Synthesis and structure of fluorescent chelate boron complexes of 4-anilinomethylidene-1-benzazepine-2,5-dione ligands

Article abstract of DOI:10.1055/s-0030-1260165

As analogues to the paullone kinase inhibitor family, boron chelate complexes of 4-anilinomethylidene-1-benzazepine-2,5-diones were prepared by reacting the ligands with boron trifluoride etherate or triphenylborane. The structures of the novel heterocycl

Full text of DOI:10.1055/s-0030-1260165

2848
PAPER
Synthesis and Structure of Fluorescent Chelate Boron Complexes of
4-Anilinomethylidene-1-benzazepine-2,5-dione Ligands
S
ynthesis andStru
a
c
ture of Flu
d
orescent Bor
i
on
C
he
n
lates e Tolle,a Ute Dunkel,a Luciano Oehninger,a Ingo Ott,a Lutz Preu,a Tobias Haase,b Soenke Behrends,b
Peter G. Jones,c Frank Totzke,d Christoph Schächtele,d Michael H. G. Kubbutat,d Conrad Kunick*a
a
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstr. 55,
38106 Braunschweig, Germany
Fax +49(531)3912799; E-mail: c.kunick@tu-braunschweig.de
Institut für Pharmakologie, Toxikologie und Klinische Pharmazie, Technische Universität Braunschweig, Mendelssohnstr. 1,
b
38106 Braunschweig, Germany
c
Institut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig,
Germany
ProQinase GmbH, Breisacher Str. 117, 79106 Freiburg, Germany
d
Received 7 April 2011; revised 1 June 2011
cent tags has been used to locate kinase inhibitors inside a
cell by fluorescence microscopy.8 However, depending on
the nature and the position of attachment of the fluores-
cent tag, the modification can change both the cellular
Abstract: As analogues to the paullone kinase inhibitor family, bo-
ron chelate complexes of 4-anilinomethylidene-1-benzazepine-2,5-
diones were prepared by reacting the ligands with boron trifluoride
etherate or triphenylborane. The structures of the novel heterocyclic
ring systems were established by X-ray structure analysis of two drug distribution and target interaction.9 In this context,
representative derivatives. The stability of the compounds in dime-
we were interested in developing novel autofluorescent
kinase inhibitors. Recent papers by Xia et al.10 and
thylsulfoxide solution is dependent on the electronic properties of
the aryl ring substituents. The fluorescent properties of the mole-
Gardinier et al.11 inspired us to design compounds 3 as po-
cules are suitable for imaging the intracellular compound distribu-
tential kinase inhibitors; such compounds represent d-an-
tion by confocal laser microscopy.
nulated 1-benzazepin-2-ones involving the fluorescent
chelated difluoroboron moiety (Figure 1).
Key words: boron, chelates, lactams, ligands, spectroscopy
O
O
H
N
H
Inhibitors of cancer-related protein kinases have been es-
tablished as antitumor drugs during the past decade.1
Since the successful introduction of Imatinib as a therapy
for chronic myeloic leukaemia (CML),2 several further
protein kinase inhibitors were approved as anticancer
drugs. Because of the encouraging results seen with these
compounds, the search for new chemical entities that in-
hibit cancer-related protein kinases is currently a main fo-
cus in drug developme .1 Within the many ongoing studies
in this field, certain heterocyclic ring systems have
emerged as privileged scaffolds; among them, anilino-
quinazolines, aminopyrimidines, and indolinones.3 In the
course of projects directed at finding new antitumor
kinase inhibitor chemotypes, we discovered the 1-benz-
azepin-2-one element as a useful platform for the develop-
ment of kinase inhibitors. For instance, indole annulation
at the d-site of the parent scaffold led to the paullone fam-
ily of cyclin-dependent kinase (CDK) inhibitors 1,4–6 and
d-fusion with a pyrimidine ring resulted in the dual inhib-
itors 2 of the kinases VEGF-R2 and PLK1.7 Both structure
classes 1 and 2 exhibited potent antiproliferative activities
against human cancer cells in vitro. To assess the mecha-
nism underlying cell growth inhibition, it was not only of
interest which protein kinases are inhibited in vitro, but
also whether the compounds enter the cell and how they
are distributed inside the cell. Conjugation with fluores-
N
R1
R1
R2
N
HN
N
O
H
N
HN
1
R1
R2
2
O
N
B
R2
F
F
3
Figure 1 Structures of d-annulated 1-benzazepin-2-ones: paullones
1, dual VEGFR-2/PLK1 inhibitors 2, and difluoroboron chelate com-
plexes 3
For the synthesis of 3, the enaminones 5a and 5n were
prepared as starting materials by heating the correspond-
ing cyclic ketones 4a and 4n with dimethylformamide
dimethyl acetal following a procedure published by Chen
and Gilman.12 According to a method reported by Dutta,13
stirring the enaminones 5a and 5n in acetic acid with a
suitably substituted aniline at room temperature resulted
in the formation of the N-aryl enaminones 6a–n in modest
to acceptable yields (Scheme 1).
All products 6 in which the phenyl ring bears a substituent
in the 2-position (6f, 6l, 6m, and 6n) were obtained as
single diastereoisomers. It was assumed on the basis
of literature reports that these molecules exist in the
SYNTHESIS 2011, No. 17, pp 2848–2858
Advanced online publication: 08.08.2011
DOI: 10.1055/s-0030-1260165; Art ID: T37511SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

PAPER
Synthesis and Structure of Fluorescent Boron Chelates
2849
R2
H2N
O
O
O
H
H
H
N
N
N
DMF-DMA
115–120 °C, 1 h
67–72%
AcOH, r.t.
32–86%
R1
R1
R1
CH3
CH3
N
O
O
O
HN
R2
4a (R1 = H)
4n (R1 = I)
5a (R1 = H)
5n (R1 = I)
6a–n
Scheme 1 Synthesis of N-arylenamines 6
Z-configuration, which is stabilized by an intramolecular (23–62%) after purification by crystallization (Scheme 2,
hydrogen bond between the enaminone carbonyl oxygen Table 1).
and the enamine nitrogen.13,14 This assumption was con-
firmed for compound 6l by means of a nuclear Overhauser
experiment (NOE), in which irradiation at the azepine
Table 1 Substitution Pattern and Yields of 3, 6, and 7 According to
Schemes 1 and 2
CH2-group produced a signal enhancement of the enam-
ine C,H-signal and vice versa (Figure 2). All derivatives 6
unsubstituted at the 2-position of the phenyl ring were iso-
lated as E/Z-mixtures that favoured the Z-diastereoisomer.
The configurations of the diastereoisomers in the mixtures
Product R1
R2
Yield 6
Yield 3
Yield 7
(%)a
(%)b
(%)c
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
I
H
72
32
73
81
86
77
80
65
76
72
82
75
79
66
45
45
23
46
62
42
30
52
53
54
47
54
47
44
32
4-CF3
4-NO2
4-OEt
4-Et
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
14
1
were assigned on the basis of the H NMR spectra, in
which the enaminone NH-proton of the Z-diastereoisomer
showed a prominent downfield shift compared with the
corresponding signal of the E-diastereoisomer.
O
H
2-Cl
N
3.19 ppm
CH2
g
h
i
4-I
8.15 ppm
CH3
H
4-Me
4-OMe
3,5-Cl
3-OMe
2-Me
2-OMe
2-OMe
O
N
H
j
6l
k
l
Figure 2 Determination of Z-configuration in 6l by NOE
n.a.
n.a.
n.a.
.
m
n
Heating the enaminones 6 to reflux with BF3 OEt2 in a tol-
uene/acetic acid mixture, as suggested by Xia et al.,10 led
to the formation of mixtures of products 3 and starting ma-
terials 6, which were difficult to separate. Better results
were obtained by heating the substrates in toluene under a
nitrogen atmosphere in the presence of diisopropylethyl-
amine (DIPEA) as a scavenger for hydrogen fluoride, ap-
plying a procedure reported by Zhou.15 The method
yielded the title compounds in modest to acceptable yields
a Yield after purification by crystallization from EtOH.
b Yield after purification by crystallization from toluene.
c Yield after purification by crystallization from acetone.
The diphenylboron derivatives 7a and 7k were synthe-
sized as analogues of the difluoroboron complexes 3a and
3k, respectively. In a first attempt, reaction of 3a with ex-
O
H
O
H
N
N
R1
R1
Ph3B
BF3•OEt2
6
O
O
DIPEA, toluene, reflux
23–62%
toluene, reflux
14–32%
N
B
R2
N
B
F
R2
F
3a–n
7a, k
Scheme 2 Synthesis of boron chelate complexes 3 and 7
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

2850
N. Tolle et al.
PAPER
cess phenyl magnesium bromide16 failed to yield 7a but
instead led to a mixture of decomposition products. Com-
pounds 7 were, however, obtained successfully following
a method published by Liu et al.17 by heating the enami-
nones 6a and 6k to refux with triphenylborane in toluene
(Scheme 2, Table 1).
