Regiospecific three-component access to fluorescent 2,4-disubstituted quinolines via one-pot coupling-addition-cyclocondensation-sulfur extrusion sequence

Article abstract of DOI:10.1002/ejoc.201000212

2,4-Di- and 2,4,7-trisubstituted quinolines are readily synthesized in a regioselective fashion from, acyl chlorides, terminal alkynes, and 2-aminothiophenols by a consecutive, microwave-assisted one-pot three-component Sonogashira coupling-Michael addition-cyclocondensation sequence and following sulfur extrusion in moderate to good yields. The terminal sulfur extrusion step was studied by DFT computations. The absorption spectra of 2,4-disubstituted quinolines can be rationalized by DFT-ZINDO-CI calculations and all derivatives show intense blue emission upon UV excitation.

Full text of DOI:10.1002/ejoc.201000212

FULL PAPER
DOI: 10.1002/ejoc.201000212
Regiospecific Three-Component Access to Fluorescent 2,4-Disubstituted
Quinolines via One-Pot Coupling-Addition-Cyclocondensation-Sulfur Extrusion
Sequence
Sven Rotzoll,[a] Benjamin Willy,[a] Jan Schönhaber,[a] Frank Rominger,[b] and
Thomas J. J. Müller*[a]
Dedicated to Prof. Dr. Franz Effenberger on the occasion of his 80th birthday
Keywords: Multicomponent reactions / C-C coupling / Fluorescence / Microwave chemistry / Quinolines / Computations
2,4-Di- and 2,4,7-trisubstituted quinolines are readily synthe-
sized in a regioselective fashion from acyl chlorides, terminal
alkynes, and 2-aminothiophenols by a consecutive, micro-
wave-assisted one-pot three-component Sonogashira cou-
pling-Michael addition–cyclocondensation sequence and fol-
lowing sulfur extrusion in moderate to good yields. The ter-
minal sulfur extrusion step was studied by DFT computa-
tions. The absorption spectra of 2,4-disubstituted quinolines
can be rationalized by DFT-ZINDO-CI calculations and all
derivatives show intense blue emission upon UV excitation.
is needed to ensure complete conversion to the desired
alkynones.[11] Based upon this facile catalytic access to
alkynones under mild conditions we could establish a gene-
ral diversity-oriented access to many classes of heterocycles
based upon multi-component reactions that proceed in the
sense of consecutive one-pot coupling–addition–cyclocon-
densation or coupling–cycloaddition sequences.[12] Upon
reaction of dinucleophilic o-phenylene diamines with the in
situ generated alkynones cryofluorescent 2,4-disubstituted
3H-benzo[b][1,4]diazepines were obtained in good yields.[13]
The analogous reaction with 2-aminothiophenols as dinu-
cleophiles leads to a three-component access to benzo-
[b][1,5]thiazepines.[14] Literature precedence has shown, that
at elevated temperatures benzo[b][1,5]thiazepines tend to
loose elementary sulfur furnishing quinolines.[15] Here we
report a regiospecific, microwave-assisted three-component
synthesis of 2,4-disubstituted quinolines in the sense of a
Introduction
Quinolines constitute an important class of bicyclic ni-
trogen-containing heterocycles. Their framework is an inte-
gral part of important natural products,[1] many with con-
siderable biological activity,[2] some of them play an impor-
tant role as antimalaria drugs.[3] In addition, quinolines are
also interesting as ligands for transition-metal complexes[4]
and have received attention as important building blocks
in organic chemistry.[1d] Furthermore, due to their inherent
fluorescent properties quinolines are of general interests as
emitting chromophores.[5] As a consequence the quest for
new syntheses of quinolines and substituted derivatives is
an ongoing theme.[6] Among recent quinoline syntheses are
e.g. aromatic annelations by reaction of arylimidoyl radicals
with alkynes[7] or the Pd-catalyzed hydroarylation of α-(2-
aminoaryl)-α,β-ynones with organoboron derivatives.[8]
These innovations prompted us to devise multi-component
accesses to quinolines. Alkynones are easily accessible by
Sonogashira coupling[9] of acyl chlorides with terminal al-
kynes.[10] Recently, we could establish particularly favorable
conditions for the coupling of acyl chlorides, where only
one stoichiometrically necessary equivalent of triethylamine
consecutive
coupling-addition–cyclocondensation–sulfur
extrusion sequence, mechanistic computations on the sulfur
extrusion, and first studies on the electronic properties of
the quinoline derivatives by UV/Vis and fluorescence spec-
troscopy and ZINDO-CI computations.
[a] Institut für Organische Chemie und Makromolekulare Chemie,
Lehrstuhl für Organische Chemie, Heinrich-Heine-Universität
Düsseldorf,
Results and Discussion
Universitätsstr. 1, 40225 Düsseldorf, Germany
Fax: +49-211-8114324
Sulfur extrusion is a well-precedented method for ring
contraction,[16] and in particular thiepines undergo aromati-
zation to benzoid arenes upon thermal treatment. There-
fore, coupling of acyl chlorides 1 and alkynes 2 under modi-
fied Sonogashira conditions in the presence of 2 mol-% of
E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
[b] Organisch-Chemisches Institut, Universität Heidelberg,
Neuenheimer Feld 270, 69120 Heidelberg, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000212.
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Regiospecific Access to Fluorescent 2,4-Disubstituted Quinolines
Scheme 1. One-pot three-component synthesis of 2,4-disubstituted quinolines 4.
PdCl2(PPh3)2 and 4 mol-% of CuI[11] furnished the corre- tion of quinoline 4c. The geometries were optimized using
sponding alkynones that were reacted in the same reaction the B3LYP functional and the def-SVP basis set as im-
vessel with 2-aminothiophenols 3 in the presence of glacial plemented in the program package Turbomole for DFT cal-
acetic acid and 2-propanol upon microwave irradiation culations.[18] The obtained minima and transition state
(150 °C, 60 min) to give 2,4-disubstituted quinolines 4 in structures were confirmed by analytical frequency analysis
moderate to good yields (Scheme 1, Table 1). The structures (Figure 2). Hence, the calculations revealed that after the
of all quinoline derivatives were unambiguously supported formation of the 2,4-diphenylbenzo[b][1,5]thiazepine an 6π-
by spectroscopy and combustion analyses or HRMS, and electrocyclic ring closure with a transition state energy of
later by X-ray structure analysis for quinoline 4l (Fig- 104.6 kJ/mol furnishes a 1aH-1-thia-4-azacyclopropa[d]-
ure 1).[17]
naphthalene containing a thiirane ring. This isomer is
82.1 kJ/mol less stable than 2,4-diphenylbenzo[b][1,5]thi-
azepine. In the transition state structure the distance of the
carbon atoms forming the later thiirane is significantly
shortened, while the carbon–sulfur bonds are elongated.
The final sulfur extrusion from the thiirane intermediate
was not calculated due to substantial computational com-
plexity. But according to experimental and theoretical
mechanistic studies on thiepine model systems by Glei-
ter,[19] Miller,[20] and Kassaee[21] this final step is nucleo-
phile-assisted and proceeds via sulfur–sulfur extraction
where the 2,4-diphenylquinoline (4c) and S8 are formed.
