCO3 (25 mL), the mixture was ex-
tracted with CH2Cl2 (3ϫ 10 mL), washed with water and brine,
and dried (Na2SO4). The solvent was removed under reduced pres-
sure. Column chromatography (silica gel, cyclohexane/EtOAc, 50:1)
afforded 11 (376 mg, 77%) as a colorless solid. Rf = 0.20 (cyclohex-
2.43 (s, 1.14 H), 2.40 (s, 1.86 H) ppm. MS (EI+): m/z = 240 [M]+,
196 [M – CO2]+, 163 [M – Ph]+, 105 [PhCO]+.
2-Benzoyl-5-bromobenzoic Acid (22a) and 2-Benzoyl-4-bromo-
benzoic Acid (22b): 4-Bromophthalic anhydride (20; 1.98 g,
8.72 mmol) was added to benzene (15 mL). Anhydrous AlCl3
(2.34 mg, 17.6 mmol) was added, and the reaction mixture was
stirred at 90 °C for 3 h. After cooling to room temp., ice was added
to the reaction mixture, which was then acidified with HCl (conc.).
The solution was extracted with CH2Cl2 (3ϫ 30 mL), the organic
layer was extracted with 10% aq. Na2CO3, and the aqueous layer
was acidified with HCl (conc.) and stored at 4 °C for 15 h. The
resulting precipitate was filtered and dried to afford 22a and 22b
in a ratio of 35:65 (2.56 g, 96%, 2 isomers) as a light-beige solid.
1H NMR (400 MHz, [D6]DMSO): δ = 13.43 (s, 1 H), 8.10 (d, J =
2.0 Hz, 0.35 H), 7.94 (dd, J = 8.2, 2.1 Hz, 0.35 H), 7.92 (d, J =
8.3 Hz, 0.65 H), 7.87 (dd, J = 8.4, 2.0 Hz, 0.65 H), 7.69 (d, J =
1.9 Hz, 0.65 H), 7.65–7.61 (m, 3 H), 7.52–7.48 (m, 2 H), 7.41 (d, J
= 8.1 Hz, 0.35 H) ppm. MS (EI+): m/z = 304 [M]+, 227 [M – Ph]+,
181 [Ph – CO2 – Br]+, 105 [PhCO]+.
1
ane/EtOAc, 20:1). H NMR (400 MHz, CDCl3): δ = 7.76–7.73 (m,
2 H), 7.69–7.65 (m, 4 H), 7.55–7.50 (m, 3 H), 7.41–7.36 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 195.6, 195.2, 142.1,
138.5, 137.0, 136.7, 133.5, 133.4, 133.3, 132.5, 131.4, 129.9, 129.9,
128.6, 128.6, 125.3 ppm.
S,SЈ-Dipyridin-2-yl 4-Chlorobenzene-1,2-dicarbothioate (16): Com-
pound 16 was prepared in analogy to a published procedure.[29]
A
mixture of 4-chlorophthalic acid (15; 3.50 g, 15.8 mmol) and PCl5
(9.87 g, 47.4 mmol) was stirred at 170 °C for 2 h. The suspension
was filtered. Distillation afforded 4-chlorophthaloyl dichloride (31;
2.65 g, 71%) as a colorless liquid. The product could not be ob-
tained in pure form and was therefore used in the next step without
further purification. 2-Mercaptopyridine (1.92 g, 17.24 mmol) was
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O43315
/KAP1
Date: 15-12-14 12:37:05
Pages: 12
M. Bovenkerk, B. Esser
FULL PAPER
5-Methyl-3-phenylisobenzofuran-1(3H)-one (23a) and 6-Methyl-3- 138.0, 131.3, 129.8, 129.6, 128.4, 127.7, 127.1, 123.6, 121.1 ppm.
phenylisobenzofuran-1(3H)-one (23b): Compounds 23a and 23b
were prepared in analogy to a published procedure.[31] The mixture
of 21a and 21b from the previous step (1.5 g, 6.24 mmol) was added
to a solution of KOH (323 mg, 8.08 mmol) in water (6.20 mL).
NaBH4 (200 mg, 5.31 mmol) was then added within 15 min and
the reaction mixture stirred at room temp. for 24 h. The solution
was acidified to pH 0 with HCl (conc.) and extracted with CH2Cl2
(8 ϫ 50 mL). The organic extracts were washed with 10 % aq.