As illustrated in Figure 3, both boron complex families 3
and 7 can be considered as hybrids of resonance forms I
or II with a formal positive charge either at the oxygen or
nitrogen atom, respectively. Gardinier et al.11 have postu-
lated that in difluoroboron chelates of open-chain enami-
nones the resonance form with a more dative B–N and a
more covalent B–O bond (similar to form II) contributes
more significantly to the electron distribution.
Figure 4 X-ray structure of compound 3a; ellipsoids correspond to
50% probability levels
O
O
H
H
N
N
R1
R1
O
O
N
N
B
B
R2
R2
R
R
R
R
I
II
Figure 3 Resonance forms of boron chelate complexes 3 and 7
The structures of the representative compounds 3a and 7a
were studied by X-ray crystallography (Figure 4 and
Figure 5, see the Supporting Information for details). The
results underscored the extent of electron delocalisation in
the boron-containing ring systems. In both compound
classes, the C–C bond lengths within the chelate rings cor-
respond closely to aromatic bonds [3a: 1.3835(15) and
1.4078(15) Å; 7a: 1.377(2) and 1.411(2) Å]. Similarly,
the cyclic C–O bond lengths [3a: 1.3181(13) Å; 7a:
1.3176(17) Å] and the C–N bond lengths [3a: 1.3196(14)
Å; 7a: 1.317(2) Å] lie between reported values for single
and double bonds. Consistent with sp3 hybridization of the
boron atom, the O–B–N bond angles in both structures
[3a: 109.05(9)°; 7a: 106.24(11)°] deviated strongly from
the standard 120° angle expected in a benzene-like planar
six-membered ring. A search of the Cambridge Crystallo-
graphic Database revealed 42 examples of analogous six-
membered rings, with mean C–N and C–O distances of
1.316 and 1.320 Å, respectively, and a mean angle at bo-
ron (two outliers omitted) of 109.6°. As a further conse-
quence of sp3 hybridization, in both 3a and 7a the boron
atom is puckered out of the chelate ring plane, by 0.260(2)
and 0.446(2) Å, respectively. In both compounds, the
molecules are linked to form inversion-symmetric dimers
by hydrogen bonds of the form N-H···O=C.
Figure 5 X-ray structure of compound 7a (solvent omitted for cla-
rity); ellipsoids correspond to 50% probability levels
and electron-withdrawing substituents in the 4-position
cause a prominent bathochromic shift (cf. compounds 3c,
3d, and 3i), substituents in the 3-position are less relevant
(cf. compounds 3j and 3k). The blue-shifts observed with
compounds that bear a 2-substituent at the phenyl ring (cf.
compounds 3f and 3l) probably result from a rotation of
the phenyl ring out of the boron chelate ring plane, thus at-
tenuating resonance between the two systems. The diphe-
nyl boron parent structure 7a showed a UV/Vis spectrum
similar to that of 3a, albeit with a strong bathochromic
shift of the long-wave maximum. Upon excitation with
light of the long-wavelength absorption maximum, the
compounds produced emission spectra with broad maxi-
ma located between 476 (3l) and 570 nm (7k). Displaying
Stokes shifts above 100 nm, both series 3 and 7 appear to
be well suited for biological imaging purposes using fluo-
rescence microscopy.
The crystalline boron chelate complexes are stable as an-
hydrous powders at room temperature even in the pres-
ence of air. However, when used in biological studies,
biochemical reagents are typically dissolved in water or
water/organic solvent mixtures. Often, test compounds
are stored as frozen stock solutions in dimethylsulfoxide
over longer periods of time. Thus, the stability of the com-
plexes 3 and 7 in dimethylsulfoxide solution at room tem-
To determine the spectroscopic properties of the novel bo-
ron chelate complexes 3 and 7, absorption spectra were re-
corded in the ranges of 200–550 nm using acetonitrile as
solvent (Table 2). The unsubstituted parent structure 3a
showed two maxima at 227 and 374 nm. The substitution
patterns at the N-phenyl rings considerably influence the
long-wave maximum. Whereas both electron-donating
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

PAPER
Synthesis and Structure of Fluorescent Boron Chelates
2851
Table 2 Spectroscopic Properties of Boron Chelate Complexes 3 and 7
3 and 7
3a
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
I
R2
lmaxabs (nm)
227, 374
227, 377
226, 391
227, 385
227, 377
221, 364
227, 380
227, 377
227, 384
226, 379
226, 376
225, 359
224, 369
235, 248, 370
231, 403
404
e (M–1·cm–1)a
2.3·104
2.3·104
2.5·104
2.3·104
2.3·104
2.2·104
2.5·104
2.4·104
2.3·104
2.5·104
2.2·104
2.4·104
2.0·104
1.9·104
1.4·104
1.4·104
lmaxem (nm) b
506
Stokes shift (nm)
H
132
117
108
163
141
115
137
142
163
121
148
117
149
150
165
166
3b
3c
4-CF3
4-NO2
4-OEt
4-Et
494
499
3d
3e
548
518
3f
2-Cl
479
3g
4-I
517
3h
3i
4-Me
4-OMe
3,5-Cl
3-OMe
2-Me
2-OMe
2-OMe
H
519
547
3j
500
3k
3l
524
476
3m
3n
7a
518
521
H
H
568
7k
3-OMe
570
a Extinction coefficient at wavelength of the italicised maximum.
b Excitation by wavelength of the italicised maximum.
perature was determined by HPLC (Table 3). For both The intracellular distribution of compound 3d in the HT-
diphenylboron complexes 7a and 7k, incipient decompo- 29 cells was visualized by confocal laser scanning micros-
sition was detected after 7 days and incubation for 28 days copy. After incubation with 20 mM of the test compound
left only a small fraction of intact material. The stability for 10 hours, an image was generated by excitation at 405
of the difluoroboron complexes 3 was found to depend on nm and recording the fluorescence emission between 500
the electronic properties of the phenyl substituents. and 550 nm (Figure 6). The image clearly illustrates that
Whereas compounds with electron-withdrawing substitu- the compound penetrated the cell membrane and concen-
ents at either ring position turned out to be rather unstable trated in the cytosol but avoided the nuclei, which re-
(cf. 3b, 3c, 3f, and 3j), compounds with either no substit- mained dark.
uents or electron-releasing phenyl substituents, remained
unchanged even after one month (cf. 3a, 3d, 3h, 3k, and
3m). Compounds that showed either more than 5% de-
composition over the first 7 days or more than 10% de-
composition over 28 days were rated as unsuitable for
biological screening procedures.
Because compound 3d showed good stability in DMSO
solution and the highest Stokes shift of all difluoro deriv-
atives 3, it was selected for preliminary biological evalu-
ation studies. In an array of 16 cancer-related protein
kinases, a 10 mM solution of 3d inhibited the kinases IGF-
1R, SRC, and VEGF-R2 by more than 25%. The other ki-
nases of the screen (AKT1, ALK, ARK5, Aurora B, AXL,
FAK, MEK1, MET, NEK2, NEK6, PIM1, and PRK1)
were either inhibited less or not at all. Furthermore, 3d ex-
hibited a modest antiproliferative activity in vitro for the
human breast cancer cell line MCF-7 and the colon cancer
cell line HT-29, with IC50-values (concentration for 50%
growth inhibition) of 25.5 ( 0.1) and 46.4 ( 7.6) mM, re-
spectively.
Figure 6 Image of intracellular distribution of 3d in HT-29 cells by
confocal laser scanning microscopy. The fluorescence color shown
was chosen arbitrarily. The white bar represents a length of 20 mM.
The test compound is exclusively localized in the cytosol, avoiding
cell nuclei.
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

2852
N. Tolle et al.
PAPER
solved in DMSO-d6 containing TMS as internal standard; signals
are given in ppm (d scale). Mass spectra were obtained with a Finni-
gan-MAT 90 instrument. UV/Vis spectra were recorded with a
Specord 40 instrument with software from WinASPEKT (Analytik
Jena AG, Jena, Germany), using 10 mm quartz cuvettes 100 QS
(Hellma GmbH & Co. KG, Müllheim). Fluorescence spectra were
recorded with a Cary Eclipse spectrophotometer, with Cary Eclipse
Scan Application software (Varian GmbH, Darmstadt, Germany),
using 10 mm fluorescence cuvettes 101 QS (Hellma GmbH &
Co. KG, Müllheim, Germany). HPLC were performed with a
Merck/Hitachi LaChrome Elite system and LiChroCART 125–4
[LiChrospher 100 RP-18 (5 mM) column (column length 125 mm);
flow rate 1.000 mL/min; tm (DMSO) = 1.01–1.03 min; detection
wavelength 254 nm; area percent method].
Table 3 Stability of Boron Chelate Complexes 3 and 7 in DMSO
Solutiona
3 or 7
3a
3b
3c
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
I
R2
% at day 0b % at day 7c % at day 28c
H
99.6
95.2
90.6
97.2
98.5
95.7
94.5
99.5
97.9
96.0
97.2
99.1
99.0
96.4
94.7
94.0
99.5
7.6
98.5
0
4-CF3
4-NO2
4-OEt
4-Et
11.0
98.9
96.0
29.8
91.7
99.6
97.8
35.4
97.6
91.0
96.6
85.5
86.9
75.8
0
3d
3e
97.4
97.4
13.0
80.8
99.4
96.8
0
3f
2-Cl
X-ray Structure Determinations: Numerical details are available in
the Supporting Information. Data were recorded with an Oxford
Diffraction Xcalibur Nova diffractometer using mirror-focused Cu
Ka radiation. The structures were refined on F2 using the program
SHELXL-97 (G. M. Sheldrick, University of Göttingen, Germany).