Figure 1. Molecular structure of quinoline 4l (hydrogen atoms were
omitted for clarity).
The quantitative terminal sulfur extrusion represents the
crucial point in this sequence. Otherwise mixtures of the
desired quinolines and the preceding benzothiazepines are
obtained which are very difficult to separate by column
chromatography due to similar polarity. Further attempts
to trigger the sulfur extrusion, for instance by variation of
the pH-conditions (pH 3–8) or by addition of tri-
phenylphosphane[16b] met with failure. Hence, dielectric
heating in a microwave cavity at 150 °C for 1 h turned out
to be the best solution in most cases for complete conver-
sion. The methodological scope for 2-(hetero)aryl and 4-
silyl and 4-aryl substituents is fairly broad and electron-
withdrawing, electroneutral, and electron-donating groups
are well tolerated. Unfortunately, 2-alkyl substituents (stem-
ming from the alkyne) could not be successfully applied. As
a consequence of the mechanism the substitution pattern
on the quinoline is regiospecific and the orientation of the
substituents is dictated by the Michael addition furnishing
benzo[b][1,5]thiazepines[14] (vide infra).
Figure 2. Calculated Gibbs free energies profile of the final sulfur
extrusion from 2,4-diphenylbenzo[b][1,5]thiazepine to give 2,4-di-
phenylquinoline (4c) and S8.
All 2,4-disubstituted quinolines 4 display long-wave-
Mechanistically intriguing, however, is the sulfur ex- length absorption bands between 342 and 379 nm with
trusion by which the benzo[b][1,5]thiazepines are converted moderate extinction coefficients and intense blue lumines-
into quinolines. In a DFT-computational study the mecha- cence in a relatively narrow range from 367–393 nm with
nism of the sulfur extrusion was investigated for the forma- small Stokes shifts between 700 and 3000 cm–1 (Table 2).
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Table 1. One-pot three-component synthesis of 2,4-disubstituted quinolines 4.
FULL PAPER
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Regiospecific Access to Fluorescent 2,4-Disubstituted Quinolines
Table 1. (Continued).
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FULL PAPER
Table 2. Selected electronic properties (absorption, emission data, and Stokes shifts ∆ν) of 2,4-disubstituted quinolines 4 (recorded in
˜
CH2Cl2 at 293 K).
Compound
Absorption λmax,abs [nm] (ε)[a]
Emission
Stokes shift
˜
λmax,em [nm][b]
∆ν[c] [cm–1]
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
277 (24200), 306 (16800), 374 (4300)
270 (42800), 330 (9600), 344 (7400)
268 (40200), 327 (9600), 343 (5000)
284 (28300), 338 (13100), 353 (11700)
270 (25800), 302 (14900), 379 (6000)
268 (40200), 327 (9600), 343 (5000)
260 (9500), 301 (12800), 376 (3400)
281 (28200), 334 (6500), 347 (5400)
268 (17500), 329 (5800), 343 (3500)
269 (32100), 330 (13100), 344 (10900)
287 (60800), 338 (27400), 352 (24500)
265 (7300), 287 (4100), 330 (2900), 343 (2600), 367 (900)
269 (93200), 330 (25700), 342 (13500)
282 (36700), 335 (25400), 349 (11100)
271 (13500), 302 (8600), 315 (9700), 334 (4000)
280 (32700), 340 (13900)
391
399
373
389
390
373
384
368
375
381
390
390
379
389
388
393
377
1200
4000
2300
2600
700
2300
600
3000
2500
2800
2800
1600
2900
2900
3300
4000
2400
266 (18300), 334 (4700), 346 (3700)
[a] Recorded in CH2Cl2 at c = 10–3 . [b] Recorded in CH2Cl2 at c = 10–6 . [c] ∆ν = λ
– λmax,em [cm–1].
˜
max,abs
The absorption and emission behavior of 2-substituted LUMO and 24% of HOMO–LUMO transitions, which are
quinolines has intensively been studied in the past and have represented by a π-π* transitions within the quinoline core
revealed a substantial solvent effect on the efficiency and (Figure 3). In addition a FMO transition from HOMO to
shift of the bands, particularly by hydrogen bonding in pro- LUMO+1 (19%) also contributes to the S1 state. The band
tic solvents.[22] Hence, the electronic properties of 2,4-disub- at 327 nm possesses higher oscillator strength, a signifi-
stituted quinolines should display comparable features.
cantly higher state dipole moment (4.18 D) and is based
The absorption spectra of the consanguineous series of on the S3 singlet state, where substantial contributions of
4-phenyl-substituted derivatives 4a–4f reveal that 2-substi- HOMO–LUMO (52%) and HOMO-1-LUMO (13%) are
tution on the quinoline core only exerts a bathochromic
effect if the donor capacity is sufficiently strong. Both a
potent donor such as p-anisyl (4a) or the sterically less de-
manding 2-thienyl (4d) and 2-furyl (4e) donor moieties en-
hance the ground state coplanarity and thus generate a
push-pull system. All other aryl groups with para-substitu-
ents absorb around 343 nm. Interestingly, in the related
series of p-anisyl 2-substituted quinolines 4a, 4g, 4h, and
4n, subtle changes in the electronic properties of the 4-sub-
stituent cause substantial hypsochromic shifts of the long-
wavelength absorption bands upon altering the substituents
phenyl (4a) or trimethylsilyl (4g) to p-tolyl (4h) or p-tert-
butylphenyl (4n).
The parent derivative of 2,4-diaryl-substituted quino-
lines, 2,4-diphenylquinoline (4c) was chosen as a model for
the assignment of the absorption bands in the electronic
spectra. First the geometry optimization was computed on
the DFT level of theory to obtain a reasonable geometry for
the subsequent electronic structure computation.[23] Based
upon the DFT structure optimization of 4c a single-point
ZINDO-CI computation was performed as an inexpensive,
rapid and relatively accurate calculation[24] for qualitatively
assigning the electronic structure of the longest wavelength
absorption bands.[25] The three longest wavelength bands of
4c at 268, 327, and 343 nm are qualitatively reproduced by
the computated absorption bands at 263, 288, and 326 nm.
The lowest energy band at 343 nm, i.e. the S1 state, displays
moderate oscillator strength and a state dipole moment of
2.57 D. This absorption consists to 34% of HOMO-1 to energies of 4c.
Figure 3. Selected frontier molecular orbitals (FMOs) and orbital
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Regiospecific Access to Fluorescent 2,4-Disubstituted Quinolines
quadruple spectrometer. Absorption spectra were recorded with an
HP8452 (Hewlett–Packard, Palo Alto, CA, USA) and a Lambda
19 (Perkin–Elmer, Waltham, MA, USA). Emission spectra were
recorded with a LS-55 spectrometer (Perkin–Elmer, Waltham, MA,
USA).
found. Finally, the S6 singlet state displays the highest oscil-
lator strength and arises from the absorption band at
268 nm. It predominantly consists of HOMO–LUMO+1
(37%) and HOMO-1-LUMO (34%) transitions. As a conse-
quence of relatively small orbital coefficients in the 4-phenyl
moiety in all relevant frontier orbitals only minor substitu-
ent effects on the absorption spectra can be expected.
