Three-component synthesis of cryofluorescent 2,4-disubstituted 3H-1,5-benzodiazepines - Conformational control of emission properties

Article abstract of DOI:10.1002/ejoc.200800619

2,4-Disubstituted benzodiazepines are readily synthesized in good yields from acyl chlorides, terminal alkynes, and benzene-1,2-diamines by a consecutive one-pot, three-component Sonogashira coupling/Michael addition/ cyclocondensation sequence. These diazepines display intense solid-state fluorescence, but only weak emission in solution at room temperature. The absorption and emission maxima can be controlled by the substitution pattern. Upon cooling, however, the phenomenon of cryofluorescence can be observed. X-ray structure analysis and temperature-dependent NMR indicate that freezing out of conformational interconversions is the source of the thermochromicity observed upon UV excitation. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800619

FULL PAPER
DOI: 10.1002/ejoc.200800619
Three-Component Synthesis of Cryofluorescent 2,4-Disubstituted 3H-1,5-
Benzodiazepines – Conformational Control of Emission Properties
Benjamin Willy,[a] Timea Dallos,[b] Frank Rominger,[c] Jan Schönhaber,[a] and
Thomas J. J. Müller*[a]
Keywords: Benzodiazepines / C–C coupling / Cyclocondensation / Fluorescence / Microwave-assisted reactions / Multicom-
ponent reactions
2,4-Disubstituted benzodiazepines are readily synthesized in
good yields from acyl chlorides, terminal alkynes, and ben-
ever, the phenomenon of cryofluorescence can be observed.
X-ray structure analysis and temperature-dependent NMR
zene-1,2-diamines by a consecutive one-pot, three-compo- indicate that freezing out of conformational interconversions
nent Sonogashira coupling/Michael addition/cyclocondensa- is the source of the thermochromicity observed upon UV ex-
tion sequence. These diazepines display intense solid-state
fluorescence, but only weak emission in solution at room
temperature. The absorption and emission maxima can be
controlled by the substitution pattern. Upon cooling, how-
citation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
3H-1,4-Benzodiazepines 1 and 3H-1,5-benzodiazepines 2
and their dihydro derivatives constitute an important class
of psychopharmaca.[1] In particular, derivatives of 2 have
aroused considerable interest as CNS-active anticonvulsant
drugs[2] and as antianxiety, analgesic, sedative, antidepres-
sive, and hypnotic agents,[3] and also as anti-inflammatory
agents.[4] In addition, their use as in vitro non-nucleoside
inhibitors of HIV-1 reverse transcriptase has also been re-
ported.[5] Besides their biological relevance, benzodiazepine
derivatives have also found application as dyes for acrylic
fibers.[6] Moreover, benzodiazepine derivatives 2 are also
valuable synthons in the preparation of annelated systems
such as triazolo-, oxadiazolo-, oxazino-, or furo-benzo-
diazepines.[7] With respect to expected enhanced pharmaco-
logical activity, syntheses of this class of heterocycles are
currently being intensively pursued.
Among the most frequently used methods for the synthe-
sis of benzodiazepines 2 is the cyclocondensation of ben-
zene-1,2-diamines with 1,3-dicarbonyl compounds[8] or
equivalent 1,3-biselectrophiles such as epoxy ketones, α,β-
unsaturated carbonyl compounds,[9] or β-haloketones.[1a]
A
broad variety of Brønsted and Lewis acids – such as InBr3,
CeCl3/SiO2, lanthanoide triflates, Amberlyst15, Al2O3/
P2O5, or acetic acid – have been utilized to catalyze these
cyclocondensation reactions.[10] In addition, approaches
with ionic liquids[11] or on solid supports have also been
reported.[12] With respect to the interesting pharmaceutical
properties of diazepines, and moreover to the increasing
quest for tailor-made functional π-systems through diver-
sity-oriented strategies,[13] we set out to develop and explore
a concise one-pot synthesis of 1,5-benzodiazepines. As part
of our program directed towards the design of new multi-
component syntheses of heterocycles initiated by Sonoga-
shira cross coupling, we have focused on a cross coupling-
cyclocondensation approach.[14] Here we report on a con-
cise, consecutive one-pot, three-component synthesis of 3H-
1,5-benzodiazepines with flexibility of substitution pattern,
their absorption and emission properties, as well as their
unusual conformationally dependent cryofluorescence.
[a] Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf,
Universitätsstraße 1, 40225 Düsseldorf, Germany
Fax: +49-211-81-14324
E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
[b] Babes-Bolyai University Cluj-Napoca, Faculty of Chemistry
and Chemical Engineering,
Arany Janos Str. No. 11, Cluj-Napoca 400428, Romania
[c] Organisch-Chemisches Institut, Ruprecht-Karls-Universität
Heidelberg,
INF 270, 69120 Heidelberg, Germany
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Cryofluorescent 3H-1,5-Benzodiazepines
Table 1. One-pot, three-component synthesis of 1,5-benzodiazep-
ines 6 under conductive heating conditions.
Results and Discussion
Alkynones are easily accessible through Sonogashira
couplings[15] between acyl chlorides and terminal al-
kynes.[16] We have reported that the use of THF as a solvent
enables a variation in which only one equivalent of triethyl-
amine is applied as a base to achieve an efficient alkynone
synthesis.[17] The resulting alkynones are reactive towards
cyclocondensations with binucleophiles, such as hydrazines,
in a one-pot fashion.[14b,14c,18] Therefore, after reactions be-
tween acyl chlorides 3 and terminal alkynes 4 under modi-
fied Sonogashira conditions for 1 h at room temperature
to furnish the expected alkynones, subsequent addition of
benzene-1,2-diamines 5 and acetic acid gives rise to the for-
mation of benzodiazepines 6, which can be obtained in
moderate to very good yields as yellow solids and oils
(Scheme 1, Table 1). In some cases dielectric heating in a
microwave cavity turned out to be favorable and led to
shorter reaction times (Table 2). However, in most cases
conductive heating proved to give better yields.
Scheme 1. One-pot three-component synthesis of 1,5-benzodiazep-
ines 6.
The structures of the 1,5-benzodiazepines 6 were unam-
1
biguously assigned by H, 13C, and 2D NMR spectroscopy
and mass spectroscopy. Considerable line broadening for
the methylene protons and carbon nuclei at room tempera-
ture suggests that, of the possible tautomers 6–8, only tau-
tomer 6 appears to be populated, but in conjunction with
a dynamic phenomenon (vide infra).[19] In addition, the
structural assignment was corroborated by an X-ray analy-
sis of compound 6f (Figure 1 and Table 6).[20]
The X-ray crystal structure analysis of 6f clearly shows a
locked half-boat conformation with a folding angle of 96°.
1,5-Benzodiazepines 6 would be expected to be prone to
rapid conformational interconversion at elevated tempera-
ture, leveling out the non-equivalence of the methylene pro-
tons. This dynamic process was therefore studied by tem-
perature-dependent NMR spectroscopy in CDCl3 between
218 and 323 K (Figure 2).
At room temperature the methylene protons appear as
extremely broad singlets. The resonances of protons Ha and
Hb of the benzodiazepine 6j are thus barely visible at this
temperature, whereas with increasing temperature a sharp
singlet at δ = 3.30 ppm gradually evolves.
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B. Willy, T. Dallos, F. Rominger, J. Schönhaber, T. J. J. Müller
FULL PAPER
Table 2. One-pot, three-component synthesis of 1,5-benzodiazep- to the anisotropic shielding by the annelated benzene ring.
ines 6 under dielectric heating conditions.
Consequently, the signal at lower field can be assigned to
the endo proton. The coalescence temperature (Tc) is ob-
served at ca. 280 K. Through application of the Eyring
equation the ring flip barrier (∆G*) can be calculated to be
50.1Ϯ1 kJmol–1, which is in good agreement with literature
precedence.[19] Hence, the ring flip rate constant at Tc equals
2512 s–1 (Scheme 2). Likewise, the carbon resonances of the
characteristic methylene groups appearing at δ = 38 ppm
are difficult to assign at room temperature. However, below
–20 °C this signal becomes sharp and can be unambigu-
ously assigned by HETCOR spectra.
Scheme 2. Ring flip of 1,5-benzodiazepine 6j, together with barrier
and kinetic data.
Furthermore, the ring flip barrier (∆G*) for the 2,4-di-
phenyl-substituted 1,5-benzodiazepine was calculated at the
DFT level by use of the B3LYP functional[21] and different
Pople basis sets. The optimized transition state shows a
completely planar 1,5-benzodiazepine structure of C2v sym-
metry (Figure 3).
Figure 1. Molecular structure of compound 6f.
Figure 3. Optimized transition state of the 2,4-diphenyl-substituted
1,5-benzodiazepine.
Lowering the temperature to 250 K results in a splitting
into two signals, which upon further cooling to 218 K re-
solve further into two doublets at δ = 2.19 and 4.46 ppm.