Hydrogen atoms of the NH groups were refined freely, others with
a riding model. Complete data (excluding structure factors) have
been deposited at the Cambridge Crystallographic Data Centre as
CCDC-818572 (3a) and CCDC-818573 (7a). These data can be ob-
tained free of charge from www.ccdc.cam.ac.uk/data_request/cif.
Starting materials 4a,18 4n,19,20 and 5a12 were prepared according to
published procedures. Other starting materials and reagents were
used without further purification and purchased from Acros Organ-
ics (Geel, Belgien) or Sigma Aldrich (St. Louis, MO, USA), with
the exception of triphenylborane, which was purchased from Alfa
Aesar GmbH & Co KG (Ward Hill, MA, USA). Toluene was dried
with CaCl2 and purified by distillation.
3g
3h
3i
4-I
4-Me
4-OMe
3,5-Cl
3-OMe
2-Me
2-OMe
2-OMe
H
3j
3k
3l
97.6
78.2
98.7
82.9
21.2
12.6
3m
3n
7a
7k
H
H
3-OMe
A proprietary protein kinase assay (33PanQinase Activity Assay)
was used to measure the kinase activity of the 16 protein kinases.
All assays were performed with a BeckmanCoulter/Sagian robotic
system and 96-well FlashPlates from Perkin Elmer/NEN (Boston,
MA, USA) in a 50 mL reaction volume. The reaction cocktails con-
taining enzyme, substrate, and inhibitor were incubated at 30 °C for
60 min. The reaction was stopped with 50 mL of 2% (v/v) H3PO4,
plates were aspirated and washed two times with 200 mL of 0.9%
(w/v) NaCl. Incorporation of 33Pi was determined with a microplate
scintillation counter (Microbeta Trilux, Wallac).
a Percentage of intact material determined by HPLC (AUC 100%
method).
b Determined with freshly prepared compound solution.
c Storage days at room temperature after preparation of DMSO solu-
tion.
In conclusion, 1-benzazepin-2-ones annulated at the d-site
with a boron chelate structural element were synthesized
by reacting precursor enaminones 6 with BF3·OEt2 or
triphenylborane. Results from X-ray crystallography cor-
roborated a resonance stabilization of the boron chelate
moiety in 3 and 7. The compounds showed fluorescence
with high Stokes shifts. Structures 3, with electron-with-
drawing substituents at the phenyl ring, were unstable in
dimethylsulfoxide when stored for several days at room
temperature. Although the stable compound 3d tended to
inhibit distinct protein kinases, its antiproliferative activi-
ty on cancer cells was rather modest. The intracellular dis-
tribution of 3d in HT-29 colon cancer cells was imaged by
confocal laser scanning microscopy. Based on these find-
ings, the basic structure 3 is proposed as a suitable starting
point for the development of autofluorescent inhibitors of
cancer-related protein kinases.
Antiproliferative effects were determined essentially as described
previously.21 Results are expressed as IC50 values standard devia-
tion obtained from repeated experiments.
Confocal laser scanning microscopy was undertaken with an in-
verse microscope (Nikon Ti) connected to a confocal laser-scanning
microscopy system (Nikon A1), 100 × oil immersion objective
(Nikon, Plan Apo VC, NA 1.4), Nikon GmbH, Düsseldorf, Germany;
fluorescence excitation was performed with a 405 nm diode laser,
CVI Melles Griot, Albuquerque, NM, USA; the emission spectra
were recorded using a band pass filter 525/50.
4-[(Dimethylamino)methylidene]-7-iodo-3,4-dihydro-1H-1-
benzazepine-2,5-dione (5n)
7-Iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (4n; 1.20 g, 4.00
mmol) was stirred for 1 h in N,N-dimethylformamide dimethyl
acetal (15 mL) at 115–120 °C. After keeping the mixture for 12 h at
4–8 °C, a precipitate formed, which was filtered off and crystallized
from EtOH to give 5n.
Melting points were recorded with an IA 9100 instrument (Barnst-
edt Electrothermal), and are not corrected. Elemental analyses were
measured with a CE Instruments Flash EA 1112 Elemental Analyz-
er, Fa. Thermo Quest, San Jose, CA, USA. Infrared spectra were re-
corded from KBr pellets with a Thermo FT-IR 200 (Thermo
Nicolet). NMR spectra were recorded with Bruker Avance DRX-
400 and Bruker Avance II-600 spectrometers; samples were dis-
Yield: 0.95 g (67%); yellow crystals; mp 246 °C (dec. starting at
213 °C).
IR (KBr): 3186, 1675, 1638 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.23 (s, 8 H, CH2 and 2¢CH3),
6.85 (d, J = 8.6 Hz, 1 H, ArH), 7.62 (s, 1 H, =CH- methylidene),
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

PAPER
Synthesis and Structure of Fluorescent Boron Chelates
2853
7.72 (dd, J = 2.3, 8.3 Hz, 1 H, ArH), 7.95 (d, J = 2.3 Hz, 1 H, ArH),
HRMS: m/z calcd for C17H13N3O4: 323.0906; found: 323.0894.
10.00 (s, 1 H, NH lactam).
(4EZ)-4-[(4-Ethoxyanilino)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dione (6d)
Synthesized according to General Procedure A; reaction time 21 h.
13C NMR (100.6 MHz, DMSO-d6): d = 43.6 (2 C; 1° C), 31.0 (2°
C), 123.4, 138.5, 139.3, 150.7 (3° C), 87.4, 98.8, 134.7, 137.1,
172.7, 186.2 (4° C).
Diastereomeric mixture (E/Z = 1:4); mp 227 °C (dec. starting at
215 °C).
IR (KBr): 3208, 1675, 1638 cm–1.
Anal. Calcd for C13H13IN2O2: C, 43.84; H, 3.68; N, 7.87. Found: C,
43.82; H, 3.56; N, 7.60.
4-(Anilinomethylidene)-3,4-dihydro-1H-1-benzazepine-2,5-di-
ones 6a–n; General Procedure A
1H NMR (400 MHz, DMSO-d6): d = 1.32 (t, J = 7.1 Hz, 3 H, CH3),
3.13 (s, 1.5 H, CH2), 3.40 (s, 0.5 H, CH2), 3.97–4.04 (m, 2 H, CH2-
CH3), 6.92–6.95 (m, 2 H, ArH), 7.06–7.10 (m, 1 H, ArH), 7.16–
7.32 (m, 3 H, ArH), 7.44–7.49 (m, 1 H, ArH), 7.73 (ddd, J = 1.5,
7.8, 8.1 Hz, 1 H, ArH), 7.94 (d, J = 12.4 Hz, 0.7 H, =CH- meth-
ylidene), 8.03 (d, J = 14.2 Hz, 0.3 H, =CH- methylidene), 9.68 (d,
J = 14.2 Hz, 0.2 H, NH enamine), 9.93 and 9.96 (2 × s, 1 H, NH
lactam E- and Z-form, overlapping), 12.31 (d, J = 12.6 Hz, 0.8 H,
NH enamine).
A suitably substituted aniline (1.00 mmol) was added to a solution
of an appropriate 4-[(dimethylamino)methylidene]-3,4-dihydro-
1H-1-benzazepine-2,5-dione 5a or 5n (1.00 mmol) in glacial acetic
acid (4 mL). After stirring at r.t. for the indicated reaction time, the
mixture was poured into ice-cold H2O (30 mL). A precipitate was
formed, which was filtered off and crystallized from EtOH.
(4EZ)-4-(Anilinomethylidene)-3,4-dihydro-1H-1-benzazepine-
2,5-dione (6a)
Synthesized according to General Procedure A; reaction time 21 h.
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.51; H, 5.60; N, 8.53.
Diastereomeric mixture (E/Z = 3:7); mp 222 °C (dec.).
IR (KBr): 3192, 1680, 1643 cm–1.
(4EZ)-4-[(4-Ethylanilino)methylidene]-3,4-dihydro-1H-1-benz-
azepine-2,5-dione (6e)
Synthesized according to General Procedure A; reaction time 21 h.
1H NMR (400 MHz, DMSO-d6): d = 3.17 (s, 1.5 H, CH2), 3.46 (s,
0.5 H, CH2), 7.03–7.12 (m, 2 H, ArH), 7.17–7.24 (m, 1 H, ArH),
7.28–7.41 (m, 4 H, ArH), 7.45–7.51 (m, 1 H, ArH), 7.73 (ddd,
J = 1.5, 6.3, 7.8 Hz, 1 H, ArH), 8.04 (d, J = 12.6 Hz, 0.7 H, =CH-
methylidene), 8.11 (d, J = 13.9 Hz, 0.3 H, =CH- methylidene), 9.75
(d, J = 13.9 Hz, 0.3 H, NH enamine), 9.96 and 9.99 (2 × s, 1 H, NH
lactams of E- and Z-forms, overlapping), 12.21 (d, J = 12.4 Hz,
0.7 H, NH enamine).
Diastereomeric mixture (E/Z = 3:7); mp 225 °C (dec. starting at
204 °C).