Elemental analyses were carried out in the microanalytical labora-
tory of the Pharmazeutisches Institut of the Heinrich-Heine-Uni-
versität, Düsseldorf. Dielectric heating was performed in a single-
mode microwave cavity producing continuous irradiation at
2450 MHz.
Conclusions
General Procedure for the Synthesis of 2,4-Substituted Quinolines 4
(GP): In
a 10 mL microwave tube, PdCl2(PPh3)2 (15 mg,
In conclusion, we have dicovered a versatile and regio-
specific one-pot multi-component synthesis of 2,4-di- and
2,4,7-trisubstituted quinolines based upon a microwave-
0.02 mmol) and CuI (8 mg, 0.04 mmol) were dissolved in degassed
THF (4 mL). Then, (hetero)aroyl chloride 1 (1.00 mmol), alkyne 2
(1.00 mmol), and triethylamine (1.05 mmol) were added to the
orange solution. The reaction mixture was stirred at room tempera-
ture for 1 h. Finally, the 2-aminothiophenol 3 (1.10 mmol), fol-
lowed by glacial acetic acid (0.5 mL) and propan-2-ol (0.5 mL),
were added to this suspension, and the reaction mixture was heated
in the microwave cavity at 150 °C for 60 min. 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 quinolines
Table 3).
2-(4-Methoxyphenyl)-4-phenylquinoline (4a):[8] According to the GP
4a was obtained as yellow solid; m.p. 76 °C. H NMR (500 MHz,
CDCl3): δ = 3.87 (s, 3 H, OCH3), 7.04 (d, J = 8.9 Hz, 2 H), 7.15
accelerated
coupling–addition–cyclocondensation–sulfur
extrusion sequence. After addition of 2-aminothiophenols
in the addition–cyclocondensation step dielectric heating at
150 °C has proven to effectively assist the terminal sulfur
extrusion. The electronic spectra of 2,4-disubstituted
quinolines are dominated by the rigid quinoline core struc-
ture as shown by rapid DFT-ZINDO-CI calculations, and
intense blue fluorescence with moderate Stokes shifts are
observed for all derivatives. Studies expanding this novel
modular approach to enhance molecular diversity in targets
which are of special interest to pharmaceutical or photonic
applications and more detailed photophysical investigations
are currently underway.
4 (for experimental details, see
1
3
(s, 1 H, C3-H), 7.19–7.22 (m, 1 H), 7.40–7.44 (m, 3 H), 7.51–7.52
(m, 1 H), 7.60–7.61 (m, 1 H), 7.72–7.74 (m, 1 H), 7.95–7.96 (m,
2 H), 8.09–8.11 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
56.8 (CH3), 115.6 (2 CH), 115.8 (CH), 126.4 (CH), 128.0 (CH),
128.1 (CH), 129.3 (2 CH), 130.4 (2 CH), 131.3 (2 CH), 131.4 (CH),
131.5 (Cquat), 134.4 (CH), 134.6 (Cquat), 140.6 (Cquat), 150.4 (Cquat),
152.3 (Cquat), 164.0 (Cquat), 165.9 (Cquat) ppm. EI MS (70 eV, m/z
(%)): 312 (22), 311 ([M]+, 100), 310 (80), 268 (11), 267 (28), 266
Experimental Section
General Considerations: All reactions involving water-sensitive
compounds were carried out in flame-dried glassware under nitro-
gen atmosphere unless stated otherwise. Reagents and catalysts
were purchased reagent grade and used without further purifica-
tion. Solvents were dried by a solvent purification system. Flash
column chromatography: silica gel 60, mesh 230–400. TLC: silica
gel plates (60 F254). 1H-, 13C-, DEPT-, NOESY-, COSY-,
HMQC-, and HMBC spectra were recorded with a 500 MHz NMR
spectrometer by using CDCl3 as solvent unless stated otherwise.
The assignments of quaternary C, CH, CH2 and CH3 were made
on the basis of DEPT spectra. Mass spectra were recorded with a
(11), 156 (14), 139 (12), 134 (14), 133 (19), 121 (12). IR (film): ν =
˜
2935 (w), 1609 (s), 1514 (w), 1481 (w), 1355 (m), 1340 (w), 1321
(w), 1176 (m), 1120 (m), 1072 (s), 1035 (s), 866 (m), 765 (w), 702
(w), 534 (w). C22H17NO (311.4): C 84.86, H 5.50, N 4.50; found
C 84.60, H 5.59, N 4.39.
4-Phenyl-2-(4-tolyl)quinoline (4b):[6e] According to the GP 4b was
obtained as yellow solid; m.p. 102 °C. 1H NMR (500 MHz,
Table 3. Experimental details of the synthesis of 2,4-disubstituted quinolines 4.
Entry
Acyl chloride 1 [mg] (mmol)
Alkyne 2 [mg] (mmol) ortho-Aminothiophenol 3 [mg] (mmol) Quinoline 4 [mg] (yield, %)
1
2
3
4
5
6
7
8
171 (1.00) of 1a
155 (1.00) of 1b
141 (1.00) of 1c
147 (1.00) of 1d
131 (1.00) of 1e
175 (1.00) of 1f
171 (1.00) of 1a
171 (1.00) of 1a
155 (1.00) of 1b
155 (1.00) of 1b
147 (1.00) of 1d
175 (1.00) of 1f
175 (1.00) of 1f
171 (1.00) of 1a
175 (1.00) of 1f
171 (1.00) of 1a
155 (1.00) of 1b
102 (1.00) of 2a
102 (1.00) of 2a
102 (1.00) of 2a
102 (1.00) of 2a
102 (1.00) of 2a
102 (1.00) of 2a
98 (1.00) of 2b
116 (1.00) of 2c
158 (1.00) of 2d
116 (1.00) of 2c
158 (1.00) of 2d
147 (1.00) of 2e
181 (1.00) of 2f
158 (1.00) of 2d
102 (1.00) of 2a
102 (1.00) of 2a
158 (1.00) of 2d
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
176 (1.10) of 3b
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
138 (1.10) of 3a
176 (1.10) of 3b
176 (1.10) of 3b
176 (1.10) of 3b
181 (58) of 4a
168 (57) of 4b
133 (47) of 4c
203 (71) of 4d
149 (55) of 4e
186 (59) of 4f
191 (52) of 4g
168 (52) of 4h
211 (60) of 4i
149 (48) of 4j
218 (63) of 4k
260 (72) of 4l
178 (45) of 4m
238 (65) of 4n
210 (60) of 4o
193 (56) of 4p
184 (48) of 4q
9
10
11
12
13
14
15
16
17
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FULL PAPER
CDCl3): δ = 2.43 (s, 3 H, CH3), 7.33 (d, J = 8.0 Hz, 2 H), 7.44– 316 [M + H]+. HRMS (EI): calcd. for C21H13NCl ([M – H]+)
3
7.56 (m, 6 H), 7.72 (m, 1 H), 7.80 (s, 1 H, C3-H), 7.89 (d, 3J = 314.07310; found 314.07294.