Use of the triple-zeta basis set 6-311G furnishes a ring
The coupling constants, with J = 11 Hz, are characteristic flip barrier (∆G2϶98) of 47.3 kJmol–1 (Table 3). Again, these
for geminal coupling. The huge signal separation (∆ν) of the results reproduce well the experimental data of this work
two methylene resonances, by 1131 Hz, can be attributed and other literature precedence.[19]
1
Figure 2. Temperature-dependent H NMR spectra of compound 6j, selected signals (recorded in CDCl3, 500 MHz).
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Cryofluorescent 3H-1,5-Benzodiazepines
Table 3. Energies of the ring flip barrier (∆G*) of the 2,4-diphenyl- emission properties. In solution, the longest-wavelength ab-
substituted 1,5-benzodiazepine as computed with the B3LYP func-
tional.
sorption maxima (λmax,abs) of 6 are found in the near UV
between 270 and 300 nm, with molar extinction coefficients
∆G2϶98[kJmol–1]
(ε) ranging from 16400 to 44400 Lmol–1 cm–1. In solution
at room temperature, all compounds are essentially nonflu-
orescent. At concentrations such as those used for the ab-
sorption measurements (10–3 to 10–4 ) weak emission sig-
nals can just be detected, revealing large Stokes shifts rang-
ing from 2800 to 8000 cm–1. These emission maxima
(λmax,em) lie between 385 and 516 nm. For compound 6c,
the fluorescence quantum yield (Φf) was determined and
found to be less than 0.01 (Table 4). Interestingly, the inten-
sities of the fluorescence signals increase slightly with di-
lution of the solutions, but at a concentration of 10–5  the
residual fluorescence vanishes completely. From the NMR
dynamic behavior, the origin of minimal fluorescence can
be attributed to the ring flip, which opens up a facile path-
way for deactivation of the excited state by internal conver-
sion. Therefore, in the solid state, in which the ring flip is
frozen out, fluorescence occurs to its greatest extent, all so-
lid 1,5-benzodiazepines 6 hence displaying intense fluores-
cence. The emission maxima of compounds 6 in the solid
state (λmax,em) are found between 420 and 535 nm (i.e., they
are red-shifted by approximately 100 nm in comparison
with the maxima in solution; Figure 5, Table 4).
Entry
Method
1
2
3
4
5
B3LYP/3-21G
B3LYP/3-21G*
B3LYP/6-31G
B3LYP/6-31G**
B3LYP/6-311G
36.8
39.6
41.2
44.0
47.3
The 1,5-benzodiazepines 6 are intensively yellow to
orange solids. Upon addition of trifluoroacetic acid to a
dichloromethane solution of 6i the deep violet benzodiazep-
inium salt is formed (Figure 4). Protonation causes a de-
crease in the absorption band at 359 nm and a concomitant
increase in the band at 550 nm, caused by the formation of
a horseshoe-shaped trimethine cyanine system.[22]
Figure 4. Absorption (recorded in CH2Cl2 at 293 K) spectra of 6i
(solid line) and 6i-H+ (dotted line).
Our diversity-oriented one-pot approach to 1,5-benzodi-
azepines gives rise to flexibility in substitution patterns, and
the structure/property relationships can be studied for elec-
tronic absorption and emission spectra (Table 4). Minute
substituent variations strongly affect both absorption and Figure 5. Solid state emission spectrum of 6c (recorded at 293 K).
Table 4. Selected electronic properties (UV/Vis and fluorescence data, and Stokes shifts ∆ν) of the 1,5-benzodiazepines 6.
˜
Compound
Absorption[a]
λmax,abs [nm] (ε)
Emission in solution[a]
Stokes shift ∆ν[b] [cm–1]
Emission solid state
˜
λmax,em [nm]
λmax,em [nm]
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
345 (sh), 285 (29900)
347 (sh), 275 (16400)
370 (sh), 284 (44400)
348 (sh), 266 (21600)
335 (sh), 268 (18800)
341 (sh), 291 (41300)
349 (sh), 272 (29200)
337 (sh), 276 (45400)
345 (sh), 276 (23100)
359 (sh), 284 (27200)
333 (sh), 272 (30900)
348 (sh), 294 (14500)
331 (sh), 285 (33700)
366 (sh), 292 (29300)
357 (sh), 284 (24500)
442
385
516
388
458
420
418
412
385
450
447
416
388
436
494
6400
2800
7600
3000
8000
5500
4700
5400
3000
5600
7700
4700
4400
4400
7800
502
509
527
508
535
493
510
426
420
525
490
510
495
530
517
[a] Recorded in CH2Cl2, 293 K at c = 10–3 to 10–4 . Emissions in solution are measured without further dilution. [b] ∆ν = λ
–
˜
max,abs
λmax,em [cm–1].
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B. Willy, T. Dallos, F. Rominger, J. Schönhaber, T. J. J. Müller
FULL PAPER
Besides locking the ring flip by crystallization, decreasing HOMO is predominantly localized in the central benzodi-
the temperature should also cause thermochromic fluores- azepinium core, whereas the LUMO is delocalized over the
cence in solution, and solutions of 1,5-benzodiazepines 6 whole structural framework. In the LUMO the central
cooled to –78 °C thus indeed show the phenomenon of cry- methine carbon atom is part of the nodal plane, and no
ofluorescence; at low temperature the ring flip is frozen and coefficient is therefore found (Figure 6).
fluorescence appears. The emissions at –78 °C are found at
about the same wavelengths as in the solid state, indicating ponent reaction to ortho-aminothiophenol (9) as a bisnucleo-
significant aggregation of the fluorophores. phile, giving rise to benzo-thiazepine. However, upon sub-
Finally, we sought to expand the scope of the three-com-
The spectral properties suggested that a closer look jection of acyl chloride 3a, alkyne 4c and ortho-aminothio-
should be taken at the electronic structure of 1,5-benzodia- phenol (9) to the sequence the yellow quinoline 10 was-
zepines. Calculations based upon a starting geometry de- obtained in 40% yield. According to literature precedence
rived from the X-ray structure analysis of 6f were therefore the initially formed benzo-thiazepine is not stable under the
carried out with use of the B3LYP functional[21] and the reaction conditions, and after sulfur extrusion the quinoline
Pople 6-311++G basis set for geometry optimization. The is generated (Scheme 3).[23]
same methodology was then used to scrutinize the influence
of push–pull substitution on the properties of the electronic
ground and excited states. These computations were carried
out for 1,5-benzodiazepine 6n and the corresponding
benzodiazepinium cation 6n-H+. The frontier orbitals of
the push–pull systems 6n and 6n-H+ thus clearly show that
the longest-wavelength absorption band, which can be as-
signed to HOMO–LUMO transitions, possesses significant
charge transfer character (Figure 6). For structure 6n, elec-
tron density is shifted upon photonic excitation from the p-
Scheme 3. One-pot three-component synthesis of quinoline 10.
methoxyphenyl donor moiety and the benzo ring, localized
in the HOMO, to the p-nitrophenyl acceptor unit, where
LUMO coefficients are largest.
Conclusions
In conclusion, we have established a versatile one-pot,
three-component synthesis of 2,4-disubstituted 3H-benzo-
[b][1,4]-diazepines in a consecutive coupling/addition/cy-
clocondensation sequence. Interestingly, all representatives
are highly fluorescent in the solid state, but essentially non-
fluorescent in solution at room temperature. Upon cooling
the solutions show cryofluorescence that can be attributed
to a freezing of the ring flip and aggregation. This thermo-
responsive behavior of fluorophores as a consequence of
restricted conformational changes opens new avenues for
the development of tailor-made emitters in thermosensors
and the fluorescence labeling of biomolecules, surfaces, or
mesoporous materials. Studies expanding this novel modu-
lar approach to enhancing molecular diversity in targets of
special interest to pharmaceutical and materials science ap-
plications are currently underway.
Experimental Section
Figure 6. DFT-computed frontier orbitals of 1,5-benzodiazepines
6n (left) and 6n-H+ (right), LUMOs (top) and HOMOs (bottom).
General Considerations: All reactions involving water-sensitive
compounds were carried out in flame-dried glassware under argon.
Reagents and catalysts were purchased as reagent grade and were
used without further purification. Solvents were dried with a sol-
vent purification system. Flash column chromatography: silica
gel 60, mesh 230–400. TLC: silica gel plates (60 F254). 1H NMR,
13C NMR, DEPT, NOESY, COSY, HMQC, and HMBC spectra
were recorded with a 500 MHz NMR spectrometer in CDCl3 as
solvent. The assignments of quaternary Cquat, CH, CH2, and CH3
were made on the basis of DEPT spectra. Mass spectra were re-
As might be expected, push–pull substitution causes red
shifts both in absorption and in emission. Therefore, this
facile and versatile synthetic route is perfectly suited for
fine-tuning of the solid-state fluorescence colors of 1,5-
benzodiazepines. For the cyanine system 6n-H+, not only is
planarization of the conjugated seven-membered ring
found, as indicated by a small folding angle of 18°, but the
electronic structure has also changed significantly. The corded with a quadruple spectrometer. The melting points are un-
4800
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Eur. J. Org. Chem. 2008, 4796–4805

Cryofluorescent 3H-1,5-Benzodiazepines
corrected. Elemental analyses were carried out in the microanalyti-
cal laboratory of the Pharmazeutisches Institut of the Heinrich-
Heine-Universität Düsseldorf. Dielectric heating was performed in
a single-mode microwave cavity producing continuous irradiation
at 2450 MHz.