IR (KBr): 3181, 1677, 1642 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.17 (t, J = 7.6 Hz, 3 H, CH3),
2.54–2.61 (m, 2 H, CH2-CH3), 3.15 (s, 1.5 H, CH2), 3.43 (s, 0.5 H,
CH2), 7.07–7.10 (m, 1 H, ArH), 7.17–7.30 (m, 5 H, ArH), 7.44–
7.50 (m, 1 H, ArH), 7.73 (ddd, J = 1.5, 7.8, 8.6 Hz, 1 H, ArH), 8.01
(d, J = 12.4 Hz, 0.7 H, =CH- methylidene), 8.08 (d, J = 13.9 Hz,
0.3 H, =CH- methylidene), 9.72 (d, J = 14.2 Hz, 0.3 H, NH enam-
ine), 9.94 and 9.97 (2 × s, 1 H, NH lactam of E- and Z-forms, over-
lapping), 12.25 (d, J = 12.4 Hz, 0.7 H, NH enamine).
Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.08; H, 5.09; N, 9.92.
(4EZ)-4-{[4-(Trifluoromethyl)anilino]methylidene}-3,4-dihy-
dro-1H-1-benzazepine-2,5-dione (6b)
Synthesized according to General Procedure A; reaction time 23 h.
Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C,
74.11; H, 6.14; N, 9.01.
Diastereomeric mixture (E/Z = 2:3); mp 242 °C (dec. starting at
229 °C).
IR (KBr): 3206, 1675, 1645 cm–1.
(4Z)-4-[(2-Chloroanilino)methylidene]-3,4-dihydro-1H-1-benz-
azepine-2,5-dione (6f)
Synthesized according to General Procedure A; reaction time 31 h.
1H NMR (400 MHz, DMSO-d6): d = 3.22 (s, 1.3 H, CH2), 3.51 (s,
0.7 H, CH2), 7.09–7.12 (m, 1 H, ArH), 7.19–7.25 (m, 1 H, ArH),
7.46–7.53 (m, 2 H, ArH), 7.57–7.59 (m, 1 H, ArH), 7.67–7.75 (m,
3 H, ArH), 8.09 (d, J = 12.1 Hz, 0.6 H, =CH- methylidene), 8.11 (d,
J = 13.6 Hz, 0.4 H, =CH- methylidene), 9.97 (d, J = 13.6 Hz, 0.4 H,
NH enamine), 10.01 (s, 0.4 H, NH lactam of the E-form), 10.02 (s,
0.6 H, NH lactam), 12.11 (d, J = 12.1 Hz, 0.6 H, NH enamine).
Mp 290 °C (dec. starting at 234 °C).
IR (KBr): 3188, 1686, 1637 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.24 (s, 2 H, CH2), 7.08–7.13
(m, 2 H, ArH), 7.23 (ddd, J = 1.0, 7.1, 8.1 Hz, 1 H, ArH), 7.40 (ddd,
J = 1.0, 7.3, 8.3 Hz, 1 H, ArH), 7.49–7.55 (m, 2 H, ArH), 7.76–7.78
(m, 2 H, ArH), 8.15 (d, J = 11.9 Hz, 1 H, =CH- methylidene), 10.03
(s, 1 H, NH lactam), 12.56 (d, J = 11.9 Hz, 1 H, NH enamine).
13C NMR (100.6 MHz, DMSO-d6): d = 36.3 (2° C), 115.4, 121.5,
123.7, 124.1, 128.5, 129.8, 130.0, 132.2, 143.1 (3° C), 105.1, 120.9,
131.5, 136.5, 137.2, 172.3 (C lactam), 190.3 (C=O).
Anal. Calcd for C18H13F3N2O2: C, 62.43; H, 3.78; N, 8.09. Found:
C, 62.38; H, 3.65; N, 7.83.
(4EZ)-4-[(4-Nitroanilino)methylidene]-3,4-dihydro-1H-1-ben-
zazepine-2,5-dione (6c)
Synthesized according to General Procedure A; reaction time 79 h.
Anal. Calcd for C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96. Found:
C, 65.53; H, 4.14; N, 8.56.
Diastereomeric mixture (E/Z = 2:3); mp 299 °C (dec. starting at
289 °C).
IR (KBr): 3202, 1680, 1641 cm–1.
(4EZ)-4-[(4-Iodoanilino)methylidene]-3,4-dihydro-1H-1-benz-
azepine-2,5-dione (6g)
1H NMR (400 MHz, DMSO-d6): d = 3.26 (s, 1.2 H, CH2), 3.55 (s,
0.8 H, CH2), 7.09–7.12 (m, 1 H, ArH), 7.20–7.26 (m, 1 H, ArH),
7.47–7.54 (m, 2 H, ArH), 7.59–7.63 (m, 1 H, ArH), 7.74 (ddd,
J = 1.8, 2.0, 7.8 Hz, 1 H, ArH), 8.09–8.12 (m, 1 H, =CH- meth-
ylidene), 8.20–8.24 (m, 2 H, ArH), 10.04 (s, 0.4 H, NH lactam),
10.05 (s, 0.6 H, NH lactam), 10.18 (d, J = 10.1 Hz, 0.4 H, NH
enamine), 12.09 (d, J = 12.1 Hz, 0.6 H, NH enamine).
Synthesized according to General Procedure A; reaction time 24 h.
Diastereomeric mixture (E/Z = 3:7); mp 253 °C (dec. starting at
245 °C).
IR (KBr): 3186, 1679, 1643 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.17 (s, 1.4 H, CH2), 3.45 (s,
0.6 H, CH2), 7.07–7.25 (m, 4 H, ArH), 7.46–7.51 (m, 1 H, ArH),
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

2854
N. Tolle et al.
PAPER
(4EZ)-4-[(3-Methoxyanilino)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dione (6k)
Synthesized according to General Procedure A; reaction time 6 h.
7.65–7.74 (m, 3 H, ArH), 8.00 (d, J = 12.4 Hz, 0.7 H, =CH- meth-
ylidene), 8.03 (d, J = 13.9 Hz, 0.3 H, =CH- methylidene), 9.77 (d,
J = 13.6 Hz, 0.3 H, NH enamine), 9.97 and 9.98 (2 × s, 1 H, NH
lactams of E- and Z-forms, overlapping), 12.09 (d, J = 12.1 Hz,
0.7 H, NH enamine).
Diastereomeric mixture (E/Z = 1:4); mp 208 °C (dec.).
IR (KBr): 3186, 1683, 1646 cm–1.
Anal. Calcd for C17H13IN2O2: C, 50.51; H, 3.24; N, 6.93. Found: C,
50.72; H, 3.06; N; 6.63.
1H NMR (400 MHz, DMSO-d6): d = 3.18 (s, 1.5 H, CH2), 3.44 (s,
0.5 H, CH2), 3.78 and 3.80 (2 × s, 3 H, CH3 of E- and Z-forms, over-
lapping), 6.63 (dd, J = 1.8, 8.1 Hz, 0.3 H, ArH), 6.66 (dd, J = 1.8,
8.1 Hz, 0.7 H, ArH), 6.84 (t, J = 2.0 Hz, 0.3 H, ArH), 6.86 (dd,
J = 1.8, 7.8 Hz, 0.3 H, ArH), 6.92 (dd, J = 1.8, 7.8 Hz, 0.7 H, ArH),
7.01 (t, J = 2.0 Hz, 0.7 H, ArH), 7.07–7.11 (m, 1 H, ArH), 7.17–
7.28 (m, 2 H, ArH), 7.45–7.51 (m, 1 H, ArH), 7.71–7.75 (m, 1 H,
ArH), 8.06 (d, J = 12.4 Hz, 0.7 H, =CH- methylidene), 8.08 (d,
J = 13.9 Hz, 0.3 H, =CH- methylidene), 9.71 (d, J = 13.9 Hz, 0.2 H,
NH enamine), 9.97 and 10.00 (2 × s, 1 H, NH lactams of E- and Z-
forms, overlapping), 12.16 (d, J = 12.4 Hz, 0.8 H, NH enamine).
(4EZ)-4-(4-Toluidinomethylidene)-3,4-dihydro-1H-1-benz-
azepine-2,5-dione (6h)
Synthesized according to General Procedure A; reaction time 23.5
h.
Diastereomeric mixture (E/Z = 1:4); mp 248 °C (dec. starting at
234 °C).
IR (KBr): 3202, 1674, 1640 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.27 and 2.28 (2 × s, 3 H, CH3
of E- and Z-forms, partially overlapping), 3.15 (s, 1.5 H, CH2), 3.43
(s, 0.5 H, CH2), 7.06–7.10 (m, 1 H, ArH), 7.15–7.28 (m, 5 H, ArH),
7.44–7.50 (m, 1 H, ArH), 7.71–7.74 (m, 1 H, ArH), 8.00 (d,
J = 12.4 Hz, 0.8 H, =CH- methylidene), 8.08 (d, J = 14.1 Hz, 0.2 H,
=CH- methylidene), 9.71 (d, J = 14.2 Hz, 0.2 H, NH enamine), 9.94
and 9.97 (2 × s, 1 H, NH lactams of E- and Z-forms, partially over-
lapping), 12.24 (d, J = 12.4 Hz, 0.8 H, NH enamine).
Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
69.79; H, 5.22; N, 8.82.
(4Z)-4-(2-Toluidinomethylidene)-3,4-dihydro-1H-1-benz-
azepine-2,5-dione (6l)
Synthesized according to General Procedure A; reaction time 23 h.
Mp 259.2 °C (dec.).
Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
73.58; H, 5.37; N, 9.34.
IR (KBr): 3184, 1691, 1637 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.33 (s, 3 H, CH3), 3.19 (s, 2 H,
CH2), 7.03 (ddd, J = 0.8, 7.6, 7.6 Hz, 1 H, ArH), 7.11 (dd, J = 0.8,
8.1 Hz, 1 H, ArH), 7.22 (ddd, J = 1.3, 7.8, 7.8 Hz, 1 H, ArH), 7.24–
7.29 (m, 2 H, ArH), 7.49 (ddd, J = 1.5, 1.8, 8.1 Hz, 1 H, ArH), 7.58
(d, J = 8.1 Hz, 1 H, ArH), 7.77 (dd, J = 1.5, 7.8 Hz, 1 H, ArH), 8.15
(d, J = 12.1 Hz, 1 H, =CH- methylidene), 10.00 (s, 1 H, NH lac-
tam), 12.50 (d, J = 12.1 Hz, 1 H, NH enamine).
13C NMR (100.6 MHz, DMSO-d6): d = 16.8 (1° C), 36.2 (2° C),
113.8, 121.2, 123.2, 123.4, 127.0, 129.6, 130.7, 131.7, 144.6 (3° C),
103.7, 125.3, 131.8, 137.1, 137.9, 172.6, 189.4 (4° C).
(4EZ)-4-[(4-Methoxyanilino)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dione (6i)
Synthesized according to General Procedure A; reaction time 19 h.
Diastereomeric mixture (E/Z = 1:4); mp 240 °C (dec. starting at
202 °C).
IR (KBr): 3187, 1670, 1638 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.13 (s, 1.5 H, CH2), 3.40 (s,
0.5 H, CH2), 3.74 and 3.75 (2 × s, 3 H, CH3 of E- and Z-forms, over-
lapping), 6.94–6.98 (m, 2 H, ArH), 7.08 (ddd, J = 0.8, 7.3, 7.3 Hz,
1 H, ArH), 7.16–7.24 (m, 1.5 H, ArH), 7.31–7.35 (m, 1.5 H, ArH),
7.44–7.49 (m, 1 H, ArH), 7.73 (ddd, J = 1.5, 7.8, 8.1 Hz, 1 H, ArH),
7.95 (d, J = 12.4 Hz, 0.8 H, =CH- methylidene), 8.04 (d,
J = 14.2 Hz, 0.2 H, =CH- methylidene), 9.69 (d, J = 14.2 Hz, 0.2 H,
NH enamine), 9.94 and 9.96 (2 × s, 1 H, NH lactam of E- and Z-
forms, overlapping), 12.32 (d, J = 12.4 Hz, 0.8 H, NH enamine).
Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
74.07; H, 5.44; N, 9.36.
(4Z)-4-[(2-Methoxyanilino)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dione (6m)
Synthesized according to General Procedure A; reaction time 5 h.
Mp 258 °C (dec. starting at 233 °C).
IR (KBr): 3207, 1675, 1642 cm–1.
Anal. Calcd for C18H16IN2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
70.03; H, 5.23; N, 8.90.
1H NMR (400 MHz, DMSO-d6): d = 3.18 (s, 2 H, CH2), 3.92 (s, 3 H,
CH3), 7.00 (ddd, J = 1.5, 7.3, 7.8 Hz, 1 H, ArH), 7.05–7.12 (m, 3 H,
ArH), 7.21 (ddd, J = 1.0, 7.8, 8.3 Hz, 1 H, ArH), 7.48 (ddd, J = 1.5,
7.3, 8.1 Hz, 1 H, ArH), 7.59 (dd, J = 1.0, 7.8 Hz, 1 H, ArH), 7.75
(dd, J = 1.5, 7.8 Hz, 1 H, ArH), 8.06 (d, J = 12.6 Hz, 1 H, =CH-
methylidene), 9.96 (s, 1 H, NH lactam), 12.34 (d, J = 12.6 Hz, 1 H,
NH enamine).
13C NMR (100.6 MHz, DMSO-d6): d = 56.0 (1° C), 36.6 (2° C),
111.6, 113.7, 121.2, 121.4, 123.6, 123.8, 129.9, 131.8, 143.4 (3° C),
103.7, 128.7, 131.9, 137.1, 147.6, 172.6, 189.1 (4° C).
(4EZ)-4-[(3,5-Dichloroanilino)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dione (6j)
Synthesized according to General Procedure A; reaction time 48 h.
Diastereomeric mixture (E/Z = 3:7); mp 272 °C (dec.).
IR (KBr): 3207, 1680, 1636 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.20 (s, 1.4 H, CH2), 3.46 (s,
0.6 H, CH2), 7.08–7.11 (m, 1 H, ArH), 7.16–7.24 (m, 2 H, ArH),
7.35 (d, J = 1.8 Hz, 0.6 H, ArH), 7.46–7.51 (m, 1 H, ArH), 7.56 (d,
J = 1.5 Hz, 1.4 H, ArH), 7.72 (dd, J = 1.5, 7.8 Hz, 1 H, ArH), 8.00
(d, J = 12.1 Hz, 0.3 H, =CH- methylidene), 8.03 (d, J = 12.1 Hz,
0.7 H, =CH- methylidene), 9.79 (d, J = 13.4 Hz, 0.3 H, NH enam-
ine), 10.00 (s, 1 H, NH lactam), 11.89 (d, J = 12.1 Hz, 0.7 H, NH
enamine).
Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
70.06; H, 5.20; N, 8.81.
(4Z)-7-Iodo-4-[(2-methoxyanilino)methylidene]-3,4-dihydro-
1H-1-benzazepine-2,5-dione (6n)
Synthesized according to General Procedure A; reaction time 6.5 h.
Anal. Calcd for C17H12Cl2N2O2: C, 58.81; H, 3.48; N, 8.07. Found:
C, 58.96; H, 3.40; N, 7.81.
Mp 287 °C (dec. starting at 273 °C).
IR (KBr): 3202, 1679, 1639 cm–1.
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

PAPER
Synthesis and Structure of Fluorescent Boron Chelates
2855
1H NMR (400 MHz, DMSO-d6): d = 3.19 (s, 2 H, CH2), 3.93 (s, 3 H,
CH3), 6.91 (d, J = 8.3 Hz, 1 H, ArH), 7.00 (ddd, J = 2.0, 8.1, 8.3 Hz,
1 H, ArH), 7.06–7.12 (m, 2 H, ArH), 7.61 (d, J = 7.8 Hz, 1 H, ArH),
7.79 (dd, J = 2.0, 8.3 Hz, 1 H, ArH), 8.01 (d, J = 2.0 Hz, 1 H, ArH),
8.11 (d, J = 12.6 Hz, 1 H, =CH- methylidene), 10.06 (s, 1 H, NH
lactam), 12.36 (d, J = 12.6 Hz, 1 H, NH enamine).
13C NMR (100.6 MHz, DMSO-d6): d = 56.0 (1° C), 36.3 (2° C),
111.7, 113.9, 121.2, 123.7, 124.1, 138.1, 140.0, 144.1 (3° C), 87.5,
103.1, 128.5, 133.7, 136.8, 147.7, 172.5, 187.2 (4° C).
HRMS: m/z calcd for C18H12BF5N2O2: 393.09482; found:
393.09280.
Difluoro{(4Z)-4-{[4-nitro(phenylamino-kN)]methylidene}-3,4-
dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3c)
Synthesized according to General Procedure B; reaction time 12.0
h.
Mp 239 °C (dec.).
IR (KBr): 3214, 3114, 3079, 3050, 2971, 2914, 1684 cm–1.
Anal. Calcd for C18H15IN2O3: C, 49.79; H, 3.48; N, 6.45. Found: C,
49.45; H, 3.35; N, 6.25.
1H NMR (600.1 MHz, DMSO-d6): d = 3.27 (s, 2 H, azepine CH2),
7.26 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.34 (ddd, J = 7.9, 7.3, 1.1 Hz,
1 H, ArH), 7.67 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.87–7.89 (m,
2 H, ArH, part of an AA¢XX¢-system) overlaid with 7.90 (dd,
J = 7.9, 1.6 Hz, 1 H, ArH), 8.39–8.41 (m, 2 H, ArH, part of an
AA¢XX¢-system), 8.73 (s, 1 H, CH), 10.56 (s, 1 H, NH).