Na2CO3 and brine. The solvent was removed under reduced pres-
sure to afford a mixture of 23a and 23b (1.00 g, 71%) in a ratio of
MS (EI+): m/z = 358 [M]+. HRMS (EI+): calcd. for C26H17N2
357.1386 [M – H]+; found 357.1390.
Polymer P1: (5Z,11Z)-6-Phenyl-12-(4-vinylphenyl)dibenzo[b,f]-
[1,5]diazocine (4; 130 mg, 0.34 mmol) was dissolved in toluene
(0.17 mL), and the solution was degassed with argon. AIBN
(1.5 mg, 0.01 mmol) was added, and the flask was immersed in an
oil bath preheated to 60 °C. After 75 min the reaction was
quenched by the addition of MeOH (1 mL). The yellow precipitate
was dissolved in CHCl3 (50 mL), precipitated in MeOH, and iso-
lated by centrifuge. These steps were repeated four times. 40 mg
(30%) of P1 as a yellow solid were obtained. 1H NMR (400 MHz,
CDCl3): δ = 7.60 (vbr. s), 7.36 (vbr. s), 7.10 (vbr. s), 6.89 (vbr. s),
1.58 ppm (vbr. s). Anal. GPC (eluent: THF, polystyrene standard):
Mn = 1.23ϫ105 a.u., Mw/Mn = 2.05; DSC (10 °C/min, N2): Tg =
260 °C; TGA (10 °C/min, N2): Td10% (temperature for 10% weight
loss) = 397 °C.
1
38:62 as a colorless solid. H NMR (400 MHz, CDCl3): δ = 7.84
(d, J = 7.8 Hz, 0.62 H), 7.76 (ddd, J = 1.6, 0.8 Hz, 0.38 H), 7.46
(ddd, J = 7.9, 1.5, 0.8 Hz, 0.38 H), 7.41–7.34 (m, 3.62 H), 7.30–
7.26 (m, 2 H), 7.22 (d, J = 7.8 Hz, 0.38 H), 7.12 (ddd, J = 1.5,
0.8 Hz, 0.62 H), 6.37 (s, 0.38 H), 6.35 (s, 0.62 H), 2.48 (s, 1.14 H),
2.44 (s, 1.86 H) ppm. MS (EI+): m/z = 224 [M]+.
5-Bromo-3-phenylisobenzofuran-1(3H)-one (24a) and 6-Bromo-3-
phenylisobenzofuran-1(3H)-one (24b): Compounds 24a and 24b
were prepared in analogy to a published procedure.[31] The mixture
of 22a and 22b from the previous step (2.50 g, 8.20 mmol) was
added to a solution of KOH (600 mg, 10.7 mmol) in water
(8.20 mL). NaBH4 (264 mg, 6.97 mmol) was added within 15 min
and the reaction mixture was stirred at room temp. for 22 h. The
solution was acidified to pH 0 with HCl (conc.) and extracted with
CH2Cl2 (3ϫ 50 mL). The organic extracts were washed with 10%
aq. Na2CO3 and brine. The organic layer was dried with Na2SO4
and the solvent removed under reduced pressure to afford a mix-
ture of 24a and 24b (1.42 g, 58%) in a ratio of 35:65 as a colorless
Acknowledgments
M. B. thanks R. Hahn for preparative assistance. The authors also
thank G. Schnakenburg and C. Rödde (Institute for Inorganic
Chemistry, University of Bonn, Germany) for X-ray structural elu-
cidation and S. Höger (Kekulé Institute for Organic Chemistry and
Biochemistry, University of Bonn, Germany) for providing labora-
tory facilities. Generous support by the German Research Founda-
tion (Emmy Noether fellowship to B. E., ES 361/2-1) and by the
Chemical Industry Trust (Liebig Fellowship to B. E., Li 189/11) is
gratefully acknowledged.