(CH), 139.8 (Cquat), 141.0 (Cquat), 142.9 (Cquat), 148.7 (Cquat), 152.7
(Cquat), 161.9 (Cquat) ppm. IR (KBr): ν = 2958 (m), 1561 (w), 1522
˜
(w), 1463 (m), 1409 (w), 1274 (s), 1177 (w), 1125 (m), 1073 (m),
1029 (m), 910 (m), 847 (m), 800 (m), 759 (s), 695 (s), 602 (w) cm–1.
UV/Vis (CH2Cl2): λmax (ε) = 285 (29900), 313 (25000), 345 nm
(12200). Emission (CH2Cl2): λmax (Stokes shift)
= 442 nm
General Procedure for the Synthesis of 2,4-Disubstituted 3H-1,5-
Benzodiazepines 6 under Conductive Heating Conditions (GP A): In
a 20 mL Schlenk tube, PdCl2(PPh3)2 (15 mg, 0.02 mmol) and CuI
(8 mg, 0.04 mmol) were dissolved in degassed THF (4 mL). Acyl
chloride 3 (1.00 mmol), alkyne 4 (1.00 mmol), and triethylamine
(1.05 mmol) were then added to this orange solution. The reaction
mixture was stirred at room temperature for 1 h. Finally, the ben-
zene-1,2-diamine 5 (1.10 mmol), followed by glacial acetic acid
(1.0 mL), were added to this suspension, and the reaction mixture
was heated at 90 °C in an oil bath for 16 h. After the system had
cooled to room temperature, the solvent was removed under re-
duced pressure and the crude products were purified by flash
chromatography on silica gel (hexane/ethyl acetate) to afford the
analytically pure benzodiazepines 6 (for experimental details see
Table 5, Entries 1–12).
(6400 cm–1). Emission (solid state): λmax = 502 nm. EI MS (70 eV):
m/z (%) = 326 (13) [M]+·, 272 (16), 244 (22), 238 (100), 90 (23), 107
(21), 92 (32), 77 (55), 76 (14), 64 (14), 57 (14). C22H18N2O (326.39):
calcd. C 80.96, H 5.56, N 8.58; found C 80.44, H 5.60, N 8.45.
4-[(4-Methoxyphenyl)-3H-1,5-benzodiazepin-2-yl]benzonitrile (6b):
Compound 6b was obtained as a yellow powder by GP A. m.p.
1
3
168 °C. H NMR (500 MHz, CDCl3): δ = 3.80 (s, 3 H), 6.90 (d, J
4
= 8.9 Hz, 2 H), 7.31 (dq, 3J = 7.2, J = 2.2 Hz, 2 H), 7.53–7.56 (m,
2 H), 7.64 (d, 3J = 8.6 Hz, 2 H), 7.86 (d, 3J = 8.9 Hz, 2 H), 8.01 (d,
3J = 8.6 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 34.5
(CH2), 55.4 (CH3), 113.6 (Cquat), 114.1 (2ϫCH), 118.3 (Cquat),
125.3 (CH), 126.1 (CH), 128.4 (2ϫCH), 128.68 (CH), 128.74 (CH),
129.3 (Cquat), 130.0 (2ϫCH), 132.3 (2ϫCH), 139.9 (Cquat), 141.0
(Cquat), 141.2 (Cquat), 151.6 (Cquat), 152.8 (Cquat), 161.8
(Cquat) ppm. IR (KBr): ν = 2954 (s), 2230 (s), 1601 (m), 1510 (w),
˜
General Procedure for the Synthesis of 2,4-Disubstituted 3H-1,5-
Benzodiazepines 6 under Microwave Conditions (GP B): In a 10 mL
microwave tube, PdCl2(PPh3)2 (15 mg, 0.02 mmol) and CuI (8 mg,
0.04 mmol) were dissolved in degassed THF (4 mL). Acyl chloride
1463 (s), 1381 (m), 1285 (s), 1123 (s), 1074 (s), 1038 (m), 841 (m),
745 (s), 705 (m), 652 (w), 544 (w) cm–1. UV/Vis (CH2Cl2): λmax (ε)
= 275 (16400), 324 (9100), 347 nm (6300). Emission (CH2Cl2): λmax
(Stokes shift) = 385 nm (2800 cm–1). Emission (solid state): λmax
=
3
(1.00 mmol), alkyne
4
(1.00 mmol), and triethylamine
509 nm. EI MS (70 eV): m/z (%) = 352 (25), 351 (100) [M]+, 350
(53), 336 (28), 320 (21), 307 (13), 299 (19), 298 (24), 297 (57), 296
(49), 271 (18), 270 (10), 269 (52), 263 (14), 262 (19), 253 (13), 252
(56), 249 (23), 219 (10), 191 (11), 190 (30), 135 (82), 133 (37), 127
(16), 107 (12), 92 (14), 77 (22). C23H17N3O (351.40): calcd. C 78.61,
H 4.88, N 11.96; found: C 78.60, H 4.80, N 12.17.
(1.05 mmol) were then added to this orange solution. The reaction
mixture was stirred at room temperature for 1 h. Finally, the ben-
zene-1,2-diamine 5 (1.10 mmol), followed by glacial acetic acid
(1.0 mL), were added to this suspension, and the reaction mixture
was heated at 120 °C in the microwave cavity for 1 h. After the
system had cooled to room temperature, the solvent was removed
under reduced pressure and the crude products were purified by
flash chromatography on silica gel (hexane/ethyl acetate) to afford
the analytically pure 1,5-benzodiazepines 6 or the quinoline 10 (for
experimental details see Table 5, Entries 13–16).
2-(4-Nitrophenyl)-4-p-tolyl-3H-1,5-benzodiazepine (6c): Compound
6c was obtained as a yellow powder by GP A; m.p. 161 °C.
1H NMR (500 MHz, CDCl3): δ = 2.39 (s, 3 H), 7.26 (d, 3J = 8.2 Hz,
3
2 H), 7.35–7.40 (m, 2 H), 7.60–7.62 (m, 2 H), 7.86 (d, J = 8.2 Hz,
2-(4-Methoxyphenyl)-4-phenyl-3H-1,5-benzodiazepine (6a): Com-
pound 6a was obtained as a yellow resin by GP A. 1H NMR
2 H), 8.11 (d, 3J = 9.0 Hz, 2 H), 8.24 (d, 3J = 9.0 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 21.4 (CH3), 34.8 (CH2), 123.8
(500 MHz, CDCl3): δ = 3.85 (s, 3 H), 6.95 (d, 3J = 8.7 Hz, 2 H), (2ϫCH), 125.5 (CH), 126.3 (CH), 128.2 (2ϫCH), 128.8 (4ϫCH),
3
4
7.30–7.36 (m, 5 H), 7.37 (dq, J = 7.1, J = 1.3 Hz, 2 H), 7.60 (dd,
3J = 7.5, 4J = 1.6 Hz, 2 H), 7.94 (d, 3J = 8.7 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 34.7 (CH2), 55.4 (CH3), 123.8
(2ϫCH), 125.4 (CH), 126.3 (CH), 128.7 (CH), 128.7 (2ϫCH),
128.8 (CH), 129.2 (2ϫCH), 129.4 (Cquat), 130.0 (2ϫCH), 131.0
129.6 (2ϫCH), 134.0 (Cquat), 139.9 (Cquat), 141.0 (Cquat), 141.6
(Cquat), 142.9 (Cquat), 148.7 (Cquat), 151.3 (Cquat), 153.3
(Cquat) ppm. IR (KBr): ν = 2923 (m), 2853 (w), 1595 (m), 1562 (w),
˜
1542 (w), 1521 (s), 1458 (w), 1436 (m), 1407 (w), 1376 (w), 1341
(s), 1323 (m), 1257 (m), 1186 (w), 1112 (m), 1051 (w), 1005 (m),
Table 5. Experimental details of the synthesis of 2,4-disubstituted 3H-1,5-benzodiazepines 6.