Difluoro{(4Z)-4-[(phenylamino-kN)methylidene]-3,4-dihydro-
1H-1-benzazepine-2,5-dionato-kO5}boron Complexes 3a–n;
General Procedure B
An appropriate 4-(anilinomethylidene)-3,4-dihydro-1H-1-benz-
azepine-2,5-dione 6a–n (0.500 mmol) was dissolved or suspended
by heating to reflux in toluene (10 mL) under a nitrogen atmo-
sphere. After addition with diisopropylethylamine (DIPEA; 85 mL,
0.500 mmol), a solution of BF3·Et2O (0.317 mL, 2.50 mmol) in tol-
uene (1 mL) was added dropwise. After stirring under reflux for the
indicated reaction time, the mixture was cooled to r.t. The precipi-
tate thus formed was filtered off and washed successively with aq
10% HCl (3 × 10 mL) and H2O (3 × 10 mL). Similarly, the filtrate
was washed successively with aq 10% HCl (3 × 10 mL) and H2O
(3 × 10 mL), dried, and concentrated in vacuo. The resulting residue
was combined with the isolated precipitate and crystallized from
toluene.
13C NMR (150.9 MHz, DMSO-d6): d = 33.8 (2° C), 122.0, 123.9,
124.2 (2 C), 124.9 (2 C), 129.3, 133.9, 163.6 (3° C), 104.2, 123.9,
139.1, 146.3, 146.8, 169.4, 171.6 (4° C).
HRMS: m/z calcd for C17H12BF2N3O4: 370.09250; found:
370.09127.
Difluoro{(4Z)-4-{[4-ethoxy(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3d)
Synthesis according to General Procedure B; reaction time 1.0 h.
Mp 234 °C (dec.).
IR (KBr): 3215, 3068, 2979, 1677 cm–1.
1H NMR (600.1 MHz, DMSO-d6): d = 1.35 (t, J = 6.8 Hz, 3 H, CH2-
CH3), 3.20 (s, 2 H, azepine CH2), 4.08 (q, J = 6.8 Hz, 2 H, CH2-
CH3), 7.04–7.06 (m, 2 H, ArH, part of an AA¢XX¢-system), 7.24
(dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.30–7.33 (m, 1 H, ArH), 7.49–7.51
(m, 2 H, ArH, part of an AA¢XX¢-system), 7.62 (ddd, J = 8.1, 7.3,
1.6 Hz, 1 H, ArH), 7.86 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 8.51 (s,
1 H, CH), 10.48 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 14.5 (1° C), 33.7, 63.4 (2°
C), 114.8 (2 C), 121.9, 123.8, 124.3 (2 C), 128.9, 133.1, 161.8 (4°
C), 103.3, 134.7, 138.6, 158.2, 166.3, 171.8 (4° C); 1 C not detected.
Difluoro{(4Z)-4-[(phenylamino-kN)methylidene]-3,4-dihydro-
1H-1-benzazepine-2,5-dionato-kO5}boron (3a)
Synthesized according to General Procedure B; reaction time 1.5 h.
Mp 277 °C (dec.).
IR (KBr): 3293, 3064, 2982, 1679 cm–1.
1H NMR (600.1 MHz, DMSO-d6): d = 3.23 (s, 2 H, azepine CH2),
7.25 (dd, J = 8.2, 1.1 Hz, 1 H, ArH), 7.33 (ddd, J = 7.9, 7.3, 1.1 Hz,
1 H, ArH), 7.45 (tt, J = 7.3, 1.1 Hz, 1 H, ArH), 7.52–7.54 (m, 2 H,
ArH), 7.57–7.59 (m, 2 H, ArH), 7.64 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H,
ArH), 7.88 (dd, J = 7.9, 1.6 Hz, 1 H, ArH), 8.59 (s, 1 H, CH), 10.51
(s, 1 H, NH).
Anal. Calcd for C19H17BF2N2O3: C, 61.65; H, 4.63; N, 7.57. Found:
C, 61.34; H, 4.61; N, 7.43.
13C NMR (150.9 MHz, DMSO-d6): d = 33.7 (2° C), 122.0, 123.2 (2
C), 123.8, 128.1, 129.1, 129.4 (2 C), 133.4, 162.9 (3° C), 103.5,
124.2, 138.8, 141.8, 167.3, 171.8 (4° C).
Difluoro{(4Z)-4-{[4-ethyl(phenylamino-kN)]methylidene}-3,4-
dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3e)
Synthesized according to General Procedure B; reaction time 2.0 h.
Anal. Calcd for C17H13BF2N2O2: C, 62.61; H, 4.02; N, 8.59. Found:
C, 62.69; H, 4.10; N, 8.62.
Mp 238 °C (dec.).
IR (KBr): 3213, 3121, 3071, 3036, 2974, 1678 cm–1.
Difluoro{(4Z)-4-{[4-(trifluoromethyl)(phenylamino-kN)]meth-
ylidene}-3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}bo-
ron (3b)
1H NMR (600.1 MHz, DMSO-d6): d = 1.21 (t, J = 7.5 Hz, 3 H, CH2-
CH3), 2.66 (q, J = 7.5 Hz, 2 H, CH2-CH3), 3.21 (s, 2 H, azepine
CH2), 7.24 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.32 (ddd, J = 8.0, 7.3,
1.1 Hz, 1 H, ArH), 7.35–7.36 (m, 2 H, ArH, part of an AA¢XX¢-sys-
tem), 7.48–7.49 (m, 2 H, ArH, part of an AA¢XX¢-system), 7.63
(ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.1, 1.6 Hz, 1 H,
ArH), 8.55 (s, 1 H, CH), 10.50 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 15.4 (1° C), 27.6, 33.7 (2°
C), 121.9, 123.0 (2 C), 123.8, 128.6 (2 C), 129.0, 133.2, 162.4 (3°
C); 103.4, 124.3, 138.7, 139.5, 144.0, 166.9, 171.8 (4° C).
Synthesized according to General Procedure B; reaction time 1.0 h.
Mp 238 °C (dec.).
IR (KBr): 3211, 3083, 2977, 2922, 1686 cm–1.
1H NMR (600.1 MHz, DMSO-d6): d = 3.25 (s, 2 H, azepine CH2),
7.26 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.34 (ddd, J = 7.9, 7.3, 1.1 Hz,
1 H, ArH), 7.66 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.82–7.84 (m,
2 H, ArH, part of an AA¢XX¢-system), 7.89 (dd, J = 7.9, 1.6 Hz,
1 H, ArH), 7.92–7.94 (m, 2 H, ArH, part of an AA¢XX¢-system),
8.68 (s, 1 H, CH), 10.54 (s, 1 H, NH).
Anal. Calcd for C19H17BF2N2O2: C, 64.44; H, 4.84; N, 7.91. Found:
C, 64.30; H, 4.96; N, 7.84.
13C NMR (150.9 MHz, DMSO-d6): d = 33.8 (2° C), 122.0, 123.8,
124.1 (2 C), 126.6 (q, 3JC–F = 3.6 Hz, 2 C, C-C-CF), 129.2, 133.7,
163.6 (3° C), 103.9, 123.9 (q, 1JC–F = 272.0 Hz, C-F), 124.0, 128.2
(q, 2JC–F = 32.3 Hz, C-CF), 139.0, 144.9, 168.6, 171.7 (4° C).
Difluoro{(4Z)-4-{[2-chloro(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3f)
Synthesized according to General Procedure B; reaction time 4.5 h.
Mp 266 °C (dec.).
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

2856
N. Tolle et al.
PAPER
IR (KBr): 3209, 3121, 3057, 2986, 2964, 1684 cm–1.
Anal. Calcd for C18H15BF2N2O3: C, 60.71; H, 4.25; N, 7.87. Found:
C, 60.69; H, 4.29; N, 7.82.
1H NMR (600.1 MHz, DMSO-d6): d = 3.21 (s, 2 H, azepine CH2),
7.26 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.34 (ddd, J = 8.0, 7.3, 1.1 Hz,
1 H, ArH), 7.49–7.55 (m, 3 H, ArH), 7.66 (ddd, J = 8.2, 7.3, 1.6 Hz,
1 H, ArH), 7.69–7.72 (m, 1 H, ArH), 7.89 (dd, J = 8.0, 1.6 Hz, 1 H,
ArH), 8.57 (s, 1 H, CH), 10.53 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 33.5 (2° C), 122.0, 123.9,
127.6, 127.9, 129.2, 130.0, 130.3, 133.6, 166.5 (3° C), 102.7, 124.2,
128.8, 138.6, 138.9, 168.7, 171.7 (4° C).
Difluoro{(4Z)-4-{[3,5-dichloro(phenylamino-kN)]meth-
ylidene}-3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}bo-
ron (3j)
Synthesized according to General Procedure B; reaction time 1.5 h.
Mp 260 °C.
IR (KBr): 3212, 3086, 2976, 1678 cm–1.
Anal. Calcd for C17H12BClF2N2O2: C, 56.63; H, 3.35; N, 7.77.
Found: C, 56.33; H, 3.28; N, 7.52.
1H NMR (600.1 MHz, DMSO-d6): d = 3.23 (s, 2 H, azepine CH2),
7.25 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.33 (ddd, J = 8.0, 7.3, 1.1 Hz,
1 H, ArH), 7.66 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.72 (d,
J = 1.8 Hz, 2 H, ArH), 7.75 (t, J = 1.8 Hz, 1 H, ArH), 7.88 (dd,
J = 8.1, 1.6 Hz, 1 H, ArH), 8.67 (s, 1 H, CH), 10.54 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 33.8 (2° C), 122.0, 122.2 (2
C), 123.9, 127.5, 129.2, 133.8, 164.0 (3° C), 103.8, 123.9, 134.5 (2
C), 139.1, 143.7, 168.9, 171.7 (4° C).