3
3
8.4 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 2 H), 8.24 (d, J = 8.5 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 119.4 (CH),
125.8 (CH), 125.9 (CH), 126.3 (CH), 127.6 (2 CH), 128.5 (CH),
128.8 (2 CH), 129.6 (CH), 129.8 (2 CH), 130.2 (CH), 137.0 (Cquat),
138.7 (Cquat), 139.6 (Cquat), 149.0 (Cquat), 149.2 (Cquat), 157.0
2-(4-Methoxyphenyl)-4-(trimethylsilyl)quinoline (4g):[6f] According
to the GP 4g was obtained as pale yellow solid; m.p. 109 °C. 1H
NMR (500 MHz, CDCl3): δ = 0.25 (s, 9 H, SiMe3), 3.86 (s, 3 H,
3
OCH3), 6.99 (s, 1 H, C3-H), 7.04 (d, J = 8.8 Hz, 2 H), 7.15–7.17
(m, 1 H), 7.26–7.31 (m, 2 H), 7.35–7.39 (m, 1 H), 7.95 (d, 3J =
8.8 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 1.8 (3 CH3),
56.2 (CH3), 115.2 (2 CH), 127.4 (2 CH), 130.4 (CH), 130.4 (2 CH),
131.2 (Cquat), 132.4 (Cquat), 133.1 (CH), 138.3 (Cquat), 152.1 (Cquat),
155.7 (Cquat), 158.7 (Cquat), 166.7 (Cquat) ppm. EI MS [70 eV, m/z
(%)]: 308 (24), 307 ([M]+·, 100), 306 (73), 293 (15), 292 (56), 249
(Cquat) ppm. IR (KBr): ν = 3051 (br., m), 2199 (m), 1590 (s), 1542
˜
(m), 1355 (br., m), 1285 (br., w), 822 (m), 774 (s), 704 (m). MALDI-
TOF MS (Matrix: 4,5-dihydroxyanthracen-10(9H)-one): m/z (%) =
296 [M + H]+. HRMS (EI): calcd. for C22H16N ([M – H]+)
294.12773, found 294.12771.
(22), 146 (27), 73 (22). IR (KBr): ν = 3037 cm–1 (w), 2964 (w), 2833
2,4-Diphenylquinoline (4c):[7b] According to the GP 4c was obtained
as yellow solid; m.p. 109 °C. 1H NMR (500 MHz, CDCl3): δ = 7.46
(m, 2 H), 7.50–7.56 (m, 7 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.82 (s, 1
˜
(w), 1594 (s), 1557 (m), 1510 (m), 1424 (m), 1316 (m), 1290 (w),
1256 (s), 1182 (s), 1025 (m), 950 (w), 844 (s), 698 (w), 616 (m), 602
(w), 547 (w), 531 (w). C19H21NOSi (307.5): C 74.22, H 6.88, N 4.56;
found C 73.98, H 6.92, N 4.48.
3
H, C3-H), 7.90 (m, 1 H), 8.18 (m, 2 H), 8.24 (m, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 119.8 (CH), 125.6 (CH), 125.8 (CH),
126.3 (CH), 127.6 (CH), 128.4 (CH), 128.6 (CH), 128.8 (CH), 129.3
(CH), 129.5 (CH), 129.6 (CH), 130.1 (CH), 138.9(Cquat), 140.0
2-(4-Methoxyphenyl)-4-(4-tolyl)quinoline (4h):[8] According to the
GP 4h was obtained as yellow solid; m.p. 115–117 °C. 1H NMR
(500 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 3.87 (s, 3 H, OCH3),
(Cquat), 149.1 (Cquat), 149.7 (Cquat), 157.3 (Cquat) ppm. IR (KBr): ν
˜
3
3
7.03 (d, 3J = 8.7 Hz, 2 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.41 (d, J =
= 2924 (m), 1588 (br., m), 1544 (s), 1488 (m), 1356 (m), 1073 (br.,
m), 766 (m), 702 (m). MALDI-TOF MS [matrix: 4,5-dihydroxy-
anthracen-10(9H)-one]: m/z (%) = 282 [M + H]+.
3
8.0 Hz, 1 H), 7.45 (d, J = 7.9 Hz, 2 H), 7.69 (m, 1 H), 7.75 (s, 1
H, C3-H), 7.90 (d, J = 8.4 Hz, 1 H), 8.16 (d, J = 8.7 Hz, 2 H),
3
3
8.20 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
3
4-(Phenyl)-2-(thiophen-2-yl)quinoline (4d):[6a] According to the GP
4d was obtained as yellow solid; m.p. 91 °C. H NMR (500 MHz,
21.5 (CH3), 55.6 (CH3), 114.4 (2 CH), 119.1 (CH), 125.8 (Cquat),
125.9 (CH), 126.0 (CH), 129.1 (2 CH), 129.5 (2 CH), 129.6 (CH),
129.7 (2 CH), 130.1 (CH), 135.8 (Cquat), 138.4 (Cquat), 149.0 (Cquat),
1
CDCl3): δ = 7.14 (m, 1 H), 7.42–7.54 (m, 7 H), 7.67–7.73 (m, 3 H),
7.82 (d, 3J = 8.4 Hz, 1 H), 8.20 (d, 3J = 8.4 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 118.3 (CH), 126.1 (CH), 126.3 (CH),
126.6 (CH), 126.6 (Cquat), 128.5 (CH), 128.9 (CH), 129.0 (CH),
129.0 (2 CH), 129.9 (2 CH), 130.1 (CH), 130.1 (CH), 138.5 (Cquat),
145.8 (Cquat), 149.0 (Cquat), 149.5 (Cquat), 152.3 (Cquat) ppm. IR
149.2 (Cquat), 156.6 (Cquat), 161 (Cquat) ppm. IR (KBr): ν = 2934
˜
(br., w), 2345 (w), 1606 (m), 1592 (br., m), 1543 (m), 1497 (m),
1250 (br. m), 1031 (br., m), 822 (m). MALDI-TOF MS [Matrix:
4,5-dihydroxyanthracen-10(9H)-one]: m/z (%) = 326 [M + H]+.
HRMS (EI): calcd. for C23H19NO ([M – H]+) 325.14612; found
325.14579.
(KBr): ν = 3062 (br., m), 2362 (br., w), 1723 (br., w), 1590 (m),
˜
1549 (m), 1428 (m), 1356 (br. m), 1228 (br., m), 770 (br., m).
MALDI-TOF MS [matrix: 4,5-dihydroxyanthracen-10(9H)-one]:
m/z (%) = 288 [M + H]+. C19H13NS (287.4): C 79.41, H 4.56, N
4.87; found C 79.37, H 4.49, N 4.90.