Entry
mg (mmol) of acyl chloride 3 mg (mmol) of alkyne 4
mg (mmol) of benzene-1,2-diamine 5 mg (% yield) of 1,5-benzodiazepines 6
1
2
3
4
5
6
7
8
171 (1.00), 3a
171 (1.00), 3a
155 (1.00), 3b
147 (1.00), 3c
147 (1.00), 3c
147 (1.00), 3c
147 (1.00), 3c
176 (1.00), 3d
105 (1.00), 3e
186 (1.00), 3f
176 (1.00), 3d
147 (1.00), 3c
171 (1.00), 3a
171 (1.00), 3a
186 (1.00), 3f
176 (1.00), 3d
103 (1.00), 4a
128 (1.00), 4b
148 (1.00), 4c
128 (1.00), 4b
83 (1.00), 4d
104 (1.00), 4e
161 (1.00), 4f
159 (1.00), 4g
161 (1.00), 4f
83 (1.00), 4d
83 (1.00), 4d
104 (1.00), 4e
133 (1.00), 4h
148 (1.00), 4c
83 (1.00), 4d
148 (1.00), 4c
119 (1.10), 5a
119 (1.10), 5a
119 (1.10), 5a
119 (1.10), 5a
119 (1.10), 5a
119 (1.10), 5a
195 (1.10), 5b
195 (1.10), 5b
195 (1.10), 5b
195 (1.10), 5b
195 (1.10), 5b
195 (1.10), 5b
119 (1.10), 5a
119 (1.10), 5a
119 (1.10), 5a
138 (1.10), 9
287 (88), 6a
187 (53), 6b
160 (45), 6c
177 (54), 6d
164 (58), 6e
164 (54), 6f
275 (64), 6g
246 (54), 6h
314 (81), 6i
336 (86), 6j
224 (59), 6k
164 (44), 6l
225 (63), 6m
149 (40), 6n
151 (47), 6o
145 (40), 10
9
10
11
12
13
14
15
16
Eur. J. Org. Chem. 2008, 4796–4805
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4801

B. Willy, T. Dallos, F. Rominger, J. Schönhaber, T. J. J. Müller
FULL PAPER
867 (m), 854 (s), 786 (w), 767 (s), 753 (m), 733 (w), 691 (m), 614
(s), 1466 (m), 1425 (s), 1356 (w), 1325 (s), 1263 (m), 1215 (m), 1198
(w), 578 (m) cm–1. UV/Vis (CH2Cl2): λmax (ε) = 268 (44400), 284 (m), 1155 (w), 1115 (w), 1089 (w), 1054 (m), 1037 (m), 1089 (m),
(40100), 313 (30300), 343 (22000), 370 nm (16600). Emission
(CH2Cl2): λmax (Stokes shift) = 516 nm (7600 cm–1). Emission (so-
lid state): λmax = 527 nm. EI MS (70 eV): m/z (%) = 356 (27) [M +
H]+·, 355 (100) [M]+·, 354 (35) [M – H]+, 341 (11), 340 (42), 309
(11), 308 (24), 307 (10), 294 (17), 293 (11), 292 (22), 233 (22), 117
994 (w), 981 (m), 898 (w), 874 (m), 758 (s), 741 (m), 705 (s), 681
(s), 656 (w), 622 (m), 517 (s) cm–1. UV/Vis (CH2Cl2): λmax (ε) =
259 (40900), 274 (40100), 291 (41300), 341 nm (26000). Emission
(CH2Cl2): λmax (Stokes shift) = 420 nm (5500 cm–1). Emission (so-
lid state): λmax = 493 nm. EI MS (70 eV, m/z ): 304 [M + H]+ (25),
(35), 116 (10), 115 (23), 102 (11), 91 (22), 90 (14), 89 (12), 76 (11). 303 [M]+· (100), 302 (40), 271 (11), 270 (37), 225 (12), 195 (34), 194
C22H17N3O2 (355.39): calcd. C 74.35, H 4.82, N 11.82; found
C 74.05, H 4.94, N 11.61.
(38), 167 (14), 109 (25), 90 (17), 89 (19), 79 (11), 78 (55), 77 (12),
76 (14), 69 (12), 65 (24), 64 (13), 63 (18), 52 (12), 51 (32), 50 (12), 45
(13), 39 (26). C18H13N2S (303.38): calcd. C 71.26, H 4.32, N 13.85;
found C 70.81, H 4.40, N 13.57.
4-[(Thien-2-yl)-3H-1,5-benzodiazepin-2-yl]benzonitrile (6d): Com-
pound 6d was obtained as a yellow solid by GP A; m.p. 155 °C.
3
1H NMR (500 MHz, CDCl3): δ = 3.60 (br. s, 2 H), 7.09 (dd, J =
Table 6. Crystal data and structure refinement for 6f.
3
3
4
5.1, J = 3.8 Hz, 1 H), 7.34–7.37 (m, 2 H), 7.48 (dd, J = 5.1, J =
3
4
Structure
6f
1.0 Hz, 1 H), 7.55–7.59 (m, 2 H), 7.63 (dd, J = 3.8, J = 1.0 Hz,
1 H), 7.74 (d, 3J = 8.7 Hz, 2 H), 8.15 (d, 3J = 8.7 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 35.1 (CH2), 113.9 (Cquat), 118.3
(Cquat), 125.7 (CH), 126.4 (CH), 127.9 (CH), 128.5 (2ϫCH), 128.7
(CH), 128.87 (CH), 128.91 (CH), 131.7 (CH), 132.4 (2ϫCH), 140.2
(Cquat), 140.3 (Cquat), 140.9 (Cquat), 143.6 (Cquat), 148.0 (Cquat),
Empirical formula
Formula weight
Temperature
Wavelength
C18H13N3S
303.37
200(2) K
0.71073 Å
Crystal system
Space group
Z
orthorhombic
Pnma
4
151.7 (Cquat) ppm. IR (KBr): ν = 2956 (w), 2230 (s), 1542 (w), 1425
˜
(w), 1289 (s), 1124 (m), 1076 (m), 852 (s), 803 (s), 763 (s), 701 (s),
621 (m), 559 (m), 537 (w), 517 (w) cm–1. UV/Vis (CH2Cl2): λmax (ε)
= 266 (21600), 304 (14400), 325 (13100), 348 nm (10400). Emis-
sion (CH2Cl2): λmax (Stokes shift) = 338 nm (3000 cm–1). Emission
(solid state): λmax = 508 nm. EI MS (70 eV): m/z = 328 [M + H]+
(24), 327 [M]+· (100), 326 (81), 295 (17), 294 (76), 275 (21), 274
(37), 273 (56), 272 (80), 252 (13), 239 (15), 238 (20), 219 (16), 210
(30), 209 (19), 190 (14), 164 (10), 149 (15), 128 (11), 127 (22), 111
(69), 109 (49), 102 (10), 84 (14), 83 (15), 39 (20). C20H13N2S
(327.40): calcd. C 73.37, H 4.00, N 12.83; found C 73.51, H 4.19,
N 12.81.
Unit cell dimensions
a = 17.721(3) Å, α = 90°
b = 16.894(3) Å, β = 90°
c = 4.8192(9) Å, γ = 90°
1442.7(4) Å3
1.40 gcm–3
Volume
Density (calculated)
Absorption coefficient µ
Crystal shape
Crystal size
Crystal color
Theta range for data collection 2.6–28.4°
Index ranges
Reflections collected
0.22 [mm–1]
polyhedron
0.31ϫ0.20ϫ0.12 mm3
yellow
–8 Յ h Յ 23, –17 Յ k Յ 18, –6 Յ l Յ 3
4911
Independent reflections
Observed reflections
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I Ͼ 2σ(I)]
Largest diff. peak and hole
1602 [R(int) = 0.0356]
1062 [I Ͼ2σ(I)]
2-Butyl-4-(thien-2-yl)-3H-1,5-benzodiazepine (6e): Compound 6e
was obtained as a yellow resin by GP A. 1H NMR (500 MHz,
CDCl3): δ = 0.91 (t, 3J = 7.4 Hz, 3 H), 1.38 (sext, 3J = 7.4 Hz, 2 H),
1.73 (q, 3J = 7.6 Hz, 2 H), 2.57 (t, 3J = 7.6 Hz, 2 H), 3.23 (br. s,
2 H), 7.14–7.16 (m, 1 H), 7.26–7.30 (m, 2 H), 7.44–7.47 (m, 1 H),
7.51–7.53 (m, 2 H), 7.64–7.65 (m, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.8 (CH3), 22.3 (CH2), 28.2 (CH2), 38.4 (CH2), 40.1
(CH2), 125.0 (CH), 125.1 (CH), 127.7 (CH), 127.8 (CH), 128.4
(CH), 128.8 (CH), 131.3 (CH), 140.0 (Cquat), 140.7 (Cquat), 144.2
semiempirical from equivalents
0.97 and 0.93
full-matrix least-squares on F2
1602/47/108
1.04
R1 = 0.048, wR2 = 0.119
0.37 and –0.23 eÅ–3
(Cquat), 148.4 (Cquat), 161.4 (Cquat) ppm. IR (KBr): ν = 2956 (s),
˜
Methyl 4-[7,8-Dichloro-4-(thien-2-yl)-3H-1,5-benzodiazepin-2-yl]-
benzoate (6 g): Compound 6g was obtained as a yellow solid by
GP A; m.p. 192 °C. 1H NMR (500 MHz, CDCl3): δ = 3.94 (s, 3 H),
3.96 (br. s, 2 H), 7.08 (dd, J = 5.0, J = 3.8 Hz, 1 H), 7.49 (dd, J
= 5.0, 4J = 1.0 Hz, 1 H), 7.65 (dd, 3J = 3.8, 4J = 1.0 Hz, 1 H),
7.676 (s, 1 H), 7.684 (s, 1 H), 8.08–8.13 (m, 4 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 35.6 (CH2), 52.4 (CH3), 127.3 (CH), 128.0
(CH), 128.2 (2ϫCH), 128.9 (Cquat), 129.5 (Cquat), 129.6 (CH),
129.7 (CH), 129.9 (2ϫCH), 132.2 (Cquat), 132.4 (CH), 139.5
(Cquat), 139.9 (Cquat), 140.3 (Cquat), 143.2 (Cquat), 149.3 (Cquat),
2927 (s), 2870 (m), 1630 (m), 1603 (m), 1573 (s), 1544 (w), 1525
(w), 1460 (m), 1424 (s), 1358 (w), 1313 (m), 1265 (m), 1206 (m),
1110 (w), 1059 (w), 981 (w), 856 (m), 762 (s), 714 (s), 622 (w) cm–1.