Difluoro{(4Z)-4-{[4-iodo(phenylamino-kN)]methylidene}-3,4-
dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3g)
Synthesized according to General Procedure B; reaction time 3.5 h.
Mp 299 °C.
IR (KBr): 3237, 3057, 3036, 2986, 2964, 1684 cm–1.
Anal. Calcd for C17H11BCl2F2N2O2: C, 51.69; H, 2.81; N, 7.09.
Found: C, 51.74; H, 2.76; N, 6.70.
1H NMR (600.1 MHz, DMSO-d6): d = 3.22 (s, 2 H, azepine CH2),
7.24 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.32 (ddd, J = 7.9, 7.3, 1.1 Hz,
1 H, ArH), 7.39–7.41 (m, 2 H, ArH, part of an AA¢XX¢-system),
7.64 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.0, 1.6 Hz,
1 H, ArH) overlaid with 7.88–7.90 (m, 2 H, ArH, part of an
AA¢XX¢-system), 8.59 (s, 1 H, CH), 10.52 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 33.7 (2° C), 122.0, 123.8,
125.3 (2 C), 129.1, 133.5, 138.1 (2 C), 162.8 (3° C), 94.1, 103.7,
124.2, 138.8, 141.4, 167.7, 171.8 (4° C).
Difluoro{(4Z)-4-{[3-methoxy(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3k)
Synthesized according to General Procedure B; reaction time 1.0 h.
Mp 219 °C.
IR (KBr): 3214, 3121, 3075, 2981, 2937, 2911, 1683 cm–1.
1H NMR (600.1 MHz, DMSO-d6): d = 3.23 (s, 2 H, azepine CH2),
3.82 (s, 3 H, OCH3), 7.02–7.04 (m, 1 H, ArH), 7.15–7.17 (m, 2 H,
ArH), 7.25 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.33 (ddd, J = 8.0, 7.3,
1.1 Hz, 1 H, ArH), 7.41–7.44 (m, 1 H, ArH), 7.64 (ddd, J = 8.2, 7.3,
1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 8.59 (s,
1 H, CH), 10.51 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 55.4 (1° C), 33.7 (2° C),
109.0, 113.7, 115.5, 122.0, 123.8, 129.1, 130.1, 133.4, 163.0 (3° C),
103.4, 124.2, 138.8, 142.9, 159.8, 167.3, 171.8 (4° C).
HRMS: m/z calcd for C17H12BF2IN2O2: 451.00412; found:
451.00252.
Difluoro{(4Z)-4-{[4-methyl(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3h)
Synthesized according to General Procedure B; reaction time 1.0 h.
Mp 239 °C (dec.).
IR (KBr): 3233, 3050, 2929, 1686 cm–1.
Anal. Calcd for C18H15BF2N2O3: C, 60.71; H, 4.25; N, 7.87. Found:
C, 60.81; H, 4.26; N, 7.61.
1H NMR (600.1 MHz, DMSO-d6): d = 2.36 (s, 3 H, CH3), 3.22 (s,
2 H, azepine CH2), 7.24 (dd, J = 8.2, 0.8 Hz, 1 H, ArH), 7.30–7.33
(m, 3 H, ArH), 7.46–7.47 (m, 2 H, ArH), 7.63 (ddd, J = 8.2, 7.3,
1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 8.55 (s,
1 H, CH), 10.49 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 20.5 (1° C), 33.7 (2° C),
121.9, 122.9 (2 C), 123.8, 129.0, 129.7 (2 C), 133.2, 162.3 (3° C),
103.4, 124.3, 137.7, 138.7, 139.3, 166.9, 171.8 (4° C).
Difluoro{(4Z)-4-{[2-methyl(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3l)
Synthesized according to General Procedure B; reaction time 4.5 h.
Mp 244 °C (dec.).
IR (KBr): 3224, 3136, 2971, 2921, 1683 cm–1.
Anal. Calcd for C18H15BF2N2O2: C, 63.56; H, 4.44; N, 8.24. Found:
C, 63.43; H, 4.54; N, 8.21.
1H NMR (600.1 MHz, DMSO-d6): d = 2.23 (s, 3 H, CH3), 3.19 (s,
2 H, azepine CH2), 7.25 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.27–7.28
(m, 1 H, ArH), 7.31–7.34 (m, 2 H, ArH), 7.37 (ddd, J = 7.5, 7.4,
1.5 Hz, 1 H, ArH), 7.40–7.41 (m, 1 H, ArH), 7.64 (ddd, J = 8.2, 7.3,
1.6 Hz, 1 H, ArH), 7.88 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 8.44 (s,
1 H, CH), 10.50 (s, 1 H, NH).
Difluoro{(4Z)-4-{[4-methoxy(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3i)
Synthesized according to General Procedure B; reaction time 1.0 h.
Mp 252 °C.
IR (KBr): 3240, 3036, 2964, 2929, 1681 cm–1.
13C NMR (150.9 MHz, DMSO-d6): d = 17.2 (1° C), 33.5 (2° C),
121.9, 123.8, 126.0, 126.4, 128.4, 129.0, 131.0, 133.3, 165.6 (3° C),
102.6, 124.4, 132.8, 138.7, 140.8, 167.4, 171.8 (4° C).
1H NMR (600.1 MHz, DMSO-d6): d = 3.21 (s, 2 H, azepine CH2),
3.81 (s, 3 H, OCH3), 7.06–7.08 (m, 2 H, ArH, part of an AA¢XX¢-
system), 7.24 (dd, J = 8.2, 1.0 Hz, 1 H, ArH), 7.32 (ddd, J = 8.0,
7.3, 1.1 Hz, 1 H, ArH), 7.50–7.53 (m, 2 H, ArH, part of an AA¢XX¢-
system), 7.62 (ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.86 (dd,
J = 8.0, 1.6 Hz, 1 H, ArH), 8.51 (s, 1 H, CH), 10.48 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 55.4 (1° C), 33.7 (2° C),
114.4 (2 C), 121.9, 123.8, 124.3 (2 C), 128.9, 133.1, 161.9 (3° C),
103.3, 134.8, 138.6, 158.9, 166.3, 171.8 (4° C); 1 C not detected.
Anal. Calcd for C18H15BF2N2O2: C, 63.56; H, 4.44; N, 8.24. Found:
C, 63.24; H, 4.44; N, 7.90.
Difluoro{(4Z)-4-{[2-methoxy(phenylamino-kN)]methylidene}-
3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron (3m)
Synthesized according to General Procedure B; reaction time 4.5 h.
Mp 255 °C (dec.).
IR (KBr): 3214, 3050, 2960, 1680 cm–1.
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

PAPER
Synthesis and Structure of Fluorescent Boron Chelates
2857
1H NMR (600.1 MHz, DMSO-d6): d = 3.18 (s, 2 H, azepine CH2),
3.81 (s, 3 H, OCH3), 7.07 (ddd, J = 7.7, 7.7, 1.2 Hz, 1 H, ArH), 7.25
(dd, J = 8.2, 1.0 Hz, 1 H, ArH) overlaid with 7.26 (dd, J = 8.5,
1.2 Hz, 1 H, ArH), 7.33 (ddd, J = 8.0, 7.3, 1.1 Hz, 1 H, ArH), 7.38–
7.39 (m, 1 H, ArH), 7.42 (ddd, J = 8.3, 7.5, 1.7 Hz, 1 H, ArH), 7.64
(ddd, J = 8.2, 7.3, 1.6 Hz, 1 H, ArH), 7.87 (dd, J = 8.0, 1.6 Hz, 1 H,
ArH), 8.45 (s, 1 H, CH), 10.50 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 56.1 (1° C), 33.5 (2° C),
112.9, 120.3, 122.0, 123.9, 125.9, 129.1, 129.5, 133.3, 166.2 (3° C),
102.5, 124.5, 130.0, 138.6, 152.7, 167.2, 171.8 (4° C).
{(4Z)-4-[(3-Methoxyphenylamino-kN)methylidene]-3,4-dihy-
dro-1H-1-benzazepine-2,5-dionato-kO5}diphenylboron (7k)
Synthesized according to General Procedure C; reaction time 21.0
h.
Mp 199–200 °C.
IR (KBr): 3202, 3065, 3003, 2965, 2910, 1677 cm–1.