4-(4-tert-Butylphenyl)-2-(4-tolyl)quinoline (4i): According to the GP
1
4i was obtained as yellow solid; m.p. 120 °C. H NMR (500 MHz,
3
CDCl3): δ = 1.43 (s, 9 H, CMe3), 2.43 (s, 3 H, CH3), 7.33 (d, J =
3
3
4
7.9 Hz, 2 H), 7.45 (ddd, J = 8.2 Hz, J = 6.8 Hz, J = 1.2 Hz, 1
2-(Furan-2-yl)-4-phenylquinoline (4e):[6e] According to the GP 4e
was obtained as yellow solid; m.p. 109 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.17–7.19 (m, 1 H), 7.27–7.30 (m, 3 H), 7.44–7.47 (m,
H), 7.51 (dd, 3J = 8.5 Hz, 4J = 1.1 Hz, 2 H), 7.57 (dd, J = 8.5 Hz,
3
4J = 1.1 Hz, 2 H), 7.72 (ddd, 3J = 8.2 Hz, 3J = 6.8 Hz, 4J = 1.2 Hz,
1 H), 7.82 (s, 1 H, C3-H), 7.97 (dd, 3J = 8.4 Hz, J = 0.9 Hz, 1 H),
4
3
8.11 (d, 3J = 7.9 Hz, 2 H), 8.25 (dd, 3J = 8.4 Hz, J = 0.9 Hz, 1 H)
4
3 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.78–7.79 (m, 2 H), 7.80–7.82 (m,
1 H), 8.10–8.12 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
124.7 (CH), 126.5 (CH), 127.4 (CH), 128.6 (2 CH2), 129.0 (CH),
129.2 (CH), 129.8 (2 CH), 130.9 (CH), 131.2 (CH), 131.5 (CH),
133.0 (Cquat), 134.7 (CH), 135.9 (Cquat), 138.9 (Cquat), 146.5 (Cquat),
150.7 (Cquat), 155.7 (Cquat) ppm. EI MS [70 eV, m/z (%)]: 272 (21),
271 ([M]+·, 100), 270 (21), 243 (17), 242 (16), 241 (22), 121 (21). IR
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 31.6 (3ϫ CH3),
34.9 (Cquat), 119.4 (CH), 125.7 (2 CH), 126.0 (CH), 126.0 (Cquat),
126.2 (CH), 127.6 (2 CH), 129.5 (2 CH), 129.6 (CH), 129.7 (2 CH),
130.2 (CH), 135.7 (Cquat), 137.1 (Cquat), 139.5 (Cquat), 149.0 (Cquat),
149.2 (Cquat), 151.6 (Cquat), 157.0 (Cquat) ppm. IR (KBr): ν = 2960
˜
(br., m), 2866 (m), 1592 (s), 1543 (m), 1360 (br., m), 1019 (m), 820
(m), 765 (br., s), 597 (m). MALDI-TOF MS [Matrix: 4,5-di-
hydroxyanthracen-10(9H)-one]: m/z (%) = 352 [M + H]+. C26H25N
(351.5): C 88.85, H 7.17, N 3.99; found C 88.64, H 7.28, N 3.79.
(KBr): ν = 1600 (m), 1564 (m), 1558 (s), 1470 (s), 1317 (m), 1202
˜
(w), 1152 (w), 1088 (w), 1065 (w), 1019 (m), 883 (w), 859 (w), 830
(w), 802 (w), 774 (s), 689 (m), 536 (w). C19H13NO (271.3): C 84.11,
H 4.83, N 5.16; found C 84.48, H 4.92, N 5.05.
4-(4-Tolyl)-2-(4-tolyl)quinoline (4j): According to the GP 4j was ob-
1
2-(4-Chlorophenyl)-4-phenylquinoline (4f):[6g] According to the GP
4f was obtained as yellow solid; m.p. 103 °C. H NMR (200 MHz,
tained as yellow solid; m.p. 88 °C. H NMR (500 MHz, CDCl3): δ
1
3
= 2.44 (s, 3 H, CH3), 2.49 (s, 3 H, CH3), 7.35 (Јt’, J = 7.9 Hz, 4
3
CDCl3): δ = 7.45–7.55 (m, 8 H), 7.68–7.73 (m, 1 H), 7.76 (s, 1 H, H), 7.47 (m, 3 H), 7.72 (m, 1 H), 7.81 (s, 1 H, C3-H), 7.94 (d, J =
3
3
C3-H), 7.86–7.91 (m, 1 H), 8.12–8.24 (m, 3 H) ppm. 13C NMR 7.6 Hz, 1 H), 8.13 (d, J = 8.2 Hz, 2 H), 8.27 (d, J = 8.2 Hz, 1 H)
(75 MHz, CDCl3): δ = 119.1 (CH), 125.9 (CH), 126.0 (Cquat), 126.8 ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 21.5 (CH3),
(CH), 128.7 (CH), 128.8 (2 CH), 129.0 (2 CH), 129.2 (2 CH), 129.7
(2 CH), 129.9 (CH), 130.3 (CH), 135.8 (Cquat), 138.2 (Cquat), 138.5
119.3 (CH), 125.8 (CH), 125.9 (Cquat), 126.2 (CH), 127.6 (2 CH),
129.4 (2 CH), 129.5 (CH), 129.6 (2 CH), 129.7 (2 CH), 130.2 (CH),
(Cquat), 149.0 (Cquat), 149.6 (Cquat), 155.7 (Cquat) ppm. IR (KBr): ν 135.7 (Cquat), 137.0 (Cquat), 138.4 (Cquat), 139.5 (Cquat), 149.0
˜
= 1719 (w), 1655 (m), 1594 (br. m), 1544 (m), 1489 (br., m), 1356
(br., m), 1094 (m), 1016 (w), 831 (m), 770 (s), 700 (s). MALDI- 2920 (br., m), 1721 (br., w), 1592 (s), 1543 (m), 1497 (m), 1421 (br.
TOF MS [matrix: 4,5-dihydroxyanthracen-10(9H)-one]: m/z (%) = m), 1357 (br., m), 114 (br., w), 819 (s), 764 (m). MALDI-TOF MS
(Cquat), 149.2 (Cquat), 157.0 (Cquat) ppm. IR (KBr): ν = 3027 (m),
˜
3522
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3516–3524

Regiospecific Access to Fluorescent 2,4-Disubstituted Quinolines
[matrix: 4,5-dihydroxyanthracen-10(9H)-one]: m/z (%) = 310 [M +
H]+. C23H19N (309.4): C 89.23, H 6.19, N 4.53; found C 88.96, H
6.28, N 4.79.
MALDI-TOF MS [matrix: 4,5-dihydroxyanthracen-10(9H)-one]:
m/z (%) = 368 [M + H]+. C26H25O (367.5): C 84.98, H 6.86, N
3.81; found C 84.81, H 6.78, N 3.83.