UV/Vis (CH2Cl2): λmax (ε) = 268 (18800), 288 (14500), 335 nm
3
3
3
(12300). Emission (CH2Cl2): λmax (Stokes shift)
= 458 nm
(8000 cm–1), 500. Emission (solid state): λmax = 535 nm. EI MS
(70 eV ): m/z (%) = 282 (5) [M]+·, 241 (18), 240 (100), 207 (14), 200
(11), 109 (15). C17H18N2S (282.40): calcd. C 72.30, H 6.42, N 9.92;
found C 72.05, H 6.44, N 9.81.
2-(Pyridin-2-yl)-4-(thien-2-yl)-3H-1,5-benzodiazepine (6f): Com-
pound 6f (Table 6) was obtained as light yellow crystals by GP A;
m.p. 130 °C. 1H NMR (500 MHz, CDCl3): δ = 4.03 (br. s, 2 H),
154.0 (Cquat), 166.3 (Cquat) ppm. IR (KBr): ν = 2961 (s), 2873 (s),
˜
1723 (s), 1654 (w), 1583 (s), 1517 (w), 1447 (m), 1379 (w), 1277 (s),
1192 (w), 1277 (s), 1121 (s), 1074 (m), 1017 (m), 879 (w), 855 (w),
798 (w), 768 (m), 744 (m), 721 (m), 552 (w), 520 (w) cm–1. EI MS
(70 eV ): m/z (%) = 432 (16), 431 (20), 430 (69), 429 (48), 428 (100),
427 (43) [M]+·, 397 (47), 396 (14), 395 (50), 371 (43), 370 (17), 369
(60), 268 (14), 109 (87). UV/Vis (CH2Cl2): λmax (ε) = 272 (29200),
349 nm (13900). Emission (CH2Cl2): λmax (Stokes shift) = 418 nm
3
7.05–7.08 (m, 1 H), 7.32–7.38 (m, 3 H), 7.43 (d, J = 5.0 Hz, 1 H),
3
4
7.57–7.61 (m, 2 H), 7.76 (dt, J = 8.0, J = 1.0 Hz, 1 H), 8.11 (d,
3J = 3.7 Hz, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.76 (d, J = 4.8 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 32.8 (CH2), 123.2
(CH), 124.8 (CH), 125.2 (CH), 126.0 (CH), 127.7 (CH), 128.7
(CH), 128.8 (CH), 130.9 (CH), 131.2 (CH), 136.6 (CH), 140.8
3
3
(4700 cm–1). Emission (solid state): λmax
=
510 nm.
(Cquat), 140.9 (Cquat), 144.0 (Cquat), 148.7 (CH), 150.3 (Cquat), 153.7 C21H14Cl2N2O2S (429.32): calcd. C 58.75, H 3.29, N 6.53; found
(Cquat), 154.9 (Cquat) ppm. IR (KBr): ν = 3054 (w), 1596 (m), 1576 C 58.56, H 3.38, N 6.40.
˜
4802
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4796–4805

Cryofluorescent 3H-1,5-Benzodiazepines
2-(4-tert-Butylphenyl)-7,8-dichloro-4-(4-chlorophenyl)-3H-1,5-benzo- (30), 347 (100), 346 (17). C19H17Cl2N3O2 (390.26): calcd. C 58.47,
diazepine (6h): Compound 6h was obtained as a light yellow solid
by GP A; m.p. 97 °C. 1H NMR (500 MHz, CDCl3): δ = 1.33 (s,
9 H), 3.72 (br. s, 2 H), 7.40 (d, 3J = 8.4 Hz, 2 H), 7.45 (d, 3J =
H 4.39, N 10.77; found C 58.50, H 4.33, N 11.21.
2-Butyl-7,8-dichloro-4-(4-chlorophenyl)-3H-1,5-benzodiazepine (6k):
1
Compound 6k was obtained as a yellow resin by GP A. H NMR
3
8.3 Hz, 2 H), 7.67 (s, 1 H), 7.68 (s, 1 H), 7.88 (d, J = 8.3 Hz, 2 H),
3
3
(500 MHz, CDCl3): δ = 0.85 (t, J = 7.4 Hz, 3 H), 1.29 (sext, J =
7.88 (d, 3J = 8.4 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 32.1 (3ϫCH3), 34.8 (CH2), 34.9 (Cquat), 125.9 (2ϫCH), 128.0
(2ϫCH), 128.7 (Cquat), 128.98 (Cquat), 129.04 (2ϫCH), 129.5
(2ϫCH), 129.75 (CH), 129.80 (CH), 133.7 (Cquat), 135.1 (Cquat),
137.4 (Cquat), 139.7 (Cquat), 140.1 (Cquat), 154.0 (Cquat), 154.9
3
3
7.4 Hz, 2 H), 1.60 (q, J = 7.5 Hz, 2 H), 2.49 (t, J = 7.5 Hz, 2 H),
3
3.10 (br. s, 2 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.54 (s, 1 H), 7.60 (s,
1 H), 7.94 (d, 3J = 8.6 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.7 (CH3), 22.2 (CH2), 28.0 (CH2), 37.7 (CH2), 40.0
(CH2), 128.3 (Cquat), 128.6 (Cquat), 129.0 (CH), 129.1 (2ϫCH),
129.5 (3ϫCH), 134.9 (Cquat), 137.5 (Cquat), 139.66 (Cquat), 139.72
(Cquat), 155.0 (Cquat) ppm. IR (KBr): ν = 2964 (s), 1590 (s), 1560
˜
(s), 1491 (m), 1446 (s), 1400 (m), 1364 (w), 1306 (s), 1192 (s), 1119
(s), 1094 (s), 1012 (s), 942 (w), 888 (m), 858 (m), 839 (m), 807 (s),
750 (w), 723 (w), 678 (w), 648 (w), 571 (s) cm–1. UV/Vis (CH2Cl2):
λmax (ε) = 276 (45400), 337 nm (15400). Emission (CH2Cl2): λmax
(Cquat), 153.3 (Cquat), 162.5 (Cquat) ppm. IR (KBr): ν = 2957 (s),
˜
2870 (s), 1655 (m), 1592 (s), 1490 (s), 1449 (s), 1399 (m), 1290 (m),
1179 (m), 1092 (s), 1011 (s), 886 (m), 842 (m), 752 (w), 675
(m) cm–1. UV/Vis (CH2Cl2): λmax (ε) = 272 (30900), 330 nm
(Stokes shift) = 412 nm (5400 cm–1). Emission (solid state): λmax
=
(10200). Emission (CH2Cl2): λmax (Stokes shift)
= 447 nm
426 nm. EI MS (70 eV ): m/z (%) = 458 (8), 456 (19), 454 (16)
[M]+·, 399 (19), 397 (21), 353 (17), 351 (21), 317 (19), 315 (14), 299
(14), 298 (11), 297 (12), 283 (19), 281 (19), 277 (42), 276 (15), 275
(60), 241 (24), 161 (26), 159 (13), 149 (11), 144 (20), 143 (19), 141
(36), 139 (100), 137 (19), 129 (17), 117 (12), 116 (17), 115 (32), 113
(19), 111 (59), 105 (26), 103 (17), 102 (16), 101 (17), 91 (22), 77
(17), 76 (12), 75 (24), 71 (11), 69 (10), 58 (17), 57 (51), 55 (16), 43
(84), 41 (50), 40 (12), 39 (12). C25H21Cl3N2 (455.81): calcd. C 65.88,
H 4.64, N 6.15; found C 65.57, H 4.71, N 6.04.