1H NMR (600.1 MHz, DMSO-d6): d = 3.07 (s, 2 H, azepine CH2),
3.54 (s, 3 H, OCH3), 6.66 (dd, J = 2.3, 2.2 Hz, 1 H, ArH), 6.74 (ddd,
J = 8.3, 2.4, 0.7 Hz, 1 H, ArH), 6.79 (ddd, J = 8.0, 2.1, 0.7 Hz, 1 H,
ArH), 7.11–7.13 (m, 2 H, ArH) overlaid with 7.13 (dd, J = 8.2,
8.0 Hz, 1 H, ArH), 7.16–7.18 (m, 5 H, ArH), 7.22 (ddd, J = 7.9, 7.3,
1.0 Hz, 1 H, ArH), 7.34–7.36 (m, 4 H, ArH), 7.55 (ddd, J = 8.1, 7.3,
1.6 Hz, 1 H, ArH), 7.75 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 8.45 (s,
1 H, CH), 10.40 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 54.9 (1° C), 33.6 (2° C),
109.9, 112.8, 116.2, 121.6, 123.5, 126.1 (2 C), 126.7 (4 C), 129.3,
129.8, 132.8, 133.2 (4 C), 161.6 (3° C), 104.8, 125.1, 138.5, 146.0,
147.3 (2 C), 158.8, 168.6, 172.0 (4° C).
Anal. Calcd for C18H15BF2N2O3: C, 60.71; H, 4.25; N, 7.87. Found:
C, 60.97; H, 4.32; N, 7.71.
Difluoro{(4Z)-4-{[2-methoxy(phenylamino-kN)]methylidene}-
7-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dionato-kO5}boron
(3n)
Synthesized according to General Procedure B; reaction time 4.0 h.
Mp 274 °C (dec.).
IR (KBr): 3200, 3114, 3057, 2943, 1686 cm–1.
Anal. Calcd for C30H25BN2O3: C, 76.28; H, 5.33; N, 5.93. Found: C,
76.43; H, 5.27; N, 5.69.
1H NMR (600.1 MHz, DMSO-d6): d = 3.20 (s, 2 H, azepine CH2),
3.80 (s, 3 H, OCH3), 7.05 (d, J = 8.6 Hz, 1 H, ArH) overlaid with
7.07 (ddd, J = 7.8, 7.7, 1.1 Hz, 1 H, ArH), 7.26 (dd, J = 8.3, 1.1 Hz,
1 H, ArH), 7.37–7.39 (m, 1 H ArH), 7.43 (ddd, J = 8.3, 7.6, 1.6 Hz,
1 H, ArH), 7.95 (dd, J = 8.6, 2.1 Hz, 1 H, ArH), 8.07 (d, J = 2.1 Hz,
1 H, ArH), 8.48 (s, 1 H, CH), 10.58 (s, 1 H, NH).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
13C NMR (150.9 MHz, DMSO-d6): d = 56.1 (1° C), 33.3 (2° C),
112.9, 120.4, 124.1, 125.9, 129.6, 136.7, 141.3, 165.4 (3° C), 87.6,
102.8, 126.3, 129.8, 138.3, 152.7, 166.6, 171.6 (4° C).
Acknowledgment
We are grateful to R. Rubbiani, A. Meyer, S. Ludewig, and M.
Buske for discussions and technical assistance. We thank L. Ernst,
K. Ibrom, and P. Holba-Schulz for recording NMR spectra and U.
Papke for performing mass spectrometry measurements. Funding of
the project by the European Commission (Contract No LSHB-CT-
2004–503467, to N.T., U.D., F.T., C.S., M.H.G.K., and C.K.) is
gratefully acknowledged.
HRMS: m/z calcd for C18H14BF2IN2O3: 481.01465; found:
481.01358.
{(4Z)-4-[(phenylamino-kN)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dionato-kO5}diphenylboronComplexes7aand
7k; General Procedure C
An appropriate 4-(anilinomethylidene)-3,4-dihydro-1H-1-benza-
zepine-2,5-dione 6a or 6k (0.500 mmol) was dissolved or suspend-
ed by heating to reflux in toluene (10 mL) under a nitrogen
atmosphere. A solution of triphenylborane (182 mg, 0.750 mmol) in
toluene (2 mL) was added dropwise. After heating to reflux for the
indicated reaction time, the mixture was cooled to r.t. and the pre-
cipitate thus formed was filtered off. The filtrate was dried
(Na2SO4) and concentrated in vacuo. The residue was combined
with the isolated precipitate and crystallized from acetone.
References
(1) Zhang, J.; Yang, P. L.; Gray, N. S. Nat. Rev. Cancer 2009,
9, 28.
(2) Hunter, T. J. Clin. Invest. 2007, 117, 2036.
(3) Ghose, A. K.; Herbertz, T.; Pippin, D. A.; Salvino, J. M.;
Mallamo, J. P. J. Med. Chem. 2008, 51, 5149.
(4) Kunick, C.; Zeng, Z.; Gussio, R.; Zaharevitz, D.; Leost, M.;
Totzke, F.; Schächtele, C.; Kubbutat, M. H. G.; Meijer, L.;
Lemcke, T. ChemBioChem 2005, 6, 541.
(5) Pies, T.; Schaper, K.-J.; Leost, M.; Zaharevitz, D. W.;
Gussio, R.; Meijer, L.; Kunick, C. Arch. Pharm. Pharm.
Med. Chem. 2004, 337, 486.
{(4Z)-4-[(Phenylamino-kN)methylidene]-3,4-dihydro-1H-1-
benzazepine-2,5-dionato-kO5}diphenylboron (7a)
Synthesized according to General Procedure C; reaction time 18.0
h.
(6) Wieking, K.; Knockaert, M.; Leost, M.; Zaharevitz, D. W.;
Meijer, L.; Kunick, C. Arch. Pharm. Pharm. Med. Chem.
2002, 335, 311.
(7) Egert-Schmidt, A.-M.; Dreher, J.; Dunkel, U.; Kohfeld, S.;
Preu, L.; Weber, H.; Ehlert, J. E.; Mutschler, B.; Totzke, F.;
Schächtele, C.; Kubbutat, M. H. G.; Baumann, K.; Kunick,
C. J. Med. Chem. 2010, 53, 2433.
(8) Barnes, K. R.; Blois, J.; Smith, A.; Yuan, H.; Reynolds, F.;
Weissleder, R.; Cantley, L. C.; Josephson, L. Bioconjugate
Chem. 2008, 19, 130.
Mp 215–217 °C.
IR (KBr): 3200, 3065, 3005, 2968, 2908, 1677 cm–1.
1H NMR (600.1 MHz, DMSO-d6): d = 3.07 (s, 2 H, azepine CH2),
7.09–7.12 (m, 2 H, ArH), 7.15–7.22 (m, 11 H, ArH), 7.34–7.36 (m,
4 H, ArH), 7.54 (ddd, J = 8.1, 7.3, 1.5 Hz, 1 H, ArH), 7.73 (dd,
J = 7.9, 1.5 Hz, 1 H, ArH), 8.46 (s, 1 H, CH), 10.41 (s, 1 H, NH).
13C NMR (150.9 MHz, DMSO-d6): d = 33.5 (2° C), 121.6, 123.5,
123.9 (2 C), 126.0 (2 C), 126.6 (4 C), 126.9, 128.4 (2 C), 129.8,
132.8, 133.3 (4 C), 161.5 (3° C), 104.8, 125.0, 138.4, 144.8, 147.1
(2 C), 168.4, 171.9 (4° C).
(9) Marks, D. L.; Bittman, R.; Pagano, R. E. Histochem. Cell
Biol. 2008, 130, 819.
(10) Xia, M.; Wu, B.; Xiang, G. J. Fluorine Chem. 2008, 129,
402.
Anal. Calcd for C29H23BN2O2: C, 78.75; H, 5.24; N, 6.33. Found: C,
78.41; H, 5.18; N, 6.19.
(11) Macedo, F. P.; Gwengo, C.; Lindeman, S. V.; Smith, M. D.;
Gardinier, J. R. Eur. J. Inorg. Chem. 2008, 3200.
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York

2858
N. Tolle et al.
PAPER
(12) Chen, W.-Y.; Gilman, N. W. J. Heterocycl. Chem. 1983, 20,
663.
(17) Liu, Q.-D.; Mudadu, M. S.; Thummel, R.; Tao, Y.; Wang, S.
Adv. Funct. Mater. 2005, 15, 143.
(13) Dutta, M. C.; Chanda, K.; Karim, E.; Vishwakarma, J. N.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2004, 43, 2471.
(14) Al-Saleh, B.; El-Apasery, M. A.; Abdel-Aziz, R. S.; Elnagdi,
M. H. J. Heterocycl. Chem. 2005, 42, 563.
(15) Zhou, Y.; Xiao, Y.; Chi, S.; Qian, X. Org. Lett. 2008, 10,
633.
(18) Kunick, C. Arch. Pharm. (Weinheim, Ger.) 1991, 324, 579.
(19) Reichwald, C.; Shimony, O.; Dunkel, U.; Sacerdoti-Sierra,
N.; Jaffe, C. L.; Kunick, C. J. Med. Chem. 2008, 51, 659.
(20) Xie, X.; Lemcke, T.; Gussio, R.; Zaharevitz, D. W.; Leost,
M.; Meijer, L.; Kunick, C. Eur. J. Med. Chem. 2005, 40, 655.
(21) Schäfer, S.; Ott, I.; Gust, R.; Sheldrick, W. S. Eur. J. Inorg.
Chem. 2007, 3034.
(16) Ulrich, G.; Goze, C.; Goeb, S.; Retailleau, P.; Ziessel, R.
New J. Chem. 2006, 30, 982.
Synthesis 2011, No. 17, 2848–2858 © Thieme Stuttgart · New York