4-(4-tert-Butylphenyl)-2-(thiophen-2-yl)quinoline (4k): According to
the GP 4k was obtained as yellow solid; m.p. 158 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.41 (s, 9 H, CMe3), 7.14 (dd, 3J = 5.0 Hz,
3J = 5.0 Hz, 1 H), 7.42 (ddd, 3J = 8.2 Hz, 3J = 6.8 Hz, 4J = 1.2 Hz,
1 H), 7.45 (dd, 3J = 5.0 Hz, 3J = 1.1 Hz, 1 H), 7.48 (dd, 3J = 8.5 Hz,
7-Chloro-2-(4-chlorophenyl)-4-phenylquinoline (4o): According to
the GP 4o was obtained as yellow solid; m.p. 124 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.25 (s, 1 H, C3-H), 7.43–7.46 (m, 2 H),
3
7.53–7.62 (m, 4 H), 7.90 (m, J = 8.9 Hz, 1 H), 8.05 (s, 1 H), 8.14
3
(d, J = 8.8 Hz, 2 H), 8.39 (d, 3J = 8.9 Hz, 2 H) ppm. 13C NMR
3
4
4J = 1.2 Hz, 2 H), 7.56 (dd, J = 8.5 Hz, J = 1.2 Hz, 2 H), 7.67
(125 MHz, CDCl3): δ = 120.5 (CH), 126.3 (CH), 129.5 (2 CH),
130.4 (CH), 130.4 (2 CH), 130.6 (CH), 131.2 (2 CH), 131.6 (CH),
131.8 (2 CH), 134.1 (CH), 135.8 (Cquat), 141.0 (Cquat), 151.5 (Cquat),
152.3 (Cquat), 153.5 (Cquat), 158.2 (Cquat), 165.6 (Cquat) ppm. EI MS
[70 eV, m/z (%)]: 353 (11), 352 (19), 351 (61), 350 (87), 349 (93),
348 (100), 316 (14), 314 (43), 278 (15), 277 (14), 238 (13), 236 (21),
202 (15), 201 (26), 176 (17), 158 (12), 157 (34), 140 (13), 139 (66),
3
3
4
3
(ddd, J = 8.2 Hz, J = 6.8 Hz, J = 1.2 Hz, 1 H), 7.72 (dd, J =
5.0 Hz, 4J = 1.1 Hz, 1 H), 7.72 (s, 1 H, C3-H), 7.89 (dd, 3J = 8.4 Hz,
3
4
4J = 0.9 Hz, 1 H), 8.13 (dd, J = 8.4 Hz, J = 0.9 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 31.6 (3 CH3), 35.0 (Cquat), 118.2
(CH), 125.8 (2 CH), 126.0 (CH), 126.1 (CH), 126.2 (Cquat), 126.2
(CH), 128.3 (CH), 128.7 (CH), 129.5 (2 CH), 129.8 (CH), 129.9
(CH), 135.4 (Cquat), 145.7 (Cquat), 148.6 (Cquat), 148.9 (Cquat), 151.8
138 (21), 126 (13), 125 (30), 124 (10). IR (KBr): ν = 1611 (m), 1529
˜
(Cquat), 152.0 (Cquat) ppm. IR (KBr): ν = 2963 (br., m), 2864 (br.,
˜
(m), 1451 (s), 1435 (m), 1352 (w), 1301 (s), 1247 (s), 1182 (s), 1110
(w), 1056 (w), 1030 (s), 1011 (m), 835 (s), 783 (m), 705 (m), 672
(w), 609 (m), 527 (w). C21H13Cl2N (350.2): C 72.01, H 3.74, N 4.00;
found C 71.82, H 3.86, N 3.91.
w), 3005 (w), 1592 (s), 1499 (m), 1364 (br., s), 1021 (br. w), 840
(m), 769 (m), 713 (m). MALDI-TOF MS [matrix: 4,5-dihydroxy-
anthracen-10(9H)-one]: m/z (%) = 344 [M + H]+. C23H21NS
(343.5): C 80.42, H 6.16, N 4.08; found C 80.38, H 6.03, N 4.16.
7-Chloro-2-(4-methoxyphenyl)-4-phenylquinoline (4p): According to
the GP 4p was obtained as yellow solid; m.p. 106 °C. 1H NMR
2-(4-Chlorophenyl)-4-(4-nitrophenyl)quinoline (4l):[13] According to
the GP 4l was obtained as yellow solid; 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 (2 CH), 123.9 (2 CH), 124.3
(Cquat), 124.8 (2 CH), 125.0 (Cquat), 127.3 (CH), 128.8 (2 CH),
129.1 (2 CH), 130.5 (2 CH), 132.3 (Cquat), 133.4 (Cquat), 144.8
(Cquat), 148.0 (Cquat), 150.5 (Cquat), 155.5 (Cquat) ppm. EI MS
[70 eV, m/z (%)]: 362 (11), 361 ([M]+·, 12), 360 (33), 359 (14), 313
(14), 292 (17), 257 (17), 256 (100), 235 (15), 226 (12), 210 (41), 209
3
(500 MHz, CDCl3): δ = 3.87 (s, 3 H, OMe), 7.02 (d, J = 8.9 Hz,
3
4
2 H), 7.36 (dd, J = 8.9 Hz, J = 2.1 Hz, 1 H), 7.52 (m, 5 H), 7.74
(s, 1 H, C3-H), 7.78 (d, J = 8.9 Hz, 1 H), 8.14 (m, 2 H), 8.18 (s,
3
4J = 2.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.6
(CH3), 114.5 (2 CH), 119.1 (CH), 124.2 (Cquat), 127.0 (CH), 127.2
(CH), 128.8 (CH), 128.9 (2 CH), 129.0 (CH), 129.2 (2 CH), 129.7
(2 CH), 131.9 (Cquat), 135.6 (Cquat), 138.3 (Cquat), 149.3 (Cquat),
149.5 (Cquat), 157.6 (Cquat), 161.3 (Cquat) ppm. IR (KBr): ν = 2975
˜
(br., m), 1601 (br., s), 1421 (m), 1248 (br., m), 1049 (br., s), 838
(m), 769 (m), 699 (br., m). MALDI-TOF MS [matrix: 4,5-di-
hydroxyanthracen-10(9H)-one]: m/z (%) = 346 [M + H]+. HRMS
(27), 198 (14), 139 (20), 91 (13), 43 (12). IR (KBr): ν = 1587 cm–1
˜
(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). C21H13ClN2O2 (360.8): C 69.91, H 3.63,
N 7.76; found C 69.64, H 3.69, N 7.67.
(EI): calcd. for C22H15ClNO ([M
344.08351.
–
H]+) 344.08367; found
4-(4-tert-Butylphenyl)-7-chloro-2-(4-tolyl)quinoline (4q): According
1
2-(4-Chlorophenyl)-4-(4-bromophenyl)quinoline (4m): According to
the GP 4m was obtained as yellow solid; m.p. 149 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.39–7.52 (m, 5 H), 7.65–7.74 (m, 4 H),
7.81 (d, 3J = 8.4 Hz, 1 H), 8.10–8.15 (m, 2 H), 8.20 (d, 3J = 8.5 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 119.2 (CH), 125.6
(Cquat), 125.7 (CH), 127.3 (CH), 129.3 (2 CH), 130.4 (CH), 130.5
(CH), 131.5 (2 CH), 132.3 (2 CH), 136.0 (Cquat), 137.3 (Cquat),
137.9 (Cquat), 148.5 (Cquat), 148.8 (Cquat), 154.3 (Cquat), 155.7
to the GP 4q was obtained as yellow solid; m.p. 42 °C. H NMR
(500 MHz, CDCl3): δ = 1.41 (s, 9 H, CMe3), 2.42 (s, 3 H, CH3),
7.31 (d, 3J = 8.2 Hz, 2 H), 7.38 (dd, 3J = 8.9 Hz, 4J = 2.0 Hz, 1
3
3
H), 7.46 (d, J = 8.2 Hz, 2 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.78 (s,
1 H, C3-H), 7.87 (d, J = 8.9 Hz, 1 H), 8.07 (d, J = 8.2 Hz, 2 H),
3
3
8.20 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
4
21.6 (CH3), 31.6 (2 CH3), 35.0 (Cquat), 119.5 (CH), 124.5 (Cquat),
125.8 (2 CH), 127.0 (CH), 127.4 (CH), 127.7 (2 CH), 129.0 (CH),
129.4 (2 CH), 129.8 (2 CH), 135.3 (Cquat), 135.5 (Cquat), 136.6
(Cquat), 139.9 (Cquat), 149.3 (Cquat), 149.6 (Cquat), 152.0 (Cquat),
(Cquat) ppm. IR (KBr): ν = 1655 (m), 1594 (br., m), 1484 (br., m),
˜
1421 (m), 1356 (br., w), 1092 (br. s), 1011 (s), 582 (w). MALDI-
TOF MS [matrix: 4,5-dihydroxyanthracen-10(9H)-one]: m/z (%) =
396 [M + H]+. C21H13BrClN (394.7): C 63.90, H 3.32, N 3.55;
found C 63.64, H 3.18, N 3.51.