(7700 cm–1). Emission (solid state): λmax = 490 nm. EI MS (70 eV):
m/z (%) = 382 [37Cl,37Cl,35Cl M]+· (2), 380 [37Cl,35Cl,35Cl M]+· (4),
378 [35Cl,35Cl,35Cl M]+· (4), 340 [37Cl,37Cl,35Cl M – C3H6]+· (32),
338 [37Cl,35Cl,35Cl M – C3H6]+· (97), 336 [35Cl,35Cl,35Cl M –
C3H6]+· (100), 300 (10), 299 (10), 298 (13), 296 (12), 200 (14), 193
(12), 191 (37), 139 (13), 137 (14). C19H17Cl3N2 (379.71): calcd.
C 60.10, H 4.51, N 7.38; found C 60.41, H 4.19, N 7.35.
7,8-Dichloro-2-(pyridin-2-yl)-4-(thien-2-yl)-3H-1,5-benzodiazepine (6l):
Compound 6l was obtained as a light yellow crystals by GP A;
m.p. 269 °C. 1H NMR (500 MHz, CDCl3): δ = 1.65 (br. s, 2 H),
7.08 (t, 3J = 4.4 Hz, 1 H), 7.39 (dd, 3J = 6.7, 4J = 4.9 Hz, 1 H),
7.46 (d, 3J = 5.0 Hz, 1 H), 7.69 (s, 2 H), 7.78 (dt, 3J = 7.6, 4J =
1.0 Hz, 1 H), 8.14 (d, 3J = 3.7 Hz, 1 H), 8.32 (d, 3J = 14.0 Hz, 1 H),
Methyl 4-(7,8-Dichloro-4-cyclopropyl-3H-1,5-benzodiazepin-2-yl)-
benzoate (6i): Compound 6i was obtained as a light greenish pow-
der by GP A; m.p. 118 °C. 1H NMR (500 MHz, CDCl3): δ = 0.89–
0.96 (m, 4 H), 1.85–1.91 (m, 1 H), 3.32 (br. s, 2 H), 3.96 (s, 3 H),
3
3
7.49 (s, 1 H), 7.61 (s, 1 H), 8.09 (d, J = 8.3 Hz, 2 H), 8.15 (d, J =
3
8.76 (d, J = 4.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
8.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ
=
12.2
33.2 (CH2), 123.3 (CH), 125.2 (CH), 127.9 (CH), 128.5 (Cquat),
129.8 (CH), 129.9 (CH), 131.8 (CH), 132.0 (CH), 136.7 (CH), 140.1
(Cquat), 140.3 (Cquat), 143.4 (Cquat), 148.8 (2ϫCquat), 153.3 (Cquat),
(2ϫCH2), 15.9 (CH), 38.5 (CH2), 52.4 (CH3), 128.0 (Cquat), 128.2
(2ϫCH), 129.0 (Cquat), 129.1 (CH), 129.6 (CH), 130.0 (2ϫCH),
132.1 (Cquat), 139.4 (Cquat), 139.8 (Cquat), 140.7 (Cquat), 153.7
156.0 (Cquat), 165.9 (Cquat) ppm. IR (KBr): ν = 2924 (w), 1694 (w),
˜
(Cquat), 163.7 (Cquat), 166.4 (Cquat) ppm. IR (KBr): ν = 3007 (w),
˜
1591 (m), 1564 (s), 1524 (m), 1464 (m), 1448 (s), 1427 (s), 1376 (m),
1353 (m), 1316 (s), 1255 (m), 1193 (s), 1156 (m), 1122 (s), 1089 (m),
1059 (m), 1037 (m), 995 (w), 958 (w), 933 (w), 882 (s), 858 (w), 846
(m), 807 (s), 787 (s), 776 (s), 741 (m), 714 (s), 682 (w), 663 (w), 621
(m), 566 (m), 548 (m), 520 (m) cm–1. UV/Vis (CH2Cl2): λmax (ε) =
264 (14600), 294 (14500), 348 nm (9300). Emission (CH2Cl2): λmax
2952 (w), 1722 (s), 1611 (s), 1439 (s), 1402 (m), 1374 (w), 1279 (s),
1193 (m), 1179 (m), 1117 (s), 1056 (w), 1018 (w), 970 (w), 948 (w),
887 (m), 767 (m), 698 (m), 669 (w), 611 (w), 557 (w) cm–1. UV/
Vis (CH2Cl2): λmax (ε) = 255 (20500), 276 (23100), 345 nm (7500).
Emission (CH2Cl2): λmax (Stokes shift) = 385 nm (3000 cm–1).
Emission (solid state): λmax = 420 nm. EI MS (70 eV ): m/z (%) =
390 (14), 389 (26), 388 (67), 387 (54), 386 (100) [M]+·, 385 (36), 373
(15), 371 (22), 360 (20), 359 (13), 358 (28), 329 (12), 327 (18), 291
(10), 251 (12), 227 (20), 226 (19), 225 (29), 161 (14), 115 (12), 102
(21), 101 (11), 77 (10), 76 (13), 67 (12), 65 (11), 59 (24), 41 (37), 39
(14). C20H16Cl2N2O2 (387.26): calcd. C 62.03, H 4.16, N 7.23;
found C 61.82, H 4.23, N 7.12.
(Stokes shift) = 416 nm (4700 cm–1). Emission (solid state): λmax
=
510 nm. EI MS (70 eV ): m/z (%) = 375 (12), 374 (16), 373 (60),
372 (36), 371 (100) [M]+·, 370 (20), 340 (16), 338 (27), 267 (10), 265
(20), 264 (21), 263 (29), 262 (23), 109 (40), 105 (11), 97 (13), 79
(11), 78 (56), 69 (13), 65 (23), 45 (12), 39 (11). C18H11Cl2N3S
(372.27): calcd. C 58.07, H 2.98, N 11.29; found C 57.92, H 3.06,
N 11.10.
2-Butyl-7,8-dichloro-4-(4-nitrophenyl)-3H-1,5-benzodiazepine (6j):
Compound 6j was obtained as a yellow solid by GP A; m.p. 143 °C.
2,4-Bis(4-methoxyphenyl)-3H-1,5-benzodiazepine (6m): Compound
6m was obtained as a yellow powder by GP B; m.p. 173 °C.
1H NMR (500 MHz, CDCl3): δ = 3.83 (s, 6 H), 6.92 (d, 3J = 8.9 Hz,
3
1H NMR (500 MHz, CDCl3): δ = 0.85 (t, J = 7.4 Hz, 3 H), 1.30
(sext, 3J = 7.4 Hz, 2 H), 1.62 (q, 3J = 7.5 Hz, 2 H), 2.53 (t, 3J =
3
3
4
3
4
7.5 Hz, 2 H), 7.55 (s, 1 H), 7.62 (s, 1 H), 8.18 (d, J = 8.7 Hz, 2 H),
4 H), 7.31 (dd, J = 6.1, J = 3.5 Hz, 2 H), 7.57 (d, J = 6.1, J =
3.5 Hz, 2 H), 7.95 (d, 3J = 8.9 Hz, 4 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 34.5 (CH2), 55.4 (2ϫCH3), 114.0 (4ϫCH), 125.0
(2ϫCH), 128.6 (2ϫCH), 129.9 (4ϫCH), 130.0 (2ϫCquat), 140.8
3
8.32 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
13.7 (CH3), 22.2 (CH2), 28.1 (CH2), 37.9 (CH2), 40.1 (CH2), 123.9
(2ϫCH), 128.6 (Cquat), 129.1 (3 CH), 129.4 (Cquat), 129.7 (CH),
139.2 (Cquat), 139.8 (Cquat), 141.9 (Cquat), 149.0 (Cquat), 152.1 (2ϫCquat), 153.6 (2ϫCquat), 161.6 (2ϫCquat) ppm. IR (KBr): ν =
˜
(Cquat), 162.1 (Cquat) ppm. IR (KBr): ν = 2997 (w), 1637 (m), 1598 3012 (w), 2968 (w), 2840 (w), 1605 (s), 1593 (s), 1514 (s), 1458 (m),
˜
(m), 1520 (s), 1443 (s), 1347 (s), 1302 (m), 1180 (m), 1119 (m), 1049 1434 (m), 1323 (s), 1231 (s), 1214 (m), 1172 (s), 1110 (m), 1023 (s),
(w), 888 (s), 856 (s), 801 (m), 753 (m), 717 (m), 694 (s), 671 (w), 854 (m), 837 (m), 815 (w), 801 (w), 763 (s), 722 (w), 644 (w), 563
617 (w) cm–1. UV/Vis (CH2Cl2): λmax (ε) = 359 (14600), 284 nm
(w), 561 (w), 516 (s) cm–1. UV/Vis (CH2Cl2): λmax (ε) = 285 (33700),
331 nm (13700). Emission (CH2Cl2): λmax (Stokes shift) = 388 nm
(4400 cm–1), 440. Emission (solid state): λmax = 495 nm. EI MS
(70 eV ): m/z (%) = 357 (25) [M + H]+, 356 (88) [M]+·, 355 (35),
(27200). Emission (CH2Cl2): λmax (Stokes shift)
= 450 nm
(5600 cm–1). Emission (solid state): λmax = 525 nm. EI MS (70 eV
): m/z (%) = 391 (2), 389 (3), 351 (13), 350 (14), 349 (68), 348
Eur. J. Org. Chem. 2008, 4796–4805
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4803

B. Willy, T. Dallos, F. Rominger, J. Schönhaber, T. J. J. Müller
FULL PAPER
341 (15), 249 (13), 224 (39), 209 (15), 192 (10), 181 (12), 178 (11),
134 (11), 133 (100), 118 (17), 103 (13), 90 (20), 89 (14), 77 (22).