1
solid. Rf = 0.84 (CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.09
(d, J = 1.7 Hz, 0.35 H), 7.82 (d, J = 8.1 Hz, 0.65 H), 7.76 (dd, J =
8.1, 1.8 Hz, 0.35 H), 7.69 (ddd, J = 8.1, 1.6, 0.7 Hz, 0.65 H), 7.49
(dt, J = 1.5, 0.7 Hz, 0.65 H), 7.43–7.37 (m, 3 H), 7.29–7.25 (m, 2
H), 7.22 (dt, J = 8.2, 0.8 Hz, 0.35 H), 6.37 (s, 1 H) ppm. MS (EI+):
m/z = 288 [M]+, 211 [M – Ph]+, 105 [PhCO]. HRMS (EI+): calcd.
for C14H9BrO2 287.9780 [M]+; found 287.9787.
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(5Z,11Z)-6-(4-Bromophenyl)-12-phenyldibenzo[b,f][1,5]diazocine
(30) and (5Z,11Z)-6,12-Diphenyl-dibenzo[b,f][1,5]diazocine (5):
(5Z,11Z)-6,12-Bis(4-bromophenyl)dibenzo[b,f][1,5]diazocine (3;[10]
1.95 g, 3.78 mmol) was dissolved in dry THF (45 mL), and nBuLi
(2.6 mL, 4.16 mmol) was added during 10 min at –78 °C. After 1 h,
MeOH (30 mL) and water (30 mL) were added to the reaction mix-
ture, and the solution was extracted with CH2Cl2 (3ϫ 50 mL). The
organic layer was washed with brine (50 mL), dried with Na2SO4,
and the solvent evaporated under reduced pressure resulting in a
yellow foam. The crude product was purified by flash column
chromatography (silica gel, cyclohexane/CH2Cl2, 5:2) to give
900 mg (54%) of 30 as a yellow solid as well as 200 mg (15%) of 5
as a yellow solid.
Analytical Data for (5Z,11Z)-6-(4-Bromophenyl)-12-phenyldi-
benzo[b,f]-[1,5]diazocine (30): Rf = 0.76 (CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.77–7.75 (m, 2 H), 7.64 (d, J = 8.6 Hz, 2
H), 7.47 (d, J = 8.6 Hz, 2 H), 7.45–7.41 (m, 1 H), 7.37–7.30 (m, 4
H), 7.05–6.93 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.7, 168.7, 152.1, 151.7, 138.0, 137.0, 131.5, 131.2, 131.0, 130.0,
129.8, 129.5, 128.4, 127.7, 127.4, 126.9, 126.4, 126.0, 123.7, 123.7,
123.6, 121.1, 120.9 ppm. MS (EI+): m/z = 436 [M]+. HRMS (EI+):
calcd. for C26H17BrN2 436.0570 [M]+; found 436.0575.
Analytical Data for (5Z,11Z)-6,12-Diphenyldibenzo[b,f][1,5]diazoc-
ine (5): Rf = 0.54 (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.81–
7.78 (m, 4 H), 7.45–7.41 (m, 2 H), 7.38–7.31 (m, 6 H), 7.06–6.97
[10] Synthesized according to: X. Wang, J. Li, N. Zhao, X. Wan,
Org. Lett. 2011, 13, 709–711.
[11] Measured against a polystyrene standard.
(m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9, 151.8, [12] R. W. Koch, R. E. Dessy, J. Org. Chem. 1982, 47, 4452–4459.
10
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Job/Unit: O43315
/KAP1
Date: 15-12-14 12:37:05
Pages: 12
Isoindoles by One-Electron Reductions of Dibenzodiazocines
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[26] CCDC-1016537 contains the supplementary crystallographic
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[27] M. Nandakumar, R. Sivasakthikumaran, A. K. Mohanakrish-
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Received: October 7, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O43315
/KAP1
Date: 15-12-14 12:37:05
Pages: 12
M. Bovenkerk, B. Esser
FULL PAPER
Isoindole Synthesis
M. Bovenkerk, B. Esser* ................ 1–12
Synthesis of Isoindoles by One-Electron
Reductions of Dibenzo[1,4]diazocines
Keywords: Synthetic methods / Electro-
chemistry / Electron transfer / Reduction /
Heterocycles
A protocol for the synthesis of isoindoles
through one-electron reductions of di-
benzo[1,4]diazocines is reported. Six novel
isoindole derivatives have been synthesized,
and the reaction mechanism has been stud-
ied by 1H NMR spectroscopy and quan-
tum chemical calculations.
12
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