158.0 (Cquat) ppm. IR (KBr): ν = 2971 (br., w), 1589 (br., w), 1543
˜
(w), 1491 (w), 1050 (br., w), 909 (w), 826 (br., w). MALDI-TOF
MS [matrix: 4,5-dihydroxyanthracen-10(9H)-one]: m/z (%) = 386
[M + H]+. C26H24ClN (385.9): C 80.92, H 6.27, N 3.63; found C
80.26, H 6.97, N 3.43.
4-(4-tert-Butylphenyl)-2-(4-methoxyphenyl)quinoline (4n): Accord-
ing to the GP 4n was obtained as yellow solid; m.p. 133 °C. 1H
NMR (500 MHz, CDCl3): δ = 1.42 (s, 9 H, CMe3), 3.86 (s, 3 H,
OMe), 7.03 (d, 3J = 8.7 Hz, 2 H), 7.43 (m, 1 H), 7.50 (d, 3J =
Acknowledgments
3
8.1 Hz, 2 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.70 (m, 1 H), 7.77 (s, 1
3
3
H, C3-H), 7.94 (d, J = 8.3 Hz, 1 H), 8.16 (d, J = 8.7 Hz, 2 H),
Financial support of the Fonds der Chemischen Industrie is grate-
fully acknowledged. The authors also cordially thank CEM for a
research cooperation and BASF SE and Clariant AG for the gener-
ous donations of chemicals.
8.21 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
3
31.6 (3ϫ CH3), 34.9 (Cquat), 55.6 (CH3), 114.4 (2 CH), 119.1 (CH),
125.7 (2 CH), 125.8 (Cquat), 126.0 (CH), 126.0 (CH), 129.1 (2 CH),
129.5 (2 CH), 129.6 (CH), 130.0 (CH), 132.4 (Cquat), 135.7 (Cquat),
148.9 (Cquat), 149.2 (Cquat), 151.7 (Cquat), 156.6 (Cquat), 161.0(Cquat
)
ppm. IR (KBr): ν = 2962 (br., m), 1686 (w), 1607 (br., m), 1459
(w), 1363 (br., w), 1250 (br., m), 1180 (m), 1030 (br., w), 835 (m).
˜
[1] a) T. Eicher, S. Hauptmann, The Chemistry of Heterocycles,
2nd ed., Wiley-VCH, Weinheim, 2003, p. 316–336; b) J. P.
Eur. J. Org. Chem. 2010, 3516–3524
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3523

S. Rotzoll, B. Willy, J. Schönhaber, F. Rominger, T. J. J. Müller
FULL PAPER
Michael, Nat. Prod. Rep. 1995, 12, 465–475; c) J. P. Michael,
Nat. Prod. Rep. 1997, 14, 605–618; d) M. Balasubramanian,
J. G. Kway, in: Comprehensive Heterocyclic Chemistry II (Eds.:
A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon, Ox-
ford, 1996, vol. 5, p 245–300; e) J. A. Spicer, S. A. Gamage,
G. J. Atwell, G. J. Finlay, B. C. Baguley, W. A. Denny, J. Med.
Chem. 1997, 40, 1919–1929; f) J. P. Michael, Nat. Prod. Rep.
2001, 18, 543–559; g) S. Funayama, K. Murata, T. Noshita,
Heterocycles 2001, 54, 1139–1148; h) P. M. S. Chauhan, S. K.
Srivastava, Curr. Med. Chem. 2001, 8, 1535–1542; i) J. P.
Michael, Nat. Prod. Rep. 2002, 19, 742–760; j) A. N. Pearce,
D. R. Appleton, R. C. Babcock, B. R. Copp, Tetrahedron Lett.
2003, 44, 3897–3899; k) J. P. Michael, Nat. Prod. Rep. 2003, 20,
476–493.
[11]
[12]
a) D. M. D’Souza, T. J. J. Müller, Nat. Protoc. 2008, 3, 1660–
1665; b) A. S. Karpov, T. J. J. Müller, Org. Lett. 2003, 5, 3451–
3454.
a) B. Willy, T. J. J. Müller, Curr. Org. Chem. 2009, 13, 1777–
1790; b) B. Willy, T. J. J. Müller, ARKIVOC 2008, 1, 195–208;
c) T. J. J. Müller, Chimica Oggi 2007, 25, 70–78; d) T. J. J.
Müller, Targets Heterocycl. Syst. 2006, 10, 54–65.
B. Willy, T. Dallos, F. Rominger, J. Schönhaber, T. J. J. Müller,
Eur. J. Org. Chem. 2008, 4796–4805.
B. Willy, T. J. J. Müller, Mol. Div.; DOI: 10.1007/s11030-009-
[13]
[14]
[15]
9223-z.
a) W. Ried, E. König, Justus Liebigs Ann. Chem. 1972, 755,
24–31; b) W. Ried, W. Marx, Chem. Ber. 1957, 90, 2683–2687;
c) G. Cabarrocas, S. Rafel, M. Ventura, J. M. Villalgordo, Syn-
lett 2000, 595–598.
[2] For HIV-1 replication inhibition, see: a) F. Zouhiri, M. Danet,
C. Bérnard, M. Normand-Bayle, J. F. Mouscadet, H. Leh,
C. M. Thomas, G. Mbemba, J. d’Angelo, D. Desmaële, Tetra-
hedron Lett. 2005, 46, 2201–2205; b) M. Normand-Bayle, C.
Bérnard, F. Zouhiri, J. F. Mouscadet, H. Leh, C. M. Thomas,
G. Mbemba, D. Desmaële, J. d’Angelo, Bioorg. Med. Chem.
Lett. 2005, 15, 4019–4022. For antimicrobial activity, see: P.