C23H20N2O2 (356.42): calcd. C 77.51, H 5.66, N 7.86; found
C 77.15, H 5.69, N 7.76.
235 (15), 226 (12), 210 (41), 209 (27), 198 (14), 139 (20), 91 (13),
43 (12). C21H13ClN2O2 (360.79): calcd. C 69.91, H 3.63, N 7.76;
found C 69.64, H 3.69, N 7.67.
2-(4-Methoxyphenyl)-4-(4-nitrophenyl)-3H-1,5-benzodiazepine (6n):
Compound 6n was obtained as a yellow solid by GP B; m.p.
156 °C. H NMR (500 MHz, CDCl3): δ = 3.85 (s, 3 H), 6.95 (d, J
Acknowledgments
1
3
Financial support from the Romanian Ministry of Education and
Research (T.D.’s research stage was supported by the program ID
564 PNII CNCSIS), the Fonds der Chemischen Industrie, and the
Dr.-Otto-Röhm Gedächtnisstiftung is gratefully acknowledged, to-
gether with BASF AG for the generous donation of chemicals. We
also cordially thank Marco Teiber and Alexandra Schmidt for ex-
perimental assistance.
3
4
3
= 8.7 Hz, 2 H), 7.37 (dq, J = 7.1, J = 1.3 Hz, 2 H), 7.60 (dd, J
4
3
3
= 7.5, J = 1.6 Hz, 2 H), 7.94 (d, J = 8.7 Hz, 2 H), 8.12 (d, J =
8.6 Hz, 2 H), 8.24 (d, 3J = 8.6 Hz, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 34.7 (CH2), 55.4 (CH3), 123.8 (2ϫCH), 125.4 (CH),
126.3 (CH), 128.7 (CH), 128.77 (2ϫCH), 128.83 (CH), 129.4
(Cquat), 130.0 (2ϫCH), 139.8 (Cquat), 141.0 (Cquat), 142.9 (Cquat),
148.7 (Cquat), 151.3 (Cquat), 152.7 (Cquat), 161.9 (Cquat) ppm. IR
(KBr): ν = 2923 (w), 2844 (w), 1686 (w), 1607 (s), 1585 (s), 1563
˜
(m), 1515 (s), 1458 (m), 1436 (m), 1345 (s), 1325 (s), 1261 (s), 1216
(w), 1203 (w), 1172 (m), 1056 (w), 1031 (m), 867 (m), 855 (m), 841
(s), 767 (m), 732 (w), 692 (m), 617 (w), 534 (w), 519 (m) cm–1. UV/
Vis (CH2Cl2): λmax (ε) = 277 (27000), 292 (29300), 313 (22700),
366 nm (8300). Emission (CH2Cl2): λmax (Stokes shift) = 436
(4400 cm–1), 512 nm. Emission (solid state): λmax = 530 nm. EI MS
(70 eV ): m/z (%) = 371 (12) [M]+·, 317 (16), 292 (10), 289 (22), 283
(26), 255 (12), 165 (17), 136 (11), 135 (100), 107 (21), 92 (32), 77
(46), 76 (14), 71 (12), 64 (14), 63 (11), 57 (14), 43 (11). C22H17N3O3
(371.39): calcd. C 71.15, H 4.61, N 11.31; found C 70.87, H 4.66,
N 11.18.
[1] For reviews, see, for example a) G. A. Archer, L. H. Sternbach,
Chem. Rev. 1968, 68, 747–784; b) F. D. Popp, A. C. Noble, Adv.
Heterocycl. Chem. 1967, 8, 21–82; c) L. H. Sternbach, Angew.
Chem. 1971, 83, 70–79; Angew. Chem. Int. Ed. Engl. 1971, 10,
34–43; d) J. L. Vanderheyden, J. E. Vanderheyden, J. Pharm.
Belg. 1981, 36, 354–364; e) G. R. Jones, P. P. Singer, Adv. Anal.
Toxicol. 1989, 2, 1–69; f) J. B. Bremner in Comprehensive Het-
erocyclic Chemistry II (Eds.: A. R. Katritzky, C. W. Rees,
E. F. V. Scriven), Pergamon Press, Oxford, New York, Toronto,
Sydney, Paris, Frankfurt, 1996, Vol. 9, 183–189.
[2] For synthetic and pharmacological studies, see, for example a)
A. Zellou, Y. Cherrah, M. Hassar, E.-M. Essassi, Ann. Pharm.
Fr. 1998, 56, 169–174; b) F. Savelli, A. Boido, A. Mule, L. Piu,
M. C. Alamanni, G. Pirisino, M. Satta, A. Peana, Farmaco
1989, 44, 125–140; c) A. Nawojski, W. Nawrocka, H. Liszkiew-
icz, Pol. J. Pharmacol. Pharm. 1985, 37, 69–72; d) M. Wilimow-
ski, K. Orzechowsa-Juzwenko, J. Barczynska, L. Kedzierska-
Gozdzik, M. Witkowska, W. Wojewodzki, E. Dus, T. Plawiak,
J. Gryska, H. Maska, Pol. J. Pharmacol. Pharm. 1983, 35, 89–
102; e) V. K. Srivastava, R. K. Satsangi, K. Kishore, Arzneim.-
Forsch. 1982, 32, 1512–1514.
2-Butyl-4-(4-nitrophenyl)-3H-1,5-benzodiazepine (6o): Compound
6o was obtained as a yellow resin by GP B. 1H NMR (500 MHz,
CDCl3): δ = 0.84 (t, 3J = 7.3 Hz, 3 H), 1.30 (sext, 3J = 7.5 Hz, 2 H),
1.62 (q, 3J = 7.6 Hz, 2 H), 2.53 (t, 3J = 7.6 Hz, 2 H), 3.29 (br. s,
2 H), 7.29–7.31 (m, 2 H), 7.44–7.47 (m, 1 H), 7.52–7.54 (m, 1 H),
8.19 (d, 3J = 8.8 Hz, 2 H), 8.32 (d, 3J = 8.8 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 13.7 (CH3), 22.2 (CH2), 28.3
(CH2), 37.5 (CH2), 40.1 (CH2), 123.8 (2ϫCH), 125.2 (CH), 126.1
(CH), 127.8 (CH), 128.7 (CH), 128.9 (2ϫCH), 140.0 (Cquat), 140.3
(Cquat), 142.6 (Cquat), 148.8 (Cquat), 151.0 (Cquat), 160.8
[3] a) H. Schutz, Benzodiazepines, Springer, Heidelberg, 1982; b)
J. K. Landquist, in Comprehensive Heterocyclic Chemistry
(Eds.: A. R. Katritzky, C. W. Rees), Pergamon, Oxford, 1984,
vol. 1, pp. 166–170; c) R. I. Fryer, Bicyclic Diazepines, in Com-
prehensive Heterocyclic Chemistry (Ed.: E. C. Taylor), Wiley,
New York, 1991, vol. 50, chapter II; d) L. O. Randall, B. Kap-
pel, in Benzodiazepines (Eds.: S. Garattini, E. Musini, L. O.
Randall), Raven Press, New York, 1973, p. 27.
(Cquat) ppm. IR (KBr): ν = 2958 (m), 1662 (m), 1599 (s), 1521 (s),
˜
1461 (m), 1346 (s), 1109 (m), 1048 (m), 1011 (m), 855 (s), 765 (s),
713 (m), 696 (w) cm–1. UV/Vis (CH2Cl2): λmax (ε) = 266 (24100),
284 (24500), 357 nm (14700). Emission (CH2Cl2): λmax = 494 nm
(7800 cm–1). Emission (solid state): λmax = 517 nm. EI MS (70 eV):
m/z (%) = 321 (2) [M]+·, 280 (20), 279 (100), 278 (16), 264 (11), 239
(13), 233 (10), 232 (23), 231 (22), 219 (12), 217 (11), 193 (14), 192
(19), 190 (10), 145 (11), 132 (32), 131 (22), 130 (20), 104 (14), 103
(14), 102 (28), 90 (22), 89 (30), 78 (11), 77 (26), 76 (33), 75 (13), 65
(11), 63 (14), 55 (12), 51 (12), 50 (14), 43 (17), 42 (14), 41 (41), 39
(20). C19H19N3O2 (321.37): calcd. C 71.01, H 5.96, N 13.08; found
C 70.75, H 5.98, N 12.93.