Narender, U. Srinivas, M. Ravinder, B. Anada Rao, C. Ra-
mesh, K. Harakishore, B. Gangadasu, U. S. N. Murthy, V. Jay-
athirtha Rao, Bioorg. Med. Chem. 2006, 14, 4600–4609. For
activity against the west Nile virus, see: J. R. Goodell, F. Puig-
Basagoiti, B. M. Forshey, P. Y. Shi, D. M. Ferguson, J. Med.
Chem. 2006, 49, 2127–2137. For antihelmintic properties, see:
S. Rossiter, J. M. Péron, P. J. Whitfield, K. Jones, Bioorg. Med.
Chem. Lett. 2005, 15, 4806–4808.
[3] For antimalaric properties, see: a) P. G. Bray, S. A. Ward, P. M.
O’Neill, Curr. Top. Microbiol. Immunol. 2005, 295, 3–38; b)
A. A. Joshi, C. L. Viswanathan, Bioorg. Med. Chem. Lett.
2006, 16, 2613–2617.
[4] a) P. J. Steel, Coord. Chem. Rev. 1990, 106, 227–265; b) S. Ernst,
W. Kaim, J. Am. Chem. Soc. 1986, 108, 3578–3586; c) A.
Mamo, S. Nicolleti, N. Cam Tat, Molecules 2002, 7, 618–627;
d) H. Qaseer, Croat. Chem. Acta 2005, 78, 79–84.
[16]
a) L. A. Paquette, Acc. Chem. Res. 1968, 1, 209–216; b) M.
Roth, P. Dubs, E. Gotschi, A. Eschenmoser, Helv. Chim. Acta
1971, 54, 710–734; c) B. Zurawski, W. Kutzelnigg, J. Am. Chem.
Soc. 1978, 100, 2654–2659; d) F. G. Bordwell, J. M. Williams,
E. B. Hoyt, B. B. Jarvis, J. Am. Chem. Soc. 1968, 90, 429–435;
e) R. Hoffmann, J. Am. Chem. Soc. 1968, 90, 1475–1485; f)
S. C. Farmer, S. H. Berg, Molecules 2008, 13, 1345–1352; g)
M. M. B. Marques, M. M. M. Santos, A. M. Lobo, S. Prab-
hakar, Tetrahedron Lett. 2000, 41, 9835–9838; h) E. Vogel, E.
Schmidbauer, H. J. Altenbach, Angew. Chem. Int. Ed. Engl.
1974, 13, 736–737; i) M. Wilhelm, P. Schmidt, Helv. Chim. Acta
1970, 53, 1697–1704.
CCDC-765925 (for 4l) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
for B3LYP, see: a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–
5652; b) A. D. Becke, J. Chem. Phys. 1993, 98, 1372–1377; c)
R. G. Parr, W. Yang, Density-functional theory of atoms and
molecules, Oxford University Press, Oxford, 1989; for def-SVP,
see: A. Schäfer, C. Huber, R. Ahlrichs, J. Chem. Phys. 1994,
100, 5829–5835; for the program Turbomole, see: R. Ahlrichs,
M. Bär, M. Häser, H. Horn, C. Kölmel, Chem. Phys. Lett.
1989, 162, 165–169.
[17]
[18]
[5] G. E. Tumambac, C. M. Rosencrance, C. Wolf, Tetrahedron
2004, 60, 11293–11297.
[6] a) K. Kobayashi, K. Yoneda, K. Miyamoto, O. Morikawa, H.
Konishi, Tetrahedron 2004, 60, 11639–11645; b) G. Abbiati, A. [19] R. Gleiter, G. Krennrich, D. Cremer, K. Yamamoto, I. Murata,
Arcadi, F. Marinelli, E. Rossi, M. Verdecchia, Synlett 2006, J. Am. Chem. Soc. 1985, 107, 6874–6879.
3218–3224; c) O. G. Schramm, T. Oeser, M. Kaiser, R. Brun, [20] K. J. Miller, K. F. Moschner, K. T. Potts, J. Am. Chem. Soc.
T. J. J. Müller, Synlett 2008, 359–362; d) E. Ramu, N. Sreelatha,
K. Vijay, V. Ravi, A. Srinivas, Heterocycles 2008, 75, 2523–
2533; e) R. Martinez, D. J. Ramon, M. Yus, Eur. J. Org. Chem.
2007, 1599–1605; f) R. P. Korivi, C. H. Cheng, J. Org. Chem.
2006, 71, 7079–7082; g) F. Xiao, Y. Chen, Y. Liu, J. Wang,
Tetrahedron 2008, 64, 2755–2761.
1983, 105, 1705–1712.
[21] M. Z. Kassaee, S. M. Musavi, M. R. Momeni, F. A. Shakib,
M. Ghambarian, J. Mol. Struct. 2008, 117–121.
[22] See, e.g.; a) N. Mataga, S. Tsuno, Bull. Chem. Soc. Jpn. 1957,
30, 368–374; b) B. L. van Duuren, Anal. Chem. 1960, 32, 1436–
1442; c) M. Wilk, J. Rochlitz, Justus Liebigs Ann. Chem. 1966,
699, 107–111; d) M. Wilk, J. Rochlirz, Justus Liebigs Ann.
Chem. 1967, 701, 6–22; e) C. M. O’Donnell, G. A. Knesel, T. S.
Spencer, F. R. Stermitz, J. Phys. Chem. 1970, 74, 3555–3559; f)
R. E. Atkinson, P. R. H. Speakman, J. Chem. Soc. B 1971,
2077–2081.
[7] a) R. Leardini, G. F. Pedulli, A. Tundo, G. Zanardi, J. Chem.
Soc., Chem. Commun. 1984, 1320–1321; b) R. Leardini, D.
Nanni, A. Tundo, G. Zanardi, F. Ruggieri, J. Org. Chem. 1992,
57, 1842–1848.
[8] a) A. Arcadi, M. Aschi, F. Marinelli, M. Verdecchia, Tetrahe-
dron 2008, 64, 5354–5361.
[9] For leading 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-Cata-
lyzed Cross-Coupling Reactions (Eds.: F. Diederich, P. J. Stang),
Wiley-VCH, Weinheim, 1998, p. 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, p. 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.
[23] Applying B3LYP 6-31G* density functionals as implemented
in the program PC Spartan Pro, Wavefunction Inc., Irvine, CA,
1999.
[24] For lead references on ZINDO calculations, see for example a)
M. A. Thompson, M. C. Zerner, J. Am. Chem. Soc. 1991, 113,
8210–8215; b) M. A. Thompson, E. D. Glendening, D. Feller,
J. Phys. Chem. 1994, 98, 10465–10476; c) M. A. Thompson,
G. K. Schenter, J. Phys. Chem. 1995, 99, 6374–6386; d) M. A.
Thompson, J. Phys. Chem. 1996, 100, 14492–14507; e) M. C.
Zerner, G. H. Loew, R. F. Kirchner, U. T. Mueller-Westerhoff,
J. Am. Chem. Soc. 1980, 102, 589–599.
[25] As implemented in the program ArgusLab 4.0, M. A. Thomp-
son, Planaria Software LLC, Seattle, WA, USA, 2004.
Received: February 16, 2010
[10] Y. Toda, K. Sonogashira, N. Hagihara, Synthesis 1977, 777–
778.
Published Online: May 7, 2010
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