[4] J. R. De Baun, F. M. Pallos, D. R. Baker, U. S. Patent, US
3978227 19760831, 1976.
[5] For synthetic and pharmacological studies, see, for example a)
K. A. Parker, A. Dermatakis, J. Org. Chem. 1997, 62, 4164–
4167; b) K. D. Hargrave, G. Schmidt, W. Engel, V. Austel,
Patent Application: US 91-650141 19910204. Patent Priority:
US 89-340937 19890420; US 89-372728 19890628; US 89-
438922 19891117; US 90-600554 19901019.
[6] R. C. Harris, J. M. Straley, French Patent, FR 1537757
19680830, 1968.
2-(4-Chlorophenyl)-4-(4-nitrophenyl)quinoline (10): Compound 10
was obtained as a yellow solid by GP B; m.p. 145 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.41–7.49 (m, 4 H), 7.63–7.74 (m, 5 H),
8.10 (d, 3J = 8.6 Hz, 2 H), 8.36 (d, 3J = 8.8 Hz, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 118.7 (2ϫCH), 123.9 (2ϫCH),
124.3 (Cquat), 124.8 (2ϫCH), 125.0 (Cquat), 127.3 (CH), 128.8
(2ϫCH), 129.1 (2ϫCH), 130.5 (2ϫCH), 132.3 (Cquat), 133.4
(Cquat), 144.8 (Cquat), 148.0 (Cquat), 150.5 (Cquat), 155.5
[7] a) M. C. Aversa, A. Ferlazzo, P. Gionnetto, F. H. Kohnke, Syn-
thesis 1986, 230–231; b) M. Essaber, A. Hasnaoui, A. Benhar-
ref, J. P. Lavergne, Synth. Commun. 1998, 28, 4097–4104; c)
A. M. ElSayed, H. Abdel-Ghany, A. M. M. El-Saghier, Synth.
Commun. 1999, 29, 3561–3572; d) A. Chimirri, S. Grasso, R.
Ottana, G. Romeo, M. Zappala, J. Heterocycl. Chem. 1990, 27,
371–374.
[8] W. Ried, E. Torinus, Chem. Ber. 1959, 92, 2902–2916.
[9] a) P. Stahlhofen, W. Ried, Chem. Ber. 1957, 90, 815–824; b)
G. K. Nagaraja, V. P. Vaidya, K. S. Rai, K. M. Mahadevan,
Phosphorus Sulfur Silicon Relat. Elem. 2006, 181, 2797–2806;
Independently from our studies, yet with our general concept
(see ref.[14b,14c]), a related synthesis was recently published; see
c) S. S. Palimkar, R. J. Lahoti, K. V. Srinivasan, Green Chem.
(Cquat) ppm. IR (KBr): ν = 1587 (s), 1544 (m), 1520 (s), 1488 (m),
˜
1422 (w), 1347 (s), 1106 (m), 1090 (m), 1016 (m), 971 (w), 857 (m),
830 (m), 766 (m), 716 (w), 699 (m), 581 (w), 539 (w) cm–1. UV/Vis
(CH2Cl2): λmax (ε) = 265 nm (7300), 287 (4100), 330 (2900), 343
(2600), 367 (900). EI MS (70 eV ): m/z (%) = 362 (11), 361 (12)
[M]+·, 360 (33), 359 (14), 313 (14), 292 (17), 257 (17), 256 (100),
4804
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4796–4805

Cryofluorescent 3H-1,5-Benzodiazepines
2007, 9, 146–152; d) T. J. J. Müller, A. S. Karpov, Ger. Offen.
2005, DE 10328400 A1 20050113.
A. S. Karpov, E. Merkul, F. Rominger, T. J. J. Müller, Angew.
Chem. 2005, 117, 7112–7117; Angew. Chem. Int. Ed. 2005, 44,
6951–6956; d) A. S. Karpov, E. Merkul, F. Rominger, T. J. J.
Müller, Eur. J. Org. Chem. 2006, 2991–3000; e) E. Merkul,
T. J. J. Müller, Chem. Commun. 2006, 4817–4819; f) B. Willy, F.
Rominger, T. J. J. Müller, Synthesis 2008, 293–303.
[10] a) J. S. Yadav, B. V. S. Reddy, S. Praveenkumar, K. Nagaiah,
Synthesis 2005, 480–484; b) G. Sabitha, G. S. K. Reddy, K. B.
Reddy, N. M. Reddy, J. S. Yadav, Adv. Synth. Catal. 2004, 346,
921–923; c) M. Curini, F. Epifano, M. C. Marcotullio, O. Ros-
ati, Tetrahedron Lett. 2001, 42, 3195–3197; d) J. S. Yadav,
B. V. S. Reddy, B. Eshwaraiah, K. Anuradha, Green Chem.
2002, 4, 592–594; e) B. Kaboudin, K. Naveen, Heterocycles
2001, 55, 1443–1446; f) M. Pozaretzi, J. S. Stephanatou, C. A.
Tsoleridis, Tetrahedron Lett. 2002, 43, 1755–1758.
[18] B. Willy, T. J. J. Müller, Eur. J. Org. Chem. 2008, 4157–4168.
[19] a) A. Mannschreck, G. Rissmann, F. Vögtle, D. Wild, Chem.
Ber. 1967, 100, 335–346; b) R. Ahmad, M. Zia-ul-Haq, H.
Duddeck, L. Stefaniak, J. Sitkowski, Monatsh. Chem. 1997,
128, 633–640.
[11] D. V. Jarikote, S. A. Siddiqui, R. Rajagapol, T. Daniel, R. J.
Lahoti, K. V. Srinivasan, Tetrahedron Lett. 2003, 44, 1835–
1838.
[20] CCDC-692628 (of 6f) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336-033; or
deposit@ccdc.cam.ac.uk).
[12] M. S. Balakrishna, B. Kaboudin, Tetrahedron Lett. 2001, 42,
1127–1129.
[13] a) T. J. J. Müller, D. M. D’Souza, Pure Appl. Chem. 2008, 80,
609–620; b) T. J. J. Müller in Functional Organic Materials –
Synthesis Strategies, and Applications (Eds.: T. J. J. Müller,
U. H. F. Bunz), Wiley-VCH, Weinheim, 2007, pp. 179–223.
[14] For a recent review on multicomponent synthesis of heterocy-
cles by transition metal catalysis, see: a) D. M. D’Souza, T. J. J.
Müller, Chem. Soc. Rev. 2007, 36, 1095–1108; b) T. J. J. Müller,
Chim. Oggi/Chem. Today 2007, 25, 70–78; c) T. J. J. Müller, Tar-
gets Heterocycl. Systems 2006, 10, 54–65.
[15] For lead reviews on Sonogashira couplings, see for example
a) S. Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagihara,
Synthesis 1980, 627–630; b) K. Sonogashira in Metal catalyzed
Cross-coupling Reactions (Eds.: F. Diederich, P. J. Stang),
Wiley-VCH, Weinheim, 1998, pp. 203–229; c) K. Sonogashira,
J. Organomet. Chem. 2002, 653, 46–49; d) E.-I. Negishi, L. An-
astasia, Chem. Rev. 2003, 103, 1979–2018; e) J. A. Marsden,
M. M. Haley in Metal catalyzed Cross-coupling Reactions
(Eds.: A. de Meijere, F. Diederich), Wiley-VCH, Weinheim,
2004, 319–345; f) H. Doucet, J.-C. Hierso, Angew. Chem. Int.
Ed. 2007, 46, 834–871; g) L. Yin, J. Liebscher, Chem. Rev. 2007,
107, 133–173.
[21] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok-
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Re-
vision B.03 ed., Gaussian Inc., Wallingford CT, 2004.
[22] D. Lloyd, H. McNab, Adv. Heterocycl. Chem. 1998, 71, 1–56.
[23] G. Cabarrocas, S. Rafel, M. Ventura, J. M. Villalgordo, Synlett
2000, 595–598.
[16] Y. Toda, K. Sonogashira, N. Hagihara, Synthesis 1977, 777–
778.
[17] a) A. S. Karpov, T. J. J. Müller, Org. Lett. 2003, 5, 3451–3454;
b) A. S. Karpov, T. J. J. Müller, Synthesis 2003, 2815–2826; c)
Received: June 23, 2008
Published Online: August 26, 2008
Eur. J. Org. Chem. 2008, 4796–4805
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4805